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The viral hemorrhagic fevers Lassa fever (LF) and Ebola virus disease (EVD) have been documented to cause long-term health problems in survivors. Limited studies have noted the presence of adverse reproductive health outcomes, including menstrual irregularities and pregnancy loss, after recovery from infection. The objective of this systematic review and meta-analysis is to summarize existing knowledge surrounding reproductive health in female survivors of LF and EVD. Literature was gathered from PubMed, Embase, Ovid Medline, Cumulative Index of Nursing and Allied Health (CINAHL) Complete, Web of Science, and Global Health databases and subsequently reviewed in Covidence. Included studies described at least one reproductive health outcome in women after recovery from EVD or LF. Thirteen studies were identified in the systematic review, all of which only discussed reproductive health in EVD survivors. No studies of reproductive health among survivors of LF were identified. The included studies were conducted in Guinea, Sierra Leone, and Liberia, and they reported irregular menstruation, pregnancy loss, decreased libido, pelvic inflammatory disease, sexual dysfunction, female reproductive odor, and genital problems/infections among survivors. In a meta-analysis of nine studies, 14.0% of female EVD survivors experienced any adverse reproductive health outcome. However, there was significant heterogeneity among the included studies. This study highlights the health problems faced by female EVD survivors and underscores the need for more research surrounding the effects of viral hemorrhagic fevers on women's health.

Biomedical research and clinical practice are in the midst of a transition toward significantly increased use of artificial intelligence (AI) and machine learning (ML) methods. These advances promise to enable qualitatively deeper insight into complex challenges formerly beyond the reach of analytic methods and human intuition while placing increased demands on ethical and explainable artificial intelligence (XAI), given the opaque nature of many deep learning methods. The U.S. National Institutes of Health (NIH) has initiated a significant research and development program, Bridge2AI, aimed at producing new "flagship" datasets designed to support AI/ML analysis of complex biomedical challenges, elucidate best practices, develop tools and standards in AI/ML data science, and disseminate these datasets, tools, and methods broadly to the biomedical community. An essential set of concepts to be developed and disseminated in this program along with the data and tools produced are criteria for AI-readiness of data, including critical considerations for XAI and ethical, legal, and social implications (ELSI) of AI technologies. NIH Bridge to Artificial Intelligence (Bridge2AI) Standards Working Group members prepared this article to present methods for assessing the AI-readiness of biomedical data and the data standards perspectives and criteria we have developed throughout this program. While the field is rapidly evolving, these criteria are foundational for scientific rigor and the ethical design and application of biomedical AI methods.

BACKGROUNDInhibition of Bruton's tyrosine kinase with ibrutinib blocks the function of myeloid-derived suppressor cells (MDSC). The combination of ibrutinib and nivolumab was tested in patients with metastatic solid tumors.METHODSSixteen patients received ibrutinib 420 mg p.o. daily with nivolumab 240 mg i.v. on days 1 and 15 of a 28-day cycle. The effect of ibrutinib and nivolumab on MDSC, the immune profile, and cytokine levels were measured. Single-cell RNA-Seq and T cell receptor sequencing of immune cells was performed.RESULTSCommon adverse events were fatigue and anorexia. Four patients had partial responses and 4 had stable disease at 3 months (average 6.5 months, range 3.5-14.6). Median overall survival (OS) was 10.8 months. Seven days of Bruton's tyrosine kinase (BTK) inhibition significantly increased the proportion of monocytic-MDSC (M-MDSC) and significantly decreased chemokines associated with MDSC recruitment and accumulation (CCL2, CCL3, CCL4, CCL13). Single-cell RNA-Seq revealed ibrutinib-induced downregulation of genes associated with MDSC-suppressive function (TIMP1, CXCL8, VEGFA, HIF1A), reduced MDSC interactions with exhausted CD8+ T cells, and decreased TCR repertoire diversity. The addition of nivolumab significantly increased circulating NK and CD8+ T cells and increased CD8+ T cell proliferation. Exploratory analyses suggest that MDSC and T cell gene expression and TCR repertoire diversity were differentially affected by BTK inhibition according to patient response.CONCLUSIONIbrutinib and nivolumab were well tolerated and affected MDSC and T cell function in patients with solid metastatic tumors.TRIAL REGISTRATIONClinicalTrials.gov NCT03525925.FUNDINGNIH; National Cancer Institute Cancer; National Center for Advancing Translational Sciences; Pelotonia.

This article reviews emerging surgical techniques and prosthetic innovations related to amputation rehabilitation. Osseointegration is discussed from conception to modern implant designs. Motor and sensory reinnervation techniques are reviewed and compared. Prosthetic socket casting, interface, and design innovations are discussed, including direct molded sockets, water casting, adjustable sockets, and magnetic suspension. Advanced components with hydraulic and microprocessor control, power and crossover prosthetic feet are described., Competing Interests: Disclosure The contents of this article and opinions expressed do not represent the views of the Department of Veterans Affairs or United States Government. The authors have no relevant financial relationships., (Published by Elsevier Inc.)

Objectives: Dental caries and periodontitis are among the most prevalent chronic diseases worldwide and have been associated with atherosclerotic cardiovascular diseases (ASCVD). This study aimed to determine (1) the independent associations between subclinical ASCVD markers (carotid intima media thickness [CIMT] and coronary artery calcification [CAC]) and quantitative indices of oral disease including the decayed, missing, and filled teeth (DMFT) index, gingivitis parameters, periodontal status, and number of teeth lost and (2) the extent to which metabolites altered in individuals with oral disease overlapped with those altered in individuals with ASCVD., Methods: We used data from 552 participants recruited through the Dental Strategies Concentrating on Risk Evaluation project. Oral examinations were conducted, and CIMT and CAC were measured. Multiple linear regression models were constructed with CIMT and CAC as dependent variables in the epidemiologic analysis. In the metabolomic analysis, logistic or linear regression was used to test 1,228 metabolites for association with each phenotype adjusted for age, sex, race, blood pressure, smoking, diabetes, cholesterol, high-sensitivity C-reactive protein, and interleukin-6., Results: None of the oral disease markers were significant predictors of ASCVD markers in the fully adjusted models. However, critical lipid and lipid-signaling pathway metabolites were significantly associated with gingivitis, periodontitis, and DMFT: the lysophospholipid pathway (odds ratio [OR] = 2.29, false discovery rate [FDR]-adjusted P = 0.038) and arachidonate with gingivitis (OR = 2.35, FDR-adjusted P = 0.015), the sphingolipid metabolism pathway with periodontitis (OR = 2.09, FDR-adjusted P = 0.029), and borderline associations between plasmalogen and lysophospholipid pathways and DMFT (P = 0.055). Further, the same metabolite from the sphingolipid metabolism pathway, sphingomyelin (d17:1/14:0, d16:1/15:0), was inversely associated with both CIMT (β = -0.14, FDR-adjusted P = 0.014) and gingivitis (OR = 0.04, FDR-adjusted P = 0.033)., Conclusions: The discovery of a common sphingomyelin metabolite in both disease processes is a novel finding suggesting that gingivitis and periodontitis may be associated with some overlapping metabolic pathways associated with ASCVD and indicating potential shared mechanisms among these diseases., Knowledge Transfer Statement: The same metabolites may be altered in atherosclerosis and oral disease. Specifically, a common sphingomyelin metabolite was inversely associated with gingivitis and carotid intima media thickness, a subclinical marker of atherosclerotic cardiovascular disease. These findings can provide valuable insights for future mechanistic studies to establish potential causal relationships, with the hope of influencing disease prevention and targeted early treatment., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Movement as medicine is the premise behind Running Medicine (RM), a community-based wellness program that began in 2016 in New Mexico. RM is centered in the Indigenous traditions of running and is oriented to improving the four dimensions of wellness-mind, body, spirit, and social. Using retroactive surveys of RM's Spring 2019 participants, we investigated the program's effectiveness in the realms of physical, mental, spiritual, and social wellness. Based on data from participant surveys, RM appears to be effective at improving the four realms of wellness. Indigenous participants improved to a greater degree in mental and social wellness than non-Indigenous participants, while the opposite was true for physical and spiritual wellness. For both groups, the largest effect size among the four domains was seen in social wellness. Among our participants, this culturally grounded approach to wellness appears to be effective at improving the four realms of physical, mental, spiritual, and social wellness., Competing Interests: None of the authors above have conflicts of interest related to this project

