4) Brian J. Morris' first set of reviewer comments (December 17, 2010)

REVIEWER REPORT ON Frisch et al. “Male circumcision and sexual function in men and women: A survey-based-cross-sectional study in Denmark This study purports to provide information on sexual function and satisfaction in men in Sweden who are either circumcised or uncircumcised, as well as their sexual partners. A strength of the study lies in the large sample size. It is, however, observational, and this needs to be considered now that results from large randomized controlled trails (RCTs) are available on the topic being studied. Moreover, although the study started with 10,916 people, as it progressed the numbers diminished to 7,275, then 5,552, then, for men, to the 1,996 who were sexually active. Of these, only 103 were circumcised. This would obviously mean a reduction in power of the study to draw conclusions on this subset. More so when one looks at the n values for those men (and their female partners) who were judged as having some sort of problem, with n values of 10 or less. Thus the Abstract, which states an n value of 5,552 for the survey, and then goes on to emphasize negative outcomes without also stating the small n values of the subgroup these were derived from is completely misleading. Since the Abstract is the most widely read text of any publication this page has to be rewritten completely so as to convey in a BALANCED and honest manner the REAL findings of the study.

Overall, there was no difference in most parameters between the circumcised and uncircumcised. One difference was that circumcised men were found to have more partners on average (OR=1.55). Other than this, statements that suggest differences, but then go on to say there no statistical difference, should simply say at the outset that the results were not significantly different for all of the parameters found to be so. This would avoid misleading the reader, and help reduce the excessive length of the paper. ALL of the parameters found to be not different statistically should be listed in the Abstract. At present the Abstract communicates “difficulties”, and is not a balanced communication of the findings.

They did find a few parameters to be different. The Abstract erroneously states “circumcised men were more likely to report “orgasm difficulties”. Circumcised men were found to have ‘orgasm difficulties’ (defined as ‘delayed orgasm or complete anorgasmia’). But Table 4 shows 60% of circumcised men had ‘no difficulties’, so the statement in the Abstract is quite misleading. More so when one sees that only 10 of the 95 men in Table 4 had frequent ‘difficulties’. Use of the word ‘difficulties’ when referring to this parameter throughout the manuscript introduces a subjective term and should be deleted. Did they determine whether the men themselves considered this a ‘difficulty’? In other studies that I will discuss below, delayed orgasm is seen as a good thing by many, perhaps the majority, of men, and their sexual partners, as it provides the female partner more time to attain a climax(es).

Previous extensive research in multiple countries (see below) has found little difference between insertion and orgasm for each category of penis, albeit with a slightly longer, nonsignificant, time for circumcised men (see below). The authors should provide data on how long it took the men to reach orgasm in each category.

The terms ‘often’ and ‘every time’ are subjective. What is the man comparing himself with? There is no data on condom use. This would reduce sensation during intercourse, and so delay orgasm. In various studies men found condom application easier after having been circumcised. So were these results a consequence of condom use being greater in the circumcised men?

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Not surprisingly, the women in the study reporting a circumcised spouse were from a non-Danish background. This indicates likely cultural bias and non-matching of study groups, so reducing the reliability of any findings. Membership of a ‘religious community’ could mean anything, and unless information is provided about what that community is and its teachings regarding sex and sexual mores, one will be left wondering about any finding arising. In particular the attitudes to women by men in each culture could have a bearing on approaches to sex, and pleasure the women experience from the sex act(s). Since the women with circumcised partners were more likely to have better education, the greater number of partners they had could reflect a more outgoing attitude. Regardless, they were different, so possibly confounding the results. Once again the low number of women with circumcised spouses means low power and difficulty in generating reliable results, especially so for data obtained for the only 75 who were sexually active. Might the reporting more often of sexual needs not being fulfilled by these women be culturally driven (as alluded to above) and might it correspond to the higher number of partners.

The so-called ‘difficulties’ supposedly identified may be random and certainly the confidence intervals are so wide that one would be hard pressed to accept these data as convincing. Only a minority of women in each category reported such problems. If the authors were to present the opposite, ie, the proportion of women who did NOT experience difficulties, a more reliable appreciation of the findings would be apparent: e.g., 69% vs 78%, 81% vs 86%, 88% vs 96%, 86% vs 88%, 91% vs 96%.

The ‘robustness analysis’ then attempts to overcome the various apparent confounding factors. But the small numbers reporting such “difficulties” makes the analysis unconvincing. … e.g., only 10 men in the circumcised group listed under the ‘frequent orgasm difficulties’ category. From this they make a point that circumcised men are 3 times as likely to experience difficulties. Then they draw a conclusion based on n=8 women that they are 8 times more likely to experience dyspareunia if their make partner is circumcised. In the robustness analysis these n values disappear as Table 6 presents the 3-fold difference data. Dyspareunia can also be caused by disturbances in the vaginal vault. Since twice as many women of circumcised male partners had sexual intercourse more than 3 times a week (24% vs 13%) this could explain the finding, where frequent sexual intercourse is a risk factor for bacterial vaginosis, thrush, etc. One might also wonder whether the women (or their male partners) might, if not a medical problem, have thought of using a vaginal lubricant?

The survey does not consider explanations along these lines. The corollary to this particular observation is that circumcised men in the study should have been having sexual intercourse more frequently as were the uncircumcised men. It is well-known that men can ‘last’ longer after having orgasmed the first time and then in the same session of sex later engage in intercourse again (and perhaps again and again). But the survey did not explore this as a factor in offering a possible explanation for the 10+ of men in the circumcised group supposedly finding it ‘difficult’ in reaching orgasm. More importantly, it seems that in Table 2 similar proportions of men of each category were having sex more than 3 times a week in the past year. Moreover, whereas 8 circumcised men were in the latter category, for the women this was n=17.

This implies either misreporting or sex with men other than their regular partner. This would increase risk of STIs and other causes of dyspareunia.

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Why didn’t the survey ask about problems in women who had experienced EACH type of penis for sexual activity? This would provide a much better sample and more reliable conclusion that attempting to evoke a conclusion based on samples confined to women whose male partners were circumcised and women whose male partners were uncircumcised.

Overall, the study provides more questions than answers, although by and large the answers have been provided in the extensive research by others that will be referred to below and that the authors either ignore or gloss over, often in a dismissive manner. Importantly, the statistical analyses are questionable, especially being based on n values that are too low to give reliable results and the fact that correction for multiple testing was not carried out. A more reasonable conclusion may be that there is no difference between the circumcised and uncircumcised categories for ANY of the parameters surveyed. Since no clinical testing was done, the survey is more social than scientific.

