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BACKGROUND AND AIMS: Despite the substantial impact of environmental factors, individuals with a family history of liver cancer have an increased risk for HCC. However, genetic factors have not been studied systematically by genome-wide approaches in large numbers of individuals from European descent populations (EDP). APPROACH AND RESULTS: We conducted a 2-stage genome-wide association study (GWAS) on HCC not affected by HBV infections. A total of 1872 HCC cases and 2907 controls were included in the discovery stage, and 1200 HCC cases and 1832 controls in the validation. We analyzed the discovery and validation samples separately and then conducted a meta-analysis. All analyses were conducted in the presence and absence of HCV. The liability-scale heritability was 24.4% for overall HCC. Five regions with significant ORs (95% CI) were identified for nonviral HCC: 3p22.1, MOBP , rs9842969, (0.51, [0.40-0.65]); 5p15.33, TERT , rs2242652, (0.70, (0.62-0.79]); 19q13.11, TM6SF2 , rs58542926, (1.49, [1.29-1.72]); 19p13.11 MAU2 , rs58489806, (1.53, (1.33-1.75]); and 22q13.31, PNPLA3 , rs738409, (1.66, [1.51-1.83]). One region was identified for HCV-induced HCC: 6p21.31, human leukocyte antigen DQ beta 1, rs9275224, (0.79, [0.74-0.84]). A combination of homozygous variants of PNPLA3 and TERT showing a 6.5-fold higher risk for nonviral-related HCC compared to individuals lacking these genotypes. This observation suggests that gene-gene interactions may identify individuals at elevated risk for developing HCC. CONCLUSIONS: Our GWAS highlights novel genetic susceptibility of nonviral HCC among European descent populations from North America with substantial heritability. Selected genetic influences were observed for HCV-positive HCC. Our findings indicate the importance of genetic susceptibility to HCC development.

Despite the adoption of pre-exposure prophylaxis (PrEP) as a crucial HIV intervention, uptake remains suboptimal among men who have sex with men, a sexual minority group, due to barriers like cost and stigma. Peer change agents (PCAs) disseminate PrEP information within their social networks. This study explores the reciprocal effects of an online community-based participatory intervention on PCAs, focusing on their transformed PrEP uptake perceptions--leadership efficacy, social network dynamics, attitudes, perceived benefits and barriers and self-efficacy. Leveraging insights from the PrEP Chicago Study, our research addresses a key gap in community-based participatory interventions for PrEP uptake: the transformative experiences and perception shifts of PCAs involved in these interventions. We engaged 20 men who have sex with men, aged 18-45, as PCAs in a one-group pretest-posttest design intervention, which disseminated PrEP communications within their preferred online networks. We utilized the PrEP Chicago Study's 45 Likert items, tailored to reveal the PCAs' transformative potential. Data on PrEP uptake perceptions, sociodemographics and social media use were captured and analyzed using the Wilcoxon matched-pairs signed-rank test, a nonparametric method. PCAs demonstrated significant changes in their PrEP uptake perceptions, including leadership capacity, social network dynamics, attitudes toward PrEP, perceived benefits, barriers and self-efficacy. Our intervention highlights the reciprocal transformation PCAs undergo when disseminating PrEP information. This study adds a new dimension to community-based PrEP interventions and underscores the need for continued refinement of peer-led strategies to optimize the transformative potential of PCAs.

Abstract Aberrant DNA methylation patterns have been used for cancer detection. However, DNA hemi-methylation, present at about 10% CpG dinucleotides, has been less well studied. Here we show that a majority of differentially hemi-methylated regions (DHMRs) in liver tumor DNA or plasma cells free (cf) DNA do not overlap with differentially methylated regions (DMRs) of the same samples, indicating that DHMRs could serve as independent biomarkers. Furthermore, we analyzed the cfDNA methylomes of 215 samples from individuals with liver or brain cancer and individuals without cancer (controls), and trained machine learning models using DMRs, DHMRs or both. The models incorporated with both DMRs and DHMRs show a superior performance compared to models trained with DMRs or DHMRs, with AUROC being 0.978, 0.990, and 0.983 in distinguishing control, liver and brain cancer, respectively, in a validation cohort. This study supports the potential of utilizing both DMRs and DHMRs for multi-cancer detection.

