Ijcp august 2016

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Volume 27, Number 3

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August 2016, Pages 201–300

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yy American Family Physician yy Cardiology yy Community Medicine yy Gastroenterology yy Hematology yy Internal Medicine yy Obstetrics and Gynecology yy Pediatrics

an i c i ys ians

yy Respiratory Infections yy Medilaw

Phly Physic y l mi ami

yy Conference Proceedings

Fademy of F n ica Aca

yy Around the Globe

er merican m A eA

yy Inspirational Story

ingurnal of th t a or d Jo

yy Lighter Reading

rp-reviewe o c In eer AP

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IJCP Group of Publications Dr Sanjiv Chopra Prof. of Medicine & Faculty Dean Harvard Medical School Group Consultant Editor Dr Deepak Chopra Chief Editorial Advisor

Dr KK Aggarwal Group Editor-in-Chief IJCP Group, eMedinewS and eMediNexus Dr Veena Aggarwal MD, Group Executive Editor

IJCP Editorial Board Obstetrics and Gynaecology Dr Alka Kriplani, Dr Thankam Verma, Dr Kamala Selvaraj Cardiology Dr Praveen Chandra, Dr SK Parashar Paediatrics Dr Swati Y Bhave Diabetology Dr CR Anand Moses, Dr Sidhartha Das, Dr A Ramachandran, Dr Samith A Shetty, Dr Vijay Viswanathan, Dr V Mohan, Dr V Seshiah, Dr Vijayakumar ENT Dr Jasveer Singh, Dr Chanchal Pal Dentistry Dr KMK Masthan, Dr Rajesh Chandna Gastroenterology Dr Ajay Kumar, Dr Rajiv Khosla, Dr JS Rajkumar Dermatology Dr Hasmukh J Shroff, Dr Pasricha, Dr Koushik Lahiri, Dr Jayakar Thomas Nephrology Dr Georgi Abraham Neurology Dr V Nagarajan, Dr Vineet Suri, Dr AV Srinivasan Oncology Dr V Shanta Orthopedics Dr J Maheshwari

Anand Gopal Bhatnagar Editorial Anchor Advisory Bodies Heart Care Foundation of India Non-Resident Indians Chamber of Commerce & Industry World Fellowship of Religions

This journal is indexed in IndMED (http://indmed.nic.in) and full-text of articles are included in medIND databases (http://mednic.in) hosted by National Informatics Centre, New Delhi.

Volume 27, Number 3, August 2016 FROM THE DESK OF THE GROUP EDITOR-IN-CHIEF

205 Commonly Used Medications and Nutritional Supplements may Cause or Worsen Heart Failure

KK Aggarwal

AMERICAN FAMILY PHYSICIAN

207 Cancer Screening in Older Patients

Brooke Salzman, Kathryn Beldowski, Amanda De La Paz

217 Practice Guidelines 219 Photo Quiz CARDIOLOGY

222 Interesting Case of Single Ventricle

Bharath Raj Kidambi, Kalpana Ramanathan, Babu Peter S, Sabaratnavel R, Srinivasagalu K

COMMUNITY MEDICINE

225 Prevalence of Tobacco Use Among Adult Population in a Semi-urban Area of Bihar

RR Jha, A Kumar

229 The Importance Bioethics in Everyday Clinical Practice

Smita N Deshpande

GASTROENTEROLOGY

234 Clinicopathological Characterization of Gastric Carcinoma in a Tertiary Care Center

C Simon Durai Raj, Sandhya Sundaram, Krishnakumar Ramanathan, Ganesh Venkatraman, Shanthi Vijayaraghavan, S Sankar

HEMATOLOGY

240 A Rare Case of Hemophagocytic Lymphohistiocytosis in an 18-year-old Patient

Tashi Agarwal, Shashi Bansal, Upendra Sharma

INTERNAL MEDICINE

245 A Case of Leptospirosis Presenting as Multiorgan Failure

AK Badrinath, K Suresh, R Raghunathan, Suresh Babu S

OBSTETRICS AND GYNECOLOGY

250 Comparative Study of Clinical Efficacy of Placentrex and Azithromycin in Pelvic Inflammatory Disease

Madhuri S, Kavya D Sharma, Prameela HJ

255 Outcomes of High-risk Cesarean Sections: An Ongoing Challenge

Vivek Chhari, Somen Bhattacharjee

OBSTETRICS AND GYNECOLOGY

Published, Printed and Edited by Dr KK Aggarwal, on behalf of IJCP Publications Ltd. and Published at E - 219, Greater Kailash Part - 1 New Delhi - 110 048 E-mail: editorial@ijcp.com

260 Mifepristone for Preinduction Cervical Ripening at Term: A Hospital-based Study

Indu Kaul, Amandeep K Anand, Renu Gupta

PEDIATRICS

Printed at New Edge Communications Pvt. Ltd., New Delhi E-mail: edgecommunication@gmail.com

266 Profile of HIV Infection in Children and Its Correlation with their CD4 Counts

Copyright 2016 IJCP Publications Ltd. All rights reserved.

VL Raghuvanshi, Raj Kamal, T Husain, K Katoch, R Dayal

RESPIRATORY INFECTIONS

The copyright for all the editorial material contained in this journal, in the form of layout, content including images and design, is held by IJCP Publications Ltd. No part of this publication may be published in any form whatsoever without the prior written permission of the publisher.

274 Prevalence of Undiagnosed COPD in Western Indian Population

Anand Yannawar, Damanjit Duggal, Ram Chopra

MEDILAW

Editorial Policies

277 Resolving Patient-Doctor Conflict

The purpose of IJCP Academy of CME is to serve the medical profession and provide print continuing medical education as a part of their social commitment. The information and opinions presented in IJCP group publications reflect the views of the authors, not those of the journal, unless so stated. Advertising is accepted only if judged to be in harmony with the purpose of the journal; however, IJCP group reserves the right to reject any advertising at its sole discretion. Neither acceptance nor rejection constitutes an endorsement by IJCP group of a particular policy, product or procedure. We believe that readers need to be aware of any affiliation or financial relationship (employment, consultancies, stock ownership, honoraria, etc.) between an author and any organization or entity that has a direct financial interest in the subject matter or materials the author is writing about. We inform the reader of any pertinent relationships disclosed. A disclosure statement, where appropriate, is published at the end of the relevant article.

CONFERENCE PROCEEDINGS

280 68th Annual National Conference of Indian Psychiatric Society (ANCIPS 2016) 283 22nd Annual Conference of Indian Society of Critical Care Medicine (Critical Care 2016) 286 National Interventional Council Mid-Term Meet 2016 AROUND THE GLOBE

290 News and Views INSPIRATIONAL STORY

295 This Too Shall Pass LIGHTER READING

Note: Indian Journal of Clinical Practice does not guarantee, directly or indirectly, the quality or efficacy of any product or service described in the advertisements or other material which is commercial in nature in this issue.

296 Lighter Side of Medicine

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FROM THE DESK OF THE GROUP EDITOR-IN-CHIEF

Dr KK Aggarwal

Group Editor-in-Chief IJCP Group, eMedinewS and eMediNexus

Commonly Used Medications and Nutritional Supplements may Cause or Worsen Heart Failure

T

he American Heart Association (AHA) has cautioned that commonly used medications and nutritional supplements may cause or worsen heart failure in its first scientific statement, which provides guidance on avoiding drug-drug or drug-condition interactions for people with heart failure. The statement provides comprehensive information about specific drugs and 'natural' remedies that may have serious unintended consequences for heart failure patients.

In addition to prescription medications, over-the-counter drugs may also have unintended consequences for heart failure patients. ÂÂ

For example, nonsteroidal anti-inflammatory drugs (NSAIDs), including commonly used painkillers such as ibuprofen, can trigger or worsen heart failure by causing sodium and fluid retention and making diuretic medications less effective.

ÂÂ

Over-the-counter heartburn medications and cold remedies may also contain significant amounts of sodium, which is usually restricted in patients with heart failure.

Heart failure patients have, on average 5 or more separate medical conditions and they take 7 or more prescription medications daily, often prescribed by different healthcare providers. And, according to the statement, medications can cause problems in several ways: being toxic to heart muscle cells or changing how the heart muscle contracts; interacting with medications used to treat heart failure, so that some of their benefits are lost; and containing more sodium than advised for patients with heart failure.

Robert L. Page II, PharmD, MSPH, chair of the writing committee for the new scientific statement said that healthcare providers should talk to patients with heart failure at every visit about all prescription and over-thecounter medications they may be taking, as well as nutritional supplements and herbs.

The statement suggests that patients should show each of their healthcare providers a complete list of their medications, including over-the-counter drugs and natural supplements. They should consult with a health professional before starting or stopping any medication.

(Source: AHA)

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AMERICAN FAMILY PHYSICIAN

Cancer Screening in Older Patients BROOKE SALZMAN, KATHRYN BELDOWSKI, AMANDA DE LA PAZ

ABSTRACT Although cancer is the second leading cause of death among persons 65 years and older, there is a paucity of clinical trial data about the effectiveness and harms of cancer screening in this population. Given the heterogeneous nature of the older population, cancer screening in these patients should not be based on age alone. Studies suggest that a life expectancy of at least 10 years is necessary to derive a survival benefit from screening for breast and colorectal cancers; therefore, screening for these cancers is not recommended in those with a life expectancy of less than 10 years. Prostate cancer screening, if per­formed at all, should not be performed after 69 years of age. Cervical cancer screening may be stopped after 65 years of age if the patient has an adequate history of negative screening results. An individu­alized approach to cancer screening decisions involves estimating life expectancy, determining the potential benefits and harms of screenings, and weighing those benefits and harms in relation to the patient’s values and preferences.

Keywords: Cancer screening, older patients, life expectancy, survival benefit, individu­alized approach

C

ancer is the second leading cause of death among those 65 years and older, and the incidence of can­cer increases with age.1 Because of a lack of clinical trials that include older patients, there is a paucity of data about the effectiveness and harms of cancer screen­ing in this population. Recommendations for cancer screening in older adults vary, particularly regarding when to stop screen­ing. Such guidelines are based on evidence derived at population levels; are based on younger patients; and generally do not address individual variations in life expec­tancy, comorbid conditions, functional sta­tus, or personal preference.

Basing guidelines for cancer screening in older adults on age alone is problematic given the heterogeneous nature of this pop­ulation. As Americans live longer, there is a need for more evidence-based guidance. This article reviews current guidelines and data, and offers suggestions on how physi­cians can incorporate these guidelines into their daily practice.

BROOKE SALZMAN, MD, is an associate professor in the Department of Family and Community Medicine and the Division of Geriatric Medicine and Palliative Care at Thomas Jefferson University, Philadelphia, Pa. KATHRYN BELDOWSKI, MD, is an attending physician in the Division of Geriatric Medicine at Crozer-Chester Medical Center, Upland, Pa. AMANDA DE LA PAZ, MD, is an assistant professor in the Department of Family, Community, and Preventive Medicine at Drexel University College of Medicine, Philadelphia.

Source: Adapted from Am Fam Physician. 2016;93(8):659-667.

A FRAMEWORK FOR DECISION MAKING The paradox of screening in the United States is that healthy older patients are often underscreened, whereas those in poor health are too often overscreened.2-5 For example, 18% of women with advanced dementia had a screening mammogram in 2002, despite a median survival of 3.3 years.5 A framework for guiding an indi­vidualized approach to cancer screening involves estimating life expectancy, deter­mining the potential benefits and harms of screenings, and weighing those benefits and harms in relation to the patient’s values and preferences.6 Estimating life expectancy is particularly important because there is lag time between cancer screening and its ben­efits, whereas the harms are often imme­diate and more prevalent in older adults.7 Studies suggest that a life expectancy of at least 10 years is necessary to derive a sur­vival benefit from screening for breast or colorectal cancers.8 Table 1 lists the average life expectancy for different ages in the United States.9 In 2011, the average life expectancy was 6.5 years for 85-year-olds.9 However, there is tremendous variation in life expectancy within age groups (Figure 1).10 The healthiest quartile of 85-year-olds will live about 10 years, whereas the sickest quartile will live less than three years.6 Strong predictors of life expectancy other than age include the number and severity of comorbid conditions, and the presence of functional impairments.11 Prognostic tools (Table 2) can guide clinical judgment in estimating life expectancy.11

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AMERICAN FAMILY PHYSICIAN Table 1. Average Life Expectancy in the United States Age (years)

Men (years)

Women (years)

76.3

81.1

Birth 65

17.8

20.3

70

14.3

16.5

75

11.1

12.9

80

8.2

9.6

85

5.9

6.9

90

4.1

4.8

95

2.9

3.3

100

2.1

2.3

Task Force (USPSTF) states there is insufficient evidence to recommend for or against screening women 75 years and older.35 In contrast, the American Cancer Society (ACS) recommends continuing screening for as long as the patient is in good health and has a life expectancy of at least 10 years.12 The American Geriatrics Society also does not recommend screening for patients with a life expectancy of less than 10 years.16 In the only RCT of mammography that includes women 70 to 74 years of age, a subgroup analysis of this age group did not demonstrate a significant reduction in breast cancer mortality (relative risk = 1.12; 95% confidence interval, 0.73 to 1.72).36

Information from reference 9.

Breast Cancer

Observational, retrospective cohort studies have shown that regular screening mammography in women 75 years and older is associated with detection of earlierstage disease and lower breast cancer mortality.37-39 However, these findings may be affected by leadtime, length-time, and selection bias.37-39 In addition, a mortality benefit was not demonstrated in older women with severe or multiple comorbidities.38

Mammography is the only screening test shown to reduce breast cancer deaths in randomized controlled trials (RCTs).33 Even though advancing age is the greatest risk factor for breast cancer,13 RCTs evaluating mam­mography have not included women older than 74 years.13,33,34 As a result, the U.S. Preventive Services

In the absence of clinical trial data, statistical modeling studies have assessed the impact of screening mammography for women 70 to 84 years of age.

Studies suggest a mortality benefit from mammography screening beyond 69 years of age, with one to four fewer breast cancer deaths per 1,000 women.40-42

SCREENING GUIDELINES Table 3 summarizes cancer screening guidelines for older adults,12-31 and Table 4 defines terms related to can­cer screening.32

25 22

20 17

16 15

13

13 10

10

10

10 7

7 5

5

0

7 5 3

70

75

80 Age (years)

85

2 90

Life expectancy for men (years)

Life expectancy for women (years)

25

20

19

15

15

14

12

11

10

8

8

8 6

6

6 4

5

4 2

0

70

75

80

85

2 90

Age (years) 75th percentile

50th percentile

25th percentile

Figure 1. Upper, middle, and lower quartiles of life expectancy for older women and men. The bars indicate the number of years in which a percentage of the corresponding age and sex cohort will die. For example, in a cohort of 70-year-old men, 25% will be dead in eight years (by 78 years of age), 50% will be dead in 14 years, and 75% will be dead in 19 years. The presence of conditions such as congestive heart failure, end-stage renal disease, oxygen-dependent chronic obstructive lung disease, severe dementia, or dependency in activities of daily living would reduce life expectancy to less than average for a given age. High functional status and the absence of chronic conditions can identify older adults with greater-than-average life expectancy.

Information from reference 10.

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AMERICAN FAMILY PHYSICIAN Table 2. Tools to Aid in Cancer Screening Decisions for Older Adults Prognostic tools for physicians See Table 1 for average U.S. life expectancy by age See Figure 1 for upper, middle, and lower quartiles of life expectancy by sex and age Lee Index: http://eprognosis.ucsf.edu/lee.php Palliative Performance Scale: www.npcrc.org/files/news/palliative_ performance_scale_PPSv2.pdf Schonberg Index: http://eprognosis.ucsf.edu/schonberg.php Decision aids for physicians Clinical Frailty Scale: http://geriatricresearch.medicine.dal.ca/pdf/Clinical%20Faily%20Scale.pdf ePrognosis iPhone or iPad applications for breast and colon cancer screening: https://itunes.apple.com/us/app/eprognosis-cancerscreening/id714539993 ePrognosis website for breast and colon cancer screening: http://cancerscreening.eprognosis.org U.S. Preventive Services Task Force Electronic Preventive Services Selector tool: http://epss.ahrq.gov/PDA/index.jsp Decision aids for patients Breast cancer Should I Continue Having Mammograms to Screen for Breast Cancer?: https://sydney.edu.au/medicine/public-health/shdg/ resources/Mammo_DA.pdf Should I Continue Getting Mammograms After Age 75?: http://archinte.jamanetwork.com/data/Journals/INTEMED/929788/ IOI130136supp1_ prod.pdf Should I Get a Mammogram? Ages 75+: http://www.wvmedical.com/Site/Content/Departments/Womens_Imaging_Center/CH_ Mammography_ Ages_75_Pamphlet_2015_WEB.pdf Colon cancer Making a Decision About Colon Cancer Screening: http://www.shareddecisionmaking.org/Site/Female%20Age%2080.pdf and http:// www.shareddecisionmaking.org/Site/DICE_LowLiteracy.pdf Screening for Colon Cancer. What You Need to Know (video): http:// www.shareddecisionmaking.org/Site/CHOICE6/Choice.swf Lung cancer Helping You Decide About Lung Cancer Screening: http://cancer.dartmouth.edu/lung_thoracic/documents/NCCC__Decision_Lung_ Cancer_Screening.pdf Prostate cancer The PSA Decision. Is Testing for Prostate Cancer Right for You?: http:// www.dartmouth-hitchcock.org/dhmc-internet-upload/file_ collection/ PSA.pdf

However, the rate of false positives and overdiagnosis increased with age, par­ticularly in the oldest age groups.42 Mortality benefit must be weighed against the potential harms of screening. Harms can include pain, anxiety, and complications from subsequent testing and treatment. In patients 66 to 74 years of age, falsepositive rates from mammography approach 50% for those screened annu­ally and 30% for those screened biennially over 10 years.43 Although the sensitivity and specificity of mammography increase with age,42 overdiagnosis also increases because of reduced life expectancy and an increased proportion of slowergrowing cancers.44 In other words, women with breast cancer diagnosed at an older age are more likely to die of something else, compared with younger women.

In addition, treatment of breast cancer in advanced age is associated with greater morbidity, including an increased risk of postoperative complica­tions and toxicity from chemotherapy.45,46 The psychological impact of a false-positive result can be substantial for some women. Although few studies include women 75 years and older, one meta-analysis showed that psychological distress can per­ sist for three years following a false-positive mammogram result.47

Prostate Cancer Most prostate cancers have a good prognosis even without treatment, although some can­cers are aggressive. Prostate cancer increases with age, and 75% of diagnoses are in those 65 years and older.48 Screening recommendations are largely based on two

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AMERICAN FAMILY PHYSICIAN Table 3. Cancer Screening Guidelines for Older Adults Organizations

Recommendation

Breast cancer ACS12

Yearly mammograms are recommended from 45 to 54 years of age. Women 55 years and older may opt for biennial mammograms. Screening should continue as long as overall health is good and life expectancy is at least 10 years. Women with serious health problems or short life expectancy should discuss with their physicians whether to continue mammograms.

USPSTF,13 AAFP14

Screening decisions should be individualized for women 40 to 49 years of age. Women 50 to 74 years of age should be screened biennially. There is insufficient evidence to assess the additional benefits and harms of screening mammography in women 75 years and older.

ACOG15

Women 75 years and older should weigh the benefits and risks of screening. Comorbidity and life expectancy should be considered.

AGS16

Women with a life expectancy of less than 10 years should not be screened.

Prostate cancer USPSTF,17 AAFP18

Routine prostate-specific antigen–based screening should not be performed in the general U.S. male population regardless of age because the harms generally outweigh the benefits.

ACS19

A discussion about screening should begin at 50 years of age for men who are at average risk of prostate cancer and are expected to live at least 10 more years.

AUA20

Screening should not be performed in men who are 70 years or older or who have a life expectancy of less than 10 to 15 years. For men 55 to 69 years of age, shared decision making is recommended.

Cervical cancer ACOG,21 ACS,22 USPSTF,23 AAFP24

Screening should be stopped after 65 years of age in patients who have had adequate prior negative screening results (i.e., three consecutive negative cytology or two consecutive negative cotest [human papillomavirus and Papanicolaou] results within the previous 10 years, with the most recent one occurring in the previous five years). Women who have had a total hysterectomy with cervix removal and who do not have a history of grade 2 or higher cervical intraepithelial neoplasia should not be screened.

Colorectal cancer USPSTF,25,26 AAFP27

Patients 50 to 75 years of age should be screened with fecal occult blood testing, sigmoidoscopy, or colonoscopy. Routine screening in those 76 to 85 years of age is not recommended but may be considered in certain individuals. Persons older than 85 years should not be screened.

ACS28

Screening should start at 50 years of age for those at average risk, with no age cutoff, using sigmoidoscopy, colonoscopy, double-contrast enema, computed tomography colonography, fecal occult blood testing, fecal immunochemical testing, or stool DNA testing.

AGS16

Screening should not be performed in patients with a life expectancy of less than 10 years.

Lung cancer USPSTF29

Annual screening for lung cancer using low-dose computed tomography should be performed in patients 55 to 80 years of age who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years. Screening should be discontinued once the patient has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery.

ACS30

A discussion about lung cancer screening should be initiated with patients 55 to 74 years of age in relatively good health who have at least a 30 pack-year smoking history and currently smoke or have quit within the past 15 years.

AAFP31

Evidence is insufficient to recommend for or against screening for lung cancer with low-dose computed tomography.

AAFP = American Academy of Family Physicians; ACOG = American College of Obstetricians and Gynecologists; ACS = American Cancer Society; AGS = American Geriatrics Society; AUA = American Urological Association; USPSTF = U.S. Preventive Services Task Force.

Information from references 12 through 31.

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AMERICAN FAMILY PHYSICIAN Table 4. Terms Related to Cancer Screening

Cervical Cancer

Overdiagnosis: When screening results in the detection (and often treatment) of asymptomatic disease that would not have become clinically important during a patient’s lifetime and would not have impacted morbidity or mortality.

Data from the National Cancer Institute show that 20% of new cases of cervical cancer and 34% of deaths from cervical cancer between 2008 and 2012 occurred in women 65 years and older.53 Most new cases in older women (72%) occur in those who have never been adequately screened.54 Coordinated guidelines for cervical cancer screening were issued in 2012 by the American College of Obstetricians and Gynecologists,21 ACS,22 and USPSTF.23 All advise stopping cervical cancer screening after 65 years of age in patients who have had adequate prior negative screening results (i.e., three consecutive negative cytology results or two consecutive negative cotest [human papillomavirus and Papanicolaou (Pap)] results within the previous 10 years, with the most recent one occurring in the previous five years). Additionally, screening should not be performed in women who have had a total hysterectomy with cervix removal and do not have a history of grade 2 or higher cervical intraepithelial neoplasia.21-23

Lead-time bias: When screening results in the earlier diagnosis of disease, leading to an apparent increase in survival time when measured from the time of diagnosis (“five-year survival”), even though overall mortality and the overall length of a person’s life may be the same in screened and unscreened groups.

Length-time bias: Screening tests are more likely to detect indolent, slow-growing tumors than aggressive, rapidly growing tumors, leading to an apparent improvement in survival.

Healthy participant bias: Those who choose to be screened may be in better health and have more favorable health habits in general, causing improvements in survival and other health outcomes that are unrelated to screening.

large RCTs conducted in the United States and Europe that evalu­ated the effect of prostate-specific antigen (PSA) testing on mortality. The U.S. study, including men 55 to 74 years of age, showed no reduction in prostate cancer mortality after 13 years.49 The European trial, includ­ing men 50 to 74 years of age, showed a small reduction in prostate cancer mortality after 11 years (number needed to screen = 1,055) in men 55 to 69 years of age, but no mortality benefit in those 70 years and older.50 Based on these trials, and considering the known harms of overtreatment for prostate cancer, the USPSTF recommends against PSA-based prostate cancer screening in average-risk men regard­less of age.17 The American Urological Association recommends a discussion of the harms and benefits of PSA screening in men 55 to 69 years of age, and they do not recommend screening in men who are 70 years and older or who have a life expectancy of less than 10 to 15 years.20 Additionally, the ACS recommends that men expected to live at least 10 years receive information about the uncertainties, risks, and potential benefits of screening starting at 50 years of age.19 Overdiagnosis from PSA screening increases with age.

A modeling study of men 55 to 69 years of age found that 43% of prostate cancers detected with screening were overdiagnosed. When screening was extended to 74 years of age, 48% of cancers detected were overdiagnosed.51 Many men with elevated PSA levels undergo prostate biopsy, and at least one-third of these men will have pain, fever, bleeding, infection, urinary incontinence, or erec­tile dysfunction; about 1% require hospitalization.52

Data show that more than one-half of all new cases of cervical cancer occur in women who have never or rarely been screened.54 The percentage of abnormal cytology results decreases with age and with subsequent screen­ings. In the Centers for Disease Control and Prevention’s National Breast and Cervical Cancer Early Detection Program, the detection rate for grade 3 or higher cervical intraepithelial neoplasia was two per 1,000 cytology tests in women 65 years and older, compared with 14.6 per 1,000 tests in those 18 to 29 years of age.55 Modeling stud­ies indicate no substantial benefit to screening beyond 65 years of age, but there is increased risk of potential harms, including false-positive results, and unnecessary colposcopies and cervical biopsies.56 Furthermore, the risk of cytologic abnormalities after hysterectomy is low. Dysplasia was rarely identified after hysterectomy (0.19 per 1,000 women screened) in a cross-sectional study of more than 5,000 cytology tests among women older than 50 years.57 In another study of nearly 10,000 Pap tests in a similar population, the rate was 0.42 high-grade lesion per 1,000 screens.58 Underscreening of eligible women for cervical cancer is common. A survey of about 70 million U.S. women 21 to 65 years of age revealed that an estimated 8.2 million (11.4%) had not been screened for cervical cancer in the previous five years, with higher percentages of non­screening among women 60 to 65 years of age (12.6%).59 Overscreening is also common.

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AMERICAN FAMILY PHYSICIAN The National Health Interview Survey, which included 27,404 women 65 years or older, showed that 56% of participants were screened for cervical cancer.60 Stratified by life expectancy, 31% of those with a life expectancy of less than 10 years received a Pap test.

Among women who had a hysterectomy for benign reasons, 34% to 56% received a Pap test.

Colorectal Cancer In its 2008 guideline and in a new draft recommendation statement, the USPSTF recommends screening for colorectal cancer using fecal occult blood testing, sigmoidoscopy, or colonoscopy beginning at 50 years of age and continuing until 75 years of age.25,26 Screening those older than 85 years is not recommended. Routine screening in those 76 to 85 years of age is also not recom­mended because of a small net benefit in this population; however, there may be considerations to support colorec­tal screening in an individual patient in this age group. For example, screening may be more likely to benefit those who have never been screened previously or those in the highest quartile of life expectancy.61,62 Rather than basing guidelines on age alone, the American Geriatrics Society recommends against colorectal can­ cer screening in patients with a life expectancy less than 10 years because the immediate risk of harms outweighs the minimal likelihood of benefit.16 The ACS recommends colorectal cancer screening starting at 50 years of age for those at average risk, without an explicit age cutoff.28 Meta-analysis data demonstrate a lag time of 10 years before patients receive any benefit from colorectal cancer screening. At least 1,000 persons would need to undergo fecal occult blood testing at least twice to prevent one death from colorectal cancer in 10.3 years.8 It also takes 9.4 years to prevent one colorectal cancer– related death among every 1,000 persons who are screened using flex­ible sigmoidoscopy.63 The benefit-to-risk ratio worsens with advancing age and increased comorbidity. In a meta-analysis, the pooled incidence of adverse events (i.e., perforation, bleeding, or cardiopulmonary complications) was 26 per 1,000 colonoscopies in patients 65 years and older, and it increased to 35 per 1,000 in those 80 years and older.64 Overscreening for colon cancer is common. Of the 27,404 participants in the National Health Interview Survey, 31% of those 85 years and older and 46% of those 75 to 84 years of age were screened. Stratified by

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life expectancy, 41% of those with a life expectancy of less than 10 years received a screening colonoscopy.60 In another study, 46% of Medicare beneficiaries 75 to 79 years of age and 33% of those 80 years or older with a pre­vious normal result on screening colonoscopy received another colonoscopy within seven years, most with no clear indication. In this study, older patients with three or more medical conditions were actually more likely to undergo early repeated screening colonoscopy.65 Conversely, 23% of all persons older than 75 years in the United States have never been screened for colorec­tal cancer. A recent modeling study found that colorectal cancer screening for older adults remains cost-effective and may be indicated beyond 75 years of age, but only in those who have not had previous screenings.66

Lung Cancer The USPSTF recommends annual lung cancer screening using low-dose computed tomography in adults 55 to 80 years of age who have at least a 30 pack-year smoking history and currently smoke or have quit within the past 15 years. Screening should be discontinued once the patient has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery.29 The ACS recommends initiating a discussion about screening in those 55 to 74 years of age who are in relatively good health.30 The USPSTF and ACS guidelines are primarily based on the results from the National Lung Screening Trial (NLST).67 The NLST is a large, good-quality trial conducted in the United States that compared three annual screen­ings with either low-dose computed tomography or singleview posteroanterior chest radiography in current or former smokers between 55 and 74 years of age.

The computed tomography group had a significant reduc­tion in lung cancer and all-cause mortality (20% and 7% reduction, respectively) compared with the radiography group. The number needed to screen over 6.5 years was 320 to prevent one lung cancer death and 210 to prevent one death from any cause.68 Of note, more than 95% of positive screening results were false positives. Addition­ally, patients enrolled in the NLST were relatively healthy, and less than 10% were older than 70 years. The NLST excluded persons who were unlikely to complete curative lung cancer surgery or who had medical conditions with a substantial risk of death during the eight-year trial, which may limit its applicability to many older adults.

AMERICAN FAMILY PHYSICIAN To inform its recommendations, the USPSTF initiated a modeling study to further assess the long-term ben­efits and harms of lung cancer screening and to evaluate different screening intervals and eligibility criteria.

The modeling scenarios suggested that extending the screen­ing eligibility to 80 years of age has a mortality benefit while maintaining a modest level of harm related to false positives, overdiagnosis, and radiationrelated lung can­cer deaths.69 Screening beyond 80 years of age was not recommended because of concerns about increased operative mortality, comorbidity, and reduced eligibility for surgery with curative intent. The modeling scenarios assumed that screened older adults were healthy and without comorbidities influencing life expectancy.

Ultimately, the applicability of lung cancer screening guidelines is uncertain with advancing age and increased comorbidity. The decision to screen for lung cancer in older adults should be individualized and take into account life expectancy, potential benefits and harms, and the patient’s values and preferences.

A recent analysis con­cluded that the greatest benefit of screening is in smokers, with relatively little, if any, benefit in former smokers.70 IMPLICATIONS FOR PRACTICE Although cancer screening decisions for older adults should be individualized, there is little information on how clinicians should approach such complex, shared decisions with patients. Many physicians recommend screening to older patients with advanced illness who would not benefit,71 and feel uncomfortable and unprepared to talk about stopping screening.72,73 Additionally, many older patients perceive cancer screening as a rou­tine part of their health and may feel taken aback by the prospect of not being screened.74,75 Studies show that most older adults with serious ill­ness want to know their prognosis so that they can make medical decisions76 and want to discuss the possibility of stopping cancer screening with their physicians.75 Many family caregivers of patients with dementia are open to discussions about screening cessation that focus on qual­ity of life, burdens, and benefits.77 Given the uncertainty of the relative benefits and harms of cancer screening in older adults, the patient’s preferences should be a key consideration. Decision aids (Table 2) can improve patient involvement, knowledge, and realistic percep­tions of outcomes.78 Experts recommend that physicians introduce the idea of stopping cancer screening in advance to set up the

expectation that a time will come when the burdens of screening will outweigh the potential benefits.79 Discussions should be revisited periodically, in the context of the patient’s health status, to help him or her weigh the benefits and harms of screening, and to clarify patient preferences. It is important to convey that a decision to stop cancer screening does not translate into decreased health care. Rather, discussions can focus on health promotion strat­egies that are most likely to benefit patients in the more immediate future, such as exercise and immunizations.

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2. Walter LC, et al. Relationship between health status and use of screen­ing mammography and Papanicolaou smears among women older than 70 years of age. Ann Intern Med. 2004;140(9):681-688.

3. Walter LC, Lindquist K, Nugent S, et al. Impact of age and comorbidity on colorectal cancer screening among older veterans. Ann Intern Med. 2009;150(7):465-473.

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8. Lee SJ, Boscardin WJ, Stijacic-Cenzer I, Conell-Price J, O’Brien S, Walter LC. Time lag to benefit after screening for breast and colorectal cancer: meta-analysis of survival data from the United States, Sweden, United Kingdom, and Denmark. BMJ. 2013;346:e8441.

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20. Carter HB, Albertsen PC, Barry MJ, et al. Early detection of prostate cancer: AUA Guideline. J Urol. 2013;190(2):419-426.

21. Committee on Practice Bulletins—Gynecology. ACOG practice bulle­tin number 131: screening for cervical cancer. Obstet Gynecol. 2012;120(5):1222-1238.

22. Saslow D, Solomon D, Lawson HW, et al.; ACS-ASCCPASCP Cervi­cal Cancer Guideline Committee. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. CA Cancer J Clin.

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25. U.S. Preventive Services Task Force. Colorectal cancer: screening. October 2008. http://www.uspreventive services task force.org/Page/ Document/Update Summary Final/colorectal-cancer-screening? ds= 1&s= colorectal%20 cancer. Accessed February 16, 2016.

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27. American Academy of Family Physicians. Clinical preventive service rec­ommendation.

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28. Levin B, Lieberman DA, McFarland B, et al. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. CA Cancer J Clin. 2008;58(3):130-160.

29. Moyer VA. Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2014;160(5):330-338.

30. Smith RA, Manassaram-Baptiste D, Brooks D, et al. Cancer screening in the United States, 2015: a review of current American Cancer Soci­ety guidelines and current issues in cancer screening. CA Cancer J Clin. 2015;65(1):30-54.

31. American Academy of Family Physicians. Clinical preventive service rec­ommendation. Lung cancer. http:// www.aafp.org/patient-care/clinical-recommendations/ all/lung-cancer.html. Accessed December 15, 2015.

32. Gates TJ. Screening for cancer: concepts and controversies.

Am Fam Physician. 2014;90(9):625-631.

33. Gøtzsche PC, Jørgensen KJ. Screening for breast cancer with mammog­raphy. Cochrane Database Syst Rev. 2013;(6):CD001877.

34. Independent UK Panel on Breast Cancer Screening.

The benefits and harms of breast cancer screening: an independent review. Lancet. 2012;380(9855):1778-1786.

35. U.S. Preventive Services Task Force. Final recommendation statement. Breast cancer: screening. January 2016. http:// www.uspreventiveservicestaskforce.org/Page/Document/ RecommendationSt atementFinal/ b reast-cancerscreening1. Accessed February 16, 2016.

36. Nyström L, Andersson I, Bjurstam N, Frisell J, Nordenskjöld B, Rutqvist LE. Long-term effects of mammography screening: updated overview of the Swedish randomised trials [published correction appears in Lan­cet. 2002;360(9334):724]. Lancet. 2002;359(9310): 909-919.

37. Badgwell BD, Giordano SH, Duan ZZ, et al. Mammography before diag­nosis among women age 80 years and older with breast cancer. J Clin Oncol. 2008;26(15):2482-2488.

38. McPherson CP, Swenson KK, Lee MW. The effects of mammographic detection and comorbidity on the survival of older women with breast cancer. J Am Geriatr Soc. 2002;50(6):1061-1068.

39. McCarthy EP, Burns RB, Freund KM, et al. Mammography use, breast cancer stage at diagnosis, and survival among older women. J Am Geri­atr Soc. 2000;48(10):1226-1233.

AMERICAN FAMILY PHYSICIAN 40. Schousboe JT, Kerlikowske K, Loh A, Cummings SR. Personalizing mam­mography by breast density and other risk factors for breast cancer: analysis of health benefits and cost-effectiveness. Ann Intern Med. 2011;155(1): 10-20.

41. Barratt A, Howard K, Irwig L, Salkeld G, Houssami N. Model of out­comes of screening mammography: information to support informed choices. BMJ. 2005;330(7497):936.

42. Mandelblatt JS, Cronin KA, Bailey S, et al.; Breast Cancer Working Group of the Cancer Intervention and Surveillance Modeling Net­work. Effects of mammography screening under different screening schedules: model estimates of potential benefits and harms [published correction appears in Ann Intern Med. 2010;152(2):136].

Ann Intern Med. 2009;151(10):738-747.

43. Braithwaite D, Zhu W, Hubbard RA, et al.; Breast Cancer Surveillance Consortium. Screening outcomes in older US women undergoing multiple mammograms in community practice: does interval, age, or comorbidity score affect tumor characteristics or false positive rates?

J Natl Cancer Inst. 2013;105(5):334-341.

44. Welch HG, Black WC. Overdiagnosis in cancer. J Natl Cancer Inst. 2010;102(9):605-613.

45. de Glas NA, Kiderlen M, Bastiaannet E, et al. Postoperative compli­cations and survival of elderly breast cancer patients: a FOCUS study analysis. Breast Cancer Res Treat. 2013;138(2):561-569.

46. Muss HB, Woolf S, Berry D, et al.; Cancer and Leukemia Group B. Adju­vant chemotherapy in older and younger women with lymph node-positive breast cancer. JAMA. 2005;293(9):1073-1081.

47. Bond M, Pavey T, Welch K, et al. Systematic review of the psychological consequences of false-positive screening mammograms. Health Tech­nol Assess. 2013;17(13):1-170.

