Neonatal Male Circumcision: Clearly Beneficial for Public Health or an Ethical Dilemma? A Systematic Review.

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.

FOXO3 longevity genotype attenuates the impact of hypertension on cerebral microinfarct risk.

OBJECTIVE: The G -allele of FOXO3 SNP rs2802292 , which is associated with human resilience and longevity, has been shown to attenuate the impact of hypertension on the risk of intracerebral hemorrhage (ICH). We sought to determine whether the FOXO3 G -allele similarly attenuates the impact of hypertension on the risk of cerebral microinfarcts (CMI). METHODS: From a prospective population-based cohort of American men of Japanese ancestry from the Kuakini Honolulu Heart Program (KHHP) and Kuakini Honolulu-Asia Aging Study (KHAAS) that had brain autopsy data, age-adjusted prevalence of any CMI on brain autopsy was assessed. Logistic regression models, adjusted for age at death, cardiovascular risk factors, FOXO3 and APOE-ε4 genotypes, were utilized to determine the predictors of any CMI. Interaction of FOXO3 genotype and hypertension was analyzed. RESULTS: Among 809 men with complete data, 511 (63.2%) participants had evidence of CMI. A full multivariable model demonstrated that BMI [odds ratio (OR) 1.07, 95% confidence interval (CI) 1.01-1.14, P  = 0.015) was the only predictor of CMI, while hypertension was a borderline predictor (OR 1.44, 95% CI 1.00-2.08, P  = 0.052). However, a significant interaction between FOXO3 G -allele carriage and hypertension was observed ( P  = 0.020). In the stratified analyses, among the participants without the longevity-associated FOXO3 G -allele, hypertension was a strong predictor of CMI (OR 2.25, 95% CI 1.34-3.77, P  = 0.002), while among those with the longevity-associated FOXO3 G -allele, hypertension was not a predictor of CMI (OR 0.88, 95% CI 0.51-1.54, P  = 0.66). CONCLUSION: The longevity-associated FOXO3 G -allele mitigates the impact of hypertension on the risk of CMI.

Genes That Extend Lifespan May Do So by Mitigating the Increased Risk of Death Posed by Having Hypertension.

BACKGROUND: Genetic factors influence lifespan. In humans, there appears to be a particularly strong genetic effect in those aged ≥ 90 years. An important contribution is nutrient sensing genes which confer cell resilience. METHODS: Our research has been investigating the genetic factors by longitudinal studies of American men of Japanese descent living on the island of Oahu in Hawaii. This cohort began as the Honolulu Heart Program in the mid-1960s and most subjects are now deceased. RESULTS: We previously discovered various genes containing polymorphisms associated with longevity. In recent investigations of the mechanism involved we found that the longevity genotypes ameliorated the risk of mortality posed by having a cardiometabolic disease (CMD)-most prominently hypertension. For the gene FOXO3 the protective alleles mitigated the risk of hypertension, coronary heart disease (CHD) and diabetes. For the kinase MAP3K5 it was hypertension, CHD and diabetes, for the kinase receptor PIK3R1 hypertension, CHD and stroke, and for the growth hormone receptor gene (GHR) and vascular endothelial growth factor receptor 1 gene (FLT1), it was nullifying the higher mortality risk posed by hypertension. Subjects with a CMD who had a longevity genotype had similar survival as men without CMD. No variant protected against risk of death from cancer. We have postulated that the longevity-associated genotypes reduced mortality risk by effects on intracellular resilience mechanisms. In a proteomics study, 43 "stress" proteins and associated biological pathways were found to influence the association of FOXO3 genotype with reduced mortality. CONCLUSIONS: Our landmark findings indicate how heritable genetic components affect longevity.

Incidence of Alzheimer's Disease in Men with Late-Life Hypertension Is Ameliorated by FOXO3 Longevity Genotype.

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, APOEɛ4, 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, APOEɛ4, and other cardiovascular risk factors, there was a significant interaction effect of late-life hypertension and FOXO3 longevity genotype on incident AD (ß= -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.

