INVESTIGATING THE FACTORS AFFECTING BURN PATIENT SURVIVAL

Data from patients on mechanical ventilation offers insight into factors affecting survival

Amore effective and tailored treatment for sufferers of severe burns could soon be available. KAIMRC researchers have assessed the mortality rates of burn patients in need of mechanical ventilation and identified factors contributing to their survival.

Burns affect the skin or other tissues to various degrees. Minor burns, which involve the surface of the skin and some underlying layers, can heal rapidly with simple pain medication. Major burns spread to all skin layers and to deeper tissues, such as muscles, organs and bones, and often lead to the loss of the burned area. These life-threatening injuries require intensive and prolonged treatment in a specialised unit.

State-of-the-art critical care methods and dedicated teams have substantially reduced the mortality rate of burn patients. To ensure that a patient’s vital signs are stable, intensive care treatment typically starts with intubation and mechanical ventilation, which are essential to ensure that severely burnt patients can breathe without difficulty. Nonetheless, mortality rates remain quite high.

Fatmah Othman, who led the study, says that data on the survival of burn patients admitted to intensive care units and requiring mechanical ventilation varies widely, and information on this topic is also scarce at the national level. The researchers evaluated the mortality rate of 356 patients admitted to the burn units of King Abdulaziz Medical City and King Abdullah Specialist Children’s Hospital between January 2016 and July To ensure a patient’s vital signs are stable, intensive care treatment typically starts with intubation and mechanical ventilation, which are essential to ensure that severely burnt patients can breathe without difficulty.

survived their injury, a better rate than in other developing countries. “This can be explained by our highly advanced practices and specialised team,” Othman says. Unfortunately, 20% of the mechanically ventilated cohort died.

Patients older than 14 had a higher mortality rate than younger patients, probably due to differences in physiological mechanisms and immune responses. Othman says that comorbidities, which are more prevalent in the non-survivor group, can also increase mortality rates in older patients.

Burns exceeding 60% of the body resulted in a higher mortality rate than minor injuries. Inhalation injury and medical complications extending the hospital stay also aggravated the mortality rate. In particular, ventilator-associated pneumonia, organ failure, and sepsis—a body’s severe response to infection that destroys its own tissues and organs—were the most significant causes of death in mechanically ventilated patients.

The team plans to expand this study to other centres around the Kingdom.

2019. Eighty of these patients received mechanical ventilation because of inhalation injury.

More than 95% of the admitted patients

Ismaeil, T., et al. Survival analysis of mechanically ventilated patients in the burn unit at King Abdulaziz Medical City in Riyadh 2016-2019. International Journal of Burns and Trauma10, 169–173 (2020).

Data on the survival of burn patients admitted to intensive care units and requiring mechanical ventilation varies widely.

A fatty diet disturbs circadian brain metabolism

A high-fat diet changes metabolic oscillations in brain regions that control circadian rhythms

The circadian rhythms that keep processes such as the sleep/ wake cycle, body temperature and hormone levels in step with light/dark cycles are tightly linked with the oscillation of metabolites during a 24-hour period. An international study led by researchers in the US showed that a high-fat diet (HFD) can disturb circadian metabolic rhythms in the brain, revealing an unexpected susceptibility of brain clocks to nutritional choices.

Diet affects the function of many organs, such as the liver, intestines or pancreas, by modifying their endogenous clock. This alters the daily production cycles of important molecular factors and metabolites. However, little is known about the effects of diet and changes in metabolite production on the master clock in the brain, the suprachiasmatic nucleus (SCN), which keeps our other biological clocks in sync.

Paola Tognini and her colleagues examined the complete set of metabolites in the SCN and medial prefrontal cortex (mPFC), a brain area related to higher cognitive functions and emotional behaviour.

“Understanding how diet impinges on the metabolism of these two brain areas is relevant for the health of the body and the mind,” she says, explaining that the researchers compared metabolites in these tissues in mice fed either a HFD or a normal diet.

They found that a HFD altered the number, type and oscillation phase of circadian metabolites. “We saw how metabolites, which were not oscillating upon consumption of a balanced diet,

A high-fat diet in mice altered the number, type and oscillation phase of circadian metabolites.

started to oscillate after high-fat feeding,” Tognini explains.

The effects differed drastically between the SCN and mPFC. The metabolic profiles of these regions were also consistent with changes in their gene expression profile, confirming that a HFD affected the oscillation of metabolites in a region-specific manner. “We were surprised at both the extent of the effect of a high-fat diet on oscillating metabolites in the brain and its specificity,” says Tognini.

Some of these changes involve metabolites with established roles in neuronal plasticity, communication and survival. “Our results raise the possibility that prolonged consumption of high-fat foods could have deleterious effects on various aspects of brain function and behaviour,” says Tognini.