48. Ilic D, Neuberger MM, Djulbegovic M, Dahm P. Screening for prostate cancer. Cochrane Database Syst Rev. 2013;(1):CD004720.

49. Andriole GL, Crawford ED, Grubb RL III, et al.; PLCO Project Team. Pros­tate cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after 13 years of follow-up. J Natl Cancer Inst. 2012;104(2):125-132.

50. Schröder FH, Hugosson J, Roobol MJ, et al.; ERSPC Investigators. Prostate-cancer mortality at 11 years of follow-up [published correc­tion appears in N Engl J Med. 2012;366(22):2137]. N Engl J Med. 2012;366(11): 981-990.

51. Heijnsdijk EA, Wever EM, Auvinen A, et al. Quality-oflife effects of prostate-specific antigen screening. N Engl J Med. 2012;367(7):595-605.

52. Rosario DJ, Lane JA, Metcalfe C, et al. Short term outcomes of prostate biopsy in men tested for cancer by prostate specific antigen: prospec­tive evaluation within ProtecT study. BMJ. 2012;344:d7894.

53. National Cancer Institute. SEER stat fact sheets: cervix uteri cancer. http://seer.cancer.gov/statfacts/html/cervix. html. Accessed December 15, 2015.

54. Leyden WA, Manos MM, Geiger AM, et al. Cervical cancer in women with comprehensive health care access: attributable factors in the screening process. J Natl Cancer Inst. 2005;97(9):675-683.

55. Benard VB, Eheman CR, Lawson HW, et al. Cervical screening in the National Breast and Cervical Cancer Early Detection Program, 1995-2001. Obstet Gynecol.

2004;103(3):564-571.

56. Kulasingam SL, Havrilesky L, Ghebre R, Myers ER. Screening for cer­vical cancer: a decision analysis for the U.S. Preventive Services Task Force. http://www.ncbi.nlm. nih.gov/books/NBK92546/pdf/Bookshelf_ NBK92546.pdf.

Accessed December 15, 2015.

57. Fox J, Remington P, Layde P, Klein G. The effect of hysterectomy on the risk of an abnormal screening Papanicolaou test result. Am J Obstet Gynecol.

1999;180(5):1104-1109.

58. Pearce KF, Haefner HK, Sarwar SF, Nolan TE. Cytopathological findings on vaginal Papanicolaou smears after hysterectomy for benign gyneco­logic disease.

N Engl J Med. 1996;335(21):1559-1562.

59. Benard VB, Thomas CC, King J, Massetti GM, Doria-Rose VP, Saraiya M; Centers for Disease Control and Prevention (CDC). Vital signs: cervical cancer incidence, mortality, and screening—United States, 2007-2012. MMWR Morb Mortal Wkly Rep. 2014;63(44):1004-1009.

60. Royce TJ, Hendrix LH, Stokes WA, Allen IM, Chen RC. Cancer screening rates in individuals with different life expectancies. JAMA Intern Med. 2014;174(10):1558-1565.

61. Screening for colorectal cancer: U.S. Preventive Services Task Force rec­ommendation statement. Ann Intern Med. 2008;149(9):627-637.

62. Zauber AG, Lansdorp-Vogelaar I, Knudsen AB, Evaluating test strategies for colorectal cancer screening: a decision analysis for the U.S. Preventive Services Task Force. Ann Intern Med. 2008;149(9):659-669.

63. Tang V, Boscardin WJ, Stijacic-Cenzer I, Lee SJ. Time to benefit for colorectal cancer screening: survival metaanalysis of flexible sigmoid­oscopy trials [published correction appears in BMJ. 2015;350:h2228]. BMJ. 2015;350:h1662.

64. Day LW, Kwon A, Inadomi JM, Walter LC, Somsouk M. Adverse events in older patients undergoing colonoscopy: a systematic review and meta-analysis. Gastrointest Endosc. 2011;74(4):885-896.

65. Goodwin JS, Singh A, Reddy N, Riall TS, Kuo YF. Overuse of screen­ing colonoscopy in the Medicare population.

Arch Intern Med. 2011;171(15):1335-1343.

66. van Hees F, Habbema JD, Meester RG, Lansdorp-Vogelaar I, van Bal­legooijen M, Zauber AG. Should colorectal cancer screening be consid­ ered in elderly persons without previous screening? A cost-effectiveness analysis. Ann Intern Med. 2014;160(11):750-759.

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AMERICAN FAMILY PHYSICIAN 67. Humphrey LL, Deffebach M, Pappas M, et al. Screening for lung cancer with low-dose computed tomography: a systematic review to update the US Preventive Services Task Force recommendation. Ann Intern Med. 2013;159(6):411-420.

68. Aberle DR, Adams AM, Berg CD, et al.; National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose com­ puted tomographic screening. N Engl J Med. 2011;365(5):395-409.

69. de Koning HJ, Meza R, Plevritis SK, et al. Benefits and harms of com­puted tomography lung cancer screening strategies: a comparative modeling study for the U.S. Preventive Services Task Force. Ann Intern Med. 2014;160(5):311-320.

70. Black WC, Gareen IF, Soneji SS, et al. Cost-effectiveness of CT screen­ing in the National Lung Screening Trial.

N Engl J Med. 2014;371(19):1793-1802.

71. Haggstrom DA, Klabunde CN, Smith JL, Yuan G. Variation in primary care physicians’ colorectal cancer screening recommendations by patient age and comorbidity. J Gen Intern Med. 2013;28(1):18-24.

72. Schonberg MA, Ramanan RA, McCarthy EP, Marcantonio ER. Decision making and counseling around mammography screening for women aged 80 or older.

J Gen Intern Med. 2006;21(9):979-985.

screening in the elderly: a qualita­tive study. J Gen Intern Med. 2009;24(7):816-821.

74. Torke AM, Schwartz PH, Holtz LR, Montz K, Sachs GA. Older adults and forgoing cancer screening: “I think it would be strange”. JAMA Intern Med. 2013;173(7): 526-531.

75. Lewis CL, Kistler CE, Amick HR, et al. Older adults’ attitudes about con­tinuing cancer screening later in life: a pilot study interviewing residents of two continuing care communities. BMC Geriatr. 2006;6:10.

76. Ahalt C, Walter LC, Yourman L, Eng C, Pérez-Stable EJ, Smith AK. “Knowing is better”: preferences of diverse older adults for discussing prognosis. J Gen Intern Med. 2012;27(5):568-575.

77. Torke AM, Schwartz PH, Holtz LR, Montz K, Sachs GA. Caregiver per­spectives on cancer screening for persons with dementia: “why put them through it?”. J Am Geriatr Soc. 2013;61(8):1309-1314.

78. Stacey D, Légaré F, Col NF, et al. Decision aids for people facing health treatment or screening decisions. Cochrane Database Syst Rev. 2014;1:CD001431.

79. Schonberg MA, Walter LC. Talking about stopping cancer screening-not so easy. JAMA Intern Med. 2013;173(7): 532-533.

80. Albert RH, Clark MM. Cancer screening in the older 73. Lewis CL, Griffith J, Pignone MP, Golin C. Physicians’ decisions about continuing or stopping colon cancer patient. Am Fam Physician. 2008;78(12):1369-1374.

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AMERICAN FAMILY PHYSICIAN

Practice Guidelines ACS RELEASES GUIDELINE ON BREAST CANCER SCREENING Breast cancer remains a leading cause of cancer-related mortality among women in the United States, even as early detection and treatment advances have helped contribute to a decline in deaths from breast cancer in recent decades. Mammography is an important screening tool, and the publication of long-term followup studies has led to a bet­ter understanding of the impact its use has on patient health.

The American Cancer Society (ACS) organized an interdisciplinary guideline development group to review the available evidence on breast cancer mortality, quality of life, life expectancy, false-positive find­ings, overdiagnosis, and overtreatment, and to update their 2003 guideline on breast can­cer screening in averagerisk women. The 2015 recommendations emphasize the need to inform patients of the balance of potential harms and benefits of screening and engage in shared decision making.

Recommendations Screening Mammography In women who are at average risk of breast cancer, routine screening with mammogra­ phy should be initiated at 45 years of age. Screening should continue on an annual basis until 54 years of age. For women 55 years and older, biennial screening is the preferred approach, with the option to screen each year. Annual screening mammography should be offered to patients between 40 and 44 years of age, although the five-year abso­lute risk of breast cancer is lower in this age group than for women older than 45 years.

The previous guideline directed clini­cians to screen women annually starting at 40 years of age, and continue screening throughout the patient’s lifetime unless the patient was in poor health or would not be able to withstand treatment for breast cancer.

High-quality evidence demonstrates that there is significant benefit to using mam­mography long term to

Source: Adapted from Am Fam Physician. 2016;93(8):711-712.

screen for breast cancer compared with other screening methods or a no-screening approach. Life-expectancy gains from screening mammog­raphy are meaningful in the context of individual patients in whom the intervention prevented a premature death. However, the effect of these gains on measures of life expectancy across the entire population is not discernable.

Screening mammography commonly results in falsepositive test results, which can lead to repeat imaging, and poten­tially biopsy. Understanding that factors such as the use of digital vs. screen-film mammography or the absence of sufficient comparison images may increase rates of false-positive findings is key for implement­ing practices to reduce harm associated with this outcome.

Screening mammography may detect can­ cers that do not need to be treated because they otherwise would not become symptom­atic breast cancer. Harm from unnecessary treatment is a significant concern and may represent the greatest risk associated with mammography. However, reliable numbers are not available regarding the degree to which overdiagnosis can be expected to occur among women who undergo breast cancer screening.

Modeling studies suggest that screening with mammography may lead to a slight increase in qualityadjusted life expectancy. This association has not been further stud­ied in a real-world setting, and the available evidence for this outcome is not high quality enough to inform the selection of screening practices.

Discontinuation of Screening The decision to discontinue screening mam­mography should be based on the patient’s overall health and life expectancy. Healthy women who are expected to live at least 10 years are likely to benefit from continued screening. It is important that clinicians con­sider an individual’s values and preferences when determining whether to recommend that screening be stopped because of a seri­ous illness or increasing age.

Breast cancer incidence begins to decline once women reach 75 to 79 years of age. However, about 25% of 85-year-old women can be expected to live at least 10 years. Because mammography’s sensitivity and specificity increase as a patient ages, it remains an effective tool for detecting breast cancer in older women.

Studies in this popu­lation are limited, but findings

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AMERICAN FAMILY PHYSICIAN suggest that screening healthy women older than 75 years with mammography can reduce deaths from breast cancer. Clinicians can consult mortality indices to predict the likelihood that a patient will live at least 10 years, indicating whether screening should continue.

When inform­ing women about the potential harms and benefits of screening mammography later in life, decision aids can be useful for ensuring that the direction of care is in line with indi­vidual patient preferences.

Clinical Examination

Clinical breast examination is a time bur­den for clinicians. Although the 2003 guide­line encouraged clinicians to perform a breast examination, focus should be shifted away from this practice and toward careful assessment of family history and patient counseling on screening mammography and breast changes that may require medi­cal follow-up. Self-examination may not be more effective than incidental discovery, and evidence has not been sufficient to rec­ommend that it be performed routinely.

Evidence has not shown clinical breast exami­nation to be effective in detecting breast can­cer in women of average risk among any age group. It is not recommended as an approach to screening for breast cancer. Mammogra­phy alone detects a higher number of breast cancers than clinical breast examination, and clinical breast examination performed in addition to mammography may lead to a higher number of falsepositive test results.

These updated recommendations repre­sent a complete revision in the approach to screening. Rather than letting patients choose whether to receive more information about the possible implications of breast cancer screening, it is now strongly sug­gested that clinicians familiarize women with general aspects of early detection, including associated harms, benefits, and limitations.

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Photo Quiz RED TENDER NODULE ON A PREGNANT PATIENT A 22-year-old pregnant woman (gravida 2, para 1) presented with a sore throat and tonsillar exudates at eight weeks’ gestation. Group A rapid streptococcus antigen test results were positive, and streptococcal phar­yngitis was diagnosed. She was treated with amoxicillin. On the seventh day of antibiotic treatment, she returned to the clinic with a tender skin nodule on her left anterior leg, and a different antibiotic was prescribed.

On physical examination, the patient had a low-grade fever and multiple erythema­tous nodules on both of her shins (Figures 1 and 2). The nodules were tender but had no ulceration or drainage. After no response to two weeks of oral antibiotic therapy, she was admitted to the hospital and intravenous antibiotics were initiated. A wound culture had no bacterial growth, and a complete blood count was within normal limits.

Figure 1.

Question Based on the patient’s history, physical examination findings, and laboratory results, which one of the following is the most likely diagnosis?

A. Bacterial cellulitis.

Figure 2.

B. Erythema nodosum.

C. Polyarteritis nodosa.

D. Sarcoidosis.

SEE THE FOLLOWING PAGE FOR DISCUSSION.

Source: Adapted from Am Fam Physician. 2016;93(8):701-702.

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AMERICAN FAMILY PHYSICIAN Discussion

Summary Table

The answer is B: erythema nodosum. Ery­thema nodosum is a hypersensitivity reaction that causes inflammation of the subcutaneous fat. Up to 50% of cases are idiopathic, but the condition can be triggered by a wide variety of stimuli. Causes include medications, such as oral contraceptives and antibiotics includ­ing penicillins and sulfonamides; infections, most commonly streptococci; pregnancy; systemic illnesses, such as sarcoidosis and inflammatory bowel disease; and malignan­cies, such as lymphoma. Erythema nodosum typically presents in the teens and 20s and is more common in women.1

Condition

Characteristics

Bacterial cellulitis

Infection of the subcutaneous tissues; erythema, warmth, and tenderness over an area of skin

Erythema nodosum presents as tender, erythematous, subcutaneous nodules that are 1 to 10 cm in diameter.

The lesions are typically located symmetrically on the ante­rior surface of the lower extremities. Nod­ules often take one to two months to heal completely but usually do not ulcerate. After the history and physical examination, evaluation should include testing for streptococcal infection, as well as risk strati­fication for tuberculosis. Erythema nodosum is typically selflimited. Pain can be managed with nonsteroidal anti-inflammatory drugs. Any underlying disorders should be treated and supportive care provided.2 This patient has multiple factors associated with erythema nodosum, including streptococcal pharyngitis, antibiotic treatment, and pregnancy.

Bacterial cellulitis is an infection of the dermis and subcutaneous tissues that is characterized by edema, warmth, and tenderness over an area of skin.

Cellulitis commonly occurs near breaks in the skin, such as surgical wounds, trauma, or ulcerations, but occasionally presents in normal skin. Patients may have a fever and an elevated white blood cell count.3 Polyarteritis nodosa is a systemic necrotizing vasculi­tis that typically affects medium-sized muscular arteries and occasionally small muscular arteries, resulting in secondary tissue ischemia. The kidneys, skin, joints, muscles, peripheral nerves, and gastrointestinal tract are most commonly affected. Cutaneous manifestations include livedo reticularis, skin ulcers, tender erythematous nodules, bullous or vesicular eruptions, infarc­tion and gangrene of fingers or toes, or a combination. Unlike with erythema nodosum, the nodules in polyar­teritis nodosa can ulcerate.4 Sarcoidosis is characterized by noncaseating epithelioid granulomas affecting any organ system. The disease most commonly involves granuloma formation in the lungs, with some pulmonary involvement in

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Erythema nodosum Tender, erythematous, subcutaneous nodules located symmetrically on the anterior surface of the lower extremities; nodules usually do not ulcerate Polyarteritis nodosa

Systemic necrotizing vasculitis that typically affects medium-sized muscular arteries; cutaneous manifestations include livedo reticularis, skin ulcers, tender and erythematous nodules, bullous or vesicular eruptions, infarction and gangrene of fingers or toes, or a combination

Sarcoidosis

Noncaseating epithelioid granulomas affecting any organ system; cutaneous manifestations include erythema nodosum; lupus pernio; subcutaneous nodules; and maculopapular, nodular, scar, plaque, angiolupoid, ichthyosiform, lichenoid, annular, verrucous, psoriasiform, and ulcerative lesions

90% to 95% of cases. Dermatologic manifestations occur in 25% of patients with sarcoidosis. Specific lesions manifest as noncaseating granulomas, whereas nonspecific lesions do not reveal granulomas on histopathologic examina­tion. Erythema nodosum is the main nonspecific cuta­neous disease. Specific cutaneous diseases include lupus pernio; subcutaneous nodules; and maculopapular, nod­ular, scar, plaque, angiolupoid, ichthyosiform, lichenoid, annular, verrucous, psoriasiform, and ulcerative lesions.5 REFERENCES 1. Blake T, Manahan M, Rodins K. Erythema nodosum - a review of an uncommon panniculitis. Dermatol Online J. 2014;20(4):22376.

2. Schwartz RA, Nervi SJ. Erythema nodosum: a sign of systemic disease. Am Fam Physician. 2007;75(5):695-700.

3. Stulberg DL, Penrod MA, Blatny RA. Common bacterial skin infections. Am Fam Physician. 2002;66(1):119-124.

4. Gota CE. Polyarteritis nodosa (PAN). Merck Manual Professional Ver­sion. http://www.merckmanuals.com/ professional/musculoskeletal-and-connective-tissuedisorders/vasculitis/polyarteritis-nodosa-%28pan%29.

Accessed August 10, 2015.

5. Merola JF. Dermatologic manifestations of sarcoidosis. http://emedicine.medscape.com/article/1123970overview. Accessed January 20, 2016.

CARDIOLOGY

Interesting Case of Single Ventricle BHARATH RAJ KIDAMBI*, KALPANA RAMANATHAN†, BABU PETER S‡, SABARATNAVEL R#, SRINIVASAGALU K#

ABSTRACT Single ventricle or double inlet left ventricle (DILV) is an uncommon congenital heart disease with very dismal prognosis if left un-operated. Very rarely few cases survive till adulthood, if they have a favorable physiology. We present one such interesting case who was diagnosed incidentally with DILV, and the complete characterization of its nature with a cardiac magnetic resonance imaging.

Keywords: Single ventricle, double inlet left ventricle, Van Praagh classification, patent ductus arteriosus, true single ventricle, functional single ventricle, univentricular heart

T

here is an increased prevalence of adults with congenital heart disease (CHD) in the last few years due to better detection using noninvasive echocardiography and cardiac magnetic resonance imaging (MRI). The most common CHD detected is isolated ventricular septal defect. Ventricular septal defect may be associated with a number of other complex CHDs. One such complex CHD is single ventricle wherein both the morphological right and left atrium drain into a single chamber, which may be morphological left ventricle (more common) or morphological right ventricle or into a ventricle with indeterminate morphology. It is usually more common in males. Single ventricle can be easily detected using a 2D echocardiography. Usually prognosis is very dismal without early surgery.

CASE REPORT A 17-year-old girl, came to our emergency department with features suggestive of drug-induced dystonia,

*Junior Resident †Assistant Professor Institute of Internal Medicine, Rajiv Gandhi Government General Hospital Chennai, Tamil Nadu ‡Professor Barnard Institute of Radiology, Rajiv Gandhi Government General Hospital Chennai, Tamil Nadu #Professor Institute of Internal Medicine,Rajiv Gandhi Government General Hospital Chennai, Tamil Nadu Address for correspondence Dr Bharath Raj Kidambi No. 5 Gokulam Colony, No. 2 Ramavaram Main Road Valasaravakkam, Chennai - 600 087, Tamil Nadu E-mail: drbkid@gmail.com, drbkid@icloud.com

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which was managed conservatively. However on examination, she was thin built, moderately nourished and anxious looking patient. General examination revealed mild pallor. There was no cyanosis or clubbing.

Vitals were normal. Cardiovascular examination revealed a single second heart sound, with soft systolic murmur in the pulmonary area. Rest of the systemic examination was normal. Electrocardiogram showed normal sinus rhythm with rightward axis deviation.

Lead V1 showed a dominant R and large biphasic RS complex in mid-precordial leads (Fig. 1).

Transthoracic echocardiogram revealed situs solitus, two atria’s with an intact interatrial septum, a single ventricle with fine trabeculations and absence of moderator band. A small patent ductus arteriosus (PDA) was seen. We performed 3 Tesla cardiac MRI (Siemens) done with both white blood and black blood imaging, gradient echo cine imaging and contrast-enhanced pulmonary angiogram with timeresolved angiography with stochastic trajectories (TWIST) protocol of Siemens to delineate vessel

Figure 1. ECG with normal sinus rhythm with rightward axis deviation, dominant R waves in V1 and biphasic RS complexes in mid-precordial leads.

CARDIOLOGY relationship to chambers. Entire study was completed in approximately 25 minutes, which is considerably less than the time needed for a conventional 1.5 Tesla MRI. Segmental analysis of the MRI revealed normal visceroatrial situs, two atria’s, with intact interatrial septum draining into a common ventricle of left ventricular morphology, with the rudimentary right ventricle (rRV) lying anterior and to the left of the common ventricle (Figs. 2 and 3). There is venoatrial concordance, ventriculoatrial and ventriculoarterial

Figure 2. Three-chamber view in cardiac MRI. The rudimentary right ventricle (rRV) being situated to the left and anterior of the common ventricle (CV). Main pulmonary artery (MPA) is seen arising from the CV.

Figure 3. Four-chamber view in cardiac MRI. There are two atria’s right atrium (RA) and left atrium (LA) with intact interatrial septum (grey arrow), draining to a common ventricle (CV) by two valves, right atrioventricular valve (white arrow) and left atrioventricular valve (black arrow).

discordance. There is subvalvular pulmonary stenosis. There is no obstruction to the aortic outflow (Figs. 4 and 5). The right atrium measures 3.5 cm, left atrium measures 3.1 cm and common ventricle measures 6.1 cm. Main pulmonary artery is significantly dilated measuring 5 cm. Left pulmonary artery measures 10 mm, and the right pulmonary artery measures 16 mm. Small PDA is present (Fig. 6).

Figure 4. White blood imaging (True FISP sequence) showing right atrium (RA) draining into the common ventricle (CV).

A dilated main pulmonary artery (MPA) is seen arising from the CV, where a subvalvular pulmonary stenosis (black arrow) is noted.

Figure 5. TWIST MR angiogram. Superior vena cava (SVC) is seen draining into the right atrium (RA) indicating venoatrial concordance. The relationship of the great vessels are welldelineated here, with the main pulmonary artery which is dilated (MPA) situated on the right and the aorta (Ao) situated on the left.

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CARDIOLOGY

Figure 6. TWIST MRA. A small PDA with width 3 mm and length 7.2 mm (black arrow) connecting the aorta and the main pulmonary artery.

DISCUSSION Single ventricle is an exceedingly rare and complex CHD. Worldwide incidence of double inlet left ventricle (DILV) is reported as 1% of all congenital heart malformations.1 There is usually a male predominance with sex ratio of 3:1. Single ventricle is classified morphologically by Van Praagh et al into types (A-D).

It may be double inlet with left ventricular morphology, absence of right ventricular sinus (type A), double inlet with right ventricular morphology and absence of left ventricular sinus (type B), double inlet with mixed ventricular morphology and absence of ventricular septum (type C) or double inlet ventricle with indeterminate morphology (type D). Great arteries may be normally related (type I or Holmes heart), aorta may be anterior and rightward (type II) or leftward (type III), “inverted” in a posterior and leftward orientation (type IV).2 Our patient has the commonest type of DILV (type A-III) (Fig. 7).

The natural course of the patients with un-operated single ventricle is usually poor. The death rate in a wellformed single ventricle of left ventricular morphology is 4.8% per year, with 70% of them dying before the age of 16. Prognosis is far worse for patients with right ventricular or indeterminate morphology.3 The univentricular heart physiology depends on key factors such as systemic and pulmonary venous return, flow across the AV valves, obstruction to systemic outflow and pulmonary vascular resistance. Pulmonary stenosis

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Figure 7. 3D volume rendering of MRA with the aorta situated anterior to the dilated main pulmonary artery (MPA). The aorta seems to arise from the rudimentary right ventricular chamber (white arrow).

has shown to be beneficial for these patients and prevent them from developing pulmonary hypertension early on in their life.4 They exhibit favorable streaming due to the preferential flow of systemic venous blood to the pulmonary artery and pulmonary venous blood to the aorta. Select patients with left ventricular morphology and well-balanced physiology can sometimes survive till late adulthood. They have also been able to successfully complete their families and withstand the physiological derangements during pregnancy. Similar hemodynamic parameters allowed our patient to have good functional capacity with minimal symptoms. Very few of the DILV patients have this kind of favorable circulation, which shows the rarity of this condition.

REFERENCES 1. Franklin RC, Spiegelhalter DJ, Anderson RH, Macartney FJ, Rossi Filho RI, Douglas JM, et al. Double-inlet ventricle presenting in infancy. I. Survival without definitive repair.

J Thorac Cardiovasc Surg. 1991;101(5):767-76.

2. Van Praagh R, Ongley PA, Swan HJ. Anatomic types of single or common ventricle in man. Morphologic and geometric aspects of 60 necropsied cases. Am J Cardiol.

1964;13:367-86.

3. Moodie DS, Ritter DG, Tajik AJ, O’Fallon WM. Long-term follow-up in the unoperated univentricular heart. Am J Cardiol. 1984;53(8):1124-8.

4. Ammash NM, Warnes CA. Survival into adulthood of patients with unoperated single ventricle. Am J Cardiol.

1996;77(7):542-4.

COMMUNITY MEDICINE

Prevalence of Tobacco Use Among Adult Population in a Semi-urban Area of Bihar RR JHA*, A KUMAR*

ABSTRACT Background: Tobacco use is a major preventable risk factor for all major noncommunicable diseases (NCDs). According to GATS 2009-10, more than half of adult population of Bihar uses tobacco in one or other form. There is a steady increase in the number of deaths due to cancer in Bihar, of which oropharyngeal cancer has the highest burden. Material and methods: A crosssection study was carried out in Sasaram, a subdivision of Rohtas district from January to March 2016. With 54% prevalence, 412 sample size was calculated. Two wards of SMC were randomly selected and door-to-door survey was done to meet the adequate sample. Results: Total 517 participants were included in the study, where lifetime tobacco use was found to be 77.9% (403) that of current use was 66.9% (346). Nineteen percent of participants were using smoked tobacco and 47% were using smokeless, while 7% were dual users. Use of tobacco by near relatives among users and nonusers was statically significant as after friends, the major influence for tobacco initiation were relatives. Conclusion: Use of tobacco is widely prevalent. Knowledge about adverse effects of tobacco use and its association with diseases like hypertension and diabetes mellitus was inadequate.

There is urgent need of intervention in form of education and counseling to the community.

Keywords: Tobacco use, oropharyngeal cancer, hypertension, diabetes mellitus, counseling

E

very year 6 million people die due to tobacco use; of these 5 million die directly due to tobacco and 6 lakhs people die due to second hand smoke.1 In India, noncommunicable diseases (NCDs) has surpassed communicable diseases in terms of morbidity and mortality.2 Tobacco use is a major preventable risk factor for all major NCDs. In India, the use of tobacco is ancient and culturally acknowledged, especially in form of paan. Tobacco in both forms, smoked and smokeless, is widely used in Bihar. According to the Global Adult Tobacco Survey (GATS) 2009-10, more than half of adult population of Bihar uses tobacco in one or other form. Study shows that children less than 15 years, use both form of tobacco with prevalence of smokeless and smoked, 6.2% and 0.3%, respectively.3 There is high risk of cardiovascular diseases, diabetes mellitus, ischemic heart disease, cancers, etc. due to

*Assistant Professor Dept. of Community Medicine Narayan Medical College and Hospital, Jamuhar, Sasaram, Bihar Address for correspondence Dr RR Jha Assistant Professor Dept. of Community Medicine Narayan Medical College and Hospital, Jamuhar, Sasaram, Bihar E-mail: drravirjha@gmail.com

tobacco use. In Bihar, there has been steep increase in mortality due to cancer from 38,968 in 2011 to 43,272 in 2014.4 As chewable tobacco is more common, thus oropharyngeal cancer has greatest burden. Health cost of tobacco users is more than 472 crores in Bihar. Low income families spend 40% of their income on tobacco products5 and added with its ill-health effects it further deepens their burden of poverty. Hence, a study was conducted on tobacco in Rohtas district of Bihar. The objectives of the study were to find the prevalence of tobacco use among adult population and to assert the factors influencing its initiation.

MATERIAL AND METHODS A cross-section study was carried out in Sasaram, a subdivision of Rohtas district. Approval from Institutional Ethical Committee was taken and study was conducted from January to March 2016. Study was done using structured, pre-tested and pre-designed questionnaire, asserting brief sociodemographic profile and questions related to tobacco use and factors influencing it. To obtain adequate sample size, prevalence of tobacco use in Bihar was taken as 54%6 and sample size was calculated to be 382 with 10% nonresponse rate, final sample size was calculated to be 421. To get sampling unit, two wards of Sasaram

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COMMUNITY MEDICINE Municipal Council were randomly selected and adequate sample size was achieved by doing doorto-door survey. All the members of house hold aged 15 and above were surveyed till requisite sample size was achieved. Operational definitions: Smoked tobacco includes all the form of smoking i.e., cigarette or bidi.

Smokeless tobacco - includes all varieties of paan, gutka, guul, khaini, etc. Lifetime user - used ever in life even once. Current users - using tobacco once or more in a day.

RESULTS

Information about harmful effect of tobacco use was adequate in surveyed population, 92% and major source Table 2. Use of Tobacco Among Different Educational Strata Educational status

In the study, prevalence of lifetime tobacco use was found to be 77.9% (403) that of current use was 66.9% (346). More than 19% of participants were using smoked tobacco and 47% were using smokeless, while 7% were dual users.

The difference in type of tobacco use among both gender was found to be statistically significant where, p = 0.18214 (Table 1). Majority of male respondents were using smokeless tobacco i.e., 55% which was 38% among females. Males were using gutka/paan masala, whereas females were using guul and other tobacco products applicable on gums. Almost 7% of population was using both types of tobacco. During survey, it was found that the minimum age for initiation of tobacco use was 7 years.

Use of tobacco was different across different educational strata found highest among illiterates (Table 2). In the survey, emphasis was laid on use of tobacco by respondent’s near relatives. It was found to be statistically highly significant where, p ≤ 0.00001 Table 1. Use of Different Types of Tobacco Across Gender Type

Smoked tobacco

Smokeless tobacco

Both

Remarks

Male (n = 208)

49 (23.55%)

159 (76.44%)

23 (11.05%)

χ2 = 8.0111

Female (n = 138)

52 (37.68%)

86 (62.32%)

15 (10.87%)

Total (n = 346)

101 (29.19%)

245 (70.80%)

38 (10.98%)

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Yes

No

Illiterate (119)

97 (82%)

22 (18%)

High School (223)

131 (58%)

92 (41%)

Graduate (149)

107 (72%)

42 (28%)

Professionals (26)

11 (42%)

15 (58%)

Total

346 (67%)

171 (33%)

Table 3. Use of Tobacco by their Parents Tobacco use by relatives

Participants using tobacco Yes

No

Tobacco users

253

26

Nonusers

93

145

Total

346

171

80

Remarks χ2 =154.52

74.55

70 60 Percentage (%)

Total 526 people were surveyed, of which 517 forms were scrutinized in this study, rest being incompletely filled. Out of 517 participants 56% (289) were males.

Most the participants were in middle age group with extreme of 15-87 years. Mean age of respondent was 41.5 years.

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(Table 3). The major influence for tobacco initiation was friends followed by relatives (Fig. 1). The family history of major NCDs was asserted and most respondents had inadequate knowledge about it. In this table, recall bias cannot be ruled out (Table 4).

50 40 30 20

14.30 6.67

10 0

Friends

Relatives

4.48

Multimedia

Personality Dev

Figure 1. Factors influencing tobacco initiation.

Table 4. Family History of NCDs Use of tobacco

DM

HTN

IHD

Cancer

Yes

108

155

53

2

No

281

178

87

28

DNK

128

184

377

487

DM = Diabetes mellitus; HTN = Hypertension; IHD = Ischemic heart disease; DNK = Do not know.

COMMUNITY MEDICINE

9%

Newspaper

Health worker

Multimedia

Friends

12%

38%

93%

Figure 2. Source of information (% ≠ 100; multiple response).

of information was multimedia specially television (Fig. 2).

DISCUSSION

had higher odds of using tobacco. Similarly, Kahar et al9 found tobacco use least among graduates. Prabhakar et al11 on analysis of GATS 2009-10 data found similar inverse relation of tobacco use and education i.e., highest use among illiterates (67%) and least among graduates or higher (29%).

The influence for tobacco initiation was mainly from peers followed by relatives, as reported by most respondents. Knowledge about ill effects was adequately reported by respondents. Majority reported for cancer but most of the respondents didn’t have knowledge about association of tobacco with diabetes and ischemic heart disease. Raute et al,7 in their survey reported adequate knowledge among people where majority of smokeless tobacco users had knowledge about cancer followed by gum diseases and submucosal fibrosis. Similarly, Kahar et al9 found in their survey that most of the respondents were able to associate tobacco use with cancer.

This study reconfirms GATS6 report that prevalence of tobacco use is higher in Bihar than that of national average. In this study, prevalence of current tobacco use was 66.9%, which is not unique as in 2000, when a study done at Sitamarhi’s rural area,3 prevalence of tobacco use was found to be 59.5% and in 2006 at Patna,7 it was found to be 63%. Similarly in 2009, study done in semi-urban area of Tamil Naidu8 found the prevalence to be 20.9% and in 2010 study done in rural area of Gujarat9 found prevalence to be 18.2%.

Study among fishermen of Udupi10 of Karnataka in 2015 found the prevalence to be 64%.

CONCLUSION

In Bihar, use of smokeless tobacco is more than smoked tobacco, which is 70% and 29%, respectively.

Use of both types of tobacco was found in 11% of survey population. Sinha et al3 found 32% and 28% use of smokeless and smoked tobacco, while Raute et al7 found approximately 31% use of both variety of tobacco. Kahar et al9 found 14% used smoked tobacco, while 9% used smokeless form. In the present study, more females were using smoked tobacco compared to male respondents; this may be related to their literacy status.

2. Annual Report to the People on Health. Govt. of India, Ministry of Health and Family Welfare, New Delhi.

December 2011. Available at: http://mohfw.nic.in/ WriteReadData/l892s/6960144509Annual%20Report%20 to%20the%20People%20on%20Health.pdf

Use of tobacco was inversely proportional to educational status. In this study, it was found that 82% of illiterate people were using one or other form of tobacco and the usage decreased among graduate and professionals. Rane et al10 did their survey among fishermen found that those with no formal education

The observation of this study found tobacco use widely prevalent across gender and has inverse relation with educational status. Knowledge about adverse effects of tobacco use was adequate as regards cancer but not for other NCDs. There is urgent need of intervention in form of education and counseling to the community.

REFERENCES 1. World Health Organization. Factsheet: Tobacco. July 2015.

Available at: http://www.who.int/mediacentre/factsheets/ fs339/en/ [Accessed on 30th May, 2016].

3. Sinha ND, Gupta PC, Pednakar MS. Tobacco use in a rural area of Bihar, India. IJCM. 2003;XXVIII(4):167-70.

4. Cases of cancer. Govt. of India, Ministry of Health and Family Welfare. July 2014. Available at: http://pib.nic.in/ newsite/PrintRelease.aspx?relid=106424 [Accessed on 30th May, 2016].

5. Efroymson D, Ahmed S, Townsend J, Alam SM, Dey AR, Saha R, et al. Hungry for tobacco: an analysis of the economic impact of tobacco consumption on the poor in Bangladesh. Tob Control. 2001;10(3):212-7.

6. Global Adult Tobacco Survey India 2009-2010. Govt. of India, Ministry of Health and Family Welfare.

Available at: http://mohfw.nic.in/WriteReadData/ l892s/1455618937GATS%20India.pdf

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COMMUNITY MEDICINE 7. Raute LJ, Sansone G, Pednekar MS, Fong GT, Gupta PC, Quah AC, et al. Knowledge of health effects and intentions to quit among smokeless tobacco users in India: findings from the International Tobacco Control Policy Evaluation (ITC) India Pilot Survey. Asian Pac J Cancer Prev. 2011;12(5):1233-8.

9. Kahar P, Misra R, Patel TG. Sociodemographic correlates of tobacco consumption in rural Gujarat, India. Biomed Res Int. 2016;2016:5856740.

10. Rane PP, Narayanan P, Binu V, Unnikrishnan B. Prevalence of tobacco and alcohol consumption among fishermen in Udupi Taluk’ Karnataka, India: a cross-sectional study.

Asian Pac J Cancer Prev. 2016;17(4):1733-7.

8. Chockalingam K, Vedhachalam C, Rangasamy S, Sekar G, Adinarayanan S, Swaminathan S, et al. Prevalence of 11. Prabhakar B, Narake SS, Pednekar MS. Social disparities tobacco use in urban, semi urban and rural areas in and in tobacco use in India: the roles of occupation, education and gender. Indian J Cancer. 2012;49(4):401-9. around Chennai City, India. PLoS One. 2013;8(10):e76005.

■■■■

Blood Banks in the Country The Government under National AIDS Control Program-IV is strengthening the program for Blood Transfusion Services where efforts are directed towards promotion of voluntary nonremunerative blood donation in partnership with NGOs and Voluntary organizations and through IEC activities, component separation, coordination and networking of blood transfusion services. The efforts are also directed towards streamlining blood collection and storage facilities in order to ensure optimum utilization of collected blood in the country.

