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While current research is largely consistent as to the harms of heavy drinking in terms of both cancer incidence and mortality, there are disparate messages regarding the safety of light-moderate alcohol consumption, which may confuse public health messages. We aimed to evaluate the association between average lifetime alcohol intakes and risk of both cancer incidence and mortality. We report a population-based cohort study using data from 99,654 adults (68.7% female), aged 55-74 years, participating in the U.S. Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Cox proportional hazards models assessed the risk of overall and cause-specific mortality, cancer incidence (excluding nonmelanoma skin cancer), and combined risk of cancer and death across categories of self-reported average lifetime alcohol intakes, with adjustment for potential confounders. During 836,740 person-years of follow-up (median 8.9 years), 9,599 deaths and 12,763 primary cancers occurred. Positive linear associations were observed between lifetime alcohol consumption and cancer-related mortality and total cancer incidence. J-shaped associations were observed between average lifetime alcohol consumption and overall mortality, cardiovascular-related mortality, and combined risk of death or cancer. In comparison to lifetime light alcohol drinkers (1-3 drinks per week), lifetime never or infrequent drinkers (<1 drink/week), as well as heavy (2-<3 drinks/day) and very heavy drinkers (3+ drinks/day) had increased overall mortality and combined risk of cancer or death. Corresponding hazard ratios (HRs) and 95% confidence intervals (CIs) for combined risk of cancer or death, respectively, were 1.09 (1.01-1.13) for never drinkers, 1.08 (1.03-1.13) for infrequent drinkers, 1.10 (1.02-1.18) for heavy drinkers, and 1.21 (1.13-1.30) for very heavy drinkers. This analysis is limited to older adults, and residual confounding by socioeconomic factors is possible. The study supports a J-shaped association between alcohol and mortality in older adults, which remains after adjustment for cancer risk. The results indicate that intakes below 1 drink per day were associated with the lowest risk of death. NCT00339495 (ClinicalTrials.gov).

Background Mosaic loss of the Y chromosome (mLOY) in circulating leukocytes is the most frequently detected age-related chromosomal mosaic event in men. Current mLOY detection approaches use genotyping arrays and employ a phase-based approach that identifies B allele frequency (BAF) deviations in the pseudo-autosomal region (PAR) shared between the X and Y chromosome. As some widely used genotyping arrays lack sufficient probe coverage of the PAR, methods for accurately measuring mLOY utilizing the median log 2 R ratio across the male-specific region of Y chromosome (mLRR_Y) are needed for detecting mLOY on these platforms. Results We derived a formula from mLRR_Y to estimate the cellular fraction (CF) of cells with Y loss and validated the approach, finding high alignment with the CF estimation from female data and lab-generated qPCR data (R 2  = 0.98). Additionally, we compared the correlation between phase-based BAF and mLRR_Y methods for CF estimation, achieving a high correlation with R 2  > 0.80. Conclusion Although mLRR_Y is a noisier metric for mosaic chromosomal alteration detection relative to BAF, we demonstrate mLRR_Y across non-PAR variants can accurately estimate mLOY CF, especially for high CF mLOY.

Meningiomas represent a phenotypically and genetically diverse group of tumors which often behave in ways that are not simply explained by their pathologic grade. The genetic landscape of meningiomas has become a target of investigation as tumor genomics have been found to impact tumor location, recurrence risk, and malignant potential. Additionally, targeted therapies are being developed that in the future may provide patients with personalized chemotherapy based on the genetic aberrations within their tumor. This review focuses on the most common genetic mutations found in meningiomas of all grades, with an emphasis on the impact on tumor location and clinically relevant tumor characteristics. NF-2 and the non-NF-2 family of genetic mutations are summarized in the context of low-grade and high-grade tumors, followed by a comprehensive discussion regarding the genetic and embryologic basis for meningioma location and phenotypic heterogeneity. Finally, targeted therapies based on tumor genomics currently in use and under investigation are reviewed and future avenues for research are suggested. The field of meningioma genomics has broad implications on the way meningiomas will be treated in the future, and is gradually shifting the way clinicians approach this diverse group of tumors.