An improved understanding of how diet affects circadian regulation and the function of the SCN and mPFC could point the way towards novel therapeutic approaches for a range of chronic diseases associated with the disruption of circadian rhythms, such as mood disorders and dementia.

Tognini, P. , Samad, M., Kinouchi, K., Liu, Y., Helbling, J.C. et al. Reshaping circadian metabolism in the suprachiasmatic nucleus and prefrontal cortex by nutritional challenge. PNAS117, 29904–29913 (2020).

A properly packaged mix overcomes antibiotic-resistant bacteria

Liposomes carrying the right drug combination could help in the fight against drug-resistant microbes

Combining the antibiotic azithromycin with a mucous-clearing drug called N-acetylcysteine within lipid bubbles could provide a new treatment for drug-resistant bacterial infections. Tests by researchers at KAIMRC and King Saud bin Abdulaziz University for Health Sciences suggest the formulation has the potential to improve the ability of azithromycin to inhibit and kill antibiotic-resistant E. coli.

Harmful strains of E. coli, gram-negative bacteria found in the lower intestine of warm-blooded organisms and in fecal matter, can cause urinary tract infections, respiratory illnesses and fatal diarrhoea. Antibiotic-resistant strains are on the rise globally. “Drug-resistant bacteria are a major problem that threatens many lives,” says Alaa Eldeen Yassin, who led the study. “Clinicians need more treatment options.”

Previous research has shown that N-acetylcysteine can be combined with antibiotics to prevent the formation of treatment-resistant microbial biofilms on surfaces such as dental implants and catheters. It is also known that the antibacterial activity of azithromycin and other antibiotics can be increased when encapsulated in lipid-based drug delivery systems called liposomes.

The researchers tested azithromycin alone, within a liposome (LA) and combined with N-acetylcysteine within a liposome (LAN). These three formulations were evaluated against an E. coli strain with some resistance to antibiotics and a multi-drug resistant (MDR) strain.

The lowest concentrations needed to prevent growth of the antibiotic-resistant strain and to kill it were 21 times lower for the LA formulation than for azithromycin in its own. Likewise, these formulations were effective against the MDR strain at one-fifth of the concentration needed for azithromycin.

The inclusion of N-acetylcysteine caused a 17% reduction in the lowest concentrations needed to prevent growth of the MDR strain and to kill it but provided no benefit against the antibiotic-resistant strain.

The researchers then tested the lowest concentrations of azithromycin, LA and

Experimental formulations in lipid bubbles could help combat drugresistant bacteria. LAN needed to prevent growth of biofilms of the bacteria. Azithromycin was no more effective against the MDR strain when in the LA and LAN formulations than when alone. However, the LA and LAN formulations were better at reducing biofilm formation by the antibiotic-resistant strain.

Yassin adds that he expects LA and LAN will prove to be effective against other drug-resistant bacteria, not just E. coli. Despite the fact that LA and LAN were stable at biological temperatures, further tests found that their formulations were unstable when exposed to sputum and blood plasma. The researchers believe this problem can be overcome by changing the lipid content of the liposomes.

The group plans to change the formulation in an effort to further increase its antibacterial activity, and also hopes to test it in animals and, ultimately, in clinical trials.

Aljihani, S.A. et al. Enhancing azithromycin antibacterial activity by encapsulation in liposomes/liposomal-N-acetylcysteine formulations against resistant clinical strains of Escherichia coli. Saudi Journal of Biological Sciences 27, 3065-3071 (2020).

Animating the inanimate

Swimming crystalline microwires could be the progenitors of futuristic microrobotics systems

Molecular crystals are not known for their dynamism, according to Rabih Al-Kaysi. Chemists pay them little interest, because they’re not generally thought of as exciting substances. Al-Kaysi, a professor at King Saud bin Abdulaziz University for Health Sciences and KAIMRC, has recently published a paper which bucks this trend. The study, carried out with a team from Saudi Arabia, Japan and the USA, reports a ‘smart’ molecular crystal that continuously oscillates when illuminated with two wavelengths of light, a discovery the researchers hope will lead to further developments in microrobotics.

Motile materials are not new. Other researchers have previously demonstrated that certain materials can be made to change form in response to external stimuli, such as light or an electrical or magnetic field. However, this capability has mostly been demonstrated in soft materials such as polymers.

Examples of hard molecular crystals that move are few, and their ability to move is limited. Light causes a change in the geometry of individual molecules in these crystals. However, these hard photomechanical crystals tend to only do one thing when activated, says Al-Kaysi. Whether it’s a jumping motion, a twisting one, or bending, “you shine a light on them, they do that action, it’s gone,” he says.