The Introduction is weak and is not an accurate, scholarly presentation of the more credible literature on male circumcision (MC). Moreover, instead of stating findings to date on the subject of the research field of sexual function and satisfaction relevant to their study of MC, it presents erroneous information on peripheral circumcisionrelated matters in a manner that does no credit to the impartiality of the authors. As such, most readers would dismiss the paper as not being objective or informed.

To be more specific, what is said comes across as an ideological rant against male circumcision, rather than a portrayal of the numerous studies published to date on sexual function and satisfaction and that support some, but not all, of the present findings. The quality of the literature in the MC field ranges from superior, including large randomized controlled trials (RCTs) and meta-analyses, to poor. The latter includes personal opinions in book chapters written by well-known anti-circumcision identities, and studies that have been discredited in critical publications by experts in the field. Examples include Refs 3, 5, 8, 11, 20, 27, 33, 36, 37 [of cornflakes fame), 39, 46, 47, 48, 51, 53, and 56. The authors uncritically dwell on the weakest literature at the expense of the quality research in good journals. They selectively cite outlier studies and discredited the good quality studies, rather than it would seem having attempted to conduct a systematic review of the MC literature in order to find a selection of scientifically sound research especially when it comes to the circumcision and sexual function, sensitivity, sensation and satisfaction literature.

Only later in the Discussion is the RCT data cited, but this should have been cited as part of a more relevant, focussed literature review in the Introduction. Moreover, the manner in which the RCT data is discussed is indicative of extraordinary author bias, and even contains undertones of racism, knowing that these studies were conducted in sub-Saharan African countries amongst the majority Black populations therein.

The findings suggest overall no significant difference in most of the parameters tested. Those differences that were found were based on small n values, lack of correction for multiple testing by, say, the Bonferroni method, and could easily have been a result of random chance. A proper statistical analysis could in fact show no significant difference between circumcised and uncircumcised groups for all or most of the parameters tested in each sex. If this were to be the case it would then not support the author biases evident in the manner the paper has been written.

Considerably more objectivity is thus required.

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Thus, overall the manuscript would need considerable revision to convert it to a document having a sufficient level of scholarship, including evidence-based and impassioned presentation, as to merit publication in ANY journal. The authors do themselves a disservice by the manner they have chosen to present information intended for publication and a scientific readership. If they do in fact want to be believed then a complete re-think is needed by them regarding the expectations that journals require for scientific writing and data analysis. As such, this Reviewer gets the impression that the authors may be na茂ve when it comes to journal requirements and scientific publication.

Some more specific comments will now be made: PAGE 4, para 1, lines 1-3: It is not true that 99% of males are free of physiological phimosis by age 17, where the authors selectively cite a single-author study from 1968. Phimosis affects at least 10% of uncircumcised males. Whiles rates are substantial in pre- and postpubertal boys up to age 18 (Gairdner 1949; Oster 1968; Kayaba et al. 1996; Ishikawa & Kawakita 2004; Concepci贸n et al. 2008; Yang et al.

2009), British, German, US and other studies of men in the late teens and adult years show rates of 9%-14% (Osmond 1953; Saitmacher 1960; Schoeberlein 1966; Ohjimi & Ohjimi 1981; Boon et al. 1989; Velazquez et al. 2003; Ben et al. 2008). p. 4,para 2, Lines 5-7: Their claim that penile cancer can be prevented by good hygiene is contradicted by research - there being no scientific evidence that improved penile hygiene is effective in reducing the risk in an uncircumcised man (Moses et al. 1998). A study in California saw no correlation between penile cancer and frequency of bathing or method of cleaning the anogenital area before or after sex (Tsen et al. 2001).

The literature, including meta-analyses and RCTs, shows that there is no question that MC reduces risk of high-risk HPVs, ulcerative STIs, including HSV-2, Trichomonas, HIV and others; moreover, condoms are not a panacea and at best only lower risk, rather than eliminate it. That is why each is recommended by health authorities. See reviews: (Morris 2007; Smith et al. 2010; Tobian et al. 2010). p. 4, para 2, Line 8: It is not true that MC does not reduce UTIs. To supports this claim the authors cite an opinion piece and a seriously flawed publication by R.S. Van Howe, apparently not realizing that his arguments and various meta-analyses of various conditions that MC protects against have been shown by experts in the MC filed to be fundamentally flawed (Moses et al. 1999; Van Howe 1999; O'Farrell & Egger 2000; Van Howe 2007; Waskett et al. 2009). One of his analyses (Van Howe 2007) used false source data (Waskett et al. 2009) in arriving at the conclusion he was seeking to support his biases. UTIs are approx. 10 times higher in uncircumcised infant males, as shown by various credible meta-analyses (Wiswell & Hachey 1993; Singh-Grewal et al. 2005) and a randomized controlled trial (Nayir 2001). In Sweden where the present study was conducted cumulative incidence of UTI was 2.2% by age 2 (Jakobsson et al. 1999), reflecting incidences elsewhere in the world in uncircumcised infant males. A meta-analysis of febrile male infants found UTI was the cause of the fever in 20.1% of the uncircumcised compared to 2.4% the circumcised (Shaikh et al. 2008). Other studies have found cumulative prevalence figures of 2-6% for uncircumcised children, many of these highlighting the seriousness of UTIs and the renal damage caused to a significant proportion of

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patients (Craig et al. 1996; Coulthard et al. 1997; To et al. 1998; Newman et al. 2002; Zorc et al. 2005; Hsiao et al. 2006). Recurrent UTIs and ensuing acute pyelonephritis and renal scarring can be prevented by infant MC (Elder 2007; Mukherjee et al. 2009; Shim et al. 2009). UTIs continue through life, being 6 times higher in uncircumcised men (Spach et al. 1992). Frisch et al. also cite an Isreali study of UTI after infant MC [Ref 4], but this is irrelevant as there was no control group of uncircumcised baby boys. More importantly, the reason for the UTI was more to do with the technique used by the traditional circumciser, notably absence of sterilization of equipment, and these data are outliers, having no relationship with medical MC or the issues being addressed here.

P. 4, para 2, line 9-11: The outmoded 1999 AAP statement [Ref 5] has been subject to severe criticism. In a joint response the Chair of the 1989 AAP Taskforce on Circumcision, Edgar Schoen, and others more expert than those on the 1999 Taskforce, rebutted the 1999 statement (Schoen et al. 2000; Schoen et al. 2001).