The landscape of BRCA1 and BRCA2 large rearrangements in an international cohort of over 20 000 ovarian tumors identified using next-generation sequencing.

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.

Vascular endothelial growth factor receptor 1 gene (FLT1) longevity variant increases lifespan by reducing mortality risk posed by hypertension.

Longevity is written into the genes. While many so-called "longevity genes" have been identified, the reason why particular genetic variants are associated with longer lifespan has proven to be elusive. The aim of the present study was to test the hypothesis that the strongest of 3 adjacent longevity-associated single nucleotide polymorphisms - rs3794396 - of the vascular endothelial growth factor receptor 1 gene, FLT1, may confer greater lifespan by protecting against mortality risk from one or more adverse medical conditions of aging - namely, hypertension, coronary heart disease (CHD), stroke, and diabetes. In a prospective population-based longitudinal study we followed 3,471 American men of Japanese ancestry living on Oahu, Hawaii, from 1965 until death or to the end of December 2019 by which time 99% had died. Cox proportional hazards models were used to assess the association of FLT1 genotype with longevity for 4 genetic models and the medical conditions. We found that, in major allele recessive and heterozygote disadvantage models, genotype GG ameliorated the risk of mortality posed by hypertension, but not that posed by having CHD, stroke or diabetes. Normotensive subjects lived longest and there was no significant effect of FLT1 genotype on their lifespan. In conclusion, the longevity-associated genotype of FLT1 may confer increased lifespan by protecting against mortality risk posed by hypertension. We suggest that FLT1 expression in individuals with longevity genotype boosts vascular endothelial resilience mechanisms to counteract hypertension-related stress in vital organs and tissues.

Proteomic basis of mortality resilience mediated by FOXO3 longevity genotype.

FOXO3 is a ubiquitous transcription factor expressed in response to cellular stress caused by nutrient deprivation, inflammatory cytokines, reactive oxygen species, radiation, hypoxia, and other factors. We showed previously that the association of inherited FOXO3 variants with longevity was the result of partial protection against mortality risk posed by aging-related life-long stressors, particularly cardiometabolic disease. We then referred to the longevity-associated genotypes as conferring "mortality resilience." Serum proteins whose levels change with aging and are associated with mortality risk may be considered as "stress proteins." They may serve as indirect measures of life-long stress. Our aims were to (1) identify stress proteins that increase with aging and are associated with an increased risk of mortality, and (2) to determine if FOXO3 longevity/resilience genotype dampens the expected increase in mortality risk they pose. A total of 4500 serum protein aptamers were quantified using the Somalogic SomaScan proteomics platform in the current study of 975 men aged 71-83 years. Stress proteins associated with mortality were identified. We then used age-adjusted multivariable Cox models to investigate the interaction of stress protein with FOXO3 longevity-associated rs12212067 genotypes. For all the analyses, the p values were corrected for multiple comparisons by false discovery rate. This led to the identification of 44 stress proteins influencing the association of FOXO3 genotype with reduced mortality. Biological pathways were identified for these proteins. Our results suggest that the FOXO3 resilience genotype functions by reducing mortality in pathways related to innate immunity, bone morphogenetic protein signaling, leukocyte migration, and growth factor response.

Forkhead box O3 longevity genotype may attenuate the impact of hypertension on risk of intracerebral haemorrhage.

