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Abstract Background Early reports showed that patients with COVID-19 had recrudescence of previously resolved coccidioidomycosis (Valley fever, VF), and there were indications that coinfection had more severe outcomes. We therefore investigated serial infection of Coccidioides posadasii and SARS-CoV-2 in a K18-hACE2 mouse model to assess disease outcomes. Methods In our model, we challenged K18-hACE2 mice sequentially with a sub-lethal dose of SARS-CoV-2 and 24 hours later with low virulence strain of Coccidioides posadasii, and vice versa, compared to mice that only received a single infection challenge. We performed survival and pathogenesis mouse studies as well as looked at the systemic immune response differences between treatment groups. Results Here we show that co-infected groups have a more severe disease progression as well as a decrease in survival. Importantly, results differ depending on the SARS-CoV-2 variant (WA-1, Delta, or Omicron) and infection timing (SARS-CoV-2 first, C. posadasii second or vice versa). We find that groups that are infected with the virus first had a decrease in survival, increased morbidity and weight loss, increased fungal and viral burdens, differences in immune responses, and the amount and size of fungal spherules. We also find that groups coinfected with C. posadasii first have a decrease fungal burden and inflammatory responses. Conclusions This is the first in vivo model investigation of a coinfection of SARS-CoV-2 and Coccidioides. Because of the potential for increased severity of disease in a coinfection, we suggest populations that live in areas of high coccidioidomycosis endemicity may experience higher incidence of complicated disease progression with COVID-19.

Abstract Background Handgun purchaser licensing (HPL) laws mandate individuals to obtain a license from law enforcement before buying a firearm. Research indicates these laws effectively reduce various forms of fatal firearm violence, including homicides, suicides, and mass shootings. Our study sought to assess the impact of HPL laws on non-fatal firearm violence. Methods Utilizing the augmented synthetic control method (ASCM), we estimated the average treatment effect on the treated (ATT) resulting from a full repeal of an HPL law in Missouri (2007), a partial repeal in Michigan (2012), and an adoption on HPL law in Maryland (2013) on firearm injury hospitalizations. We utilized RAND's healthcare cost and utilization project-based dataset from 2000 to 2016 for our outcome variable. We conducted in-time placebo testing and leave-one-out donor pool testing as sensitivity analyses. Results Maryland’s adoption was associated with a statistically significant 32.3% reduction in firearm-related injury hospitalization (FIH) rates (ATT = − 0.497, standard error (SE) = 0.123); Missouri’s repeal was associated with a statistically significant 35.7% increase in FIH rates (ASCM = 0.456, SE = 0.155); and Michigan’s partial repeal showed no statistically significant associations with FIH rates (ATT = − 0.074, SE = 0.129). Sensitivity analyses confirm the robustness of the estimated HPL effects. Discussion HPL laws appear to be protective against hospitalizations for nonfatal firearm injuries. These findings align with prior research indicating that HPL laws are effective in reducing fatal firearm violence. States without such licensing systems ought to consider these robust policies as a means to address firearm violence.

Abstract The global average daily minimum temperatures are increasing at a quicker pace than the average daily maximum temperatures, which are predicted to increase in severity impacting global food production. This study focuses on elucidating the physiological and transcriptional response to high night‐time temperature (HNT) stress in 12 US commercial maize (Zea mays) hybrids using unique field‐based infrastructure. Our experimental objectives were to (i) impose an accurate and uniformly distributed post‐flowering HNT stress of +4.0°C until physiological maturity, (ii) quantify the impact of HNT stress on physiological and yield‐related traits, (iii) establish the impact on end‐use quality of maize kernels formed under HNT stress, and (iv) analyze the differential expression of genes involved in grain starch metabolism. Accurate and uniformly distributed HNT stress of 3.8°C higher than the ambient night‐time temperature throughout the grain‐filling period reduced yield (−14%), kernel weight (−8%), and significantly reduced kernel nutrient content, specifically magnesium in the susceptible hybrids. HNT significantly increased the expression of key genes involved in starch metabolism in the tolerant hybrid. Although HNT stress had a negative impact on yield and quality in field grown maize, two hybrids had physiological and transcriptional regulation that favored higher level of resilience which lays the platform for developing climate smart maize hybrids.

Summary: Background: Exocrine Pancreatic insufficiency (EPI) occurs following acute pancreatitis (AP) at variably reported rates and with unclear recovery timeline. The aim of this study was to establish the prevalence and predictors of EPI at 12 months after AP in a prospective cohort. Methods: In this prospective, multicentre, longitudinal cohort study, adult participants (≥18 years) admitted to the hospital with an AP attack (defined by Revised Atlanta Classification) were enrolled in a United States multi-centre longitudinal cohort (Sites: The Ohio State University, University of Pittsburgh, and Johns Hopkins University). Patients were excluded if they had pancreatic cancer, chronic pancreatitis, or malabsorptive disease (including previously diagnosed EPI). Participant data was obtained by interview and by review of the electronic medical record. EPI was assessed by stool fecal elastase (FE-1) levels collected at baseline, 3 months, and 12 months (primary endpoint). EPI was defined by FE-1

Social scientists have long recognized field of study as an important mechanism of gender differentiation and stratification in U.S. higher education, but they have rarely attended to how elective curriculums mediate gender differentiation in major selection. Under elective curriculums, major selection is an iterative process, in which students select courses in stepwise fashion at the beginning of each academic term, and are able to change majors early in their undergraduate careers. We observe how an elective curriculum mediates gendered patterns of major selection, using a novel data set describing 11,730 students at a large public research university. We find (a) gender and intended major are strongly correlated upon college entry; (b) large proportions of students change majors between entry and declaration; (c) because most changes are to academically adjacent fields, gendered patterns in field of study persist through the undergraduate career. Findings suggest the value of an iterative conception of major selection and offer tractable means for intervening in the process through which students select majors. JEL codes: I21, I24, I26, J16.

