Comparative Analysis of Circulating Metabolomic Profiles Identifies Shared Metabolic Alterations Across Distinct Multi-Stressor Military Training Operations.

Military training provides insight into metabolic responses under unique physiological demands that can be comprehensively characterized by global metabolomic profiling to identify potential strategies for improving performance. This study identified shared changes in metabolomic profiles across three distinct military training exercises varying in magnitude and types of stress. Blood samples collected before and after three real or simulated military training exercises were analyzed using the same untargeted metabolomic profiling platform. Exercises included a three-week survival school course (ST, n=36), a four-day arctic cross country ski march (AT, n=24), and a 28-day controlled diet- and exercise-induced energy deficit (CED, n=26). Log2-fold changes of >±1 in 191, 121 and 64 metabolites were identified in the ST, AT and CED datasets, respectively. Most metabolite changes were within lipid (57-63%) and amino acid metabolism (18-19%) pathways, and changes in 87 were shared across studies. The largest and most consistent increases in shared metabolites were found in acylcarnitine, fatty acid, ketone, and glutathione metabolism pathways, whereas the largest decreases were in diacylglycerol and urea cycle metabolism pathways. Multiple shared metabolites were consistently correlated with biomarkers of inflammation, tissue damage, and anabolic hormones across studies. These three studies of real and simulated military training revealed overlapping alterations in metabolomic profiles despite differences in environment and the stressors involved. Consistent changes in metabolites related to lipid metabolism, ketogenesis and oxidative stress suggest a potential common metabolomic signature associated with inflammation, tissue damage and suppression of anabolic signaling that may characterize unique physiological demands of military training.

Longitudinal changes in adverse effects reporting in multiple dietary supplement classifications: The US military dietary supplement use study.

Over 70% of United States military service members (SMs) regularly use dietary supplements (DSs) and about 18% have reported adverse effects (AEs) associated with use. This investigation examined longitudinal changes in AEs reporting among DS users. On two separate occasions 1.3 ± 0.2 years apart (mean ± standard deviation), 5778 SMs completed identical questionnaires on DS use and associated AEs. Among SMs reporting DS use ≥1 time/week, ≥1 AE was reported by 19% and 15% in the baseline and follow-up phases, respectively. The risk of reporting DS use at follow-up was similar among those reporting and not reporting AEs at baseline for most DS categories including prohormones, proteins/amino acids, individual vitamins and minerals, multivitamin/multiminerals, herbals, fish oils, joint health products, and other DSs. An exception was combination products where those reporting AEs at baseline had an increased risk of use at follow-up (risk ratio = 1.13, 95% confidence interval = 1.06-1.09). Those reporting AEs at baseline and continuing DS use in the follow-up were more likely to report AEs at follow-up compared to those not reporting baseline AEs. In conclusion, AEs reported at baseline did not deter many participants from using DSs in the follow-up period, and many SMs reporting AEs at baseline continued reporting them at follow-up.

Understanding therapeutic radiographers' confidence in assessing, managing & teaching radiation induced skin reactions (RISR): A national survey in the UK.

INTRODUCTION: The standard toxicity tools adopted for assessing Radiation Induced Skin Reactions (RISR) do not currently reflect how skin changes occur across all skin tones. A one size fits all approach is adopted currently for RISR assessment. The aim of this study was to understand what evidence-based practice and RISR tools are being used across the therapeutic radiography workforce and the levels of confidence in using these tools. METHODS: A survey using Likert scales to assess confidence in RISR assessment and management was made available to 77 departments in the UK between August-November 2021. Descriptive statistics were used to understand respondents' confidence in assessing, managing, and teaching RISR between white, brown, and black skin tones; Fisher's exact test was used to assess the significance of differences between groups. RESULTS: Complete responses were received from 406 therapeutic radiographers. Radiation Therapy Oncology Group (RTOG) was the most used RISR assessment tool (58% of respondents n = 237). Most respondents (74.2% n = 303) reported use of locally produced patient information on skin care, rather than the Society and College of Radiographers evidence-based patient leaflets. Confidence in assessing and managing RISR in white skin was higher than that in brown and black skin. Similarly, confidence was higher in teaching of appropriate RISR assessment and management in white skin tones when compared to brown and black skin. CONCLUSION: White skin tones appear to be more confidently assessed and managed for RISR along with taught appropriate assessment and management, than brown and black skin tones in the sample of the workforce that responded. IMPLICATIONS FOR PRACTICE: A greater understanding of the reasons for these differences is required but this study aims to instigate change and positive growth within this area.