Others also levelled valid criticisms (Bailis 2000; Kunin 2000).

Why don’t the authors refer to the much more recent American Urological Association’s statement on circumcision that, albeit brief, is very much in keeping with the medical evidence of its wide-ranging benefits (American 2007). The CDC has stated in recent times that it is moving to advocacy of infant MC in the USA [ Smith et al. 2010] and a new policy is pending. The WHO, UNAIDS and other bodies several years ago incorporated MC into a package of preventative measures, this being the only proven measure to reduce HIV is high prevalence settings at the population level. Therefore statements by the authors and others that MC is not recommended by pediatric bodies appear antiquated.

P. 4, para 2, lines 11-13: Bias is evident here. Rather than “widespread belief”, the protections the authors list are backed up by an enormous body of scientific data, including meta-analyses, RCTs, Cochrane reviews, and evidence on biological plausibility (see reviews such as: (Morris 2007; Smith et al. 2010; Tobian et al.

2010). On a minor point “venereal disease” is an old term no longer in common use in medical and scientific circles.

P. 4, para 2, lines 1-3. The refs cited here are too limited and one [ref 11] has been shown to be flawed. But even in this survey, Richters et al. [ref 11] found circumcised men had FEWER sexual difficulties (Richters et al. 2006), and 27% of uncircumcised men ages over 50 found it difficult keeping an erection [a REAL difficulty, as opposed to Frisch et al.’s use of the word “difficulty”] compared to15% of circumcised men (Richters et al. 2006). Physical pain during intercourse was also LESS common among circumcised men in this study, and this contradicts the supposed findings in the present study.

The RCT data (Kigozi et al. 2008; Krieger et al. 2008) is not mentioned in the Introduction but should be, because this has a high level of epidemiological credibility. The RCTs found circumcised men (and their female partners) appeared to have no loss of sensitivity, sensation during arousal, function or satisfaction … if anything the opposite. Instead, the authors wait until the Discussion before mentioning these trials, and then do so in a disparaging way.

Also on page 4, para 2, lines 1-3, Frisch et al. should mention that in the US National Health and Social Life Survey (NHSLS) [Ref 9] it was found that uncircumcised men

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were more likely to experience sexual dysfunctions with age (Laumann et al. 1997).

Their female partners preferred the esthetics of a circumcised penis over an uncircumcised one, and the circumcised men received more fellatio, all of which is consistent with Williamson & Williamson [ref 52] who noted a strong preference by women for circumcised men when it came to most sexual activities. A recurrent theme in many of the surveys is better hygiene by MC (Williamson & Williamson 1988; Afsari et al. 2002; Canada 2009).

PAGE 5, para 1, lines 2-3: The statement here that MC “is associated with increased rates of sexual dysfunction in a non-trivial proportion of men and women” does not ring true, raising serious concerns about aspects of the study that would arrive at a conclusion so at variance with the bulk of the scientific literature.

Sexual dysfunction is a common problem, the RCT data for example (Krieger et al.

2008), obtained in a Black African population, found a baseline rate of sexual dysfunction almost identical to the British National Survey of Sexual Attitudes and Lifestyles of 24% (Mercer et al. 2005), and studies in the USA (Laumann et al. 1999) and globally (Nicolosi et al. 2004).

PAGES 5 to 13 (Methods and Results): The problems in the presentation of data here have been discussed above,. One is their inclusion of interpretation of data. This should be omitted and left to the Discussion, especially so when an inference is made that certain parameters differed, when in fact there was NO STATISTICAL difference.

PAGE 14, par 1 & 2: This is all too emotionally charged, even though it “tries” not to be. Best to stay away from this kind of discussion and confine the Discussion to the data at hand.

P 14, para 3, line 6: Here one sees the 3-fold higher difficulties assertion based on insufficient data. The limitations of this data should be stated. After correction for multiple testing the authors may in fact find that the statistical difference disappears, so will need to be changed to reflect this.

PAGE 15: It is incredulous that ‘religious authorities’ and later pronouncements by a rabbi are being referred to if their opinions have any relevance to a supposedly scientific study!

Please delete.

On p 15, para 1, lines 5-6 (--- elaborated on in the case of Ref 27 on page 17, para 2, lines 7-11 ) the authors then refer to studies such as that by Sorrels et al. [Ref 27] as providing ‘neurophysiological support’ for greater sensitivity of the uncircumcised penis (specifically the foreskin), failing to realize the flawed nature of these. The Sorrells study has been discredited in a published critique (Waskett & Morris 2007).

This San Francisco Bay Area (?Michigan) study conducted by notable anticircumcision activists and funded by NOCIRC, purported to measure (in an unbiased manner!?!) “fine-touch pressure thresholds” at 19 locations on the uncircumcised and 11 on the circumcised penis (Sorrells et al. 2007). Although the authors claimed that their study showed the glans of the uncircumcised penis to be more sensitive than the

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circumcised, an analysis of these data (not reported in the Sorrells paper itself) showed there was in fact NO statistical difference (Waskett & Morris 2007). Despite other claims, the actual statistics in the Sorrells paper showed only a marginally significant difference (P = 0.03) for just ONE site, namely the orifice rim. However, their statistical analysis was naïve and incomplete. After a Bonferroni correction of their data, as should have been done by the authors in order to eliminate false positives arising from the multiple testing they carried out, this marginal statistical difference was shown later by critics to disappear (Waskett & Morris 2007). The Sorrells data thus in reality show that there is no difference in sensitivity between the circumcised and uncircumcised penis. Frisch et a. therefore need to correct their statement to reflect this. Moreover, serious design flaws, subjects in the Methods section who were unaccounted for in the data presented in their Results section, biased presentation, and other omissions, as reported (Waskett & Morris 2007), make this study lack any credibility whatsoever. It is this kind of biased presentation, selective citing of outlier studies that have no credibility that makes the current paper

by Frisch et al., especially the reporting and interpretation of the results, unacceptable.

