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Background: The prevalence of injection drug use (IDU)-associated infections and associated hospitalizations has been increasing for nearly two decades. Due to issues ranging from ongoing substance use to peripherally inserted central catheter safety, many clinicians find discharge decision-making challenging. Typically, clinicians advise patients to remain hospitalized for several weeks for intravenous antimicrobial treatment; however, some patients may desire other antimicrobial treatment options. A structured conversation guide, delivered by infectious disease physicians, intended to inform hospital discharge decisions has the potential to enhance patient participation in decisions. We developed a conversation guide in order to: (1) investigate its feasibility and acceptability and (2) examine experiences, outcomes, and lessons learned from use of the guide. Methods: We interviewed physicians after they each piloted the conversation guide with two patients. We interviewed patients immediately after the conversation and again 4–6 weeks later. Two analysts indexed transcriptions and used the framework method to identify and organize relevant information. We conducted retrospective chart review to corroborate and contextualize qualitative data. Results: Eight patients and four infectious disease physicians piloted the conversation guide. All patients ( N = 8) completed antimicrobial treatment. Nearly all participants believed the conversation guide was important for incorporating patient values and preferences. Patients reported an increased sense of autonomy, but felt post-discharge needs could be better addressed. Physician participants identified the guide’s long length and inclusion of pain management as areas for improvement. Conclusions: A novel conversation guide to inform hospital discharge decision-making for patients with IDU-associated infections was feasible, acceptable, and fostered the incorporation of patient preferences and values into decisions. While we identified areas for improvement, overall participants believed that this novel conversation guide helped to improve patient care and autonomy.

Metastatic spinal melanoma is a rare and aggressive disease process with poor prognosis. We review the literature on metastatic spinal melanoma, focusing on its epidemiology, management, and treatment outcomes. Demographics of metastatic spinal melanoma are similar to those for cutaneous melanoma, and cutaneous primary tumors tend to be most common. Decompressive surgical intervention and radiotherapy have traditionally been considered mainstays of treatment, and stereotactic radiosurgery has emerged as a promising approach in the operative management of metastatic spinal melanoma. While survival outcomes for metastatic spinal melanoma remain poor, they have improved in recent years with the advent of immune checkpoint inhibition, used in conjunction with surgery and radiotherapy. New treatment options remain under investigation, especially for patients with disease refractory to immunotherapy. We additionally explore several of these promising future directions. Nevertheless, further investigation of treatment outcomes, ideally incorporating high-quality prospective data from randomized controlled trials, is needed to identify optimal management of metastatic spinal melanoma.

Summary: While gaining interest as treatment for cancer and infectious disease, the clinical efficacy of Vγ9Vδ2 T cell-based immunotherapeutics has to date been limited. An improved understanding of γδ T cell heterogeneity across lymphoid and non-lymphoid tissues, before and after pharmacological expansion, is required. Here, we describe the phenotype and tissue distribution of Vγ9Vδ2 T cells at steady state and following in vivo pharmacological expansion in pigtail macaques. Intravenous phosphoantigen administration with subcutaneous rhIL-2 drove robust expansion of Vγ9Vδ2 T cells in blood and pulmonary mucosa, while expansion was confined to the pulmonary mucosa following intratracheal antigen administration. Peripheral blood Vγ9Vδ2 T cell expansion was polyclonal, and associated with a significant loss of CCR6 expression due to IL-2-mediated receptor downregulation. Overall, we show the tissue distribution and phenotype of in vivo pharmacologically expanded Vγ9Vδ2 T cells can be altered based on the antigen administration route, with implications for tissue trafficking and the clinical efficacy of Vγ9Vδ2 T cell immunotherapeutics.

BackgroundSquamous cell carcinoma of the anus (SCCA) is a rare gastrointestinal cancer. Factors associated with progression of HPV infection to anal dysplasia and cancer are unclear and screening guidelines and approaches for anal dysplasia are less clear than for cervical dysplasia. One potential contributing factor is the anorectal microbiome. In this study, we aimed to identify differences in anal microbiome composition in the settings of HPV infection, anal dysplasia, and anal cancer in this rare disease.MethodsPatients were enrolled in two prospective studies. Patients with anal dysplasia were part of a cross-sectional cohort that enrolled women with high-grade lower genital tract dysplasia. Anorectal tumor swabs were prospectively collected from patients with biopsy-confirmed locally advanced SCCA prior to receiving standard-of-care chemoradiotherapy (CRT). Patients with high-grade lower genital tract dysplasia without anal dysplasia were considered high-risk (HR Normal). 16S V4 rRNA Microbiome sequencing was performed for anal swabs. Alpha and Beta Diversity and composition were compared for HR Normal, anal dysplasia, and anal cancer.Results60 patients with high-grade lower genital tract dysplasia were initially enrolled. Seven patients had concurrent anal dysplasia and 44 patients were considered HR Normal. Anorectal swabs from 21 patients with localized SCCA were included, sequenced, and analyzed in the study. Analysis of weighted and unweighted UniFrac distances demonstrated significant differences in microbial community composition between anal cancer and HR normal (p=0.018). LEfSe identified that all three groups exhibited differential enrichment of specific taxa. Peptoniphilus (p=0.028), Fusobacteria (p=0.0295), Porphyromonas (p=0.034), and Prevotella (p=0.029) were enriched in anal cancer specimens when compared to HR normal.ConclusionAlthough alpha diversity was similar between HR Normal, dysplasia and cancer patients, composition differed significantly between the three groups. Increased anorectal Peptoniphilus, Fusobacteria, Porphyromonas, and Prevotella abundance were associated with anal cancer. These organisms have been reported in various gastrointestinal cancers with roles in facilitating the proinflammatory microenvironment and neoplasia progression. Future work should investigate a potential role of microbiome analysis in screening for anal dysplasia and investigation into potential mechanisms of how these microbial imbalances influence the immune system and anal carcinogenesis.

Prescription drug use is prevalent during pregnancy, yet there is limited knowledge about maternal-fetal safety and efficacy of this drug use because pregnant individuals have historically been excluded from clinical trials. Underrepresentation has resulted in a lack of data available to estimate or predict fetal drug exposure. Approaches to study fetal drug pharmacology are limited and must be evaluated for feasibility and accuracy. Anatomic and physiological changes throughout pregnancy fluctuate based on gestational age and can affect drug pharmacokinetics (PK) for both mother and fetus. Drug concentrations have been studied throughout different stages of gestation and at or following delivery in tissue and fluid biospecimens. Sampling amniotic fluid, umbilical cord blood, placental tissue, meconium, umbilical cord tissue, and neonatal hair present surrogate options to quantify and characterize fetal drug exposure. These sampling methods can be applied to all therapeutics including small molecule drugs, large molecule drugs, conjugated nanoparticles, and chemical exposures. Alternative approaches to determine PK have been explored, including physiologically based PK modeling, in vitro methods, and traditional animal models. These alternative approaches along with convenience sampling of tissue or fluid biospecimens can address challenges in studying maternal-fetal pharmacology. In this narrative review, we 1) present an overview of the current understanding of maternal-fetal drug exposure; 2) discuss biospecimen-guided sampling design and methods for measuring fetal drug concentrations throughout gestation; and 3) propose methods for advancing pharmacology research in the maternal-fetal population.

Community Music Therapy (CoMT) practices are continuing to develop within the international music therapy community. However, the development and implementation of music therapy through a CoMT lens in the United States has not been widely written about. Only a handful of published studies and clinical reports detail music therapy programs that seemingly fit within a CoMT framework. In comparison to more traditional approaches to music therapy practice, CoMT practices in the United States are underrepresented. This thematic analysis informed by a hermeneutical method was undertaken to begin a dialogue with music therapists who consider their music therapy practice to fall within the boundaries of CoMT, in order to increase awareness of ways in which CoMT principles are being implemented within the US healthcare and educational systems. We interviewed 6 board certified music therapists asking them to 1) define CoMT, 2) explain role relationships (therapist, client, and community), and 3) speculate on how their approach to the work could influence health policy and access to services in the United States. Our findings suggest that participatory, performative, and social action elements of CoMT are evident in the clinical work of the music therapists who were interviewed, and that there is a place for CoMT practices within the United States healthcare system.