Complete Genomic Assembly of Mauritian Cynomolgus Macaque Killer Ig-like Receptor and Natural Killer Group 2 Haplotypes.

Mauritian-origin cynomolgus macaques (MCMs) serve as a powerful nonhuman primate model in biomedical research due to their unique genetic homogeneity, which simplifies experimental designs. Despite their extensive use, a comprehensive understanding of crucial immune-regulating gene families, particularly killer Ig-like receptors (KIR) and NK group 2 (NKG2), has been hindered by the lack of detailed genomic reference assemblies. In this study, we employ advanced long-read sequencing techniques to completely assemble eight KIR and seven NKG2 genomic haplotypes, providing an extensive insight into the structural and allelic diversity of these immunoregulatory gene clusters. Leveraging these genomic resources, we prototype a strategy for genotyping KIR and NKG2 using short-read, whole-exome capture data, illustrating the potential for cost-effective multilocus genotyping at colony scale. These results mark a significant enhancement for biomedical research in MCMs and underscore the feasibility of broad-scale genetic investigations.

The CARD8 inflammasome dictates HIV/SIV pathogenesis and disease progression.

While CD4+ T cell depletion is key to disease progression in people living with HIV and SIV-infected macaques, the mechanisms underlying this depletion remain incompletely understood, with most cell death involving uninfected cells. In contrast, SIV infection of "natural" hosts such as sooty mangabeys does not cause CD4+ depletion and AIDS despite high-level viremia. Here, we report that the CARD8 inflammasome is activated immediately after HIV entry by the viral protease encapsulated in incoming virions. Sensing of HIV protease activity by CARD8 leads to rapid pyroptosis of quiescent cells without productive infection, while T cell activation abolishes CARD8 function and increases permissiveness to infection. In humanized mice reconstituted with CARD8-deficient cells, CD4+ depletion is delayed despite high viremia. Finally, we discovered loss-of-function mutations in CARD8 from "natural hosts," which may explain the peculiarly non-pathogenic nature of these infections. Our study suggests that CARD8 drives CD4+ T cell depletion during pathogenic HIV/SIV infections.

Mutation of novel ethanol-responsive lncRNA Gm41261 impacts ethanol-related behavioral responses in mice.

Chronic alcohol exposure results in widespread dysregulation of gene expression that contributes to the pathogenesis of Alcohol Use Disorder (AUD). Long noncoding RNAs are key regulators of the transcriptome that we hypothesize coordinate alcohol-induced transcriptome dysregulation and contribute to AUD. Based on RNA-Sequencing data of human prefrontal cortex, basolateral amygdala and nucleus accumbens of AUD versus non-AUD brain, the human LINC01265 and its predicted murine homolog Gm41261 (i.e., TX2) were selected for functional interrogation. We tested the hypothesis that TX2 contributes to ethanol drinking and behavioral responses to ethanol. CRISPR/Cas9 mutagenesis was used to create a TX2 mutant mouse line in which 306 base-pairs were deleted from the locus. RNA analysis revealed that an abnormal TX2 transcript was produced at an unchanged level in mutant animals. Behaviorally, mutant mice had reduced ethanol, gaboxadol and zolpidem-induced loss of the righting response and reduced tolerance to ethanol in both sexes. In addition, a male-specific reduction in two-bottle choice every-other-day ethanol drinking was observed. Male TX2 mutants exhibited evidence of enhanced GABA release and altered GABAA receptor subunit composition in neurons of the nucleus accumbens shell. In C57BL6/J mice, TX2 within the cortex was cytoplasmic and largely present in Rbfox3+ neurons and IBA1+ microglia, but not in Olig2+ oligodendrocytes or in the majority of GFAP+ astrocytes. These data support the hypothesis that TX2 mutagenesis and dysregulation impacts ethanol drinking behavior and ethanol-induced behavioral responses in mice, likely through alterations in the GABAergic system.

Temporal changes in micronutrient intake among United States Adults, NHANES 2003 through 2018: A cross-sectional study.

BACKGROUND: Changes in the United States food supply and food choices make examination of temporal changes in micronutrient intake and their effect on meeting nutrient recommendations necessary. OBJECTIVES: This study aimed to examine 15-year trends of the contribution of foods and beverages (FB) and dietary supplements (DSs) to meeting nutrient recommendations among United States adults aged 19 y or older and compare usual mean intake distributions of FB alone with those of FB+DSs with dietary reference intakes [percentage below the estimated average requirement (%AI)]. METHODS: This cross-sectional study used food, beverage, and DSs intake data from NHANES 2003-2018 (N = 39,925) to determine usual mean intakes for 21 micronutrients. Changes in intakes from FB and from FB+DSs, by sex, were compared in a time-trend analysis of 2-y cycles. Changes in mean intake as %AI were determined. RESULTS: Over the time studied, United States adults underconsumed vitamins A, C, D, E, and K; calcium; potassium; magnesium; and choline, even when DSs intake was included. Sodium was overconsumed. In males, there were significant increases in %

TiO2 nanorod arrays@PDA/Ag with biomimetic polydopamine as binary mediators for duplex SERS detection of illegal food dyes.