Researchers in biomedical research, public health and the life sciences often spend weeks or months discovering, accessing, curating, and integrating data from disparate sources, significantly delaying the onset of actual analysis and innovation. Instead of countless developers creating redundant and inconsistent data pipelines, BioBricks.ai offers a centralized data repository and a suite of developer-friendly tools to simplify access to scientific data. Currently, BioBricks.ai delivers over ninety biological and chemical datasets. It provides a package manager-like system for installing and managing dependencies on data sources. Each 'brick' is a Data Version Control git repository that supports an updateable pipeline for extraction, transformation, and loading data into the BioBricks.ai backend at https://biobricks.ai. Use cases include accelerating data science workflows and facilitating the creation of novel data assets by integrating multiple datasets into unified, harmonized resources. In conclusion, BioBricks.ai offers an opportunity to accelerate access and use of public data through a single open platform., Competing Interests: 10.Conflict of Interest The authors declare the following potential conflicts of interest regarding the research and publication of this paper: BioBricks is a product developed by Insilica LLC, and many of the authors are employees of Insilica LLC. As such, there may be a perceived or real financial interest in the outcomes of the research and the development of BioBricks. The authors affirm that their contributions to the research and the manuscript were conducted with scientific integrity and without bias influenced by their association with Insilica LLC.

While uniprofessional education programs develop strong student identities, they may limit the development of behaviors needed for interprofessional socialization. Interprofessional education (IPE) creates an essential platform for student engagement in the development of interprofessional socialization and cultural humility, thus enabling improvement in collaborative communication. In this quasi-experimental observational study, health professional students attended one of three Grand Rounds Interprofessional Workshops (GRIW) and completed online pre- and post-workshop surveys including sociodemographic background, the Interprofessional Socialization and Valuing Scale (ISVS), and the Cultural Competence Self-Assessment Checklist (CCSAC). A total of 394 students from eight professions participated in the workshop with 287 (73%) of attendees completing both pre- and post-workshop surveys. No significant differences were observed in ISVS and CCSAC scores between students across workshops. Significant pre- to post-workshop differences were found in ISVS [t (284) = 13.5, p  < .001, 95%], CCSAC [t (286) = 13.8, p  < .001] and the cultural competence components of cultural awareness [t (285) = 12.9, p  < .001, 95%], knowledge [t (285) = 9.5, p  < .001, 95%], and skills [t (286) = 13.3, p  < .001, 95%]. Interprofessional education learning opportunities that integrate socialization with health professional students and cultural humility education can improve educational awareness of cultural values and communication for collaborative professional practice.

Caries is a partially heritable disease, raising the possibility that a polygenic score (PS, a summary of an individual's genetic propensity for disease) might be a useful tool for risk assessment. To date, PS for some diseases have shown clinical utility, although no PS for caries has been evaluated. The objective of the study was to test whether a PS for caries is associated with disease experience or increment in a cohort of Swedish adults. A genome-wide PS for caries was trained using the results of a published genome-wide association meta-analysis and constructed in an independent cohort of 15,460 Swedish adults. Electronic dental records from the Swedish Quality Registry for Caries and Periodontitis (SKaPa) were used to compute the decayed, missing, and filled tooth surfaces (DMFS) index and the number of remaining teeth. The performance of the PS was evaluated by testing the association between the PS and DMFS at a single dental examination, as well as between the PS and the rate of change in DMFS. Participants in the highest and lowest deciles of PS had a mean DMFS of 63.5 and 46.3, respectively. A regression analysis confirmed this association where a 1 standard deviation increase in PS was associated with approximately 4-unit higher DMFS ( P < 2 × 10 -16 ). Participants with the highest decile of PS also had greater change in DMFS during follow-up. Results were robust to sensitivity analysis, which adjusted for age, age squared, sex, and the first 20 genetic principal components. Mediation analysis suggested that tooth loss was a strong mediating factor in the association between PS and DMFS but also supported a direct genetic effect on caries. In this cohort, there are clinically meaningful differences in DMFS between participants with high and low PS for caries. The results highlight the potential role of genomic data in improving caries risk assessment., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Competing Interests: Competing interests: None declared.

Problem: Climate change is a public health and health equity crisis. Health professionals are well positioned to advance solutions but may lack the training and self-efficacy needed to achieve them., Approach: The Center for Health Equity Education and Advocacy at Cambridge Health Alliance, a Harvard Medical School Teaching Hospital, developed a novel, longitudinal fellowship that taught health professionals about health and health equity effects of climate change, as well as community organizing practices that may help them mitigate these effects. The fellowship cohort included 40 fellows organized into 12 teams and was conducted from January to June 2022. Each team developed a project to address climate change and received coaching from an experienced community organizer coach. Effects of the fellowship on participants' knowledge, skills, and attitudes were evaluated using pre- and postfellowship surveys., Outcomes: Surveys were analyzed for 38 of 40 (95%) participants who consented to the evaluation and completed both surveys. Surveys used a 7-point Likert scale for item responses. McNemar's test for paired data was used to assess changes in the proportion of respondents who agreed ("somewhat agree"/"agree"/"strongly agree") with statements in pre- vs postfellowship surveys. Statistically significant improvements were found for 11 of the 17 items assessing knowledge, skills, and attitudes. Participants' views of the fellowship and its effects were assessed through additional items in the postfellowship survey. Most respondents agreed that the fellowship increased their knowledge of the connections between climate change and health equity (32/38, 84.2%) and prepared them to effectively participate in a community organizing campaign (37/38, 94.7%). Each of the 12 groups developed climate health projects by the fellowship's end., Next Steps: This novel fellowship was well received and effective in teaching community organizing to health professionals concerned about climate change. Future studies are needed to assess longer-term effects of the fellowship., (Copyright © 2024 the Association of American Medical Colleges.)

Background: Dyslipidemia is becoming prevalent in Africa, where malaria is endemic. Observational studies have documented the long-term protective effect of malaria on dyslipidemia; however, these study designs are prone to confounding. Therefore, we used Mendelian randomization (MR, a method robust to confounders and reverse causation) to determine the causal effect of severe malaria (SM) and the recurrence of non-severe malaria (RNM) on lipid traits., Method: We performed two-sample MR using genome wide association study (GWAS) summary statistics for recurrent non-severe malaria (RNM) from a Benin cohort (N = 775) and severe malaria from the MalariaGEN dataset (N = 17,000) and lipid traits from summary-level data of a meta-analyzed African lipid GWAS (MALG, N = 24,215) from the African Partnership for Chronic Disease Research (APCDR) (N = 13,612) and the Africa Wits-IN-DEPTH partnership for genomics studies (AWI-Gen) dataset (N = 10,603)., Result: No evidence of significant causal association was obtained between RNM and high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol and triglycerides. However, a notable association emerged between severe malarial anaemia (SMA) which is a subtype of severe malaria and reduced HDL-C levels, suggesting a potential subtype-specific effect. Nonetheless, we strongly believe that the small sample size likely affects our estimates, warranting cautious interpretation of these results., Conclusion: Our findings challenge the hypothesis of a broad causal relationship between malaria (both severe and recurrent non-severe forms) and dyslipidemia. The isolated association with SMA highlights an intriguing area for future research. However, we believe that conducting larger studies to investigate the connection between malaria and dyslipidemia in Africa will enhance our ability to better address the burden posed by both diseases., (© 2024 The Authors. Annals of Human Genetics published by University College London (UCL) and John Wiley & Sons Ltd.)