Objective: Offering comprehensive lesbian, gay, bisexual, transgender, queer/questioning, intersex, asexual (LGBTQIA+) friendly and sex-positive student health centers are central to institutions of higher education being able to retain and support students. Positive sexual experiences for LGBTQIA + students can have an impact on academic success but many LGBTQIA+ students are discriminated against and are often victims of microaggressions. Participants: Twenty undergraduate students enrolled in a LGBTQIA+ health course. Methods: Students in an LGBTQIA+ Health undergraduate course at a private Northeastern university assessed what mattered most to them when it came to creating a sex-positive healthcare environment that promotes LGBTQIA+ inclusiveness and removes perceived barriers. Results: The themes included expanding mental health care, greater involvement of culturally-competent provider, establishing a stigma-free clinical environment, re-imagining the clinic waiting room, and facilitating sexual health advocacy. Conclusion: Re-envisioning the role of student health centers is critical for ensuring every student has a fair and just opportunity to achieve their full health potential.

BackgroundPolycyclic aromatic hydrocarbon (PAH) exposures from tobacco smoke, automobile exhaust, grilled or smoked meat and other sources are widespread and are a public health concern, as many are classified as probable carcinogens and suspected endocrine-disrupting chemicals. PAH exposures can be quantified using urinary biomarkers.MethodsSeven urinary metabolites of naphthalene, fluorene, phenanthrene, and pyrene were measured in two samples collected from girls aged 6-16 years from the San Francisco Bay Area. We used Spearman correlation coefficients (SCC) to assess correlations among metabolite concentrations (corrected for specific gravity) separately in first (n = 359) and last (N = 349) samples, and to assess consistency of measurements in samples collected up to 72 months apart. Using multivariable linear regression, we assessed variation in mean metabolites across categories of participant characteristics and potential outdoor, indoor, and dietary sources of PAH exposures.ResultsThe detection rate of PAH metabolites was high (4 metabolites in ≥98% of first samples; 5 metabolites in ≥95% of last samples). Correlations were moderate to strong between fluorene, phenanthrene and pyrene metabolites (SCC 0.43-0.82), but weaker between naphthalene and the other metabolites (SCC 0.18-0.36). SCC between metabolites in first and last samples ranged from 0.15 to 0.49. When classifying metabolite concentrations into tertiles based on single samples (first or last samples) vs. the average of the two samples, agreement was moderate to substantial (weighted kappa statistics 0.52-0.65). For specific metabolites, concentrations varied by age, race/ethnicity, and body mass index percentile, as well as by outdoor sources (season of sample collection, street traffic), indoor sources (heating with gas, cigarette smoke), and dietary sources (frequent use of grill, consumption of smoked meat or fish) of PAH exposures.ConclusionsUrinary PAH exposure was widespread in girls aged 6-16 years and associated with several sources of exposure. Tertile classification of a single urine sample provides reliable PAH exposure ranking.