This short essay discusses the relationship between ownership of creative works and music therapy. We ask the following question: what do we mean by ownership of stories and songs in music therapy? We answer this question by highlighting examples from music therapy literature. We base the essay on the notion that children may have certain rights concerning their intellectual properties and products made in therapy, but these rights are not always honored. Musical products such as lyrics or narratives made in music therapy are protected by most countries' national copyright laws, and music therapists working with music should pay close attention to the rights of the creator. Music therapy should not be a free zone or grey area where the laws on copyright do not matter. The essay offers suggestions for practitioners and researchers.

Summary: Background: Schools are high-risk settings for SARS-CoV-2 transmission, but necessary for children's educational and social-emotional wellbeing. Previous research suggests that wastewater monitoring can detect SARS-CoV-2 infections in controlled residential settings with high levels of accuracy. However, its effective accuracy, cost, and feasibility in non-residential community settings is unknown. Methods: The objective of this study was to determine the effectiveness and accuracy of community-based passive wastewater and surface (environmental) surveillance to detect SARS-CoV-2 infection in neighborhood schools compared to weekly diagnostic (PCR) testing. We implemented an environmental surveillance system in nine elementary schools with 1700 regularly present staff and students in southern California. The system was validated from November 2020 to March 2021. Findings: In 447 data collection days across the nine sites 89 individuals tested positive for COVID-19, and SARS-CoV-2 was detected in 374 surface samples and 133 wastewater samples. Ninety-three percent of identified cases were associated with an environmental sample (95% CI: 88%–98%); 67% were associated with a positive wastewater sample (95% CI: 57%–77%), and 40% were associated with a positive surface sample (95% CI: 29%–52%). The techniques we utilized allowed for near-complete genomic sequencing of wastewater and surface samples. Interpretation: Passive environmental surveillance can detect the presence of COVID-19 cases in non-residential community school settings with a high degree of accuracy. Funding: County of San Diego, Health and Human Services Agency, National Institutes of Health, National Science Foundation, Centers for Disease Control.

Abstract Background Clonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of mutant hematopoietic stem cells, confers risk for multiple diseases of aging including hematologic cancer and cardiovascular disease. Whole-exome or genome sequencing can detect CHIP, but due to those assays’ high cost, most population studies have been cross-sectional, sequencing only a single timepoint per individual. Results We developed and validated a cost-effective single molecule molecular inversion probe sequencing (smMIPS) assay for detecting CHIP, targeting the 11 most frequently mutated genes in CHIP along with 4 recurrent mutational hotspots. We sequenced 548 multi-timepoint samples collected from 182 participants in the Women’s Health Initiative cohort, across a median span of 16 years. We detected 178 driver mutations reaching variant allele frequency ≥ 2% in at least one timepoint, many of which were detectable well below this threshold at earlier timepoints. The majority of clonal mutations (52.1%) expanded over time (with a median doubling period of 7.43 years), with the others remaining static or decreasing in size in the absence of any cytotoxic therapy. Conclusions Targeted smMIPS sequencing can sensitively measure clonal dynamics in CHIP. Mutations that reached the conventional threshold for CHIP (2% frequency) tended to continue growing, indicating that after CHIP is acquired, it is generally not lost. The ability to cost-effectively profile CHIP longitudinally will enable future studies to investigate why some CHIP clones expand, and how their dynamics relate to health outcomes at a biobank scale.

Abstract Background Pregnant women were excluded from investigational trials of COVID-19 vaccines. Limited data are available to inform pregnant and postpartum women on their decisions to receive a COVID-19 vaccine. Methods The goal of this observational, prospective cohort study is to evaluate the immunogenicity and safety of various Emergency Use Authorization (EUA) or licensed COVID-19 vaccines administered to pregnant or lactating women and describe the transplacental antibody transfer and kinetics of antibodies in mothers and infants. The study is adaptive, allowing additional groups to be added as new vaccines or vaccine regimens are authorized. Up to 20 clinical research institutions in the United States (U.S.) will be included. Approximately 200 pregnant women and 65 postpartum women will be enrolled per EUA or licensed COVID-19 vaccine formulation in the U.S. This study will include pregnant and postpartum women of all ages with and without chronic medical conditions. Their infants will be enrolled and followed beginning at birth in the pregnant cohort and beginning at the earliest possible time point in the postpartum cohort. Blood samples will be collected for immunogenicity outcomes and pregnancy and birth outcomes assessed among women and infants. Primary analyses will be descriptive and done by vaccine type and/or platform. Discussion Given the long-standing and legitimate challenges of enrolling pregnant individuals into clinical trials early in the vaccine development pipeline, this study protocol describes our current study and provides a template to inform the collection of data for pregnant individuals receiving COVID-19 or other vaccines. Trial registration NCT05031468 .

Abstract Background Diagnostic testing accessibility and asymptomatic transmission of SARS-CoV-2 present major challenges for curbing and preventing community prevalence of COVID-19. At-home sample collection for molecular testing provides a convenient and effective solution for disease containment and prevention. Methods This is a retrospective, cross-sectional, case-control study. Our primary aim was to determine the prevalence and relative risk of SARS-CoV-2 among asymptomatic versus symptomatic individuals using at-home sample collection kits for diagnosis. Participants included adults from across the United States who completed a COVID-19 Home Collection kit between May 2020 and September 2021. Main measurements included self-reported symptoms and at-home self-collected anterior nasal swab RT-PCR test results for SARS-CoV-2. Results Data from 282,831 individuals were included in this analysis. The overall SARS-CoV-2 prevalence of at-home test takers was low compared to national averages during this period (3.28% vs. 7.68%). Those reporting no symptoms were at lower risk of positive test results compared to those with symptoms (risk ratio: 0.080, 95% CI, 0.078–0.082). However, of all positive SARS-CoV-2 tests, 48.75% were from individuals reporting no symptoms at the time of testing. Conclusions We conclude that at-home sample collection is a viable option and potentially important strategy for improving access to testing, detecting asymptomatic cases, and curbing preventable transmission of COVID-19.

Abstract This paper presents a new computational framework for mapping state-sponsored information operations into distinct strategic units. Utilizing a novel method called multi-view modularity clustering (MVMC), we identify groups of accounts engaged in distinct narrative and network information maneuvers. We then present an analytical pipeline to holistically determine their coordinated and complementary roles within the broader digital campaign. Applying our proposed methodology to disclosed Chinese state-sponsored accounts on Twitter, we discover an overarching operation to protect and manage Chinese international reputation by attacking individual adversaries (Guo Wengui) and collective threats (Hong Kong protestors), while also projecting national strength during global crisis (the COVID-19 pandemic). Psycholinguistic tools quantify variation in narrative maneuvers employing hateful and negative language against critics in contrast to communitarian and positive language to bolster national solidarity. Network analytics further distinguish how groups of accounts used network maneuvers to act as balanced operators, organized masqueraders, and egalitarian echo-chambers. Collectively, this work breaks methodological ground on the interdisciplinary application of unsupervised and multi-view methods for characterizing not just digital campaigns in particular, but also coordinated activity more generally. Moreover, our findings contribute substantive empirical insights around how state-sponsored information operations combine narrative and network maneuvers to achieve interlocking strategic objectives. This bears both theoretical and policy implications for platform regulation and understanding the evolving geopolitical significance of cyberspace.

Incidence of Legionnaires’ disease is increasing, particularly in the Mid-Atlantic states in the United States; since 2015, New Jersey has documented ≈250–350 legionellosis cases per year. We used SaTScan software to develop a semiautomated surveillance tool for prospectively detecting legionellosis clusters in New Jersey. We varied temporal window size and baseline period to evaluate optimal parameter selections. The surveillance system detected 3 community clusters of Legionnaires’ disease that were subsequently investigated. Other, smaller clusters were detected, but standard epidemiologic data did not identify common sources or new cases. The semiautomated processing is straightforward and replicable in other jurisdictions, likely by persons with even basic programming skills.