In contrast, the crystalline microwires developed by Al-Kaysi and his team oscillate continuously. The microwires are composed of the compound (Z)-DVAM. When exposed to a continuous source of UV and visible light, they oscillate, moving forward at a speed of 7 micrometers per second (0.007 millimeters per second). This mimics the behaviour of flagella, the whip-like apparatus that some biological cells use to move.

This discovery is the fruit of methodical effort to find a crystal structure with such properties, says Al-Kaysi, as theory predicted that one should exist. “With a lot of experiments, eventually you find that ‘sweet spot,’” he

Molecular crystals are rarely dynamic and their ability to move is limited.

says, where the “thickness, length, and the photochemistry [of the crystal microwires] all work together and give you this autonomous motion.”

The (Z)-DVAM flagella not only exhibit superior properties compared with other molecular machines but are also significantly smaller than polymer ones, expanding their potential uses. With the discovery of these crystalline microwires, researchers now have a light-activated actuator that needs no wires. Al-Kaysi describes this as “a quantum leap forward.”

Tong, F. et al. Light-powered autonomous flagella-like motion of molecular crystal microwires. Angewandte Chemie International Edition 60, 24142423 (2020).

Seatbelt use in Saudi Arabia remains low

A survey reveals that young adults, women and people suffering from depression and anxiety are less likely to buckle up

ASaudi survey reports that around 40% of participants regularly fasten their seatbelt when in a car, and the compliance rate is correlated with age, gender, mental health and other habits. These findings can support the Kingdom’s efforts to improve traffic safety.

Seatbelt usage is an effective method to reduce road injuries and fatalities. However, the Saudi population has a lower level of seatbelt compliance and a higher rate of fatal road traffic crashes (RTCs) than other developed countries. In the United States, 2% of RTCs are fatal, but in Saudi Arabia the proportion is 23% according to one study and 15% according to a more recent study. Nevertheless, these high estimations can reflect the number of losses in the workforce, hospital resources and human capital, leading to a significant burden on the Saudi population, economy and public health.

Wearing seatbelts became compulsory for drivers and front-seat passengers in 2000 and has been enforced with surveillance cameras since 2018.

In this study, KAIMRC researchers surveyed 5,790 adults affiliated with the Ministry of National Guard Health Affairs in Riyadh. The survey was conducted between 2017 and 2019, and the data is part of the Saudi National Biobank, an on- going project that evaluates the health behaviours of the Saudi population.

The analysis showed a higher compliance rate among older individuals. Respondents between 26 and 45 years of age were nearly 50% more likely to fasten their seatbelts than those who were 18-25 years old. Interviewees who The Saudi population has a lower level of seatbelt compliance and a higher rate of fatal road traffic crashes than other developed countries, leading to a burden on the economy and public health.

reported depression and anxiety were 26% less likely to wear seatbelts than those who did not report a mood disorder. Women were 86% less likely to fasten their seatbelt than men. However, many women sit in the rear of the car, where the use of the seatbelt is not compulsory in KSA. Seatbelt compliance among Saudi women who have obtained their driving licenses since 2018 needs further studies.

Furthermore, cancer patients were twice as likely to buckle up as those without cancer, and people who brush their teeth more than twice a day were also in the habit of fastening their seatbelts. The researchers say that this demonstrates that people who follow a healthy lifestyle may tend to adopt safe habits in the car as well.

“This study highlights the need for further investment in public health programmes that target specific groups and focus on seatbelt compliance for injury prevention,” says public health researcher Suliman Alghnam of KAIMRC and KSAU-HS. “A significant commitment is required to curb road deaths as KSA works to reduce the RTCs mortality rate by 7% annually in alignment with the Saudi Vision 2030.”

Alghnam, S. et al. Predictors of seatbelt use among Saudi adults: Results from the National Biobank Project. Frontiers in Public Health8 (2020).

Wearing a seatbelt significantly improves traffic safety, but compliance with seatbelt laws varies between different groups in Saudi Arabia. Targeted interventions to increase compliance could help.

Drugs formulated using nanocrystals (seen at left) help prevent preterm births in mice.

Nanotechnology prevents preterm birth in mice

Formulation helps overcome mucus barriers for targeted drug delivery

Anew nanomedicine strategy for delivering drugs to the female reproductive tract could help prevent women from going into labour prematurely.

Each year, around 1 in 10 babies worldwide are born before 37 weeks of gestation, resulting in more than 1 million deaths due to complications resulting from preterm birth. The steroid hormone progesterone is sometimes used to prevent early delivery in at-risk women, but current treatment formulations often have little effect because they fail to deliver the hormone to the appropriate tissues of the cervix and uterus.

A team from Johns Hopkins University in the USA designed a nanosuspension system that enables vaginally dosed drugs to overcome the mucus barrier of the female reproductive tract and reach uterine tissues, where they can forestall labour.

