Background:The United Kingdom (UK) does not have an evidence-based policy on circumcision for non-medical reasons. The aim of this systematic review is to address the question "Is non-therapeutic male circumcision (NTMC) a beneficial public health intervention for the UK?". Methods:A PRISMA-compliant, PROSPERO-registered, systematic review was conducted involving PubMed, EMBASE, SCOPUS and Cochrane databases searches for male circumcision articles to January 2024. Those rated high-quality by the Scottish Intercollegiate Grading Network (SIGN) system were included in results. Results:Searches retrieved 183 articles rated as high-quality and relevant to the objectives. These showed early circumcision provided immediate and lifetime medical benefits by protecting against urinary tract infections, penile dermatological inflammation, phimosis, inferior penile hygiene, candida, sexually transmitted infections (STIs) such as human papillomavirus, genital herpes virus type-2, human immunodeficiency virus, and penile and prostate cancers. NTMC had no long-term adverse effect on sexual function or pleasure. Female partners were at lower STI and cervical cancer risk. A risk-benefit analysis for the UK found benefits of early circumcision exceeded procedural risks by over 200 to one, and that as many as half of uncircumcised males may be affected during their lifetime from an adverse medical condition attributable to foreskin retention. Costs for treatment of these exceeds procedural costs for early NTMC. A recent systematic review found NTMC of male minors is legal and supported by ethical arguments as well as the United Nations Convention of the Rights of the Child which emphasizes the right to health. Routine provision of accurate, evidence-based information on risks and benefits should assist parents in making an informed decision about circumcision should they have a boy. Cost coverage is warranted. Conclusions:In summary, the medical evidence supports early circumcision as a public health recommendation in the UK.

Background. Cervical screening with high-precision assays such as human papillomavirus (HPV) DNA testing is essential for the detection and treatment of precancerous lesions. HPV genotypes have different oncogenic potential and require different clinical management, illustrating the importance of extended genotyping. HPV quantification has demonstrated clinical relevance in both diagnosis and treatment. Objective. To develop a droplet digital PCR assay for the detection and quantification of 16 HPV genotypes, with comparison to a commercial test and validation on clinical samples. Methods. Primers and probes were designed to target the E6 region of 16 HPV genotypes: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 73 and 82. Each target was evaluated to assess performance and reliability using synthetic DNA constructs, quantified international reference standards and clinical screening samples (n=303) genotyped using the Seegene Anyplex II HR HPV Detection assay. Results. Each assay demonstrated high target specificity, without cross-reactivity observed among the HPV genotypes selected. Using international molecular standards, the assay reliably detected high-risk genotypes across serial dilutions, with detection down to the level of one international unit or genome equivalent per microlitre. When applied to clinical samples with and without a histological diagnosis of cervical intraepithelial neoplasia 2 or worse (CIN2+), the assay reliably detected key HPV genotypes, with the exception of 7 of 234 (3%) of HPV-positive samples, all of which exhibited very low viral load. Conclusion. Although previous studies have described digital PCR methods targeting HPV E6, they have typically focused on a limited number of genotypes. This study expands upon existing methodology by introducing a sensitive and specific method for detection and quantification of 16 high-risk and potentially high-risk HPV genotypes.

Circumcision of males is one of the world's most common and oldest surgical procedures. It is practiced by a wide diversity of cultures worldwide but is also a matter of considerable social and medical controversy. Advocates claim that it has substantial lifetime medical and health benefits, particularly in countries with high rates of HIV, where there is evidence that it may have a protective effect. Critics claim that it is an unnecessary mutilation, particularly when carried out on an infant who is unable to consent to the procedure. In their view, the risk/benefit ratio does not justify the intervention, particularly in developed countries. US doctors have traditionally been more enthusiastic advocates than their counterparts in the United Kingdom and Europe. Social scientists may be called upon to provide accurate information regarding contemporary circumcision practices. There is also a considerable research agenda on the sexual politics of circumcision and the various faith and material interests involved in the controversy over the risk/benefit balance in developed countries.