Objective Patients with immune‐mediated diseases treated with anti‐CD20 monoclonal antibodies may have worse coronavirus disease 2019 (COVID‐19) outcomes due to impaired humoral immunity, but differences compared with the general population are unknown. Methods We identified patients with immune‐mediated diseases who received anti‐CD20 monoclonal antibodies within 1 year prior to the index date of polymerase chain reaction–confirmed COVID‐19 between January 31, 2020, and January 31, 2021. General population comparators with COVID‐19 were matched up 5:1 by age, sex, and polymerase chain reaction date. Unadjusted and multivariable adjusted (for age, race, body mass index, and Charlson Comorbidity Index) hazard ratios (HRs) and 95% confidence intervals (CIs) for hospitalization, mechanical ventilation, and death in recipients of anti‐CD20 monoclonal antibodies versus comparators were estimated by using Cox regression. Results We identified 114 cases patients COVID‐19 who had received anti‐CD20 monoclonal antibodies for immune‐mediated diseases (mean age 55 years, 70% female) and 559 matched comparators with COVID‐19 (mean age 54 years, 70% female). Patients treated with anti‐CD20 monoclonal antibodies had higher mortality (adjusted HR 2.16; 95% CI: 1.03‐4.54) than matched comparators. Risks of hospitalization (adjusted HR 0.88; 95% CI: 0.62‐1.26) and mechanical ventilation use (adjusted HR 0.82; 95% CI: 0.36‐1.87) were similar. Similar trends were seen in analyses according to type of indication (eg, rheumatic or neurologic disease) and duration of anti‐CD20 monoclonal antibody use (

Villazana-Kretzer et al. compare histology, physiology and gene expression in cotyledons from term placentas perfused with either active or UV-inactivated Zika virus. They show that ZIKV can infect human term placentas in the absence of maternal factors and identify unique transcriptional responses to active ZIKA virus.

Abstract Throughout the COVID-19 pandemic, massive sequencing and data sharing efforts enabled the real-time surveillance of novel SARS-CoV-2 strains throughout the world, the results of which provided public health officials with actionable information to prevent the spread of the virus. However, with great sequencing comes great computation, and while cloud computing platforms bring high-performance computing directly into the hands of all who seek it, optimal design and configuration of a cloud compute cluster requires significant system administration expertise. We developed ViReflow, a user-friendly viral consensus sequence reconstruction pipeline enabling rapid analysis of viral sequence datasets leveraging Amazon Web Services (AWS) cloud compute resources and the Reflow system. ViReflow was developed specifically in response to the COVID-19 pandemic, but it is general to any viral pathogen. Importantly, when utilized with sufficient compute resources, ViReflow can trim, map, call variants, and call consensus sequences from amplicon sequence data from 1000 SARS-CoV-2 samples at 1000X depth in

Background and Purpose: Gliomas have been found to alter iron metabolism and transport in ways that result in an expansion of their intracellular iron compartments to support aggressive tumor growth. This study used deep neural network trained quantitative susceptibility mapping to assess basal ganglia iron concentrations in glioma patients. Materials and Methods: Ninety-two patients with brain lesions were initially enrolled in this study and fifty-nine met the inclusion criteria. Susceptibility-weighted images were collected at 3.0 T and used to construct quantitative susceptibility maps via a deep neural network-based method. The regions of interest were manually drawn within basal ganglia structures and the mean voxel intensities were extracted and averaged across multiple slices. One-way ANCOVA tests were conducted to compare the susceptibility values of groups of patients based on tumor grade while controlling for age, sex, and tumor type. Results: The mean basal ganglia susceptibility for patients with grade IV tumors was higher than that for patients with grade II tumors (p = 0.00153) and was also higher for patients with grade III tumors compared to patients with grade II tumors (p = 0.020), after controlling for age, sex, and tumor type. Patient age influenced susceptibility values (p = 0.00356), while sex (p = 0.69) and tumor type (p = 0.11) did not. Conclusions: The basal ganglia iron content increased with glioma severity. Basal ganglia iron levels may thus be a useful biomarker in glioma prognosis and treatment, especially with regard to iron-based cancer therapies.

Natural gas (NG) leaks from below-ground pipelines pose safety, economic, and environmental hazards. Despite walking surveys using handheld methane (CH4) detectors to locate leaks, accurately triaging the severity of a leak remains challenging. It is currently unclear whether CH4 detectors used in walking surveys could be used to identify large leaks that require an immediate response. To explore this, we used above-ground downwind CH4 concentration measurements made during controlled emission experiments over a range of environmental conditions. These data were then used as the input to a novel modeling framework, the ESCAPE−1 model, to estimate the below-ground leak rates. Using 10-minute averaged CH4 mixing/meteorological data and filtering out wind speed < 2 m s−1/unstable atmospheric data, the ESCAPE−1 model estimates small leaks (0.2 kg CH4 h−1) and medium leaks (0.8 kg CH4 h−1) with a bias of −85%/+100% and −50%/+64%, respectively. Longer averaging (≥3 h) results in a 55% overestimation for small leaks and a 6% underestimation for medium leaks. These results suggest that as the wind speed increases or the atmosphere becomes more stable, the accuracy and precision of the leak rate calculated by the ESCAPE−1 model decrease. With an uncertainty of ±55%, our results show that CH4 mixing ratios measured using industry-standard detectors could be used to prioritize leak repairs.

The COVE trial randomized participants to receive two doses of mRNA-1273 vaccine or placebo on Days 1 and 29 (D1, D29). Anti-SARS-CoV-2 Spike IgG binding antibodies (bAbs), anti-receptor binding domain IgG bAbs, 50% inhibitory dilution neutralizing antibody (nAb) titers, and 80% inhibitory dilution nAb titers were measured at D29 and D57. We assessed these markers as correlates of protection (CoPs) against COVID-19 using stochastic interventional vaccine efficacy (SVE) analysis and principal surrogate (PS) analysis, frameworks not used in our previous COVE immune correlates analyses. By SVE analysis, hypothetical shifts of the D57 Spike IgG distribution from a geometric mean concentration (GMC) of 2737 binding antibody units (BAU)/mL (estimated vaccine efficacy (VE): 92.9% (95% CI: 91.7%, 93.9%)) to 274 BAU/mL or to 27,368 BAU/mL resulted in an overall estimated VE of 84.2% (79.0%, 88.1%) and 97.6% (97.4%, 97.7%), respectively. By binary marker PS analysis of Low and High subgroups (cut-point: 2094 BAU/mL), the ignorance interval (IGI) and estimated uncertainty interval (EUI) for VE were [85%, 90%] and (78%, 93%) for Low compared to [95%, 96%] and (92%, 97%) for High. By continuous marker PS analysis, the IGI and 95% EUI for VE at the 2.5th percentile (519.4 BAU/mL) vs. at the 97.5th percentile (9262.9 BAU/mL) of D57 Spike IgG concentration were [92.6%, 93.4%] and (89.2%, 95.7%) vs. [94.3%, 94.6%] and (89.7%, 97.0%). Results were similar for other D29 and D57 markers. Thus, the SVE and PS analyses additionally support all four markers at both time points as CoPs.

The goal of this narrative review is to highlight the healthcare challenges faced by adults with cerebral palsy, including the management of long-term motor deficits, difficulty finding clinicians with expertise in these long-term impairments, and scarcity of rehabilitation options. Additionally, this narrative review seeks to examine potential methods for maintaining functional independence, promoting social integration, and community participation. Although the brain lesion that causes the movement disorder is non-progressive, the neurodevelopmental disorder worsens from secondary complications of existing sensory, motor, and cognitive impairments. Therefore, maintaining the continuum of care across one’s lifespan is of utmost importance. Advancements in healthcare services over the past decade have resulted in lower mortality rates and increased the average life expectancy of people with cerebral palsy. However, once they transition from adolescence to adulthood, limited federal and community resources, and health care professionals’ lack of expertise present significant obstacles to achieving quality healthcare and long-term benefits. This paper highlights the common impairments seen in adults with cerebral palsy. Additionally, it underscores the critical role of long-term healthcare and management to prevent functional decline and enhance quality of life across physical, cognitive, and social domains.

