Mendelian Randomization of Blood Metabolites Suggests Circulating Glutamine Protects Against Late-Onset Alzheimer's Disease.

Background: Late-onset Alzheimer's disease (LOAD) represents a growing health burden. Previous studies suggest that blood metabolite levels influence risk of LOAD. Objective: We used a genetics-based study design which may overcome limitations of other epidemiological studies to assess the influence of metabolite levels on LOAD risk. Methods: We applied Mendelian randomization (MR) to evaluate bi-directional causal effects using summary statistics from the largest genome-wide association studies (GWAS) of 249 blood metabolites (n = 115,082) and GWAS of LOAD (ncase = 21,982, ncontrol = 41,944). Results: MR analysis of metabolites as exposures revealed a negative association of genetically-predicted glutamine levels with LOAD (Odds Ratio (OR) = 0.83, 95% CI = 0.73, 0.92) that was consistent in multiple sensitivity analyses. We also identified a positive association of genetically-predicted free cholesterol levels in small LDL (OR = 1.79, 95% CI = 1.36, 2.22) on LOAD. Using genetically-predicted LOAD as the exposure, we identified associations with phospholipids to total lipids ratio in large LDL (OR = 0.96, 95% CI = 0.94, 0.98), but not with glutamine, suggesting that the relationship between glutamine and LOAD is unidirectional. Conclusions: Our findings support previous evidence that higher circulating levels of glutamine may be a target for protection against LOAD.

Serum per- and polyfluoroalkyl substance concentrations and longitudinal change in post-infection and post-vaccination SARS-CoV-2 antibodies.

Per- and polyfluoroalkyl substances (PFAS) are ubiquitous throughout the United States. Previous studies have shown PFAS exposure to be associated with a reduced immune response. However, the relationship between serum PFAS and antibody levels following SARS-CoV-2 infection or COVID-19 vaccination has not been examined. We examined differences in peak immune response and the longitudinal decline of antibodies following SARS-CoV-2 infection and COVID-19 vaccination by serum PFAS levels in a cohort of essential workers in the United States. We measured serum antibodies using an in-house semi-quantitative enzyme-linked immunosorbent assay (ELISA). Two cohorts contributed blood samples following SARS-CoV-2 infection or COVID-19 vaccination. We used linear mixed regression models, adjusting for age, race/ethnicity, gender, presence of chronic conditions, location, and occupation, to estimate differences in immune response with respect to serum PFAS levels. Our study populations included 153 unvaccinated participants that contributed 316 blood draws over a 14-month period following infection, and 860 participants and 2451 blood draws over a 12-month period following vaccination. Higher perfluorooctane sulfonic acid (PFOS), perfluorohexane sulfonic acid (PFHxS), and perfluorononanoic acid (PFNA) concentrations were associated with a lower peak antibody response after infection (p = 0.009, 0.031, 0.015). Higher PFOS, perfluorooctanoic acid (PFOA), PFHxS, and PFNA concentrations were associated with slower declines in antibodies over time after infection (p = 0.003, 0.014, 0.026, 0.025). PFOA, PFOS, PFHxS, and PFNA serum concentrations prior to vaccination were not associated with differences in peak antibody response after vaccination or with differences in decline of antibodies over time after vaccination. These results suggest that elevated PFAS may impede potential immune response to SARS-CoV-2 infection by blunting peak antibody levels following infection; the same finding was not observed for immune response to vaccination.

Loneliness and depression: bidirectional mendelian randomization analyses using data from three large genome-wide association studies.

Major depression (MD) is a serious psychiatric illness afflicting nearly 5% of the world's population. A large correlational literature suggests that loneliness is a prospective risk factor for MD; correlational assocations of this nature may be confounded for a variety of reasons. This report uses Mendelian Randomization (MR) to examine potentially causal associations between loneliness and MD. We report on analyses using summary statistics from three large genome wide association studies (GWAS). MR analyses were conducted using three independent sources of GWAS summary statistics. In the first set of analyses, we used available summary statistics from an extant GWAS of loneliness to predict MD risk. We used two sources of outcome data: the Psychiatric Genomics Consortium (PGC) meta-analysis of MD (PGC-MD; N = 142,646) and the Million Veteran Program (MVP-MD; N = 250,215). Finally, we reversed analyses using data from the MVP and PGC samples to identify risk variants for MD and used loneliness outcome data from UK Biobank. We find robust evidence for a bidirectional causal relationship between loneliness and MD, including between loneliness, depression cases status, and a continuous measure of depressive symptoms. The estimates remained significant across several sensitivity analyses, including models that account for horizontal pleiotropy. This paper provides the first genetically-informed evidence that reducing loneliness may play a causal role in decreasing risk for depressive illness, and these findings support efforts to reduce loneliness in order to prevent or ameliorate MD. Discussion focuses on the public health significance of these findings, especially in light of the SARS-CoV-2 pandemic.