Contrasting ethical and legal arguments have been made concerning neonatal male circumcision (NMC) that merit the first systematic review on this topic. We performed PRISMA-compliant keyword searches of PubMed, EMBASE, SCOPUS, LexisNexis, and other databases and identified 61 articles that met the inclusion criteria. In the bibliographies of these articles, we identified 58 more relevant articles and 28 internet items. We found high-quality evidence that NMC is a low-risk procedure that provides immediate and lifetime medical and health benefits and only rarely leads to later adverse effects on sexual function or pleasure. Given this evidence, we conclude that discouraging or denying NMC is unethical from the perspective of the United Nations Convention on the Rights of the Child, which emphasizes the right to health. Further, case law supports the legality of NMC. We found, conversely, that the ethical arguments against NMC rely on distortions of the medical evidence. Thus, NMC, by experienced operators using available safety precautions, appears to be both legal and ethical. Consistent with this conclusion, all of the evidence-based pediatric policies that we reviewed describe NMC as low-risk and beneficial to public health. We calculated that a reduction in NMC in the United States from 80% to 10% would substantially increase the cases of adverse medical conditions. The present findings thus support the evidence-based NMC policy statements and are inconsistent with the non-evidence-based policies that discourage NMC. On balance, the arguments and evidence reviewed here indicate that NMC is a medically beneficial and ethical public health intervention early in life because it reduces suffering, deaths, cases, and costs of treating adverse medical conditions throughout the lifetimes of circumcised individuals.

BACKGROUND:Approximately half of ovarian tumors have defects within the homologous recombination repair pathway. Tumors carrying pathogenic variants (PVs) in BRCA1/BRCA2 are more likely to respond to poly-ADP ribose polymerase (PARP) inhibitor treatment. Large rearrangements (LRs) are a challenging class of variants to identify and characterize in tumor specimens and may therefore be underreported. This study describes the prevalence of pathogenic BRCA1/BRCA2 LRs in ovarian tumors and discusses the importance of their identification using a comprehensive testing strategy. METHODS:Sequencing and LR analyses of BRCA1/BRCA2 were conducted in 20 692 ovarian tumors received between March 18, 2016 and February 14, 2023 for MyChoice CDx testing. MyChoice CDx uses NGS dosage analysis to detect LRs in BRCA1/BRCA2 genes using dense tiling throughout the coding regions and limited flanking regions. RESULTS:Of the 2217 PVs detected, 6.3% (N = 140) were LRs. Overall, 0.67% of tumors analyzed carried a pathogenic LR. The majority of detected LRs were deletions (89.3%), followed by complex LRs (5.7%), duplications (4.3%), and retroelement insertions (0.7%). Notably, 25% of detected LRs encompassed a single or partial single exon. This study identified 84 unique LRs, 2 samples each carried 2 unique LRs in the same gene. We identified 17 LRs that occurred in multiple samples, some of which were specific to certain ancestries. Several cases presented here illustrate the intricacies involved in characterizing LRs, particularly when multiple events occur within the same gene. CONCLUSIONS:Over 6% of PVs detected in the ovarian tumors analyzed were LRs. It is imperative for laboratories to utilize testing methodologies that will accurately detect LRs at a single exon resolution to optimize the identification of patients who may benefit from PARP inhibitor treatment.