The results from a four-year study of a freshwater pond on Long Island, NY, USA, do not point to a single source of boron (and by proxy other elements including nutrients) in this system. However, boron data from samples associated with this pond can be explained by mixing between average precipitation (weighted average δ11B = 22.7) in the area and the local sources of boron, both natural and anthropogenic. This multiyear study provided the opportunity to see both yearly and seasonal differences. One algae sample from the pond showed significant fractionation and enrichment in light boron relative to the water and suggests algae may act as a boron sink. This type of biological fractionation could explain an observed down-gradient trend to heavier boron isotope values in pond water, which corresponds to the slight reduction in boron concentration seen in 2021. However, the trend was subdued in the following year, likely due to differences in the water flow rates and/or rate of algal growth. An opposite trend was seen with depth in the water, where δ11B showed a positive correlation to boron concentration, which increased with depth from the surface of the pond. This gradient may be explained by the stratification of the pond with a heavy source concentrating in the bottom waters. The bottom water composition was consistent with goose feces (δ11B = 25.8) or the addition of chemicals from the application of rock salt to local roads in winter. Surprisingly, boron from seawater (average δ11B = 39.8) did not appear to have a direct impact on Setauket Pond, other than its influence on precipitation, providing heavy δ11B and very low boron concentrations.

Abstract Background Many second-generation antipsychotics (SGAs) are associated with weight gain and cardiometabolic effects. Antipsychotic-associated weight gain is linked to treatment interruptions, potentially increasing risk of relapse and hospitalization. This retrospective study assessed clinically significant weight gain (CSWG), treatment interruptions, and development of cardiometabolic conditions in patients with schizophrenia (SZ) or bipolar I disorder (BD-I) following initiation of oral SGAs with moderate to high weight gain risk. Methods Patients with no prior use of moderate to high weight gain risk oral SGAs were identified from patient-level medical/pharmacy claims and electronic medical records (January 2013–February 2020; OM1 Real-World Data Cloud). Those with ≥ 1 weight measurement in both the 12 months preceding and 3 months after SGA initiation (index date) were analyzed for continuous changes in weight, CSWG (≥ 7% and ≥ 10% increases from baseline), treatment interruptions (switches/discontinuations), and development of cardiometabolic conditions. Results Median follow-up times in the SZ (n = 8174) and BD-I (n = 9142) cohorts were 153.4 and 159.4 weeks, respectively; 45.5% and 50.7% were obese at baseline. Mean (SD) percent weight increase during treatment was 3.3% (7.2) and 3.7% (7.0) for patients with SZ and BD-I, respectively, and was highest for underweight/normal weight patients (SZ: 4.8% [8.1]; BD-I: 5.5% [8.7]). More than 96% had treatment interruptions during follow-up, primarily discontinuations. CSWG and treatment interruptions occurred within a median of 13 and 14 weeks after treatment initiation, respectively. Of patients with CSWG and treatment interruptions, approximately 75% did not return to baseline weight during follow-up. Among those without baseline cardiometabolic conditions, 14.7% and 11.3% of patients with SZ or BD-I, respectively, developed ≥ 1 condition over 12 months post-index. Incidence was generally highest among those who were overweight/obese at baseline and those who experienced CSWG. Conclusions In this analysis of real-world data, both weight gain and treatment interruptions occurred early in treatment for patients with SZ or BD-I. Treatment-associated weight gain persisted despite switching or discontinuing index treatment. Additionally, cardiometabolic morbidity increased within 12 months of treatment initiation. Patients with SZ or BD-I are at greater risk than the general population for cardiometabolic conditions; weight gain associated with SGAs may exacerbate these health risks.

Abstract Background PubMed contains millions of abstracts that co-mention terms that describe drugs with other biomedical terms such as genes or diseases. Unique opportunities exist for leveraging these co-mentions by integrating them with other drug-drug similarity resources such as the Library of Integrated Network-based Cellular Signatures (LINCS) L1000 signatures to develop novel hypotheses. Results DrugShot is a web-based server application and an Appyter that enables users to enter any biomedical search term into a simple input form to receive ranked lists of drugs and other small molecules based on their relevance to the search term. To produce ranked lists of small molecules, DrugShot cross-references returned PubMed identifiers (PMIDs) with DrugRIF or AutoRIF, which are curated resources of drug-PMID associations, to produce an associated small molecule list where each small molecule is ranked according to total co-mentions with the search term from shared PubMed IDs. Additionally, using two types of drug-drug similarity matrices, lists of small molecules are predicted to be associated with the search term. Such predictions are based on literature co-mentions and signature similarity from LINCS L1000 drug-induced gene expression profiles. Conclusions DrugShot prioritizes drugs and small molecules associated with biomedical search terms. In addition to listing known associations, DrugShot predicts additional drugs and small molecules related to any search term. Hence, DrugShot can be used to prioritize drugs and preclinical compounds for drug repurposing and suggest indications and adverse events for preclinical compounds. DrugShot is freely and openly available at: https://maayanlab.cloud/drugshot and https://appyters.maayanlab.cloud/#/DrugShot .

Abstract Limited research exists on carbohydrate intake and oral microbiome diversity and composition assessed with next-generation sequencing. We aimed to better understand the association between habitual carbohydrate intake and the oral microbiome, as the oral microbiome has been associated with caries, periodontal disease, and systemic diseases. We investigated if total carbohydrates, starch, monosaccharides, disaccharides, fiber, or glycemic load (GL) were associated with the diversity and composition of oral bacteria in subgingival plaque samples of 1204 post-menopausal women. Carbohydrate intake and GL were assessed from a food frequency questionnaire, and adjusted for energy intake. The V3–V4 region of the 16S rRNA gene from subgingival plaque samples were sequenced to identify the relative abundance of microbiome compositional data expressed as operational taxonomic units (OTUs). The abundance of OTUs were centered log(2)-ratio transformed to account for the compositional data structure. Associations between carbohydrate/GL intake and microbiome alpha-diversity measures were examined using linear regression. PERMANOVA analyses were conducted to examine microbiome beta-diversity measures across quartiles of carbohydrate/GL intake. Associations between intake of carbohydrates and GL and the abundance of the 245 identified OTUs were examined by using linear regression. Total carbohydrates, GL, starch, lactose, and sucrose intake were inversely associated with alpha-diversity measures. Beta-diversity across quartiles of total carbohydrates, fiber, GL, sucrose, and galactose, were all statistically significant (p for PERMANOVA p

Challenges in batch normalization and data integration limit the comparison of existing mass cytometry datasets. Here, the authors report CytofIn that can integrate mass cytometry datasets from the public domain and reveal cellular features associated with immune oncology by analyzing five public cancer datasets.