Myeloid-derived suppressor cell (MDSC) levels are elevated in patients with cancer and contribute to reduced efficacy of immune checkpoint therapy. MDSC express Bruton's tyrosine kinase (BTK) and BTK inhibition with ibrutinib, an FDA-approved irreversible inhibitor of BTK, leads to reduced MDSC expansion/function in mice and significantly improves the antitumor activity of anti-PD-1 antibody treatments. Single-cell RNA sequencing (scRNA-seq) was used to characterize the effect of ibrutinib on gene expression of fluorescence-activated cell sorting-enriched MDSC from patients with different cancer types [breast, melanoma, head and neck squamous cell cancer (HNSCC)]. Melanoma patient MDSC were treated in vitro for 4 hours with 5 μmol/L ibrutinib or DMSO, processed for scRNA-seq using the Chromium 10× Genomics platform, and analyzed via the Seurat v4 standard integrative workflow. Baseline gene expression of MDSC from patients with breast, melanoma, and HNSCC cancer revealed similarities among the top expressed genes. In vitro ibrutinib treatment of MDSC from patients with melanoma resulted in significant changes in gene expression. GBP1, IL-1β, and CXCL8 were among the top downregulated genes whereas RGS2 and ABHD5 were among the top upregulated genes (P < 0.001). Double positive CD14+CD15+ MDSC and PMN-MDSC responded similarly to BTK inhibition and exhibited more pronounced gene changes compared with early MDSC and M-MDSC. Pathway analysis revealed significantly downregulated pathways including TREM1, nitric oxide signaling, and IL-6 signaling (P < 0.004)., Implications: scRNA-seq revealed characteristic gene expression patterns for MDSC from different patients with cancer and BTK inhibition led to the downregulation of multiple genes and pathways important to MDSC function and migration., (©2023 American Association for Cancer Research.)

For a Rydberg atom-based sensor to change its sensing frequency, the wavelength of the Rydberg state excitation laser must be altered. The wavelength shifts required can be on the order of 10 nm. A fast-tunable narrow-linewidth laser with broadband tuning capability is required. Here, we present a demonstration of a laser system that can rapidly switch a coupling laser as much as 8 nm in less than 50 μs. The laser system comprises a frequency-stabilized continuous wave laser and an electro-optic frequency comb. A filter enables selection of individual comb lines. A high-speed electro-optic modulator is used to tune the selected comb line to a specific frequency, i.e., an atomic transition. Through Rydberg atom-based sensing experiments, we demonstrate frequency hopping between two Rydberg states and a fast switching time of 400 μs, which we show can be reduced to ∼50 μs with a ping-pong scheme. If updating the RF frequency is not required during frequency hopping, a 200 ns switching time can be achieved. These results showcase the potential of the laser system for advanced Rydberg atom-based radio frequency sensing applications, like communications and radar.

Global health photography has historically been commissioned and, therefore, dominated by the gaze of Western photographers on assignments in the Global South. This is changing as part of international calls to decolonise global health and stimulate 'empowerment', spawning a growing initiative to hire local photographers. This article, based on interviews with global health photographers, reflects on this paradigm shift. It highlights how behind the laudable aim of 'empowerment' of local global health photography there is a simultaneous exploitation of precarious photographer labour and the emergence of 'glocal' photography elites. The paper argues that empowerment of local photographers can become a euphemism for reducing image production costs and maintaining control over the image content, while extending the scope of mainstream global health visual culture without challenging it. Finally, the article amplifies the growing concern that uncritical engagement with institutionalised empowerment becomes a warrant for the reproduction of local inequalities behind the fashionable façade of cooperation and care.

Purpose: Infusion-related hypersensitivity reactions with paclitaxel are common despite the use of dexamethasone and diphenhydramine premedications. Paclitaxel titration protocols that may reduce reactions are empirically derived from clinical observations, and there are no phase III trials that confirm superiority of any management recommendations. The purpose of this study was to compare the frequency and severity of hypersensitivity reactions associated with a recently initiated standardized paclitaxel titration protocol verses standard-of-care (SOC) infusion protocols., Materials and Methods: This was a retrospective review of hypersensitivity reactions in patients receiving paclitaxel infusions at five ambulatory infusion centers using a standardized titration protocol (February 2021 to April 2021) versus SOC paclitaxel (November 2018 to December 2019). Patients were age 18 years or older and presented for their first or second infusions. The primary study measure was the rate of hypersensitivity reactions. Secondary evaluations included the timing of the reaction after the start of the infusion, use of premedications, and severity of reactions., Results: A total of 451 patients were included in this study. Eighty-four (18.6%) patients were identified in the titration protocol group and 367 (81.4%) patients in the SOC group. Hypersensitivity reactions occurred in 4.8% of the titration group and 18.3% of the SOC group (odds ratio [OR], 0.224; 95% CI, 0.09 to 0.74; P = .002). Grade 3 or greater infusion reactions were 0% in the titration group versus 18% in the SOC group (OR, 0.28; P < .008). Reactions occurred later with the titration protocol, compared with the SOC paclitaxel infusion. Finally, no differences were observed in the use of appropriate premedications., Conclusion: A standardized paclitaxel titration protocol was associated with a significant reduction in the rate of infusion-related hypersensitivity reactions in patients receiving their first and second infusions. A prospective randomized trial is needed to validate these observations.

Atmospheric Solids Analysis Probe (ASAP) mass spectrometry is a versatile technique allowing direct sampling of solid and liquid samples, but its adoption is limited due to the high cost of commercial ASAP systems. To address this, we present OpenASAP, an open-source ASAP system for mass spectrometers that can be fabricated for $20 or less using 3D-printing. Our design is readily adaptable to instruments from different manufacturers and can be produced with a variety of additive manufacturing techniques on consumer-grade 3D-printers. The probe allows for rapid sampling of solid and liquid samples without sample preparation, making it useful for high throughput screening, investigating spatial localization and function of analytes in biological samples, and incorporating mass spectrometry in instructional settings. We demonstrate its effectiveness by obtaining mass spectra of three natural product standards at levels as low as 10 ng/ml in liquid samples, and detecting these metabolites in microbial cultures that are difficult to analyze due to complex sample matrices or analyte properties. Furthermore, we demonstrate direct sampling of thin layer chromatography (TLC) spots of these cultures., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Published by Elsevier Ltd.)