The SARS-CoV-2 outbreak has resulted in a considerable number of deaths worldwide. The virus damages the pulmonary artery endothelium, leading to a condition known as microvascular pulmonary inflammatory thrombotic syndrome (MPITS), which can be fatal and cause multiple organ failure. The presence of preexisting comorbidities has been shown to significantly impact the severity and prognosis of patients with SARS-CoV-2 infection. The objective of this study was to compare the age groups of patients with coronavirus disease 2019 (COVID-19) and to identify the prevalence of comorbidities associated with death and survival in an area of southern Italy. The data set consisted of 1985 patients with confirmed cases of SARS-CoV-2 infection who were admitted to the A.O.U. San Giovanni di Dio e Ruggi d’Aragona Hospital in Salerno between January 2021 and December 2022. The results were presented for the overall population and stratified by outcome and age group. All analyses were performed using the XLSTAT (Lumivero, 2024, Paris, France) and STATA software (release 16.1, StataCorp LLG, College Station, TX, USA, 2019) packages. In the study, population, 636 cases (32%) resulted in death, with a higher prevalence in the 60–79 age group, followed by the ≥80 and 30–59 age groups. The most prevalent diseases among deceased and surviving patients with confirmed cases of SARS-CoV-2 infection were those affecting the circulatory system (61.5% vs. 55.5%), the respiratory system (55.8% vs. 26.2%), and the metabolic system (25.9% vs. 25.4%). In patients aged 30–79, respiratory diseases were the primary cause of mortality, whereas in those aged ≥80, circulatory system diseases were more prevalent. Among survivors, cardiovascular diseases were the most common comorbidities across all age groups, followed by respiratory diseases and endocrine, metabolic, and immune disorders. Moreover, these comorbidities were associated with an elevated risk of mortality. The study emphasizes the substantial influence of age and comorbidities on the mortality associated with SARS-CoV-2 infection. These findings highlight the necessity for targeted interventions to manage comorbid conditions in patients with SARS-CoV-2 infection, particularly in older adults.

Sea urchin eggs are covered with layers of extracellular matrix, namely, the vitelline layer (VL) and jelly coat (JC). It has been shown that sea urchin eggs’ JC components serve as chemoattractants or ligands for the receptor on the fertilizing sperm to promote the acrosome reaction. Moreover, the egg’s VL provides receptors for conspecific sperm to bind, and, to date, at least two sperm receptors have been identified on the surface of sea urchin eggs. Interestingly, however, according to our previous work, denuded sea urchin eggs devoid of the JC and VL do not fail to become fertilized by sperm. Instead, they are bound and penetratedby multiple sperm, raising the possibility that an alternative pathway independent of the VL-residing sperm receptor may be at work. In this research, we studied the roles of the JC and VL using intact and denuded eggs and the synthetic polyamine BPA-C8. BPA-C8 is known to bind to the negatively charged macromolecular complexes in the cells, such as the JC, VL, and the plasma membrane of echinoderm eggs, as well as to the actin filaments in fibroblasts. Our results showed that, when added to seawater, BPA-C8 significantly repressed the Ca2+ wave in the intact P. lividus eggs at fertilization. In eggs deprived of the VL and JC, BPA-C8 binds to the plasma membrane and increases fibrous structures connecting microvilli, thereby allowing the denuded eggs to revert towards monospermy at fertilization. However, the reduced Ca2+ signal in denuded eggs was nullified compared to the intact eggs because removing the JC and VL already decreased the Ca2+ wave. BPA-C8 does not cross the VL and the cell membrane of unfertilized sea urchin eggs to diffuse into the cytoplasm at variance with the fibroblasts. Indeed, the jasplakinolide-induced polymerization of subplasmalemmal actin filaments was inhibited in the eggs microinjected with BPA-C8, but not in the ones bath-incubated with the same dose of BPA-C8.

Background/Objectives: ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) pose a serious public health threat as they are resistant to multiple antimicrobial agents. Bloodstream infections (BSIs) caused by ESKAPE bacteria have high mortality rates due to the limited availability of effective antimicrobials. This study aimed to evaluate the prevalence and susceptibility of ESKAPE pathogens causing BSIs over three years in a large tertiary hospital in Salerno. Methods: Conducted at the Clinical Microbiology Laboratory of San Giovanni di Dio e ‘‘Ruggi D’Aragona’’ Hospital from January 2020 to December 2022, blood culture samples from different departments were incubated in the BD BACTEC™ system for 5 days. Species identification was performed using MALDI-TOF MS, and antimicrobial resistance patterns were determined by the VITEK2 system. Results: Out of 3197 species isolated from positive blood cultures, 38.7% were ESKAPE bacteria. Of these, 59.9% were found in blood culture samples taken from men, and the most affected age group was those aged >60 years. (70.6%). Staphylococcus aureus was the main BSI pathogen (26.3%), followed by Klebsiella pneumoniae (15.8%). Significant resistance rates were found, including 35% of Staphylococcus aureus being resistant to oxacillin and over 90% of Acinetobacter baumannii being resistant to carbapenems. Conclusions: These results highlight the urgent need for antimicrobial stewardship programs to prevent incurable infections.