Blood having been classified as a Drug, Blood Bank activities are regulated under Drugs & Cosmetics Act & Rules. Every Blood Bank is required to obtain/timely renewal of the license from DCG(I) for operation under this Act & Rules, and follow the conditions of license for conduct of its activities. National Blood Transfusion Council (NBTC) has constituted a ‘‘National Blood Transfusion Services Core Coordination Committee”, chaired by the Director General of Health Services, Govt. of India, (Member, NBTC) to review the functioning of blood banks in the country … (PIB, 29th July, 2016)

WHO Declares Kenya Free of Polio The World Health Organization (WHO) has declared Kenya a polio free country. More than 1,000 wild poliovirus type 2 isolates were destroyed, beating the global deadline of containing Sabin type poliovirus materials by 3 days. This marks the end of the virus in Kenya and the Horn of Africa where its last strains were stored. In an elaborate exercise held at the Kenya Medical Research Institute headquarters in Nairobi, vials of the virus and circulating vaccine derived materials stored in freezers were killed after being subjected to a heat of 121° and were later burnt to ashes in an incinerator. The move is meant to avoid the possibilities of the virus by accident or deliberate being reintroduced after it was declared nonexistent across the world on September 20, last year…

(Source: mediamaxnetwork.co.ke, 29th July, 2016)

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COMMUNITY MEDICINE

The Importance Bioethics in Everyday Clinical Practice SMITA N DESHPANDE

ABSTRACT Doctors attacked, doctors abused, doctors fined - these are regular headlines in the press. From being viewed as a replacement for God, we have now been deemed service providers and open to all types of litigation. We need a broader set of principles to guide our day-to-day interactions with our patients, healthcare colleagues and our research. The answer may lie in imbibing and practicing the Universal Principles of Bioethics as embodied in the United Nations Educational, Scientific and Cultural Organization (UNESCO) Universal Declaration on Bioethics and Human Rights, adopted on 19 October 2005. The term, bioethics was first coined by Fritz Jahr but later popularized by the American biochemist Van Rensselaer Potter to indicate ‘global ethics’ i.e., the ethical application of technology to protect the environment and all species.

Keywords: Bioethics, human behavior, ethical principles, autonomy, informed consent

D

octors attacked, doctors abused, doctors finedthese are regular headlines in the press.1 Conflicting information about health issues, the limits of healthcare and a growing sense of entitlement among patients have muddied relations between healthcare givers and receivers. Health technology is running far ahead of our capacity to manage it.

Test tube babies, designer babies, cloning, artificial human organs were science fiction a few years ago.

But now they are a reality. Couples who do not have time to conceive babies and go through pregnancy can now order them off the shelf, so to speak.

In India, unregulated clinical trials received the adverse attention of the Supreme Court, leading to a complete overhaul in the way clinical trials will be conducted in this country. What is the missing link? Where did we, as a medical fraternity and leaders, go wrong? From being viewed as a replacement for God, we have now been deemed service providers and open to all types of litigation.

WHY BIOETHICS? The answer perhaps lies in the field of human behavior rather than science. We need to evolve a set of guidelines which will help us define our relationships

Consultant, Professor and Head Dept. of Psychiatry and De-addiction Services PGIMER-Dr Ram Manohar Lohia Hospital, Park Street, New Delhi – 110 001 E-mail: smitadeshp@gmail.com

with our patients. Medical atrocities during the Second World War, which helped evolve the Nuremberg code of ethics,2 was only the first step as it developed a code to be primarily used in medical research.

We need a broader set of principles to guide our day-to-day interactions with our patients, healthcare colleagues and our research. These are topics which have received scant attention in our medical education.

The answer may lie in imbibing and practicing the Universal Principles of Bioethics as embodied in the United Nations Educational, Scientific and Cultural Organization (UNESCO) Universal Declaration on Bioethics and Human Rights, adopted on 19 October 2005.3 Bioethics is based on the premise of complexity.

This discipline approaches problems inherent to humanity and its environment in a transdisciplinary manner. Its object of study and of intervention is the perpetual and specific interplay of the interrelationships between humans, humans and their environment and humans moved by ethical principles in accordance with their respective nationalities and cultures. The term was first coined by Fritz Jahr but later popularized by the American biochemist Van Rensselaer Potter to indicate ‘global ethics’ i.e., the ethical application of technology to protect the environment and all species.

The year 2016 is special because for the first time, the World Bioethics Day is to be celebrated on October 19, the day the Universal Declaration was signed by countries including India.

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229

COMMUNITY MEDICINE WHAT ARE THE BASIC PRINCIPLES OF BIOETHICS?

or reject treatment, seek another opinion or ask for justification from the healthcare provider.

There are 16 principles of bioethics pertaining to all aspects of scientific work. Section II of the Universal Declaration on Bioethics and Human Rights states important substantive principles relating to bioethics, such as:

Patient Autonomy In medicine, this signifies the freedom of the individual to choose her healthcare giver, the type of intervention and even the discipline under which she wants to be treated. Of course one person’s autonomy must not infringe on autonomy of others, and each should respect the freedom of choice of all other persons.

One’s own freedom cannot be at the cost of other’s freedom. Autonomy at the level of the patient signifies ‘self-determination’ or ‘self-rule’. It means that it is the patient who has total control over what will be done to her body, person and health. The doctor has to respect her free will about what will be of most benefit to her.

ÂÂ

Respect for human dignity and human rights (Article 3.1)

ÂÂ

Priority of the individual’s interests and welfare over the sole interest of science or society (Article 3.2)

ÂÂ

Beneficence and nonmaleficence (Article 4)

ÂÂ

Autonomy (Article 5)

ÂÂ

Informed consent (Article 6)

ÂÂ

Protection of persons unable to consent (Article 7)

ÂÂ

Special attention to vulnerable persons (Article 8)

Physician Autonomy

ÂÂ

Privacy and confidentiality (Article 9)

ÂÂ

Equality, justice and equity (Article 10)

ÂÂ

Nondiscrimination (Article 11)

ÂÂ

Respect for cultural diversity and pluralism (Article 12)

ÂÂ

Solidarity and cooperation (Article 13)

ÂÂ

Access to healthcare and essential medicines (Article 14)

ÂÂ

Benefit sharing (Article 15)

ÂÂ

Protection of future generations (Article 16)

ÂÂ

Protection of the environment, the biosphere and biodiversity (Article 17).

At the level of the doctor, it indicates shared decisionmaking. Whatever the patient’s decision, it is to be respected because it is made of the patient’s own free will. Nevertheless medical personnel do NOT have a duty to inform their patients about futile or harmful health inputs even if popular. Medical personnel do have the autonomy to protect their own personal information, so long as it does not harm the healthcare of the patient. But ‘conscientious objection’ on personal or religious grounds may not be enough for a doctor to refuse to provide specific services especially in emergency care. The doctor’s commitment, both as a professional and as altruism, must prevail over his or her religious or other scruples for patient care.

and

nonstigmatization

Four main principles are recognized for medicine and healthcare namely autonomy, beneficence, nonmaleficence, justice (some add consent).

The first principle of the Universal Declaration is “respect for human dignity and human rights”. This is also the theme of the First World Bioethics Day. This principle signifies that the interests of the individual are always greater than the “sole interest of science or society”, and that fundamental human freedoms are inviolable. By virtue of being a member of the human race, every human being is entitled to concern and respect. No human being can be treated without due respect for her very existence as a person.

Autonomy This principle indicates the right of every person to decide her own choice, including the right to accept

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Indian Journal of Clinical Practice, Vol. 27, No. 3, August 2016

Some Examples of Bioethical Issues Around Autonomy ÂÂ

Should hospitals disclose a physician’s infectious disease to all patients who may have come in contact with the doctor?

ÂÂ

Should all records of a mentally ill person be disclosed to her?

ÂÂ

Should terminally ill persons be permitted to starve themselves to death?

ÂÂ

Can a physician force a patient to receive lifesustaining treatment against his will?

ÂÂ

Can severely intellectually disabled person give consent to donate an organ?

ÂÂ

Should a wife be permitted to harvest the sperm of her brain dead husband for future possible pregnancy?4

COMMUNITY MEDICINE Beneficence and Nonmaleficence (Benefit and Harm) Physician’s Duty It is the physician’s primary duty to ‘do no harm’.

Even if she cannot benefit the patient, she should not undertake any activity that may harm him or his interests. The benefits include carrying out research to advance human knowledge or medical science.

But even in these cases no harm should come to the individual participant. Thus in research, we can no longer have ‘subjects’ who will be ‘subjected’ to new technology, we have active thoughtful participants who have agreed with full knowledge and consent.

ÂÂ

Can contraceptive advice or intervention be provided to minors without parental consent?

ÂÂ

Should doctors undertake selective feticide to save a healthy twin?

ÂÂ

Can doctors select what treatment to offer - in general?

ÂÂ

Can doctors utilize biological samples obtained in routine treatment for research without patient’s consent? A case in the point is the HeLa cell line, research on which has saved thousands of lives but benefited neither the patient nor her descendants?

ÂÂ

Does the government have a duty to provide new effective drugs but whose hazards are unknown, for free distribution in public hospitals?

Of course, it may not be possible to avoid all harmsphysical, emotional or financial. But they should be minimized to the extent possible. In case of experimental yet lifesaving or unproven treatment, the patient must be fully aware of risks.

Justice

The physician therefore, should be academically up-todate about the possibility of risk, harm and benefit and be able to explain the probabilities of each outcome.

Before ordering any test or investigation, he should know what he expects as an outcome. He should be able to explain these issues to the patient and caregivers.

Some Examples of Bioethical Issues Around Justice6

Justice means all persons should enjoy the benefits and if required, be exposed to similar risks of treatment, not depending on their social position other extraneous considerations. ÂÂ

Doctor shopping: Patients often consult several doctors; try to play off one prescription against another. They may consult privately but expect the government services to provide these medicines for free.

ÂÂ

Sex selection, designer babies is a raging debate which has still not found societal response. Is it just to ‘make’ ‘designer babies’? Is it just to selectively abort fetuses on the basis of their sex, genetic disorders or some other reason?

ÂÂ

Availability of health resources for all- especially scarce ones such as new and more effective but highly expensive medicines, availability of ICU care, dialysis services.

ÂÂ

Prevention of acquired immune deficiency syndrome (AIDS) - discrimination against certain groups of people.

Patient Issues Patients need to understand that every intervention has up and down sides. He should be able to ask for information from the physician but understand the limits of modern medicine. Blaming the doctor for every outcome, resorting to violence or abuse, may affect care adversely. That said the patient should have at least a minimal knowledge about unproven therapies and ‘pathies’.

Some Examples of Bioethical Issues Around Benefit and Harm5 ÂÂ

Should lifesaving treatment such as blood transfusions be denied to a patient because of religious beliefs?

ÂÂ

Can a surgeon undertake major surgery such as amputation of a limb without patient’s consent?

ÂÂ

Should surreptitious treatment be allowed? If yes, under what circumstances and with what safeguards?

ÂÂ

Should newborns be tested at birth in spite of parents’ refusal?

ÂÂ

Can human immunodeficiency virus (HIV) positive mothers refuse HIV testing for their minor children?

Informed Consent Issues around informed consent, it is hoped are now well-known to all medical personnel. Yet involuntary treatment, forced treatment, covert treatments are all issues around which many legal cases have occurred.

UNESCO bioethics principles state that any medical intervention-for therapeutic or preventive purposesmust only be undertaken after full information and freely given consent. The participant should be free to withdraw at any time without loss or prejudice. The key issues for the patient are consent freely given after

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COMMUNITY MEDICINE full information, and the right to withdraw. Even the old, frail and mentally ill should be given the chance to express their own choice. Many are capable of taking decisions which will benefit them provided all information is made available to them. This implies that a patient should be informed of alternatives, and must be permitted to ask questions and take an informed decision.

Some Examples of Bioethical Issues Around Consent ÂÂ

ÂÂ

ÂÂ

ÂÂ

Most people can understand issues around their health, provided the information is provided in a suitable form. Simply because persons are old, mentally ill, illiterate or compromised in some other way does not mean they cannot understand need for health interventions even ones such as amputation or colostomy.

In the course of the surgery for a malignant prostate tumor on a middle-aged father, an additional seminoma was found. Hence, the surgeon removed both prostate and both testes. As a result, Mr N sued the surgeon because prior consent was not obtained, he felt the treatment was harmful as his right of reproduction was terminated.7 Should an amputation be performed in a lifethreatening condition, when the patient is unwilling but the relative agrees due to threat to the patient’s life?

Can the doctor perform genetic tests on a forensic biological sample when the ‘suspect’ has specifically refused the same?

Vulnerable populations, people without capacity to consent are special populations and even more care must be taken not to harm them, to tailor information according to their understanding, interventions only after consent and right to withdraw.

Privacy and Confidentiality Privacy is the right of an individual to permit access to his body, thoughts or feelings. In medical practice, the patient expects a private space where she can share information as well as permit access to her body. The right of the patient to privacy enjoins upon the clinician, to provide confidentiality. Confidentiality means that privately shared information will not be disclosed to anyone else without the patients’ consent. The right to privacy and the confidentiality of health information protect autonomy or self-determination.

Some Examples of Bioethical Issues Around Privacy and Confidentiality ÂÂ

Health information about a patient is not shared without his explicit consent. For health records, this consent has to be in writing. However, health information can be shared with a legal guardian or legal representative after due permission of the patient, or with courts after due summons or subpoena.

ÂÂ

Doctors are not expected to reveal the name and other personal particulars of their patients e.g., in the common room, or during conferences or meetings.

Other bioethics principles are listed above, and every clinician will surely remember cases, which illustrate one principle or other. Mere recollection is of no use unless the memory is used to learn and remedy one’s professional conduct. Ethical conduct must be accompanied by an understanding of the patient’s culture and local constraints so that treatment is not only scientifically accurate but also humane.

REFERENCES 1. Indian Medical Association. Violence against doctors.

2015. Available at: http://www.ima-india.org/ima/leftside-bar.php?pid=298 [Accessed on July 7, 2016].

2. Nuernberg Military Tribunal: Permissible Medical Experiments. Trials of War Criminals before the Nuernberg Military Tribunals under Control Council Law No. 10: Nuremberg October 1946–April 1949. Washington: U.S. Government Printing Office (n.d.); Vol. 2, pp. 181-2.

Available at: https://www.loc.gov/rr/frd/Military_Law/ pdf/NT_war-criminals_Vol-II.pdf 3. Universal Declaration on Bioethics and Human Rights, (2005). Available at: http://www.unesco.org/ en/university-twinning-and-networking/accessby-domain/social-and-human-sciences/bioethics/.

[Accessed on July 12, 2016].

4. UNESCO Bioethics Casebook Series: Human Dignity and Human Rights. Available at: http://unesdoc.unesco.org/ images/0019/001923/192371e.pdf 5. UNESCO Bioethics Casebook Series: Benefit and Harm.

Available at: http://unesdoc.unesco.org/ images/0019/001923/192370e.pdf 6. UNESCO: Bioethics Core Curriculum (Section 2): Study Materials Ethics Education Programme. Available at: http://unesdoc.unesco.org/images/0021/002109/210933e. pdf

7. Carmi: 2003- Informed Consent. Available at: http:// unesdoc.unesco.org/images/0014/001487/148713e.pdf ■■■■

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GASTROENTEROLOGY

Clinicopathological Characterization of Gastric Carcinoma in a Tertiary Care Center C SIMON DURAI RAJ*, SANDHYA SUNDARAM†, KRISHNAKUMAR RAMANATHAN*, GANESH VENKATRAMAN‡, SHANTHI VIJAYARAGHAVAN#, S SANKAR$

ABSTRACT Introduction: Gastric cancer is the fifth most common cancer in the world. Incidence of gastric cancer varies among various ethnic groups and geographical location. In India, gastric cancer remains the fifth most common cancer among males and seventh most common cancer among females. Aims and objectives: The aim of this study was to pathologically analyze the incidence of gastric cancer from Sri Ramachandra Hospital and to determine the clinicopathological characteristics of gastric cancer in South Indian population. Results: We retrospectively analyzed all the cases of gastric adenocarcinoma that underwent gastrectomy procedure at Sri Ramachandra Hospital, Chennai, India, from 2011 to 2015. A total of 117 patients underwent gastrectomy following a diagnosis of gastric adenocarcinoma. The mean age of the patients at diagnosis was 58.4 years (SD = 12.3) and the male-to-female ratio was 2.34:1. Abdominal pain and vomiting were the most frequent complaints at diagnosis and distal part of the stomach was the commonest site of tumor. Lymphovascular invasion and perineural invasions was seen to be higher in advanced stage compared to early stage gastric cancer cases. Conclusion: The overall incidence of gastric cancer was found to be higher in patients less than 60 years, which was a surprising revelation and these cases appeared to have a more aggressive behavior. In-depth study on a larger sample and research on molecular genetics of gastric cancer in younger age patients are needed to elucidate the mechanistic basis of the disease.

Keywords: Gastric cancer, South India, clinicopathological factors

G

cancer occur in less developed countries is 65-70%.4 In both developed and developing countries, gastric cancer is more common in male.5

*Research Scholar †Professor and Senior Consultant Dept. of Pathology ‡Associate Professor Dept. of Human Genetics #Professor Dept. of Gastroenterology $Professor and Head Dept. of Surgical Gastroenterology Sri Ramachandra University, Porur, Chennai, Tamil Nadu Address for correspondence Dr Sandhya Sundaram Professor and Senior Consultant Dept. of Pathology, Sri Ramachandra University, Porur, Chennai, Tamil Nadu E-mail: sandsrid@gmail.com

AIMS AND OBJECTIVES

astric cancer is the fifth most common cancer in the world with 9,52,000 new cases diagnosed in 2012 followed by lung, breast, colorectal and prostate and the third leading cause of death due to cancer with 7,23,000 deaths (8.8% of the total) worldwide.1 Gastric cancer incidence varies among various ethnic groups and geographical location.

Adenocarcinoma is the most common malignant tumors of the stomach, which accounts for 90-95% of cases.2,3 Overall, the incidence and death of gastric

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The rate of new cases of gastric cancer is more than four times higher in Asia compared with Africa.6 In India, gastric cancer remains the fifth most common cancer among males and seventh most common cancer among females.7 The epidemiological studies suggest that the incidence of gastric carcinoma is approximately four times higher in the south- and north-eastern states of India.8 Report from the National Cancer Registry Program (NCRP) suggest that in India, the mean age-adjusted rate (AAR) of gastric cancer among urban registries varied from 3.0 to 13.2, with the highest rate being recorded in the Chennai registry.9 Smoking is identified as an independent risk factor in the development of gastric cancer by Cancer Institute, Chennai.10

The aim of this study was to pathologically analyze the incidence of gastric cancer from Sri Ramachandra Hospital medical records (2011-2015). This study would help to understand the clinicopathological

GASTROENTEROLOGY characteristics of gastric cancer in a South Indian population, which has a distinct social, cultural and geographic background.

MATERIAL AND METHODS We retrospectively analyzed all the cases of gastric adenocarcinoma that underwent gastrectomy procedure at Sri Ramachandra Hospital, Chennai, India, from 2011 to 2015. All the cases were histologically proven adenocarcinoma of the stomach on endoscopic biopsy or resected specimen. The pathological tumor staging was done according to the 7th Edition of the AJCC Cancer Staging Manual: Stomach.11 The relevant clinical and histopathological data including demographic data, histological type and grade, pathological staging, tumor location, tumor size, smoking habits, consumption of alcohol, chief presenting complaints, and presence of other relevant clinical features were retrieved from Sri Ramachandra Medical Centre records. The study was conducted after obtaining the approval from the Institutional Ethical Committee of Sri Ramachandra University. Descriptive statistics were used for analyzing the data and results were presented in percentage and simple frequency.

(32%) followed by signet ring cell carcinoma (13%) (Fig. 1). In the remaining cases, the exact histological type was not specified. The average size of the tumor was 3.91 Âą 3.47 cm.

Stage According to Tumor, Node and Metastasis (TNM) staging, stage IIIB was proportionately higher (20%) followed by stage IIB (19%) (Fig 2). Majority of the patients were of N0 nodal stage (35%) followed by N3 (29%), N2 (25%) and N1 (11%). Data on distant metastasis was available for 7 cases and among them 4 cases showed liver metastasis.

Chief Complaints Abdominal pain and vomiting were the most common complaints accounting for 53% and 46%, respectively (Fig. 3). Loss of weight, loss of appetite, melena, nausea,

Diffuse

Mucinous

Intestinal

Mixed

Signet

Not specified

7%

RESULTS

Demographic Data A total of 117 patients had undergone gastrectomy after being diagnosed as gastric adenocarcinoma between the periods 2011-2015 at Sri Ramachandra Hospital.

Among these, 82 (70%) were male and 35 (30%) were female, with the sex ratio of 2.34:1. The mean age of the patients at diagnosis was 58.4 years (standard deviation [SD] = 12.3, median 59 years) with an age variation of 21-85 years. The mean age of males at diagnosis was slightly greater than females.

34%

32%

9%

13%

5%

Figure 1. Histological classification of gastric cancer.

Location

Histology In this study, we observed a higher proportion of moderately differentiated adenocarcinoma (51%), while poorly differentiated adenocarcinoma accounted for 45% and well-differentiated adenocarcinoma was 4%.

The common histological type was intestinal type

25 Percentage (%)

On analysis of the site of occurrence, the tumor was located most frequently in the distal part of the stomach (62%), followed by proximal region (27%). For 11% of patients tumor was located in both the distal and proximal regions.

19

20 15

13

15

20 16 11

10 5

4

2

0 IA

IB

IIA

IIB

IIIA

IIIB

IIIC

IV

Stages

Figure 2. Frequency of TNM stages in gastrectomy patients between 2011-2015.

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GASTROENTEROLOGY Table 1. The Clinicopathological Characteristics of Patients with Gastric Adenocarcinoma

60

Percentage (%)

50

53 46

40

Variables 42

Subgroup

n (%)

<40

10 (9)

40-50

19 (16)

51-60

39 (33)

61-70

30(26)

>70

19 (16)

Age 34

30 20 11 10

9

Gender

0 Abdomen Vomiting pain

Weight loss

Appetite loss

Melena

Nausea

Figure 3. Most common symptoms in gastric cancer patients.

Location

Histological grade

indigestion were the other common complaints with patients diagnosed as gastric adenocarcinoma.

Operative Procedure and Chemotherapy Subtotal gastrectomy was the procedure done for nearly 55% of patients diagnosed with gastric carcinoma followed by partial gastrectomy (21%).

Adjuvant chemotherapy was given in 35% of patients after surgery.

Depth of tumor

Lymph node metastasis

Personal History History of smoking and alcohol consumption was available for 15% of the patients. Out of the available data, 88% of patients were smokers with alcohol consumption and 22% gave a history of tobacco chewing. The clinicopathological characteristics of patients are shown in Table 1. Relationships between clinicopathological characteristics and pathological tumor stages are shown in Table 2. Figure 4 shows the hematoxylin and eosin (H&E) staining of gastric adenocarcinoma histological type.

DISCUSSION The pattern and incidence of gastric cancer vary among the different locations of the world.5,6,12,13 Countries of Asia, Latin America and Caribbean14 have a higher incidence of gastric cancer. In India, the incidence of gastric cancer is less compared to other countries;15,16 however, southern and north-eastern states of India show higher incidence.7,9 In our study, the highest incidence of gastric cancer cases was in age group 51-60 years old (33%), followed by 61-70 years (26%), which is slightly different

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Indian Journal of Clinical Practice, Vol. 27, No. 3, August 2016

Distant metastasis Stages

Male

82 (70)

Female

35 (30)

Proximal

31 (27)

Distal

73 (62)

Both

13 (11)

Well differentiated

4 (4)

Moderately differentiated

60 (51)

Poorly differentiated

53 (45)

T1

3 (3)

T2

29 (25)

T3

53 (45)

T4

32 (27)

N0

41 (35)

N1

13 (11)

N2

29 (25)

N3

34 (29)

M0

112 (96)

M1

5 (4)

IA

2 (2)

IB

15 (13)

IIA

18 (15)

IIB

22 (19)

IIIA

19 (16)

IIIB

23 (20)

IIIC

13 (11)

IV

5 (4)

from studies reported in the literature.7,17 The higher incidence of gastric cancer in the younger age group may be due to environmental factors, genetic causes and hormonal status.18 Chung et al observed the relationship between hormonal status and gastric cancer development.19 We found a male predominance with 2.34:1 of male and female ratio, which supports many clinicopathological studies in gastric cancer.7,12,17,20-22 This male predominance may be due to smoking and

GASTROENTEROLOGY Table 2. Relationships Between Clinicopathological Characteristics and Pathological Tumor Staging Variables

IA

IB

IIA

IIB

IIIA

IIIB

IIIC

IV

Sex

Male

2 (2%)

13 (16%)

8 (10%)

14 (17%)

14 (17%)

18 (22%)

9 (11%)

4 (5%)

Female

0

2 (6%)

10 (29%)

8 (23%)

5 (14%)

5 (14%)

4 (11%)

1 (3%)

<40

0

0

3 (30%)

4 (40%)

1 (10%)

0

2 (20%)

0

40-50

1 (5%)

3 (16%)

1 (5%)

5 (26%)

3 (16%)

3 (16%)

2 (11%)

1 (5%)

51-60

0

1 (3%)

4 (10%)

6 (15%)

10 (26%)

12 (31%)

3 (8%)

3 (8%)

Age (n = 88)

61-70

0

9 (30%)

4 (13%)

2 (7%)

4 (13%)

5 (17%)

5 (17%)

1 (3%)

>70

1 (5%)

2 (11%)

6 (32%)

5 (26%)

1 (5%)

3 (16%)

1 (5%)

0

Proximal

0

2 (6%)

7 (23%)

1 (3%)

5 (16%)

6 (19%)

6 (19%)

4 (13%)

Distal

2 (3%)

10 (14%)

11 (15%)

19 (26%)

10 (14%)

15 (21%)

5 (7%)

1 (1%)

Both

0

3 (23%)

0

2 (15%)

4 (31%)

2 (15%)

2 (15%)

0

1 (25%)

2 (50%)

0

0

1 (25%)

0

0

0

Location

Histological grade Well differentiated Moderately differentiated

1 (2%)

10 (17%)

10 (17%)

13 (22%)

9 (15%)

11 (18%)

4 (7%)

2 (3%)

Poorly differentiated

0

3 (6%)

8 (15%)

9 (17%)

9 (17%)

12 (23%)

9 (17%)

3 (6%)

Present

0

3 (5%)

4 (7%)

9 (15%)

15 (25%)

15 (25%)

10 (17%)

3 (5%)

Absent

2 (3%)

12 (21%)

14 (24%)

13 (22%)

4 (7%)

8 (14%)

3 (5%)

2 (3%)

Lymphovascular invasion

Perineural invasion

Present

0

3 (9%)

6 (17%)

2 (6%)

7 (20%)

9 (26%)

5 (14%)

3 (9%)

Absent

2 (2%)

12 (15%)

12 (15%)

20 (24%)

12 (15%)

14 (17%)

8 (10%)

2 (2%)

a

b

c

d

Figure 4. H&E staining showing mucinous adenocarcinoma (a); H&E staining showing mucinous adenocarcinoma with signet cell features (b); H&E staining showing intestinal type poorly differentiated adenocarcinoma (c) and H&E staining showing intestinal type moderately differentiated adenocarcinoma (d).

other environmental carcinogens for which males are more exposed.17,23 We also found that the distal part of the stomach is the most common site of tumor, but advanced gastric cancer cases have a higher incidence of tumor in proximal regions. The patients with advanced stage of gastric cancer show higher incidence of poorly differentiated adenocarcinoma and most of the patients were diagnosed with moderately differentiated adenocarcinoma. Most of the female patients were diagnosed with poorly differentiated adenocarcinoma (51%), while males showed moderately differentiated adenocarcinoma. Lymphovascular invasions and perineural invasions were predominantly identified in advanced stage compared to early gastric cancer. The chief complaints of patients at diagnosis with gastric cancer were abdominal pain (53%), vomiting (46%) and weight loss (42%). This result was concordant with other reported studies.7,17

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GASTROENTEROLOGY CONCLUSION In conclusion, our study shows a steady increase in the occurrence of gastric carcinoma in patients less than 60 years with a more aggressive behavior. Further research on molecular genetics of gastric cancer in younger age patients are needed to support the results of our study. In addition, comprehensive study of clinicopathological data of gastric cancer in larger group of patients including risk factors, etiology and clinical outcome will prove useful in understanding the pathobiology of the disease and in instituting appropriate therapy.

REFERENCES 1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359-86.

2. American Cancer Society - Stomach Cancer. Available at: http://www.cancer.org/acs/groups/cid/documents/ webcontent/003077-pdf.pdf.

3. Brzozowa M, Mielańczyk L, Michalski M, Malinowski L, Kowalczyk-Ziomek G, Helewski K, et al. Role of Notch signaling pathway in gastric cancer pathogenesis.

Contemp Oncol (Pozn). 2013;17(1):1-5.

4. Crew KD, Neugut AI. Epidemiology of gastric cancer.

World J Gastroenterol. 2006;12(3):354-62.

5. Stewart BW, Kleihues P (Eds.). World Cancer Report.

Lyon: IARC Press; 2003.

6. World Cancer Research Fund International. Stomach Cancer Statistics. Available at: http://www.wcrf.org/int/ cancer-facts-figures/data-specific-cancers/stomachcancer-statistics 7. Barad AK, Mandal SK, Harsha HS, Sharma BM, Singh TS. Gastric cancer - a clinicopathological study in a tertiary care centre of North-eastern India. J Gastrointest Oncol.

2014;5(2):142-7.

8. Sharma A, Radhakrishnan V. Gastric cancer in India.

Indian J Med Paediatr Oncol. 2011;32(1):12-6.

9. Yeole BB. Trends in cancer incidence in esophagus, stomach, colon, rectum and liver in males in India. Asian Pac J Cancer Prev. 2008;9(1):97-100.

11. Washington K. 7th edition of the AJCC cancer staging manual: stomach. Ann Surg Oncol. 2010;17(12):3077-9.

12. Sasagawa T, Solano H, Mena F. Gastric cancer in Costa Rica. Gastrointest Endosc. 1999;50(4):594-5; discussion 595-6.

13. Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ. Cancer statistics, 2003. CA Cancer J Clin. 2003;53(1): 5-26.

14. Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC Cancer Base No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available at: http://globocan. iarc.fr [Accessed on 25th July, 2016].

15. Satyanarayana L, Asthana S. Life time risk for development of ten major cancers in India and its trends over the years 1982 to 2000. Indian J Med Sci. 2008;62(2):35-44.

16. Rastogi T, Devesa S, Mangtani P, Mathew A, Cooper N, Kao R, et al. Cancer incidence rates among South Asians in four geographic regions: India, Singapore, UK and US. Int J Epidemiol. 2008;37(1):147-60.

17. Safaee A, Moghimi-Dehkordi B, Fatemi SR, Ghiasi S, Pourhoseingholi MA, Zali MR. Clinicopathological features of gastric cancer: a study based on cancer registry data. Iran J Can Prevent. 2009;2:67-70.

18. Oliveira C, Seruca R, Carneiro F. Genetics, pathology, and clinics of familial gastric cancer. Int J Surg Pathol.

2006;14(1):21-33.

19. Chung HW, Noh SH, Lim JB. Analysis of demographic characteristics in 3242 young age gastric cancer patients in Korea. World J Gastroenterol. 2010;16(2):256-63.

20. Sadjadi A, Malekzadeh R, Derakhshan MH, Sepehr A, Nouraie M, Sotoudeh M, et al. Cancer occurrence in Ardabil: results of a population-based cancer registry from Iran. Int J Cancer. 2003;107(1):113-8.

21. Kong SH, Park DJ, Lee HJ, Jung HC, Lee KU, Choe KJ, et al. Clinicopathologic features of asymptomatic gastric adenocarcinoma patients in Korea. Jpn J Clin Oncol.

2004;34(1):1-7.

22. Yao JC, Tseng JF, Worah S, Hess KR, Mansfield PF, Crane CH, et al. Clinicopathologic behavior of gastric adenocarcinoma in Hispanic patients: analysis of a single institution’s experience over 15 years. J Clin Oncol.

2005;23(13):3094-103.

23. Sumathi B, Ramalingam S, Navaneethan U, Jayanthi V. 10. Gajalakshmi CK, Shanta V. Lifestyle and risk of stomach Risk factors for gastric cancer in South India. Singapore cancer: a hospital-based case-control study. Int J Med J. 2009;50(2):147-51.

Epidemiol. 1996;25(6):1146-53.

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2016 2015

Rx

HEMATOLOGY

A Rare Case of Hemophagocytic Lymphohistiocytosis in an 18-year-old Patient TASHI AGARWAL*, SHASHI BANSAL†, UPENDRA SHARMA‡

ABSTRACT Hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially fatal syndrome characterized by multisystem inflammation resulting in an uncontrolled and ineffective immune response. It usually presents in children less than 1 year of age as unexplained peripheral blood pancytopenia with history of fever and presence of hepatosplenomegaly. We present a rare case of an adolescent, 18-year-old patient who presented with fever, pancytopenia and hepatosplenomegaly. Bone marrow aspirate showed marked hemophagocytosis. After diagnosing the condition as HLH according to the established criteria of International Histiocytic Society, she was treated with corticosteroids, etoposide and cyclosporine followed by good response. The prompt diagnosis of HLH may be an important strategy to optimizing the clinical approach and outcome.

Keywords: Hemophagocytic lymphohistiocytosis, familial hemophagocytic lymphohistiocytosis, treatment, diagnosis

H

emophagocytic lymphohistiocytosis (HLH) is a generalized, nonmalignant histiocytic proliferation with prominent phagocytosis of formed blood cells resulting in pancytopenia. The prolonged and excessive activation of T-lymphocytes and antigen presenting cells with subsequent hypercytokinemia leads to systemic manifestations and progressive organ dysfunction. It presents with fever and symptoms of anemia, thrombocytopenia and neutropenia. On clinical examination, there is typically splenomegaly, hepatitis and lymphadenopathy and evidence of central nervous system (CNS) involvement.

Pathologically, there is accumulation of hemophagocytic histiocytes in the bone marrow, spleen, lymph nodes and CNS.1

HLH can be divided into two forms which are difficult to distinguish from one another, primary (genetic) and secondary (acquired) form. The primary form can be inherited in an autosomal recessive fashion or X-linked

*Resident †Associate Professor Dept. of Pathology ‡Consultant Dept. of Hematology Mahatma Gandhi Medical College and Hospital, Jaipur, Rajasthan Address for correspondence Dr Tashi Agarwal B-202, Rajendra Marg, Bapu Nagar, Jaipur, Rajasthan E-mail: tashagarwal@gmail.com

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Indian Journal of Clinical Practice, Vol. 27, No. 3, August 2016

manner, also called as familial hemophagocytic lymphohistiocytosis (FHL). FHL is a rare and rapidly fatal disorder presenting in infancy and early childhood with the typical features of HLH. The acquired/ secondary forms are associated with a variety of viral, bacterial, fungal, parasitic causative organisms as well as collagen vascular diseases and malignancies. The diagnosis of HLH requires either molecular diagnosis of FHL or the demonstration of hemophagocytic histiocytes in tissue biopsies in association with pancytopenia, fever and hepatosplenomegaly, and may be supported by the demonstration of hypofibrinogenemia, hypertriglyceridemia, decreased NK cell function and increased concentrations of soluble CD25. Raised cerebrospinal fluid (CSF) protein concentrations and CSF pleocytosis are found in 50% of patients.2-3 CASE REPORT An 18-year-old girl presented with 15 days of generalized weakness, fatigue and high-grade fever with chills and rigours since 1 day. It was not accompanied by upper respiratory or urinary complaints. There was no history of jaundice or blood transfusion. On presentation, she was conscious, oriented to time, space and person.

Temperature of 103°F, pulse of 130/min, blood pressure of 130/72 mmHg with respiratory rate of 18 cycles/min.

Findings on examination were presence of pallor with pronounced hepatosplenomegaly (liver - 3 cm below costal margin, spleen - 5 cm below costal margin),

HEMATOLOGY there was no icterus or lymphadenopathy and systemic examination was within normal limits.

On the day of admission (5/7/2013), her complete blood count (CBC) findings were: hemoglobin concentration was 3.7 g/dL, white blood cell count was 0.90 × 103/uL, red blood cell count was 1.23 × 106/uL, platelets were 51 × 103/uL, differential white cell count was (neutrophils - 38%, lymphocytes - 51%, monocytes - 10%, eosinophils - 0% and basophils - 1%).

On peripheral blood film, smear showed marked anisopoikilocytosis, red cells being hypochromic, both microcytic and macrocytic, with few tear drop cells and macro-ovalocytes. Also, 2 nucleated red blood cells/100 white blood cells were seen. There was marked leukopenia but no immature white blood cells were seen, platelets were markedly reduced on smear. No hemoparasite was seen.

Serum bilirubin total was 2.3 mg% (normal, 0.1-1.2 mg%), serum bilirubin direct was 1.2 mg% (normal, 0.0-0.3 mg%), SGOT and SGPT were 80 U/L and 38 U/L, respectively. Serum alkaline phosphatase was 123 U/L (normal, 64-306 U/L), lactate dehydrogenase was 1,430 IU/L (normal, 60-265 IU/L), triglyceride levels were 168.4 mg% (normal, <170 mg%). Malarial antigen test and hepatitis B surface antigen (HBsAg) were negative, test for human immunodeficiency virus (HIV) was nonreactive, anti-HCV antibodies (spot test) was nonreactive, VDRL (TRUST) was negative, Widal for typhoid was negative, dengue immunoglobulin M (IgM) antibody was weakly positive, scrub typhus IgM was negative. Blood culture was sterile, potassium hydroxide (KOH) mount was negative.