Introduction: Acute respiratory distress syndrome (ARDS) is a life-threatening condition commonly seen in the intensive care unit. COVID-19 has dramatically increased the incidence of ARDS-with this rise in cases comes the ability to detect predisposing factors perhaps not recognised before, such as metabolic syndrome (MetS) and its associated conditions (hypertension, obesity, dyslipidaemia and type 2 diabetes mellitus). In this systematic review, we seek to describe the complex relationship between MetS, its associated conditions and ARDS (including COVID-19 ARDS)., Methods and Analysis: A systematic search of PubMed, Embase, Cochrane Central Register of Controlled Trials, CINAHL and Web of Science will be conducted. The population of interest is adults with ARDS and MetS (as defined according to the study author recognising that MetS definitions vary) or any MetS-associated condition. The control group will be adult patients with ARDS without MetS or any individual MetS-associated condition. We will search studies published in English, with a date restriction from the year 2000 to June 2023 and employ the search phrases 'metabolic syndrome', 'acute respiratory distress syndrome' and related terms. Search terms including 'dyslipidaemia', 'hypertension', 'diabetes mellitus' and 'obesity' will also be utilised. Outcomes of interest will include mortality (in-hospital, ICU, 28-day, 60-day and 90-day), days requiring mechanical ventilation and hospital and/or ICU length of stay. Study bias will be assessed using the NIH Bias Scale., Ethics and Dissemination: Ethical approval is not required because this study includes previously published and publicly accessible data. Findings from this review will be disseminated via publication in a peer-reviewed journal., Prospero Registration Number: CRD42023405816., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: With the onset of the COVID-19 pandemic, a large urban academic hospital responded by creating the temporary role of a "Safety Officer (SO)." The key task of the SO role was to supervise staff donning and doffing personal protective equipment (PPE) and provide real-time feedback on their performance. The support for safe donning and doffing would contribute to staff well-being by reducing their fear of infection transmission., Methods: A Collaborative Change Leadership (CCL) approach was used to facilitate the development, implementation, and evaluation of the role. This included an iterative feedback process with clinicians and safety officers to continually refine the role., Findings: Feedback indicated value in the initiative as increasing staff confidence about preventing virus transmission, as well as their sense of safety at work. Areas for future improvement included additional communication strategies for interprofessional teams and external partners, as well as planning around logistics to better support the safety officers in performing this new, temporary role., Conclusions/application to Practice: The Safety Officer role was able to help alleviate concerns regarding potential infection transmission and contribute positively to staff well-being., Competing Interests: Conflict of InterestThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: To evaluate the associations between time-varying factors (mother's oral health, oral hygiene, smoking habits, diet, food insecurity and stress) socioeconomic factors (mother's employment, marital status, household income, insurance status, household size) and medical history on children's risk of developing a carious lesion in the first 3 years of life., Methods: Longitudinal data from the Center for Oral Health Research in Appalachia Cohort Two (COHRA2) were analysed. Pregnant women ≥18 years in the USA were recruited during pregnancy; all consenting women delivering at term and their babies had regular dental assessments and complete in-person surveys and telephone interviews regarding sociodemographic factors, medical and dental history, and oral health behaviours., Results: In a logistic regression model adjusting for covariates, children whose mother had two or more prior pregnancies, smoked cigarettes post-partum, or had a recent unfilled carious lesion were at least twice as likely to experience a dental lesion by the three-year visit. The magnitude of these associations varied by maternal education and state of residence., Conclusions: Untreated maternal decay but not maternal oral hygiene or diet were associated with cumulative risk of childhood caries by age three but were modified by maternal education and state of residence. Addressing structural and behavioural issues that reduce use of restorative dental care are needed to prevent the adverse impacts associated with early childhood caries., (© 2022 The Authors. Community Dentistry and Oral Epidemiology published by John Wiley & Sons Ltd.)

Most genome-wide association studies (GWAS) for lipid traits focus on the separate analysis of lipid traits. Moreover, there are limited GWASs evaluating the genetic variants associated with multiple lipid traits in African ancestry. To further identify and localize loci with pleiotropic effects on lipid traits, we conducted a genome-wide meta-analysis, multi-trait analysis of GWAS (MTAG), and multi-trait fine-mapping (flashfm) in 125,000 individuals of African ancestry. Our meta-analysis and MTAG identified four and 14 novel loci associated with lipid traits, respectively. flashfm yielded an 18% mean reduction in the 99% credible set size compared to single-trait fine-mapping with JAM. Moreover, we identified more genetic variants with a posterior probability of causality >0.9 with flashfm than with JAM. In conclusion, we identified additional novel loci associated with lipid traits, and flashfm reduced the 99% credible set size to identify causal genetic variants associated with multiple lipid traits in African ancestry., (© 2023. Springer Nature Limited.)

By age 5, approximately one-fifth of children have early childhood caries (ECC). Both the oral microbiome and host genetics are thought to influence susceptibility. Whether the oral microbiome modifies genetic susceptibility to ECC has not been tested. We test whether the salivary bacteriome modifies the association of a polygenic score (PGS, a score derived from genomic data that summarizes genetic susceptibility to disease) for primary tooth decay on ECC in the Center for Oral Health Research in Appalachia 2 longitudinal birth cohort. Children were genotyped using the Illumina Multi-Ethnic Genotyping Array and underwent annual dental examinations. We constructed a PGS for primary tooth decay using weights from an independent, genome-wide association meta-analysis. Using Poisson regression, we tested for associations between the PGS (high versus low) and ECC incidence, adjusting for demographic characteristics ( n = 783). An incidence-density sampled subset of the cohort ( n = 138) had salivary bacteriome data at 24 mo of age. We tested for effect modification of the PGS on ECC case status by salivary bacterial community state type (CST). By 60 mo, 20.69% of children had ECC. High PGS was not associated with an increased rate of ECC (incidence rate ratio, 1.09; 95% confidence interval [CI], 0.83-1.42). However, having a cariogenic salivary bacterial CST at 24 mo was associated with ECC (odds ratio [OR], 7.48; 95% CI, 3.06-18.26), which was robust to PGS adjustment. An interaction existed between the salivary bacterial CST and the PGS on the multiplicative scale ( P = 0.04). The PGS was associated with ECC (OR, 4.83; 95% CI, 1.29-18.17) only among individuals with a noncariogenic salivary bacterial CST ( n = 70). Genetic causes of caries may be harder to detect when not accounting for cariogenic oral microbiomes. As certain salivary bacterial CSTs increased ECC risk across genetic risk strata, preventing colonization of cariogenic microbiomes would be universally beneficial.

Background: The decision to initiate pediatric mechanical ventilation via tracheostomy ("home ventilation") is complex and parents often desire information from other parents who have faced this decision. However, parent-to-parent communication is challenging as it is difficult to connect new families to experienced families in ways that optimize informed, balanced decision-making., Objective: Create a parent-to-parent web-based tool to support decision-making about pediatric home ventilation., Patient Involvement: The tool was created based on interviews and feedback from parents., Methods: We interviewed parents who previously chose for, or against, home ventilation for their child. Interview themes and family comments guided website development. Viewer feedback was solicited via an embedded survey in the tool., Results: We created 6 composite character families to communicate 6 themes about home ventilation: 1) Considering treatment options, 2) Talking with medical team, 3) Impact on life at home, 4) Impact on relationships, 5) Experience for the child, and 6) If the child's life is short. Nine families who reviewed the draft tool felt it would have helped with their decision about home ventilation. Specifically, it supported families in thinking through what was "most important about their child's breathing problems" (7 of 9 parents) and feeling "more at peace with the decision" (8 of 9 parents). Between 6/1/20-12/31/22, nearly 5500 viewers have accessed the tool and 56 viewers completed the survey (including 13 families and 39 clinicians). Feedback from experienced families and clinicians reported the tool taught them something new., Discussion: This novel parent-to-parent tool shows promise for expanding access to balanced, family-centered information about pediatric home ventilation., Practical Value: The diverse stories and decisions let parents access multiple family perspectives. The tool's focus is on family-centric information that parents reported was usually missing from clinician counseling., Funding: This work was supported by the National Palliative Care Research Center., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Importance: Recently, several states have granted optometrists privileges to perform select laser procedures (laser peripheral iridotomy, selective laser trabeculoplasty, and YAG laser capsulotomy) with the aim of increasing access. However, whether these changes are associated with increased access to these procedures among each state's Medicare population has not been evaluated., Objective: To compare patient access to laser surgery eye care by estimated travel time and 30-minute proximity to an optometrist or ophthalmologist., Design, Setting, and Participants: This retrospective cohort database study used Medicare Part B claims data from 2016 through 2020 for patients accessing new patient or laser eye care (laser peripheral iridotomy, selective laser trabeculoplasty, YAG) from optometrists or ophthalmologists in Oklahoma, Kentucky, Louisiana, Arkansas, and Missouri. Analysis took place between December 2021 and March 2023., Main Outcome and Measures: Percentage of each state's Medicare population within a 30-minute travel time (isochrone) of an optometrist or ophthalmologist based on US census block group population and estimated travel time from patient to health care professional., Results: The analytic cohort consisted of 1 564 307 individual claims. Isochrones show that optometrists performing laser eye surgery cover a geographic area similar to that covered by ophthalmologists. Less than 5% of the population had only optometrists (no ophthalmologists) within a 30-minute drive in every state except for Oklahoma for YAG (301 470 [7.6%]) and selective laser trabeculoplasty (371 097 [9.4%]). Patients had a longer travel time to receive all laser procedures from optometrists than ophthalmologists in Kentucky: the shortest median (IQR) drive time for an optometrist-performed procedure was 49.0 (18.4-71.7) minutes for YAG, and the the longest median (IQR) drive time for an ophthalmologist-performed procedure was 22.8 (12.1-41.4) minutes, also for YAG. The median (IQR) driving time for YAG in Oklahoma was 26.6 (12.2-56.9) for optometrists vs 22.0 (11.2-40.8) minutes for ophthalmologists, and in Arkansas it was 90.0 (16.2-93.2) for optometrists vs 26.5 (11.8-51.6) minutes for ophthalmologists. In Louisiana, the longest median (IQR) travel time to receive laser procedures from optometrists was for YAG at 18.5 (7.6-32.6) minutes and the shortest drive to receive procedures from ophthalmologists was for YAG at 20.5 (11.7-39.7) minutes., Conclusions and Relevance: Although this study did not assess impact on quality of care, expansion of laser eye surgery privileges to optometrists was not found to lead to shorter travel times to receive care or to a meaningful increase in the percentage of the population with nearby health care professionals.