Parasite-derived new permeation pathways (NPPs) expressed at the red blood cell (RBC) membrane enable Plasmodium parasites to take up nutrients from the plasma to facilitate their survival. Thus, NPPs represent a potential novel therapeutic target for malaria. The putative channel component of the NPP in the human malaria parasite P. falciparum is encoded by mutually exclusively expressed clag3.1/3.2 genes. Complicating the study of the essentiality of these genes to the NPP is the addition of three clag paralogs whose contribution to the P. falciparum channel is uncertain. Rodent malaria P. berghei contains only two clag genes, and thus studies of P. berghei clag genes could significantly aid in dissecting their overall contribution to NPP activity. Previous methods for determining NPP activity in a rodent model have utilised flux-based assays of radioisotope-labelled substrates or patch clamping. This study aimed to ratify a streamlined haemolysis assay capable of assessing the functionality of P. berghei NPPs. Several isotonic lysis solutions were tested for their ability to preferentially lyse infected RBCs (iRBCs), leaving uninfected RBCs (uRBCs) intact. The osmotic lysis assay was optimised and validated in the presence of NPP inhibitors to demonstrate the uptake of the lysis solution via the NPPs. Guanidinium chloride proved to be the most efficient reagent to use in an osmotic lysis assay to establish NPP functionality. Furthermore, following treatment with guanidinium chloride, ring-stage parasites could develop into trophozoites and schizonts, potentially enabling use of guanidinium chloride for parasite synchronisation. This haemolysis assay will be useful for further investigation of NPPs in P. berghei and could assist in validating its protein constituents.

Abstract Background Fatal and nonfatal shootings by police are a public health issue that warrants additional research. Prior research has documented associations between fatal shootings by police and gun ownership, legislative strength scores, and lax concealed carry weapons laws. Despite research on other firearm-related outcomes, little is known about the impact of permit-to-purchase (PTP) laws on shootings by police. We generated counts of fatal and nonfatal OIS from the Gun Violence Archive from 2015 to 2020. We conducted cross-sectional regression modeling with a Poisson distribution and robust standard errors. In addition to PTP, we included several state-level policies that may be associated with shootings by police: comprehensive background check only (CBC-only) laws, concealed carry licensing laws, stand your ground laws, violent misdemeanor prohibitions, and extreme risk protection orders (ERPO). We controlled for state-level demographic characteristics and included a population offset to generate incidence rate ratios (IRR). Findings PTP laws were associated with a 28% lower rate in shootings by police [IRR = 0.72, 95% confidence interval (CI) 0.64–0.81]. Shall Issue (IRR = 1.34, 95% CI 1.17–1.53) and Permitless (IRR = 1.61, 95% CI 1.35–1.91) concealed carry laws and CBC-only laws (IRR = 1.12, 95% CI 1.01–1.25) were associated with higher rates of shootings by police. Stand your ground, violent misdemeanor prohibitions, and ERPO laws were not associated with shootings by police. Conclusions Our study found that PTP laws were associated with significantly lower rates of shootings by police. Removing restrictions on civilian concealed carry was associated with significantly higher rates. State-level firearm policies may be a lever to address shootings by police.

ABSTRACT Tetracyclines serve as broad-spectrum antibiotics to treat bacterial infections. The discovery of new tetracycline resistance genes has led to new questions about the underlying mechanisms of resistance, gene transfer, and their relevance to human health. We tracked changes in the abundance of a 55-kbp conjugative transposon (CTn214) carrying tetQ, a tetracycline resistance gene, within a Bacteroides fragilis metagenome-assembled genome derived from shotgun sequencing of microbial DNA extracted from the ileal pouch of a patient with ulcerative colitis. The mapping of metagenomic reads to CTn214 revealed the multi-copy nature of a 17,044-nt region containing tetQ in samples collected during inflammation and uninflamed visits. B. fragilis cultivars isolated from the same patient during periods of inflammation harbored CTn214 integrated into the chromosome or both a circular, multi-copy, extrachromosomal region of the CTn214 containing tetQ and the corresponding integrated form. The tetracycline-dependent mechanism for the transmission of CTn214 is nearly identical to a common conjugative transposon found in the genome of B. fragilis (CTnDOT), but the autonomously amplified nature of a circular 17,044-nt region of CTn214 that codes for tetQ and the integration of the same sequence in the linear chromosome within the same cell is a novel observation. Genome and transcriptome sequencing of B. fragilis cultivars grown under different concentrations of tetracycline and ciprofloxacin indicates that tetQ in strains containing the circular form remains actively expressed regardless of treatment, while the expression of tetQ in strains containing the linear form increases only in the presence of tetracycline.IMPORTANCEThe exchange of antibiotic production and resistance genes between microorganisms can lead to the emergence of new pathogens. In this study, short-read mapping of metagenomic samples taken over time from the illeal pouch of a patient with ulcerative colitis to a Bacteroides fragilis metagenome-assembled genome revealed two distinct genomic arrangements of a novel conjugative transposon, CTn214, that encodes tetracycline resistance. The autonomous amplification of a plasmid-like circular form from CTn214 that includes tetQ potentially provides consistent ribosome protection against tetracycline. This mode of antibiotic resistance offers a novel mechanism for understanding the emergence of pathobionts like B. fragilis and their persistence for extended periods of time in patients with inflammatory bowel disease.