The system involves grinding drugs into miniature crystals about 200 to 300 nanometers in diameter—smaller than the size of a typical bacterium. A stabilizing agent is then added to keep the nanoparticles from getting stuck in the vagina’s protective mucus, which normally traps foreign particles such as microbes—but also medicines—and prevents their entry into the body.

The researchers tested the system in mice experimentally induced to develop uterine inflammation, an unpredictable major condition that often leads to premature labour in humans and results in nearly 4 million global premature births annually. They focused on vaginal administration of two types of drugs: histone deacetylase (HDAC) inhibitors, which they showed can help to inhibit the contractility of the uterine wall in human cell experiments, and progesterone, which has known anti-inflammatory effects.

Mice treated with mucus-penetrating nanosuspensions of HDAC inhibitors showed improved rates of full-term delivery.

The researchers found that mice treated with mucus-penetrating nanosuspensions of HDAC inhibitors, both with and without progesterone, showed improved rates of full-term delivery. Large litters of healthy, normal pups were born. By comparison, mice injected with the drugs in their body cavity—like untreated mice— went into labour prematurely, with no surviving offspring.

“Delivery matters,” says Laura Ensign of Johns Hopkins, who led the research. “And we must sometimes think outside the box of pills and injections to develop effective treatments.”

In other mouse studies, Ensign and her colleagues have used their nanosuspension system to enhance drug delivery in the gut, in the airways and at other mucosal surfaces. Kala Pharmaceuticals, a company cofounded by Ensign’s close collaborator and mentor, Justin Hanes, has licensed the technology and developed two topical eye treatments for people, one for dry eye disease and one for post-operative ocular inflammation and pain.

“There are many diseases affecting mucosal surfaces that would benefit from more targeted local and sustained drug delivery,” Ensign says. Fortunately, her technology now makes that possible.

Zierden, H.C. et al. Enhanced drug delivery to the reproductive tract using nanomedicine reveals therapeutic options for prevention of preterm birth. Science Translational Medicine 13, eabc6245 (2021).

Algorithms that can predict an individual’s risk of diabetes will play an important role in managing the increased worldwide prevalence of the disease.

An artificially intelligent route to better prediction of diabetes risk

A neural network model developed at KAIMRC can identify patients at risk of diabetes with unprecedented accuracy

The use of artificial intelligence (AI) to predict risk of certain diseases could not only save lives but also reduce the workload of over-burdened medical staff. Now, KAIMRC’s Riyad Alshammari and his co-workers have developed a highly accurate model to identify patients with diabetes based on simple test results and details about lifestyle.

Diabetes cases are on the rise worldwide, bringing associated risks of complications including heart disease and strokes. In Saudi Arabia alone, experts predict that there will be 2.5 million more diabetes patients by 2030.

While genetic factors account for only a small fraction of diabetes risk, it is established that the disease is more closely associated with obesity and other lifestyle parameters. This means that models based on personal data can be successful without the need for complex laboratory tests.

“AI can help healthcare providers redefine their strategies to prevent and manage diabetes,” says Alshammari. “This will save medical expenses for both patients and healthcare authorities.”

Alshammari and a team at KAIMRC, King Saud Bin Abdulaziz University for Health Sciences, and Simon Fraser University in Canada used a cloud computing service to build and test four algorithms based on machine learning. They also acquired data on more than 66,000 patients from Ministry of National Guard Hospital Affairs between 2013 and 2015 who had undergone hemoglobin A1c (HgbA1c) tests to determine whether they were diabetic. The dataset included 17 attributes per patient, such as age, body mass index, blood pressure, and several lab tests.

To test each algorithm, the researchers used a 10-fold cross-validation process. “We divided the original data randomly into ten equal-sized sub-datasets,” Alshammari explains. “One of the ten was used to train the model, and the rest were used to validate the model. We repeated the process until every sub-dataset served as the training set.”

The most successful model was a neural network algorithm called Deepnet, which correctly identified 88.5% of patients as diabetic or non-diabetic. “Deepnets are an advanced form of AI that mimic the human brain. They can be trained to learn about data and pick out patterns,” says Alshammari.

The researchers are hopeful that such accurate predictions from routine health checks will lead to earlier detection and allow for improved initial management of the disease. If so, Deepnet could help healthcare authorities save some of the billions of dollars that are currently spent on managing diabetes. Alshammari plans to explore how models such as Deepnet could empower individuals to monitor their own health risks using the Internet of Things. “AI could be deployed in small devices attached to the body and connected to smart phones,” he says.

Alshammari, R, Atiyah, N., Daghistani, T. & Alshammari, A. Improving accuracy for diabetes mellitus prediction by using Deepnet. OJPHI12(1):e11 (2020).