This study aimed to determine the associations between acculturation, dental anxiety, and dental utilization among Hispanics/Latinos living in the US. A proxy measure of dental anxiety was available for 7539 adults who had not visited a dentist within the last year. All completed the Short Acculturation Scale for Hispanics (SASH). Bivariate logistic regression and adjusted multivariable logistic regression analysis were conducted. Approximately 22% of the sample was dentally anxious. Dental anxiety was significantly associated with SASH language scale score (OR 1.09, 95%CI 1.02, 1.18, p = 0.04), years in US (OR 1.53, 95%CI 1.23, 1.91, p < 0.0001), and preferred Spanish language (OR 1.30, 95%CI 1.05, 1.63, p = 0.0192); lower acculturation corresponded to higher dental anxiety. Adjusting for sex, age, education, income, insurance, and oral health status, level of acculturation was associated with dental anxiety (AOR 0.87, 95%CI 0.75, 0.91, p = 0.009), but neither were associated with utilization. Acculturation may be an important predictor of dental anxiety for Hispanics/Latinos living in the US., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Altered hematopoietic stem cell (HSC) fate underlies primary blood disorders but microenvironmental factors controlling this are poorly understood. Genetically barcoded genome editing of synthetic target arrays for lineage tracing (GESTALT) zebrafish were used to screen for factors expressed by the sinusoidal vascular niche that alter the phylogenetic distribution of the HSC pool under native conditions. Dysregulated expression of protein kinase C delta (PKC-δ, encoded by prkcda) increases the number of HSC clones by up to 80% and expands polyclonal populations of immature neutrophil and erythroid precursors. PKC agonists such as cxcl8 augment HSC competition for residency within the niche and expand defined niche populations. CXCL8 induces association of PKC-δ with the focal adhesion complex, activating extracellular signal-regulated kinase (ERK) signaling and expression of niche factors in human endothelial cells. Our findings demonstrate the existence of reserve capacity within the niche that is controlled by CXCL8 and PKC and has significant impact on HSC phylogenetic and phenotypic fate., Competing Interests: Declaration of interests L.I.Z. is a founder and stockholder of Fate Therapeutics, CAMP4 Therapeutics, Amagma Therapeutics, Scholar Rock, and Branch Biosciences. He is a consultant for Celularity and Cellarity., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The metabolite acetyl-CoA is necessary for both lipid synthesis in the cytosol and histone acetylation in the nucleus. The two canonical precursors to acetyl-CoA in the nuclear-cytoplasmic compartment are citrate and acetate, which are processed to acetyl-CoA by ATP-citrate lyase (ACLY) and acyl-CoA synthetase short-chain 2 (ACSS2), respectively. It is unclear whether other substantial routes to nuclear-cytosolic acetyl-CoA exist. To investigate this, we generated cancer cell lines lacking both ACLY and ACSS2 [double knockout (DKO) cells]. Using stable isotope tracing, we show that both glucose and fatty acids contribute to acetyl-CoA pools and histone acetylation in DKO cells and that acetylcarnitine shuttling can transfer two-carbon units from mitochondria to cytosol. Further, in the absence of ACLY, glucose can feed fatty acid synthesis in a carnitine responsive and carnitine acetyltransferase (CrAT)-dependent manner. The data define acetylcarnitine as an ACLY- and ACSS2-independent precursor to nuclear-cytosolic acetyl-CoA that can support acetylation, fatty acid synthesis, and cell growth.

Richter's Transformation (RT) is a poorly understood and fatal progression of chronic lymphocytic leukemia (CLL) manifesting histologically as diffuse large B-cell lymphoma. Protein arginine methyltransferase 5 (PRMT5) is implicated in lymphomagenesis, but its role in CLL or RT progression is unknown. We demonstrate herein that tumors uniformly overexpress PRMT5 in patients with progression to RT. Furthermore, mice with B-specific overexpression of hPRMT5 develop a B-lymphoid expansion with increased risk of death, and Eµ-PRMT5/TCL1 double transgenic mice develop a highly aggressive disease with transformation that histologically resembles RT; where large-scale transcriptional profiling identifies oncogenic pathways mediating PRMT5-driven disease progression. Lastly, we report the development of a SAM-competitive PRMT5 inhibitor, PRT382, with exclusive selectivity and optimal in vitro and in vivo activity compared to available PRMT5 inhibitors. Taken together, the discovery that PRMT5 drives oncogenic pathways promoting RT provides a compelling rationale for clinical investigation of PRMT5 inhibitors such as PRT382 in aggressive CLL/RT cases., (© 2023. The Author(s).)

Despite a significant reduction in the burden of malaria in children under five years-old, the efficient implementation of seasonal malaria chemoprevention (SMC) at large scale remains a major concern in areas with long malaria transmission. Low coverage rate in the unattainable areas during the rainy season, a shift in the risk of malaria to older children and the rebound in malaria incidence after stopping drug administration are mainly reported in these areas. These gaps represent a major challenge in the efficient implementation of SMC measures. An open randomized study was conducted to assess the effect of a fifth additional round to current regime of SMC in older children living in Dangassa, a rural malaria endemic area. Poisson regression Model was used to estimate the reduction in malaria incidence in the intervention group compared to the control group including age groups (5-9 and 10-14 years) and the use of long-lasting insecticidal nets (LLINs; Yes or No) with a threshold at 5%. Overall, a downward trend in participation rate was observed from August (94.3%) to November (87.2%). In November (round 4), the risk of malaria incidence was similar in both groups (IRR = 0.66, 95%CI [0.35-1.22]). In December (round 5), a decrease of 51% in malaria incidence was observed in intervention group compared to control group adjusted for age groups and the use of LLINs (IRR = 0.49, 95%CI [0.26-0.94]), of which 17% of reduction is attributable to the 5th round in the intervention group. An additional fifth round of SMC resulted in a significant reduction of malaria incidence in the intervention group. The number of SMC rounds could be adapted to the local condition of malaria transmission., Competing Interests: We declare any competing interests here. All authors read and approved the version submitted., (© 2023 The Authors.)

There is growing interest in therapeutic intervention that targets disease-relevant RNAs using small molecules. While there have been some successes in RNA-targeted small-molecule discovery, a deeper understanding of structure-activity relationships in pursuing these targets has remained elusive. One of the best-studied tertiary-structured RNAs is the theophylline aptamer, which binds theophylline with high affinity and selectivity. Although not a drug target, this aptamer has had many applications, especially pertaining to genetic control circuits. Heretofore, no compound has been shown to bind the theophylline aptamer with greater affinity than theophylline itself. However, by carrying out a high-throughput screen of low-molecular-weight compounds, several unique hits were identified that are chemically distinct from theophylline and bind with up to 340-fold greater affinity. Multiple atomic-resolution X-ray crystal structures were determined to investigate the binding mode of theophylline and four of the best hits. These structures reveal both the rigidity of the theophylline aptamer binding pocket and the opportunity for other ligands to bind more tightly in this pocket by forming additional hydrogen-bonding interactions. These results give encouragement that the same approaches to drug discovery that have been applied so successfully to proteins can also be applied to RNAs.