Abstract Purpose To evaluate the feasibility of a home-based moderate-to-vigorous intensity, phased (introduction, intermediate, maintenance), exercise prescription in breast cancer patients receiving cardiotoxic neoadjuvant chemotherapy. Methods Nineteen breast cancer patients were randomized to intervention or control for the duration of chemotherapy (16–24 weeks). The intervention was one aerobic exercise session at 80–90% VO2max for 25 min/week and 65%-75% VO2max for ≥ 50 min/week. Adherence to the tailored home-based program was assessed by heart rate monitors. Acceptability, tolerability, feasibility, efficacy, change in VO2max, and patient reported outcomes, safety, and clinical events were assessed. Results 25.7% of eligible women consented (acceptability). Adherence was 87.6%. Women were not able to maintain exercise intensity as chemotherapy progressed (23.7% of exercise minutes were completed at prescribed heart rate during maintenance). Efficacy of the intervention was demonstrated by maintenance of VO2max (−1.0 ± 13.2%) compared to (−27.5 ± 7.4%) the control group. Further, during and after therapy, patients in the intervention arm reported less fatigue (control-baseline: 14.4 ± 15.9; midpoint: 19.0 ± 11.4; follow-up: 29.4 ± 20.0; intervention-baseline: 29.2 ± 24.6; midpoint: 24.6 ± 14.4; follow-up: 23.6 ± 11.9), impairment in activities (control-baseline: 13.7 ± 16.0; midpoint: 32.8 ± 17.0; follow-up: 58.6 ± 27.9; intervention-baseline: 38.7 ± 31.8; midpoint: 47.1 ± 27.5; follow-up: 47.5 ± 31.0), and pain (control-baseline: 80.8 ± 17.1; midpoint: 73.9 ± 20.7; follow-up: 50.7 ± 25.7; intervention-baseline: 68.7 ± 28.4; midpoint: 61.4 ± 22.5; follow-up: 65.3 ± 22.4). There were no differences in adverse events, treatment delays, or pathological complete response. Conclusions Neoadjuvant breast cancer patients maintained approximately one hour/week of moderate-intensity exercise over the course of their treatment. Further, this volume of exercise was sufficient to maintain fitness capacity and quality of life compared to the control group. Trial registry: ClinicalTrials.gov Identifier: NCT03280836, prospectively registered 9/13/2017, https://clinicaltrials.gov/ct2/show/NCT03280836 .

Women with obstructive sleep apnea (OSA) are at increased risk of poor pregnancy outcomes such as fetal growth restriction, hypertensive disorders of pregnancy, and gestational diabetes mellitus. Given this increased risk, we aimed to study the screening prevalence of OSA in women seeking fertility treatment. We performed a cross sectional study of patients presenting to a university-affiliated fertility clinic between March-April 2021. Patients were asked to complete OSA screening (STOP-BANG), anxiety screening (GAD-7), and depression screening (PHQ-2) questionnaires. 107 women completed the surveys. Mean age was 35.1 years and mean body mass index (BMI) was 25.7 kg/m2. Nine (8.4%) women screened positive for OSA using the STOP-BANG screening tool. Women who screened positive for OSA were more likely to be older (37.8 years vs. 34.7 years, p = 0.02) and have a higher BMI (42.6 kg/m2 vs. 27.4 kg/m2, p < 0.001). Women who screened positive for OSA were also more likely to screen positive for mild-severe depressive symptoms (22.2% vs. 3.1%, p = 0.006) and mild-severe anxiety (66.7% vs. 21.4%, p = 0.003) symptoms. 24.3% of the population had polycystic ovary syndrome (PCOS). Women with PCOS were more likely to screen positive for OSA (19.2% vs. 4.9%; p = 0.04). Despite this being a low-risk population of young women seeking fertility evaluation or treatment, 8% screened positive for OSA. Given the association between OSA and adverse pregnancy outcomes, our results underline the need to screen women seeking fertility treatment.

Plain English summary Internet-based prevention programs for eating disorders are effective, but a variety of challenges have been found when offering them in real-world settings. The current study aimed to test ProYouth OZ, an Internet-based eating disorder prevention program consisting of multiple components including peer support. In total, 50 young adults (18–25 years) with eating disorder symptoms were allocated to one of three versions of the program. In total, 21% did not access the program. From 17 participants in the peer support group, 60% attended at least one chat session and 12% attended all six sessions. Given that only fifteen participants (30%) completed the questionnaire after the intervention, it is not possible to draw reliable conclusions about the effectiveness of the program. Findings demonstrate the difficulty of recruiting emerging adults, engaging them with the program and collecting data after participation. The majority of interested participants experienced an eating disorder, suggesting they may be searching for help online. Future studies should investigate the use of peer support, identify strategies for reaching eligible participants and develop approaches to increase engagement. Finally, it is important to develop innovative programs that provide self-help strategies and facilitate help-seeking for those who are experiencing an eating disorder.

Objective To describe patterns of glucocorticoid use in a large real‐world cohort with early rheumatoid arthritis (RA) and assess the impact on disease activity and treatment. Methods Data are from adults with new RA (≤1 year) recruited to the Canadian Early Arthritis Cohort (CATCH) and are stratified on the basis of whether a person was prescribed oral glucocorticoids within 3 months of study entry. Disease activity was compared over 24 months. Mixed‐effects logistic regression was used for adjusted odds ratios (aORs) of escalation to biologics separately for 12 and 24 months, with random effects terms to account for prescribing patterns clustering by study site. Results Among 1891 persons, 30% received oral steroids. Users were older, were less often employed, and had shorter disease duration and higher disease activity. Disease activity improved over time, with early glucocorticoid users starting at higher levels of disease activity. Participants with early oral glucocorticoids were more likely to be on a biologic at 12 months (aOR = 2.4; 95% confidence interval [CI], 1.5‐3.7) and 24 months (aOR = 1.9; 95% CI, 1.3‐3.0). Despite Canadian clinical practice guidelines to limit corticosteroid use to short‐term or ‘bridge’ therapy, 30% of patients who used oral glucocorticoids still used them 2 years later. Conclusion Early steroids were prescribed sparingly in CATCH and were often indicative of more active baseline disease as well as the need for progression to biologics.

El-Shennawy et al. report that ACE2+ circulating extracellular vesicles (evACE2) are associated with COVID-19 severity and that evACE2 inhibits the infection of SARS-CoV-2 variants of concern at a higher efficacy than soluble ACE2.

Abstract Zika virus (ZIKV) is a mosquito-borne arbovirus that can cause severe congenital birth defects. The utmost goal of ZIKV vaccines is to prevent both maternal-fetal infection and congenital Zika syndrome. A Zika purified inactivated virus (ZPIV) was previously shown to be protective in non-pregnant mice and rhesus macaques. In this study, we further examined the efficacy of ZPIV against ZIKV infection during pregnancy in immunocompetent C57BL6 mice and common marmoset monkeys (Callithrix jacchus). We showed that, in C57BL/6 mice, ZPIV significantly reduced ZIKV-induced fetal malformations. Protection of fetuses was positively correlated with virus-neutralizing antibody levels. In marmosets, the vaccine prevented vertical transmission of ZIKV and elicited neutralizing antibodies that remained above a previously determined threshold of protection for up to 18 months. These proof-of-concept studies demonstrate ZPIV’s protective efficacy is both potent and durable and has the potential to prevent the harmful consequence of ZIKV infection during pregnancy.

Background & Aims: Hyperbaric oxygen therapy (HBOT) is a promising treatment for moderate-to-severe ulcerative colitis. However, our current understanding of the host and microbial response to HBOT remains unclear. This study examined the molecular mechanisms underpinning HBOT using a multi-omic strategy. Methods: Pre- and post-intervention mucosal biopsies, tissue, and fecal samples were collected from HBOT phase 2 clinical trials. Biopsies and fecal samples were subjected to shotgun metaproteomics, metabolomics, 16s rRNA sequencing, and metagenomics. Tissue was subjected to bulk RNA sequencing and digital spatial profiling (DSP) for single-cell RNA and protein analysis, and immunohistochemistry was performed. Fecal samples were also used for colonization experiments in IL10-/- germ-free UC mouse models. Results: Proteomics identified negative associations between HBOT response and neutrophil azurophilic granule abundance. DSP identified an HBOT-specific reduction of neutrophil STAT3, which was confirmed by immunohistochemistry. HBOT decreased microbial diversity with a proportional increase in Firmicutes and a secondary bile acid lithocholic acid. A major source of the reduction in diversity was the loss of mucus-adherent taxa, resulting in increased MUC2 levels post-HBOT. Targeted database searching revealed strain-level associations between Akkermansia muciniphila and HBOT response status. Colonization of IL10-/- with stool obtained from HBOT responders resulted in lower colitis activity compared with non-responders, with no differences in STAT3 expression, suggesting complementary but independent host and microbial responses. Conclusions: HBOT reduces host neutrophil STAT3 and azurophilic granule activity in UC patients and changes in microbial composition and metabolism in ways that improve colitis activity. Intestinal microbiota, especially strain level variations in A muciniphila, may contribute to HBOT non-response.