Chest radiograph was normal, abdominal ultrasound showed bilateral pleural effusion with ascites, no obvious lymph nodes were evident. Computerized tomography (CT) of chest showed evidence of bilateral pleural effusion with minimal pericardial effusion.

Pleural fluid examination was normal.

dual maturation, both megaloblastic and normoblastic.

Myeloid series showed normal maturation, no evidence of toxic granulation or atypia seen. Megakaryocytic series was adequate in number and morphology, with hypersegmentation of megakaryocytes seen at few places.

There was increase in marrow macrophages, and a few of these macrophages showed engulfed numerous cells of various hemopoietic lineage like platelets, red cells, white cells and myeloid and erythroid precursor cells called hemophagocytes (Figs. 1 and 2). On screening, occasional mononuclear and very occasional binucleated, Reed-Sternberg like cells were seen.

Bone marrow biopsy findings were similar to that

Figure 1. Photomicrograph of the bone marrow aspirate showing macrophage with marked hemophagocytic activity.

(Giemsa stain × 100X).

The clinical spectrum of fever, hepatosplenomegaly, unexplained cytopenias and elevated liver enzymes indicated an underlying cytokine storm, possibly due to macrophage activation.

Further tests were done to confirm the possibility of hemophagocytic syndrome. Serum ferritin was elevated up to >500 μg/L (normal, 15-200 μg/L) and fibrinogen was reduced to 0.5 g/L (normal, 2-4 g/L).

A bone marrow aspirate from the posterior superior iliac spine was normocellular with erythroid hyperplasia. Erythroid series showed hyperplasia with

Figure 2. Photomicrograph showing nuclei of RBC’s and WBC precursor cells within cytoplasm of macrophage (Giemsa stain × 100X).

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HEMATOLOGY Table 1. Review of CBC Findings 6/7/2013

8/7/2013

9/7/2013

11/7/2013

WBC

(103/uL)

0.90

2.25

7.71

10.37

RBC

(106/uL)

1.23

1.95

2.99

3.12

Hb (g/dL)

3.7

5.8

8.9

9.3

HCT (%)

11.2

17.6

27.1

29.4

Platelet

(103/uL)

RDW-CV (%)

51

53

67

80

31.4

24.5

22.9

24.7

Neutrophil (%)

38

38

73

86

Lymphocyte (%)

51

52

20

10

Monocyte (%)

10

8

6

4

Eosinophil (%)

0

2

1

0

Basophil (%)

1

0

0

0

WBC = White blood cell; RBC = Red blood cell; Hb = Hemoglobin; HCT = Hematocrit; RDW-CV = Red cell distribution width.

of aspirate findings with sighting of histiocytes and hemophagocytes. However, immunohistochemistry findings were negative for lymphomas.

As the criterion required for the diagnosis of HLH was fulfilled according to HLH 2009 diagnostic criteria, she was started on chemotherapy protocol of HLH 2004 trial. The patient responded to initial treatment with decrescendo course of dexamethasone 8 mg/twice-daily (10 mg/m2) and cyclosporine along with vitamin B12.

On 11/7/13, the counts were raised to, hemoglobin concentration - 9.3 mg%, white blood cell count - 10.37 × 103/uL, red blood cell count - 3.12 × 106/uL and platelets - 80,000/uL. Differential count being (neutrophils - 86%, lymphocytes - 10%, monocytes - 4%) (Table 1).

Patient was discharged on 12/7/2013.

DISCUSSION Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition, which is characterized by multisystem inflammation.4 It is a rare disorder in which hereditary and sporadic cases are reported primarily in children;5 a crude annual incidence of 1.2 cases of FHL per million children has been reported in Sweden.6 HLH is a reactive process resulting from prolonged and excessive activation of antigen presenting cells (macrophages, histiocytes) and CD8+ T leading to hypersecretion of pro-inflammatory cytokines. This exaggerated inflammatory response is responsible for necrosis and organ failure and results in uncontrolled proliferation and phagocytic activity of histiocytes, leading to extensive systemic damage.7 This disorder is divided into primary/genetic hemophagocytic syndrome (FHL), and secondary/reactive hemophagocytic syndrome. The HLH, whether familial or acquired, share one common feature, namely a highly stimulated but ineffective immune response that threatens the life of the patient and may lead to death unless arrested by prompt and appropriate treatment.8

On follow-up, the patient developed a continuous headache, non-relieved by symptomatic treatment along with seizures. On further examination, her CT of brain, electroencephalography and CSF examination were normal. Cyclosporine levels were detected to be normal, so as to rule out drug-induced seizures. The patient was taken off cyclosporine and started with etoposide 150 mg/m2 twice-daily with tapering dose of dexamethasone. She developed neutropenia with the advent of etoposide, so was again put on cyclosporine.

However, persistence of headaches with cyclosporine led to the withdrawal of cyclosporine and introduction of etoposide again.

Until recently, it was widely believed that symptoms of FHL generally arose during infancy and early childhood. With the more widespread availability of genetic testing, it is apparent that the first significant episode of FHL can occur throughout life, including in utero (Table 29-16).17

Now on weekly follow-ups, there is evidence of gradual clinical improvement and normalization of hematological abnormalities.

The secondary or acquired HLH can have a constellation of causes. First described in adults with a viral infection following organ transplantation,18 later it

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HEMATOLOGY Table 2. The Genetic Causes of HLH9-16

Table 3. Proposed HLH Diagnostic Criteria, 2009

HLH related to defects in the perforin/granule-mediated pathway of cytotoxicity

Molecular diagnosis of HLH or X-linked lymphoproliferative syndrome (XLP).

yy FHL 2 - Perforin (PRF1) AR yy FHL 3 - MUNC 13-4 AR yy FHL4 - STX11 AR yy Griscelli s. type 2 - Rab27A AR yy Chediak Higashi s. - LYST1 AR yy Hermansky Pudlak s. type II - AP3B1 AR

Or at least 3 of 4:

X-linked syndromes associated with HLH yy XLP1 - SH2D1A (SAP) X yy XLP2 - BIRC4 (XIAP) X AR indicates autosomal recessive; X indicates X-linked.

yy Fever yy Splenomegaly yy Cytopenias (minimum 2 cell lines reduced) yy Hepatitis And at least 1 of 4: yy Hemophagocytosis yy ↑ Ferritin yy ↑ soluble IL-2Rα (age-based) yy Absent or very decreased NK function Other results supportive of HLH diagnosis

was established that most patients had no underlying immune defect and that also nonviral agents such as bacteriae, fungi, parasites could trigger HLH. EpsteinBarr virus infection is an important trigger of both FHL and acquired HLH.19 Cytomegalovirus, herpes simplex, HIV, bacteria and parasitic agents have also been implicated. Non-Hodgkin’s lymphoma, leukemia, connective tissue diseases and autoimmune diseases may also be associated with HLH.3 However, the identification of an infectious organism does not help to discriminate between genetic and acquired forms of HLH, since many episodes in genetic HLH can be triggered by infections.20 Because of financial constraints of the patient, a conclusive cause of the hemophagocytic syndrome could not be determined. However, as the blood culture and KOH mount were found to be negative and bone marrow biopsy was negative for any malignancy by immunohistochemistry, it was thought to be of viral origin because of the presence of atypical mononuclear cells. The predominant clinical findings of HLH are fever (often hectic and persistent), pancytopenia, hepatitis and splenomegaly, which were consistent in our patient. To assist with the rapid diagnosis of HLH, the Histiocyte Society has developed a set of diagnostic guidelines that encompass both clinical and laboratory findings.21 With additional experience these diagnostic criteria have been modestly modified as HLH diagnostic criteria 2009 (Table 3).22 The patient fulfilled the criteria and was diagnosed as HLH. Due to the life-threatening implications of the diagnosis of HLH, chemotherapy protocol of HLH 2004 trial consisting of steroids, etoposide or antithymocyte globulin (ATG), should be instituted promptly, along with treatment of the underlying etiology in cases of secondary HLH or followed by curative hematopoietic

yy Hypertriglyceridemia yy Hypofibrinogenemia yy Hyponatremia Table adapted from reference 22.

cell transplantation in FHL.23-25 As seen in our case, when a patient presents with fever and unexplained cytopenias it is important to consider the possibility of HLH and do the required follow-up with further investigations for a prompt diagnosis and rapid recovery.

REFERENCES 1. Henter JI, Aricò M, Elinder G, Imashuku S, Janka G. Familial hemophagocytic lymphohistiocytosis. Primary hemophagocytic lymphohistiocytosis. Hematol Oncol Clin North Am. 1998;12(2):417-33.

2. Janka GE, Schneider EM. Modern management of children with haemophagocytic lymphohistiocytosis. Br J Haematol. 2004;124(1):4-14.

3. Janka G, Imashuku S, Elinder G, Schneider M, Henter JI. Infection- and malignancy-associated hemophagocytic syndromes. Secondary hemophagocytic lymphohistiocytosis. Hematol Oncol Clin North Am. 1998;12(2):435-44.

4. Janka G. Hemophagocytic lymphohistiocytosis: when the immune system runs amok. Klin Padiatr. 2009;221(5): 278-85.

5. Aricò M, Janka G, Fischer A, Henter JI, Blanche S, Elinder G, et al. Hemophagocytic lymphohistiocytosis.

Report of 122 children from the International Registry. FHL Study Group of the Histiocyte Society. Leukemia. 1996;10(2): 197-203.

6. Henter JI, Elinder G, Söder O, Ost A. Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis. Acta Paediatr Scand. 1991;80(4): 428-35.

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HEMATOLOGY 7. Jordan MB, Hildeman D, Kappler J, Marrack P. An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder. Blood. 2004;104(3):735-43.

8. Janka G, zur Stadt U. Familial and acquired hemophagocytic lymphohistiocytosis. Hematology Am Soc Hematol Educ Program. 2005:82-8.

9. Bizario JC, Feldmann J, Castro FA, Ménasché G, Jacob CM, Cristofani L, et al. Griscelli syndrome: characterization of a new mutation and rescue of T-cytotoxic activity by retroviral transfer of RAB27A gene. J Clin Immunol.

2004;24(4):397-410.

10. Enders A, Zieger B, Schwarz K, Yoshimi A, Speckmann C, Knoepfle EM, et al. Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type II. Blood. 2006;108(1):81-7.

11. Rigaud S, Fondanèche MC, Lambert N, Pasquier B, Mateo V, Soulas P, et al. XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature.

2006;444(7115):110-4.

12. Feldmann J, Callebaut I, Raposo G, Certain S, Bacq D, Dumont C, et al. Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell.

2003;115(4):461-73.

13. Stepp SE, Dufourcq-Lagelouse R, Le Deist F, Bhawan S, Certain S, Mathew PA, et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science.

1999;286(5446):1957-9.

14. zur Stadt U, Schmidt S, Kasper B, Beutel K, Diler AS, Henter JI, et al. Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. Hum Mol Genet. 2005;14(6):827-34.

16. Westbroek W, Adams D, Huizing M, Koshoffer A, Dorward H, Tinloy B, et al. Cellular defects in ChediakHigashi syndrome correlate with the molecular genotype and clinical phenotype. J Invest Dermatol.

2007;127(11):2674-7.

17. Malloy CA, Polinski C, Alkan S, Manera R, Challapalli M. Hemophagocytic lymphohistiocytosis presenting with nonimmune hydrops fetalis. J Perinatol. 2004;24(7):458-60.

18. Risdall RJ, McKenna RW, Nesbit ME, Krivit W, Balfour HH Jr, Simmons RL, et al. Virus-associated hemophagocytic syndrome: a benign histiocytic proliferation distinct from malignant histiocytosis. Cancer. 1979;44(3):993-1002.

19. Imashuku S. Clinical features and treatment strategies of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Crit Rev Oncol Hematol.

2002;44(3):259-72.

20. Henter JI, Ehrnst A, Andersson J, Elinder G. Familial hemophagocytic lymphohistiocytosis and viral infections.

Acta Paediatr. 1993;82(4):369-72.

21. Henter JI, Horne A, Aricó M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis.

Pediatr Blood Cancer. 2007;48(2):124-31.

22. Filipovich AH. Hemophagocytic lymphohistiocytosis (HLH) and related disorders. Hematology Am Soc Hematol Educ Program. 2009:127-31.

23. Shuper A, Attias D, Kornreich L, Zaizov R, Yaniv I. Familial hemophagocytic lymphohistiocytosis: improved neurodevelopmental outcome after bone marrow transplantation. J Pediatr. 1998;133(1):126-8.

24. Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat hemophagocytic lymphohistiocytosis. Blood. 2011;118(15):4041-52.

25.

15. Arneson LN, Brickshawana A, Segovis CM, Schoon RA, Dick CJ, Leibson PJ. Cutting edge: syntaxin 11 regulates lymphocyte-mediated secretion and cytotoxicity.

J Immunol. 2007;179(6):3397-401.

■■■■

Horne A, Janka G, Maarten Egeler R, Gadner H, Imashuku S, et al; Histiocyte Society. Haematopoietic stem cell transplantation in haemophagocytic lymphohistiocytosis. Br J Haematol. 2005;129(5):622-30.

A Point-of-care Measure of Hemostasis Predictive of Post-TAVR Aortic Regurgitation The presence of defects in high-molecular-weight (HMW) multimers of von Willebrand factor and a high value for closure time with adenosine diphosphate (CT-ADP), a point-of-care measure of hemostasis, were each predictive of the presence of aortic regurgitation after TAVR and were associated with higher mortality 1 year after the procedure, reports a study in the July 28 issue of the New England Journal of Medicine. A CT-ADP value of more than 180 seconds had sensitivity, specificity and negative predictive value of 92.3%, 92.4% and 98.6%, respectively, for aortic regurgitation.

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INTERNAL MEDICINE

A Case of Leptospirosis Presenting as Multiorgan Failure AK BADRINATH*, K SURESH†, R RAGHUNATHAN†, SURESH BABU S‡

ABSTRACT Leptospirosis, an infection of worldwide distribution has come to international attention as a re-emerging infectious disease.

It is caused by spirochetes of the genus Leptospira, which infect most of the domestic and wild animals and spread to humans by the infected urine of animals. Patients with leptospirosis may present with acute febrile illness to life-threatening multiorgan failure. Here we present a 25-year-old female with fever, jaundice and altered sensorium admitted as a case of sepsis with multiple organ dysfunction syndrome who was later diagnosed as a case of leptospirosis.

Keywords: Leptospirosis, icterus, renal failure, meningitis

CASE REPORT A 25-year-old female presented with complaints of fever for 7 days, continuous high-grade fever, no chills or rigor with generalized body pain. Patient had altered sensorium since 1 day. Patient had one episode of seizure (generalized tonic-clonic seizure [GTCS]) with frothing from mouth and post-ictal confusion a few hours prior to admission in the hospital. No history of vomiting or cough with expectoration. No history of decreased urine output or abdominal pain. Patient was not a diabetic and he had no history of pulmonary tuberculosis in the past. Patient was married, had 2 children and had no menstrual irregularities at present.

On examination, patient was irritable, not obeying to oral commands, responded to pain. Patient's general physical examination revealed patient febrile 100.6°F with pallor++; icterus+ and subconjunctival hemorrhage. Pulse - 126/min and regular, blood pressure (BP) - 100/60 mmHg, cardiac examination

*Professor †Associate Professor ‡Resident Dept. of General Medicine Sri Manakula Vinayagar Medical College and Hospital, Puducherry, Tamil Nadu Address for correspondence Dr AK Badrinath No. 4, Shree Apartments, II Floor, 29 #, Avvai Nagar, Lawspet Puducherry - 605 008, Tamil Nadu E-mail: akbsts@yahoo.co.in

was normal, respiratory system - patient tachypneic, normal vesicular breathe sounds present with scattered crepitations and per abdomen - soft, hepatomegaly present. Central nervous system - patient had altered sensorium, agitated responded to pain, moved all limbs, reflexes diminished bilaterally and bilateral plantars extensor. Bilateral pupils equal and reacting to light and terminal neck rigidity present. Patient was admitted with the provisional diagnosis of meningitis with multiorgan dysfunction syndrome and evaluated.

Her complete hemogram revealed anemia with hemoglobin - 9.9 g/dL, total leukocyte count - 8,400/mm3, differential count: polymorphs - 67% and lymphocytes 24% with severe thrombocytopenia platelets 24,000/mm3. She had hypoglycemia with random blood glucose of 60 mg/dL. Her renal function tests and serum electrolytes were normal. Her liver function was deranged: total bilirubin - 4.6 mg/dL, SGOT - 430 IU/L, SGPT - 190 IU/L, ALP - 190 IU/L, total protein 7.0 g/dL and albumin - 3.7 g/dL. Her urine examination showed microalbuminuria with plenty of RBCs and hemogranular casts were present suggestive of acute tubular necrosis. Arterial blood gas analysis revealed metabolic acidosis. ECG showed sinus tachycardia but was otherwise normal and chest X-ray revealed increased bronchovascular markings.

Patient was started on intravenous (IV) fluids, Ryle’s tube feeding, nasal O2, antipyretics and IV antibiotics (injection ceftriaxone 1 g IV b.i.d. and injection vancomycin 1 g IV b.i.d.). Patient treatment was continued with glucose and platelet monitoring in

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INTERNAL MEDICINE intensive care unit. Since, patient had altered sensorium a computed tomography (CT) brain was done and showed multiple small calcifications but was otherwise normal.

A lumbar puncture was done for cerebrospinal fluid (CSF) analysis - cytology showed moderate cellularity with 240 cells predominant of neutrophils - 70% and monocytes - 20%. However, CSF protein was normal - 25 mg/dL, glucose - 55 mg/dL and lactate dehydrogenase (LDH) - 80.

Dengue serology, scrub typhus and viral markers were negative. Blood, urine and CSF culture were negative and peripheral smear normal. On Day 2 of admission, her platelets decreased to 12,000/mm3 and prothrombin time prolonged and was transfused with 4 units of platelet concentrate and 2 units of fresh frozen plasma. On Day 3 of admission, we had a suspicion of leptospirosis and serum leptospirosis antibody test (IgM) was negative. A serum microagglutination test (MAT) for leptospirosis was positive - 1:160 dilution (significant >1:80 dilution). Patient continued on injection ceftriaxone 1 g IV b.i.d. and injection vancomycin 1 g IV b.i.d. for 7 days. Patient gradually improved over a period of 7 days; sensorium improved, no fever spikes, platelets returned to normal and liver function improved. After 10 days of intensive care treatment patient was discharged. Final diagnosis Leptospirosis with multiorgan failure.

DISCUSSION Leptospirosis is a re-emerging infectious disease of worldwide distribution but more commonly seen in the tropical countries and outbreaks occur in the rainy season. The causative organism is Leptospira interrogans, a Gram-negative thin and motile bacteria, 6-20 Âľm in length with flagella and it includes around 250 serovars. It is the most common zoonosis and humans are accidental hosts infected from body fluids especially urine of infected animal and rodents are the most common source worldwide.

Leptospirosis presents after a incubation period of 5-14 days. Often a good clinical history is needed to suspect and diagnose leptospirosis. Studies have shown that most of the patients (around 90%) present with acute febrile illness due to bacteremia (anicteric leptospirosis), which is often self-limiting. Patients typically present with fever associated with headache and muscle ache (typically calf pain) and conjunctival suffusion. Also patients may have symptoms of vomiting, diarrhea and pharyngitis. Inspite of fever being the cardinal symptom, studies have shown that about 5% of cases have no history of fever.

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The second phase (immune stage) of illness occurs 1-3 days of symptom free after the initial bacteremic phase. The exact pathogenesis of this immune phase remains still unclear. This is probably due to the host immune response to the leptospiral antigens and protein. The two phases are often indistinguishable in icteric leptospirosis. Renal manifestations include oliguric acute tubular necrosis due to hypovolemia and decreased renal perfusion, direct tissue injury, presence of vasoconstrictor agents and some studies suggest rhabdomyolysis but could not prove it. Acute renal failure is associated with increased mortality. Patients present with jaundice and deranged liver function because of hepatic necrosis. Acalculous cholecystitis though rare is clinically significant. Weilâ&#x20AC;&#x2122;s syndrome, the severe form of leptospirosis, manifests with hepatic, renal and pulmonary dysfunction is associated with increased mortality.

The pulmonary complications are life-threatening; these include acute respiratory distress syndrome and massive hemoptysis. Aseptic meningitis is seen in patients in anicteric immune stage and cranial nerve palsies, encephalitis and altered sensorium are uncommon and our patient had meningitis with icterus and altered sensorium. Conjunctival hemorrhage is common in immune stage and uveitis may be observed and persist for a year.

The complications of leptospirosis are Weilâ&#x20AC;&#x2122;s disease, disseminated intravascular coagulation, meningoencephalitis, massive hemoptysis, acute renal failure, myocarditis, acalculous cholecystitis and pancreatitis has been observed in severe illness. Thus leptospirosis can involve most of the vital organs in the body.

Diagnosis is made by rapid diagnostic kits by detecting antibodies IgM and IgG but are negative during first week of illness. Limitation of serology is that antibodies are lacking in the acute phase of the disease. In recent years, several real-time polymerase chain reaction assays have been described. Culturing the bacteria in the blood during first week of illness and in urine from Day 7 of illness is diagnostic but it takes weeks for diagnosis. The MAT represents growth of battery of serovars of 26 leptospiral groups. Detection of agglutination by dark field microscopy is definitive of diagnosis but it usually is negative in first week of illness and is done in specialized centers.

Most of the antibiotics are sensitive in leptospirosis and the drugs commonly used are doxycycline, penicillins and macrolides. Some studies suggest no definite

INTERNAL MEDICINE role of antibiotics in milder form of disease. But early antibiotic treatment is found to reduce mortality in recent studies. Patients with Weil’s disease require IV antibiotics. Cefotaxime and ceftriaxone have replaced penicillin in treatment of leptospirosis. Patients with Weil’s disease should be treated in intensive care unit.

Renal failure requires dialysis and other supportive care should be given.

Patients should be carefully monitored for the pulmonary complications, which are life-threatening.

Few studies showed that oliguria, hypotension and abnormal chest auscultations were important prognostic factors in leptospirosis. There are few case reports of patients with Weil’s disease managed successfully with plasma exchange.

CONCLUSION To conclude, physicians should be aware of complicated leptospirosis. A high-degree of clinical suspicion is required to diagnose leptospirosis. If any patient presents with multiorgan dysfunction, leptospirosis should be ruled out as earlier is the diagnosis and treatment better the prognosis.

SUGGESTED READING 1. Vijayachari P, Sugunan AP, Shriram AN. Leptospirosis: an emerging global public health problem. J Biosci.

2008;33(4):557-69.

Consortium. Leptospirosis: a zoonotic disease of global importance. Lancet Infect Dis. 2003;3(12):757-71.

3. Togal T, Sener A, Yucel N, Demirbilek S, Akgun FS, Aydogan M, et al. Intensive care of a Weil’s disease with multiorgan failure. J Clin Med Res. 2010;2(3):145-9.

4. Aydemir S, Ustundag Y, Borazan A, Sekitmez N, Ozdemir H. A case with jaundice, acute renal failure and thrombocytopenia: Weil’s disease. Acad Gastroenterol J. 2004;3(1):42-5.

5. Abdulkader RC. Acute renal failure in leptospirosis. Ren Fail. 1997;19(2):191-8.

6. Thammakumpee K, Silpapojakul K, Borrirak B. Leptospirosis and its pulmonary complications.

Respirology. 2005;10(5):656-9.

7. Pappas MG, Ballou WR, Gray MR, Takafuji ET, Miller RN, Hockmeyer WT. Rapid serodiagnosis of leptospirosis using the IgM-specific Dot-ELISA: comparison with the microscopic agglutination test. Am J Trop Med Hyg. 1985;34(2):346-54.

8. Kee SH, Kim IS, Choi MS, Chang WH. Detection of leptospiral DNA by PCR. J Clin Microbiol. 1994;32(4): 1035-9.

9. Trivedi SV, Vasava AH, Bhatia LC, Patel TC, Patel NK, Patel NT. Plasma exchange with immunosuppression in pulmonary alveolar haemorrhage due to leptospirosis.

Indian J Med Res. 2010;131:429-33.

10. Tse KC, Yip PS, Hui KM, Li FK, Yuen KY, Lai KN, et al.

Potential benefit of plasma exchange in treatment of severe icteric leptospirosis complicated by acute renal 2. Bharti AR, Nally JE, Ricaldi JN, Matthias MA, Diaz failure. Clin Diagn Lab Immunol. 2002;9(2):482-4.

MM, Lovett MA, et al; Peru-United States Leptospirosis ■■■■

Lixisenatide Approved for Type 2 Diabetes The US Food and Drug Administration (FDA) has approved Adlyxin (lixisenatide), a once-daily injection to improve glycemic control, along with diet and exercise, in adults with type 2 diabetes. Adlyxin is a glucagonlike peptide-1 (GLP-1) receptor agonist, a hormone that helps normalize blood sugar levels. Adlyxin should not be used to treat people with type 1 diabetes or patients with increased ketones in their blood or urine (diabetic ketoacidosis).

CDC Warns About Dangerous Outcomes with New Opioid Substitute Reports of exposure to a plant-based drug with opioid-like effects, kratom (Mitragyna speciosa), could lead to dangerous outcomes, and have been on the rise for the past few years, according to a CDC analysis of poison center calls in Morbidity and Mortality Weekly Report. In 2015 the number of calls that poison centers received regarding exposures to kratom was 10 times higher than in 2010 (26 in 2010; 263 in 2015). The signs and symptoms associated with the drug include tachycardia, agitation/irritability, drowsiness, nausea and hypertension.

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Every citizen of India should have the right to accessible, affordable, quality and safe heart care irrespective of his/her economical background

Sameer Malik Heart Care Foundation Fund An Initiative of Heart Care Foundation of India

E-219, Greater Kailash, Part I, New Delhi - 110048 E-mail: heartcarefoundationfund@gmail.com Helpline Number: +91 - 9958771177

“No one should die of heart disease just because he/she cannot afford it” About Sameer Malik Heart Care Foundation Fund

Who is Eligible?

“Sameer Malik Heart Care Foundation Fund” it is an initiative of the Heart Care Foundation of India created with an objective to cater to the heart care needs of people.

Objectives Assist heart patients belonging to economically weaker sections of the society in getting affordable and quality treatment.

Raise awareness about the fundamental right of individuals to medical treatment irrespective of their religion or economical background.

Sensitize the central and state government about the need for a National Cardiovascular Disease Control Program.

Encourage and involve key stakeholders such as other NGOs, private institutions and individual to help reduce the number of deaths due to heart disease in the country.

To promote heart care research in India.

All heart patients who need pacemakers, valve replacement, bypass surgery, surgery for congenital heart diseases, etc. are eligible to apply for assistance from the Fund. The Application form can be downloaded from the website of the Fund. http://heartcarefoundationfund.heartcarefoundation. org and submitted in the HCFI Fund office.

Important Notes The patient must be a citizen of India with valid Voter ID Card/ Aadhaar Card/Driving License.

The patient must be needy and underprivileged, to be assessed

by Fund Committee.

The HCFI Fund reserves the right to accept/reject any application for financial assistance without assigning any reasons thereof.

The review of applications may take 4-6 weeks.

All applications are judged on merit by a Medical Advisory Board who meet every Tuesday and decide on the acceptance/rejection of applications.

The HCFI Fund is not responsible for failure of treatment/death of patient during or after the treatment has been rendered to the patient at designated hospitals.

To promote and train hands-only CPR.

Activities of the Fund Financial Assistance

The HCFI Fund reserves the right to advise/direct the beneficiary to the designated hospital for the treatment.

Financial assistance is given to eligible non emergent heart patients.

Apart from its own resources, the fund raises money through donations, aid from individuals, organizations, professional bodies, associations and other philanthropic organizations, etc.

The financial assistance granted will be given directly to the treating hospital/medical center.

After the sanction of grant, the fund members facilitate the patient in getting his/her heart intervention done at state of art heart hospitals in Delhi NCR like Medanta – The Medicity, National Heart Institute, All India Institute of Medical Sciences (AIIMS), RML Hospital, GB Pant Hospital, Jaipur Golden Hospital, etc. The money is transferred directly to the concerned hospital where surgery is to be done.

Drug Subsidy

The HCFI Fund has the right to print/publish/webcast/web post details of the patient including photos, and other details. (Under taking needs to be given to the HCFI Fund to publish the medical details so that more people can be benefitted).

The HCFI Fund does not provide assistance for any emergent heart interventions.

Check List of Documents to be Submitted with Application Form Passport size photo of the patient and the family A copy of medical records Identity proof with proof of residence Income proof (preferably given by SDM)

The HCFI Fund has tied up with Helpline Pharmacy in Delhi to facilitate

BPL Card (If Card holder)

patients with medicines at highly discounted rates (up to 50%) post surgery.

Details of financial assistance taken/applied from other sources (Prime Minister’s Relief Fund, National Illness Assistance Fund Ministry of Health Govt of India, Rotary Relief Fund, Delhi Arogya Kosh, Delhi Arogya Nidhi), etc., if anyone.

The HCFI Fund has also tied up for providing up to 50% discount on imaging (CT, MR, CT angiography, etc.)

Free Diagnostic Facility

Free Education and Employment Facility

The Fund has installed the latest State-of-the-Art 3 D Color Doppler EPIQ 7C Philips at E – 219, Greater Kailash, Part 1, New Delhi.

HCFI has tied up with a leading educational institution and an export house in Delhi NCR to adopt and to provide free education and employment opportunities to needy heart patients post surgery. Girls and women will be preferred.

This machine is used to screen children and adult patients for any heart disease.

Laboratory Subsidy HCFI has also tied up with leading laboratories in Delhi to give up to 50% discounts on all pathological lab tests.

About Heart Care Foundation of India

Help Us to Save Lives The Foundation seeks support, donations and contributions from individuals, organizations and establishments both private and governmental in its endeavor to reduce the number of deaths due to heart disease in the country. All donations made towards the Heart Care Foundation Fund are exempted from tax under Section 80 G of the IT Act (1961) within India. The Fund is also eligible for overseas donations under FCRA Registration (Reg. No 231650979). The objectives and activities of the trust are charitable within the meaning of 2 (15) of the IT Act 1961.

Heart Care Foundation of India was founded in 1986 as a National Charitable Trust with the basic objective of creating awareness about all aspects of health for people from all walks of life incorporating all pathies using low-cost infotainment modules under one roof.

HCFI is the only NGO in the country on whose community-based health awareness events, the Government of India has released two commemorative national stamps (Rs 1 in 1991 on Run For The Heart and Rs 6.50 in 1993 on Heart Care Festival- First Perfect Health Mela). In February 2012, Government of Rajasthan also released one Cancellation stamp for organizing the first mega health camp at Ajmer.

Objectives Preventive Health Care Education Perfect Health Mela Providing Financial Support for Heart Care Interventions Reversal of Sudden Cardiac Death Through CPR-10 Training Workshops Research in Heart Care

Donate Now...

Heart Care Foundation Blood Donation Camps The Heart Care Foundation organizes regular blood donation camps. The blood collected is used for patients undergoing heart surgeries in various institutions across Delhi.

Committee Members

Chief Patron

President

Raghu Kataria

Dr KK Aggarwal

Entrepreneur

Padma Shri, Dr BC Roy National & DST National Science Communication Awardee

Governing Council Members Sumi Malik Vivek Kumar Karna Chopra Dr Veena Aggarwal Veena Jaju Naina Aggarwal Nilesh Aggarwal H M Bangur

Advisors Mukul Rohtagi Ashok Chakradhar

Executive Council Members Deep Malik Geeta Anand Dr Uday Kakroo Harish Malik Aarti Upadhyay Raj Kumar Daga Shalin Kataria Anisha Kataria Vishnu Sureka

This Fund is dedicated to the memory of Sameer Malik who was an unfortunate victim of sudden cardiac death at a young age.

Rishab Soni

HCFI has associated with Shree Cement Ltd. for newspaper and outdoor publicity campaign HCFI also provides Free ambulance services for adopted heart patients HCFI has also tied up with Manav Ashray to provide free/highly subsidized accommodation to heart patients & their families visiting Delhi for treatment.

http://heartcarefoundationfund.heartcarefoundation.org

OBSTETRICS AND GYNECOLOGY

Comparative Study of Clinical Efficacy of Placentrex and Azithromycin in Pelvic Inflammatory Disease MADHURI S*, KAVYA D SHARMA*, PRAMEELA HJâ&#x20AC;

ABSTRACT Pelvic inflammatory disease (PID), an infection and inflammation of upper genital tract organs typically involving fallopian tubes, ovaries and surrounding structures is one of the most frequent infections seen in reproductive age group. Therapeutic goal in management of PID is to prevent chronic residual disease. Failure of antibiotic therapy to prevent sequelae of salpingitis reflects the emphasis of additional therapy along with antibiotics. Therefore, there is a need of a therapeutic agent with comprehensive anti-inflammatory action, debridement action to clear up the necrosed tissue and debris and also collagenase activity to break the bands and adhesions formed by earlier episodes of infection. Placentrex, a drug derived from an extract of fresh term, healthy, human placenta has multi-pronged anti-inflammatory action, debridement action, causes tissue regeneration and remodeling promotes wound healing, has significant immunotropic action involving both humoral and cellular immunity. An open randomized prospective clinical trial was conducted in Dept. of Obstetrics and Gynecology, MMC&RI, Mysuru from December 2013 to May 2015 to find efficacy of Placentrex in comparison with Azithromycin for the treatment of PID.

Keywords: Pelvic inflammatory disease, Placentrex, Azithromycin, Chlamydia trachomatis

P

elvic inflammatory disease (PID) is one of the most frequent infections seen in reproductive age group and is associated with major clinical and pelvic health problem. It is infection and inflammation of upper genital tract organs typically involving fallopian tubes, ovaries and surrounding structures.

PID is polymicrobial in nature and is associated with different etiological agents. Clinical presentations may vary from mild-to-severe. No specific signs and symptoms are pathognomic of PID. Laboratory tests are also poor predictors of PID. There may be subclinical symptoms and patient later may present with infertility.

The Centers for Disease Control and Prevention (CDC) recommends treatment for even mild cases of PID. Therapeutic goal in management of PID is to prevent chronic residual disease. Failure of antibiotic therapy to

*Junior Resident â&#x20AC; Professor Dept. of Obstetrics and Gynecology MMC&RI, Mysuru, Karnataka Address for correspondence Dr Prameela HJ Professor Dept. of Obstetrics and Gynecology MMC&RI, Mysuru, Karnataka E-mail: hjprameela@gmail.com

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Indian Journal of Clinical Practice, Vol. 27, No. 3, August 2016

prevent sequelae of salpingitis reflects the emphasis of additional therapy along with antibiotics.

Recent studies from India have revealed the prevalence of Chlamydia trachomatis infection to be 23% in gynecology outpatient department (OPD) and 19.9% in sexually transmitted disease (STD) patients. It has been recovered from 30 to 60% cases of salpingitis and PID patients in India, while seroprevalence is shown to be higher in at least one recent study.

Many Indian women suffer from PID. Only 40% seem to present with overt symptoms of which 4% are severe and 36% present with mild-to-moderate symptoms.

Rest 60% of the rising PID cases in India, present as subclinical or asymptomatic. There has been a change in the epidemiology of PID cases in India, where there is a shift from in-patient to outpatient PID cases. Infection with C. trachomatis seems to be on the rise and at present out numbering gonococcus infections (Fig. 1).

The sequelae of PID also differs widely. Management of squealae includes periodic courses of antibiotic, steroids and surgery. Treatment is mainly aimed at alleviating symptoms, and preventing the disabling squealae like infertility, ectopic, etc. Antimicrobial therapy improves prognosis for fertility but actual fertility results are not satisfactory. Antibiotics alone cannot prevent sequelae of PID. Antibiotics alone can neither

OBSTETRICS AND GYNECOLOGY

Case rate, cases/1,00,000

1,000

They also prevented growth of clinically isolated bacteria like E. coli from urine and blood culture and S. aureus from pus. Drug-resistant strains e.g., E. coli DHSoc and Pseudomonas aeruginosa Cam R have also been significantly inhibited by the extract with a dosedependent response.

Chlamydia PID EP

800 600 400 200 0 1995

2000

2005

Year

Figure 1. Case rates for C. trachomatis infection (age, 15-39 years), PID (age, 15-44 years) and EP (age, 15-44 years), British Columbia, Canada, 1992-2009.

PID = Pelvic inflammatory disease; EP = Ectopic pregnancy.

prevent sequelae of salpingitis nor reverse the damage that has already set in. Therefore, there is a need of a therapeutic agent with comprehensive antiinflammatory action, debridement action to clear up the necrosed tissue and debris and also collagenase activity to break the bands and adhesions formed by earlier episodes of infection and inflammation and that the drug can be continued for long without much adverse effects.

Placentrex is a drug containing Peptides (FNP-III, Ubiquitin, CRF), Nucleotides (PDRN) and Glutamate and is derived from an extract of fresh term, healthy, human placenta. It has significant anti-inflammatory effect involving chemical mediators of immunological response. Effect of Placentrex is well-documented in wound healing1 and in treatment of burns and radiation effects.2 The primary modes of action of ‘Placentrex’ in PID are: ÂÂ

Anti-inflammatory action

The drug exerts comprehensive anti-inflammatory action thus offers better control of PID due to the presence of polydeoxyribonucleotides (PDRNs), which inhibit the proinflammatory cytokines possibly acting via adenosine receptors.

PDRN components act by entering the microbes and interfere with their replication thus also exert both bacteriostatic and fungistatic activities in vitro.