Membrane pressure monitoring during extracorporeal membrane oxygenation (ECMO) is integral to monitoring circuit health. We compared a disposable vascular pressure device (DVPD) to the transducer pressure bag arterial line (TPBAL) monitoring system to determine whether the DVPD can reliably and accurately monitor membrane pressures during venovenous extracorporeal membrane oxygenation (VV ECMO). We analyzed existing quality assurance data collected at a single center as part of routine circuit performance monitoring and process improvement on a convenience sample of four VV ECMO circuits. We placed and zeroed a DVPD in line with the pre- and postmembrane TPBAL setups in coordination with a standard transducer setup. We recorded DVPD and TPBAL pressure measurements every 4 hours for 2.5 days on the four separate VV ECMO circuits. We compared the standard and DVPD pressures using Bland-Altman plots and methods that accounted for repeated measures in the same subject. We recorded 58 pre/postmembrane pressures. Mean membrane pressure values were similar in the DVPD (pre: 208 mmHg [SD, 50.8]; post: 175 mmHg [46.3]) compared to the standard TPBAL setup (pre: 205 mmHg [52.0]; post: 177 mmHg [46.3]). Using Bland-Altman methods, premembrane pressures were found to be 2.2 mmHg higher (95% confidence interval [CI]: -5.3 to 9.7) in the standard TPBAL setup compared to DVPD and 1.8 mmHg higher (95% CI: -5.3 to 8.9) than the postmembrane pressures. The DVPD provided an accurate measurement of circuit pressure as compared to the TPBAL setup. Across the range of pre- and postmembrane pressures, both methods reliably agreed. Future trials should investigate DVPD accuracy in different environments such as prehospital field cannulation or critical care transport of ECMO patients., Competing Interests: Disclosures: The authors have no conflicts of interest to report., (Copyright © ASAIO 2022.)

Dental care-related fear and anxiety (DFA) is prevalent, affects oral health care utilization, and is related to poor oral health and decreased quality of life. In addition to learned and cultural factors, genetics is hypothesized to contribute to DFA. Therefore, we performed a genome-wide association study to identify genetic variants contributing to DFA. Adult and adolescent participants were from 4 cohorts (3 from the US-based Center for Oral Health Research in Appalachia, n = 1,144, 1,164, and 535, and the UK-based Avon Longitudinal Study of Parents and Children [ALSPAC], n = 2,078). Two self-report instruments were used to assess DFA: the Dental Fear Survey (US cohorts) and Corah's Dental Anxiety Scale (ALSPAC). Genome-wide scans were performed for the DFA total scores and subscale scores (avoidance, physiological arousal, fear of dental treatment-specific stimuli), adjusting for age, sex, educational attainment, recruitment site, and genetic ancestry. Results across cohorts were combined using meta-analysis. Heritability estimates for DFA total and subscale scores were similar across cohorts and ranged from 23% to 59%. The meta-analysis revealed 3 significant ( P < 5E-8) associations between genetic loci and 2 DFA subscales: physiological arousal and avoidance. Nearby genes included NTSR1 ( P = 3.05E-8), DMRTA1 ( P = 4.40E-8), and FAM84A ( P = 7.72E-9). Of these, NTSR1 , which was associated with the avoidance subscale, mediates neurotensin function, and its deficiency may lead to altered fear memory in mice. Gene enrichment analyses indicated that loci associated with the DFA total score and physiological arousal subscale score were enriched for genes associated with severe and persistent mental health (e.g., schizophrenia) and neurocognitive (e.g., autism) disorders. Heritability analysis indicated that DFA is partly explained by genetic factors, and our association results suggested shared genetic underpinnings with other psychological conditions.

Dairy cattle are subjected to oxidative stress, inflammation, and altered immune function during the transition to lactation. The objective of this study was to evaluate the effects of a dietary Saccharomyces cerevisiae fermentation product (SCFP; NutriTek, Diamond V) on oxidative status, inflammation, and innate and adaptive immune responses during the transition period. Holstein cows were blocked by parity, expected calving date, and previous milk yield and then randomly assigned to treatment within block. Treatment was a control total mixed ration (n = 30) or SCFP total mixed ration (n = 34) fed from -29 ± 5 to 42 d relative to calving (RTC). Blood was sampled during wk -4, -2, 1, 2, and 5 and liver tissue at wk -3 and 2 RTC. Oxidative status was evaluated in plasma by retinol, α-tocopherol, and malondialdehyde concentrations, glutathione peroxidase activity, and Trolox equivalent antioxidant capacity, and in liver by mRNA abundance of nuclear factor E2-related factor 2 (NFE2L2), metallothionein 1E (MT1E), and glutathione peroxidase 3 (GPX3). Inflammation was evaluated in plasma by haptoglobin (HP) and serum amyloid A (SAA) concentrations and in liver by mRNA abundance of HP, serum amyloid A3 (SAA3), and nuclear factor kappa-light-chain-enhancer of activated B cells (NFKB1). Innate immune response was measured by stimulated oxidative burst of polymorphonuclear cells (neutrophils) isolated from blood. Ovalbumin (OVA) was administered with adjuvant on d 7 and 21 RTC, and adaptive immune response was evaluated by serum anti-OVA IgG content on d 28 and 35. Mixed models were used to assess effects of treatment, time, parity, and all interactions. We previously reported that SCFP had limited effects on productivity in this cohort, although milk fat yield was transiently increased and subclinical ketosis incidence was increased. Supplementation with SCFP did not affect overall oxidative, inflammatory, or immune parameters. The only treatment × week interaction detected was for plasma α-tocopherol concentration, which tended to be greater in control cows during wk 2 RTC. A tendency for a treatment × parity interaction was detected for serum anti-OVA IgG titer, which tended to be greater for SCFP than for controls among primiparous cows. Plasma inflammatory biomarkers were not affected by SCFP but, unexpectedly, plasma HP was elevated at both prepartum time points and plasma SAA was elevated during wk -2 RTC compared with the expected increases in both biomarkers postpartum. In this cohort of transition cows with low disease incidence, SCFP generally did not affect oxidative, inflammatory, or immune parameters., (The Authors. Published by Elsevier Inc. and Fass Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Genetic risk factors play important roles in the etiology of oral, dental, and craniofacial diseases. Identifying the relevant risk loci and understanding their molecular biology could highlight new prevention and management avenues. Our current understanding of oral health genomics suggests that dental caries and periodontitis are polygenic diseases, and very large sample sizes and informative phenotypic measures are required to discover signals and adequately map associations across the human genome. In this article, we introduce the second wave of the Gene-Lifestyle Interactions and Dental Endpoints consortium (GLIDE2) and discuss relevant data analytics challenges, opportunities, and applications. In this phase, the consortium comprises a diverse, multiethnic sample of over 700,000 participants from 21 studies contributing clinical data on dental caries experience and periodontitis. We outline the methodological challenges of combining data from heterogeneous populations, as well as the data reduction problem in resolving detailed clinical examination records into tractable phenotypes, and describe a strategy that addresses this. Specifically, we propose a 3-tiered phenotyping approach aimed at leveraging both the large sample size in the consortium and the detailed clinical information available in some studies, wherein binary, severity-encompassing, and "precision," data-driven clinical traits are employed. As an illustration of the use of data-driven traits across multiple cohorts, we present an application of dental caries experience data harmonization in 8 participating studies ( N = 55,143) using previously developed permanent dentition tooth surface-level dental caries pattern traits. We demonstrate that these clinical patterns are transferable across multiple cohorts, have similar relative contributions within each study, and thus are prime targets for genetic interrogation in the expanded and diverse multiethnic sample of GLIDE2. We anticipate that results from GLIDE2 will decisively advance the knowledge base of mechanisms at play in oral, dental, and craniofacial health and disease and further catalyze international collaboration and data and resource sharing in genomics research.