P. 15, para 2: Here the authors present an historically inaccurate account of masturbation in Victorian times and so so in an emotional charged manner reflective of the dubious sources they cite. Although it is often claimed (by anti-circumcision activists whose writings, misleading statements and propaganda the present authors seem to have drawn on) that circumcision was popular in the Victorian era as a cure for masturbation, the truth is quite different. This hypothesis appeared in an 1891 commentary (Hutchinson 1891) [Ref 36] by an author who, decades earlier, was the first to observe that circumcision protects against syphilis (Hutchinson 1855) (a REAL benefit of MC, that is now well-established). But the idea that circumcision prevented masturbation had no common currency in Victorian times. For example, the purported “evil” of masturbation occupies much of the 1913 book “Youth and Sex”, yet circumcision is not mentioned (Scharlieb & Silby 1913). A well-known book on circumcision by Felix Bryke completely rubbishes the idea (Bryk 1882) and Whitla’s ‘Dictionary of Treatment’ does not list ‘circumcision’, whereas, under ‘masturbation, only suggests performing circumcision if irritation from a tight prepuce is responsible (Whitla 1912). One can refer to minority views today, and perhaps in a hundred years time a distorted view of these as being mainstream might also apply. The mainstream views on MC in Victorian times were not unlike those today, ie, that MC improves hygiene, reduces STIs (syphilis being rampant back then), etc. The fact that MC does not reduce masturbation was noted in the Laumann study referred to above … the circumcised men in that study masturbated more!

At the end of page 15 it gets worse. We see the highly emotive, and inaccurate term ‘surgical amputation’! ... woven into a declaration that somehow this HAS TO mean loss of penile sensistivity. Very unscientific, and in fact now disproven by science, including the RCT data above. Instead of citing the research, Frisch et al. instead cite a review article by Morris that does provide these references, but Frisch et al. call the review an opinion, which it is not, instead being an extensive, scholarly review that draws an obvious conclusion that does now have common support amongst informed individuals in the scientific community, including the CDC and other health bodies (Morris 2007; Brady 2010; Smith et al. 2010; Tobian et al. 2010)

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PAGE 16, para 1, lines 3-6: The Masters & Johnson discussion should state the findings, not various people’s use of the data for their own ends. Clinical and neurological testing of the ventral and dorsal surfaces of the penis as well as the glans

by Masters & Johnson found no difference in penile sensitivity between circumcised and uncircumcised men (Masters & Johnson 1966).

P 16, para 1, lines 9-12: They refer to a US survey (Collins et al. 2002) [Ref 42] of men after adult circumcision (av. age around 40] that found no difference in sexual drive, erection, ejaculation, problem assessment or satisfaction compared with what the men recalled sex being like prior to foreskin removal. Penile sensitivity was the same. The Collins paper stated that their study was prompted by reports by proponents of “foreskin restoration”, in particular the “disparity between the mythology and medical reality of circumcision regarding male sexuality” (Collins et al. 2002). It is unfortunate that the mind-set of the present authors seems to have been tainted by such mythology.

P 16, para 1, lines 12-13: Ref 43 was a US study involving a battery of quantitative somatosensory tests to evaluate the spectrum of small to large axon nerve fiber function found no difference in sensitivity of the glans penis between 43 uncircumcised and 36 neonatally circumcised men (Bleustein et al. 2005). The authors controlled, moreover, for factors that can alter neurologic testing (age, erectile function status, diabetes, and hypertension). Although small, the studies in Refs 43 and 44 were quite detailed and the biological testing removed the kind of bias that cannot be eliminated in a survey such as that by Frisch et al. here. I wonder too why Frisch et al. seem to combine the n values for each study? This needs to be removed. The Payne study [Ref 44] was about SENSATION during arousal (not ‘sensitivity’ as such). Indeed, the MOST IMPORTANT issue is not the sensitivity of the flaccid penis, but the SENSATION of the penis experienced during arousal.

Payne stated in the published news media at the time that she is an opponent of MC, so expected to see a diminution in sensation in circumcised men in the study. It is to her credit that she did not and reported her findings accurately as a true scientist should. This is a role model that perhaps the present authors should seek to emulate.

The study in Montreal by Payne et el. used thermal imaging of the penis, and found no difference between circumcised and uncircumcised men aged 18-45 (mean age 24) (Payne et al. 2007). Sensation was assessed by measurement of surface skin temperature just below the glans adjacent to the coronal ridge on the lateral right surface of the penile shaft. Both penile temperature and touch thresholds were lower at baseline in the uncircumcised men, indicating LOWER SENSITIVITY OF THE FLACCID UNCIRCUMCISED. More circumcised participants reported an increase in their level of arousal, while more UNCIRCUMCISED men reported being unaffected by the erotic stimulus (movie). SENSITIVITY to touch on the forearm as compared to the glans penis or shaft DECREASED during arousal in BOTH groups.

These workers found, interestingly, in a similar study in women an increase in vulvar sensitivity during sexual arousal (Payne et al. 2007).

P 16, para 2, lines 3-5: The authors also misrepresent the Fink study of 123 men (Fink et al. 2002) [Ref 45], in which, after circumcision 62% of the men said they were satisfied with having been circumcised and liked their new appearance and 50% reported benefits. There was no change in sexual activity. Penile sensitivity, although not tested directly, was thought by some of the men in this study to be slightly lower (but NOT statistically so), although any small decrease, if true, may have contributed

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to their claims of better sex. Although there was no change in sexual activity, some of the men thought erectile function was slightly less (category scores: 12.3 vs 11.1, P = 0.05, not less than 0.5, so not significant), which is the opposite of the very much larger National Health and Social Life Survey (Laumann et al. 1997) [Ref 9]. Fink and co-workers point out that this would, however, have to be confirmed by duplex Doppler ultrasound before a definitive conclusion could be made. Furthermore, the outcome of this study could have been affected by the fact that 93% of the men had been circumcised for a medical problem. Both the men and their partners preferred the appearance of the penis after it had been circumcised. As in other studies (Laumann et al. 1997) oral sex became more frequent, but there was no change in anal sex or masturbation (Fink et al. 2002). They then refer to a weak study by anticircumcision identities, presumable recruited via a center focused on “restoration” of a foreskin [?!], and where the circumcised men attending may have been duped by the rampant internet (mostly) propaganda of anti-circumcision activists into (falsely) believing that their sexual problems stemmed from having been circumcised as an infant [Ref 46]. So this study of such a selected, psychologically vulnerable, easily duped population of men has no credibility, so should be deleted. Next a reference is made to ‘reseaerch’ by Denniston [Ref 47], but this reference does not belong here and should be deleted, as it is a non-peer-reviewed study in a BOOK BY WELLKNOWN ANTI-CIRC ACTIVISTS, including the international President of NOCIRC! Denniston is the first-named Editor of that book. And the study suffers from the same problems as that in Ref 46, namely selection bias. As part of the loaded discussion in this paragraph we twice see the word ‘complained’ (not true!).