OBJECTIVE: Since the G allele of forkhead box O3 ( FOXO3 ) single nucleotide polymorphism (SNP) rs2802292 is associated with resilience and longevity, ostensibly by mitigating the adverse effects of chronic cardiometabolic stress on mortality, our aim was to determine the association between the FOXO3 SNP rs2802292 genotype and risk of hypertension-mediated intracerebral haemorrhage (ICH). METHODS: From a prospective population-based cohort of Japanese American men from the Kuakini Honolulu Heart Program (KHHP), age-adjusted prevalence of ICH by hypertension 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 relative risk of hypertension's effect on ICH. All models were created for the whole cohort and stratified by FOXO3 G -allele carriage vs. TT genotype. RESULTS: Among 6469 men free of baseline stroke, FOXO3 G -allele carriage was seen in 3009 (46.5%) participants. Overall, 183 participants developed ICH over the 34-year follow-up period. Age-adjusted ICH incidence was 0.90 vs. 1.32 per 1000 person-years follow-up 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 (relative risk [RR] = 1.70, 95% confidence interval [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 FOXO3 G -allele carriers (RR = 1.39, 95% CI 0.88, 2.19; P  = 0.15). CONCLUSIONS: The longevity-associated FOXO3   G allele may attenuate the impact of hypertension on ICH risk.

Evidence-based circumcision policy for Australia.

The aim was (1) to perform an up-to-date systematic review of the male circumcision (MC) literature and (2) to determine the number of adverse medical conditions prevented by early MC in Australia. Searches of PubMed using "circumcision" with 39 keywords and bibliography searches yielded 278 publications meeting our inclusion criteria. Early MC provides immediate and lifetime benefits, including protection against: urinary tract infections, phimosis, inflammatory skin conditions, inferior penile hygiene, candidiasis, various STIs, and penile and prostate cancer. In female partners MC reduces risk of STIs and cervical cancer. A risk-benefit analysis found benefits exceeded procedural risks, which are predominantly minor, by approximately 200 to 1. It was estimated that more than 1 in 2 uncircumcised males will experience an adverse foreskin-related medical condition over their lifetime. An increase in early MC in Australia to mid-1950s prevalence of 85% from the current level of 18.75% would avoid 77,000 cases of infections and other adverse medical conditions over the lifetime for each annual birth cohort. Survey data, physiological measurements, and the anatomical location of penile sensory receptors responsible for sexual sensation indicate that MC has no detrimental effect on sexual function, sensitivity or pleasure. US studies found that early infant MC is cost saving. Evidence-based reviews by the AAP and CDC support early MC as a desirable public health measure. Although MC can be performed at any age, early MC maximizes benefits and minimises procedural risks. Parents should routinely be provided with accurate, up-to-date evidence-based information in an unbiased manner early in a pregnancy so that they have time to weigh benefits and risks of early MC and make an informed decision should they have a son. Parental choice should be respected. A well-trained competent practitioner is essential and local anaesthesia should be routinely used. Third party coverage of costs is advocated.

Pharmaceutical and nutraceutical activation of FOXO3 for healthy longevity.

Life expectancy has increased substantially over the last 150 years. Yet this means that now most people also spend a greater length of time suffering from various age-associated diseases. As such, delaying age-related functional decline and extending healthspan, the period of active older years free from disease and disability, is an overarching objective of current aging research. Geroprotectors, compounds that target pathways that causally influence aging, are increasingly recognized as a means to extend healthspan in the aging population. Meanwhile, FOXO3 has emerged as a geroprotective gene intricately involved in aging and healthspan. FOXO3 genetic variants are linked to human longevity, reduced disease risks, and even self-reported health. Therefore, identification of FOXO3-activating compounds represents one of the most direct candidate approaches to extending healthspan in aging humans. In this work, we review compounds that activate FOXO3, or influence healthspan or lifespan in a FOXO3-dependent manner. These compounds can be classified as pharmaceuticals, including PI3K/AKT inhibitors and AMPK activators, antidepressants and antipsychotics, muscle relaxants, and HDAC inhibitors, or as nutraceuticals, including primary metabolites involved in cell growth and sustenance, and secondary metabolites including extracts, polyphenols, terpenoids, and other purified natural compounds. The compounds documented here provide a basis and resource for further research and development, with the ultimate goal of promoting healthy longevity in humans.

Transoral robotic surgery with neck dissection versus nonsurgical treatment in stage I and II human papillomavirus-negative oropharyngeal cancer.