Background/objectivesGermline genetic testing is recommended for younger patients with idiopathic pancreatitis but there has been a lack of consensus in recommendations for those over age 35. We aimed to analyze the results of genetic testing among subjects of varying ages.MethodsIndividuals who underwent germline multigene testing for pancreatitis susceptibility genes (CASR, CFTR, CPA1, CTRC, PRSS1, SPINK1) through a large commercial laboratory between 2017 and 2022 were included. Test results and information collected from test requisition forms were evaluated. Multivariable logistic regression models were performed to identify factors associated with a positive pancreatitis panel (pathogenic, likely pathogenic, and/or increased risk variants) in pancreatitis-related genes.ResultsOverall, 2,468 subjects with primary indication of acute pancreatitis (AP) (n = 401), chronic pancreatitis (CP) (n = 631), pancreatic cancer (n = 128), or other indications (n = 1,308) completed germline testing. Among patients with AP or CP, the prevalence of any positive result for those ConclusionsThe highest prevalence of pathogenic variants is seen in younger individuals with a positive family history of pancreatitis. However, clinically meaningful results are identified in older subjects, suggesting that genetic counseling and testing should be considered for all age groups.

ABSTRACTBacteroides fragilis comprises 1%–5% of the gut microbiota in healthy humans but can expand to >50% of the population in ulcerative colitis (UC) patients experiencing inflammation. The mechanisms underlying such microbial blooms are poorly understood, but the gut of UC patients has physicochemical features that differ from healthy patients and likely impact microbial physiology. For example, levels of the secondary bile acid deoxycholate (DC) are highly reduced in the ileoanal J-pouch of UC colectomy patients. We isolated a B. fragilis strain from a UC patient with pouch inflammation (i.e., pouchitis) and developed it as a genetic model system to identify genes and pathways that are regulated by DC and that impact B. fragilis fitness in DC and crude bile. Treatment of B. fragilis with a physiologically relevant concentration of DC reduced cell growth and remodeled transcription of one-quarter of the genome. DC strongly induced expression of chaperones and select transcriptional regulators and efflux systems, and down-regulated protein synthesis genes. Using a barcoded collection of ≈50,000 unique insertional mutants, we further defined B. fragilis genes that contribute to fitness in media containing DC or crude bile. Genes impacting cell envelope functions including cardiolipin synthesis, cell surface glycosylation, and systems implicated in sodium-dependent bioenergetics were major bile acid fitness factors. As expected, there was limited overlap between transcriptionally regulated genes and genes that impacted fitness in bile when disrupted. Our study provides a genome-scale view of a B. fragilis bile response and genetic determinants of its fitness in DC and crude bile.IMPORTANCEThe Gram-negative bacterium Bacteroides fragilis is a common member of the human gut microbiota that colonizes multiple host niches and can influence human physiology through a variety of mechanisms. Identification of genes that enable B. fragilis to grow across a range of host environments has been impeded in part by the relatively limited genetic tractability of this species. We have developed a high-throughput genetic resource for a B. fragilis strain isolated from a UC pouchitis patient. Bile acids limit microbial growth and are altered in abundance in UC pouches, where B. fragilis often blooms. Using this resource, we uncovered pathways and processes that impact B. fragilis fitness in bile and that may contribute to population expansions during bouts of gut inflammation.

Abstract Accumulation of α-synuclein into toxic oligomers or fibrils is implicated in dopaminergic neurodegeneration in Parkinson’s disease. Here we performed a high-throughput, proteome-wide peptide screen to identify protein-protein interaction inhibitors that reduce α-synuclein oligomer levels and their associated cytotoxicity. We find that the most potent peptide inhibitor disrupts the direct interaction between the C-terminal region of α-synuclein and CHarged Multivesicular body Protein 2B (CHMP2B), a component of the Endosomal Sorting Complex Required for Transport-III (ESCRT-III). We show that α-synuclein impedes endolysosomal activity via this interaction, thereby inhibiting its own degradation. Conversely, the peptide inhibitor restores endolysosomal function and thereby decreases α-synuclein levels in multiple models, including female and male human cells harboring disease-causing α-synuclein mutations. Furthermore, the peptide inhibitor protects dopaminergic neurons from α-synuclein-mediated degeneration in hermaphroditic C. elegans and preclinical Parkinson’s disease models using female rats. Thus, the α-synuclein-CHMP2B interaction is a potential therapeutic target for neurodegenerative disorders.

NANOS3 is expressed in migrating primordial germ cells (PGCs) to protect them from apoptosis, and it is known to be a critical factor for germline development of both sexes in several organisms. However, to date, live NANOS3 knockout (KO) cattle have not been reported, and the specific role of NANOS3 in male cattle, or bulls, remains unexplored. This study generated NANOS3 KO cattle via cytoplasmic microinjection of the CRISPR/Cas9 system in vitro produced bovine zygotes and evaluated the effect of NANOS3 elimination on bovine germline development, from fetal development through reproductive age. The co-injection of two selected guide RNA (gRNA)/Cas9 ribonucleoprotein complexes (i.e., dual gRNA approach) at 6 h post fertilization achieved a high NANOS3 KO rate in developing embryos. Subsequent embryo transfers resulted in a 31% (n = 8/26) pregnancy rate. A 75% (n = 6/8) total KO rate (i.e., 100% of alleles present contained complete loss-of-function mutations) was achieved with the dual gRNA editing approach. In NANOS3 KO fetal testes, PGCs were found to be completely eliminated by 41-day of fetal age. Importantly, despite the absence of germ cells, seminiferous tubule development was not impaired in NANOS3 KO bovine testes during fetal, perinatal, and adult stages. Moreover, a live, NANOS3 KO, germline-ablated bull was produced and at sexual maturity he exhibited normal libido, an anatomically normal reproductive tract, and intact somatic gonadal development and structure. Additionally, a live, NANOS3 KO, germline-ablated heifer was produced. However, it was evident that the absence of germ cells in NANOS3 KO cattle compromised the normalcy of ovarian development to a greater extent than it did testes development. The meat composition of NANOS3 KO cattle was unremarkable. Overall, this study demonstrated that the absence of NANOS3 in cattle leads to the specific deficiency of both male and female germ cells, suggesting the potential of NANOS3 KO cattle to act as hosts for donor-derived exogenous germ cell production in both sexes. These findings contribute to the understanding of NANOS3 function in cattle and have valuable implications for the development of novel breeding technologies using germline complementation in NANOS3 KO germline-ablated hosts.