Background: Personalized breast cancer (BC) risk assessment depends on known traditional risk factors, specific germline mutations, and genome-wide polygenic risk scores (PRS). PRS explains a substantial proportion of genetic BC susceptibility. Accuracy of BC risk prediction may be improved by combining a PRS with traditional risk factors. We recently developed and validated a 149-SNP PRS for women of diverse ancestries using ancestry-informative genetic markers and combined this with version 7 of the Tyrer-Cuzick (TC) model to generate a Combined Risk Score (CRS). Here, we describe a pre-specified prospective longitudinal clinical validation of CRS as a predictor of BC risk. Methods: Women in the U.S. who were referred for clinical genetic testing between January 2017 and February 2019 were matched to medical and hospital claims in an anonymized dataset. Women with a pathogenic mutation in a BC-related gene were excluded from analysis. Follow-up began 4 months after testing and extended to the earliest date of BC diagnosis, censoring at the time of BC preventive treatment, or November 1, 2019. Incident BC events were determined by an ICD10 code of C50.* and confirmed by relevant treatment codes. CRS calibration was evaluated by the ratio of observed (O) to expected (E) incident BCs for the full cohort, and for women split into event-based 5-year CRS risk deciles. Cox proportional hazards models were used to evaluate discriminatory accuracy in terms of hazard ratios (HR) with 95% confidence intervals (CI) and p-values from likelihood ratio chi-squared statistics. Kaplan-Meier analysis was used to examine risk for women split into high- or low-risk groups according to a 3% 5-year CRS risk threshold. Results: 130,058 women with 148,349 total patient years met study eligibility criteria and were matched to claims data. Over a median (range) follow-up of 12.1 (4.0-29.5) months, 340 incident BC events were observed. The CRS was well calibrated in the overall cohort with an O/E ratio of 1.11 (95% CI=0.99-1.23) and within deciles of predicted risk (Table). Importantly, in the highest risk decile, the O/E was 0.91 (95% CI=0.63-1.27) with CRS, but 0.67 (95% CI=0.46-0.94) with TC alone, illustrating the superior calibration of CRS. In a Cox model adjusted for age at testing, PRS had an HR per standard deviation (SD) of 1.48 (95% CI=1.33-1.64, p=2.55×10-13); the HR/SD was 1.43 (95% CI=1.29-1.59, p=1.61×10-11) after adjusting for family history. In a bivariate analysis using both CRS and TC to predict time to BC, CRS added significantly to the model after accounting for TC (HR/SD=2.89, 95% CI=2.12-3.94, p=1.20×10-11), whereas TC did not add significant information after accounting for CRS. 15,986 (12.3%) women were above the CRS high-risk threshold, including 123 with events. A total of 10,248 (7.9%) women were reclassified by the CRS model compared to the TC model. Among women who were classified as high-risk by TC, 32.6% were reclassified as low-risk by CRS; among those classified as low-risk by TC, 4.3% were reclassified as high-risk by CRS. The CRS high-risk group experienced events at over three times the rate of the low-risk group (HR=3.75, 95% CI=3.00-4.68, p=6.39×10-27). Conclusion: The CRS was well-calibrated in predicting BC and significantly improved upon a traditional risk factor model. Clinical use of the CRS may lead to improved BC prevention and screening strategies. Table: Absolute risk calibration by 5-year risk decile Incidence is reported per 1,000 women-years. 34 breast cancers were observed per decile. Citation Format: Brent Mabey, Elisha Hughes, Braden Probst, Holly J. Pederson, Timothy Simmons, Brian Morris, Brooke Hullinger, Susan Domchek, Charis Eng, Monique Gary, Jennifer Klemp, Semanti Mukherjee, Vijai Joseph, Kenneth Offit, Olufunmilayo I. Olopade, Sandhya Pruthi, Allison W. Kurian, Mark E. Robson, Pat Whitworth, Susanne Wagner, Jerry Lanchbury, Thomas Slavin, Alexander Gutin. PD14-05 Prospective longitudinal validation of a breast cancer risk prediction model in a cohort of 130,058 women [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD14-05.

The British Medical Association (BMA) guidance on non-therapeutic circumcision (NTMC) of male children is limited to ethical, legal and religious issues. Here we evaluate criticisms of the BMA's guidance by Lempert et al. While their arguments promoting autonomy and consent might be superficially appealing, their claim of high procedural risks and negligible benefits seem one-sided and contrast with high quality evidence of low risk and lifelong benefits. Extensive literature reviews by the American Academy of Pediatrics and the United States Centers for Disease Control and Prevention in developing evidence-based policies, as well as risk-benefit analyses, have found that the medical benefits of infant NTMC greatly exceed the risks, and there is no reduction in sexual function and pleasure. The BMA's failure to consider the medical benefits of early childhood NTMC may partly explain why this prophylactic intervention is discouraged in the United Kingdom. The consequence is higher prevalence of preventable infections, adverse medical conditions, suffering and net costs to the UK's National Health Service for treatment of these. Many of the issues and contradictions in the BMA guidance identified by Lempert et al stem from the BMA's guidance not being sufficiently evidence-based. Indeed, that document called for a review by others of the medical issues surrounding NTMC. While societal factors apply, ultimately, NTMC can only be justified rationally on scientific, evidence-based grounds. Parents are entitled to an accurate presentation of the medical evidence so that they can make an informed decision. Their decision either for or against NTMC should then be respected.