BACKGROUND: Surgery + adjuvant therapy was shown to have improved overall survival (OS) versus nonsurgical treatment in T1-T2N1-N2b human papillomavirus (HPV)-negative oropharyngeal cancer (OPC). Our objective was to compare OS in transoral robotic surgery (TORS) with neck dissection versus nonsurgical treatment for T1-T2N0 HPV-negative OPC. METHODS: Patients with T1-T2N0 HPV-negative OPC were identified in the National Cancer Database. OS was compared between groups: (1) TORS with neck dissection +/- adjuvant therapy, (2) primary radiotherapy (>60 Gy) +/- chemotherapy using Kaplan-Meier and multivariable Cox proportional hazards models. RESULTS: There were 665 (78.4%) patients treated nonsurgically and 183 (21.6%) patients in the TORS group. Adjusting for age, comorbidity score, facility type, tumor subsite, and tumor stage, primary nonsurgical treatment was associated with worse OS (hazard ratio: 1.90, 95% CI: 1.34-2.69). CONCLUSION: For T1-T2N0 HPV-negative OPC, TORS with neck dissection may be associated with a survival benefit over nonsurgical treatment.

Association with Longevity of Phosphatidylinositol 3-Kinase Regulatory Subunit 1 Gene Variants Stems from Protection against Mortality Risk in Men with Cardiovascular Disease.

INTRODUCTION: Genetic variation in the phosphatidylinositol 3-kinase reregulatory subunit 1 gene (PIK3R1) is associated with longevity. OBJECTIVE: The aim of the study was to determine whether cardiovascular disease (CVD) affects this association. METHODS: We performed a longitudinal study of longevity-associated PIK3R1 single-nucleotide polymorphism rs7709243 genotype by CVD status in 3,584 elderly American men of Japanese ancestry. RESULTS: At baseline (1991-1993), 2,254 subjects had CVD and 1,314 did not. The follow-up until Dec 31, 2019 found that overall, men with a CVD had higher mortality than men without a CVD (p = 1.7 × 10-5). However, survival curves of CVD subjects differed according to PIK3R1 genotype. Those with longevity-associated PIK3R1 TT/CC had survival curves similar to those of subjects without a CVD (p = 0.11 for TT/CC, and p = 0.054 for TC), whereas survival curves for CVD subjects with the CT genotype were significantly attenuated compared with survival curves of subjects without a CVD (p = 0.0000012 compared with TT/CC, and p = 0.0000028 compared with TC). Men without CVD showed no association of longevity-associated genotype with life span (p = 0.58). Compared to subjects without any CVD, hazard ratios for mortality risk were 1.26 (95% CI, 1.14-1.39; p = 0.0000043) for CT subject with CVD and 1.07 (95% CI 0.99-1.17; p = 0.097) for CC/TT subjects with CVD. There was no genotypic effect on life span for 1,007 subjects with diabetes and 486 with cancer. CONCLUSION: Our study provides novel insights into the basis for PIK3R1 as a longevity gene. We suggest that the PIK3R1 longevity genotype attenuates mortality risk in at-risk individuals by protection against cellular stress caused by CVD.

New model of superior semicircular canal dehiscence with reversible diagnostic findings characteristic of patients with the disorder.