Societal impact statement Sour cherry (Prunus cerasus L.) is an agriculturally valuable tree that produces fruits used in a range of culinary dishes, beverages, and other products. The progenitor species and number of origins of sour cherry remain unresolved. Here, we performed phylogenetic analyses of plastid genomes and nuclear genes from nine wild species and three historically important sour cherry cultivars. Our analyses identified Prunus fruticosa and Prunus avium as the closest extant relatives of the progenitor species of tetraploid sour cherry. Furthermore, our analyses revealed P. fruticosa as the likely maternal contributor. These findings and transcriptomic datasets should serve as valuable new resources to guide future breeding efforts in sour cherry.

The coronavirus disease 2019 (COVID-19) pandemic has enabled the adoption of digital health platforms for self-monitoring and diagnosis. Notably, the pandemic has had profound effects on athletes and their ability to train and compete. Sporting organizations worldwide have reported a significant increase in injuries manifesting from changes in training regimens and match schedules resulting from extended quarantines. While current literature focuses on the use of wearable technology to monitor athlete workloads to guide training, there is a lack of literature suggesting how such technology can mediate the return to sport processes of athletes infected with COVID-19. This paper bridges this gap by providing recommendations to guide team physicians and athletic trainers on the utility of wearable technology for improving the well-being of athletes who may be asymptomatic, symptomatic, or tested negative but have had to quarantine due to a close exposure. We start by describing the physiologic changes that occur in athletes infected with COVID-19 with extended deconditioning from a musculoskeletal, psychological, cardiopulmonary, and thermoregulatory standpoint and review the evidence on how these athletes may safely return to play. We highlight opportunities for wearable technology to aid in the return-to-play process by offering a list of key parameters pertinent to the athlete affected by COVID-19. This paper provides the athletic community with a greater understanding of how wearable technology can be implemented in the rehabilitation process of these athletes and spurs opportunities for further innovations in wearables, digital health, and sports medicine to reduce injury burden in athletes of all ages.

Background The use of sonography is a cost-effective and reliable method to evaluate upper extremity superficial tissue structural integrity and pathology. Establishing the measurement reliability of widely used diagnostic ultrasound evaluation for musculoskeletal assessment is paramount enhance accurate clinical evaluations. The objective of this study was to establish the inter-rater and intra-rater reliability of select ulnar collateral ligament (UCL) thickness measures at two distinct anatomical locations in intercollegiate baseball athletes using ultrasound imaging (USI). Methods This was a prospective cohort study conducted in a university research laboratory and included a total of 17 NCAA Division I baseball athletes (age 20.4 ± 1.43, height = 183.63 cm ± 6.27 cm, mass = 89.28 kg ± 8.24 kg). Two trained clinicians measured UCL mid-substance and apex thickness in the throwing extremity, prospectively, on 5 occasions at 1-month intervals during rest. Intraclass correlation coefficients (ICCs) (model 3,3), associated standard error of measurement, and 95% minimal detectable change in thickness were derived. Results Intrarater reliability estimates for operator 1 were 0.90–0.98 (mid-substance) and 0.91–0.99 (apex). Operator 2’s values were 0.92–0.97 and 0.93–0.99, respectively. The standard error of measurement (SEM) ranged from 0.045–0.071 cm (mid-substance) and 0.023–0.067 cm (apex). The minimal detectable difference (MDD95) was 0.12–0.20 cm (mid-substance) and 0.07–0.19 cm (apex). Interrater reliability was 0.86–0.96 (mid-substance) and 0.79–0.98 (apex); most ICCs were >0.90. Measurement of UCL thickness at two locations demonstrated very good to excellent reliability with high precision. Using this protocol, two evaluators can obtain consistent UCL measurement at two positions. This finding has significant implications for the clinical evaluation of superficial tissue pathology of the same individual by two experienced practitioners.

Background:. Although infection following anterior cruciate ligament (ACL) reconstruction is rare, these cases have potentially catastrophic ramifications. Nontuberculous mycobacteria (NTM) are ubiquitous, located in the water supply and soil. Our objective was to review the literature to characterize NTM infection following ACL reconstruction. Methods:. A database search was performed for arthroscopic ACL reconstructions that resulted in a postoperative diagnosis of NTM infection. Results:. The literature search returned 6 case reports that met the inclusion criteria. The initial postoperative presentation occurred after 3 to 52 weeks, which is consistent with reports of postoperative NTM infection. Conclusions:. The common indolent course of NTM infection hinders prompt diagnosis and treatment. Organism susceptibility testing is crucial for effective treatment and limiting unnecessary antibiotic exposure. Clinical Relevance:. The duration of medical treatment for NTM infection is 4 to 6 months, depending on the severity of disease and species. Based on the aggregate literature, we recommend removal of local implants if the infection is localized and without articular involvement. However, in cases of articular involvement, all fixation and graft material should be removed.