Such misleading, inaccurate terms need to be deleted.

Page 16 bottom over to top of page 17: Here the authors cite the flawed Korean study

by Kim & Pang (Kim & Pang 2007) [Ref 48]. This examined masturbation, rather than a male’s typical sexual expression, namely vaginal intercourse, and confused “sexuality” (in the title of the article) with “male sexual response”. The various flaws, including poor study design, and the authors’ statement that all men in Korea are circumcised, then giving a tally of circumcised men that exceeded the n value of the cohort, makes one wonder about the source of the uncircumcised men. The serious errors and other deficiencies in their study were the subject of a damning critique (Willcourt 2007).

PAGE 17 P. 17, para 2, line 1: Frisch et al. state “In two studies” but then cite three!

P 17, para 2, lines 1-7: Here they refer to a report in 2008 [Ref 23] involving men aged 18-27 years who underwent circumcision. This found mean PEP latency was 42.0 milliseconds before circumcision and 44.7 milliseconds after circumcision, the difference (2.76 milliseconds) being statistically significant (Senol et al. 2008). Frisch et al. should add that those authors conclude that circumcision may contribute to sexual satisfaction by prolonging PEP latency by 5% and thus intercourse time. They should also indicate that that study found that sexual function was not adversely affected by circumcision Next Frisch et al. cite a study in 2004 [Ref 26] of men circumcised for non-medical reasons in Turkey that showed an increase in ejaculatory latency time, which MAY OR MAY NOT reflect decreased sensitivity, but this was considered by the men as an advantage in that they could prolong intercourse (Senkul et al. 2004). Another study, discussed below, found ejaculatory latency time was significantly lower in Turkish men compared with men in the USA, UK and

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European countries (Waldinger et al. 2005). The latter very important, large study MUST be cited. This study published in 2005 involved 500 couples, and measured intravaginal ejaculatory latency time (IELT; = time from start of vaginal intromission to start of intravaginal ejaculation, recorded by stopwatch and paper diary). IELT was 6.7 minutes (range 0.7 to 44.1) in circumcised men, being not statistically longer than the time found in uncircumcised men of 6.0 minutes (range 0.5 to 37.4) (Waldinger et al. 2005). These times were similar in the Netherlands, UK, Spain and the USA. As mentioned above, time to ejaculation in Turkey, however, (3.7 minutes; range 0.930.4) was significantly lower. Intravaginal ejaculatory latency time decreased significantly with age: in men aged 18-30 years, the time to ejaculation was 6.5 min, compared with 4.3 min in men over 51 years (P < 0.0001). The data were not affected by condom use. This group of researchers then repeated the study using a blinded timer device (to reduce any bias) in a different set of 474 men (mean age 38.5 ± 11.4 SD) from the same countries, publishing the findings in 2009 (Waldinger et al. 2009).

In circumcised men (excluding Turkey) mean IELT was 10.3 min (± 9.3 SD; range 0.6-52.7) and in uncircumcised men 8.8 min (± 6.9 SD; range 0.3-38.6) (P = 0.13): ie, NOT SIGNIFICANT. Median was 7.2 and 6.0, respectively (excluding Turkey: 4.4 min). Alcohol users had a higher mean IELT than non-users (9.0 vs 7.3; P = 0.002).

But there was no difference for condom users and nonusers (7.7 vs 9.0) nor age-group (8.2, 9.2 and 7.3 for 18-30, 31-50 and >51 years), and number of sexual events did not decrease with age category. Erectile dysfunction was 37%, 34% and 40% in the respective age categories. The men’s own estimates of IELT were 31% higher than the actual recorded values. One-third had an IELT shorter than they would have liked (4.9 min) and two-thirds of these were willing to take medication to remedy this. The omission of this study by Frisch et al. would seem to be a major oversight, and this must be remedied.

P 17, para 2, lines 7-11: This flawed study by Sorrells et al. [Ref 27] was referred to above (please see above for reasons why this has no credibility). The authors refer to Michigan, where the anti-circumcision propagandist Van Howe, a co-author on the paper, resides, whereas the study has more involvement of Bay Area residents. The conclusion in the last line is untenable and should be deleted based on the critique referred to above.

P 17, para 3 over to top of page 18: Three studies are cited, from different countries, but which of the 2 from the US they refer to in reciting the findings is not referenced.

It is also not clear what the US study found re circumcision vs lack thereof, as may be relevant to the present data. The Laumann study [Ref 9] found greater ‘sexual difficulties’ (erectile, etc) in UNCIRCUMCISED men as they got older, but this is not mentioned in the Frisch manuscript. I have already provided comments in several places above regarding the actual findings of the Laumann study. Frisch et al. should also mention that Richters et al [Ref 11) – see below – saw no difference in premature ejaculation. Frisch et al. may also like to cite a study of 150 men aged 18 to 60 circumcised for benign disease in London that found identical erectile dysfunction scores before and after (Masood et al. 2005). Of these 74% had no change in libido, 69% had less pain during intercourse (P < 0.05), 44% of the men (P = 0.04) and 38% of the partners (P = 0.02) thought appearance was better after circumcision. Sensation improved in 38% (P = 0.01), was unchanged in 44%, and was worse in 18%. Overall, 61% were pleased and 17% were not, i.e., 3.5 times more were happy with their circumcision.

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PAGE 18, para 1, lines 4-9: The Australian study [Ref 11] also found greater erection problems with age in the uncircumcised. This study was by an outspoken MC opponent, so adding credence to lack of bias in any finding supportive of MC that that study did find, even though it was criticised for various other deficiencies, unrelated to the ones the present authors invoke (Morris 2007). The telephone-based survey by Richters involved approx. 10,000 men in Australia. Fisch et al. should mention that it found circumcised men had FEWER sexual difficulties for a month or more in the previous year (Richters et al. 2006). This was greatest in men over 50, in whom 27% of uncircumcised, but only 15% of circumcised, men reported difficulty keeping an erection (Richters et al. 2006). Physical pain during intercourse was also LEES COMMON among circumcised men. Frisch attempt to dismiss the findings in that survey on grounds that not supported. This includes premature ejaculation that Richters observed was not different. Nor was masturbation different. The circumcised men had significantly more liberal sexual attitudes, just as found in the US study by Laumann et al. [Ref 9]. Although this study, unlike the one in the USA [Ref 9], found uncircumcised men received as much fellatio as the circumcised, this finding did not indicate what type of penis women preferred. Perhaps this might be one of several topics the present authors might want to explore in the future or before publishing their present data.