Background: Third window syndrome is a vestibular-cochlear disorder in humans in which a third mobile window of the otic capsule creates changes to the flow of sound pressure energy through the perilymph/endolymph. The nature and location of this third mobile window can occur at many different sites (or multiple sites); however, the most common third mobile window is superior semicircular canal dehiscence (SSCD). There are two essential objective diagnostic characteristics needed to validate a model of SSCD: the creation of a pseudoconductive hearing loss and cVEMP increased amplitude and decreased threshold. Methods: Adult Mongolian gerbils (n = 36) received surgical fenestration of the superior semicircular canal of the left inner ear. ABR and c+VEMP testing were carried out prior to surgery and over acute (small 1 mm SSCD, 1-10 days) or prolonged (large 2 mm SSCD, 28 days) recovery. Because recovery of function occurred quickly, condenser brightfield stereomicroscopic examination of the dehiscence site was carried out for the small SSCD animals post-hoc and compared to both ABRs and c+VEMPs. Micro-CT analysis was also completed with representative samples of control, day 3 and 10 post-SSCD animals. Results: The SSCD created a significant worsening of hearing thresholds of the left ear; especially in the lower frequency domain (1-4 kHz). Left (EXP)/right (CTL) ear comparisons via ABR show significant worsening thresholds at the same frequency representations, which is a proxy for the human pseudoconductive hearing loss seen in SSCD. For the c+VEMP measurements, increased amplitude of the sound-induced response (N1 2.5 ms and P1 3.2 ms) was observed in animals that received larger fenestrations. As the bone regrew, the c+VEMP and ABR responses returned toward preoperative values. For small SSCD animals, micro-CT data show that progressive osteoneogenesis results in resurfacing of the SSCD without bony obliteration. Conclusion: The large (2 mm) SSCD used in our gerbil model results in similar electrophysiologic findings observed in patients with SSCD. The changes observed also reverse and return to baseline as the SSCD heals by bone resurfacing (with the lumen intact). Hence, this model does not require a second surgical procedure to plug the SSCD.

Distinct trans-placental effects of maternal immune activation by TLR3 and TLR7 agonists: implications for schizophrenia risk.

Exposure to infection in utero predisposes towards psychiatric diseases such as autism, depression and schizophrenia in later life. The mechanisms involved are typically studied by administering mimetics of double-stranded (ds) virus or bacterial infection to pregnant rats or mice. The effect of single-stranded (ss) virus mimetics has been largely ignored, despite evidence linking prenatal ss virus exposure with psychiatric disease. Understanding the effects of gestational ss virus exposure has become even more important with recent events. In this study, in pregnant mice, we compare directly the effects, on the maternal blood, placenta and the embryonic brain, of maternal administration of ds-virus mimetic poly I:C (to activate Toll-like receptor 3, TLR3) and ss-virus mimetic resiquimod (to activate TLR7/8). We find that, 4 h after the administration, both poly I:C and resiquimod elevated the levels of IL-6, TNFα, and chemokines including CCL2 and CCL5, in maternal plasma. Both agents also increased placental mRNA levels of IL-6 and IL-10, but only resiquimod increased placental TNFα mRNA. In foetal brain, poly I:C produced no detectable immune-response-related increases, whereas pronounced increases in cytokine (e.g. Il-6, Tnfα) and chemokine (e.g. Ccl2, Ccl5) expression were observed with maternal resiquimod administration. The data show substantial differences between the effect of maternal exposure to a TLR7/8 activator as compared to a TLR3 activator. There are significant implications for future modelling of diseases where maternal ss virus exposure contributes to environmental disease risk in offspring.

Presentación de Caso Clínico: Carcinoma de mama luego de mastectomía de reducción de riesgo en paciente con mutación BRCA1 / Case report: Breast carcinoma after risk reducing mastectomy in a BRCA+ patient

Las pacientes sanas portadoras de mutaciones patogénicas del gen BRCA1 tiene un riesgo muy elevado de desarrollar cáncer de mama y ovario, con cifras reportadas que ascienden a 84% y 59% respec- tivamente.¹ Esto motivó a implementar distintas medidas de segui- miento y de reducción de riesgo, como la mastectomía bilateral de reducción de riesgo (MRR) y la salpingo-ooforectomía de reducción de riesgo (SORR). Pero aún así, distintas experiencias publicadas re- fieren que en pacientes portadoras de mutacion BRCA1 sometidas a MRR, el riesgo subsiguiente de desarrollar un cáncer primario de mama puede llegar al 10%.2 Por otro lado, las técnicas de mastectomías en general han experi- mentado modificaciones en menos, conservando las estructuras te- gumentarias y el tejido adiposo que la recubre. Últimamente se ha expuesto que, con la guía de las imágenes, se puede resecar menos tejido aun, fundamentalmente en los contornos mamarios donde se observa tejido adiposo y nada (o muy escaso) tejido glandular.3 Esta recomendación hoy es empírica, ya que no hay evidencia de la segu- ridad oncológica de conservar estos tejidos

Male circumcision and prostate cancer: a meta-analysis revisited.