Purpose: Reactive balance is a critical consideration for mobility and fall avoidance, but is under-assessed among physiotherapists. The objective of this study was to explore factors influencing physiotherapist perceptions about measuring reactive balance upon completion of a 12-month theory-based, multi-component intervention to increase use of a measure of reactive balance. Methods: A qualitative descriptive approach was used. Semi-structured interviews were conducted with 28 physiotherapists treating adults with balance impairment in three urban Canadian rehabilitation hospitals that participated in the intervention. Interviews explored perceptions of reactive balance measurement and perceived changes in clinical behavior. Thematic analysis involved multiple rounds of coding, review and discussion, theme generation, and interpretation of findings through individual analysis and team meetings. Findings: Participants expressed contrasting views about integrating reactive balance measurement in their practice, despite consistent acknowledgement of the importance of reactive balance for function. Three themes were identified highlighting factors that mediated perceptions about measuring reactive balance: patient characteristics; trust between physiotherapist and patient; and the role of physiotherapist fear. Conclusions: The findings highlight that decision making for measuring reactive balance in rehabilitation settings is complex. There is a need for additional work to facilitate long-term implementation of clinical reactive balance measurement, such as refining patient criteria for administration, ensuring sufficient time to establish a trusting relationship, and developing and testing strategies to address physiotherapist fear.IMPLICATIONS FOR REHABILITATIONReactive balance is important for falls prevention and mobility, but is under-assessed among physiotherapists.This study identified three factors that influenced uptake of reactive balance measurement among physiotherapists in rehabilitation settings: patient characteristics; trust between physiotherapist and patient; and the role of physiotherapist fear.Knowledge of the identified factors may assist with design and use of reactive and other balance measurements.Strategies aimed at developing trusting relationships between physiotherapist and patient along with addressing physiotherapist fear could facilitate the uptake of clinical reactive balance measurement.

There is limited data on the use of caplacizumab beyond the initial treatment course. We describe a patient case demonstrating the efficacy of a second course of caplacizumab in a patient with relapsed acquired thrombotic thrombocytopenic purpura (TTP). A 25-year-old female was treated for an initial event of TTP with steroids, plasma exchange, rituximab, and caplacizumab. Caplacizumab was continued 30 days post plasma exchange, which was on day 46 of treatment, at which time platelets had improved to 292 x 10 9 /L. Two weeks after completion of the first caplacizumab course, on day 60, she was readmitted with platelets of 5 x 10 9 /L. Daily plasma exchange and steroids were started on admission, with rituximab added on day 65. On day 67, the decision was made to re-initiate caplacizumab due to a platelet count of 21 x 10 9 /L. By day 72, platelets improved to 273 x 10 9 /L and the patient was able to be discharged and completed her second 30-day post plasma exchange course of caplacizumab without complications or further relapses.

Background: Best evidence suggests incorporating task-specific training, aerobics, and strengthening to improve mobility and gait in persons with stroke (PWS). Related research suggests incorporating cognitive problem-solving strategy training may lead to better skill maintenance and transfer. The present study examined the feasibility and preliminary outcomes of an evidence-based cognitive augmented mobility program (CAMP) for PWS., Methods: A single-arm pre-post and follow-up design was conducted, in two blocks (NCT03683160). Participants completed an exercise intervention with an integrated cognitive strategy component and had weekly 1:1 sessions with a physiotherapist trained in Cognitive Orientation to daily Occupational Performance (CO-OP), focusing on goal practice and cognitive strategy use. CAMP consisted of a pre-intervention education and goal-setting session and 16 90-minute sessions held in a group format, 2x/wk for 8 weeks. Assessments were conducted 1 week prior to beginning the intervention, 1 week post-intervention, and at a 4-5 week follow-up., Results: CAMP was found to be feasible with 96% session attendance and strong participant satisfaction. Pre to post-CAMP intervention, a large effect was found for endurance (r = 0.53), balance (r = 0.59), mobility (r = 0.63) and goal attainment (r = 0.63) indicators, and large effects were maintained at follow-up for balance, mobility, and goal attainment. A medium effect was found for functional independence (r = 0.38), gait speed (r = 0.39), and balance confidence (r = 0.38). A small effect was found for participation (r = 0.27) and overall stroke recovery (r = 0.25)., Conclusions: Preliminary results suggest CAMP is feasible; there may be a beneficial effect of combining best evidence for mobility and fitness with cognitive strategy training. The positive results for skill maintenance and transfer suggest further investigation is warranted.

FraR, a transcriptional repressor, was postulated to regulate the metabolism of the Amadori compound fructose-asparagine (F-Asn) in the foodborne pathogen Salmonella enterica. Here, the DNA- and inducer-binding affinities and stoichiometries of FraR were determined and cross-validated by electrophoretic mobility-shift assays (EMSAs) and online buffer exchange coupled to native mass spectrometry (OBE-nMS). We demonstrate the utility of OBE-nMS to characterize protein and protein-DNA complexes that are not amenable to offline exchange into volatile buffers. OBE-nMS complemented EMSAs by revealing that FraR binds to the operator DNA as a dimer and by establishing 6-phosphofructose-aspartate as the inducer that weakens DNA binding by FraR. These results provide insights into how FraR regulates the expression of F-Asn-catabolizing enzymes and add to our understanding of the intricate bacterial circuitry that dictates utilization of diverse nutrients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Malnutrition in children is one of the most prevalent global health challenges, and malnourished children have a higher risk of death from childhood diseases. Early childhood caries (ECC) is the most common chronic disease of childhood. Complications from ECC such as pain, loss of tooth/teeth, and infection can undermine a child's nutrition and growth., Aim: This study aims to evaluate the severity of decay, missing, and filled tooth (dmft) by nutritional status using the z scores of the anthropometric measurements: height for age (HFA), weight for age (WFA), weight for height (WFH), and body mass index for age (BMIA) among children with ECC in Nigeria., Study Design: This is a cross-sectional study conducted in 5 local government areas (LGAs) in Lagos State, Nigeria. A multistage sampling technique was used., Results: A total of 273 cases of ECC were included in the analyses (mean age 4.19 ± 0.96 y). Overall, the mean dmft was 3.04 ± 2.28, and most (96%) were accounted for by untreated decay. The distribution of dmft within the different z score categories of BMIA (<-3 = severely wasted, -2 to -3 = wasted, -2 to +2 = normal, +2 to +3 = overweight and >+3 = obese) showed the highest dmft scores among the combined severely wasted and wasted groups, lowest among children with normal z scores, and intermediate in the overweight and obese groups. There was a significant negative correlation between BMIA z score, WFH z score, and dmft ( r = -0.181, P < 0.05 and r = -0.143, P < 0.05, respectively). However, the correlations between HFA z score, WFA z score, and dmft were positive but not significant ( r = 0.048, P = 0.44 and r = 0.022, P = 0.77, respectively)., Conclusion: Our study showed an increased severity of dental caries among severely wasted or wasted children with ECC compared to those of normal or overweight., Knowledge Transfer Statement: The results from this study will raise awareness among clinicians and policy makers on the need for a primary prevention program for early childhood caries in countries with high burden of malnutrition and limited resources. Also, it will help draw the attention of clinicians to the caries status of malnourished children that can be managed to improve the nutritional outcomes.