In this study, we evaluated the efficacy of hydroxychloroquine (HCQ) against coronavirus disease 2019 (COVID-19) via a randomized controlled trial (RCT) and a retrospective study. Subjects admitted to 11 designated public hospitals in Taiwan between April 1 and May 31, 2020, with COVID-19 diagnosis confirmed by pharyngeal real-time RT-PCR for SARS-CoV-2, were randomized at a 2:1 ratio and stratified by mild or moderate illness. HCQ (400 mg twice for 1 d or HCQ 200 mg twice daily for 6 days) was administered. Both the study and control group received standard of care (SOC). Pharyngeal swabs and sputum were collected every other day. The proportion and time to negative viral PCR were assessed on day 14. In the retrospective study, medical records were reviewed for patients admitted before March 31, 2020. There were 33 and 37 cases in the RCT and retrospective study, respectively. In the RCT, the median times to negative rRT-PCR from randomization to hospital day 14 were 5 days (95% CI; 1, 9 days) and 10 days (95% CI; 2, 12 days) for the HCQ and SOC groups, respectively (p = 0.40). On day 14, 81.0% (17/21) and 75.0% (9/12) of the subjects in the HCQ and SOC groups, respectively, had undetected virus (p = 0.36). In the retrospective study, 12 (42.9%) in the HCQ group and 5 (55.6%) in the control group had negative rRT-PCR results on hospital day 14 (p = 0.70). Neither study demonstrated that HCQ shortened viral shedding in mild to moderate COVID-19 subjects.

Ropeginterferon alfa-2b is a novel mono-pegylated and extra-long-acting interferon, being developed for the treatment of myeloproliferative neoplasm (MPN) and chronic viral hepatitis. It has a favorable pharmacokinetic profile and less frequent dosing schedule, i.e., once every two to four weeks, compared to conventional pegylated interferon products, which have multiple isomers and are administered weekly. It was approved for the long-term treatment of polycythemia vera, an MPN, and has been included in the NCCN clinical practice guidelines for this indication. Ropeginterferon alfa-2b has demonstrated efficacy and showed a favorable safety profile for the treatment of chronic viral hepatitis in several clinical studies. In this article, we review its pharmacokinetics and available clinical data and suggest that ropeginterferon alfa-2b administered once every two weeks can serve as a new treatment option for patients with chronic viral hepatitis, including chronic hepatitis B, C, and D.

Associations between vitamin D biochemical status and cancer may be modified by vitamin D binding protein isoforms which are encoded by GC (group-specific component). We examined interactions between serum 25-hydroxyvitamin D [25(OH)D], the Gc isoforms Gc1-1, Gc1-2, and Gc2-2, and cancer risk within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort based on 3,795 cases and 3,856 controls. Multivariable-adjusted logistic regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs) of cancer risk according to 25(OH)D quantiles, stratified by Gc isoform. Separately, the GC -cancer risk association was examined using proportional hazards regression among 109,746 individuals with genetic data and 26,713 diagnosed with cancer. Specific vitamin D binding protein isoform subtypes were delineated and analyzed, including Gc1-1 subtypes (Gc1s-Gc1s, Gc1f-Gc1s, and Gc1f-Gc1f) and Gc2 subtypes (Gc1s-Gc2, Gc1f-Gc2, and Gc2-Gc2). For most cancers, the GC genotype did not modify the risk associations for 25(OH)D; e.g., the OR for high vs. low vitamin D quintile was 1.09 (0.89–1.33) for overall cancer risk among individuals with the Gc1-1 isoform and 1.04 (0.83–1.31) among those with either the Gc1-2 or Gc2-2 isoforms. ORs for high compared to low vitamin D tertile for colorectal, lung, breast, and prostate cancer among those with the Gc1-1 vs. any Gc2 isoforms were, respectively, 0.60 vs. 0.73, 1.96 vs. 1.03, 1.30 vs. 1.18, and 1.19 vs. 1.22 (all p-interaction ≥0.36). However, GC qualitatively modified the vitamin D-bladder cancer risk association: OR = 1.70 (95% CI 0.96–2.98) among those with the Gc1-1 isoform and 0.52 (0.28–0.96) among those with any Gc2 isoforms (p-interaction = 0.03). When modeled without regard for 25(OH)D, Gc isoforms were generally not associated with cancer risk, although melanoma risk was significantly lower among individuals with the “f” subtype of the Gc1-1 isoform, specifically HR = 0.83 (95% CI 0.70–0.98) for Gc1f-1s and 0.67 (0.45–1.00) for Gc1f-1f, compared to individuals with the Gc1s-Gc1s isoform. Vitamin D binding protein genetic isoforms may be associated with melanoma risk but do not modify the association between vitamin D status and cancer, with the possible exception of bladder cancer.