INTRODUCTION The relationship between circumcision and prostate cancer has been controversial. A recently published meta-analysis contradicted previous meta-analyses of male circumcision and prostate cancer risk. Our aim was to conduct a de novo meta-analysis and critically evaluate this recent paper published by Van Howe. MATERIALS AND METHODS: We retrieved data from each of the 12 source studies Van Howe used, then performed a random effects meta-analysis of those data. We critically examined the data and other information in Van Howe's study. RESULTS: Using the same values as Van Howe, we confirmed his finding of a positive association of circumcision with prostate cancer (random effects summary OR = 1.14; 95% CI 0.99, 1.31). However, our independent meta-analysis found a negative association of circumcision with prostate cancer (random effects summary OR= 0.87; 95% CI 0.76, 1.00; p = 0.05). The reason for this critical discrepancy was Van Howe's erroneous transposition of values for circumcised and uncircumcised men in his Table columns, leading to inversion of the result. We further critically evaluated a geographical analysis and cost analysis of circumcision and prostate cancer, as well as claims denying a role for sexually transmitted infections in prostate cancer etiology, finding these too to be misleading. CONCLUSIONS: Van Howe's 2020 meta-analysis was based on erroneous data transposition leading to an inverted outcome. The journal concerned recently corrected his Table. Van Howe's claim of a positive association of circumcision with country-level-age standardized prostate cancer prevalence and his cost analysis were found to be questionable. Our meta-analysis showed that circumcision is associated with lower prostate cancer risk.

Comprehensive Breast Cancer Risk Assessment for CHEK2 and ATM Pathogenic Variant Carriers Incorporating a Polygenic Risk Score and the Tyrer-Cuzick Model.

PURPOSE: Breast cancer risks for CHEK2 and ATM pathogenic variant (PV) carriers are modified by an 86-single nucleotide polymorphism polygenic risk score (PRS) and individual clinical factors. Here, we describe comprehensive risk prediction models for women of European ancestry combining PV status, PRS, and individual clinical variables. MATERIALS AND METHODS: This study included deidentified clinical records from 358,095 women of European ancestry who received testing with a multigene panel (September 2013 to November 2019). Model development included CHEK2 PV carriers (n = 4,286), ATM PV carriers (n = 2,666), and women negative for other breast cancer risk gene PVs (n = 351,143). Odds ratios (ORs) were calculated using multivariable logistic regression with adjustment for familial cancer history. Risk estimates incorporating PV status, PRS, and Tyrer-Cuzick v7.02 were calculated using a Fixed-Stratified method that accounts for correlations between risk factors. Stratification of PV carriers into risk categories on the basis of remaining lifetime risk (RLR) was assessed in independent cohorts of PV carriers. RESULTS: ORs for association of PV status with breast cancer were 2.01 (95% CI, 1.88 to 2.16) and 1.83 (95% CI, 1.68 to 2.00) for CHEK2 and ATM PV carriers, respectively. ORs for PRS per one standard deviation were 1.51 (95% CI, 1.37 to 1.66) and 1.45 (95% CI, 1.30 to 1.64) in CHEK2 and ATM PV carriers, respectively. Using the combined model (PRS plus Tyrer-Cuzick plus PV status), RLR was low (≤ 20%) for 24.2% of CHEK2 PV carriers, medium (20%-50%) for 63.8%, and high (> 50%) for 12.0%. Among ATM PV carriers, RLR was low for 31.5% of patients, medium for 58.5%, and high for 9.7%. CONCLUSION: In CHEK2 and ATM PV carriers, risk assessment including PRS, Tyrer-Cuzick, and PV status has the potential for more precise direction of screening and prevention strategies.