In vitro tests show growth inhibition of Escherichia coli, Staphylococcus aureus and fungi including Saccharomyces cerevisiae, Kluveromyces fragilis and Candida albicans.

These activities possibly help in treatment of bacterial infections, and eliminate bacteria in PID, which are persistent or resistant to antibiotics. PDRN also stimulate growth factors like fibroblast growth factor (FGF), placental growth factor (PIGF) and transforming growth factor (TGF)-β that help in tissue repair and healing.

Preliminary studies indicate that the drug disrupts the biofilm in bacterial infection. This property can aid in antibiotic action where it can reduce the duration of therapy and also decrease the chance of recurrence or resistance. Most of the recent clinical studies are indicative of this. Corticotropin-releasing factor like peptide in Placentrex suppresses the production of prostaglandins and leukotrienes through endogenous steroids production.

The anti-inflammatory and platelet anti-aggregatory activity of Placentrex are demonstrated in suitable animal models and in in vitro study, respectively. ÂÂ

Debridement action

Component containing fibronectin like peptide identified in Placentrex exerts debridement action by stabilizing the local trypsin or trypsin-like serine proteases (broad-spectrum proteases). Proteolytic enzymes improve blood flow by increasing the flexibility of red blood cells, inhibiting the aggregation of platelets and helps to prevent abnormal blood clotting. Enzyme activity also helps to support the cleansing of the tissues and promotes better circulation as well as stimulating formation of new, healthy tissue. They make the blood less viscous. This help to bring proper circulation to the inflamed tissue. This particularly helps in opening of fallopian tubes blocked by inflammation, necrosed tissue and debris. Reduction in inflammation, increase in proper blood formation, increase in proper circulation hinders scar tissue and adhesion formation, while reducing pain. ÂÂ

Collagenase action

Excess and faulty collagen formations lead to scar tissue formation and adhesion causing fertility issues.

Ubiquitin is known to destroy faulty collagen tissue.

Placenta derived ubiquitin-like peptide softens and breaks up adhesions, scar tissues in fallopian tubes and

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251

OBSTETRICS AND GYNECOLOGY penetrates directly to the pelvic region to clear any debris or mucus plugs formed during chronic inflammation leading to recurrent attacks of PID. This helps in maintaining the patency of the fallopian tubes, thus bringing down the chances of infertility or ectopic pregnancy. Thus Placentrex has multi-pronged anti-inflammatory action, debridement action, causes tissue regeneration and remodeling, promotes wound healing, has significant immunotropic action involving both humoral and cellular immunity.

This is conspicuous in clinical studies where it significantly relieved the cervical motion tenderness and adnexal tenderness. The drug has been recommended for prescription in PID but there is not much data in literature regarding the efficacy alone in PID. So, we conducted a trial to find efficacy of Placentrex in comparison with Azithromycin for the treatment of PID. MATERIAL AND METHODS An open randomized prospective clinical trial was conducted in Dept. of Obstetrics and Gynecology, MMC&RI, Mysuru from December 2013 to May 2015 after obtaining ethical clearance.

A total of 100 patients of PID within reproductive age group of 20-45 years were recruited. Diagnosis of PID was made on clinical history and examination.

Inclusion Criteria ÂÂ

Female subjects of childbearing age.

ÂÂ

Patients diagnosed to have PID in the last 6-12 months.

ÂÂ

Patients with primary or secondary infertility with diagnosis of PID.

ÂÂ

Patients with persistent PID despite antibiotic treatment within past 6 weeks.

ÂÂ

Willingness to receive intramuscular (IM) injections for 14 days.

Exclusion Criteria ÂÂ

Postmenopausal women reproductive age group.

or

women

outside

ÂÂ

Subjects who are pregnant or breastfeeding.

ÂÂ

Subjects on active treatment or with evidence of active tuberculosis/STD.

ÂÂ

Subjects with endometriosis.

ÂÂ

History of more than 3 episodes of documented PID/bacterial STD.

ÂÂ

Any hepatic or renal impairment.

Patients were randomly assigned to two groups.

Group 1 (50 patients) was given injection Placentrex 2 mL IM daily for 14 days, Group 2 (50 patients) were given tablet Azithromycin 1,000 mg stat and repeated the same dose after 1 week.

Table 1. Symptomatology and Signs Group 1

Group 2

Initial (50)

2 weeks (50)

4 weeks (46)

12 weeks (46)

Initial (50)

2 weeks (46)

4 weeks (40)

12 weeks (40)

Lower abdominal pain

46 (92%)

24 (48%)

20 (43.5%)

20 (43.5%)

44 (88%)

32 (69.6%)

28 (70%)

28 (70%)

Backache

32 (64%)

12 (24%)

10 (21.7%)

8 (17.4%)

34 (68%)

14 (30.4%)

16 (40%)

16 (40%)

Menstrual irregularities

16 (32%)

8 (16%)

6 (13%)

6 (13%)

18 (36%)

10 (21.7%)

12 (30%)

14 (35%)

Dysmenorrhea

32 (64%)

14 (28%)

12 (26.1%)

12 (26.1%)

22 (44%)

16 (34.8%)

14 (35%)

12 (30%)

Dyspareunia

18 (36%)

8 (16%)

6 (13%)

6 (13%)

12 (24%)

8 (17.4%)

6 (15%)

6 (15%)

Discharge per vagina 30 (60%)

18 (36%)

16 (34.8%)

10 (21.7%)

28 (56%)

10 (21.7%)

16 (40%)

16 (40%)

Uterine tenderness

32 (64%)

20 (40%)

18 (39.1%)

14 (30.4%)

32 (64%)

12 (26.1%)

22 (55%)

18 (45%)

Restricted uterine mobility

16 (32%)

6 (12%)

4 (8.7%)

4 (8.7%)

18 (36%)

12 (52.2%)

10 (25%)

10 (25%)

Fornix tenderness

38 (76%)

10 (20%)

20 (48.5%)

24 (52.2%)

40 (80%)

30 (65.2%)

20 (50%)

18 (45%)

Cervical erosion

8 (16%)

2 (4%)

4 (8.7%)

4 (8.7%)

6 (12%)

4 (8.7%)

4 (10%)

4 (10%)

Symptomatology

Signs

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Indian Journal of Clinical Practice, Vol. 27, No. 3, August 2016

OBSTETRICS AND GYNECOLOGY Patients were followed up at 2, 4 and 12 weeks after starting the treatment, the first follow-up at 2 weeks after initiation of the therapy was to assess the immediate relief of symptoms while on therapy; the 2nd follow-up at 4 weeks was to assess persistence of relief and the 3rd follow-up at 12 weeks was to assess recurrence of symptoms. History suggestive of PID is lower abdomen pain, discharge per vagina, menstrual irregularity, dysmenorrhea and dispareunia. Clinical signs consisted of presence of discharge, uterine tenderness, restricted mobility of uterus and adnexal tenderness (Table 1). The responses of treatment were made based on history and examination.

RESULTS Total 100 cases of PID were recruited, 50 in Group 1 and 50 in Group 2; mean age of patients were 30.36 years in Group 1 and 31.1 in Group 2, most of them were P2L2, 4 cases in Group 1 and 10 cases in Group 2 were lost out of follow-up. There were no major or minor side effects in both the groups except mild gastric upset seen in 2 cases in Group 2. No patients had allergic reaction, fever or pain at injection site in Group 1.

19% in Group 2 but not statistically significant. Uterine mobility improved in both groups 16.4% in Group 1 and 11% improved in Group 2, but was not statistically significant. Fornix tenderness showed improvement in both the groups but was statistically better in Group 1 (p ≤ 0.02). There was no improvement in cervical erosion in both the groups. Efficacy of Placentrex in cervical erosion has been reported but with local application of Placentrex gel.5 Thus overall, Group 1 had better and sustained effect of therapy in relieving lower abdominal pain, backache, fornix tenderness, which was statistically significant. In other symptoms, there was marginal improvement when compared with Group 2.

Complete remission with treatment at 2 weeks occurred in 24 cases (48%) in Group 1 versus 16 (32%) cases in Group 2 (Table 2 and Fig. 2). Complete remission at 12 weeks follow-up was seen in 34 cases (68%) in Group 1 versus 10 (20%) cases in Group 2 (Fig. 3). Lack of response to treatment at 2 weeks was seen in 10 (20%) in Group 1 versus 18 cases (36%) in Group 2. Recurrence at 12 weeks was seen in 8 (16%) cases in Group 1 compared to 18 (36%) in Group 2 (Fig. 4). As regards overall patient satisfaction, it was better in Group 1 (36%) versus 16% in Group 2 (Fig. 5).

DISCUSSION

On analyzing the results for each symptom and signs we found that, the lower abdominal pain markedly reduced in Group 1; 48.5% versus 18% in Group 2, which was significant statistically (p ≤ 0.01).

Relief in backache was better with Group 1; 46.6% versus 28% in Group 2 and was found to be statistically significant (p ≤ 0.01). As far as menstrual irregularity is concerned, it was observed that there was marginally better but not statistically significant (p ≤ 0.263).

A small study has shown that improvement in menstrual irregularities.3 Dysmenorrhea improved to some extent in both the groups but it was not statistically significant (p ≤ 0.11). Relief of dyspareunia did not show significant improvement in both the groups (p ≤ 0.128). A small study showed that relief of dyspareunia was better with Placentrex treatment.4 Response to vaginal discharge was present in both the groups with marginal benefit in Group 1 (p ≤ 0.50) but it was not statistically significant. Uterine tenderness improved more in Group 1 - 33.6% versus

Table 2. Overall Efficacy Parameter

Group 1

Group 2

Complete remission on Rx at 2 weeks

24 (48%)

16 (32%)

Complete remission on Rx at 12 weeks

34 (68%)

10 (20%)

Lack of response at 2 weeks

10 (20%)

18 (36%)

Recurrence at 12 weeks

8 (16%)

18 (36%)

Patient's satisfaction of more than 75% on therapy

18 (36%)

8 (16%)

60 50 Percentage (%)

Pelvic inflammatory disease is the frequent infection seen in reproductive aged women. Despite availability of antibiotics treatment of PID is still not satisfactory.

In our study, we have evaluated efficacy of Placentrex injection with Azithromycin in curing PID.

48%

40 32%

30 20 10 0

Group 1

Group 2

Figure 2. Complete remission on Rx at 2 weeks.

Indian Journal of Clinical Practice, Vol. 27, No. 3, August 2016

253

OBSTETRICS AND GYNECOLOGY CONCLUSION 80 70

68%

Percentage (%)

60 50 40 30 20%

20 10 0

Group 1

Group 2

Figure 3. Complete remission on Rx at 12 weeks.

40 36%

35

Percentage (%)

30 25 20 15

5 Group 1

Group 2

35

Percentage (%)

30 25 16%

15

4. Sarkar B, Kishore N, Mookherjee J, Nagrath A. Effect of Placentrex on tubal blockage and menstrual irregularities.

J Obstet Gynaecol India. 1976;26(5):757-61, iii-v.

7. Chandanwale A, Langade D, Mohod V, Sinha S, Ramteke A, Bakhshi GD, et al. Comparative evaluation of human placental extract for its healing potential in surgical wounds after orthopaedic surgery: an open, randomised, comparative study. J Indian Med Assoc. 2008;106(6): 405-8.

8. Kaul R, Chaudhary V, Mukhopadhayay P. To evaluate the effect of local placentrex therapy in reducing side effects of radiation in patients of cervical carcinoma. Antiseptic.

2001;98(4):131-2.

10 5 0

2. Garg R, Zahra F, Chandra JA, Vatsal P. A comparative study of injection placentrex and conventional therapy in treatment of pelvic inflammatory disease. J Indian Med Assoc. 2008;106(7):463, 467.

6. Purandare BN, Purandare CB, Hirlekar V. Placental extract injection therapy in tubal block. The Clinician.

1970;XXXIV(1):45-8.

36%

20

1. Agarwal N, Kulshrestha V, Kriplani A. Clinical efficacy of placentrex injection in pelvic inflammatory disease.

J Indian Med Assoc. 2010;108(2):117-8, 122.

5. Sen and Bhargava et al (ADL Data on file).

Figure 4. Recurrence at 12 weeks.

40

REFERENCES

3. Dahiya P, Paul A. A randomised study to evaluate the efficacy and safety of placentrex injection in patients suffering from pelvic inflammatory disease. J Indian Med Assoc. 2013;111(5):352-3.

16%

10

0

Pelvic inflammatory disease is one of the most frequent infection encountered in gynecology. Conventional antibiotic therapy does not provide adequate relief of symptoms and its sequelae. Conventional antiinflammatory and proteolytic enzymes leave the therapeutic gap. Placentrex injection is expected to fill up the gaps adequately. It leads to marked relief in symptoms than compared with antibiotic therapy alone. As Placentrex decreases adnexal inflammation to significant level it can be a good option specially to reduce symptoms and sequelae of PID.

9. Chandravati et al. Placentrex gel with electrocauterization in the treatment of cervical erosion. Obstet Gynaecol Today. Vol. 12; December 2004. pp. 823-7.

Figure 5. Patients satisfaction of more than 75% on therapy.

■■■■

254

Group 1

Group 2

Indian Journal of Clinical Practice, Vol. 27, No. 3, August 2016

OBSTETRICS AND GYNECOLOGY

Outcomes of High-risk Cesarean Sections: An Ongoing Challenge VIVEK CHHARI*, SOMEN BHATTACHARJEEâ&#x20AC;

ABSTRACT Objectives: To evaluate the high-risk cesarean sections in the perspective of optimum maternal and neonatal outcomes.

Material and methods: The study was done from 1st April 2004 to 31st March 2005. Two hundred high-risk cesarean cases were objectively studied and analyzed for the maternal and perinatal morbidity and mortality patterns. Results: The incidence of cesarean section was 23.2% in which 68.33% were high-risk cases. Fifty-five percent cases were emergency cesarean sections in this group. Intraoperative and postoperative complications were analyzed in perspective of intensive care and management.

Perinatal outcomes were determined. Incidence of maternal mortality was 3.5%. The most common cause was disseminated intravascular coagulation. Conclusion: Adequate antenatal care, early referral, critical care concept, multidisciplinary back-ups in a tertiary care institute is essential for better maternal and perinatal outcomes in high-risk cesarean sections that will be comparable to the developed world.

Keywords: Cesarean section, maternal mortality, perinatal mortality

P

regnancy is a time of unparalleled joy and expectations. Most pregnancies have a healthy outcome but for others pregnancy can be times of intense fear and uncertainty. In these instances, both mother and child need specialized care to ensure good health. These pregnancies are at high-risk for developing problems and having poor outcomes.

Cesarean section, an operation that mainly evolved to save a maternal life during difficult childbirth, has now become increasingly the procedure of choice in high-risk situations to prevent perinatal morbidity and mortality. This has become possible because of sophisticated patient care depending on effective antimicrobials, blood transfusion services, superior monitoring system, rendering safer anesthesia, improved surgical technique and reliable neonatal care, back-up services.

In the present era, there is liberalization of cesarean section particularly keeping in view safe motherhood,

*RSO, Dept. of Obstetrics and Gynecology â&#x20AC; Assistant Professor, Dept. of Surgery MGM Medical College and MY Group of Hospitals, Indore, Madhya Pradesh Address for correspondence Dr Somen Bhattacharjee 43/26, G-sector Baktawarram Nagar, Near Ajit and Ajay Club, Indore - 452 001, Madhya Pradesh E-mail: drsomenmd@yahoo.com

small family norms and decreasing the perinatal mortality and morbidity in an attempt to have satisfactory outcome in the high-risk cases.

Cesarean section still poses significant challenge regarding scrupulous decision-making, surgical expertise and competency of the roles of other allied departments.

AIMS AND OBJECTIVES To study the incidence of high-risk lower segment cesarean section (LSCS); clinical evaluation of highrisk cesarean section in terms of maternal and perinatal outcome in emergency and elective LSCS and intraoperative complications; to study the clinical follow-up of the high-risk postcesarean cases.

MATERIAL AND METHODS The present study is a clinical evaluation of 200 highrisk cesarean cases with maternal, perinatal outcome in the Dept. of Obstetrics and Gynecology at Maharaja Yeshwantrao Hospital, Indore. The study was done from 1st April 2004 to 31st March 2005. Two hundred high-risk cesarean cases were randomly selected, objectively studied and analyzed for the maternal and perinatal morbidity with mortality pattern. The cases under study included booked and emergency admission. The booked cases in general had minimum

Indian Journal of Clinical Practice, Vol. 27, No. 3, August 2016

255

OBSTETRICS AND GYNECOLOGY of three antenatal check-ups. The study was carried out by collecting detailed history and information on a predesigned proforma by interrogating the cases and/or the attendants. Scoring of the patients was done by modified Cooplandâ&#x20AC;&#x2122;s scoring system.

RESULTS During our study period, the total number of admissions were 9,746; total number of deliveries were 7,242; the total number of cesarean section were 1,680; hence, incidence of cesarean section was 23.2%. During the last 10 years, the incidence of cesarean section in our institute varied from minimum of 16% to maximum of 28% (Fig. 1). Thirty-six percent cases were booked.

In the present study, 80.5% of the cases were between the age group of 21-30 years; 11.5% were referral cases.

There were 40.5% primipara, 81% cases were term, 16% were preterm and three were post-term. Seventyseven percent were primary cesarean sections, 55% cases were operated as emergency cases, while 26.5% were electively operated and the rest were operated selectively. The most frequent indication for cesarean section was fetal distress, 28.5% (Fig. 2). Seventy-three percent of the patients had intraoperative complications in the form of adhesions, scar dehiscence and atonic postpartum hemorrhage (PPH), etc. (Table 1).

About 44.5% had postoperative maternal morbidity, which were puerperal pyrexia, paralytic ileus, urinary tract infection (UTI), wound sepsis, shock, pulmonary edema, acute renal failure, pulmonary embolism, disseminated intravascular coagulation (DIC), congestive cardiac failure (CCF) and hemolysis, elevated liver enzyme levels and low platelet level (HELLP) syndrome (Table 2).

Forty-one percent of the cases had low birth weight baby, 5.5% were stillbirth and 3.5% had early neonatal death; 23.5% babies had mild-to-severe depression and Apgar score below 6-4 (Table 3).

Perinatal morbidity was noted in 28.5%, which was in the form of prematurity, intrauterine growth restriction, respiratory distress syndrome and birth asphyxia; 4.5% and 1% cases had hospital stay between 10-15 days and more than 15 days, respectively. Fifty-four percent cases needed intensive management in the form of broad-spectrum costly antibiotics, blood transfusion, expert medical opinion and prophylactic antibiotics.

Seven percent cases had poor perinatal outcome.

The average duration of surgery in 89.5% cases was less than 1 hour, while 10.5% required operation for more than 1 hour. The incidence of maternal mortality in the study group was 3.5%. The most common causes

35

35

30

Incidence (%)

25

30

27.8 24.79 22.44

22.25

21.14

19.51

20

22.74

23.7

20.8 20

16.64

15

15

10

10

5

5 0

0 1995

1996

1997

1998

1999

2000 Year

Incidence (%)

Figure 1. Incidence of cesarean section in MY Hospital in the last 10 years.

256

25

Indian Journal of Clinical Practice, Vol. 27, No. 3, August 2016

2001

2002

2003

2004

OBSTETRICS AND GYNECOLOGY

High-risk

Indication 18.5

CP, CPD and FPD 9.5

Fetal malpresentation Dystocia

18.5

Scar dehiscence

8 23

Prev. cesarean section APH

8.5

Hypertensive disorder

11

PROM

15.5

Fetal distress

28.5

Polyhydramnios

3 2

Oligohydramnios 0

5

10

15

20

25

30

35

Percentage (%)

Figure 2. Comparative analysis of indications of cesarean section.

of death were cardiorespiratory arrest, coagulation failure, shock, atonic PPH, etc.

DISCUSSION Cesarean section is now safer than it has ever been, in terms of advances in techniques and anesthesiology, blood transfusion, surgery and the availability of ‘powerful’ antibiotics. Yet, it can never be entirely safe and therefore, is not an alternative to vaginal delivery.

In our study period, the incidence of cesarean section was 23.10%. This is comparable to studies conducted by the other authors.1,2 The main and most frequent indication of cesarean sections in our present study was fetal distress (27.5% and 28.5%) indicating the extent of burden taken by our health professionals in a pursuit to lower the rates of perinatal morbidity and mortality in our center.

The second most important indication was previous section reflecting side by side the stress given to the maternal aspects. The incidence was definitely high due to obvious reasons. Kambo et al in their study found most frequent indications to be dystocia (37.5%), fetal distress with or without meconium aspiration (33.4%),3 while in the study of Asenova et al, the leading indication was ‘previous cesarean section’; ‘contracted pelvis’ being the second.1 The maternal

complications were moderate-to-severe intraoperative bleeding (13.5%), abnormal uterine morphology and pathology (7%). This is because of the fact that most patients had low hemoglobin levels, were unbooked, turned up in the emergency hours and were late referral cases. Bergholt et al also found in their study that uterocervical lacerations and blood loss of more than 1 liter were the most frequent intraoperative complications in cesarean section.4 Many authors have studied potential intraoperative and postoperative complications associated with cesarean delivery.

Intraoperatively, uterine hemorrhage may develop from atony, extension of the incision, uterine rupture, the presence of leiomyomata or placenta accreta.

Involvement of adjacent structures may occur in the form of urinary tract injury, which may include cystotomy or ureteral injury. Vaginal or broad-ligament extension of the lower-segment uterine incision increases the risk of ureteral involvement.

The postoperative complications in our present study were in the form of postoperative pyrexia (13%), wound sepsis (5%), paralytic ileus (4%) and UTI (3.5%).

Infection is the most common postoperative sequela of cesarean delivery in other studies also. The observed incidence of endomyometritis varies greatly, with estimates ranging from 10 to 50%.

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OBSTETRICS AND GYNECOLOGY Table 1. Analysis of Intraoperative Maternal Complications

Table 2. Analysis of Postoperative Morbidities

Complications

No.

%

Postoperative complications

Previous poor quality scar at lower abdominal wall

10

5

Pyrexia (puerperal pyrexia)

Omental and flimsy adhesion

13

6.5

Scar dehiscence

9

4.5

Impending rupture

5

2.5

Atonic uterus

11

5.5

Obstructed labor

11

5.5

Chorioamnionitis

3

1.5

Abnormal uterine morphology and pathology

14

7

Retroplacental clots

5

2.5

Ruptured uterus

3

Placenta previa Minor

8

4

Major

2

1

Abnormal placenta

2

1

Hematoma

2

1

Moderate

24

12

Severe

3

1.5

Broad-ligament

7

3.5

Lower segment

5

2.5

Upper segment

2

1.0

Injury to bladder and bowels

1

0.5

Obstetric hysterectomy

3

1.5

Intraoperative bleeding

Extension of incision into

No.

%

7

3.5

19

9.5

UTI

7

3.5

Chest infection

4

2.0

Paralytic ileus

8

4.0

Thrombophlebitis

5

2.5

Malaria

5

2.5

Wound sepsis

10

5

Primary

1

0.5

Secondary

2

1.0

Postpartum shock

2

1.0

Postpartum psychosis

3

1.5

Pulmonary edema

2

1.0

ARF

2

1.0

Septicemia

1

0.5

Burst abdomen

1

0.5

Pulmonary embolism

2

1.0

Amniotic fluid embolism

-

-

PPH

Others DIC

4

2

HELLP syndrome

1

0.5

CCF, hypoxia

1

0.5

Hypoxia and dyspnea Total

2

1.0

89

44.5

Classical LSCS

2

1

Others (high-up bladder)

4

2

Table 3. Analysis of Perinatal Outcomes

149

73

Perinatal outcomes

No.

%

Total birth

200

100

Live birth

182

91

FSB

6

3.0

MSB

5

2.5

Neonatal death

7

3.5

ENND

6

3.0

LNND

1

0.5

7-10 no depression

153

76.5

4-6 mild depression

24

12.0

<4 severe

23

11.5

Total

Other, less frequent postoperative complications include wound infection, UTIs, ileus and atelectasis. LydonRochelle et al found in their study that the overall complication rate after cesarean section was 17%.5 The perinatal mortality in our study was 3.5%. This is due to the fact that our center is a tertiary one and all the draining areas refer the cases in an irreversible state; as such little could be done for the unfortunate patients.

Dimitrov A, in his study found that the same was 11.4 per 1,000 cases in the year 2000.6 In our study, the maternal mortality was 3.5%, while it was 0.27% in the study conducted by Imbert et al.7 The most important cause of maternal mortality in our study was cardiorespiratory arrest due to shock and

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Stillbirth

Perinatal mortality

Apgar score

OBSTETRICS AND GYNECOLOGY DIC; on the other hand, the same was due to anesthetic complications in the above-mentioned study.7 CONCLUSION Vigilance, observation, team approach, lifesaving drugs and multifaceted monitoring by sophisticated gadgets, continuous updating and data review are sine qua non for optimal maternal and neonatal outcome in high-risk cesarean sections.

REFERENCES 1. Asenova D, Stambolov B. Incidence and indications for cesarean section in the Obstetrics Clinic in the University Hospital of Obstetrics and Gynecology “Maichin Dom” in Sofia. Akush Ginekol (Sofiia). 2005;44(Suppl 3):15-7.

3. Kambo I, Bedi N, Dhillon BS, Saxena NC. A critical appraisal of cesarean section rates at teaching hospitals in India. Int J Gynaecol Obstet. 2002;79(2):151-8.

4. Bergholt T, Stenderup JK, Vedsted-Jakobsen A, Helm P, Lenstrup C. Intraoperative surgical complication during cesarean section: an observational study of the incidence and risk factors. Acta Obstet Gynecol Scand.

2003;82(3):251-6.

5. Lydon-Rochelle M, Holt VL, Mortin DP, Easterling TR. Association between method of delivery and maternal rehospitalization. JAMA. 2000;283(18):2411-6.

6. Dimitrov A. Rate of cesarean section and perinatal infant mortality at “Maichin dom”. Akush Ginekol (Sofiia).

2003;42(6):3-6.

7. Imbert P, Berger F, Diallo NS, Cellier C, Goumbala M, Ka AS, et al. Maternal and infant prognosis of emergency cesarean section: prospective study of the Principal Hospital in Dakar, Senegal. Med Trop (Mars). 2003; 63(4-5):351-7.

2. Olivares Morales AS, Santiago Ramirez JA, Cortes Ramirez P. Incidence and indication for cesarean section at the Central Military Hospital of Mexico. Ginecol Obstet Mex. 1996;64:79-84.

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A Dynamic Quality Assessment Tool for Laparoscopic Hysterectomy to Measure Surgical Outcomes With the aim of developing and testing a quality assessment tool for laparoscopic hysterectomy that may serve as a new outcome quality indicator, a web-based application (www.qusum.org) was developed and gynecologists who performed laparoscopic hysterectomies were requested to register their procedures in the application. The overall survey response rate was 75%, and the mean System Usability Scale was 76.5 ± 13.6; the application was rated as good to excellent. The majority of surgeons reported that the application made them more aware of their performance, the outcomes and patient safety, and they noted that the application provided motivation for improving future performance. This may serve as a real-time, dynamic quality assessment tool for measuring individual surgical outcome for laparoscopic hysterectomy and may provide opportunities for improving surgical performance. The report is published online in the American Journal of Obstetrics and Gynecology.

Ferric Carboxy Maltose: First-line Drug in the Treatment of Postpartum Iron Deficiency Anemia Ultra-short duration of treatment, fewer adverse reactions and better compliance makes ferric carboxy maltose (FCM) the drug of choice in the management of postpartum iron deficiency anemia, suggests a new study published online in the International Journal of Reproduction, Contraception, Obstetrics and Gynecology. The study compared the safety and efficacy of FCM with iron sucrose to treat iron deficiency anemia in the post-partum.

A statistically significant increase in Hb was noted in FCM group (4.68 g/dL) compared to iron sucrose group (3.92 g/dL). Mean rise of serum ferritin was 71.07 ± 27.23 in iron sucrose group and 95.39 ± 45.84 in ferric carboxy maltose group.

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OBSTETRICS AND GYNECOLOGY

Mifepristone for Preinduction Cervical Ripening at Term: A Hospital-based Study INDU KAUL*, AMANDEEP K ANAND†, RENU GUPTA‡

ABSTRACT Objective: To compare the effect of mifepristone with placebo on cervical ripening before labor induction at term. Material and methods: Four hundred primigravida women with term pregnancies were assigned randomly to receive mifepristone 400 mg or placebo and observed for 48 hours. They were then given intravaginal misoprostol 25 μg every 4 hourly to a maximum of 4 doses. Once the cervical score was >7, amniotomy was performed and oxytocin drip started. Results: The mean interval from start of induction to delivery was 33 hours 39 minutes for mifepristone-treated subjects and 49 hours 47 minutes for placebo-treated subjects. In mifepristone group, 154 (77%) women entered into labor within 48 hours of induction of which 71 (36%) delivered within 24 hours. In placebo group, 98 (49%) women went into labor within 48 hours and 19 (9.5%) delivered within 24 hours of treatment. After 24 hours of induction, 54 (27%) patients in mifepristone group, whereas 30 (15%) in placebo group had Bishop score >5 (p < 0.01). Treatment with misoprostol was needed in only 46 (23%) women in mifepristone group, whereas it was needed in 100 (50%) women of placebo group (p < 0.01). Conclusion: Mifepristone had a modest effect on cervical ripening when given 48 hours before labor induction, appearing to reduce the need for misoprostol and oxytocin compared with placebo. There was no statistical difference in neonatal outcome in the two groups.

Keywords: Mifepristone, cervical ripening, misoprostol

I

deally, all pregnancies should go to term and labor should begin spontaneously. During the past 60 years, the induction of labor got more pronounced because of availability of safe and effective methods for induction of labor. Lately, the importance of cervical factor and its improvement by using mechanical and pharmacological agents was recognized as having a major influence on success of attempts to induce labor. Cervical ripening can be obtained by mechanical methods for example hygroscopic dilators, osmotic dilators, 24-french Foley balloon, etc. or pharmacological agents which include prostaglandins (PGE1 and PGE2) by various routes, continuous intravenous oxytocin drip, extra-amniotic saline infusion, etc. Mifepristone (also called RU-486) first synthesized in April 1980, is

*Professor Dept. of Obstetrics and Gynecology Govt. Medical College and Associated Hospitals (SMGS), Jammu, Jammu and Kashmir †Consultant J&K Health Services, Jammu, Jammu and Kashmir ‡Consultant JK Medicity, Jammu, Jammu and Kashmir Address for correspondence Dr Amandeep K Anand Consultant, Govt. Hospital, Gandhi Nagar, Jammu, Jammu and Kashmir E-mail: amandeepkanand@gmail.com

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a steroid compound that has antiglucocorticoid and antiprogesterone properties. It increases uterine activity and causes cervical effacement and dilatation for pregnancy termination.1,2 Mifepristone is orally active and has good oral bioavailability. Peak plasma levels occur within 1-2 hours and the drug is slowly excreted.

In late 90s, its use in termination of 1st and 2nd trimester abortions got very well-established.3 Its potential as a method of inducing labor in term pregnancy has lately been identified through its actions in antagonizing progesterone and thus increasing uterine contractility.4 Mifepristone matures and ripens the cervix as measured by an increased in cervical diameter and decrease in cervical resistance to mechanical dilatation.

Present study was undertaken to investigate the safety and efficacy of a single dose of 400 mg of mifepristone for preinduction cervical ripening and labor induction in women at term.

MATERIAL AND METHODS The present study was conducted in the Dept. of Obstetrics and Gynecology, Govt. Medical College and Shri Maharaja Gulab Singh (SMGS) Hospital, Jammu on a total number of 400 patients. Clearance was sought from ethical committee. Informed consent was taken

OBSTETRICS AND GYNECOLOGY from the subjects. Subjects were randomly divided into 2 study groups of 200 patients each. Group A included women who received 400 mg of mifepristone, while women in Group B received placebo in the form of vitamin C. Inclusion criteria were primigravida with age group between 20-35 years, with term pregnancy, more than 37 weeks of gestation, singleton live fetus, vertex presentation, with maternal or fetal indications for labor induction, women in whom labor induction could be deferred for 48 hours, an unfavorable cervix (Bishop score of 7 or less) and intact membranes.

Exclusion criteria were contraindication to vaginal delivery, oligohydramnios, prior uterine surgery, multiparity (more than 4 deliveries), renal failure, hepatic disorders, adrenal insufficiency, blood clotting disorders, administration of anticoagulant therapy or of corticosteroid therapy during pregnancy, Bishop score >7, cervical dilatation >3 cm, >9 uterine contractions/ hour and chorioamnionitis. In all women, proper history was taken and detailed general examination and obstetrical examination including vaginal examination was done and all the routine investigations were carried out.

The trial was double-masked and the subjects were assigned by a computer generated random number sequence to receive 400 mg mifepristone or placebo.

In both groups, once the cervical score was >7, amniotomy was performed and oxytocin drip started. If labor did not start within 48 hours of administration of drug and cervical score was <7, 25 μg misoprostol was

administered vaginally every 4 hours to a maximum of 4 doses in both groups after a prior vaginal examination. If at any stage the Bishop score was ≥7, artificial rupture of the membrane (ARM) was done and oxytocin drip started. If after 4 doses of misoprostol the Bishop score did not improve, the induction attempt was categorized as failed and the patient was taken up for cesarean section. Labor was monitored by using partogram. Maternal vital parameters and fetal heart rate were checked at regular intervals. Apgar score at 1 and 5 minutes of birth was recorded.

The primary outcome measure was the number of women going into spontaneous labor within 48 hours of mifepristone administration and in those who did not go into spontaneous labor, whether cervical priming with mifepristone significantly reduced the time from misoprostol administration to delivery. Secondary outcome measures included route of delivery, need of misoprostol, number of misoprostol doses, need for oxytocin, adverse effects (especially uterine hypertonus) and neonatal outcome.

RESULTS Subjects were similar in mean age, gravidity and estimated gestational age at entry. Median Bishop score at the start of induction in both groups were comparable. Indications for induction of labor were also similar with maximum number of patients being induced because of prolonged pregnancy (Table 1).

During the 48 hours after receiving medications, 154 (77%) women in Group A and 98 (49%) women in Group

Table 1. Maternal Characteristics

Mean age (years)

Group A

Group B

Mifepristone (n = 200)

Placebo (n = 200)

25.1

25.3

Gestational age (weeks) 37-40

37 (18.5%)

46 (23%)

40.1-41.0

163 (81.5%)

154 (77%)

<5

184 (92%)

170 (85%)

>5

16 (8%)

30 (15%)

163 (81.5%)

154 (77%)

Preinduction Bishop’s score

Indication for induction of labor Prolonged pregnancy Pre-eclampsia Other

16 (8%)

22 (11%)

21 (10.5%)

24 (12%)

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OBSTETRICS AND GYNECOLOGY B went into spontaneous labor (p = 0.0001). Seventy-five (37.5%) women in Group A and 151 (75.5%) in Group B had Bishop score <5 after 24 hours of induction.

Fifty-four (27%) women in Group A and 30 (15%) in Group B had Bishop score >5 after 24 hours (p = 0.0001).

One hundred forty-six women needed misoprostol for cervical ripening, 46 (23%) in Group A and 100 (50%) in Group B. Thirty-one (15.5%) women required <2 doses and 15 (7.5%) women required >2 doses of misoprostol in Group A versus 50 (25%) in Group B requiring <2 doses and another 50 (25%) requiring >2 doses of misoprostol (p = 0.0001).

One hundred forty-two (71%) women in Group A delivered within 48 hours of induction as against 76 (38%) in Group B (p = 0.00001) (Table 2).

The mean interval from treatment to delivery was shorter for mifepristone-treated subjects than for those receiving placebo. The difference between two groups in mean induction to delivery was approximately 16 hours. Among women who delivered vaginally, the mean interval from induction to delivery were 33 hours 30 minutes for Group A and 49 hours 47 minutes for Group B. One hundred seventy women (85%) in Group

A and 145 (72.5%) in Group B delivered vaginally.

Three women in each group had instrumental delivery.

There were 27 cesareans in the Group A and 52 in the Group B (p = 0.007). In 22 women of Group A and 20 women of Group B, cesarean section was done for acute fetal distress.

One cesarean in Group A and 5 in Group B were done for inadequate progress of labor. None in Group A and 21 cesareans in Group B were done for failed induction.

Four cesareans in Group A and 6 in Group B were done for other indications (Table 3).

Six women (3%) in Group A and 2 (1%) in Group B reported nausea. Seven women (3.5%) in Group A and none in Group B reported hyperthermia. Two women (1%) in Group A and none in Group B had uterine tachysystole. Four women (2%) in Group A and none in Group B reported hypertonicity (p = 0.0001) (Table 4).

Birth outcomes did not differ between two groups.

Mean birth weight was 2.68 in both the groups. Mean Apgar score was 10/10 in both the groups. Meconium at delivery was reported in 18 (9%) women in Group A and 10 (5%) women in Group B (p = 0.11).