Dietary acid load (DAL) may be associated with all-cause mortality (ACM) and breast cancer-specific mortality (BCM), and these associations may be modified by serum polychlorinated biphenyl (PCB) levels. Participants included 519 women diagnosed with first primary in situ or invasive breast cancer in 1996/1997 with available lipid-corrected PCB data. After a median of 17 years, there were 217 deaths (73 BCM). Potential renal acid load (PRAL) and net endogenous acid production (NEAP) scores calculated from a baseline food frequency questionnaire estimated DAL. Cox regression estimated covariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between PRAL and NEAP with mortality. We evaluated effect measure modification by total serum PCB levels (>median vs. ≤median). PRAL quartile 4 versus quartile 1 was associated with an ACM HR of 1.31 (95%CI = 0.90-1.92). In the upper median of PCBs, ACM HRs were 1.43 (95%CI = 0.96-2.11) and 1.40 (95%CI = 0.94-2.07) for PRAL and NEAP upper medians, respectively. In the lower median of PCBs, the upper median of NEAP was inversely associated with BCM (HR = 0.40, 95%CI = 0.19-0.85). DAL may be associated with increased risk of all-cause mortality following breast cancer among women with high total serum PCB levels, but inversely associated with breast cancer mortality among women with low PCB levels.

Abstract Background Gastrulation is a key transition in embryogenesis; it requires self-organized cellular coordination, which has to be both robust to allow efficient development and plastic to provide adaptability. Despite the conservation of gastrulation as a key event in Metazoan embryogenesis, the morphogenetic mechanisms of self-organization (how global order or coordination can arise from local interactions) are poorly understood. Results We report a modular structure of cell internalization in Caenorhabditis elegans gastrulation that reveals mechanisms of self-organization. Cells that internalize during gastrulation show apical contractile flows, which are correlated with centripetal extensions from surrounding cells. These extensions converge to seal over the internalizing cells in the form of rosettes. This process represents a distinct mode of monolayer remodeling, with gradual extrusion of the internalizing cells and simultaneous tissue closure without an actin purse-string. We further report that this self-organizing module can adapt to severe topological alterations, providing evidence of scalability and plasticity of actomyosin-based patterning. Finally, we show that globally, the surface cell layer undergoes coplanar division to thin out and spread over the internalizing mass, which resembles epiboly. Conclusions The combination of coplanar division-based spreading and recurrent local modules for piecemeal internalization constitutes a system-level solution of gradual volume rearrangement under spatial constraint. Our results suggest that the mode of C. elegans gastrulation can be unified with the general notions of monolayer remodeling and with distinct cellular mechanisms of actomyosin-based morphogenesis.

Abstract Background To exploit the flood of data from advances in high throughput imaging of optically sectioned nuclei, image analysis methods need to correctly detect thousands of nuclei, ideally in real time. Variability in nuclear appearance and undersampled volumetric data make this a challenge. Results We present a novel 3D nuclear identification method, which subdivides the problem, first segmenting nuclear slices within each 2D image plane, then using a shape model to assemble these slices into 3D nuclei. This hybrid 2D/3D approach allows accurate accounting for nuclear shape but exploits the clear 2D nuclear boundaries that are present in sectional slices to avoid the computational burden of fitting a complex shape model to volume data. When tested over C. elegans, Drosophila, zebrafish and mouse data, our method yielded 0 to 3.7% error, up to six times more accurate as well as being 30 times faster than published performances. We demonstrate our method's potential by reconstructing the morphogenesis of the C. elegans pharynx. This is an important and much studied developmental process that could not previously be followed at this single cell level of detail. Conclusions Because our approach is specialized for the characteristics of optically sectioned nuclear images, it can achieve superior accuracy in significantly less time than other approaches. Both of these characteristics are necessary for practical analysis of overwhelmingly large data sets where processing must be scalable to hundreds of thousands of cells and where the time cost of manual error correction makes it impossible to use data with high error rates. Our approach is fast, accurate, available as open source software and its learned shape model is easy to retrain. As our pharynx development example shows, these characteristics make single cell analysis relatively easy and will enable novel experimental methods utilizing complex data sets.