P 18, para 2: Here they present an inaccurate account of the data from RCTs in Kenya [Ref 50] and Uganda [Ref 49]. The younger men in the Kenyan trial showed a decrease in so-called “sexual problems” in BOTH arms of the trial (not the circumcised arm only, as the authors write), consistent with a maturation effect in these young men. This was not evident in the Ugandan trial, where a broader range of ages was involved. The present authors question the results, calling the findings of difficulties “implausibly low”. This statement is subjective and they have no basis for making such a statement. The authors refer to data collected at 12 months, when the men who had received circumcision were not necessarily fully recovered. Instead of such selective bias in cherry picking data they should have referred to the more appropriate 24-month data which showed no difference. At the 24 month time-point of the Kenyan trial, 64.0% of the circumcised men reported that their penis was “much more sensitive” and 54.5% rated their ease of reaching orgasm as “much more”. These findings contradict claims by opponents of MC, as would appear to be the case for the present authors, that MC decreases sensitivity and sexual experience.

In the trial, more than 99% of men were “satisfied” with their circumcision and the rate of this increased with time. A large and increasing proportion of the men reported having sex more often compared to before they were circumcised. Risky behavior was decreased in the circumcised men and they found it easier to apply a condom. Although penile sensitivity was increased, this was not associated with premature ejaculation. One might therefore conclude from this RCT that, if anything, sexual experience is ENHANCED by MC. P 19, para 2, lines 1-2: The authors need to better enunciate where their findings sit in relation to the general literature on the field they are investigating rather than making flippant comments without any statement to substantiate or even say what their specific objections are. In Ref 54 by Kigozi et al., an African RCT of 455 women, 97% reported either no change (57%) or improved (40%) sexual satisfaction after their male partners had been circumcised (Kigozi et al. 2009). The authors concluded that male circumcision has no deleterious effect on female sexual satisfaction, and that it might, moreover, have social benefits in addition to the established health

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benefits. Speculation about any possible adverse effect on female sexual satisfaction was dispelled. In Africa, women seem to prefer men who are circumcised (Nnko et al. 2001; Westercamp & Bailey 2007). The foreskin was regarded as a source of a bad smell and men too thought it was cleaner. Increased sexual pleasure to both partners was stated, together with lower risk of STIs (Nnko et al. 2001). Women from tribes that do not practice circumcision reported deriving greater sexual pleasure from circumcised men (Moses et al. 1998). Across a diversity of cultures and circumcision practices, more studies than not have found have female preference is for the circumcised penis in partner(s) and son(s) (Williamson & Williamson 1988; Bailey et al. 2002; Kebaabetswe et al. 2003; Lagarde et al. 2003; Scott et al. 2005; Westercamp & Bailey 2007; Madhivanan et al. 2008). When information about benefits and risks was provided, this increased to ~90% (Kebaabetswe et al. 2003). Interestingly, most men, including those who were uncircumcised, preferred circumcision (Kebaabetswe et al. 2003; Lagarde et al. 2003; Rain-Taljaard et al. 2003; Mattson et al. 2005; Scott et al. 2005), and men who preferred to remain uncircumcised were concerned about pain and cost rather than losing their foreskin (Mattson et al. 2005). This should create discord with the present authors, who seem intent on misleading readers.

P 19, para 2, lines 6-10: Here the authors distort and misrepresent the findings in a survey by Wlliamson & Williamson [Ref 52]. In complete contrast to what Fisch et al. say, this study found that a large majority of women preferred the circumcised penis for sexual activity (Williamson & Williamson 1988). In this survey, 90% said the circumcised penis looked “sexier”, 85% said it felt nicer to touch and 55% smelled more pleasant. Even women who had only ever had uncircumcised partners preferred the look of the circumcised penis. Only 2% preferred an uncircumcised penis for fellatio, with 82% preferring the circumcised variety. Preference for intercourse was 71% for the circumcised variety compared to only 6% for the uncircumcised, manual stimulation was 75% vs. 5%, and visual appeal was 76% vs.

4%. It is therefore quite baffling as to how on earth Frisch et al. can state that “only 15% preferred to have sex with circumcised men”!? This is the kind of misinformation that appears on anti-circ websites.

PAGE 19, para 2, lines 6-10: In the Discussion the authors refer to a study by lay anti-circumcision activists [ref 53] that itself was stated by the authors (O’Hara & O’Hara) as being a “preliminary” survey of women “recruited through … an announcement in an anti-circumcision newsletter”. It should therefore come as no surprise that this survey (O'Hara & O'Hara 1999) found the opposite to more credible studies referred to above, noting the earlier Williamson & Williamson survey – which has struck many as curious in that each are by a duo with the same last name! O’Hara & O’Hara acknowledged the “shortcoming” of such recruitment bias. They also stated “this study has some obvious methodological flaws” and that “it is important that these findings be confirmed by a prospective study of a randomly selected population of women.” Thus bias arising from the seriously flawed study design causes the study by O’Hara & O’Hara to lack credibility and whereas most would ignore it, the present authors fail to have given it the critical appraisal that oters have and do not dismiss it as most would. Moreover, others have obtained findings that are the complete opposite, e.g., as far as pain experienced by the woman upon insertion of the penis is concerned, whereas the supposed finding in the present survey that accords with O’Hara & O’Hara, one of the studies that found a preference by women for circumcised men, the respondents remarked that circumcised men enter the woman more easily and cause less trauma (Bailey et al. 2002).

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P 19, para 2, lines 10-13: As to Ref 56, this very weak study in a very low rated journal and conducted by anti-circumcision activists of a biased sample group should be discounted and eliminated from the Discussion. : P 19, para 2, lines 13-16: The authors refer to a survey of women in Spain who had experienced sexual intercourse with the same partner before and 2 months after circumcision (Cortés-González et al. 2008) [Ref 55]. In contrast to what Frisch et al. say, the women found no difference in general sexual satisfaction, pain during vaginal penetration, desire, and vaginal orgasm. In relation to the claimed slight decrease in vaginal lubrication, vaginal lubrication was in fact adequate for 78% of women before, compared to 63% after their partner had been circumcised. This is only a small difference. Perhaps Frisch et al should state a possible reason for this, if it might be the case for a minority of women. In this regard, the inner layer of the foreskin lines a ‘preputial sac’, which becomes a repository for shed cells, secretions, and urinary residue that accumulates (Parkash et al. 1973; Cold & Taylor 1999). It is also a hospitable environment for the growth of bacteria and other microorganisms.