Zika virus (ZIKV) is a mosquito-borne flavivirus that causes an acute febrile illness. ZIKV can be transmitted between sexual partners and from mother to fetus. Infection is strongly associated with neurologic complications in adults, including Guillain-Barré syndrome and myelitis, and congenital ZIKV infection can result in fetal injury and congenital Zika syndrome (CZS). Development of an effective vaccine is imperative to protect against ZIKV vertical transmission and CZS. Recombinant Vesicular Stomatitis virus (rVSV) is a highly effective and safe vector for the delivery of foreign immunogens for vaccine purposes. Here, we evaluate an rVSV vaccine expressing the full length pre-membrane (prM) and ZIKV envelope (E) proteins (rVSVΔM-ZprME), shown to be immunogenic in murine models of ZIKV infection, for its capacity to induce immune responses in nonhuman primates. Moreover, we assess the efficacy of the rVSVΔM-ZprME vaccine in the protection of pigtail macaques against ZIKV infection. Administration of the rVSVΔM-ZprME vaccine was safe, but it did not induce robust anti-ZIKV T-cell responses, IgM or IgG antibodies, or neutralizing antibodies in most animals. Post ZIKV challenge, animals that received the rVSVΔM control vaccine lacking ZIKV antigen had higher levels of plasma viremia compared to animals that received the rVSVΔM-ZprME vaccine. Anti-ZIKV neutralizing Ab titers were detected in a single animal that received the rVSVΔM-ZprME vaccine that was associated with reduced plasma viremia. The overall suboptimal ZIKV-specific cellular and humoral responses post-immunization indicates the rVSVΔM-ZprME vaccine did not elicit an immune response in this pilot study. However, recall antibody response to the rVSVΔM-ZprME vaccine indicates it may be immunogenic and further developments to the vaccine construct could enhance its potential as a vaccine candidate in a nonhuman primate pre-clinical model.

ABSTRACT Industrial livestock operations (ILOs), particularly processing facilities, emerged as centers of coronavirus disease 2019 (COVID-19) outbreaks in spring 2020. Confirmed cases of COVID-19 underestimate true prevalence. To investigate the prevalence of antibodies against SARS-CoV-2, we enrolled 279 participants in North Carolina from February 2021 to July 2022: 90 from households with at least one ILO worker (ILO), 97 from high-ILO intensity areas (ILO neighbors [ILON]), and 92 from metropolitan areas (metro). More metro (55.4%) compared to ILO (51.6%) and ILON participants (48.4%) completed the COVID-19 primary vaccination series; the median completion date was more than 4 months later for ILO compared to ILON and metro participants, although neither difference was statistically significant. Participants provided a saliva swab we analyzed for SARS-CoV-2 IgG using a multiplex immunoassay. The prevalence of infection-induced IgG (positive for nucleocapsid and receptor binding domain) was higher among ILO (63%) than ILON (42.9%) and metro (48.7%) participants (prevalence ratio [PR], 1.38; 95% confidence interval [CI], 1.06 to 1.80; reference category ILON and metro combined). The prevalence of infection-induced IgG was also higher among ILO participants than among an Atlanta health care worker cohort (PR, 2.45; 95% CI, 1.80 to 3.33) and a general population cohort in North Carolina (PRs, 6.37 to 10.67). The infection-induced IgG prevalence increased over the study period. Participants reporting not masking in public in the past 2 weeks had higher infection-induced IgG prevalence (78.6%) than participants reporting masking (49.3%) (PR, 1.59; 95% CI, 1.19 to 2.13). Lower education, more people per bedroom, Hispanic/Latino ethnicity, and more contact with people outside the home were also associated with higher infection-induced IgG prevalence. IMPORTANCE Few studies have measured COVID-19 seroprevalence in North Carolina, especially among rural, Black, and Hispanic/Latino communities that have been heavily affected. Antibody results show high rates of COVID-19 among industrial livestock operation workers and their household members. Antibody results add to evidence of health disparities related to COVID-19 by socioeconomic status and ethnicity. Associations between masking and physical distancing with antibody results also add to evidence of the effectiveness of these prevention strategies. Delays in the timing of receipt of COVID-19 vaccination reinforce the importance of dismantling vaccination barriers, especially for industrial livestock operation workers and their household members.

BackgroundRisk factors for cognitive decline and physical decline have been studied independently, however older adults might experience decline in both areas i.e., dual decline. Risk factors associated with dual decline are largely unknown and have significant implications on health outcomes. The aim of this study is to explore risk factors associated with dual decline.MethodsUsing data from the Health, Aging and Body Composition (Health ABC) study, a longitudinal prospective cohort study, we examined trajectories of decline based on repeated measures of the Modified Mini-Mental State Exam (3MSE) and the Short Physical Performance Battery (SPPB) across 6 years (n=1,552). We calculated four mutually exclusive trajectories of decline and explored predictors of decline: cognitive decline (n = 306) = lowest quartile of slope on the 3MSE or 1.5 SD below mean at baseline, physical decline (n = 231) = lowest quartile of slope on the SPPB or 1.5 SD below mean at baseline, dual decline (n = 110) = lowest quartile in both measures or 1.5 SD below mean in both measures at baseline. Individuals who did not meet criteria for one of the decline groups were classified as the reference group. (n= 905).ResultsMultinomial logistic regression tested the association of 17 baseline risk factors with decline. Odds of dual decline where significantly higher for individuals at baseline with depressive symptoms (CES-D >16) (Odds Ratio (OR)=2.49, 95% Confidence Interval (CI): 1.05-6.29), ApoE-ε4 carrier (OR= 2.09, 95% CI: 1.06-1.95), or if individuals had lost 5+lbs in past year (OR=1.79, 95% CI: 1.13-2.84). Odds were significantly lower for individuals with a higher score on the Digit Symbol Substitution Test per standard deviation (OR per SD: 0.47, 95% CI 0.36-0.62) and faster 400-meter gait (OR per SD= 0.49, 95% CI: 0.37-0.64).ConclusionAmong predictors, depressive symptoms at baseline significantly increased the odds of developing dual decline but was not associated with decline in the exclusively cognitive or physical decline groups. APOE-ε4 status increased the odds for cognitive decline and dual decline but not physical decline. More research on dual decline is needed because this group represents a high risk, vulnerable subset of older adults.

Background We aim to evaluate the association between meal intervals and weight trajectory among adults from a clinical cohort. Methods and Results This is a multisite prospective cohort study of adults recruited from 3 health systems. Over the 6‐month study period, 547 participants downloaded and used a mobile application to record the timing of meals and sleep for at least 1 day. We obtained information on weight and comorbidities at each outpatient visit from electronic health records for up to 10 years before until 10 months after baseline. We used mixed linear regression to model weight trajectories. Mean age was 51.1 (SD 15.0) years, and body mass index was 30.8 (SD 7.8) kg/m2; 77.9% were women, and 77.5% reported White race. Mean interval from first to last meal was 11.5 (2.3) hours and was not associated with weight change. The number of meals per day was positively associated with weight change. The average difference in annual weight change (95% CI) associated with an increase of 1 daily meal was 0.28 kg (0.02–0.53). Conclusions Number of daily meals was positively associated with weight change over 6 years. Our findings did not support the use of time‐restricted eating as a strategy for long‐term weight loss in a general medical population.