Abstract Background “Cheat meals”, described as brief eating episodes that depart from established dietary practices to consume prohibited foods, represent a novel and increasingly common eating behavior with particular salience in adolescence and young adulthood. However, knowledge gaps remain regarding the frequency and characterization of foods and calories consumed during cheat meals, and their associations with eating disorder behaviors and psychopathology. Thus, the aims of this study were to delineate engagement in cheat meals among a large, national sample of Canadian adolescents and young adults. Methods Participants (N = 2,717) were from the Canadian Study of Adolescent Health Behaviors. Frequencies of engagement in cheat meals, and associated foods and calories consumed, in the past 12 months and 30 days were determined. The associations between engagement in cheat meals and eating disorder behaviors and psychopathology were determined using modified Poisson regression analyses. Results Engagement in cheat meals in the past 12 months was highest among men (60.9%) compared to women (53.7%) and transgender/gender non-conforming (TGNC; 52.5%) participants. Cheat meals consisting between 1,000 and 1,499 cal were those most frequently reported among all participants. Mean number of cheat meals in the past 12 months was equivalent to > 1 per week, which was similar to engagement in the past 30 days. Finally, engagement in cheat meals in the past 12 months and 30 days was associated with patterns of eating disorder behaviors and psychopathology among all participants, including binge-eating-related behaviors. Conclusions This study further characterized and extended knowledge of cheat meal engagement across genders, aligning with prior research by demonstrating that engagement is associated with greater eating disorder psychopathology. Plain english summary Findings from this study add to the growing characterization of the novel behavioral phenomenon of cheat meals. Specifically, over half of adolescents and young adults across all 13 provinces and territories in Canada reported engaging in > 1 cal dense cheat meal per week, over the past 12 months. Despite the normalization and promotion of cheat meal engagement among the general public and unique fitness communities, engagement in this behavior is linked to greater eating disorder behaviors and psychopathology, including binge-eating episodes. Our findings emphasize the need for further research, public awareness, and clinical interventions aimed at addressing this potentially harmful eating behavior.

IntroductionConfidence is defined as the feelings and thoughts people have during a task that result in judgments about their performance. Evidence suggests that confidence is trait-like, but thus far research on the relative match between confidence and accuracy has been primarily restricted to over-confidence effects, and subject to the methodological flaws involved with using difference scores. We sought to answer an exploratory question in this research, whether discrepancies in ability and confidence in either direction reliably predicted individual differences on a broad-spectrum and commercially available personality test, the California Psychological Inventory (CPI260).MethodsParticipants were 220 employed adults who had previously taken the CPI260 for career development purposes. They were invited to complete a measure of cognitive ability and confidence in return for feedback on the same. Data were modeled using polynomial regression and response surface analysis, to determine whether and how CPI260 personality traits were associated with matches or mismatches between accuracy and confidence in the same test.ResultsWe identified negative curvilinear effects along the line of disagreement for four CPI260 scales, suggesting that both under- and over-confidence were associated with personality.DiscussionIn contrast to our expectations, individuals who were under-confident and those who were over-confident had lower achievement potential, less social confidence, and more inner conflict than other individuals in this sample. Although preliminary, these findings suggest that both over-confident and under-confident individuals are aware of potential weaknesses that impede their functioning.

Introduction and Objectives: Psychosocial stressors related to the coronavirus-19 (COVID-19) pandemic increased alcohol consumption. The effect on patients with alcohol-related liver diseases remains unclear. Materials and Methods: Hospitalizations at a tertiary care center due to alcohol-related liver disease from March 1 through August 31 in 2019 (pre-pandemic cohort) and 2020 (pandemic cohort) were reviewed retrospectively. Differences in patient demographics, disease features, and outcomes were estimated in patients with alcoholic hepatitis utilizing T-tests, Mann-Whitney tests, Chi-square and Fisher Exact Tests and Anova models and logistic regression models in patients with alcoholic cirrhosis. Results: 146 patients with alcoholic hepatitis and 305 patients with alcoholic cirrhosis were admitted during the pandemic compared to 75 and 396 in the pre-pandemic cohort. Despite similar median Maddrey Scores (41.20 vs. 37.45, p=0.57), patients were 25% less likely to receive steroids during the pandemic. Patients with alcoholic hepatitis admitted during the pandemic were more likely to have hepatic encephalopathy (0.13; 95% CI:0.01, 0.25), variceal hemorrhage (0.14; 95% CI:0.04, 0.25), require oxygen (0.11; 95% CI:0.01, 0.21), vasopressors (OR:3.49; 95% CI:1.27, 12.01) and hemodialysis (OR:3.70; 95% CI:1.22, 15.13). On average, patients with alcoholic cirrhosis had MELD-Na scores 3.77 points higher (95% CI:1.05, 13.46) as compared to the pre-pandemic and had higher odds of experiencing hepatic encephalopathy (OR:1.34; 95% CI:1.04, 1.73), spontaneous bacterial peritonitis (OR:1.88; 95% CI:1.03, 3.43), ascites (OR:1.40, 95% CI:1.10, 1.79), vasopressors (OR:1.68, 95% CI:1.14, 2.46) or inpatient mortality (OR:2.00, 95% CI:1.33, 2.99) than the pre-pandemic. Conclusions: Patients with alcohol-related liver disease experienced worse outcomes during the pandemic.

Metal polymer composites combining low density, high strength composites with highly ductile and tough metals have gained traction over the last few decades as lightweight and high-performance materials for industrial applications. However, the mechanical properties are limited by the interfacial bonding strength between metals and polymers achieved through adhesives, welding, and surface treatment processes. In this paper, a novel manufacturing process combining additive manufacturing and compression molding to obtain hybrid metal polymer composites with enhanced mechanical properties is presented. Additive manufacturing enabled deposition of polymeric material with fibers in a predetermined pattern to form tailored charge or preform for compression molding. A grade 300 maraging steel triangular lattice is first fabricated using AddUp FormUp350 laser powder bed system and compression overmolded with additively manufactured long carbon fiber-reinforced polyamide-6,6 (40% wt. CF/PA66) preform. The fabricated hybrid metal polymer composites showed high stiffness and tensile strength. The stiffness and failure characteristics determined from the uniaxial tensile tests were correlated to a finite element model within 20% deviation. Fractographic analyses was performed using microscopy to investigate failure mechanisms of the hybrid structures.

Sulforaphane, a chemical found in broccoli, has known antioxidant and antiinflammatory effects. Here, the authors show that it can inhibit SARS-CoV-2 and other coronavirus infections in mammalian cells and can decrease viral load in mice when treated prior to SARS-CoV-2 infection.