Table 2. Intrapartum Characteristics Mifepristone (n = 200)

Placebo (n = 200)

<5

75 (37.5%)

151 (75.5%)

≥5

54 (27%)

30 (15%)

None

154 (77%)

100 (50%)

≤2

31 (15.5%)

50 (25%)

>2

15 (7.5%)

50 (25%)

0-12

48 (24%)

13 (6.5%)

12-24

50 (25%)

27 (13.5%)

24-36

42 (21%)

31 (15.5%)

36-48

14 (7%)

27 (13.5%)

>48

46 (23%)

102 (51%)

0-12

26 (13%)

4 (2%)

12-24

45 (22.5%)

15 (7.5%)

24-36

56 (28%)

29 (14.5%)

36-48

14 (7%)

28 (14%)

>48

58 (29%)

124 (62%)

Bishop’s score after 24 hours of induction

Misoprostol doses given

Time interval between induction to onset of spontaneous labor

Time interval between induction to delivery

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OBSTETRICS AND GYNECOLOGY Table 3. Delivery Data Mode of delivery

Mifepristone (n = 200)

Placebo (n = 200)

170 (85%)

145 (72.5%)

Vaginal Instrumental LSCS

3 (1.5%)

3 (1.5%)

27 (13.5%)

52 (26%)

22 (81.5%)

20 (38.5%)

1 (3.7%)

5 (9.6%)

0

21 (40.3%)

Indications for LSCS AFD Inadequate progress of labor Failed induction

4 (14.8%)

6 (11.6%)

Mean induction to delivery interval

33 hours 30 min

49 hours 47 min

Mean induction to onset of labour

27 hours 40 min

42 hours 12 min

Other

LSCS = Lower segment cesarean section; AFD = Acute fetal distress.

Table 4. Adverse Effects on Mother Mifepristone (n = 200)

Placebo (n = 200)

Nausea

6 (3%)

2 (1%)

Vomiting

0

0

Diarrhea

0

0

7 (3.5%)

0

Uterine tachysystole

2 (1%)

0

Hypertonicity

4 (2%)

0

Hyperthermia

DISCUSSION There are few reports of preinduction mifepristone and of subsequent intravaginal misoprostol. The mean intervals from induction to delivery or onset of active labor were shorter with ingestion of mifepristone 48 hours before administration of misoprostol. In our study, mean interval between induction to onset of spontaneous labor was 27 hours 40 minutes in Group A and 42 hours 12 minutes in Group B, which is comparable to Stenlund et al (24 hours 10 minutes and 52 hours, respectively).5 Whereas in Frydman study, it was 51 hours 45 minutes versus 74 hours 3 minutes.6 This difference could be due to the reason that the mean duration of pregnancy in Frydman study was around term, whereas in the present study as well as in Stenlund study, most of the women were post-term, thus supporting the fact that mifepristone is more effective in induction of labor in post-term pregnancies.

More women had favorable Bishop score after 24 hours of mifepristone than placebo and the difference was statistically significant. We believe that this effect

indirectly supports the role of progesterone for the maintenance of pregnancy.

Mean induction delivery time in the present study was 33 hours 39 minutes in Group A as compared to 49 hours 47 minutes in Group B. These results are comparable to Stenlund et al (36 hours 23 minutes vs. 53 hours 17 minutes).5 In Elliott study,7 it was almost double than in other studies (84 hours 6 minutes and 88 hours 14 minutes, respectively), which could be because the dose of mifepristone used was 200 mg in Elliott study as compared to 400 mg in rest of the studies.

Prostaglandin need was reduced in women who received mifepristone. In our study, 23% women in Group A and 51% in Group B required misoprostol for further ripening of cervix after treatment.

More contractile abnormalities and nonreassuring fetal heart rate patterns were observed in mifepristone than placebo-treated women, most of which were during active phase of labor and in most cases after intravaginal misoprostol. That might indicate an increase in sustained uterine activity from mifepristone8 or synergy between antiprogesterone agents and prostaglandin compound.9 There are fewer cesarean sections in Group A than in the Group B, particularly for dysfunctional labor and failed inductions.

CONCLUSION The present study shows that treatment with mifepristone is a simple and effective method in inducing labor in women with term and post-term pregnancies with unripe cervix. The use of mifepristone provides an interesting new alternative to classic uterotonic agents

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OBSTETRICS AND GYNECOLOGY when induction of labor is necessary. The potential advantage of mifepristone over prostaglandins or oxytocin requires further evaluation, mainly for situations in which prostaglandins or oxytocin are contraindicated (scarred uterus). Obstetricians may consider antiprogesterones as a simple and potentially safe method of labor induction.

REFERENCES 1. Swahn ML, Bygdeman M. The effect of the antiprogestin RU 486 on uterine contractility and sensitivity to prostaglandin and oxytocin. Br J Obstet Gynaecol.

1988;95(2):126-34.

2. Johnson N, Bryce FC. Could antiprogesterones be used as alternative cervical ripening agents? Am J Obstet Gynecol. 1990;162(3):688-90.

3. El-Refaey H, Rajasekar D, Abdalla M, Calder L, Templeton A. Induction of abortion with mifepristone (RU 486) and oral or vaginal misoprostol. N Engl J Med. 1995;332(15):983-7.

biomechanical, and molecular events. Am J Obstet Gynecol. 2006;194(5):1391-8.

5. Stenlund PM, Ekman G, Aedo AR, Bygdeman M. Induction of labor with mifepristone - a randomized, double-blind study versus placebo. Acta Obstet Gynecol Scand. 1999;78(9):793-8.

6. Frydman R, Lelaidier C, Baton-Saint-Mleux C, Fernandez H, Vial M, Bourget P. Labor induction in women at term with mifepristone (RU 486): a doubleblind, randomized, placebo-controlled study. Obstet Gynecol. 1992;80(6):972-5.

7. Elliott CL, Brennand JE, Calder AA. The effects of mifepristone on cervical ripening and labor induction in primigravidae. Obstet Gynecol. 1998;92(5):804-9.

8. Hill NC, Selinger M, Ferguson J, MacKenzie IZ. The placental transfer of mifepristone (RU 486) during the second trimester and its influence upon maternal and fetal steroid concentrations. Br J Obstet Gynaecol.

1990;97(5):406-11.

9. Rodger MW, Baird DT. Pretreatment with mifepristone (RU 486) reduces interval between prostaglandin 4. Clark K, Ji H, Feltovich H, Janowski J, Carroll C, Chien administration and expulsion in second trimester EK. Mifepristone-induced cervical ripening: structural, abortion. Br J Obstet Gynaecol. 1990;97(1):41-5.

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Diagnostic Criteria of Clinical Chorioamnionitis in Preterm Birth A retrospective cohort study re-evaluated the utility of the conventional criteria for clinical chorioamnionitis in the prediction of early-onset neonatal sepsis (EONS) in preterm birth. The following 3 diagnostic categories of clinical chorioamnionitis were evaluated: Criteria 1, conventional criteria; Criteria 2, combination of any three conventional parameters without prerequisite fever; Criteria 3, Criteria 1 plus positive maternal C-reactive protein and neutrophil left-shift into minor criteria. Among 203 cases of EONS, maternal manifestation of clinical chorioamnionitis by criteria 1 was evident in only one out of seven, suggesting 15.3% sensitivity for EONS prediction. Application of criteria 2 increased sensitivity to 34.0%, while compromising specificity from 92.3% to 78.7%. Criteria 3 showed similar diagnostic performance compared with criteria 1 (sensitivity 16.7%, specificity 91.6%). Researchers suggested that the renouncement of fever as a prerequisite for the criteria of clinical chorioamnionitis could increase sensitivity for the identification of EONS. The report is published online in BJOG.

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PEDIATRICS

Profile of HIV Infection in Children and Its Correlation with their CD4 Counts VL RAGHUVANSHI, RAJ KAMAL*, T HUSAIN, K KATOCH, R DAYAL

ABSTRACT Objectives: (i) To study the clinical profile of human immunodeficiency virus (HIV) infection in children. (ii) To establish the pattern of correlation of these clinical features with the CD4 counts. (iii) To evaluate the effect of highly active antiretroviral therapy (HAART) on CD4 count of children at 6 months of therapy. Material and methods: Sixty-eight children enrolled at our ART centre or admitted at our hospital were enrolled for the study. Their case papers were reviewed. Complete clinical profile was obtained and baseline investigations including CD4 counts done. Children were then followed up and repeat CD4 levels done 6 monthly. The children were managed as per current guidelines. Results: The mean age at presentation was 6.54 ± 2.69 years. Male-to-female ratio was 2.579:1. Vertical transmission accounted for 95.58% of cases. Prolonged fever and chronic diarrhea were the most common symptoms and hepatosplenomegaly and lymphadenopathy were the most common signs. There was strong correlation between clinical and immunological staging (p < 0.0001). Failure to thrive, recurrent skin infections and abscesses were signs and symptoms at lowest CD4 levels. Orphan-hood (p < 0.0001) and socioeconomic status (p = 0.0003) significantly affected schooling among these children. Malnutrition, anemia and stunting were features of severe immunosuppression. HAART significantly raised the CD4 count at 6 months of therapy (paired ‘t’ = 6.830, p < 0.0001) with best results at higher baseline CD4 levels. Gastritis was the most common (81.5%) adverse effect and the major cause of decreased compliance. Tuberculosis and candidiasis were the commonest opportunistic infections and pneumonia accounted for majority of hospitalizations (61.5%). Conclusions: Clinical and immunological staging have good correlation. The features of severe immunosuppression are failure to thrive, recurrent bacterial skin infections, abscesses, Pneumocystis jiroveci pneumonia, extrapulmonary tuberculosis, anemia and stunting. Orphan-hood and poor socioeconomic status affect schooling in these children. Early initiation of ART at higher baseline CD4 has best results. Gastritis is the major adverse effect causing decreased compliance.

Keywords: CD4 count, children, clinical features, HIV, immunological stage, malnutrition, schooling

T

he human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) epidemic is on the verge of entering its 4th decade. With the advent of highly active antiretroviral therapy (HAART), most of the countries have halted and begun to reverse the spread of HIV.1 Although the number of new infections has been falling, levels of new infections overall are still high and with significant reductions in mortality, the number of people living with HIV worldwide has increased. CD count has been the most widely used parameter for monitoring patients. Whereas, the clinical presentation and the opportunistic infections at different CD4 levels

*Scientist-D (Medical) Head, Dept. of Clinical Medicine NJIL&OMD, Agra, Uttar Pradesh E-mail: rajushikamal@rediffmail.com

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have been well-established in adults, data regarding the same in children are lacking. Further, certain other nutritional, social and economical factors like malnutrition, immunization, anemia, parental death and schooling, etc. further complicate the issue in children. The advent of HAART has brought about a major change in the AIDS epidemic pattern. But, the efficacy of HAART and the factors affecting compliance to drugs in children particularly in Indian setting has not been well-documented.

The decision to initiate ART is based on the CD4 count of the child. If the facilities for CD4 count are not available, then clinical staging is used for deciding the timing for initiation of ART.2 However, the best timing for initiation of HAART is still a subject of much debate.

In this study, we aim to establish the pattern of signs and symptoms, prevalence of anemia, malnutrition, vitamin A deficiency and the various opportunistic infections at various levels of CD4 counts in children.

PEDIATRICS We will evaluate the effect of HAART in children, the adverse effects associated with these drugs in children and the factors affecting compliance to these drugs.

We will also evaluate the factors which are associated with better improvements in CD4 counts in patients on HAART and try to establish their roles in determining the best timing for initiation of ART. MATERIAL AND METHODS The study was conducted in the Dept. of Pediatrics, SN Medical College, Agra and ART Centre, SN Medical College, Agra in collaboration with National JALMA Institute for Leprosy and Other Mycobacterial Diseases, (Indian Council of Medical Research), Agra from January 2010 to August 2011. A sample size of 68 was obtained assuming noncentrality parameter delta = 2.53, type 1 error = 0.05, power (1-β) = 0.90, effect size (d) = 0.40 and a t (critical), one-tailed test = 1.68.

Children less than 15 years of age were enrolled in the study as per the classification by UNAIDS.1 Known HIVpositive children attending the ART Centre, SN Medical College and those children who were diagnosed as HIVpositive during the course of their management in the hospital were included in the study. Institutional Thesis and Ethical Committee cleared the study. The study protocol was explained to the parent/guardian in detail and informed, written consent was obtained from them.

Data was obtained from the parents/guardians as per the predesigned questionnaire and by referring to their records for investigations. A detailed history covering all aspects was taken. Complete physical examination including anthropometry was done. Investigations were accessed from the records of the patient. If not available, investigations were carried out at SN Medical College. CD4 count of the child was done using the Becton Dickinson’s automated fluorescence activated cell sorter (FACS), at National JALMA Institute for Leprosy and other Mycobacterial Diseases. Protein energy malnutrition (PEM) was graded on the basis of weight for age (independent activities period [IAP] grading). Anemia was taken as hemoglobin <8 g/dL according to National AIDS Control Organization (NACO) guidelines.2 Opportunistic infections were diagnosed based on the standard protocol and investigations available. Each patient was assigned a clinical and an immunological stage as per World Health Organization (WHO) criteria. Children were followed up at monthly intervals and investigations including CD4 counts repeated at 6-monthly intervals.

ART naïve children who were eligible for initiation of ART as per the current guidelines were initiated

on appropriate treatment as per NACO guidelines.2 Pearson’s correlation coefficient (r) was used to analyze the degree of correlation of clinical and immunological stages. Independent sample t-test was used to compare the means of 2 distinct qualitative groups like males and females. Categorical variables were compared by using Chi-square test. Cochran-Armitage Chi-square test for trend was preferred, when one of the variables followed ordinal distribution. To compare the pre- and post-treatment CD4 values, we have used paired t-test.

To perform all these functions, MedCalc version 11.6 and SPSS version 16 statistical packages were utilized.

RESULTS The mean age at the time of diagnosis was 6.735 ± 2.75 years for males and 6.05 ± 2.53 years for females, with no significant difference between the groups (p > 0.05).

Whereas, 72.06% of children in our study were males, only 27.94% were females. Vertical transmission was the predominant mode of transmission of HIV in our study accounting for 95.58% of cases. The remaining 3 (4.41%) had acquired HIV through transmission of infected blood/blood products.

Prolonged fever was the predominant symptom in HIVpositive children (42.64%). Chronic diarrhea (41.17%), prolonged cough (25%), not gaining weight (17.61%), recurrent skin infection (17.61%) and ear discharge (17.61%) were some of the other common symptoms that were present in these children. On examination of these children, the most commonly noted signs were hepatosplenomegaly and lymphadenopathy, both being present in 47.06% children. Oral candidiasis and signs of vitamin A deficiency were both present in 27.94% of children. Other signs noted included pyoderma (26.42%), pneumonitis (26.42%), otitis media (17.68%), dental caries (17.68%), aphthous ulcers (8.82%) and scabies (5.888%). On classifying these children into clinical stages based on WHO clinical staging criteria, majority (35.3%) of children in our study, belonged to clinical stage 3 and 21 (30.88%) children belonged to clinical stage 2; 16.17% and 17.65% children were in clinical stage 1 and 4, respectively. There was no significant variation in clinical staging in different age groups (p = 0.491). At the time of enrollment in our study, 23 (33.82%) children were not having any immunosuppression; 13.23%, 22.06% and 30.88% children were having mild, advanced and severe immunosuppression, respectively.

Immunological stage was neither dependent on the age of the child (p > 0.05), nor was it dependent on the mode of acquisition of HIV (p = 0.46). There was a strong association between the clinical and the immunological staging of HIV in children, i.e., with

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PEDIATRICS worsening CD4 status, clinical stage of the child’s infection advanced (r = 0.6708 and p < 0.0001) (Table 1).

Whereas, prolonged fever and chronic diarrhea were the commonest presenting symptoms in children from across all immunological stages, 2 symptoms which were more common in children with severe immune suppression and less common in others were ‘failure to thrive’ and ‘recurrent skin infections’ in 38.09% and 28.57% of children with severe immune suppression.

Hepatosplenomegaly and lymphadenopathy were the

commonest clinical signs irrespective of the CD4 status of the children. Pyoderma and abscesses were signs, which were predominantly seen only when CD4 count of the children were very low. Pyoderma was seen in as many as 52.38% of children whose CD4 levels were consistent with stage of severe immune suppression, whereas, at stages of no immunosuppression and mild immunosuppression, it was seen in less than 10% of the cases (Table 2). Sixty-three out of 65 children (96.92%)

Table 1. Common Clinical Features at Different Grades of Immunosuppression WHO immunological stage

Common symptoms Symptoms

No immune suppression (n = 23)

Mild immune suppression (n = 9)

Advanced immune suppression (n = 15)

Severe immune suppression (n = 21)

Number of children

Common clinical signs Clinical signs

Number of children

Prolonged fever

08 (34.78%)

No abnormality

06 (26.08%)

Chronic diarrhea

04 (17.39%)

Lymphadenopathy

06 (26.08%)

Ear discharge

04 (17.39%)

Hepatosplenomegaly

05 (21.74%)

Asymptomatic

03 (13.04%)

Otitis media

05 (21.74%)

Chronic diarrhea

06 (66.67%)

Lymphadenopathy

05 (55.55%)

Prolonged fever

03 (33.33%)

Hepatosplenomegaly

04 (44.44%)

Recurrent oral ulceration

03 (33.33%)

Oral candidiasis

04 (44.44%)

Asymptomatic

02 (22.22%)

No abnormality

03 (33.33%)

Prolonged fever

08 (53.33%)

Signs of vitamin A deficiency

07 (46.67%)

Recurrent chest infection

05 (33.33%)

Hepatosplenomegaly

06 (40%)

Chronic diarrhea

05 (33.33%)

Lymphadenopathy

06 (40%)

Ear discharge

06 (40%)

Pneumonitis

06 (40%)

Chronic diarrhea

13 (61.9%)

Hepatosplenomegaly

14 (66.67%)

Failure to thrive

08 (38.09%)

Lymphadenopathy

13 (61.9%)

Prolonged fever

10 (47.61%)

Oral candidiasis

11 (52.38%)

Recurrent skin infection

06 (28.57%)

Pyoderma/Abscesses

11 (52.38%)

Table 2. Correlation of the WHO Clinical Stage and WHO Immunological Stage of the HIV-positive Children WHO clinical stage 1 (n = 11)

WHO clinical stage 2 (n = 21)

WHO clinical stage 3 (n = 24)

WHO clinical stage 4 (n = 12)

Stage of no immune suppression (n = 23)

10

09

03

01

Stage of mild immune suppression (n = 9)

01

04

04

NIL

Stage of advanced immune suppression (n = 15)

NIL

07

06

02

Stage of severe immune suppression (n = 21)

NIL

01

11

09

Pearson’s correlation coefficient ‘r’ = 0.6708, 95% CI for ‘r’ = 0.515 to 0.784, p < 0.0001. Concordance correlation coefficient = 0.6488, Cb(accuracy) = 0.9672 (Very strong association).

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PEDIATRICS acquiring HIV infection through mother-to-child transmission were delivered vaginally and only 2 (3%) were delivered by cesarean section. A total of 89.2% children had received breastfeeding in infancy (43.07% - exclusive breastfeeding, 46.15% - mixed feeding).

Class III had school enrollment. But when it came to socioeconomic Class IV and V, only 38.7% and 25% were enrolled at school, respectively (Table 3). Only 47.06% of children had completed immunization for their age as per the National Immunization Schedule.

A majority (52.94%) of families of children in our study belonged to socioeconomic Class IV (Kuppuswamy socioeconomic scale). There was no significant variation in clinical stages among children of different socioeconomic classes (p = 0.274). Sixteen percent of children in our study were orphans, i.e., had no alive parent. They were being taken care of by grandparents, siblings (elder) or uncle/aunt. No child was staying at orphanage. 42.6% of children had both their parents alive. Eight (11.76%) had lost their mothers and 20 (29.41%) had lost their fathers, thus implying that 57.3% children had lost one or both of their parents.

Sixty out of 68 children in our study were of schoolgoing age. Whereas, 84% of children whose both parents were alive were enrolled at school, only 9% of children who had no alive parent were enrolled at school, while 62.5% and 26.6% of children who were survived only by their fathers and mothers, respectively were enrolled at school. All children whose families belonged to socioeconomic Class I or II were enrolled at school; 83.33% of those belonging to socioeconomic

Only 17.64% of children in the study had no malnutrition (weight for age more than 80% of expected). Out of the remaining, 30.8%, 19.1%, 23.5% and 8.8% children suffered from Grade I, II, III and IV PEM, respectively.

As evident from Table 4, proportion of children with higher grades of malnutrition increased significantly in children with increasing clinical stages of infection (p = 0.0013). A similar association was found between the immunological stage and the severity of malnutrition (p = 0.0038). However, such positive association was not found between the socioeconomic status and the severity of malnutrition (p = 0.3123).

Table 5 shows that stunting was present in 25% of the children; 70.59% of children who had stunting were having CD4 counts consistent with the stage of severe immunosuppression (p = 0.0004). The prevalence of anemia was 30.9% in our study with the largest proportion of these anemics having CD4 counts consistent with stage of severe immunosuppression (66.67%). Signs of vitamin A deficiency were present in 27.9% of the children. There was no significant

Table 3. Variables Affecting the Child’s Schooling Variables

Children enrolled at school

Children not enrolled at school

(Number of children [%])

(Number of children [%])

Both parents

22 (84.61)

04 (15.38)

Father only

05 (62.5)

03 (37.5)

Mother only

04 (26.66)

11 (73.33)

No surviving parent

01 (9.09)

10 (90.9)

02 (100)

NIL

Surviving parent/s*

Socioeconomic status of the family† Socioeconomic Class I Socioeconomic Class II

01 (100)

NIL

Socioeconomic Class III

15 (83.33)

03 (16.67)

Socioeconomic Class IV

12 (38.71)

19 (61.29)

Socioeconomic Class V

02 (25)

06 (75)

Severity of the

disease‡

WHO clinical stage 1

05 (50)

05 (50)

WHO clinical stage 2

11 (52.38)

10 (47.62)

WHO clinical stage 3

15 (75)

05 (25)

01 (11.11)

08 (88.88)

WHO clinical stage 4 *Survival of parents vs. schooling: †Socioeconomic ‡Clinical

χ2

= 23.429, DF = 3, p < 0.0001.

status of family vs. schooling: χ2 = 14.378, p = 0.0006, χ2 (trend) = 12.257, p = 0.0005.

severity vs. schooling: χ2 = 10.271, p = 0.0164, χ2 (trend) = 0.653, p = 0.4190.

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PEDIATRICS Table 4. Prevalence of PEM in HIV-positive Children and Factors Affecting It Variables

PEM (IAP classification) No PEM

Grade I PEM

Grade II PEM

Grade III PEM

Grade IV PEM

WHO clinical stage 1

06 (54.54%)

02 (18.18%)

03 (27.27%)

NIL

NIL

11

WHO clinical stage 2

04 (19.04%)

09 (42.86%)

05 (23.8%)

03 (14.28%)

NIL

21

WHO clinical stage 3

02 (8.33%)

08 (33.33%)

03 (12.5%)

09 (37.5%)

02 (8.33%)

24

WHO clinical stage 4

NIL

02 (16.67%)

02 (16.67%)

04 (33.33%)

04 (33.33%)

12

No immune suppression

08 (34.78%)

09 (39.13%)

05 (21.74%)

01 (4.35%)

NIL

23

Mild Immune suppression

02 (22.22%)

04 (44.44%)

02 (22.22%)

01 (11.11%)

NIL

09

Advanced immune suppression

02 (13.33%)

04 (26.67%)

04 (26.67%)

04 (26.67%)

01 (6.66%)

15

NIL

04 (19.05%)

02 (9.52%)

10 (47.61%)

05 (23.8%)

21

01 (50%)

NIL

NIL

01 (50%)

NIL

02

Clinical severity of disease*

Immunological

stage†

Severe immune suppression Socioeconomic status of the

family‡

Class I Class II

01 (100%)

NIL

NIL

NIL

NIL

01

Class III

06 (31.58%)

05 (26.31%)

04 (21.05%)

04 (21.05%)

NIL

19

Class IV

02 (5.55%)

14 (38.89%)

08 (22.22%)

08 (22.22%)

04 (11.11%)

36

Class V

02 (20%)

02 (20%)

01 (10%)

03 (30%)

02 (20%)

10

*Clinical stage vs. Grade of PEM: χ2 = 32.233, DF= 12, Contingency coefficient = 0.567, p = 0.0013. †Immunological

stage vs. Grade of PEM: χ2 = 29.141, DF = 12, Contingency coefficient = 0.548, p = 0.0038.

‡Socioeconomic

status of the family vs. Grade of PEM: χ2 = 18.201, DF = 16, Contingency coefficient = 0.46, p = 0.3123.

Table 5. Comparison of Stunting, Anemia and Vitamin A Deficiency with the CD4 Status Features

Number of children (%) No immune suppression

Stunting Anemia Signs of vitamin A deficiency

Mild immune suppression

Advanced immune suppression

Severe immune suppression

Yes (n = 17)

02 (11.76)

00

03 (17.65)

12 (70.59)

No (n = 51)

21 (41.18)

09 (17.65)

12 (23.53)

09 (17.65)

Present (n = 21)

03 (14.28)

01 (4.76)

03 (14.28)

14 (66.67)

Absent (n = 47)

20 (4.25)

08 (17.02)

12 (25.53)

07 (14.89)

Present (n = 19)

03 (15.78)

02 (10.52)

05 (26.32)

09 (47.37)

Absent (n = 49)

20 (40.82)

07 (14.28)

10 (20.41)

12 (24.49)

association between the immunological stage and the prevalence of manifestations of vitamin A deficiency (p = 0.1565).

As depicted in Table 6, 23.5% of the HIV-positive children had no opportunistic infection at the time of enrollment in the study, 27.9% children suffered from 1 opportunistic infection and the rest 48.5% had more than 1 opportunistic infections at the time of being enrolled in the study. The chances of acquiring an opportunistic infection increased significantly as the immunological

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status of the children deteriorated (p < 0.001). The most common opportunistic infections in these children were pulmonary tuberculosis (27.94%) and oral candidiasis (27.94%). Other common opportunistic infections were pneumonia (20.6%), recurrent skin infections (17.65%), otitis media (16.18%), persistent diarrhea (16.18%), extrapulmonary tuberculosis (10.29%), scabies (5.88%) and Pneumocystis jiroveci pneumonia (4.41%). Pulmonary tuberculosis, candidiasis and otitis media were present at all immunological stages with greater prevalence

PEDIATRICS at higher levels of immunosuppression. Pneumonia was more prevalent in children with advanced (33.33%) and severe (33.33%) immunosuppression.

All children suffering from P. jiroveci pneumonia were having CD4 levels consistent with stage of severe immunosuppression. Extrapulmonary tuberculosis had higher prevalence among children with severe immunosuppression (19.05%). There were a total of 29 children whose pre-treatment CD4 and 6 months post-treatment CD4 values were available. Paired CD4

counts of the children pre-treatment and 6 months posttreatment were compared. Mean CD4 count of these children before starting ART was 384.655 ± 268.645. The mean CD4 count of the same group of children after receiving ART for 6 months was 604.241 ± 322.380 with a mean increase of 219.586 ± 173.127. We applied paired sample t-test and obtained ‘t’ = 6.830 and p < 0.0001 (Table 7).

The mean rise in CD4 count was maximally seen in the age group of 5-10 years (273.823 ± 169.041). There was a

Table 6. Prevalence of Opportunistic Infections at Different Grades of Immunosuppression Opportunistic infections

Grades of immune suppression

No opportunistic infection

No immune suppression (n = 23)

Mild immune suppression (n = 09)

Advanced immune suppression (n = 15)

Severe immune suppression (n = 21)

13 (56.52%)

02 (22.22%)

01 (6.67%)

NIL

P. jiroveci pneumonia

NIL

NIL

NIL

03 (14.28%)

Pulmonary TB (including miliary TB)

04 (17.39%)

01 (11.11%)

03 (20%)

11 (52.38%)

Extrapulmonary TB

01 (4.25%)

01 (11.11%)

01 (6.67%)

04 (19.05%)

Oral/pharyngeal candidiasis

02 (8.69%)

03 (33.33%)

03 (20%)

11 (52.38%)

Recurrent bacterial skin & soft tissue infections

03 (13.04%)

01 (11.11%)

02 (13.33%)

08 (38.09%)

Otitis media

03 (13.04%)

02 (22.22%)

04 (26.67%)

02 (9.52%)

Infective persistent diarrhea

01 (4.25%)

01 (11.11%)

02 (13.33%)

07 (33.33%)

Bacterial pneumonia

01 (4.25%)

01 (11.11%)

05 (33.33%)

07 (33.33%)

Table 7. Efficacy of HAART and the Variables Affecting Response to Treatment Variables

No. of children

Pre-HAART CD4 (mean ± SD)

Post-HAART CD4 (mean ± SD)

Change in CD4 due to treatment (mean ± SD)

Age 3-5 years

5

415.00 ± 334.829

551.40 ± 420.409

136.40 ± 212.647

p = 0.224

5-10 years

17

435.706 ± 267.149

709.529 ± 314.848

273.823 ± 169.041

p < 0.0001

10-15 years

7

239.000 ± 197.065

386.285 ± 116.914

147.285 ± 115.448

p = 0.015

1

04

653.75 ± 377.792

957.00 ± 371.064

303.250 ± 46.133

p = 0.001

2

10

358.800 ± 216.034

550.70 ± 238.325

191.90 ± 152.569

p = 0.003

3

14

340.500 ± 249.469

566.357 ± 318.65

225.859 ± 208.65

p = 0.001

4

01

185.000

259.000

NA

NA

693.500 ± 275.935

961.875 ± 308.351

268.375 ± 94.892

p < 0.0001

Clinical stage

Within stage, p < 0.001; between stages, p = 0.094

Immunological stage No immune suppression

8

Mild immune suppression

6

376.500 ± 96.529

480.333 ± 139.648

103.833 ± 128.207

p = 0.104

Advanced Immune suppression

8

319.500 ± 120.844

552.875 ± 199.415

233.375 ± 212.364

p = 0.017

Severe immune suppression

7

113.143 ± 65.098

360.429 ± 229.498

247.286 ± 212.979

p = 0.022

Within stage, p < 0.001; between stages, p < 0.001

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PEDIATRICS Table 8. Hospitalization in HIV-positive Children Variable

Number of admissions N = 13 (%)

WHO clinical stage of disease Clinical stage 1

NIL

Clinical stage 2

NIL

Clinical stage 3

05 (38.46)

Clinical stage 4

08 (61.54)

Immunological status of the child No immune suppression

NIL

Mild immune suppression

NIL

Advanced immune suppression

02 (15.39)

Severe immune suppression

11 (84.61)

significant improvement in CD4 levels on receiving ART in children irrespective of their clinical stages. The mean rise in CD4 levels in children with no, mild, advanced and severe immunosuppression were 268.375 ± 94.892, 103.833 ± 128.207, 233.375 ± 212.364 and 247.286 ± 212.979, respectively. Of those who reported at followup after starting ART, 49.09% experienced adverse effects to ART. The commonest reported adverse effect was gastritis, which was present in 81.5% of those who reported adverse effects. It was the most common event causing decreased compliance to HAART. A total of 13 (19.12%) of children in our study required hospitalization during the 1½ year study period.

The most common indication for hospitalization was pneumonia, responsible for 61.5% of the hospitalizations. Of these, 38.46% of children were in clinical stage 3 and 61.54% were in WHO clinical stage 4. No child with HIV in clinical stage 1 or 2 required hospitalization. It was seen that 15.4% of children who required admission had CD4 levels consistent with stage of advanced immunosuppression and the rest 84.6% children who were hospitalized had CD4 levels consistent with stage of severe immunosuppression (Table 8).

DISCUSSION The mean age at diagnosis was 6.54 ± 2.69 years. Most of these children were diagnosed as a part of screening after parental diagnosis. Delayed diagnosis implies delayed initiation of treatment. In the study by Shah et al, mean age at diagnosis was 4.5 ± 2.9 years.3 The maleto-female sex ratio in our study was 2.579:1, which is similar to previous studies.4-7 However, this difference is not statistically significant (p = 0.7965) at the current sample size. As many as, 95.58% of children in our study

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had acquired the infection through mother-to-child transmission. Previous studies showed a significant transmission to occur through blood transfusion,8-10 which has decreased now, due to compulsory screening of donor blood for HIV. The clinical features in our study were similar to previous studies.3,7-9,11-13 There was a very strong correlation between the clinical and the immunological stages of HIV in children (correlation coefficient, r = 0.6708, p < 0.0001). A previous study had showed good correlation.9 When we assessed the clinical features with regards to CD4 count, we noticed that while most of the signs and symptoms were present at all CD4 levels, but ‘failure to thrive’, ‘recurrent skin infection (pyoderma)’ and ‘abscesses’ occurred when CD4 levels of the children fell very low (stage of severe immunosuppression).

On analysis of the variables affecting schooling in these children, we found that orphan-hood (p < 0.0001) and poor socioeconomic status (p = 0.0003) were significant contributor to school absenteeism. In contrast, clinical severity as determined by higher clinical staging did not affect school absenteeism.

PEM was present in 82.36% of children. The factors affecting the severity of malnutrition were clinical stage (p = 0.0013) and immunological stage (p = 0.0038) implying that it’s the severity of infection evidenced by clinical and immunological stages that is a significant contributor towards malnutrition in children. Stunting and anemia were late features in HIV. Children in stage of severe immunosuppression accounted for 70% and 66.67% of cases of stunting and anemia, respectively.

Signs of vitamin A deficiency occurred early in the course of the disease.

The chances of acquiring an opportunistic infection increased significantly as the immunological status of the children deteriorated (p < 0.001). The most common opportunistic infections in these children were pulmonary tuberculosis (27.94%) and oral candidiasis (27.94%). This is in accordance with previous studies.7-8,14 Pulmonary tuberculosis, candidiasis and otitis media occurred at higher CD4 levels but their prevalence increased with increasing levels of immunosuppression. Pneumonia was more prevalent in children with advanced (33.33%) and severe (33.33%) immunosuppression. All children suffering from P. jiroveci pneumonia and extrapulmonary tuberculosis were seen when CD4 levels fell to the stage of severe immunosuppression (19.05%). All the opportunistic infections occurred at greater frequency than the

PEDIATRICS Pediatric AIDS Clinical Trials Group (PACTG) study trial.15 HAART resulted in significant rise in CD4 levels after 6 months of therapy. The maximum response to HAART was seen in the age group of 5-10 years. There was significant rise in CD4 count irrespective of the clinical staging. But, the best response of HAART in terms of raising CD4 count was seen when therapy was initiated in children with lesser immunosuppression, i.e., higher baseline CD4 count. Hence, early initiation of ART at higher CD4 levels may be more beneficial rather than waiting for the CD4 count to fall below the current cut-off as per WHO guidelines. Gastritis was the most commonly reported adverse effect of HAART and it was also the major cause of decreased compliance to therapy. About 19% of HIV-positive children required admission every year with pneumonia being the most common cause of admission among them. Average duration of hospital stay was 8.84 ± 4.35 days. The frequency of hospitalization increased as the clinical and immunological stage of the child’s illness increased; 38.46% of children requiring admission were in clinical stage 3 and 61.54% were in WHO clinical stage 4.

No child with HIV in clinical stage 1 or 2 required hospitalization. Similarly, 15.4% and 84.6% of admitted children had CD4 levels consistent with advanced and severe immunosuppression, respectively.

CONCLUSION The clinical and immunological stagings have good correlation and hence in the absence of facilities for carrying out CD4 count, clinical staging is a suitable alternative for monitoring these children. The timing of appearance of various clinical features with regards to the CD4 count can be summarized as follows: Mild immunosuppression: Vitamin A deficiency, pulmonary tuberculosis, candidiasis, otitis media, decreased weight for age, hepatosplenomegaly and lymphadenopathy.

Advanced immunosuppression: Bacterial pneumonia.

Severe immunosuppression: Anemia, stunting, pyoderma, abscesses, P. jiroveci pneumonia and extrapulmonary tuberculosis. HAART causes significant rise in CD4 count at 6 months of treatment. The best effect is seen when HAART is initiated at higher baseline CD4 count. HAART is very well-tolerated in children with good compliance. Gastritis is the major limiting side effect. Early diagnosis and early initiation of treatment will reduce the morbidity and mortality associated with HIV.

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13. Emodi IJ, Okafor GO. Clinical manifestations of HIV infection in children at Enugu, Nigeria. J Trop Pediatr.

1998;44(2):73-6.

14. Connor E, Bagarazzi M, McSherry G, Holland B, Boland M, Denny T, et al. Clinical and laboratory correlates of Pneumocystis carinii pneumonia in children infected with HIV. JAMA. 1991;265(13):1693-7.

15. Dankner WM, Lindsey JC, Levin MJ; Pediatric AIDS Clinical Trials Group Protocol Teams 051, 128, 138, 144, 152, 179, 190, 220, 240, 245, 254, 300 and 327. Correlates of opportunistic infections in children infected with the human immunodeficiency virus managed before highly active antiretroviral therapy. Pediatr Infect Dis J. 2001;20(1):40-8.

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Prevalence of Undiagnosed COPD in Western Indian Population ANAND YANNAWAR*, DAMANJIT DUGGAL, RAM CHOPRA

ABSTRACT As per World Health Organization (WHO) data, chronic obstructive pulmonary disease (COPD) ranks amongst the top five causes of death in developed as well as in developing countries. Early identification of COPD is critical for preventive care and for instituting therapy. It is widely recognized that many people with COPD are undiagnosed, including some with significant airflow obstruction. A retrospective study was conducted in a Western Indian hospital to find out undiagnosed COPD patients in all admitted and outdoor patients from year 2008 till end of year 2010 for any cause, respiratory or nonrespiratory and also to grade the severity by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines.