Background: It is well established that mid-life hypertension increases risk of dementia, whereas the association of late-life hypertension with dementia is unclear. Objective: To determine whether FOXO3 longevity-associated genotype influences the association between late-life hypertension and incident dementia. Methods: Subjects were 2,688 American men of Japanese ancestry (baseline age: 77.0 +/- 4.1 years, range 71-93 years) from the Kuakini Honolulu Heart Program. Status was known for FOXO3 rs2802292 genotype, hypertension, and diagnosis of incident dementia to 2012. Association of FOXO3 genotype with late-life hypertension and incident dementia, vascular dementia (VaD) and Alzheimer's disease (AD) was assessed using Cox proportional hazards models. Results: During 21 years of follow-up, 725 men were diagnosed with all-cause dementia, 513 with AD, and 104 with VaD. A multivariable Cox model, adjusting for age, education, APOE epsilon 4, and cardiovascular risk factors, showed late-life hypertension increased VaD risk only (HR = 1.71, 95% CI = 1.08-2.71, p = 0.022). We found no significant protective effect of FOXO3 longevity genotype on any type of dementia at the population level. However, in a full Cox model adjusting for age, education, APOE epsilon 4, and other cardiovascular risk factors, there was a significant interaction effect of late-life hypertension and FOXO3 longevity genotype on incident AD (beta = -0.52, p = 0.0061). In men with FOXO3 rs2802292 longevity genotype (TG/GG), late-life hypertension showed protection against AD (HR = 0.72; 95% CI = 0.55-0.95, p = 0.021). The non-longevity genotype (TT) (HR = 1.16; 95% CI = 0.90-1.51, p = 0.25) had no protective effect. Conclusion: This longitudinal study found late-life hypertension was associated with lower incident AD in subjects with FOXO3 genotype.

ObjectiveThe purpose of this study is to examine the relationship , if any, COVID-19 shelter-in-place orders had on mental health outcomes for undergraduate students.ParticipantsThis study was comprised of 138 students, all of which were recruited from a single four-year college in the Midwest.MethodsA pre-/post-test comparative design was adopted and was leveraged to capture data regarding students’ experiences before and after the shelter-in-place orders were enacted to determine if there was a marked effect between the pre-virus condition and the situation after stay at home orders went into effect.ResultsPaired sample t-test were conducted to determine whether the mental health outcomes of depression, anxiety and stress were significantly changed from before to after COVID-19 shelter in place disorders. While anxiety and stress scores were revealed no significant difference, significantly greater depression was revealed after COVID-19.ConclusionOverall, the results of this study highlight the need for colleges to be aware of the mental health toll that the pandemic and shelter-in-place orders may take on their students. Though this toll registered only directly in depression, there remains significant reasons to believe the situation may also affect stress and anxiety regardless of the absence of evidence for these factors in this study. There remains much to be done in assessing the ultimate impact of the pandemic on students’ mental health.