Introduction: Donation after cardiac death (DCD) has been leading the way to help bridge the growing gap between availability of donors and recipients on waitlist. With advances in technology and our understanding of DCD donation the safety profile is growing. It is becoming an increasing viable option even in marginal settings. Discussion: The ethos surroundings DCD is still a matter of contention but there is support and collaboration from larger societies and establishments with development of standardizing protocols. Preparation is key. Experience of the procurement and transplanting surgeons are pivotal. There are multiple moving parts and for the success of a DCD program, dedication is needed from the donor hospitals, organ procurement organizations and the transplant centers. Previous practices based on anecdotal experiences are now either supported by or refuted by increasing evidence and data, based on the development of consensus-based guidelines with the end goal of having uniform outcomes. Normothermic regional and machine perfusion have expanded options in the DCD world, challenging the limits and expanding our paradigm. Recognition of the weaknesses and organ specific complications allow the clinician to make choices for optimal outcomes. These advancements have allowed outcomes to be optimized. Conclusions: Expanding the organ donor pool is one solution to increase the availability of organs for transplantation. Increasing the attention to and the use of DCD organs combined with machine and normothermic perfusion is a future strategy to obtain ongoing clinical success in organ transplantation and lower the waiting list mortality.

A possible undesired outcome of CRISPR-Cas9 germline editing is unwanted karyotype alterations. Here the authors track aberrations through three divisions of embryonic development following Cas9 editing.

Committing to a major is a fateful step in an undergraduate education, yet the relationship between courses taken early in an academic career and ultimate major issuance remains little studied at scale. Using transcript data capturing the academic careers of 26,892 undergraduates enrolled at a private university between 2000 and 2020, we describe enrollment histories by using natural-language methods and vector embeddings to forecast terminal major on the basis of course sequences beginning at college entry. We find that (a) a student’s very first enrolled course predicts their major 30 times better than random guessing and more than one-third better than majority-class voting, (b) modeling strategies substantially influence forecasting metrics, and (c) course portfolios vary substantially within majors, such that students with the same major exhibit relatively modest overlap.

After a damaging insult, hair cells can spontaneously regenerate from cochlear supporting cells within the first week of life. While the regenerated cells express several markers of immature hair cells and have stereocilia bundles, their capacity to differentiate into inner or outer hair cells, and ability to form new synaptic connections has not been well-described. In addition, while multiple supporting cell subtypes have been implicated as the source of the regenerated hair cells, it is unclear if certain subtypes have a greater propensity to form one hair cell type over another. To investigate this, we used two CreER mouse models to fate-map either the supporting cells located near the inner hair cells (inner phalangeal and border cells) or outer hair cells (Deiters’, inner pillar, and outer pillar cells) along with immunostaining for markers that specify the two hair cell types. We found that supporting cells fate-mapped by both CreER lines responded early to hair cell damage by expressing Atoh1, and are capable of producing regenerated hair cells that express terminal differentiation markers of both inner and outer hair cells. The majority of regenerated hair cells were innervated by neuronal fibers and contained synapses. Unexpectedly, we also found that the majority of the laterally positioned regenerated hair cells aberrantly expressed both the outer hair cell gene, oncomodulin, and the inner hair cell gene, vesicular glutamate transporter 3 (VGlut3). While this work demonstrates that regenerated cells can express markers of both inner and outer hair cells after damage, VGlut3 expression appears to lack the tight control present during embryogenesis, which leads to its inappropriate expression in regenerated cells.

Abstract Due to advances in sequencing technologies, identification of genetic variants is rapid. However, the functional consequences of most genomic variants remain unknown. Consequently, variants of uncertain significance (VUS) that appear in clinical DNA diagnostic reports lack sufficient data for interpretation. Algorithms exist to aid prediction of a variant's likelihood of pathogenicity, but these predictions usually lack empiric evidence. To examine the feasibility of generating functional evidence in vitro for a given variant's role in disease, a panel of 29 coding sequence variants in the G6PC gene was assessed. G6PC encodes glucose‐6 phosphatase enzyme, and reduction in its function causes the rare metabolic disease glycogen storage disease type 1a (GSD1a). Variants were heterologously expressed as fusion proteins in a hepatocyte‐derived cell line and examined for effects on steady‐state protein levels, biosynthetic processing, and intracellular distribution. The screen revealed variant effects on protein levels, N‐linked glycosylation status, and cellular distribution. Of the eight VUS tested, seven behaved similar to wild‐type protein while one VUS, p.Cys109Tyr, exhibited features consistent with pathogenicity for all molecular phenotypes assayed, including significantly reduced protein levels, alteration in protein glycosylation status, and abnormally diffuse protein localization pattern, and has recently been reported in a patient with GSD1a. Our results show that such a screen can add empiric evidence to existing databases to aid in diagnostics, and also provides further classification for molecular phenotypes that could be used in future therapeutic screening approaches for small molecule or gene editing strategies directed at specific variants.

Patient‐reported outcomes (PROs) are important endpoints for clinical trials. The impact of investigational drugs on PROs of patients with advanced nonalcoholic steatohepatitis (NASH) was investigated. Patients with NASH with bridging fibrosis or compensated cirrhosis were enrolled in a phase 2, randomized, placebo‐controlled study of selonsertib, firsocostat, or cilofexor, alone or in two‐drug combinations (NCT03449446). PROs included Short Form 36 (SF‐36), Chronic Liver Disease Questionnaire (CLDQ)‐NASH, EuroQol Five Dimension (EQ‐5D), Work Productivity and Impairment (WPAI), and 5‐D Itch before and during treatment. A total of 392 patients with NASH (mean ± SD, 60 ± 9 years old; 35% men; 89% white; 72% diabetes; and 56% compensated cirrhosis) were included. Baseline Physical Functioning (PF) and Bodily Pain of SF‐36 and Fatigue and Worry of CLDQ‐NASH were significantly lower in patients with cirrhosis (total CLDQ‐NASH score mean ± SD, 4.91 ± 1.06 with cirrhosis vs. 5.16 ± 1.14 without cirrhosis; P