Heterogeneous melting near the Thwaites Glacier grounding line.

Thwaites Glacier represents 15% of the ice discharge from the West Antarctic Ice Sheet and influences a wider catchment1-3. Because it is grounded below sea level4,5, Thwaites Glacier is thought to be susceptible to runaway retreat triggered at the grounding line (GL) at which the glacier reaches the ocean6,7. Recent ice-flow acceleration2,8 and retreat of the ice front8-10 and GL11,12 indicate that ice loss will continue. The relative impacts of mechanisms underlying recent retreat are however uncertain. Here we show sustained GL retreat from at least 2011 to 2020 and resolve mechanisms of ice-shelf melt at the submetre scale. Our conclusions are based on observations of the Thwaites Eastern Ice Shelf (TEIS) from an underwater vehicle, extending from the GL to 3 km oceanward and from the ice-ocean interface to the sea floor. These observations show a rough ice base above a sea floor sloping upward towards the GL and an ocean cavity in which the warmest water exceeds 2 °C above freezing. Data closest to the ice base show that enhanced melting occurs along sloped surfaces that initiate near the GL and evolve into steep-sided terraces. This pronounced melting along steep ice faces, including in crevasses, produces stratification that suppresses melt along flat interfaces. These data imply that slope-dependent melting sculpts the ice base and acts as an important response to ocean warming.

Association of sedentary and physical activity behaviours with body composition: a genome-wide association and Mendelian randomisation study.

Objectives: Studies suggest that body composition can be independently improved through physical activity (PA). We performed a Mendelian randomisation (MR) study to test the incremental benefits of sedentary behaviour and various PA exposures on body composition outcomes as assessed by anthropometric indices, lean body mass (kg), body fat (%) and visceral adipose tissue (VAT) (kg). Methods: Genetic instruments were identified for both self-reported and accelerometer-measured sedentary behaviour and PA. Outcomes included anthropometric and dual-energy X-ray absorptiometry measures of adiposity, extracted from the UK Biobank and the largest available consortia. Multivariable MR (MVMR) included educational attainment as a covariate to address potential confounding. Sensitivity analyses were evaluated for weak instrument bias and pleiotropic effects. Results: We did not identify consistent associations between genetically predicted self-reported and accelerometer-measured sedentary behaviour and body composition outcomes. All analyses for self-reported moderate PA were null for body composition outcomes. Genetically predicted PA at higher intensities was protective against VAT in MR and MVMR analyses of both accelerometer-measured vigorous PA (MVMR ß=-0.15, 95% CI: -0.24 to -0.07, p<0.001) and self-reported participation in strenuous sports or other exercises (MVMR ß=-0.27, 95% CI: -0.52 to -0.01, p=0.034) was robust across several sensitivity analyses. Conclusions: We did not identify evidence of a causal relationship between genetically predicted PA and body composition, with the exception of a putatively protective effect of higher-intensity PA on VAT. Protective effects of PA against VAT may support prior evidence of biological pathways through which PA decreases risk of downstream cardiometabolic diseases.

Cross-Sectional Study of Clinical Predictors of Coccidioidomycosis, Arizona, USA.

Demographic and clinical indicators have been described to support identification of coccidioidomycosis; however, the interplay of these conditions has not been explored in a clinical setting. In 2019, we enrolled 392 participants in a cross-sectional study for suspected coccidioidomycosis in emergency departments and inpatient units in Coccidioides-endemic regions. We aimed to develop a predictive model among participants with suspected coccidioidomycosis. We applied a least absolute shrinkage and selection operator to specific coccidioidomycosis predictors and developed univariable and multivariable logistic regression models. Univariable models identified elevated eosinophil count as a statistically significant predictive feature of coccidioidomycosis in both inpatient and outpatient settings. Our multivariable outpatient model also identified rash (adjusted odds ratio 9.74 [95% CI 1.03-92.24]; p = 0.047) as a predictor. Our results suggest preliminary support for developing a coccidioidomycosis prediction model for use in clinical settings.

Contribution of Biologic Response Modifiers to the Risk of Coccidioidomycosis Severity.