Keywords: Chronic obstructive pulmonary disease, spirometry, FEV1, FVC, GOLD criteria

A

s per World Health Organization (WHO) data, chronic obstructive pulmonary disease (COPD) ranks amongst the top five causes of death in developed as well as in developing countries. Three million people die every year due to COPD and it ranks as 4th largest cause of death in world.1 Half a million people die every year due to COPD in India, which is over 4 times the number of people who die due to COPD in USA and Europe.2 Early identification of COPD is critical for preventive care and for instituting therapy. Majority of COPD cases are undiagnosed although magnitude of this problem is very large. Prevalence of COPD in different studies ranges from 2% to 22% in men and 1.2% to 19% in women.3

Both smokers and nonsmokers, males and females in rural and urban areas bear the brunt of progressive obstructive airways disease, which if diagnosed earlier can be prevented and treated to a larger extent with newer long-acting β2-adrenergic receptor agonists (LABAs) and long-acting muscarinic receptor antagonists (LAMAs). Indian rural women still use Chullas (kind of wood burning cooking stove)

leading to continuous smoke exposure, resulting in airways inflammation and COPD. AIMS OF STUDY To find out undiagnosed COPD patients in all admitted and outdoor patients in our hospital from year 2008 till end of year 2010 for any cause, respiratory or nonrespiratory and also to grade the severity by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines.

MATERIAL AND METHODS Spirometry data of all indoor patients and outdoor patients from year 2008 till end of year 2010 was retrieved and analyzed for missed out COPD diagnosis

by GOLD criteria i.e., forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) ratio <70%.

A total of 6,066 patients (3,964 males and 2,102 females) were included in this retrospective study. Previous COPD diagnosed cases were excluded. Demographic, health behavior and quality-of-life data was obtained from spirometry report and indoor records of the patients.

RESULTS

*Assistant Professor Dr DY Patil Medical College, Pune, Maharashtra E-mail: yannawaranand@gmail.com

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A total of 895 patients (14.75%) were found to meet COPD criteria in our study. Six hundred twenty-nine (70.27%) patients were males and 266 (29.72%) patients were females and all females patients were nonsmokers

RESPIRATORY INFECTIONS and probably they were exposed to bio fuel/wood burning smoke (Chulla smokers) (Figs. 1 and 2).

Table 1 and Figures 3-5 gives further analysis of our study.

Moderate

Mild

Severe 1%

26% COPD

Number of patients

4500 4000 3500 3000 2500 1500 1000 500 0

V. severe

30%

Normal 43%

629

266

3325

1836 Male

Figure 3. Severity of COPD in smokers.

Female Mild

Figure 1. Diagnosed COPD.

Moderate

13% Smoker

Severe

V. severe

3%

Nonsmoker

Number of patients

48% 450 400 350 300 250 200 150 100 50 0

401

36%

266

228

0 Male

Figure 4. Severity of COPD.

Female

Figure 2. Smokers and nonsmokers who developed COPD in male and female.

Moderate

Mild

Smoking status

Male

Smokers 228 (36.24%) Mild 3 (3%)

V. severe

2%

Table 1. Demographic Profile of COPD Patients Sex

Severe

15%

Severity of obstruction 41%

Moderate 68 (48.24%)

42%

Severe 95 (29.82%) Very severe 62 (20.6%) Nonsmokers 401 (63.75%)

Mild 12 (2.99%) Moderate 191 (47.63%) Severe 146 (36.40%) Very severe 52 (2.96%)

Female

All are nonsmokers 266 (29.72%)

Mild 5 (1.87%) Moderate 109 (40.97%) Severe 112 (42.0%) Very severe 40 (15. 03%)

Figure 5. Severity of COPD in females.

DISCUSSION It is widely recognized that many people with COPD are undiagnosed, including some with significant airflow obstruction. Tobacco smoking is the most important and traditionally famous risk factor for developing

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RESPIRATORY INFECTIONS COPD.4 Indian families use woods, animal dung for cooking food and making water warm for bath and its the major risk factor for developing COPD in India and developing country.5 During her lifetime, every woman who spends between 2-3 hours for cooking every day inhales a volume of 25 million liters of highly polluted air, thereby exposing her to extremely high levels of particulate matter and gaseous air pollutants.5 Burning one mosquito coil in the night emits as much particulate matter pollution, as that which is equivalent to around 100 cigarettes.6 Other causes of COPD are chronic poorly treated persistent asthma, history of tuberculosis occupational lung diseases and chemical use for killing mosquito and bed bugs.7 Making a diagnosis of COPD and its differentiation from other diseases presents an important challenge for primary care practitioners and in higher referring centers. Making diagnosis of COPD on the basis of clinical history and examination can underestimate diagnosis.

In our study, incidence of COPD in nonsmokers males is found to be higher (63.75%). Various studies found the prevalence of undiagnosed COPD between 4-18.2%.

Even though total patients visited this tertiary care center were 1,22,750, the PET was done in only 6,066 (4.94%) patients. Spirometry is a useful tool to diagnose serious respiratory disease like COPD. This 14.75% undiagnosed COPD patients of our study seems to be tip of iceberg.

CONCLUSION ÂÂ

14.75% COPD patients were undiagnosed even after suffering from long time.

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Significant number of females were undiagnosed (i.e., 29.72%).

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All females were nonsmoker and biomass exposure main factor for developing COPD.

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Smokers were suffering from severe COPD as compared to nonsmokers.

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Diagnosing undiagnosed COPD early and treatment is necessary to prevent repeated admission and early deaths.

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Chulla smoking is one of the major culprit for nonsmokers COPD in developing country like India.

REFERENCES 1. Salvi S. COPD: the neglected epidemic. In: Jindal SK (Ed.). Textbook of Pulmonary and Critical Care Medicine.

Volume 2, New Delhi: Jaypee Brothers Medical Publishers; 2011. pp. 971-4.

2. Lopez AD, Shibuya K, Rao C, Mathers CD, Hansell AL, Held LS, et al. Chronic obstructive pulmonary disease: current burden and future projections. Eur Respir J. 2006;27(2):397-412.

3. Jindal SK, Aggarwal AN, Gupta D. A review of population studies from India to estimate national burden of chronic obstructive pulmonary disease and its association with smoking. Indian J Chest Dis Allied Sci. 2001;43(3):139-47.

4. Anderson DO, Ferris BG Jr. Role of tobacco smoking in the causation of chronic respiratory disease. N Engl J Med. 1962;267:787-94.

5. Salvi S, Barnes PJ. Is exposure to biomass smoke the biggest risk factor for COPD globally? Chest. 2010;138(1):3-6.

6. Liu W, Zhang J, Hashim JH, Jalaludin J, Hashim Z, Goldstein BD. Mosquito coil emissions and health implications. Environ Health Perspect. 2003;111(12): 1454-60.

7. Salvi SS, Barnes PJ. Chronic obstructive pulmonary disease in non-smokers. Lancet. 2009;374(9691):733-43.

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Mould-sensitized Adults have Lower Th2 Cytokines Being sensitized to any aeroallergen seems to be strongly associated with current asthma, and being sensitized to any moulds with a very high risk of current asthma, revealed a new study published online in Allergy.

Researchers noted that the geometric mean (GM) levels of Th2 cytokines (IL-4, IL-5 and IL-6) for adults sensitized to Cladosporium were significantly lower than the levels for nonatopic individuals. Individuals sensitized to other aeroallergens all showed elevated Th2 cytokine levels.

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MEDILAW

Resolving Patient-Doctor Conflict A complaint was filed by the wife of a patient in the Medical Council stating that the treating doctors of the hospital, to which her husband was referred to, were negligent in their treatment; as a result of which her husband died on the same day he was hospitalized.

It may have been a misunderstanding. We did counsel the relatives of the patient present at that time.

Proceed

My patient died after a cardiac intervention. Both this GP and the specialist, he referred me to, did not explain to us about the outcome.

Misunderstanding might may have caused agitation in the mind of the complainant resulting in this complaint. As most of the misunderstandings have been cleared to the satisfaction of both parties and they have agreed to amicably resolve the financial issue, the case is dismissed.

Lesson: In an order DMC/DC/F14/237/2006, the DMC mediated and resolved the conflict between the patient and the team of doctors. The Council also allowed them to resolve their financial issues amicably outside the DMC.

CASE OVERVIEW A complaint was submitted to the Delhi Medical Council (DMC) by the Complainant alleging medical negligence in the treatment administered to her husband (Patient X) at Hospital 1, subsequent to which the patient died.

The complaint was forwarded to DMC by the Medical Council of India (MCI). The Council examined the complaint, written statements of Dr A, B including a copy of medical records of Hospital 1 and Hospital 2.

Drs C, D and E were heard in person. The son and sister-in-law of the patient were also heard in person.

Course of Events Patient X was referred to Hospital 1 from Hospital 2 on 8.6.2005. He had extensive anterior wall myocardial infarction (MI) and was in cardiogenic shock (on dopamine support) on admission. The patient was taken to the cath lab for examination. He developed complete heart block in transit and became breathless, consequent to which he was put on ventilator and a temporary pacemaker was implanted. An intra-aortic

balloon pump was also placed. A coronary angiography was done.

Coronary angiography findings: Double vessel disease with 100% proximal occlusion in left anterior descending (LAD) artery with thrombus burden and left circumflex (LCx) 90% stenosis in distal atrioventricular groove.

Procedure undertaken: Percutaneous transluminal coronary angioplasty (PTCA) and stenting along with thrombosection of LAD with integrilin infusion + other drug support. However, despite the measures taken, patient X succumbed to his illness on the same day (8.6.2005) at 8.40 pm.

Council Observations The Council observed that angioplasty was the only treatment option for the patient at that point when he came to Hospital 1. It was therefore the right management approach. The patient was in a serious condition and there were associated risks with the management, which were communicated to the relatives of the patient present at that time. The treatment given to the patient was in line with known professional practices and so, no medical negligence

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MEDILAW can be established. The complaint may have been filed due to misunderstanding, which might have caused distress to the complainant.

Council Judgement The complaint was disposed as most of the misunderstandings were cleared to the satisfaction of both parties during the hearing. The two parties also agreed to amicably resolve the financial issue.

Reference 1. DMC/14/2/Comp. 237/2006 dated 22nd August 2006.

PRINCIPLES OF INFORMED CONSENT Three essential elements of a valid informed consent are:1 ÂÂ

Information disclosure: The patient must be properly informed

ÂÂ

Voluntariness: Consent must be voluntary

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Decision-making capacity: The patient must have the mental capacity to give consent.

The level of disclosure for each patient is individualized.

The relevant information must be provided truthfully and conveyed in a language that the patient can understand using nonscientific terms.2 The information disclosed should include:2,3 ÂÂ

The condition/disorder/disease that the patient is having/suffering from

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Necessity for further testing

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Natural course of the condition and possible complications

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Consequences of nontreatment

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Treatment options available

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Potential risks and benefits of treatment options

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Duration and approximate cost of treatment

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Expected outcome

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Follow-up required

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Inability to accurately predict results.

Exceptions to Informed Consent Informed consent is not required:4 ÂÂ

In emergency situations, where a delay in treatment in order to obtain consent would harm the patient

ÂÂ

When the patient waives the consent process: Waivers should be documented in writing to protect the doctor

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ÂÂ

If a doctor believes that the patient’s emotional and physical condition could be adversely affected by full disclosure of the treatment risks, then disclosure may be legally withheld. This principle is called “therapeutic privilege.”

References 1. Gupta UC. Informed consent in clinical research: revisiting few concepts and areas. Perspect Clin Res. 2013;4(1): 26-32.

2. Satyanarayana Rao KH. Informed consent: an ethical obligation or legal compulsion? J Cutan Aesthet Surg.

2008;1(1):33-5.

3. Abbott R, Cohen M. Medico-legal issues in cardiology.

Cardiol Rev. 2013;21(5):222-8.

4. Tan SY. Medical malpractice: a cardiovascular perspective.

Cardiovasc Ther. 2012;30(3):e140-5.

WHAT THE SUPREME COURT OF INDIA HAS TO SAY In Samira Kohli vs. Dr Prabha Manchanda and Anr SCI, Civil Appeal No. 1949 of 2004, 16.01.2008, the Supreme Court of India has observed: “32 (ii). The ‘adequate information’ to be furnished by the doctor (or a member of his team) who treats the patient, should enable the patient to make a balanced judgment as to whether he should submit himself to the particular treatment or not. This means that the doctor should disclose (a) nature and procedure of the treatment and its purpose, benefits and effect; (b) alternatives if any available; (c) an outline of the substantial risks; and (d) adverse consequences of refusing treatment.

But there is no need to explain remote or theoretical risks involved, which may frighten or confuse a patient and result in refusal of consent for the necessary treatment. Similarly, there is no need to explain the remote or theoretical risks of refusal to take treatment which may persuade a patient to undergo a fanciful or unnecessary treatment.

A balance should be achieved between the need for disclosing necessary and adequate information and at the same time avoid the possibility of the patient being deterred from agreeing to a necessary treatment or offering to undergo an unnecessary treatment.”

“22. (iii) In order to recover damages for failure to give warning the plaintiff must show not only that the failure was negligent but also that if he had been warned he would not have consented to the treatment.”

MEDILAW WHAT THE MCI CODE OF ETHICS REGULATIONS 2002 HAS TO SAY Regulation 2.3 Prognosis of Chapter 2 (Duties of physicians to their patients) states: “The physician should neither exaggerate nor minimize the gravity

of a patient’s condition. He should ensure himself that the patient, his relatives or his responsible friends have such knowledge of the patient’s condition as will serve the best interests of the patient and the family.”

Communication Strategies to Redirect an Emotionally Charged Clinical Encounter Strategy

Physician actions

Examples

Active listening

Understand the patient’s priorities, let the patient talk without interruption, recognise that anger is usually a secondary emotion (e.g., to abandonment, disrespect)

“Please explain to me the issues that are important to you right now.”

Validate the emotion and empathize with the patient (understanding, not necessarily sharing, the emotion with the patient)

Name the emotion; if you are wrong, the patient will correct you; disarm the intense emotion by agreement, if appropriate

“I can see that you are angry.”

Explore alternative solutions

Engage the patient to find specific ways to handle the situation differently in the future

“Help me to understand why this upsets you so much.”

“You are right—it’s annoying to sit and wait in a cold room.”

“It sounds like you are telling me that you are scared.”

“If we had told you that appointments were running late, would you have liked a choice to wait or reschedule?”

“What else can I do to help meet your expectations for this visit?”

“Is there something else you need to tell me so that I can help you?”

Provide closure

Mutually agree on a plan for subsequent visits to avoid future difficulties

“I prefer to give significant news in person.

Would you like early morning appointments so you can be the first patient of the day?”

“Would you prefer to be referred to a specialist, or to follow-up with me to continue to work on this problem?”

Adapted from Am Fam Physician. 2013;87(6):419-25.

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68th Annual National Conference of Indian Psychiatric Society (ANCIPS 2016) clear that the genotype may influence response to medication.

PSYCHIATRY AS A REAL CLINICAL NEUROSCIENCE: NEED FOR COURSE CORRECTION Dr Matcheri S Keshavan, Boston, USA ÂÂ

ÂÂ

Despite major advances in neuroscience, psychiatry continues to utilize symptom-based diagnosis and treatments, similar to how medicine was, a century ago. Trainees still do not get enough teaching in neuroscience.

Any successful profession needs a coherent body of knowledge at its core.

ÂÂ

Psychiatry somehow did not have such a core because of its ideological divisions.

ÂÂ

Because of this, our field lost the organ of its system along the way.

ÂÂ

The last two decades have made spectacular advances in understanding the brain basis of mind and its disorders.

ÂÂ

Psychiatric disorders can now be conceptualized as neuronal network dysfunctions. Future psychiatrists need to be well-grounded in systems neuroscience, digital technology and molecular biology. Psychiatry needs to firmly embrace the brain as the organ of its specialty.

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Such transformations in future training of psychiatrists do not need one to be reductionistic, be solely biological in orientation, or dismiss clinical wisdom.

Training neuroscience is key for this to happen, and that will change the course of psychiatry.

ADHD: THE BRAIN-BEHAVIOR CONNECT

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280

Dr Abir Mukherjee, Kolkata ADHD is a neurobehavioral disorder.

Convergent data from neuroimaging, neuropsychology, genetics and neurochemical studies consistently point to the involvement of the frontostriatal network as a likely contributor to the pathophysiology of ADHD. Molecular genetic studies support dysregulation of neurotransmitter systems as the basis of genetic susceptibility to the disorder, and it is becoming

Indian Journal of Clinical Practice, Vol. 27, No. 3, August 2016

ÂÂ

ADHD is a clinical diagnosis-based on DSM-5 or ICD-10 criteria, substantiated by psychometric testing.

ÂÂ

80% of children who have ADHD will continue to have enough symptoms to qualify for diagnosis as an adolescent and over 60% of adults will maintain core symptoms of ADHD.

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The childhood syndrome of ADHD does not preclude attaining high educational and vocational goals, and most children no longer exhibit clinically significant emotional or behavioral problems once they reach their mid-twenties.

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Short- and long-term studies have proven the efficacy of short- and long-acting stimulants, atomoxetine and alpha-2 agonists for the treatment of ADHD.

NEW PSYCHOACTIVE SUBSTANCES

ÂÂ

Dr Rakesh Lal, New Delhi Profile of new psychoactive substance (NPS) users: Adolescents more likely to use, male > female, people with use of other drugs like cannabis/ cocaine, use in party settings and night clubs.

ÂÂ

Synthetic cannabinoids: alternatives to marijuana.

Marketed

as

“safe”

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Plant-based substances: Khat, kratom, salvia divinorum.

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Phenethylamines: A broad range of compounds that share a common phenylethan-2-amine structure; reports of seizures and renal failure.

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Piperazines: Two classes: (1) Benzylpiperazines (BZP) and (2) phenylpiperazines (TFMPP). Mimic effects of ecstasy (MDMA); dangerous with seizure disorders, psychiatric illness or coronary disease.

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Phencyclidine: PCP, angel dust, killer weed.

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Dextromethorphan (DXM). At high doses, may produce dissociative hallucinations, perceptual changes, drug liking, mystical-type experiences similar to use of psilocybin. Can also produce

CONFERENCE PROCEEDINGS tachycardia, hypertension, agitation, ataxia and psychosis at high doses. ÂÂ

Ketamine: Closely related to internationally controlled drug phencyclidine (also known as PCP or ‘angel dust’).

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Designer psychoactive substances - stimulants: Mephedrone, MDPV, piperazines, “bath salts”; psychedelics: 2C-B, mescaline, DMT, etc.

ÂÂ

Volatile solvents: Domestic products such as spray deodorants, glue, lighter refills, type writer eraser fluid and spray air fresheners can be used as drugs.

ÂÂ

Despite widespread availability and use, health care providers remain largely unfamiliar with these products.

ÂÂ

There is an urgent need to familiarize ourselves with the side effects and long-term consequences associated with their use.

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INCB Report 2012 & WDR 2013: Mounting evidence suggesting that many new psychoactive substances are being manufactured in China and India.

ÂÂ

Government of India has been proactive in controlling NPS - Ketamine.

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NPS as an issue requires: Education, harm reduction, prevention, research as to the harms caused.

SUCCEEDING IN TRANSLATIONAL PSYCHIATRY LEARNING FROM OUR FAILURES

time, extreme heterogeneity in course - Stages of illness (premorbid, prodrome, …), extreme heterogeneity in outcome - ranging from full recovery to ‘demence’. ÂÂ

CLINICAL PRACTICE GUIDELINES FOR TREATMENT OF DEPRESSION Shiv Gautam, ID Gupta, Manaswi Gautam, Anita Gautam, Akhilesh Jain, Tushar Jagawat (Jaipur), NN Raju (Visakhapatnam), SC Tiwari (Lucknow), Roop Sidhana (Sri Ganganagar), Vihang Vahia (Mumbai), TSS Rao (Mysore), Gautam Saha (Kolkata), Navendu Gaur (Ajmer), CL Narayaan (Patna) ÂÂ

Use of antidepressant drugs is recommended as the treatment of choice along with/or other patient centred therapies for every case of depression irrespective of the duration and severity.

ÂÂ

Treatment options including CBT and other therapies must be discussed before choosing line of treatment.

ÂÂ

All antidepressants are almost equally effective and their clinical benefits are comparable within and between various classes of the antidepressant drugs.

ÂÂ

Drug selection: As the newer drugs have a better side effect profile, safety and tolerability, they are preferred over the older drugs like TCAs and MAOIs (risk of adverse cardiac events, urinary retention, closed angle glaucoma and other cholinergic symptoms), TCAs may be preferred in patients of GI symptoms and pain disorders.

ÂÂ

Considerations that influence treatment selection: Past h/o response to antidepressant drug, comorbid mental and physical illness, h/o substance use current or in the past.

ÂÂ

Initially, the antidepressant drug should be administered in low dose and gradually stepped up till adequate response is elicited. Consider adjunct medication or switching the drug if no

Dr Rajiv Tandon, Florida ÂÂ

Translational Psychiatry - At the Cusp of Major Advances: Molecular neuroscience, neuroimaging and cognitive neuroscience, new technologies Epigenetics, ptogenetics, imaging genetics, ability to combine large datasets (OMICS) - Gen., Epigen., Prote., Metabol., Connect., etc.

ÂÂ

All we need to do is harness the opportunities to develop specific laboratory tests, better treatments, etc.

ÂÂ

Essentially, we have the same medications from the 1950s, with some minor tweaking. After the significant advances in the 1950s-60s, developments have stalled.

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Schizophrenia is clearly a brain disease; however, the precise nature is still being worked out.

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Clinical Nature of Schizophrenia: Admixture of positive, negative, cognitive symptoms, tendency towards chronicity, poor outcome, extreme heterogeneity in symptoms - Across patients, over

Reality of schizophrenia today: No specific marker - No diagnostic test; no necessary or sufficient pathology; no necessary or sufficient etiology despite impressive advances in available methods e.g., molecular biology, brain imaging; no compelling animal models. Modest improvements in outcome. Limited improvements in treatment.

Poor understanding of etiopathophysiological chain. Limited increase in understanding. Extreme heterogeneity.

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or inadequate response for 4-6 weeks or earlier as required.

After remission of symptoms, minimum effective dose at which the patient may have responded should be continued for minimum 6-9 months and then gradually tapered over 4-6 weeks.

In the event of recurrence of depression, treatment should be maintained for 2-5 years for 2nd or 3rd episode.

ÂÂ

In the event of more than three episodes, treatment may have to be maintained for 5 years or more.

ÂÂ

Psychotherapies for depressive disorders: Clinical management/psychoeducation, interpersonal therapy (IPT), cognitive therapy (CT), behavioral therapy (BT), marital therapy (MT), brief psychodynamic psychotherapy (BPD).

ÂÂ

Augmentation therapy: Lithium, quetiapine, aripiprazole, thyroxine, methylfolate, vitamin D3.

FROM GENOME TO PHENOME: LINKING GENES WITH BRAIN USING NEUROIMAGING Dr Naren P Rao, Bengaluru

Cancer Analogy ÂÂ

Postgenomic era: Genetic tests for molecular diagnostics, individualized pharmacotherapy Herceptin, prophylactic treatments - mastectomy for risk gene carriers.

ÂÂ

Psychiatry does not seem to benefit from the postgenomic era as desired.

(Asian J Neropsy Clin Neurosci. 2015)

Linking Genotype to Phenotype ÂÂ

ÂÂ

Clinical phenotypes: Based on existing nosological systems, highly variable, inherent diagnostic uncertainties, does not reflect pathophysiologic associations between behavior and genetics, product of complex interaction between gene and environment.

Need for better phenotype/intermediate phenotype.

Neuroimaging Modalities ÂÂ

Structural imaging: T1MRI - Grey matter, DT1 White matter.

ÂÂ

Functional imaging: fMRI BOLD signal, FDG PET - Metabolic imaging.

ÂÂ

Molecular imaging: PET, receptor mapping and molecular quantitation.

Genetic Analysis Techniques ÂÂ

Heritability studies: Twin studies: monozygotic vs. dizygotic.

ÂÂ

Linkage studies: Requires twin or pedigree design to compare.

ÂÂ

Association studies: Tests whether a genetic variation predicts phenotype.

ÂÂ

Genome-wide association studies (GWAS): Whole genome is analyzed.

ÂÂ

Single nucleotide polymorphisms: DNA sequence variation at a single nucleotide.

ÂÂ

Copy number variations: Structural variation in which large regions of genome are detected or duplicated.

Genome Wide - Whole Brain Analysis Hypothesis free analysis. Challenging because of the multiple testing problems arising from possibly billions of statistical tests to be performed. Specialized multivariate approaches are devised to overcome the multiple comparison problem.

Conclusion Combining the imaging and genetics generates greater insights in pathophysiology. Provides noninvasive approaches parallel to invasive approaches in animal models. Potential to generate biomarkers of clinical utility. May result in reconceptualization of nosological systems.

Preliminary results are promising but require further replications. Imaging genetics combines principles of genetics and imaging. Candidate/noncandidate genetics can be combined with candidate/whole brain phenotype. Promising results indicate feasibility of the approach. Potential to identify novel genes common to different disorders. More closer to genotype than the behavioral phenotype - intermediate phenotype.

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CONFERENCE PROCEEDINGS

22nd Annual Conference of Indian Society of Critical Care Medicine (Critical Care 2016) INFLUENZA UPDATE

ÂÂ

Dr Thierry Calandra, Switzerland ÂÂ

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Statements without consensus identify important areas for future research.

There are 3-5 million cases of severe influenza each year globally; 2,50,000-5,00,000 die due to influenza-related causes.

RESCUE THERAPY IN ARDS

Antigenic drifts (localized outbreaks) and shifts (epidemics, pandemics), constantly reemerging (H1N1, H5N1, H7N9, H10N8, …, H5N8, H5N2?)

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ARDS treatment remains supportive with low tidal volume ventilation and PEEP titration.

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Severe hypoxemia improves with prone positioning with mortality benefit. Recruitment maneuvers may be safely used to improve hypoxemia (no proven mortality benefit).

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Ventilator modes such as APRV can be beneficial in improving hypoxemia (no proven mortality benefit).

Active search for influenza in case of clinical suspicion in patients with fever and respiratory symptoms.

Dr Praveen Khilnani, New Delhi

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Prompt diagnosis (antigen, PCR) on respiratory samples, rapid TAT.

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Timing of therapy: Keep a low threshold for antiviral therapy, start early (empirical therapy, don’t wait for test results).

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HFOV continues to be used as rescue mode in pediatrics ARDS, though data from adult studies are discouraging.

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Antivirals: Neuraminidase inhibitors (oral or IV).

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Avoid steroids; IVIG in severely ill patients?

Use of corticosteroids remains controversial both in early and in late ARDS.

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Unresolved issues: Optimal route and duration of therapy, combination therapy?

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Several new antiviral agents are currently under investigation.

Venovenous ECMO is a valid life-saving option in severe intractable hypoxemia in adults and pediatric ARDS patients.

WORLDWIDE CONSENSUS ON PRINCIPLES OF END-OF-LIFE CARE

PANDEMICS: HOW TO PREPARE? Dr John C Marshall, Canada ÂÂ

Pandemics are a recurring reality of human existence.

ÂÂ

Clinical priorities in pandemic preparedness: Surge capacity planning, isolation and cohorting, healthcare worker protection, triage, illness of healthcare workers, research.

ÂÂ

We have only recently begun to think about how to address them.

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Research priorities in an emerging pandemic are identify the pathogen, define the epidemiology, understand mechanisms of pathogenesis, develop a diagnostic test and vaccine and ensure clinical capacity.

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Pandemic preparedness in the inter-pandemic period: Understand capacity and need, build large

Prof Dr Charles L Sprung, Israel ÂÂ

Although there are great differences among healthcare professionals because of culture, religion, region, training and background, the WELPICUS study was able to show that there is a consensus for most end-of-life practices in 32 countries.

ÂÂ

Consensus was found for the majority (95%) of the 81 definitions and consensus statements.

ÂÂ

The 4 statements where consensus could not be developed included: Withholding and withdrawing life-sustaining treatment, active shortening of the dying process and brain death.

ÂÂ

Statements achieving consensus provide standards of practice for end-of-life care.

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CONFERENCE PROCEEDINGS scale collaboration, harmonize data collection tools, etc., develop pre-approved protocols and platform research models - Observational studies and clinical trials. ÂÂ

Success in doing so will require new models of collaboration and funding.

COMPARING OUTCOMES FROM SEPSIS: ONE COUNTRY WITH ANOTHER Dr Kathy Rowan, UK ÂÂ

Sepsis is a syndrome that requires accurate data and a robust, reproducible definition to identify cases and their outcomes.

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Case mix varies - infection (source) and organ dysfunction (number/type) - and impacts mortality/ other outcomes and should be reported.

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Adequate specific treatment is of upmost importance not only in an individual basis but also in a population basis.

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We must carefully assess the need for fluid replacement therapy.

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Transfusions, as always, should be restricted.

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WHO goals might be to hard to get, but it is worth trying!

CO2 REMOVAL IN VENTILATION Dr Farhad Kapadia, Mumbai ÂÂ

CO2 is tightly controlled physiologically and variations are poorly tolerated.

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CO2 management with mechanical ventilation occurs in various clinical settings.

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Chronic hypercapnia syndromes: Spontaneous and noninvasive modes preferred, target symptoms not CO2 levels, home BiPAP improves QOL, daytime symptoms and may decrease CAD & CCF.

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In severe acute asthma, target PEEPa and hemodynamic parameters and not normocarbia.

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Dr Sheila Nainan Myatra, Mumbai

In ARDS, try to maintain normal pH but not at cost of high TV or PAP; consider extracorporeal options.

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Some components quality of dying may be difficult or even impossible to measure.

Is CO2 removal an important goal in ventilation? Yes (& No) Treat the patient and not the number…

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It may be that dying experiences are so heavily influenced by the culture in which they occur that any measure must be adapted to specific circumstances.

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Comparisons should adjust for severe sepsisspecific case mix (not solely risk based on our generic risk prediction models).

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Think before interpreting variation either between reports or within reports, over time.

DEATH IN ICU: AN IMPORTANT QUALITY INDICATOR

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The development of reliable, valid and responsive measures of the quality of dying important goals that will better enable us to identify interventions to improve these critical aspects of healthcare and the human experience.

CONTINUOUS EEG MONITORING IN SE Dr Sudhir Kumar, Kolkata

Let’s change the way to approach/treat Neurocritical patient… ÂÂ

Continuous EEG (cEEG) is usually required for the treatment of SE (strong recommendation, very low quality).

QOD may be an important quality indicator in ICU.

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“Not everything that counts can be measured. Not everything that can be measured counts.”

cEEG monitoring should be initiated within 1 h of SE onset if ongoing seizures are suspected.

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Duration of cEEG monitoring should be at least 48 h in comatose patients to evaluate for nonconvulsive seizures (strong recommendation, low quality).

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The person reading EEG in the ICU setting should have specialized training in cEEG interpretation, including the ability to analyze raw EEG as well as quantitative EEG tracings (strong recommendation).

ÂÂ

Despite these strength cEEG is still not part of standard monitoring in ICU.

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—Albert Einstein MALARIA MANAGEMENT Dr Flávia Machado, Brazil ÂÂ

Severe malaria represents a huge burden in our countries.

ÂÂ

The assessment of severity is necessary to prioritize ICU admission.

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Indian Journal of Clinical Practice, Vol. 27, No. 3, August 2016

CONFERENCE PROCEEDINGS CRITICAL PEARLS

CPR GUIDELINES 2015: WHAT’S NEW? Dr Manish Munjal, Jaipur

ÂÂ

Give KCl through a central venous catheter for lifethreatening hypokalemia.

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Consider calcium administration for hyperkalemia with ECG changes, followed by interventions to shift K intracellularly.

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Dr Anand Marutirao Nikalje, Aurangabad ÂÂ

Compression rate must be between 100-120 and not >120.

ÂÂ

Compression depth should be between 5-6 cm and not >6 cm.

Limit the increase in serum Na to 8-12 mmol/L in the first 24 h in symptomatic euvolemic hyponatremia.

ÂÂ

Vasopressin algorithm.

ÂÂ

Administer normal saline to patients with hypernatremia and hemodynamic instability.

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Naloxone can be used by trained rescuers in patients with high risk of opioid ingestion.

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Patients with possible adrenal insufficiency should have emergent treatment with a glucocorticoid.

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Treatment goals for hyperglycemic syndromes are to restore fluid and electrolyte balance, provide insulin and identify precipitants.

Targeted temperature management (TTM) is recommended post-CPR status between 32-36ºC for the first 24 hours.

is

being

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ACLS

RESEARCH IN RESOURCE-LIMITED SETTINGS

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In DKA, insulin infusion should be continued until acidosis and ketosis have resolved.

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Maintain glucose 250-300 mg/dL in HHS until plasma osmolality £315 mOsm/kg.

ÂÂ

Several opportunities exist in neglected diseases and in healthcare delivery.

ÂÂ

Choose a protocol for glycemic control to avoid hyperglycemia and minimize hypoglycemia in critically ill patients.

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We must learn to accept original research done in India and provide prominent platform for researchers to present their work, allow for interaction between researcher and other professional and accept Indian data and research rather than ask if there is any data from the US or Europe.

Dr Dilip R Karnad, Thane

SEPSIS IN THE ELDERLY Prof Dr Charles L Sprung, Israel ÂÂ

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Despite the fact that individuals >65 years account for only 1/8th of the US population, they account for 2/3rd of all sepsis cases.

Increases in the incidence of sepsis are weighted toward the elderly population where incidence rates are rising the fastest.

ÂÂ

Age is an independent predictor of death in septic patients.

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Elderly patients die earlier during sepsis-related hospitalizations and elderly survivors require more skilled nursing or rehabilitative care after hospitalization.

ÂÂ

Increasing life expectancy and greater rates of sepsis in the elderly will increase the need for ICUs in the future.

HOW TO COMBAT ANTIMICROBIAL RESISTANCE? Dr Tom van der Poll, The Netherlands ÂÂ

Antibiotic resistance is one of the biggest threats to global health today. It occurs naturally, but misuse of antibiotics in humans and animals is accelerating the process.

ÂÂ

A growing number of infections are becoming harder to treat as the antibiotics used to treat them become less effective.

ÂÂ

Multiple interventions can help in diminishing antimicrobial resistance, especially adequate use of antibiotics.

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285

CONFERENCE PROCEEDINGS

National Interventional Council Mid-Term Meet 2016 TIPS OF MANAGING COMPLICATIONS

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There are few clinical situations other than those mentioned above such as prosthetic valve replacement, VTE, persistent severe CHF, which warrant perpetual or longtime OAC. If they get complicated by coronary disease requiring PCI with stents, antiplatelet agents are added to OAC by default.

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However, thrombotic risk and bleeding risk must be balanced critically based on scoring systems like CHA2DS2-VASc and HAS-BLED. Based on the level of risk on both aspects as well as the type of stent BMS or DES, duration of triple anticoagulation therapy is determined for 1 month/3 months/6 months or 12 months. After 12 months, usually OAC alone is continued.

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SAMeTT2R score helps in determining whether VKA or NOACs will be suitable for a particular patient.

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CKD and varying eGFR influence duration of withholding of the OAC prior to any elective surgery.

Dr Sanjay Chugh, Gurgaon ÂÂ

Complications occur rarely in transradial interventions. Most can be prevented with preprocedure planning, training and experience.

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Though survival is better with transradial interventions compared to transfemoral, crossover or converting to femoral access because of failure to complete the case through radial is associated with higher mortality (Heart. 2016). So, it is imperative not to fail in a transradial PCI.

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Using a pre-procedure ultrasound helps choose the straightest and biggest access artery in the forearm, which minimizes risk of procedure failure or other complications such as spasm, bleeding or radial artery occlusion.

Other tips include choosing an appropriate sheath size and catheter curve size and shape to minimize catheter exchanges.

Risk of a rare forearm hematoma can be minimized by vigilance, including palpation of the forearm, because by the time a swelling is visible, it is too late.

Prompt action including inflating a sphygmomanometer cuff in the arm to above systolic pressure with intermittent short deflations and compression along the length of radial artery in forearm using gauze balls, and an elastic bandage over it to spare the ulnar to perfuse the hand is useful in checking a hematoma from developing.

This is important to prevent the rare devastating complication of compartment syndrome.

TRIPLE ANTICOAGULATION THERAPY IN CARDIAC INTERVENTIONS Dr Mrinal Kanti Das, Kolkata ÂÂ

286

Interventions in managing various cardiac diseases have become routine now-a-days. PCI in ACS is one of the commonest device therapies and requires DAPT routinely as a guideline-directed approach. However, some patients might develop either nonvalvular AF or intramural LV thrombus with potential to cause thromboembolism. These patients require triple anticoagulation therapy.

Indian Journal of Clinical Practice, Vol. 27, No. 3, August 2016

CAN INDIGENOUS STENTS COMPARE WITH BEST OF BEST? Dr Sundeep Mishra, New Delhi ÂÂ

Indigenous stents are very competitive in pricing.

ÂÂ

Indigenous stents do not lack in innovation.

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Biomime stents (Meril LifeSciences) have lower strut thickness (65 µm), lower polymer coat (2 µm), intelligent stent design and morphology-mediated expansion.

ÂÂ

Supracore stent (Sahajanand Tech) has even lower strut thickness (65 µm) and low polymer coat (5 µm).

ÂÂ

Yukon Choice PC (Translumina therapeutics) has microporous reservoirs on stent surface, which markedly reduces the requirement of polymer.

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GENX-Sync from MIV therapeutics, Surat, also has a lower strut thickness and polymer coat.

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MeRes, the bio-bsorbable scaffold from Meril LifeSciences has technical specifications which are even superior to currently available BVS: lower scaffold thickness (65 µm), lower polymer coat

CONFERENCE PROCEEDINGS (2 µm), lower crimp profile (1.4 mm), but higher radiopacity and more markers as well as wider range of sizes. ÂÂ

Indigenous stents are however, lacking in clinical data.