Insert conditions significantly influence the product quality and manufacturing efficiency of lathe machining. This study used the power spectral density distribution of the vibration signals of a lathe machining accelerometer to design an insert condition classification system applicable to different machining conditions. For four common lathe machining insert conditions (i.e., built-up edge, flank wear, normal, and fracture), herein, the insert condition classification system was established with two stages—insert condition modeling and machining model fusion. In the insert condition modeling stage, the magnitude features of the segmented frequencies were captured according to the power spectral density distributions of the accelerometer vibration signals. Principal component analysis and backpropagation neural networks were used to develop insert condition models for different machining conditions. In the machining model fusion stage, a backpropagation neural network was employed to establish the weight function between the machining conditions and insert condition models. Subsequently, the insert conditions were classified based on the calculated weight values of all the insert condition models. Cutting tests were performed on a computer numerical control (CNC) lathe and utilized to validate the feasibility of the designed insert condition classification system. The results of the cutting tests showed that the designed system could perform insert condition classification under different machining conditions, with a classification rate exceeding 80%. Using a triaxial accelerometer, the designed insert condition classification system could perform identification and classification online for four common insert conditions under different machining conditions, ensuring that CNC lathes could further improve manufacturing quality and efficiency in practice.

Oral bacteria play important roles in human health and disease. Oral samples collected using ethanol-containing mouthwash are widely used for oral microbiome studies. However, ethanol is flammable and not ideal for transportation/storage in large quantities, and some individuals may avoid ethanol due to the burning sensation or due to various personal, medical, religious, and/or cultural factors. Here, we compared ethanol-free and ethanol-containing mouthwashes using multiple microbiome metrics and assessed the stability of the mouthwash samples stored up to 10 days before processing. Forty volunteers provided oral wash samples collected using ethanol-free and ethanol-containing mouthwashes. From each sample, one aliquot was immediately frozen, one was stored at 4°C for 5 days and frozen, while the third aliquot was stored for 5 days at 4°C and 5 days at ambient temperature to mimic shipping delays and then frozen. DNA was extracted, the 16S rRNA gene V4 region was amplified and sequenced, and bioinformatic processing was performed using QIIME 2. Microbiome metrics measured in the two mouthwash types were very similar, with intraclass correlation coefficients (ICCs) for alpha and beta diversity metrics greater than 0.85. Relative abundances of some taxa were significantly different, but ICCs of the top four most abundant phyla and genera were high (> 0.75) for the comparability of the mouthwashes. Stability during delayed processing was also high for both mouthwashes based on alpha and beta diversity measures and relative abundances of the top four phyla and genera (ICCs ≥ 0.90). These results demonstrate ethanol-free mouthwash performs similarly to ethanol-containing mouthwash for microbial analyses, and both mouthwashes are stable for at least 10 days without freezing prior to laboratory processing. Ethanol-free mouthwash is suitable for collecting and shipping oral wash samples, and these results have important implications for planning future epidemiologic studies of the oral microbiome.