Based on TiO2 nanorod arrays@PDA/Ag (TNRs@PDA/Ag), a better surface-enhanced Raman scattering (SERS) sensor with effective enrichment and enhancement was investigated for duplex SERS detection of illicit food dyes. Biomimetic PDA functions as binary mediators by utilizing the structural characteristics of polydopamine (PDA), which include the conjugated structure and abundant hydrophilic groups. One PDA functioned as an electron transfer mediator to enhance the efficiency of electron transfer, and the other as an enrichment mediator to effectively enrich rhodamine B (RhB) and crystal violet (CV) through hydrogen bonding, π-π stacking, and electrostatic interactions. Individual and duplex detection of illicit food dyes (RhB and CV) was performed using TNRs@PDA/Ag to estimate SERS applications. Their linear equations and limits of detection of 1 nM for RhB and 5 nM for CV were derived. Individual and duplex food colour detection was successfully accomplished even in genuine chili meal with good results. The bifunctional TNRs@PDA/Ag-based highly sensitive and duplex SERS dye detection will have enormous potential for food safety monitoring.

A reverse translational study of PPAR-α agonist efficacy in human and rodent models relevant to alcohol use disorder.

Alcohol Use Disorder (AUD) is a chronic relapsing disorder affecting an estimated 283 million individuals worldwide, with substantial health and economic consequences. Peroxisome proliferator-activated receptors (PPARs), particularly PPAR-α and PPAR-γ, have shown promise in preclinical studies as potential therapeutic targets for AUD. In this human laboratory study, we aimed to translate preclinical findings on the PPAR-α agonist fenofibrate to a human population with current AUD. We hypothesized that, relative to placebo, fenofibrate at the highest FDA-approved dose of 145 mg/d would attenuate responsiveness to in vivo alcohol cues in the lab and reduce drinking under natural conditions. However, the results did not show significant differences in craving and alcohol consumption between the fenofibrate and placebo groups. Reverse translational studies in rodent models confirmed the lack of fenofibrate effect at human-equivalent doses. These findings suggest that inadequate translation of drug dose from rodents to humans may account for the lack of fenofibrate effects on alcohol craving and consumption in humans with AUD. The results highlight the need for new brain-penetrant PPAR-α agonists to adequately test the therapeutic potential of PPAR-α agonists for AUD, and the importance of reverse translational approaches and selection of human-equivalent doses in drug development.

Influence of prepartum dietary cation-anion difference and the magnitude of calcium decline at the onset of lactation on mineral metabolism and physiological responses.

The onset of lactation is characterized by substantially altered calcium (Ca) metabolism; recently, emphasis has been placed on understanding the dynamics of blood Ca in the peripartal cow in response to this change. Thus, the aim of our study was to delineate how prepartum dietary cation-anion difference (DCAD) diets and the magnitude of Ca decline at the onset of lactation altered blood Ca dynamics in the periparturient cow. Thirty-two multiparous Holstein cows were blocked by parity, previous 305-d milk yield and expected parturition date, and randomly allocated to either a positive (+120 mEq/kg) or negative (-120 mEq/kg) DCAD diet from 251 d of gestation until parturition (n = 16/diet). Immediately after parturition cows were continuously infused for 24 h with (1) an intravenous solution of 10% dextrose or (2) Ca gluconate (CaGlc) to maintain blood ionized (iCa) concentrations at ∼1.2 mM (normocalcemia) to form 4 treatment groups (n = 8/treatment). Blood was sampled every 6 h from 102 h before parturition until 96 h after parturition and every 30 min during 24 h continuous infusion. Cows fed a negative DCAD diet prepartum exhibited a less pronounced decline in blood iCa approaching parturition with lesser magnitude of decline relative to positive DCAD-fed cows. Cows fed a negative DCAD diet prepartum required lower rates of CaGlc infusion to maintain normocalcemia in the 24 h postpartum relative to positive DCAD-fed cows. Infusion of CaGlc disrupted blood Ca and P dynamics in the immediate 24 h after parturition and in the days following infusion. Collectively, these data demonstrate that prepartum negative DCAD diets facilitate a more transient hypocalcemia and improve blood Ca profiles at the onset of lactation whereas CaGlc infusion disrupts mineral metabolism.