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Yukon DES is the only indigenous stent, which has extensive data.

ADVANCES IN INTERVENTIONAL CARDIOLOGY Dr Balbir Singh, Gurgaon Innovations in interventional cardiology have widened its scope of practice. With new technology, newer devices have become available to the interventional cardiologist, which have further facilitated and enhanced nonsurgical management of heart diseases.

TAVI, via transapical or transfemoral approach, is now a standard of care of patients with severe symptomatic aortic stenosis who are at a high surgical risk or are inoperable. TAVI devices have also undergone modifications to either circumvent or reduce the problems associated with the first-generation TAVI devices viz. ability to reposition the valve before final deployment, features to reduce paravalvular leakage and introduction of low-profile delivery systems. The two most widely used valves for TAVI are the CoreValve (self-expanding) and the Balloon expanding valve.

The CoreValve US Pivotal High Risk study was the first major trial to demonstrate superiority of TAVI vs SAVR and showed superior hemodynamics, lower stroke rate, low rates of PVL and superior survival at 2 years. TAVI was safe and effective in patients at extreme risk of surgery in the CoreValve US Pivotal Trial Extreme Risk study. This was achieved with a low rates of stroke and paravalvular leak that improved with time. Favorable long-term outcomes, at 4 years, after successful TAVI using the third-generation Medtronic CoreValve device in high-risk patients with severe aortic stenosis have been reported (Age Ageing. 2016 Mar 24).

TAVI has shown noninferiority vs. SAVR in high-risk patients in trials and the indication may be expanded to intermediate-risk patients as evident by the results of the PARTNER 2 trial presented at ACC 2016, which showed TAVR as a reasonable alternative to SAVR in intermediate-risk patients and may be superior when using a transfemoral approach. TAVI may in due course of time be further expanded to low-risk patients in the future.

Most strokes in AF result from thrombus formation in the LAA. And, LAA closure with a device is a safe and

effective alternative to oral anticoagulation, especially when they are contraindicated or in cases at high bleeding risk. PROTECT-AF was the first randomized study to demonstrate the noninferiority of LAAC with Watchman device to warfarin for all-cause stroke and all-cause death point in patients with nonvalvular AF. A study in March 2016 issue of Catheter Cardiovascular Interventions has reported feasibility and safety of LAAC with the fourth-generation Watchman device. These trials provide evidence that LAAC with device therapy may be a viable alternative to chronic warfarin therapy for stroke reduction in nonvalvular AF patients.

DES have been a major advancement to prevent restenosis and repeat revascularization after PCI and are regarded as the standard of care for patients with diabetes undergoing stenting. Concerns about late and very late stent thrombosis with first-generation DES led to the second-generation DES, with novel stent design/ material, improved polymer biocompatibility and novel antiproliferative drugs (zotarolimus, everolimus) to improve acute performance and long-term outcome.

Zotarolimus-eluting stent (ZES) is the first and only FDA approved DES for use in CAD patients with diabetes.

It has a new hydrophilic biocompatible polymer that provides extended release of zotarolimus over about 180 days, unlike everolimus-eluting stents (EES), where everolimus is eluted over 60 days. The prolonged release of ZES enhances prevention of restenosis and reduces stent thrombosis.

HYBRID DES FOR STEMI PATIENTS Dr Rishi Sethi, Lucknow STEMI confers an increased risk of adverse outcome compared to stable CAD, which extends beyond the periprocedural phase of pPCI. Biodegradable polymer-

Indian Journal of Clinical Practice, Vol. 27, No. 3, August 2016

287

CONFERENCE PROCEEDINGS based metallic DES have been observed to reduce MACE compared to BMS among patients with STEMI undergoing pPCI at 1 year.

New-generation DES with cobalt-chromium platforms, reduced stent strut thickness and biocompatible polymers have been shown to be safe and effective in unselected patient populations and represent the current standard of care in patients undergoing PCI. Orsiro Hybrid DES, the combination of biodegradable polymers with thin strut cobalt-chromium platforms, represents the next iteration of technological progress.

Data from the randomized-controlled BIOSCIENCE study confirm that Orsiro Hybrid DES, an ultrathin strut cobalt-chromium stent releasing sirolimus from a biodegradable poly-L-lactic acid (PLLA) polymer (BP-SES) was noninferior compared to a thin strut DPEES in a patient population (n = 407) reflecting routine clinical practice. At 1 year, TLF occurred in seven (3.4%) patients treated with BP-SES and 17 (8.8%) patients treated with DP-EES, which was statistically significant (RR 0.38, 95% CI: 0.16-0.91, p = 0.024). Rates of definite and probable stents thrombosis were 1.4% for Orsiro and 4.7% for DP-EES in the STEMI patients. It was concluded that Orsiro Hybrid DES may be associated with improved clinical outcomes vs. DP-EES among STEMI patients undergoing pPCI.

SHOULD ALL TRANSFEMORALISTS KNOW TRANSRADIAL INTERVENTION? Dr Suresh Kaul, Pathankot ÂÂ

Have shifted to transradial approach in our primary PCI/STEMI interventions, despite cardiogenic shocks and complete heart blocks in most of our cases.

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In acute situations, alternative plans are a must…… thinking should never stop.

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Dogmas increase procedural time, contrast load and complications.

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If one route is troublesome, take another.

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Know all routes … and in STEMI, take the quickest and most straightforward route.

DOUBLE TROUBLE Dr Saroj Mandal, Kolkata ÂÂ

Prompt diagnosis and urgent stabilization of patient is the most important step in management.

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Development of pericardial tamponade carries a high mortality.

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While prompt surgical intervention may be needed and may be lifesaving in some cases, expertise in the use of covered stents may provide a valuable rescue option for this serious complication.

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Indian Journal of Clinical Practice, Vol. 27, No. 3, August 2016

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Asian Journal of Diabetology

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Emerging role of Cardiac MRI in Ischemic and Non-ischemic Cardiomyopathy

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Acute Renal Failure and Silent Myocardial Infarction Following Multiple Honey Bee Stings

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Superficial Brachial Artery: Its Embryological and Clinical Significance

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Glucose Tolerance in Nondiabetic Patients after First Attack of Acute Myocardial Infarction and its Outcome

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A Case of Left Atrial Myxoma Presenting as Severe Pulmonary Hypertension

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Double-Chambered Right Ventricle with Transient 2:1 Atrioventricular Block: A Rare Presentation

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Cornary Artery Air Embolism

Volume 17, Number 5

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January-March 2015

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AROUND THE GLOBE

News and Views In a First, Kerala Imposes 14.5% ‘Fat Tax’ on Junk Food

Study Finds no Link to Parkinsonism with Gadolinium

In a first-of-its-kind move in the country, Kerala has introduced a ‘fat tax’ on the consumption of junk food items like pizzas and burgers sold through branded restaurants. The newly-elected government imposed 14.5% tax on branded restaurants selling items like tacos, pizzas, burgers, sandwiches, among others. The announcement was made by state finance minister Thomas Isaac as a part of the newly-elected LDF government’s first State Budget presentation after being elected to power… (Business Standard, July 8, 2016)

A population-based study which evaluated the association between gadolinium exposure and Parkinsonism has concluded that there is no significant association between exposure to gadolinium-based contrast agents and Parkinsonism, with symptoms as abnormal gait, trouble with voluntary movements, and tremors. Results of the analysis were published online July 5, 2016 in JAMA.

El Niño Subsides But Impact on Children Set to Worsen as Disease, Malnutrition Spread: UNICEF

Outpatients with heart failure with recovered ejection fraction (HFrecEF) have a different clinical course than patients with HFpEF and HFrEF, with lower mortality, less frequent hospitalizations and fewer composite endpoints. In a retrospective study from a single, academic medical center reported July 06, 2016 in JAMA Cardiology, almost 43% of heart failure patients with left ventricular ejection fraction (LVEF) exceeding 40% were found to have recovered LVEF, rather than persistently preserved LVEF.

According to a new report titled ‘It’s not over - El Niño’s impact on children’ from the United Nations Children’s Fund (UNICEF), while the 2015-2016 El Niño - one of the strongest on record - has ended, its devastating impact on children is worsening, as hunger, malnutrition and disease continue to increase following the severe droughts and floods spawned by the event. Making matters worse, there is a strong chance La Niña - El Niño’s flip side - could strike at some stage this year, further exacerbating a severe humanitarian crisis that is affecting millions of children in some of the most vulnerable communities. In many countries, El Niño affected access to safe water, and has been linked to increases in diseases such as dengue fever, diarrhea and cholera, which are major killers of children. According to UNICEF, in South America, and particularly Brazil, El Niño has created favorable breeding conditions for the mosquito that can transmit Zika, dengue, yellow fever and chikungunya… (UN)

Omega-3 may Reduce Risk of Fatal Heart Attack A pooled study of 19 international cohorts of middleaged and older people with no prior heart disease published June 25, 2016 in JAMA Internal Medicine found that higher levels of omega-3 polyunsaturated fatty acids (PUFAs) were linked with a lower risk of having a fatal cardiac event within 10 years, but this was not true for nonfatal MI. For every 1-standard-deviation increase in levels of seafood-derived docosapentaenoic acid (DPA), docosahexaenoic acid (DHA) or plant-derived α-linolenic acid (ALA), risk of death from MI during follow-up individuals was lower by 9%.

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Indian Journal of Clinical Practice, Vol. 27, No. 3, August 2016

Recovered Ejection Fraction, a New Category in Heart Failure

New IVF Screening Method may Identify Most Viable Embryos Embryos with higher levels of mitochondrial DNA may be less likely to lead to a pregnancy during an IVF cycle. Of all the embryos with normal or low levels of mitochondrial DNA, 76% implanted successfully and led to an ongoing pregnancy compared with 0% of embryos with elevated mitochondrial DNA levels. The results of this small prospective study were presented at the recent European Society of Human Reproduction and Embryology annual meeting in Helsinki, Finland.

NAFLD Responds to Moderate Exercise Both moderate and intense exercise appeared to be equally effective in cutting intrahepatic triglyceride content in patients with nonalcoholic fatty liver disease (NAFLD). A study from China reported in 5 July, 2015 in JAMA Internal Medicine, among 220 patients in China randomized to vigorous then moderate exercise, moderate exercise or no exercise, intrahepatic triglyceride content was reduced by 5.0% in the vigorous exercise group and by 4.2% in the moderate exercise

AROUND THE GLOBE group after 1 year compared with the control group with no exercise.

FDA Approves the First Retinoid for OTC Use in Acne The US Food and Drug Administration has approved Differin Gel 0.1% (adapalene), a once-daily topical gel for the over-the-counter (OTC) treatment of acne. It is approved for use in people 12 years of age and older.

The drug should be applied once-daily in a thin layer on the affected areas of skin, and it is for external use only. People using Differin Gel 0.1% should avoid sunburn and avoid product contact with their eyes, lips and mouth.

Global Conference Sets Health Action Agenda for the Implementation of the Paris Agreement The Second Global Conference on Health and Climate, held in Paris, France has proposed key actions for the implementation of the Paris agreement to reduce health risks linked to climate change. It is predicted that by the year 2030, climate change will cause an additional 250,000 deaths each year from malaria, diarrheal disease, heat stress and undernutrition alone.

The conference highlighted the benefits of switching to cleaner energy sources to reduce levels of climate and air pollutants, as well as providing desperately needed power for health facilities in low-income countries. It also recommended that the health sector should themselves make a greater effort to promote low-carbon healthcare facilities and technologies; these can simultaneously improve service delivery and reduce costs as well as climate and environmental impacts. Participants recommended moving to more sustainable food production and healthier diets to improve the environment and reduce noncommunicable diseases. One way to do this would be to promote diets rich in fruits and vegetables including local in-season varieties… (WHO, 8th July, 2016)

New ACC Guidelines on Use of Nonstatin Cholesterol-lowering Drugs The American College of Cardiology (ACC) has released an “Expert Consensus Decision Pathway” document on the role of nonstatin therapies for lowdensity lipoprotein (LDL) cholesterol-lowering in the management of cardiovascular disease risk. The algorithms in the new guidelines endorse the four evidence-based statin benefit groups identified in the 2013 ACC/AHA cholesterol guidelines and assume that the patient is currently taking or has attempted

to take a statin, given that this is the most effective initial therapy. Two different algorithms for familial hypercholesterolemia are included. In patients with diabetes and other high-risk groups who do not already have cardiovascular disease, other drugs can be considered if LDL has not been reduced by 50% with lifestyle modification and statins. The guidelines are published in the July 5 issue of the Journal of the American College of Cardiology (JACC).

India has Nearly 21 Lakhs HIV-positive Patients India has nearly 21 lakhs HIV-positive patients in the country and about 7 lakhs of them are not even aware of their HIV-positive status. Speaking at a function to launch ‘HIV prevention, treatment and care program for Punjab prisons’ in Chandigarh on Saturday, Additional Secretary, Health cum Director General NACO (National Aids Control Organization) Navreet Singh Kang said that there was an immediate need to identify the HIVpositive patients and start their treatment. The ‘National Prison HIV Strategy’ is being implemented in a phased manner in the country. In Phase-1, ‘HIV interventions in prison settings’ project was launched in February this year in 8 northeastern states and is now being launched for Punjab and Chandigarh prisons, he further added. …. (Economic Times – IANS)

Draft Code of Practice of National Technical Advisory Group on Immunization Issued The Union Health Ministry has issued draft code of practice of National Technical Advisory Group on Immunization (NTAGI) which contains information about the responsibilities, structure, functioning and procedures of the NTAGI and Standing Technical Sub-Committee (STSC). The NTAGI provides guidance and advice to the ministry on provision of vaccination and immunization services for the effective control of vaccine preventable diseases (VPDs) in the country. The STSC is tasked with undertaking technical review of scientific evidence on matters related to immunization policy and programs. Comments and feedback on the draft guidelines are invited from all stakeholders by August 4, 2016... (Pharmabiz, Ramesh Shankar, July 11, 2016)

MRD Monitoring is an Important Prognostic Factor in Older Multiple Myeloma Patients A new study published in the journal Blood says that the second-generation 8-marker multiparameter flow cytometry (MFC) is more sensitive and specific than 4-marker flow monitoring to identify multiple myeloma patients with lower minimal residual disease (MRD)

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AROUND THE GLOBE levels of <10–4. Second-generation MFC immune profiling concomitant to MRD monitoring also helped to identify patients with different outcomes.

Bottle Size may be a Modifiable Risk Factor for Rapid Infant Weight Gain Using a large bottle in early infancy independently contributed to greater weight gain and change in weightfor-length Z score at the 6-month visit, reported a study in July 2016 issue of Pediatrics. The study used data from the Greenlight Intervention Study, a cluster randomized trial to prevent childhood obesity at 4 pediatric resident clinics. The authors suggest that growth in infancy is a complex process, but, bottle size may be a modifiable risk factor for rapid infant weight gain and later obesity among exclusively formula-fed infants.

Cardiovascular Risk Factors Impact Duration of Hospitalization and Mortality in ACS Patients According to a study reported June 26, 2016 in the International Journal of Cardiology, risk factors for cardiovascular disease such as diabetes, both type 1 and 2, hypertension, hyperlipidemia have a significant and varied impact on duration of hospitalization and mortality in patients with acute coronary syndrome (ACS) and it may be inappropriate to group them when assessing in-hospital risk. These factors should be used to identify patients at an increased risk of prolonged admissions and death post-ACS, and services should be directed accordingly.

White Matter Changes Persist After Concussion Results of a small single-center case-control study presented at the American Academy of Neurology’s Sports Concussion Conference in Chicago indicate that young athletes who had a concussion still had changes in the white matter of their brains 6 months after their injury, even though they no longer had symptoms. These findings may influence management of athletes who have experienced a sports-related concussion.

Study Identifies Clinical Characteristics of Young Type 2 Diabetes Patients with Atherosclerosis Young type 2 diabetes patients with atherosclerosis have more adverse cardiovascular risk profiles (weight, hyperlipidemia) and inadequate control of these risk factors compared to older type 2 diabetes patients with atherosclerosis. The ratio of the presence of atherosclerosis in the lower extremity arteries alone was significantly higher in young patients than older patients (26.4% vs. 14.0%). These findings are published July 8, 2016 in the journal PLoS One.

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Prognostic Significance of IgG in SLE-AIH Initially high levels of serum IgG are a poor prognostic factor for autoimmune hepatitis combined with systemic lupus erythematosus. A serum IgG level more than 2-fold the upper normal limit was associated with a high risk of cirrhosis in autoimmune hepatitis combined with systemic lupus erythematosus. The study published in the July 2016 issue of the journal Arthritis Care & Research also suggests that the long-term outcome for these patients might be better than for those with primary autoimmune hepatitis.

UNDP Projects India to Dominate Growth in the Working-age Population India is projected to dominate the growth in the workingage population in Asia-Pacific by 2050, becoming home to over a billion people eligible to enter the job market.

The United Nations Development Program (UNDP) underlined in its latest Regional Human Development Report that Asia-Pacific countries now have more working-aged people and fewer dependents than at any point in history, providing a springboard for growth.

Region-wide, 68% of people are of working age and only 32% are dependents. Asia-Pacific’s population size has tripled in the last 65 years, and is expected to reach 4.84 billion in 2050. The working-age population in the region, comprising 58% of the global total, continues to grow, the report said. China and India comprised 62% of the region’s share in 2015, with a billion and 860 million workers, respectively… (First Post)

UN Launches New ‘Sendai Seven’ Campaign to Improve Disaster Risk Management The United Nations has launched a new multi-year campaign that aims to reduce disaster losses, improve management of disaster risk, and save lives. The ‘Sendai Seven’ campaign is an advocacy initiative to encourage implementation over the next 7 years of the Sendai Framework for Disaster Risk Reduction, which was adopted by UN Member States in 2015 in the northern Japanese city after which it was named, and consists of 7 targets and 4 priorities for action that aim for the substantial reduction of disaster risk and losses in lives, livelihoods and health and in the economic, physical, social, cultural and environmental assets of persons, businesses, communities and countries. Specifically, the Sendai Framework aims to: ÂÂ

Substantially reduce global disaster mortality by 2030, aiming to lower average per 1,00,000 global mortality rate in the decade 2020-2030 compared with the period 2005-2015.

AROUND THE GLOBE ÂÂ

Substantially reduce the number of affected people globally by 2030, aiming to lower average global figure per 1,00,000 in the decade 2020-2030 compared to the period 2005-2015.

ÂÂ

Reduce direct disaster economic loss in relation to global gross domestic product (GDP) by 2030.

ÂÂ

Substantially reduce disaster damage to critical infrastructure and disruption of basic services, among them health and educational facilities, including through developing their resilience by 2030.

ÂÂ

Substantially increase the number of countries with national and local disaster risk reduction strategies by 2020.

ÂÂ

Substantially enhance international cooperation to developing countries through adequate and sustainable support to complement their national actions for implementation of this Framework by 2030.

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Substantially increase the availability of and access to multi-hazard early warning systems and disaster risk information and assessments to the people by 2030.

(UN, 11th July, 2016)

CDC Cautions Against Using Oral Liquid Docusate Stool Softener in Any Patient US health officials are continuing to investigate a multistate outbreak of infections caused by Burkholderia cepacia complex possibly linked to contaminated oral liquid docusate stool softener products. The Centers for Disease Control and Prevention (CDC) has advised against treating any patient with oral liquid docusate products in its July 8 update. The CDC has confirmed that two samples of unused oral liquid docusate product received from one of the affected hospitals have tested positive for B cepacia complex.

Recurrent Diabetic Ketoacidosis Raises Mortality Risk in Type 1 Diabetes A retrospective cohort study published in the journal Diabetologia has found that recurrent episodes of diabetic ketoacidosis (DKA) were associated with a substantially increased risk of death in patients with type 1 diabetes.

Patients with a single hospitalization for DKA during the study period had a 5.2% risk of death vs. 23.4% risk of death for patients hospitalized for DKA more than five times. Younger patients, socially disadvantaged adults and those who had very high A1c levels were at greater risk of recurrent hospital admissions for DKA. Also,

antidepressant use was greater in those with recurrent DKA than those with a single episode.

Sildenafil Prolongs Pregnancy in Women with Pre-eclampsia Therapy with sildenafil citrate was associated with pregnancy prolongation of approximately 4 days compared with placebo in women with pre-eclampsia, says a new study published online July 7, 2016 in Obstetrics & Gynecology. According to the randomized controlled trial, sildenafil citrate causes higher percent reduction in pulsatility indices of uterine and umbilical arteries and also decreases maternal mean blood pressure.

First MRI-guided Focused Ultrasound Device to Treat Essential Tremor The US Food and Drug Administration (FDA) has approved ExAblate Neuro, the first focused ultrasound device to treat essential tremor in patients who have not responded to medication.

ExAblate Neuro uses magnetic resonance (MR) images taken during the procedure to deliver focused ultrasound to destroy brain tissue in a tiny area thought to be responsible for causing tremors. To determine if the ExAblate Neuro treatment is appropriate, patients should first have MR and computerized tomography (CT) scans.

This treatment is contraindicated for patients who cannot have MR imaging (MRI), including those who have a non-MRI compatible implanted metallic device, such as a cardiac pacemaker, those with allergies to MR contrast agents or those with body size limitations for MR. It should also be avoided in pregnant women, patients with advanced kidney disease or on dialysis, those with unstable heart conditions or severe hypertension, alcohol or substance abuse or patients with a history of abnormal bleeding, hemorrhage and/or blood clotting disorders (coagulopathy).

Ventricular Arrhythmias are Common After LVAD A small retrospective study has observed that ventricular arrhythmias were common after getting a continuousflow left ventricular assist device (LVAD) but were not associated with death, heart transplantation. Over a median follow-up of 17.3 months, 30.4% of LVAD recipients had ventricular arrhythmia in the study reported online July 2016 issue of the Journal of the American College of Cardiology.

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AROUND THE GLOBE External Fixation is More Suitable for Intraarticular Fractures of the Distal Radius in Elderly Patients A study published online 21 June 2016 in the journal Bone Research suggests that internal fixation was more advantageous than external fixation in the early rehabilitation period. Patients in the plating group had slightly better range of motion at three months and slightly better grip strength at 6 months, compared with patients in the external fixation group, but the outcomes were similar after 1 year. There were, however, notable differences in complications between the groups. The plating group had significantly higher levels of wound infection and tendonitis and required more additional surgeries.

New Strategies to End Violence Against Children The WHO has defined 7 interlinked strategies to reduce violence against children, with an aim to reduce instances of violence against children. According to a recent study “Global Prevalence of Past-year Violence Against Children: A Systematic Review and Minimum Estimates” published in the March 2016 issue of the journal Pediatrics, up to 1 billion children have experienced physical, sexual or psychological violence in the last year. Homicide is among the top 5 causes of death for adolescents. The 7 strategies highlighted in the “INSPIRE” package are: 1. Implementation and enforcement of laws: such as those limiting access by young people to firearms and other weapons (South Africa) and those criminalizing the violent punishment of children by parents (many European countries).

2. Norms and values: by changing beliefs and behaviors around gender roles (India, South Africa, Uganda and the United States).

3. Safe environments: by targeting violent “hotspots” and enhancing the built environment, for example, by improving housing (Colombia, United Kingdom, and the United States).

4. Parent and caregiver support: such as the provision of training in parenting (Kenya, Liberia, Myanmar, South Africa, Thailand, and the United States).

5. Income and economic strengthening: including microfinance combined with training around gender

norms (Afghanistan, Cote d’Ivoire, South Africa, Uganda, and the United States).

6. Response and support services: such as treatment programmes for juvenile offenders (many European countries and the United States).

7. Education and life skills: for example, establishing a safe school environment and improving children’s life and social skills (China, Croatia, South Africa, Uganda, and the United States).

These strategies have been developed by WHO in collaboration with partners including: End Violence Against Children, Together for Girls, UNICEF, United Nations Office on Drugs and Crime (UNODC), US Agency for International Development (USAID), US Centers for Disease Control and Prevention (CDC), US President’s Emergency Plan for AIDS Relief (PEPFAR), and the World Bank.

(Source: WHO, 12th July, 2016)

Tobacco Use, Involuntary Secondhand Smoke Exposure High in Multiunit Housing: CDC A study published July 13, 2016 in the American Journal of Preventive Medicine says that individuals who live in multiunit housing, such as apartments and condominiums, are more likely to use tobacco products and less likely to have smoke-free home rules than people living in single-family housing. The study, which used data from the 2013-2014 National Adult Tobacco Survey found that 25% of adults aged 18 years and older who lived in multiunit housing used a tobacco product, compared with 19% of adults in single-family homes; 20% of adults in multiunit housing used combustible tobacco products, which are a source of secondhand smoke exposure. And, about 34% of multiunit housing residents who have adopted voluntary smoke-free home rules have recently been exposed to secondhand smoke that entered their living unit from nearby living units or shared areas.

Corinne Graffunder, Dr PH, director of CDC’s Office on Smoking and Health said, “These findings show the importance of protecting all people who live in multiunit housing through smoke-free building policies and access to tobacco cessation resources.”… (CDC)

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INSPIRATIONAL STORY

This Too Shall Pass

O

nce a King called upon all of his wise men and asked them, “Is there a mantra or suggestion which works in every situation, in every circumstance, in every place and in every time? In every joy, every sorrow, every defeat and every victory? One answer for all questions? Something which can help me when none of you is available to advise me? Tell me is there any mantra?”

All the wise men were puzzled by the King’s question.

They thought and thought. After a lengthy discussion, an old man suggested something which appealed to all of them. They went to the King and gave him something written on paper, with a condition that the King was not to see it out of curiosity.

Only in extreme danger, when the King finds himself alone and there seems to be no way, only then he can see it. The King put the papers under his Diamond ring.

Sometime later, the neighbors attacked the Kingdom.

King and his army fought bravely but lost the battle.

The King had to flee on his horse. The enemies were following him…getting closer and closer. Suddenly the King found himself standing at the end of the road that road was not going anywhere. Underneath there was a rocky valley thousand feet deep. If he jumped into it, he would be finished…and he could not return because it was a small road…the sound of enemy’s horses was approaching fast. The King became restless.

There seemed to be no way.

Then suddenly he saw the Diamond in his ring shining in the sun, and he remembered the message hidden in the ring. He opened the diamond and read the message.

The message was - “This too Shall Pass”.

The King read it. Again read it. Suddenly something struck him, “Yes! This too will pass. Only a few days ago, I was enjoying my Kingdom. I was the mightiest of all the Kings. Yet today, the Kingdom and all his pleasure have gone. I am here trying to escape from enemies. Like those days of luxuries have gone, this day of danger too will pass.” A calm came on his face. He kept standing there. The place where he was standing was full of natural beauty. He had never known that such a beautiful place was also a part of his Kingdom.

The revelation of the message had a great effect on him.

He relaxed and forgot about those following him. After a few minutes he realized that the noise of the horses and the enemy coming was receding. They moved into some other part of the mountains and were nowhere near him. The King was very brave. He reorganized his army and fought again. He defeated the enemy and regained his empire. When he returned to his empire after victory, he was received with much fanfare. The whole capital was rejoicing in the victory.

Everyone was in a festive mood. Flowers were being showered on King from every house, from every corner. People were dancing and singing. For a moment King said to himself, “I am one of the bravest and greatest Kings”. It is not easy to defeat me. With all the reception and celebration he saw an ego emerging in him. Suddenly, the Diamond of his ring flashed in the sunlight and reminded him of the message. He opened it and read it again: “This too Shall Pass”.

He became silent. His face went through a total change from the egoist he moved to a state of utter humbleness.

If this too is going to pass, it is not yours. The defeat was not yours, the victory is not yours. You are just a watcher. Everything passes by. We are witnesses of all this. We are the perceivers. Life comes and goes.

Happiness comes and goes. Sorrow comes and goes.

Now as you have read this story, just sit silently and evaluate your own life. This too will pass. Think of the moments of joy and victory in your life. Think of the moment of Sorrow and defeat. Are they permanent?

They all come and pass away.

Life just passes away. There is nothing permanent in this world. Everything changes except the law of change. Think over it from your own perspective.

You have seen all the changes. You have survived all setbacks, all defeats and all sorrows. All have passed away. The problems in the present, they too will pass away… Because nothing remains forever. Joy and sorrow are the two faces of the same coin. They both will pass away.

You are just a witness of change. Experience it, understand it, and enjoy the present moment – This too Shall Pass.

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LIGHTER READING

THREE VAMPIRES WALK INTO A BAR Three vampires walk into a bar and sit down at a table. The waitress comes over and asks the first vampire what he would like. The first vampire responds, “I would like some blood.”

The waitress turns to the second vampire and asks what he would like. The vampire responds, “I would like some blood.” The waitress turns to the third vampire and asks what he would like. The vampire responds, “I would like some plasma.” The waitress looks up and says, “Let me see if I have this order correct. You want two bloods and a blood light?”

IF A LION IS CHASING YOU Teacher: If a lion is chasing you, what would you do?

Student: I’d climb a tree.

Teacher: If the lion climbs a tree?

Student: I will jump in the lake and swim.

Teacher: If the lion also jumps in the water and swims after you?

THREATENING LETTERS

Student: Teacher, are you on my side or on the lion’s?

The fellow stormed into the postmaster’s office in a fury. “I’ve been getting threatening letters in the mail for months and I want them stopped.”

UPSET IS UNHEALTHY

“Of course,” said the postmaster. “Sending threatening letters through the mail is a federal offence. Do you know who’s sending them?”

“Yes,” shouted the man. “It’s those idiots down at the Internal Revenue Service.”

WHEN WILL THEY MEET? A mathematician, a physicist and an engineer were each given the following problem to solve. A school dance floor included a straight line down the middle dividing the floor in two equal halves. Boys were lined up against one wall and girls against the opposite wall, each facing the center line. They were instructed to advance in stages towards the center line every 10 seconds, where the distance from the person to the center line at each stage is equal to one– half the distance at the past stage i.e.: If the starting distance from the wall to center line was D, the progressive series of distances at t = 0, 10 seconds, 20 seconds…10n seconds to the centre line is (D, D/2, D/4, D/8, ……D/2n). The question was when will they meet at the middle?

The mathematician said that they would never meet.

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The physicist said they would meet when time equals infinity. The engineer said that in one minute they would be close enough for all practical purposes.

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The mother of a problem child was advised by a psychiatrist, “You are far too upset and worried about your son. I suggest you take tranquilizers regularly.” On her next visit the psychiatrist asked, “Have the tranquilizers calmed you down?” “Yes,” the boy’s mother answered. “And how is your son now?” the psychiatrist asked.

“Who cares?” the mother replied.

Dr. Good and Dr. Bad SITUATION: A 50-year-old male came with early morning onset of acidity.

Take an antacid

Get an ECG done

© IJCP Academy

HUMOR

Lighter Side of Medicine

LESSON: Onset of acidity after the age of 40 unless proved otherwise is acute coronary event.

Information for Authors Manuscripts should be prepared in accordance with the ‘Uniform requirements for manuscripts submitted to biomedical journals’ compiled by the International Committee of Medical Journal Editors (Ann. Intern. Med. 1992;96: 766-767).

Indian Journal of Clinical Practice strongly disapproves of the submission of the same articles simultaneously to different journals for consideration as well as duplicate publication and will decline to accept fresh manuscripts submitted by authors who have done so.

The boxed checklist will help authors in preparing their manuscript according to our requirements. Improperly prepared manuscripts may be returned to the author without review. The checklist should accompany each manuscript.

Authors may provide on the checklist, the names and addresses of experts from Asia and from other parts of the World who, in the authors’ opinion, are best qualified to review the paper.

Covering letter –

– –

The covering letter should explain if there is any deviation from the standard IMRAD format (Introduction, Methods, Results and Discussion) and should outline the importance of the paper.

Principal/Senior author must sign the covering letter indicating full responsibility for the paper submitted, preferably with signatures of all the authors.

Articles must be accompanied by a declaration by all authors stating that the article has not been published in any other Journal/Book. Authors should mentioned complete designation and departments, etc. on the manuscript.

Manuscript – Three complete sets of the manuscript should be submitted and preferably with a CD; typed double spaced throughout (including references, tables and legends to figures).

–

The manuscript should be arranged as follow: Covering letter, Checklist, Title page, Abstract, Keywords (for indexing, if required), Introduction, Methods, Results, Discussion, References, Tables, Legends to Figures and Figures.

–

All pages should be numbered consecutively beginning with the title page.

Note: Please keep a copy of your manuscript as we are not responsible for its loss in the mail. Manuscripts will not be returned to authors.

Title page Should contain the title, short title, names of all the authors (without degrees or diplomas), names and full location of the departments and institutions where the work was performed,

name of the corresponding authors, acknowledgment of financial support and abbreviations used.

– The title should be of no more than 80 characters and should represent the major theme of the manuscript.

A subtitle can be added if necessary.

– A short title of not more than 50 characters (including inter-word spaces) for use as a running head should be included.

– The name, telephone and fax numbers, e-mail and postal addresses of the author to whom communications are to be sent should be typed in the lower right corner of the title page.

– A list of abbreviations used in the paper should be included. In general, the use of abbreviations is discouraged unless they are essential for improving the readability of the text.

Summary – The summary of not more than 200 words. It must convey the essential features of the paper.

– It should not contain abbreviations, footnotes or references.

Introduction – The introduction should state why the study was carried out and what were its specific aims/objectives.

Methods – These should be described in sufficient detail to permit evaluation and duplication of the work by others.

– Ethical guidelines followed by the investigations should be described.

Statistics The following information should be given: – The statistical universe i.e., the population from which the sample for the study is selected.

– Method of selecting the sample (cases, subjects, etc. from the statistical universe).

– Method of allocating the subjects into different groups.

– Statistical methods used for presentation and analysis of data i.e., in terms of mean and standard deviation values or percentages and statistical tests such as Student’s ‘t’ test, Chi-square test and analysis of variance or non-parametric tests and multivariate techniques.

–

Confidence intervals for the measurements should be provided wherever appropriate.

Results –

These should be concise and include only the tables and figures necessary to enhance the understanding of the text.

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Discussion –

This should consist of a review of the literature and relate the major findings of the article to other publications on the subject. The particular relevance of the results to healthcare in India should be stressed, e.g., practicality and cost.

References These should conform to the Vancouver style. References should be numbered in the order in which they appear in the texts and these numbers should be inserted above the lines on each occasion the author is cited (Sinha12 confirmed other reports13,14...). References cited only in tables or in legends to figures should be numbered in the text of the particular table or illustration. Include among the references papers accepted but not yet published; designate the journal and add ‘in press’ (in parentheses). Information from manuscripts submitted but not yet accepted should be cited in the text as ‘unpublished observations’ (in parentheses).

At the end of the article the full list of references should include the names of all authors if there are fewer than seven or if there are more, the first six followed by et al., the full title of the journal article or book chapters; the title of journals abbreviated according to the style of the Index Medicus and the first and final page numbers of the article or chapter. The authors should check that the references are accurate. If they are not this may result in the rejection of an otherwise adequate contribution.

Examples of common forms of references are: Articles Paintal AS. Impulses in vagal afferent fibres from specific pulmonary deflation receptors. The response of those receptors to phenylguanide, potato S-hydroxytryptamine and their role in respiratory and cardiovascular reflexes.

Q. J. Expt. Physiol. 1955;40:89-111.

Figures – Two complete sets of glossy prints of high quality should be submitted. The labelling must be clear and neat.

– All photomicrographs should indicate the magnification of the print.

– Special features should be indicated by arrows or letters which contrast with the background.

– The back of each illustration should bear the first author’s last name, figure number and an arrow indicating the top. This should be written lightly in pencil only. Please do not use a hard pencil, ball point or felt pen.

– Color illustrations will be accepted if they make a contribution to the understanding of the article.

–

Do not use clips/staples on photographs and artwork.

–

Illustrations must be drawn neatly by an artist and photographs must be sent on glossy paper. No captions should be written directly on the photographs or illustration. Legends to all photographs and illustrations should be typed on a separate sheet of paper. All illustrations and figures must be referred to in the text and abbreviated as “Fig.”.

Please complete the following checklist and attach to the manuscript: 1. Classification (e.g. original article, review, selected summary, etc.)_______________________________ 2. Total number of pages ________________________ 3. Number of tables ____________________________ 4. Number of figures ___________________________

Books

5. Special requests _____________________________

Stansfield AG. Lymph Node Biopsy Interpretation Churchill Livingstone, New York 1985.

6. Suggestions for reviewers (name and postal address)

Articles in Books

2.____________ 2._ _______________

Strong MS. Recurrent respiratory papillomatosis. In: Scott Brown’s Otolaryngology. Paediatric Otolaryngology Evans JNG (Ed.), Butterworths, London 1987;6:466-470.

3.____________ 3._ _______________

4.____________ 4._ _______________

Tables –

These should be typed double spaced on separate sheets with the table number (in Roman Arabic numerals) and title above the table and explanatory notes below the table.

Legends – These should be typed double spaces on a separate sheet and figure numbers (in Arabic numerals) corresponding with the order in which the figures are presented in the text.

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The legend must include enough information to permit interpretation of the figure without reference to the text.

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Indian 1.____________Foreign 1._ _______________

7. All authors’ signatures________________________ 8.

Corresponding author’s name, current postal and e-mail address and telephone and fax numbers __________________________________________

Online Submission Also e-Issue @ www.ijcpgroup.com For Editorial Correspondence

Dr KK Aggarwal

Group Editor-in-Chief Indian Journal of Clinical Practice E-219, Greater Kailash, Part-1 New Delhi - 110 048. Tel: 40587513 E-mail: editorial@ijcp.com Website: www.ijcpgroup.com

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