HIV point of care testing (POCT) is a common approach to expanding testing into non-specialised settings. Dental services have untapped potential to screen for health conditions including HIV. However, the perspectives of UK dental patients, dental professionals, and people with HIV are unknown. Ten focus groups were undertaken with dental patients, professionals, and people with HIV. The Framework method was used to analyse the qualitative data. Six themes were generated from the focus group data. The themes explored perceptions of HIV, the purpose, appropriateness, and acceptability of HIV testing in dental settings, and new processes that would need to be established in order to successfully implement point of care HIV testing in UK dental settings. Training needs were identified including communication skills and updates to current knowledge about HIV. HIV testing in dental settings is generally acceptable to dental patients, dental professionals, and PWH. However, of concern were logistical challenges and the risk of patients surprised at being offered an HIV test during a visit to the dentist. Nonetheless, the public health benefits of the intervention were well understood, i.e., early detection of HIV and initiation of treatment to improve health outcomes. Dental teams were able to generate novel solutions that could help to overcome contextual and logistical challenges to implementing HIV testing in dental settings.

Infections caused by antibiotic-resistant bacteria represent a serious threat to global public health. Recently, due to its increased resistance to carbapenems and β-lactams, Klebsiella pneumoniae has become one of the main causes of septicemia, pneumonia, and urinary tract infections. It is crucial to take immediate action and implement effective measures to prevent further spread of this issue. This study aims to report the prevalence and antibiotic resistance rates of K. pneumoniae strains isolated from clinical specimens from 2015 to 2020 at the University Hospital of Salerno, Italy. More than 3,800 isolates were collected from urine cultures, blood cultures, respiratory samples, and others. K. pneumoniae isolates showed broad resistance to penicillin and cephalosporins, and increased susceptibility to fosfomycin and gentamicin. Extended spectrum beta-lactamase (ESBL) isolates accounted for 20–22%. A high percentage of strains tested were resistant to carbapenems, with an average of 40% to meropenem and 44% to ertapenem. The production of ESBLs and resistance to carbapenems is one of the major public health problems. Constant monitoring of drug-resistant isolates is crucial for developing practical approaches in implementing antimicrobial therapy and reducing the spread of K. pneumoniae in nosocomial environments.

Objective: To determine the associations between plasma creatinine (PCr), plasma uric acid (PUA), and urinary oxidative stress (OS) biomarkers with the ALSFRS-R at baseline and survival in a large epidemiological cohort study (ALS COSMOS) with a well-phenotyped patient population (N = 355).Methods: Fasting plasma and first void urine samples were obtained. PCr, PUA, urinary 8-oxo-deoxy guanosine (8-oxodG), and 15-F2t-isoprostane (IsoP) were analyzed at baseline, near the midpoint of follow-up, and at the final blood draw (before death or withdrawal from study). We estimated associations between these biomarkers and the ALSFRS-R at baseline and survival.Results: At baseline, PCr correlated with ALSFRS-R (Spearman r = 0.30), percent (%) FVC (r = 0.20), PUA (r = 0.37), and 8-oxodG (r = -0.13, all p