BACKGROUND: The risk of coccidioidomycosis (CM) as a life-threatening respiratory illness or disseminated CM (DCM) increases as much as 150-fold in immunosuppressed patients. The safety of biologic response modifiers (BRMs) as treatment for patients with autoimmune disease (AI) in CM-endemic regions is not well defined. We sought to determine that risk in the Tucson and Phoenix areas. METHODS: We conducted a retrospective study reviewing demographics, Arizona residency length, clinical presentations, specific AI diagnoses, CM test results, and BRM treatments in electronic medical records of patients ≥18 years old with International Classification of Diseases (ICD-10) codes for CM and AI from 1 October 2017 to 31 December 2019. RESULTS: We reviewed 944 charts with overlapping ICD-10 codes for CM and AI, of which 138 were confirmed to have both diagnoses. Male sex was associated with more CM (P = .003), and patients with African ancestry were 3 times more likely than those with European ancestry to develop DCM (P < .001). Comparing CM+/AI+ (n = 138) with CM+/AI- (n = 449) patients, there were no significant differences in CM clinical presentations. Patients receiving BRMs had 2.4 times more DCM compared to pulmonary CM (PCM). CONCLUSIONS: AI does not increase the risk of any specific CM clinical presentation, and BRM treatment of most AI patients does not lead to severe CM. However, BRMs significantly increase the risk of DCM, and prospective studies are needed to identify the immunogenetic subset that permits BRM-associated DCM.

Comparison of a Novel Rapid Lateral Flow Assay to Enzyme Immunoassay Results for Early Diagnosis of Coccidioidomycosis.

BACKGROUND: Coccidioidomycosis (CM) is a common cause of community-acquired pneumonia where CM is endemic. Manifestations include self-limited pulmonary infection, chronic fibrocavitary pulmonary disease, and disseminated coccidioidomycosis. Most infections are identified by serological assays including enzyme-linked immunoassay (EIA), complement fixation, and immunodiffusion. These are time-consuming and take days to result, impeding early diagnosis. A new lateral flow assay (LFA; Sona; IMMY, Norman, OK) improves time-to-result to 1 hour. METHODS: We prospectively enrolled 392 patients with suspected CM, compared the LFA with standard EIA and included procalcitonin evaluation. RESULTS: Compared with standard EIA, LFA demonstrates 31% sensitivity (95% confidence interval [CI], 20-44%) and 92% specificity (95% CI, 88-95%). Acute pulmonary disease (74%) was the most common clinical syndrome. Hospitalized patients constituted 75% of subjects, and compared with outpatients, they more frequently had ≥3 previous healthcare facility visits (P = .05), received antibacterials (P < .01), and had >3 antibacterial courses (P < .01). Procalcitonin (PCT) was <0.25 ng/mL in 52 (83%) EIA-positive patients, suggesting infection was not bacterial. CONCLUSIONS: When CM is a possible diagnosis, LFA identified nearly one-third of EIA-positive infections. Combined with PCT <0.25 ng/mL, LFA could reduce unnecessary antibacterial use by 77%.

Bilateral Basal Ganglia Hemorrhage in a Patient with Confirmed COVID-19.

Bilateral basal ganglia hemorrhage is exceedingly rare. To our knowledge, our patient is the first reported case of a confirmed coronavirus disease 2019 (COVID-19) patient who had bilateral basal ganglia hemorrhage. In the absence of other risk factors for bilateral deep cerebral involvement, we suspect that COVID-19 may be contributing to these rare pathologies. Most published data represent a correlation between COVID-19 and neurologic complications, and more research is still needed to prove causation.

The Internal Medicine Subinternship--Now More Important than Ever: A Joint CDIM-APDIM Position Paper.

For decades, the internal medicine (IM) subinternship has served as a critical interface between undergraduate and graduate medical education. As such, the vast majority of U.S. medical schools offer this rotation to help students prepare for post-graduate training. Historically an experiential rotation, a formal curriculum with specific learning objectives was eventually developed for this course in 2002. Since then, graduate medical education (GME) has changed significantly with the regulation of duty hours, adoption of competency-based education, and development of training milestones and entrustable professional activities. In response to these and many other changes to residency training and medical practice, in 2010, the Association of Program Directors in Internal Medicine (APDIM) surveyed its members-with input from the Clerkship Directors in Internal Medicine (CDIM) Subinternship Task Force-to determine which core skills program directors expected from new medical school graduates. The results of that survey helped to inform a joint CDIM-APDIM committee's decision to re-evaluate the goals of the IM subinternship in an effort to enhance the transition from medical school to residency. This joint committee defined the minimum expectations of what constitutes an IM subinternship rotation, proposed recommended skills for IM subinterns, and discussed challenges and future directions for this crucial course.

HIV latency. Specific HIV integration sites are linked to clonal expansion and persistence of infected cells.