Objective: To determine the association between the longevity-associated G allele of FOXO3 SNP rs2802292 and risk of hypertension mediated intracerebral haemorrhage (ICH). Design: Prospective population-based longitudinal study. Methods: The cohort comprised Japanese American men living on Oahu, Hawaii, who were recruited from 1965 to 1968 for the Kuakini Honolulu Heart Program. Age adjusted incidence of ICH by hypertension status was assessed for the whole cohort after stratifying by FOXO3 genotype. Cox regression models, adjusted for age, cardiovascular risk factors, and FOXO3 and APOE genotypes, were utilized to determine the relative risk of effect of hypertension on ICH. All models were created for the whole cohort and stratified by FOXO3 G allele versus TT genotype. Results: Among 6,469 men free of baseline stroke, FOXO3 G allele was present in 3,009 (46.5%) participants. Overall, 183 subjects developed ICH over the 34 year follow-up period. Age adjusted ICH incidence rates were 0.90 and 1.32 per 1,000 person years followup in those without and with hypertension, respectively (p = 0.002). After stratifying by FOXO3 genotype, this association was no longer significant in G allele carriers. In the whole cohort, hypertension was an independent predictor of ICH (RR = 1.70, 95%CI 1.25, 2.32; p = 0.0007). In stratified analyses, hypertension remained an independent predictor of ICH among the FOXO3 TT genotype group (RR = 2.02, 95% CI 1.33, 3.07; p = 0.001), but not in those who were carriers of the protective (G) allele of FOXO3 (RR = 1.39, 95% CI 0.88, 2.19; p = 0.15). Conclusions: The longevity associated FOXO3 G allele mitigates the impact of hypertension on ICH risk. Our finding has implications for risk assessment of patients with hypertension.

The association of late-life hypertension (LHTN) with Alzheimer’s disease (AD) remains controversial. We hypothesize that FOXO3 longevity-associated genotype modulates the association between LHTN and incident AD. Subjects were 2,688 American men of Japanese ancestry (baseline age: 77.0 ± 4.1 years, range 71-93 years) from the Kuakini Honolulu Heart Program. Status was known for FOXO3 rs2802292 genotype, LHTN at baseline, and diagnosis of incident dementia over 21 years follow-up. Association of FOXO3 genotype with LHTN and incident all-cause dementia, vascular dementia (VD) and Alzheimer’s disease was assessed using Cox regression. During the follow-up, 725 men were diagnosed with all-cause dementia, 513 with AD and 104 with VD. A multivariable Cox model, adjusting for age, education, APOE-ε4 and cardiovascular risk factors, showed LHTN increased VD risk (HR = 1.71, 95%CI = 1.08–2.71, p = 0.022), but not AD risk. We found no significant protective effect of FOXO3 longevity genotype, nor of LHTN, on all-cause dementia and AD at the population level. However, in a full Cox model adjusting for age, education, APOE-ε4 and other cardiovascular risk factors, there was a significant interaction effect of LHTN and FOXO3 longevity genotype on incident AD (ß = –0.52, p = 0.0061). In men with FOXO3 rs2802292 longevity genotype ( TG / GG ), LHTN showed protection against AD (HR = 0.72; 95% CI = 0.55–0.95, p = 0.021). In men with FOXO3 rs2802292 non-longevity genotype ( TT ), LHTN had no protective effect (HR = 1.16; 95% CI = 0.90-1.51, p = 0.25). Since the effect of LHTN on AD incidence differed according to FOXO3 genotype, the overall effect, namely, a weighted average effect of LHTN on AD across different FOXO3 genotypes, would be moving towards the null (i.e., HR = 1). This would explain why most studies have found no significant association between LHTN and AD. One exception is the Ibadan study, in which all participants were African American. African Americans have the highest proportion (94%) of FOXO3 rs2802292 longevity genotype (TG/GG) in all races, and the strongest effect of LHTN in protecting against AD (RR = 0.33). This longitudinal study found that FOXO3 genotype modulates the effect of late-life hypertension on incident AD, thus explaining the conflicting data on late-life hypertension and Alzheimer’s disease.

Tye and Sardi recently reviewed the evidence purporting to implicate male circumcision, especially when performed early in infancy, in psychological problems in men. Here we provide a critical evaluation to determine the veracity of their evidence and claims. Missing from their review were critiques pointing out fundamental flaws in key studies. We argue that psychological stress in some men may be caused by anti-circumcision propaganda telling them that they are victims of “genital mutilation”, a term adopted from dissimilar female practices in particular ethnic groups. Sexual dissatisfaction results. We critically discuss claims about foreskin “gliding”, the eccentric foreskin-related sexual practice of “docking”, and the use of lubricant in masturbation. We further find that a study claiming to show numerous differences in socio-affective processing in men circumcised as neonates stem from statistically flawed and one-sided data that has been misinterpreted, and in fact shows the opposite of the hypothesis that psychological problems in some men can be attributed to the pain of their circumcision as newborns. Importantly, since the brain regions responsible for empathy, namely subcortical gray matter and white matter in frontal and parietal regions, were similar in neonatally circumcised and uncircumcised men, the null hypothesis remains null. In conclusion, we find no compelling evidence to support newborn circumcision pain being responsible for psychological problems in neonatally circumcised men. Men who come to believe that they are victims of their infant circumcision are in actual fact likely victims of false claims perpetrated by activist community groups with trenchant opposition to circumcision.