The spread of antibiotic resistance represents a serious worldwide public health issue, underscoring the importance of epidemiology research in determining antimicrobial strategies. The purpose of this research was to investigate antibiotic resistance in Serratia marcescens isolates from clinical samples over seven years at the University Hospital “San Giovanni di Dio e Ruggi d’Aragona” in Salerno, Italy. S. marcescens is an important opportunistic pathogen associated with a wide spectrum of clinical diseases, including pneumonia, keratitis, meningitis, and urinary tract and wound infections. Outbreaks of nosocomial infections by S. marcescens strains have been documented in high-risk settings, mainly affecting immunocompromised patients and newborns. The primary objective of this study is to assess the rates of antibiotic resistance over the years to deal with a future emergency which includes the failure of various therapies due to antibiotic resistance. During the investigation, a total of 396 species of S. marcescens were isolated from various clinical samples, mainly from broncho-aspirates and sputum (31.6%) and blood cultures (21.5%). Antibiotics that showed the greatest susceptibility included ceftazidime/avibactam, amikacin, trimethoprim/sulfamethoxazole, and selected members of the cephalosporin class. However, a disconcerting trend of increasing rates of carbapenem resistance was outlined over the observation period. The absence of effective countermeasures, combined with growing antibiotic resistance that negates the effectiveness of multiple antibiotics, highlights the potential for S. marcescens infections to trigger serious clinical complications and increased mortality rates. The surveillance of Serratia marcescens infections constitutes a pivotal element in refining empiric therapy to mitigate the dissemination of antimicrobial resistance.

Assessing the performance of optical imaging systems is crucial to evaluate their capability to satisfy the product requirements for an Earth Observation (EO) mission. In particular, the evaluation of image quality is undoubtedly one of the most important, critical and problematic aspects of remote sensing. It involves not only pre-flight analyses, but also continuous monitoring throughout the operational lifetime of the observing system. The Ground Sampling Distance (GSD) of the imaging system is often the only parameter used to quantify its spatial resolution, i.e., its capability to resolve objects on the ground. In practice, this feature is also heavily influenced by other image quality parameters such as the image sharpness and Signal-to-Noise Ratio (SNR). However, these last two aspects are often analysed separately, using unrelated methodologies, complicating the image quality assessment and posing standardisation issues. To this end, we expanded the features of our Automatic Edge Method (AEM), which was originally developed to simplify and automate the estimate of sharpness metrics, to also extract the image SNR. In this paper we applied the AEM to a wide range of optical satellite images characterised by different GSD and Pixel Size (PS) with the objective to explore the nature of the relationship between the components of overall image quality (image sharpness, SNR) and product geometric resampling (expressed in terms of GSD/PS ratio). Our main objective is to quantify how the sharpness and the radiometric quality of an image product are affected by different product geometric resampling strategies, i.e., by distributing imagery with a PS larger or smaller than the GSD of the imaging system. The AEM allowed us to explore this relationship by relying on a vast amount of data points, which provide a robust statistical significance to the results expressed in terms of sharpness metrics and SNR means. The results indicate the existence of a direct relationship between the product geometric resampling and the overall image quality, and also highlight a good degree of correlation between the image sharpness and SNR.

BackgroundThe authors hypothesized that epigenetic changes may help to clarify the underlying biologic mechanism linking aspirin use to breast cancer prognosis. To the authors' knowledge, this is the first epidemiologic study to examine whether global methylation and/or tumor promoter methylation of breast cancer-related genes interact with aspirin use to impact mortality after breast cancer.MethodsPrediagnosis aspirin use was assessed through in-person interviews within a population-based cohort of 1508 women diagnosed with a first primary breast cancer in 1996 and 1997. Global methylation in peripheral blood was assessed by long interspersed elements-1 (LINE-1) and the luminometric methylation assay. Promoter methylation of 13 breast cancer-related genes was measured in tumor by methylation-specific polymerase chain reaction and the MethyLight assay. Vital status was determined by the National Death Index through December 31, 2014 (N = 202/476 breast cancer-specific/all-cause deaths identified among 1266 women with any methylation assessment and complete aspirin data). Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs, and the likelihood ratio test was used to evaluate multiplicative interactions.ResultsAll-cause mortality was elevated among aspirin users who had methylated promotor of BRCA1 (HR, 1.67; 95% CI, 1.26-2.22), but not among those with unmethylated promoter of BRCA1 (HR, 0.99; 95% CI, 0.67-1.45; P for interaction ≤.05). Decreased breast cancer-specific mortality was observed among aspirin users who had unmethylated promotor of BRCA1 and PR and global hypermethylation of LINE-1 (HR, 0.60, 0.78, and 0.63, respectively; P for interaction ≤.05), although the 95% CIs included the null.ConclusionsThe current study suggests that the LINE-1 global methylation and promoter methylation of BRCA1 and PR in tumor may interact with aspirin use to influence mortality after breast cancer.