Exploitation of bitumen-rich deposits in the Alberta Oil Sands Region (AOSR) by large-scale mining and processing activities has generated widespread concern about the potential for dispersal of harmful contaminants to aquatic ecosystems via fluvial and atmospheric pathways. The release of mercury has received attention because it is a potent neurotoxin for wildlife and humans. However, knowledge of baseline mercury concentration prior to disturbance is required to evaluate the extent to which oil sands development has contributed mercury to aquatic ecosystems. Here, we use stratigraphic analysis of total mercury concentration ([THg]) in radiometrically dated sediment cores from nine floodplain lakes in the AOSR and downstream Peace-Athabasca Delta (PAD) and two upland lakes in the PAD region to establish pre-1900 baseline [THg] and evaluate if [THg] has become enriched via fluvial and atmospheric pathways since oil sands mining and processing began in 1967. Concentrations of THg in sediment cores from the study lakes range from 0.022–0.096 mg/kg (dry wt.) and are below the Canadian interim sediment quality guidelines for freshwater (0.17 mg/kg). Results demonstrate no enrichment of [THg] above pre-1900 baseline via fluvial pathways at floodplain lakes in the AOSR or PAD. Enrichment of [THg] was detected via atmospheric pathways at upland lakes in the PAD region, but this occurred prior to oil sands development and aligns with long-range transport of emissions from coal combustion and other anthropogenic sources across the northern hemisphere recognized in many other lake sediment records. The inventory of anthropogenic [THg] in the upland lakes in the AOSR is less than at the Experimental Lakes Area of northwestern Ontario (Canada), widely regarded as a “pristine” area. The absence of enrichment of [THg] in lake sediment via fluvial pathways is a critical finding for stakeholders, and we recommend that monitoring at the floodplain lakes be used to inform stewardship as oil sands operators prepare to discharge treated oil sands process waters directly into the Athabasca River upstream of the PAD.

Research on firearm purchaser licensing laws has found population level reductions in firearm-related mortality. Limited research has been conducted specifically examining the impact of these laws among adolescents and emerging adults. We obtained death data from the National Center for Health Statistics from 1990 to 2019. We generated state-year rates of homicide and suicide, stratified by firearm involvement, for decedents aged 15 to 24. We stratified by race and ethnicity (white, Black, and Hispanic) to assess for differential policy effects. We used stacked difference-in-difference and augmented synthetic control modeling to estimate law repeal or adoption. Repeal of firearm purchaser licensing laws was associated with significantly higher rates of firearm homicide and suicide among those age 15 to 24. The adoption of these laws was associated with significantly lower rates of firearm homicide and suicide among this group. These laws are a promising supply-side intervention to reduce firearm mortality among those with elevated violence vulnerability.

The COVID-19 pandemic affected the ways in which school districts provide educational services to all students, especially students with disabilities. Eligible U.S. students with disabilities have a right to a free, appropriate public education (FAPE) under the Individuals with Disabilities Education Act (IDEA), and students with disabilities who are not eligible under the IDEA may also have a right to receive a FAPE under Section 504 of the Rehabilitation Act. School personnel need to attend to both of these important federal laws when providing educational services. Shortly after the pandemic began, the U.S. Department of Education, through the Office of Civil Rights and the Office of Special Education and Rehabilitation Services, issued guidance to school districts making it clear that despite school closures, school district personnel had to continue providing FAPE under the IDEA and Section 504. Following the return to school, the Office of Civil Rights investigated the Los Angeles Unified School District in California and the Fairfax County Schools for discriminating against students with disabilities by failing to provide educational services during the pandemic. In this article, we briefly review the guidance from the U.S. Department of Education and discuss important implications for teachers of students with disabilities.

The U.S. Supreme Court has heard several cases regarding special education. These cases have resulted in decisions that have addressed issues involving special education programming and procedural issues. On March 21, 2023, the U.S. Supreme Court issued a unanimous ruling in "Perez v. Sturgis Public Schools." This decision, which was the most recent special education case heard by the highest court in the United States, involved litigation in special education. In this brief article, we address the Supreme Court's decision in "Perez" by (a) examining the background of the case; (b) reviewing the decision by the lower courts and the U.S. Supreme Court; and (c) discussing the implications of the case for special educators.

Abstract Winter wheat (Triticum aestivum L.) is essential to maintain food security for a large proportion of the world’s population. With increased risk from abiotic stresses due to climate variability, it is imperative to understand and minimize the negative impact of these stressors, including high night temperature (HNT). Both globally and at regional scales, a differential rate of increase in day and night temperature is observed, wherein night temperatures are increasing at a higher pace and the trend is projected to continue into the future. Previous studies using controlled environment facilities and small field-based removable chambers have shown that post-anthesis HNT stress can induce a significant reduction in wheat grain yield. A prototype was previously developed by utilizing field-based tents allowing for simultaneous phenotyping of popular winter wheat varieties from US Midwest and advanced breeding lines. Hence, the objectives of the study were to (i) design and build a new field-based infrastructure and test and validate the uniformity of HNT stress application on a scaled-up version of the prototype (ii) improve and develop a more sophisticated cyber-physical system to sense and impose post-anthesis HNT stress uniformly through physiological maturity within the scaled-up tents; and (iii) determine the impact of HNT stress during grain filling on the agronomic and grain quality parameters including starch and protein concentration. The system imposed a consistent post-anthesis HNT stress of + 3.8 °C until maturity and maintained uniform distribution of stress which was confirmed by (i) 0.23 °C temperature differential between an array of sensors within the tents and (ii) statistically similar performance of a common check replicated multiple times in each tent. On average, a reduction in grain-filling duration by 3.33 days, kernel weight by 1.25% per °C, grain number by 2.36% per °C and yield by 3.58% per °C increase in night temperature was documented. HNT stress induced a significant reduction in starch concentration indicating disturbed carbon balance. The pilot field-based facility integrated with a robust cyber-physical system provides a timely breakthrough for evaluating HNT stress impact on large diversity panels to enhance HNT stress tolerance across field crops. The flexibility of the cyber-physical system and movement capabilities of the field-based infrastructure allows this methodology to be adaptable to different crops.