IntroductionAutoimmune diabetes occurs more often in the first 2 years of life in children with Down syndrome (DS) compared with the general population. We previously observed increased frequencies of islet autoantibodies, including insulin autoantibodies (IAA), in children with DS. Assays for IAA using 125I-labelled insulin require competition to overcome cross reactivity with antibodies to the cow’s milk protein, bovine serum albumin (BSA). 125I-IAA assay results suggested that levels of antibodies to BSA may also be increased in children with DS. The aim of this study therefore was to determine whether the levels of anti-BSA antibodies differed in children with DS compared with controls.MethodsSamples were available from two populations with DS: one from the UK, (UK DS cohort n=106, 58 male, median age 12.5 years) and one from Estonia (Estonian DS cohort: n=121, 65 male, median age 9.75 years). A UK control population was provided by sex and age-matched healthy siblings of probands participating in the Bart’s Oxford (BOX) family study of type 1 diabetes. A competitive-displacement radiobinding assay (RBA) and a Dissociation Enhanced Lanthanide Fluoroimmunoassay (DELFIA) were developed to measure and confirm anti-BSA antibody levels. HLA class II genotype was analysed by PCR using sequence specific primers (PCR-SSP).ResultsOverall, levels of anti-BSA antibodies were increased in those with DS compared with controls (p

Background & Aims: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. In contrast to two predicted protein truncating mutations (PPTMs), homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship. Methods: From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n = 31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n = 30), and with two PPTMs (BSEP3/3; n = 77). We compared clinical presentation, native liver survival (NLS), and the effect of siEHC on NLS. Results: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (p

Background and Aims. An OIV resolution provides guidelines on using glutathione as a prefermentation additive when the amount of yeast assimilable nitrogen (YAN) of a juice or must is adequate, to avoid the metabolism of glutathione by the yeast. The effect of YAN concentration on glutathione metabolism by yeast had not been determined. This study explored whether nitrogen management could be used to control glutathione consumption during fermentation. Methods and Results. An HPLC-UV method was developed to quantify reduced L-glutathione (GSH) and oxidised glutathione (GSSG) and used to monitor yeast GSH metabolism during alcoholic fermentation with two yeast strains (AWRI 1688 and AWRI 2861). The addition of GSH had no impact on the fermentation rate of the chemically defined medium, even in a limited YAN environment; however, a decrease in glutathione concentration occurred regardless of YAN concentration. The effect of GSH on volatile sulfur compound formation was yeast strain-dependent. Conclusions. Increasing the YAN status of a chemically defined medium led to a decrease in GSH consumption during fermentation, but the loss of GSH could not be prevented entirely, even with a low initial GSH concentration and high initial YAN. Significance of the Study. In the presence of higher concentrations of GSH during fermentation, there is a risk of forming undesirable fermentative sulfur compounds that are not mitigated through nitrogen supplementation. Thus, it seems unlikely that an argument could be made for the inclusion of GSH in relevant food standards codes as a wine additive especially if a lack of GSH metabolism was a criterion.

Background: Although stigma associated with South African people living with HIV has declined since the 1980s when HIV/AIDS was first identified, it still persists. Stigma is associated with poor health outcomes and avoidance of interactions with healthcare systems. The HIV stigma framework distinguishes three HIV-related self-stigma mechanisms. Aims: The aims of this study were to explore intersectionality between HIV-stigma mechanisms and selected sociodemographic as well as HIV factors, and interrelationships between three HIV-related self-stigma mechanisms. Setting and method: This study was a secondary analysis of data collected from a cross-sectional sample of people receiving HIV-related primary health care at different municipal clinics in Durban, South Africa (N = 100). Results: The average participant was Black African, female, unemployed, with a monthly income below R2 500, most had completed primary school. No sociodemographic or HIV-related factors were significantly related to total or subscale HIV stigma scores. Respondents reported experiencing (enacted) no stigmatization, did not expect to experience (anticipated) much stigmatization from their social interactions with family, community, healthcareworkers, and reported no strong stigmatizing beliefs about themselves (internalized). Conclusion: Intersectionality did not identify any particular socio-demographic or HIV-related factor associated with greater HIV stigma. Participants reported low HIV stigma arising from interactions with healthcare and social service providers or families. Although no socio-demographic or HIV-related factors were significantly associated with HIV stigma mechanisms in this relatively homogeneous sample, being marginalized can nevertheless result from living with other differences compared to societal norms and result in particular vulnerability when living with HIV/AIDS.

Mapper, a topological algorithm, is frequently used as an exploratory tool to build a graphical representation of data. This representation can help to gain a better understanding of the intrinsic shape of high-dimensional genomic data and to retain information that may be lost using standard dimension-reduction algorithms. We propose a novel workflow to process and analyze RNA-seq data from tumor and healthy subjects integrating Mapper, differential gene expression, and spectral shape analysis. Precisely, we show that a Gaussian mixture approximation method can be used to produce graphical structures that successfully separate tumor and healthy subjects, and produce two subgroups of tumor subjects. A further analysis using DESeq2, a popular tool for the detection of differentially expressed genes, shows that these two subgroups of tumor cells bear two distinct gene regulations, suggesting two discrete paths for forming lung cancer, which could not be highlighted by other popular clustering methods, including t-distributed stochastic neighbor embedding (t-SNE). Although Mapper shows promise in analyzing high-dimensional data, tools to statistically analyze Mapper graphical structures are limited in the existing literature. In this paper, we develop a scoring method using heat kernel signatures that provides an empirical setting for statistical inferences such as hypothesis testing, sensitivity analysis, and correlation analysis.

Abstract Objective: To use interrupted time-series analyses to investigate the impact of the coronavirus disease 2019 (COVID-19) pandemic on healthcare-associated infections (HAIs). We hypothesized that the pandemic would be associated with higher rates of HAIs after adjustment for confounders. Design: We conducted a cross-sectional study of HAIs in 3 hospitals in Missouri from January 1, 2017, through August 31, 2020, using interrupted time-series analysis with 2 counterfactual scenarios. Setting: The study was conducted at 1 large quaternary-care referral hospital and 2 community hospitals. Participants: All adults ≥18 years of age hospitalized at a study hospital for ≥48 hours were included in the study. Results: In total, 254,792 admissions for ≥48 hours occurred during the study period. The average age of these patients was 57.6 (±19.0) years, and 141,107 (55.6%) were female. At hospital 1, 78 CLABSIs, 33 CAUTIs, and 88 VAEs were documented during the pandemic period. Hospital 2 had 13 CLABSIs, 6 CAUTIs, and 17 VAEs. Hospital 3 recorded 11 CLABSIs, 8 CAUTIs, and 11 VAEs. Point estimates for hypothetical excess HAIs suggested an increase in all infection types across facilities, except for CLABSIs and CAUTIs at hospital 1 under the “no pandemic” scenario. Conclusions: The COVID-19 era was associated with increases in CLABSIs, CAUTIs, and VAEs at 3 hospitals in Missouri, with variations in significance by hospital and infection type. Continued vigilance in maintaining optimal infection prevention practices to minimize HAIs is warranted.

Background Short bowel syndrome (SBS) is a leading cause of intestinal failure resulting in parenteral nutrition (PN) dependence and nutritional deficiencies. Long-term PN use is associated with the development of sepsis and intestinal failure-associated liver disease. Achieving enteral autonomy is the optimal way to prevent these complications. In SBS, the decreased intestinal length, bile acid deficiency, and rapid transit time contribute to fat malabsorption and continued PN dependence. We propose the use of an immobilized lipase cartridge (ILC; RELiZORB) that connects in-line with enteral feed tubing sets and is designed to breakdown the majority of fats provided in enteral nutrition (EN). Preclinical studies have demonstrated both improved fat and fat-soluble vitamin absorption with ILC use in a porcine model of SBS. To evaluate the clinical applicability of these findings, we designed a phase 3, open labeled, single center, clinical trial to determine the safety, tolerability, and efficacy of the RELiZORB enzyme cartridge when used daily with EN for 90 days. Methods The patient population will include PN dependent children with SBS, aged 2–18 years. The primary outcome is the change in PN calories from baseline, assessed weekly throughout the study. Changes in growth Z-scores, 72-hour fecal fat and coefficient of fat absorption, plasma fatty acids and fat-soluble vitamins will also be evaluated. Assessment of change in continuous outcomes will be made using the area under the curve, expressed as a percent change relative to baseline, calculated over study day 7 to 90 (AUC7-90). The incidence of adverse events will be monitored and summarized by system organ class. Discussion If successful, RELiZORB may offer a safe alternative to reducing PN dependence and achieving enteral autonomy in pediatric intestinal failure. These results would be clinically significant given the clear association between long-term PN use and complications in SBS. Trial registration ClinicalTrials.gov NCT03530852; registered on May 21st, 2018, last update posted on September 14th, 2022.

