Application of standardized methods to evaluate the environmental safety of polyvinyl alcohol disposed of down the drain.

The purpose of this research was to use polyvinyl alcohol (PVOH) 18-88 as a case study to evaluate the environmental fate, ecotoxicity, and overall safety profile of water-soluble, nonmodified PVOH polymers used in detergent films. An OECD 303A Wastewater Treatment Plant Simulation Study was conducted with dissolved organic carbon as the analytical endpoint to evaluate the removal of PVOH 18-88 during wastewater treatment. During the plateau phase, high levels of removal due to biodegradation were observed (average 97.4 ± 7.1, range: 88%-116%). The OECD 303A study quantitatively verified that surface water is the dominant receiving compartment for PVOH 18-88 post wastewater treatment. Acute algae, invertebrate, and fish embryo (fish embryo acute toxicity test [FET]) ecotoxicity studies quanitified the 50% lethal/effect concentration (L/EC50) for PVOH 18-88. Due to the potential for the chorion to impact PVOH 18-88 bioavailability, both chorionated and dechorionated FET tests were conducted. L/EC50 > 1000 mg/L for FET (chorionated and dechorionated), invertebrate, and algae were observed. The Sustainable Futures (US) and REACH (EU) frameworks were used to evaluate environmental risk. For the US assessment, the Exposure and Fate Assessment Screening Tool was used to predict the single day lowest flow over a 10-year period (1Q10) surface water concentration and the seven consecutive days of lowest flow over a 10-year period (7Q10) surface water concentration and compared with acute and chronic concentrations of concern. For the EU assessment, the European Union System for the Evaluation of Substances was used to predict local and regional exposure concentrations and compared to the predicted no effect concentration. For both regulatory assessments, the exposure concentrations were >2 orders of magnitude below the effect concentrations. Integr Environ Assess Manag 2024;00:1-13. © 2024 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Novel protective effect of the FOXO3 longevity genotype on mechanisms of cellular aging in Okinawans.

The genetic association of FOXO3 genotypes with human longevity is well established, although the mechanism is not fully understood. We now report on the relationship of the FOXO3 longevity variant rs2802292 with telomere length, telomerase activity, FOXO3 expression, and inflammatory cytokine levels in men and women. In agreement with earlier work, the FOXO3 longevity variant conferred protection against telomere shortening of peripheral blood mononuclear cells from adults aged 55 years and older. This was accompanied by higher levels of telomerase activity in mononuclear cells for carriers of the longevity-associated FOXO3 G-allele of SNP rs2802292 (P = 0.015). FOXO3 mRNA expression increased slightly with age in both young (P = 0.02) and old (P = 0.08) G-allele carriers. Older female G-allele carriers displayed a modest decline in levels of pro-inflammatory cytokine IL-6 with age (P = 0.07). In contrast, older male G-allele carriers displayed an age-dependent increase in levels of anti-inflammatory cytokine IL-10 with age (P = 0.04). Thus, FOXO3 may act through several different pro-longevity mechanisms, which may differ by age and sex.

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.

Site-specific inhibition of the thalamic reticular nucleus induces distinct modulations in sleep architecture.

The thalamic reticular nucleus (TRN) is crucial for the modulation of sleep-related oscillations. The caudal and rostral subpopulations of the TRN exert diverse activities, which arise from their interconnectivity with all thalamic nuclei, as well as other brain regions. Despite the recent characterization of the functional and genetic heterogeneity of the TRN, the implications of this heterogeneity for sleep regulation have not been assessed. Here, using a combination of optogenetics and electrophysiology in C57BL/6 mice, we demonstrate that caudal and rostral TRN modulations are associated with changes in cortical alpha and delta oscillations and have distinct effects on sleep stability. Tonic silencing of the rostral TRN elongates sleep episodes, while tonic silencing of the caudal TRN fragments sleep. Overall, we show evidence of distinct roles exerted by the rostral and caudal TRN in sleep regulation and oscillatory activity.

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.

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.

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.

16p11.2 deletion mice exhibit compromised fronto-temporal connectivity, GABAergic dysfunction, and enhanced attentional ability.

Autism spectrum disorders are more common in males, and have a substantial genetic component. Chromosomal 16p11.2 deletions in particular carry strong genetic risk for autism, yet their neurobiological impact is poorly characterised, particularly at the integrated systems level. Here we show that mice reproducing this deletion (16p11.2 DEL mice) have reduced GABAergic interneuron gene expression (decreased parvalbumin mRNA in orbitofrontal cortex, and male-specific decreases in Gad67 mRNA in parietal and insular cortex and medial septum). Metabolic activity was increased in medial septum, and in its efferent targets: mammillary body and (males only) subiculum. Functional connectivity was altered between orbitofrontal, insular and auditory cortex, and between septum and hippocampus/subiculum. Consistent with this circuit dysfunction, 16p11.2 DEL mice showed reduced prepulse inhibition, but enhanced performance in the continuous performance test of attentional ability. Level 1 autistic individuals show similarly heightened performance in the equivalent human test, also associated with parietal, insular-orbitofrontal and septo-subicular dysfunction. The data implicate cortical and septal GABAergic dysfunction, and resulting connectivity changes, as the cause of pre-attentional and attentional changes in autism.

A consideration of the increased risk of schizophrenia due to prenatal maternal stress, and the possible role of microglia.

Schizophrenia is caused by interaction of a combination of genetic and environmental factors. Of the latter, prenatal exposure to maternal stress is reportedly associated with elevated disease risk. The main orchestrators of inflammatory processes within the brain are microglia, and aberrant microglial activation/function has been proposed to contribute to the aetiology of schizophrenia. Here, we evaluate the epidemiological and preclinical evidence connecting prenatal stress to schizophrenia risk, and consider the possible mediating role of microglia in the prenatal stress-schizophrenia relationship. Epidemiological findings are rather consistent in supporting the association, albeit they are mitigated by effects of sex and gestational timing, while the evidence for microglial activation is more variable. Rodent models of prenatal stress generally report lasting effects on offspring neurobiology. However, many uncertainties remain as to the mechanisms underlying the influence of maternal stress on the developing foetal brain. Future studies should aim to characterise the exact processes mediating this aspect of schizophrenia risk, as well as focussing on how prenatal stress may interact with other risk factors.

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.

COVID shelter in place orders and mental health outcomes among college undergraduates.

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.

Comments by opponents on the British Medical Association's guidance on non-therapeutic male circumcision of children seem one-sided and may undermine public health.

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.

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.

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.