To examine 143 diabetes risk single nucleotide polymorphisms (SNPs), identified from genome-wide association studies, in association with breast cancer (BC) incidence and subsequent mortality. A population-based sample of Caucasian women with first primary invasive BC (n = 817) and controls (n = 1021) were interviewed to assess diabetes status. Using the National Death Index, women with BC were followed for >18 years during which 340 deaths occurred (139 BC deaths). Genotyping was done using DNA extracted from blood samples. We used unconditional logistic regression to estimate age-adjusted odds ratios and 95% confidence intervals (CIs) for BC incidence, and Cox regression to estimate age-adjusted hazard ratios and CIs for all-cause and BC-specific mortality. Twelve SNPs were associated with BC risk in additive genotype models, at α = 0.05. The top three significant SNPs included SLC30A8-rs4876369 (P = 0.0034), HHEX-rs11187146 (P = 0.0086), and CDKN2A/CDKN2B-rs1333049 (P = 0.0094). Diabetes status modified the associations between rs4876369 and rs2241745 and BC incidence, on the multiplicative interaction scale. Six SNPs were associated with all-cause (CDKAL1-rs981042, P = 0.0032; HHEX-rs1111875, P = 0.0361; and INSR-rs919275, P = 0.0488) or BC-specific (CDKN2A/CDKN2B-rs3218020, P = 0.0225; CDKAL1-rs981042, P = 0.0246; and TCF2/HNF1B-rs3094508, P = 0.0344) mortality in additive genotype models, at α = 0.05. Genetic polymorphisms that increase the risk of developing diabetes may also increase the risk of developing and dying from BC.

Rasagiline is a monoamine oxidase B (MAO-B) inhibitor with possible neuroprotective effects in patients with amyotrophic lateral sclerosis (ALS). We performed a randomized, double-blind, placebo-controlled trial of 80 ALS participants with enrichment of the placebo group with historical controls (n = 177) at 10 centers in the United States. Participants were randomized in a 3:1 ratio to 2 mg/day rasagiline or placebo. The primary outcome was average slope of decline on the ALS Functional Rating Scale-Revised (ALSFRS-R). Secondary measures included slow vital capacity, survival, mitochondrial and molecular biomarkers, and adverse-event reporting. There was no difference in the average 12-month ALSFRS-R slope between rasagiline and the mixed placebo and historical control cohorts. Rasagiline did not show signs of drug-target engagement in urine and blood biomarkers. Rasagiline was well tolerated with no serious adverse events. Rasagiline did not alter disease progression compared with controls over 12 months of treatment. Muscle Nerve 59:201-207, 2019.

Abstract DNA repair phenotype can be measured in blood and may be a potential biomarker of cancer risk. We conducted a systematic review and meta-analysis of epidemiological studies of DNA repair phenotype and cancer through March 2021. We used random-effects models to calculate pooled odds ratios (ORs) of cancer risk for those with the lowest DNA repair capacity compared with those with the highest capacity. We included 55 case–control studies that evaluated 12 different cancers using 10 different DNA repair assays. The pooled OR of cancer risk (all cancer types combined) was 2.92 (95% Confidence Interval (CI) 2.49, 3.43) for the lowest DNA repair. Lower DNA repair was associated with all studied cancer types, and pooled ORs (95% CI) ranged from 2.02 (1.43, 2.85) for skin cancer to 7.60 (3.26, 17.72) for liver cancer. All assays, except the homologous recombination repair assay, showed statistically significant associations with cancer. The effect size ranged from 1.90 (1.00, 3.60) for the etoposide-induced double-strand break assay to 5.06 (3.67, 6.99) for the γ-H2AX assay. The consistency and strength of the associations support the use of these phenotypic biomarkers; however large-scale prospective studies will be important for understanding their use related to age and screening initiation.