Effects of testosterone enanthate on aggression, risk-taking, competition, mood, and other cognitive domains during 28 days of severe energy deprivation.

RATIONALE: Behavioral effects of testosterone depend on dose, acute versus sustained formulation, duration of administration, personality, genetics, and endogenous levels of testosterone. There are also considerable differences between effects of endogenous and exogenous testosterone. OBJECTIVES: This study was the secondary behavioral arm of a registered clinical trial designed to determine if testosterone protects against loss of lean body mass and lower-body muscle function induced by a severe energy deficit typical of sustained military operations. METHODS: Behavioral effects of repeated doses of testosterone on healthy young men whose testosterone was reduced by severe energy deficit were examined. This was a double-blind, placebo-controlled, between-group study. Effects of four weekly intramuscular injections of testosterone enanthate (200 mg/week, N = 24) or matching placebo (N = 26) were evaluated. Determination of sample size was based on changes in lean body mass. Tasks assessing aggression, risk-taking, competition, social cognition, vigilance, memory, executive function, and mood were repeatedly administered. RESULTS: During a period of artificially induced, low testosterone levels, consistent behavioral effects of administration of exogenous testosterone were not observed. CONCLUSIONS: Exogeneous testosterone enanthate (200 mg/week) during severe energy restriction did not reliably alter the measures of cognition. Study limitations include the relatively small sample size compared to many studies of acute testosterone administration. The findings are specific to healthy males experiencing severe energy deficit and should not be generalized to effects of other doses, formulations, or acute administration of endogenous testosterone or studies conducted with larger samples using tests of cognitive function designed to detect specific effects of testosterone.

Identification of constrained sequence elements across 239 primate genomes.

Noncoding DNA is central to our understanding of human gene regulation and complex diseases1,2, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome3-9. Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA10, the relatively short timescales separating primate species11, and the previously limited availability of whole-genome sequences12. Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis-regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals.

Transcriptome changes in the nucleus of the solitary tract induced by repeated stress, alcohol dependence, or stress-induced drinking in dependent mice.

Stress increases alcohol consumption in dependent animals and contributes to the development of alcohol use disorder. The nucleus of the solitary tract (NTS) is a critical brainstem region for integrating and relaying central and peripheral signals to regulate stress responses, but it is not known if it plays a role in alcohol dependence- or in stress-induced escalations in alcohol drinking in dependent mice. Here, we used RNA-sequencing and bioinformatics analyses to study molecular adaptations in the NTS of C57BL/6J male mice that underwent an ethanol drinking procedure that uses exposure to chronic intermittent ethanol (CIE) vapor, forced swim stress (FSS), or both conditions (CIE + FSS). Transcriptome profiling was performed at three different times after the last vapor cycle (0-hr, 72-hr, and 168-hr) to identify changes in gene expression associated with different stages of ethanol intoxication and withdrawal. In the CIE and CIE + FSS groups at 0-hr, there was upregulation of genes enriched for cellular response to type I interferon (IFN) and type I IFN- and cytokine-mediated signaling pathways, while the FSS group showed upregulation of neuronal genes. IFN signaling was the top gene network positively correlated with ethanol consumption levels in the CIE and CIE + FSS groups. Results from different analyses (differential gene expression, weighted gene coexpression network analysis, and rank-rank hypergeometric overlap) indicated that activation of type I IFN signaling would be expected to increase ethanol consumption. The CIE and CIE + FSS groups also shared an immune signature in the NTS as has been demonstrated in other brain regions after chronic ethanol exposure. A temporal-based clustering analysis revealed a unique expression pattern in the CIE + FSS group that suggests the interaction of these two stressors produces adaptations in synaptic and glial functions that may drive stress-induced drinking.

Whole Genome Analysis of SNV and Indel Polymorphism in Common Marmosets (Callithrix jacchus).

The common marmoset (Callithrix jacchus) is one of the most widely used nonhuman primate models of human disease. Owing to limitations in sequencing technology, early genome assemblies of this species using short-read sequencing suffered from gaps. In addition, the genetic diversity of the species has not yet been adequately explored. Using long-read genome sequencing and expert annotation, we generated a high-quality genome resource creating a 2.898 Gb marmoset genome in which most of the euchromatin portion is assembled contiguously (contig N50 = 25.23 Mbp, scaffold N50 = 98.2 Mbp). We then performed whole genome sequencing on 84 marmosets sampling the genetic diversity from several marmoset research centers. We identified a total of 19.1 million single nucleotide variants (SNVs), of which 11.9 million can be reliably mapped to orthologous locations in the human genome. We also observed 2.8 million small insertion/deletion variants. This dataset includes an average of 5.4 million SNVs per marmoset individual and a total of 74,088 missense variants in protein-coding genes. Of the 4956 variants orthologous to human ClinVar SNVs (present in the same annotated gene and with the same functional consequence in marmoset and human), 27 have a clinical significance of pathogenic and/or likely pathogenic. This important marmoset genomic resource will help guide genetic analyses of natural variation, the discovery of spontaneous functional variation relevant to human disease models, and the development of genetically engineered marmoset disease models.