Despite its potential drawbacks as far as hygiene and risk of bacterial vaginosis, etc in women (as shown by RCTs) such ‘smegma’ could work as a lubricant. The degree of wetness under the foreskin is a barometer for hygiene (O'Farrell et al. 2006). Wetness is, moreover, associated with a 40% increase in risk of HIV infection (O'Farrell et al.

2006). A wet penis may enhance attachment of infectious virions for longer, reduce healing after trauma, or may lead to balanitis under the foreskin and consequent micro-ulcerations (O'Farrell et al. 2006).

A more balanced appraisal of the literature than is evident in the present manuscript follows.

P 19, para 2, lines 16-17: Here they refer to studies in Africa where it has been shown previously (and not cited) that women from tribes that do not practice circumcision report deriving greater sexual pleasure from circumcised men (Moses et al. 1998).

Frisch et al. refer to a RCT [Ref 54] of 455 women aged 15-49 years that studied the effect of MC on female sexual satisfaction. This RCT found that the overwhelming majority (97%) reported either no change (57%) or improved (40%) sexual satisfaction after their male partners had been circumcised (Kigozi et al. 2009). The authors concluded that MC has no deleterious effect on female sexual satisfaction.

Frisch attempt to dismiss this study in a difficult o understand way. The statement that make (last line that flows over to page 20) makes no sense whatsoever and must be deleted. The next sentence (lines 2-3 on page 20) is ridiculous because it somehow attempts to compare what each partner having sex is experiencing, is illogical and it too must be deleted. Young adults have stated that circumcision reduces friction during sexual intercourse, enhances the sexual pleasure of both partners, and likened the presence of a foreskin to wearing a condom in that it reduced sensitivity (Kebaabetswe et al. 2003). The ridged band of the foreskin may explain some of such statements, as it may cause abrasions on the vaginal wall.

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PAGE 20, para 2, lines 5-8: This statement goes beyond the overall findings of the survey and is probably wrong anyway, but even if it has some validity applies to a minority, and so should be removed as misleading.

P 20, para 3: This puts an overly optimistic spin on their data. It also fails to refer to the fact that the so-called “difficulties” related to circumcision groups were seen in only a tiny proportion of the population studied. So the advantage claimed of “the large sample size of our study” is simply totally misleading.

PAGE 21, para 2, lines 1-3: These statements support my contention of ignorance, bias or some other questionable aspect of the authors’ ability to write factual information. It is misleading to say there is no role for circumcision in reducing HIV in industrialized nations when the main sourse of infection is receptive anal intercourse (NOT preventable by MC) and injecting drug users (also NOT preventable by MC). But studies of heterosexual intercourse show circumcised men in the US are at reduced risk of HIV infection to a similar extent as shown by the extensive studies elsewhere in the world, including Africa. An association of higher incidence of HIV with being uncircumcised in the USA was first noted in 1989 (Whittington 1989). Then a study of heterosexual couples in Miami found a higher incidence of HIV in men who were uncircumcised. A study in New York City found that risk ratio for HIV infection in heterosexual men as a result of being uncircumcised was 4.1, rate being 2.1% versus 0.6% for uncircumcised men as compared circumcised men (Telzak et al. 1993). Another US study that looked at heterosexual sex found a risk ratio of 2.9 (Kassler & Aral 1995). (See also review by (Moses et al. 1998).) In heterosexual African American men attending STI clinics in Baltimore from 1993 to 2000, the prevalence of HIV was 2.7%. Looking at the data for those with known exposure to HIV, infection was seen in 10.2% of the men who were circumcised, compared with 22.0% of the men who were uncircumcised (adjusted prevalence ratio = 0.49) (Warner et al. 2009).

As far as homosexual men are concerned a study in Seattle found a 2.2-times higher HIV-positivity in the 15% who were uncircumcised (Kreiss & Hopkins 1993). A later study in Seattle found no difference, however (Jameson et al. 2009). But caution is needed in interpretation of the latter results, since they were derived from men attending a STI clinic. Since circumcised men are protected from STI because of being circumcised they will be less likely to attend an STI clinic, meaning data from STI clinic cohorts are biased, i.e, such data do not necessarily represent the prevalence of an STI amongst men of each circumcision status in the general population. The bias is, moreover, away from showing a protective effect of circumcision. Another study, involving 3,257 homosexual men in 6 US cities studied from 1995-1997, identified various risk factors, lack of circumcision once again being found to double the risk of acquiring HIV (Buchbinder et al. 2005). A failed HIV vaccine trial stopped in 2007 noted that “infected men were less likely to be circumcised” (Fox 2007). No association between circumcision status and either HIV or syphilis infection in homosexual men was seen in a San Francisco study, although the authors noted that a large proportion of gay men practice both insertive and receptive anal intercourse (Mor et al. 2007). The latter would dampen the possibility of seeing an association with circumcision status. In New York City, the epicenter of the US HIV epidemic, a 2008 report noted that the prevalence of HIV amongst men who have sex with men is 8.4% (Manning et al. 2007), which is higher than Kenya (7.4%) or Uganda (7.0%) (McKinney et al. 2008). The earliest studies of men who

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have sex with men did not consider different sexual practices. A study in 2001 in Sydney. Australia of homosexual men found no association with circumcision status (Templeton et al. 2009). But when the authors looked at the data for men who only performed INSERTIVE anal sex, an 89% lower rate of HIV infection was seen (Templeton et al. 2009). A US study, involving only Black and Latino MSM was also negative, although men who were insertive-only had 25% and 48% lower HIV in each respective racial group (Millett et al. 2007). Frisch et al. refer to a a metaanalysis by Millett of 18 studies and found HIV was 29% lower in insertive-only MSM (Millett et al. 2008). The authors MUST refer to this important finding. Higher study quality was associated with a reduced odds of HIV infection of circumcised men in the Millett analysis. Prior to the introduction of antiretroviral therapy the protective effect was 53% (Millett et al. 2008). In Soweto, South Africa, MSM had high rates of HIV, it being 34% in gay and 6.4% in bisexual men (Lane et al. 2009).