Graph analytical approaches permit identifying novel genes involved in complex diseases, but are limited by (i) inferring structural network similarity of connected gene nodes, ignoring potentially relevant unconnected nodes; (ii) using homogeneous graphs, missing gene-disease associations’ complexity; (iii) relying on disease/gene-phenotype associations’ similarities, involving highly incomplete data; (iv) using binary classification, with gene-disease edges as positive training samples, and non-associated gene and disease nodes as negative samples that may include currently unknown disease genes; or (v) reporting predicted novel associations without systematically evaluating their accuracy. Addressing these limitations, we develop the Heterogeneous Integrated Graph for Predicting Disease Genes (HetIG-PreDiG) model that includes gene-gene, gene-disease, and gene-tissue associations. We predict novel disease genes using low-dimensional representation of nodes accounting for network structure, and extending beyond network structure using the developed Gene-Disease Prioritization Score (GDPS) reflecting the degree of gene-disease association via gene co-expression data. For negative training samples, we select non-associated gene and disease nodes with lower GDPS that are less likely to be affiliated. We evaluate the developed model’s success in predicting novel disease genes by analyzing the prediction probabilities of gene-disease associations. HetIG-PreDiG successfully predicts (Micro-F1 = 0.95) gene-disease associations, outperforming baseline models, and is validated using published literature, thus advancing our understanding of complex genetic diseases.

Adjustments of ventilation in fishes to regulate the volume of water flowing over the gills are critically important responses to match branchial gas transfer with metabolic needs and to defend homeostasis during environmental fluctuations in O2 and/or CO2 levels. In this focused review, we discuss the control and consequences of ventilatory adjustments in fish, briefly summarizing ventilatory responses to hypoxia and hypercapnia before describing the current state of knowledge of the chemoreceptor cells and molecular mechanisms involved in sensing O2 and CO2. We emphasize, where possible, insights gained from studies on early developmental stages. In particular, zebrafish (Danio rerio) larvae have emerged as an important model for investigating the molecular mechanisms of O2 and CO2 chemosensing as well as the central integration of chemosensory information. Their value stems, in part, from their amenability to genetic manipulation, which enables the creation of loss-of-function mutants, optogenetic manipulation, and the production of transgenic fish with specific genes linked to fluorescent reporters or biosensors.

Infants, children, and adolescents are at risk of experiencing a multitude of gastrointestinal disorders (GID). These disorders can adversely affect the quality of life or be life-threatening. Various interventions that span the conventional and complementary therapeutic categories have been developed. Nowadays, parents increasingly seek complementary options for their children to use concurrently with conventional therapies. Due to the high prevalence and morbidity of diarrhea, constipation, and irritable bowel syndrome (IBS) in children, in this review, we decided to focus on the current state of the evidence for conventional and complementary therapies used for the treatment of these diseases in children. Diarrhea treatment focuses on the identification of the cause and fluid management. Oral rehydration with supplementation of deficient micronutrients, especially zinc, is well established and recommended. Some probiotic strains have shown promise in reducing the duration of diarrhea. For the management of constipation, available clinical trials are insufficient for conclusive recommendations of dietary modifications, including increased use of fruit juice, fiber, and fluid. However, the role of laxatives as conventional treatment is becoming more established. Polyethylene glycol is the most studied, with lactulose, milk of magnesia, mineral oil, bisacodyl, and senna presenting as viable alternatives. Conventional treatments of the abdominal pain associated with IBS are poorly studied in children. Available studies investigating the effectiveness of antidepressants on abdominal pain in children with IBS were inconclusive. At the same time, probiotics and peppermint oil have a fair record of benefits and safety. The overall body of evidence indicates that a careful balance of conventional and complementary treatment strategies may be required to manage gastrointestinal conditions in children.

BackgroundProgressive enhancement predicted poor survival in ACRIN 6677/RTOG 0625, a multi-center trial of bevacizumab with irinotecan or temozolomide in recurrent glioblastoma, but pseudoresponse likely limited enhancement-based survival prognostication in T1 non-progressors. We aimed to determine whether early change in cerebral blood volume from baseline (ΔCBV) could further stratify the T1 non-progressors according to overall (OS) and progression-free (PFS) survival.Methods37/123 enrolled patients had DSC-MRI, including 13, 15, and 8 patients without 2D-T1 progression at 2, 8, and 16 weeks post-treatment initiation, respectively. Mean CBV normalized to white matter (nRCBV) and mean standardized CBV (sRCBV) were extracted from enhancing tumor. ROC curves were derived for ΔCBV using six-month PFS and one-year OS as reference standards. Kaplan-Meier survival estimates and log-rank test compared PFS and OS for both ΔCBV (increase vs. decrease) and T1 response status (stable vs. decreasing enhancement).ResultsPFS and OS were significantly worse for increasing CBV at 2 weeks (p=0.003 and p=0.002 for nRCBV, and p=0.03 and p=0.03 for sRCBV, respectively), but not for 2D-T1 patients with stable vs. decreasing enhancement (p=0.44 and p=0.86, respectively). ΔCBV at week 2 was also a good prognostic marker for OS-1 and PFS-6 using ROC analysis. By contrast, 2D-T1 response status at weeks 2, 8, and 16 was not associated with PFS-6. ΔCBV at 16 weeks (p=0.008 for sRCBV) but not 8 weeks (p=0.74 for nRCBV and p=0.56 for sRCBV) was associated with significant difference in median survival, but no difference in survival was observed for 2D-T1 patients with stable vs. decreasing enhancement at 8 weeks (p=0.69) or 16 weeks (p=0.21). At 16 weeks, OS did not differ significantly between 2D-T1 progressors and 2D-T1 non-progressors with increasing CBV (median survival 3.3 months post week 16 scan vs. 9.2 months, respectively; p=0.13), suggesting that 2D-T1 non-progressors with increasing CBV may have a prognosis like that of 2D-T1 progressors.ConclusionAfter 2 weeks of anti-angiogenic therapy, ΔCBV in 2D-T1 non-progressors significantly prognosticated PFS and OS, whereas 2D-T1 response status did not, identifying a subpopulation that benefits from bevacizumab. Combining 2D-T1 progression and ΔCBV may yield a response assessment paradigm with 3-tiered OS stratification.

Abstract Soil gas diffusivity (Dp/Do, gas diffusion coefficients in soil and in free air, respectively) and its relation to soil moisture is of great importance for describing and quantifying essential provisional and regulatory functions associated with terrestrial ecosystems such as soil aeration and greenhouse gas (GHG) emissions. Because gas migration in terrestrial soil systems is predominantly diffusion controlled, soil gas diffusivity becomes a fundamental prerequisite to quantify diffusive gas fluxes. Descriptive–predictive models are often used to estimate Dp/Do from easily measurable soil physical properties. Most of the available models take the form of power‐law functions and often tend to mischaracterize soil moisture effects at high moisture regimes. Based on a wide range Dp/Do data available in literature representing both intact and repacked soils, this study developed a novel air‐saturation‐dependent exponential (ASEX) gas diffusivity model to model Dp/Do in relation to soil air saturation. The model variable α, which represents the diffusivity at half air saturation normalized by the same in complete soil air saturation, could potentially differentiate moisture effects on different soil structural states. For specific applications in intact soils, we propose corresponding α values for upper‐limit (α = .6) and lower‐limit (α = .05) estimates of diffusivity, while an average value (α = .3) for general applications in both intact and repacked soils. As expected, our model based on a few a priori measured supportive data showed a better performance over the classical predictive models that do not use such measurements. The new model was further used to derive useful implications to showcase soil density effects on Dp/Do.