Background Due to the high prevalence of obesity and the difficulty in maintaining weight loss, repeated bouts of weight loss are a common occurrence. However, there are inconsistencies in epidemiological studies regarding repetitive weight fluctuations being associated with increased risk of mortality. Therefore, the purpose of this prospective cohort analysis was to determine the long-term association of the frequency of weight loss attempts on mortality. Methods This prospective cohort study used data collected from adult AARP members living in 6 states (California, Florida, Louisiana, New Jersey, North Carolina, or Pennsylvania) or 2 metropolitan areas (Atlanta, Georgia, or Detroit, Michigan) and participating in the National Institutes of Health–AARP Diet and Health Study between 2004 and 2006. Self-reported data were analyzed for 161,738 middle-aged adults. During an average 7 years of follow-up, 21,194 deaths were recorded. Hazard ratios of all-cause, cardiovascular, and cancer mortality were estimated adjusting for demographic, lifestyle, and behavioral risk factors. Results Increased frequency of weight loss attempts of at least five pounds was associated with lower mortality ( p trend  < 0.010). Multivariate hazard ratios (95% confidence intervals) for all-cause death among individuals who successfully attempted weight loss compared with those who did not make any attempts were 0.94 (0.90–0.98) for 1–2 attempts, 0.96 (0.91–1.01) for 3–4 attempts, 0.91 (0.85–0.96) for 5–6 attempts, 0.91 (0.85–0.98) for 7–8 attempts, 0.87 (0.80–0.95) for 9–10 attempts, and 0.88 (0.82–0.94) for 11+ attempts. Similar results were noted for men and women, participants with healthy weight and overweight/obesity, and even among those who gained weight over time. Protective associations were also observed for deaths due to cardiovascular disease and cancer. Conclusions Increased frequency of intentionally losing at least five pounds in mid-life was associated with a lower risk of future death. Repeated attempts with moderate amounts of weight loss may provide benefit in terms of longevity. Trial registration number ClinicalTrials.gov number, NCT00340015

Background Chronic kidney disease has been identified as a risk factor affecting stroke prognosis. High-grade carotid artery stenosis (CAS) is associated with distal hemodynamic compromise. The association between the estimated glomerular filtration rate (eGFR) and ischemic stroke (IS) outcome in patients with high-grade CAS remains unclear. We aimed to investigate the association between eGFR and outcomes of acute IS patients with high-grade CAS. Methods From January 1, 2007 to April 30, 2012, we enrolled 372 acute IS patients with high-grade CAS and prospectively observed them for 5 years. The eGFR on admission was assessed using the Modification of Diet in Renal Disease Study equation. Demographic features, vascular risk factors, comorbidities, and outcomes were compared between different eGFR levels. Results Among 372 individuals, 76 (20.4%) had an eGFR < 45, 65 (17.5%) had an eGFR between 45 and 59, and 231 (62.1%) had an eGFR ≥60 mL/min/1.73 m 2 . Compared to other groups, in the eGFR < 45 mL/min/1.73 m 2 group, the prevalence rates of hypertension, diabetes mellitus, coronary artery disease, congestive heart failure, valvular heart disease, and gout were significantly higher ( P  = 0.013, P  = 0.030, P  = 0.001, P  < 0.001, P  = 0.043, and P  < 0.001, respectively). Patients with eGFR < 45 mL/min/1.73 m 2 demonstrated lower hemoglobin and total cholesterol levels compared with other groups ( P  < 0.001 and P  = 0.048). The blood potassium and uric acid levels were significantly higher in patients with eGFR < 45 mL/min/1.73 m 2 ( P  < 0.001 and P  < 0.001). The multivariate Cox proportional hazards model indicated that eGFR < 45 mL/min/1.73 m 2 was a significant risk factor for 5-year all-cause mortality in IS patients with high-grade CAS after adjusting for these variables (hazard ratio = 2.05; 95% CI = 1.31–3.21; P  = 0.002). Conclusions eGFR < 45 mL/min/1.73 m 2 was associated with an increased risk of 5-year all-cause mortality in acute IS patients with high-grade CAS. Whether aggressive treatment of chronic kidney disease in IS patients with high-grade CAS can improve stroke outcomes should be confirmed in future studies.