Aims: Bipolar type I disorder (BD) is characterized by severe mood swings and occurs in about 1% of the population. The mechanisms underlying the disorder remain unknown. Prior studies have suggested abnormalities in brain metabolism using 1 H and 31 P magnetic resonance spectroscopy (MRS). Supporting altered metabolism, in previous studies we found T1ρ relaxation times in the cerebellum were elevated in participants with BD. In addition, T1ρ relaxation times in the basal ganglia were lower in participants with BD experiencing depressed mood. Based on these findings, this study sought to probe brain metabolism with a focus of extending these assessments to the cerebellum., Methods: This study collected data from 64 participants with Bipolar type I disorder (BD) and 42 controls. Subjects were scanned at both 3T (anatomical, functional, and T1ρ imaging data) and 7T ( 31 P and 1 H spectroscopy). Regions of interest defined by the 1H MRS data were used to explore metabolic and functional changes in the cerebellar vermis and putamen., Results: Elevated concentrations of n-Acetyl-l-aspartate (NAA), glutamate, glutathione, taurine, and creatine were found in the cerebellar vermis along with decreased intra-cellular pH. Similar trends were observed in the right putamen for glutamate, creatine, and pH. We also observed a relationship between T1ρ relaxation times and mood in the putamen. We did not observe a significant effect of medications on these measures., Limitations: The study was cross sectional in design and employed a naturalistic approach for assessing the impact of medications on the results., Conclusion: This study supports prior findings of reduced pH in mitochondrial dysfunction in BD while also showing that these differences extend to the cerebellum., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Setting nutritional standards for larval zebrafish ( Danio rerio ) that maximize growth, survival, and reproductive success is challenging. We evaluated the effects of different feeding regimens on larval zebrafish by comparing Gemma Micro 75 pelleted diet and live-type L rotifers ( Brachionus plicatilis ) in 3 feeding regimens starting at 9 days postfertilization (dpf): bolus feeding of live diet (BL), continuous feeding of live diet (CL), and pelleted diet (PD). Animals in the PD and CL groups were longer than the BL group at 4-5 weeks postfertilization. The PD group was also greater in body depth than both live diet groups. There was no significant difference in weight between the groups. There were also no significant differences in fecundity or sex ratios indicating that all feeding methods successfully promote growth of a useful breeding stock of fish. In addition, we quantified the equipment, consumable, and labor costs associated with these methods, and found that the PD regimen was superior to both live diet regimens. These data suggest that providing a high nutrient-density pelleted diet to larval and juvenile zebrafish is an effective means to increase early growth and to decrease cost and labor associated with nursery care.

The selective inhibition of RET kinase as a treatment for relevant cancer types including lung adenocarcinoma has garnered considerable interest in recent years and prompted a variety of efforts toward the discovery of small-molecule therapeutics. Hits uncovered via the analysis of archival kinase data ultimately led to the identification of a promising pyrrolo[2,3- d ]pyrimidine scaffold. The optimization of this pyrrolo[2,3- d ]pyrimidine core resulted in compound 1 , which demonstrated potent in vitro RET kinase inhibition and robust in vivo efficacy in RET-driven tumor xenografts upon multiday dosing in mice. The administration of 1 was well-tolerated at established efficacious doses (10 and 30 mg/kg, po, qd), and plasma exposure levels indicated a minimal risk of KDR or hERG inhibition in vivo , as evaluated by Miles assay and free plasma concentrations, respectively., Competing Interests: The authors declare no competing financial interest., (© 2021 American Chemical Society.)

Purpose: Chemical shift-encoded magnetic resonance imaging enables accurate quantification of liver fat content though estimation of proton density fat-fraction (PDFF). Computed tomography (CT) is capable of quantifying fat, based on decreased attenuation with increased fat concentration. Current quantitative fat phantoms do not accurately mimic the CT number of human liver. The purpose of this work was to develop and validate an optimized phantom that simultaneously mimics the MRI and CT signals of fatty liver., Methods: An agar-based phantom containing 12 vials doped with iodinated contrast, and with a granular range of fat fractions was designed and constructed within a novel CT and MR compatible spherical housing design. A four-site, three-vendor validation study was performed. MRI (1.5T and 3T) and CT images were obtained using each vendor's PDFF and CT reconstruction, respectively. An ROI centered in each vial was placed to measure MRI-PDFF (%) and CT number (HU). Mixed-effects model, linear regression, and Bland-Altman analysis were used for statistical analysis., Results: MRI-PDFF agreed closely with nominal PDFF values across both field strengths and all MRI vendors. A linear relationship (slope = -0.54 ± 0.01%/HU, intercept = 37.15 ± 0.03%) with an R 2 of 0.999 was observed between MRI-PDFF and CT number, replicating established in vivo signal behavior. Excellent test-retest repeatability across vendors (MRI: mean = -0.04%, 95% limits of agreement = [-0.24%, 0.16%]; CT: mean = 0.16 HU, 95% limits of agreement = [-0.15HU, 0.47HU]) and good reproducibility using GE scanners (MRI: mean = -0.21%, 95% limits of agreement = [-1.47%, 1.06%]; CT: mean = -0.18HU, 95% limits of agreement = [-1.96HU, 1.6HU]) were demonstrated., Conclusions: The proposed fat phantom successfully mimicked quantitative liver signal for both MRI and CT. The proposed fat phantom in this study may facilitate broader application and harmonization of liver fat quantification techniques using MRI and CT across institutions, vendors and imaging platforms., (© 2021 American Association of Physicists in Medicine.)

Purpose: Identifying at-risk infants for retinopathy of prematurity (ROP) is complex in countries with emerging economies as infants that lack conventional risk factors, such as low birth weight (BW) and young gestational age (GA), still go on to develop severe ROP. Potential biomarkers, like serum insulin-like growth factor 1 (IGF-1) and slow postnatal weight gain, have been identified as good predictors for ROP in developed countries. We sought to determine the relationship between IGF-1 levels and ROP in two Latin American countries where the burden of disease is still significant., Methods: Prospective cohort study of infants in Guadalajara, Mexico and La Plata, Argentina. Filter-paper bloodspot IGF-1 assays were performed weekly from birth until hospital discharge or 40 weeks' postmenstrual age (PMA)., Results: 112 infants were studied with a median BW of 1412 g (range 620 g-2390 g) and a median GA of 33 weeks (range 25-37). There was no significant difference in IGF-1 between infants who developed ROP and those who did not., Conclusion: Low IGF-1 was not associated with ROP in these infants. The lack of an association between ROP and IGF-1 in Latin America supports the observation that growth-based predictive models do not perform as well in this setting where more mature babies still develop severe ROP.

Background: Sleep problems are common among chronic pain patients who take opioids. There are documented effects of opioids on sleep architecture; however, the long-term effects of opioids on sleep remain unknown. This study examined whether opioid-naïve participants have better sleep quality than current and previous chronic users of opioids. We also explored whether sleep differed between methadone and buprenorphine users, and whether amount of time since abstaining from opioids was associated with sleep quality., Method: Participants were 120 people with chronic pain (84.2% Caucasian, M age  = 42.0 years, SD = 11.44). They were in one of four groups of 30 participants each: (1) current users of methadone for opioid use disorder (OUD); (2) current users of buprenorphine for OUD; (3) a history of medication-assisted therapy for OUD but currently opioid-abstinent for at least 6 months; (4) those who have less than one month of cumulative lifetime opioids (opioid-naïve group). Only participants in group 1 and group 2 were taking opioids during the time of the study. Participants completed the Pittsburgh Sleep Quality Index and the SF-36., Results: A MANCOVA revealed that all three groups with current or previous opioid use (i.e., groups 1-3) differed significantly from the opioid-naïve group (group 4) on sleep quality, sleep duration, sleep disturbances, and daytime dysfunction after controlling for sleep medications (all p < .05). For group 1 (methadone users), 2 (buprenorphine users), and 3 (prolonged abstinence), there were no statistically significant differences between each group. There was also a significant relationship between opioid-abstinent weeks and sleep disturbances in the opioid-abstinent group (r = - 0.604, p < .001)., Discussion: The results of this study suggest that opioids interfere with sleep quality, even after months of abstention. Further research into the long-term effects of opioids is warranted and may contribute further to the importance of addressing sleep problems in this population.