Abstract Parkinson’s disease is a progressive neurodegenerative disorder characterised by the accumulation of misfolded α-synuclein in selected brain regions, including the substantia nigra pars compacta (SNpc), where marked loss of dopaminergic neurons is also observed. Yet, the relationship between misfolded α-synuclein and neurotoxicity currently remains unclear. As the principal route for degradation of misfolded proteins in mammalian cells, the ubiquitin-proteasome system (UPS) is critical for maintenance of cellular proteostasis. Misfolded α-synuclein impairs UPS function and contributes to neuronal death in vitro. Here, we examine its effects in vivo using adeno-associated viruses to co-express A53T α-synuclein and the ubiquitinated reporter protein UbG76V-GFP in rat SNpc. We found that α-synuclein over-expression leads to early-onset catalytic impairment of the 26S proteasome with associated UPS dysfunction, preceding the onset of behavioural deficits and dopaminergic neurodegeneration. UPS failure in dopaminergic neurons was also associated with selective accumulation of α-synuclein phosphorylated at the serine 129 residue, which has previously been linked to increased neurotoxicity. Our study highlights a role for α-synuclein in disturbing proteostasis which may contribute to neurodegeneration in vivo.

Jill M Krapf, 1, 2 Leia Mitchell, 2 Michelle A Holton, 3 Andrew T Goldstein 1, 2 1The George Washington University, Washington, DC, USA; 2The Centers for Vulvovaginal Disorders, Washington, DC, USA; 3Department of Emergency Medicine, Baystate Medical Center, Springfield, MA, USACorrespondence: Andrew T GoldsteinThe Center for Vulvovaginal Disorders, 3 Washington Circle NW, Suite 205, Washington, DC 20037, USATel +1 202- 887-0568Email obstetrics@yahoo.comAbstract: Vulvar lichen sclerosus (LS) is a chronic, inflammatory dermatosis that may lead to scarring of the vulva and sexual dysfunction. LS affects women of all ages and often goes unrecognized and underreported. Uncertainty continues to exist around its pathogenesis, histologic diagnosis, and treatment. However, there have been great advances in our understanding of autoimmunogenic targets in disease formation and progression. In addition, there has been recent investigation of potential non-steroid-based treatments, including platelet-rich plasma therapy and energy-based modalities such as the fractional CO 2 laser, photodynamic therapy, and high intensity focused ultrasound. Refinement of surgical techniques for restoring vulvar anatomy and treating clitoral phimosis, introital stenosis, and vulvar granuloma fissuratum is leading to improved patient outcomes. This review summarizes current perspectives on the pathogenesis, symptomatology, diagnosis, and treatment for vulvar lichen sclerosus.Keywords: lichen sclerosus, clitoral phimosis, vulvar granuloma fissuratum, corticosteroids, fractional CO 2 laser, lysis of vulvar adhesions

Fusobacterium nucleatum is an anaerobe that is commensal to the human oral cavity. It is usually a component of periodontal plaque that is emerging as a pathogen and quickly attracting attention of the medical and research communities. It has been even discovered in bronchoalveolar lavage of some patients with lung cancer. Lemierre's syndrome (LS) is characterized as septic thrombophlebitis of the internal jugular vein, which usually begins with oropharyngeal infection that worsens and leads to inflammation of the wall of the jugular vein. This is the hallmark of the disease. However, in this case, there was no thrombophlebitis of the internal jugular vein. There is one other case presentation where it was diagnosed without the internal jugular vein involvement. Most sequelae involve infected thrombus of the vein, soft tissue inflammation, persistent bacteremia, and septic emboli, often leading to metastatic infections. Interestingly enough, in the age of SARS-COV-2, LS has also been mistaken for multisystem inflammatory syndrome in children (MIS-C).We present a previously healthy 20-year-old female college student who was transferred from her local hospital to Bristol-Myers Squibb Children's Hospital (BMSCH) at Robert Wood Johnson University Hospital for suspected LS with loculated pleural effusions and necrotizing pneumonia with lung abscess secondary to Fusobacterium nucleatum, systemic and emphysematous osteomyelitis possibly secondary to septic emboli, thrombocytopenia, and palatine tonsil and thyroid abscesses.

Study region: Peace-Athabasca Delta (PAD), northeastern Alberta. Study focus: Potential for downstream delivery of contaminants via Athabasca River floodwaters to lakes of the PAD has raised local to international concern. Here, we quantify enrichment of eight metals (Be, Cd, Cr, Cu, Ni, Pb, V, Zn) in aquatic biota, relative to sediment-based pre-industrial baselines, via analysis of biofilm-sediment mixtures accrued on artificial substrate samplers deployed during summers of 2017 and 2018 in > 40 lakes. Widespread flooding in the southern portion of the delta in spring 2018 allows for assessment of metal enrichment by Athabasca River floodwaters. New hydrological insights: River floodwaters are not implicated as a pathway of metal enrichment to biofilm-sediment mixtures in PAD lakes from upstream sources. MANOVA tests revealed no significant difference in residual concentrations of all eight metals in lakes that did not flood versus lakes that flooded during one or both study years. Also, no enrichment was detected for concentrations of biologically inert metals (Be, Cr, Pb) and those related to oil-sands development (Ni, V). Enrichment of Cd, Cu, and Zn at non-flooded lakes, however, suggests uptake of biologically active metals complicates comparisons of organic-rich biofilm-sediment mixtures to sediment-derived baselines for these metals. Results demonstrate that this novel approach could be adopted for lake monitoring within the federal Action Plan.