Introduction: Hypertension is a pathophysiological stress. Growth differentiation factor 15 (GDF15) is a stress-response protein, and a predictor for heart disease. The effects of the longevity genotype of FOXO3, a stress-response and prominent longevity-associated gene, on mortality vary in normotensive and hypertensive men. Hypothesis: The effect of GDF15 concentration on the risk of incident coronary heart disease (CHD) is different in men with different hypertension status. Methods: The Kuakini Honolulu Heart Program (KHHP) is a longitudinal study of cardiovascular diseases that started in 1965 involving 8,006 Japanese-American men in Hawaii. Proteomic analyses were performed using serum from KHHP exam 4 (1991-1993, ages 71-93) in a random sample (n=1,000) of men who in mid-life had been free of chronic diseases such as CHD, stroke, cancer, and diabetes. Participants were followed for incident CHD event (first event of MI, coronary insufficiency, angina, CABG, angioplasty, silent MI and CHD death) through December 1999. The Cox proportional hazards model was used to assess potential association of GDF15 concentration and hypertension (SBP/DBP≥160/95 mmHg or on anti-hypertensives) with incident CHD. Results: We excluded 5 men missing GDF15 data and 221 men with diseases including CHD, CHF, atrial fibrillation, LVH and stroke at baseline (KHHP exam 4). During 9 years of follow-up (median 7.92 years), 60 men developed CHD. To eliminate the possible recursive-effect of preclinical CHD on GDF15 at baseline, 6 CHD cases diagnosed within the first year of follow-up were excluded. So, there were 768 men available for analysis. Participants were divided, using tertiles of GDF15 concentration, into two groups: low-medium GDF15 (in low or middle tertile) and high GDF15 (in upper tertile). Multivariate Cox model adjusting for age, BMI, smoking (pack-years), cholesterol, HDL, diabetes and serum glucose showed a significant interaction effect of hypertension and high GDF15 on incident CHD (p=0.019); HR (95%CI) of high GDF15 vs low-medium GDF15 on CHD was 4.56 (1.51-13.76; p=0.007) in normotensive men, and 0.97 (0.49-1.92; p=0.93) in hypertensive men. Conclusions: High GDF15 concentration increases CHD risk in normotensive men, but not in hypertensive men.

Wastewater monitoring of SARS-CoV-2 presents a means of tracking COVID-19 community infection dynamics on a broader geographic scale. However, accounting for environmental and sample-processing losses may be necessary for wastewater measurements to readily inform our understanding of infection prevalence. Here, we present measurements of the SARS-CoV-2 N1 and N2 gene targets from weekly wastewater samples at three sites in Hamilton County, Ohio, during an increase and subsequent decline of COVID-19 infections. The concentration of N1 or N2 RNA in wastewater, measured over the course of six months, ranged from below the detection limit to over 104 gene copies/l, and correlated with case data at two wastewater treatment plants, but not at a sub-sewershed-level sampling site. We also evaluated the utility of a broader range of variables than has been reported consistently in previous work, in improving correlations of SARS-CoV-2 concentrations with case data. These include a spiked matrix recovery control (OC43), flow-normalization, and assessment of fecal loading using endogenous fecal markers (HF183, PMMoV, crAssphage). We found that adjusting for recovery, flow, and fecal indicators increased these correlations for samples from a larger sewershed (serving ~488,000 people) with greater industrial and stormwater inputs, but raw N1/N2 concentrations corresponded better with case data at a smaller, residential-oriented sewershed. Our results indicate that the optimal adjustment factors for correlating wastewater and clinical case data moving forward may not be generalizable to all sewersheds.