The persistence of HIV-infected cells in individuals on suppressive combination antiretroviral therapy (cART) presents a major barrier for curing HIV infections. HIV integrates its DNA into many sites in the host genome; we identified 2410 integration sites in peripheral blood lymphocytes of five infected individuals on cART. About 40% of the integrations were in clonally expanded cells. Approximately 50% of the infected cells in one patient were from a single clone, and some clones persisted for many years. There were multiple independent integrations in several genes, including MKL2 and BACH2; many of these integrations were in clonally expanded cells. Our findings show that HIV integration sites can play a critical role in expansion and persistence of HIV-infected cells.

A phase II study of carboplatin and paclitaxel in esophageal cancer.

BACKGROUND: This study was conducted to evaluate the efficacy and toxicity of combination carboplatin and paclitaxel in patients with esophageal cancer. MATERIALS AND METHODS: Thirty-five patients were enrolled. Patients were treated with paclitaxel 200 mg/m(2) intravenously (i.v.) over 3 h and carboplatin i.v. at an AUC of 5 mg/h/ml. Thirty-three patients were assessable for toxicity and objective response. RESULTS: A total of 166 treatment courses were administered with a median of five courses per patient. The objective response rate was 43% [90% confidence interval (CI) 0.3-0.58] by the intention-to-treat analysis. The median response duration was 2.8 months (90% CI 2.1-5.4). The median survival time was 9 months (90% CI 7-13.8) and the 1-year survival rate was 43% (90% CI 0.29-0.57). The major grade 3-4 toxicity observed was neutropenia, occurring in 17 patients (52%). There were no treatment-related deaths. CONCLUSIONS: The combination of carboplatin and paclitaxel is an moderately active and tolerable regimen in advanced esophageal cancer.

Replication of phenotypically mixed human immunodeficiency virus type 1 virions containing catalytically active and catalytically inactive reverse transcriptase.

The amount of excess polymerase and RNase H activity in human immunodeficiency virus type 1 virions was measured by using vectors that undergo a single round of replication. Vectors containing wild-type reverse transcriptase (RT), vectors encoding the D110E mutation to inactivate polymerase, and vectors encoding mutations D443A and E478Q to inactivate RNase H were constructed. 293 cells were cotransfected with different proportions of plasmids encoding these vectors to generate phenotypically mixed virions. The resulting viruses were used to infect human osteosarcoma cells, and the relative infectivity of the viruses was determined by measuring transduction of the murine cell surface marker CD24, which is encoded by the vectors. The results indicated that there is an excess of both polymerase and RNase H activities in virions. Viral replication was reduced to 42% of wild-type levels in virions with where half of the RT molecules were predicted to be catalytically active but dropped to 3% of wild-type levels when 25% of the RT molecules were active. However, reducing RNase H activity had a lesser effect on viral replication. As expected, based on previous work with murine leukemia virus, there was relatively inefficient virus replication when the RNase H and polymerase activities were encoded on separate vectors (D110E plus E478Q and D110E plus D443A). To determine how virus replication failed when polymerase and RNase H activities were reduced, reverse transcription intermediates were measured in vector-infected cells by using quantitative real-time PCR. The results indicated that using the D11OE mutation to reduce the amount of active polymerase reduced the number of reverse transcripts that were initiated and also reduced the amounts of products from the late stages of reverse transcription. If the E478Q mutation was used to reduce RNase H activity, the number of reverse transcripts that were initiated was reduced; there was also a strong effect on minus-strand transfer.

Impact of breast pumping on lactogenesis stage II after cesarean delivery: a randomized clinical trial.

OBJECTIVE: Women at risk for delayed onset of lactation are often advised to pump their breasts before lactogenesis stage II to hasten the timing of this process. The effectiveness of this clinical practice has not been previously evaluated. This study investigates the effects of breast pumping before the onset of lactation on early milk transfer and subsequent breastfeeding duration among women giving birth by cesarean delivery. METHODOLOGY: Sixty women were randomly assigned to either the pumping group (n = 30), which used a double electric breast pump for six 10- to 15-minute sessions from 24 to 72 hours postpartum, or to the control group (n = 30), which held the pump to their breasts without suction for the same amount of time. Milk transfer was assessed by test weighing infants before and after 3 breastfeeding sessions daily. Test weight data were fitted to a second-order polynomial curve, to predict milk transfer over time. RESULTS: Breast pumping between 24 and 72 hours after cesarean delivery did not improve milk transfer. Participants in the pumping group tended to have lower milk transfer than did controls. Primiparae in the pumping group breastfed for ~5 months less than their counterparts in the control group; however, this difference was not statistically significant. CONCLUSIONS: Breast pumping did not improve milk transfer during the first 72 hours postpartum and may negatively affect breastfeeding duration among primiparous women. lactation, lactogenesis, breast milk, breast pumping, milk expression, breastfeeding, cesarean delivery.