Circumcision had a 5-fold protective effect against HIV infection in this population (OR 0.20; 95% CI 0.1-0.1; P<0.0001). Most (>60%) of the men in this study practiced insertive anal sex only. Amongst 1,056 initially HIV-negative MSM in Lima, Peru, those who became infected with HIV were more likely to have acquired syphilis (31%) or HSV-2 (8%) and were 4.9 times less likely to be circumcised (4.2% versus 20.6%) (Sanchez et al. 2009). Of those who did not have syphilis or herpes, 20.5% of uncircumcised became infected, whereas none of 12 circumcised men did.

A review concluded that only MSM who are insertive-only may be at lower risk of HIV infection (Templeton et al. 2009). Modeling by these authors in a resource-rich setting (Sydney, Australia) showed that circumcision of MSM, especially those who were insertive-only, would be cost-effective for HIV prevention, with one infection prevented for every 118 circumcisions for men in the insertive-only category (Anderson et al. 2009).

The present authors refer to a 2-year unblinded randomized controlled trial in Rakai, Uganda of the uninfected female partners of men who were already infected with HIV at the time of their circumcision (Wawer et al. 2009) [Ref 61]. This was stopped early because of futility. Although all of the differences were not significantly different, it was of interest that at the first (6-month) follow-up visit, HIV infection was 28% for female partners of men who resumed sex before wound healing, as compared to 9.5% in the partners of men who delayed sex until healing was complete, suggesting that early resumption of sex could have been an important factor in the interpretation of these findings (Baeten et al. 2009; Wawer et al. 2009), which Frisch et al. do not do. Frisch et al. should in fact have cited a meta-analysis of all relevant studies and that found that male circumcision led to a non-significant reduction in risk to women of 20% (95% CI 0.54-1.19) (Weiss et al. 2009). But this did not include a later study of 7 sites in eastern Africa that noted 38% lower HIV in women who had infected male partners who were circumcised (Baeten et al. 2009; Baeten et al. 2010). The apparent contradiction between findings from the observational studies and those from the RCTs may be a result of the former being to do with men circumcised before puberty, whereas the RCT data were from men circumcised as adults (Tobian et al. 2010). A recent paper estimated that “circumcision confers a 46% reduction in the rate of male-to-female HIV transmission and that if this reduction begins 2-14;years after the procedure, the impact of circumcision is substantially enhanced and accelerated compared with previous projections with no such effect - increasing by 40% the infections averted by the intervention overall and doubling the number of infections averted among women”, leading to a conclusion that “Communities, and especially women, may

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benefit much more from circumcision interventions than had previously been predicted, and these results provide an even greater imperative to increase scale-up of safe male circumcision services” (Hallett et al. 2010). These are the refernces that the authors should have been citing, not ones slected and then misconstrued for the authors own apparent purposes. Moreover, women will see indirect benefits of male circumcision because a decrease in the pool of infected men will, in the long-term, reduce HIV transmission to women (Chersich & Rees 2008). UNAIDS has estimated that, in Africa, for every 5% increase in male circumcision, HIV would decrease by 2% in women (Kagumire 2008).

The relatively moderate HIV infection rate in the USA is likely contributed by the high prevalence of circumcision in this country (Addanki et al. 2008). A position paper in 2007 stated “it is likely that circumcision will decrease the probability of a man acquiring HIV via penile-vaginal sex with an HIV-infected woman in the USA” and that “some sexually active men may consider circumcision as an additional HIV prevention measure” (Sullivan et al. 2007). This was in addition to condoms of course, although in the USA condoms were never used during heterosexual sex with a non-primary partner in the case of 16% of men and 24% of women (Sanchez et al.

2006). The Report warned, however, that any reduction in reimbursement by public and private medical insurance for circumcision, and any decline in rate of circumcision, could reverse the benefit that the USA has enjoyed to date because of its high rate of circumcision (Sullivan et al. 2007). The Centers for Disease Control announced in 2009 that it would be recommending infant male circumcision for prevention of HIV and other medical conditions (New York Times, Aug 24, 2009) (Rabin 2009), thus answering those who had been equivocating on this issue (Xu et al. 2009) [Ref 59]. In the USA, where the overall circumcision rate is 79%, neonatal circumcision was calculated to reduce the lifetime risk of HIV amongst all males by 16% (8% in white males and 21% in black males) [Sansom et al., 2010]. It was also cost-saving, even after discounting at a rate of 3% per year. The net cost of newborn circumcision per quality-adjusted life year (QALY) saved was $87,792 for white males and was even better for black and Hispanic males.

One might expect men who have sex with men (MSM) to have a greater appreciation of differences by circumcision status. A study Sydney, Australia, of MSM in fact found no differences between the circumcised and uncircumcised in participation in insertive or receptive anal intercourse, difficulty in using condoms, or sexual problems such as loss of libido (Mao et al. 2008). Comparing those who had been circumcised in infancy with those circumcised later (because of phimosis or parental wishes), the latter were slightly more likely to practice receptive anal sex (88% vs 75%), to experience erectile difficulties (52% vs 47%), and were slightly less likely to practice insertive anal sex (15% vs 23%). Rather than this being due to circumcision per se, it was suggested that the differences reflected preferences that existed prior to circumcision, these having arising from foreskin pathologies such as phimosis.

PAGE 21, para 2 to page 22: Advice to the readership about HIV, etc is irrelevant, not novel, and should be deleted. WHO and others are better versed in the research than the present authors and do not need their advice. The ethics of MC have been considered by professional ethicists, leading them to argue that “Neonatal male circumcision is medically necessary and ethically imperative” (Clark et al. 2007).

Other ethicists have concluded that “non-therapeutic circumcision of infant boys is a

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suitable matter for parental consideration” (Benatar & Benatar 2003).A review from South Africa suggests that parents from all ethnic groups should be advised to have their sons circumcised medically at birth and that “to the objection that this flies in the face of long-standing cultural values, one may counter quite simply that cultures do, and should, change: and there is no better reason to change than in the interests of survival” (Hargrove 2008). As a result of this kind of tirade the length of the Discussion blows out excessively, and is unneccessary.

P 22, para 2: Conclusion: Must be rewritten completely to remove the unsubstantiated and distorted claims. The conclusion must provide a balanced overview consistent with the weaknesses of the study, and may mean any reference to problems will need to be deleted after adjustment of the data for multiple comparisons.

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