Prevalence and adverse effects of sport-related nutritional supplements (sport drinks, bars, and gels) in the military before and during the COVID-19 pandemic: the US Military Dietary Supplement Use Study.

BACKGROUND: Sport-related nutritional supplements (SRNS) include sport drinks, sport bars, and sport gels. This investigation examined temporal patterns in SRNS use and adverse effects (AEs) reported by a single cohort of United States active-duty service members (SMs) surveyed before and during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: A stratified random sample (n = 22,858) of SMs (Air Force, Army, Navy, and Marine Corps) who completed a questionnaire on their SRNS use and AE experiences and were still on active duty were asked to complete the identical questionnaire on a second occasion. Twenty-five percent of successfully contacted SMs completed both questionnaires (n = 5,778) and were included in this investigation. The average ± standard deviation time between questionnaires was 1.3 ± 0.2 years. RESULTS: Prevalence of reported SRNS use ≥1 time/week in the baseline (BL) and follow-up (FU) phases were as follows: any SRNS: BL = 46%, FU = 41%; sport drinks: BL = 31%, FU = 28%; sport bars: BL = 30%, FU = 24%; sport gels: BL = 4%, FU = 4%. Reported weekly aerobic and resistance training durations were reduced in the FU period (8% and 26%, respectively). The proportion of SMs reporting SRNS use in both study phases was as follows: any SRNS = 62%, sport drinks = 54%, sport bars = 50%, sport gels = 35%. Prevalence of reported AEs in the BL and FU phases were as follows: any SRNS: BL = 1.9%, FU = 1.9%; sport drinks: BL = 1.0%, FU = 1.3%; sport bars: BL = 1.7%, FU = 1.4%; sport gels: BL = 3.3%, FU = 2.5%. The proportion of SMs reporting AEs in both phases was as follows: any SRNS = 14%, sport drinks = 11%, sport bars = 17%, sport gels = 0%. CONCLUSIONS: Overall SRNS use prevalence decreased slightly in the FU period, possibly because of reduced physical training related to military restrictions imposed during the emergence of COVID-19 between surveys. A large proportion of SMs reported changing their use patterns in the FU with some discontinuing use and others initiating use. The AE incidence was similarly low in the BL and FU phases, and few SMs reported AEs in both phases suggesting AEs were transitory. AE reporting for SRNSs was much lower than previously found for dietary supplements, possibly because of greater government regulatory control over SRNSs.

Psilocybin and Other Classic Psychedelics in Depression.

Psychedelic drugs such as psilocybin and ketamine are returning to clinical research and intervention across several disorders including the treatment of depression. This chapter focusses on psychedelics that specifically target the 5-HT2A receptor such as psilocybin and DMT. These produce plasma-concentration related psychological effects such as hallucinations and out of body experiences, insightful and emotional breakthroughs as well as mystical-type experiences. When coupled with psychological support, effects can produce a rapid improvement in mood among people with depression that can last for months. In this chapter, we summarise the scientific studies to date that explore the use of psychedelics in depressed individuals, highlighting key clinical, psychological and neuroimaging features of psychedelics that may account for their therapeutic effects. These include alterations in brain entropy that disrupt fixed negative ruminations, a period of post-treatment increased cognitive flexibility, and changes in self-referential psychological processes. Finally, we propose that the brain mechanisms underlying the therapeutic effect of serotonergic psychedelics might be distinct from those underlying classical serotonin reuptake-blocking antidepressants.

The Medical Burden of Obesity and Overweight in the US Military: Association of BMI with Clinically Diagnosed Medical Conditions in United States Military Service Members.

BACKGROUND: A high BMI is associated with various medical conditions, notably type 2 diabetes, cardiovascular disease, and mental health disorders. In the US military, BMI increased linearly between 1975 and 2015. OBJECTIVE: This cross-sectional study investigated the associations between BMI and a comprehensive range of clinically diagnosed medical conditions (CDMCs) in US military service members (SMs). METHODS: A stratified random sample of SMs (n=26,177) completed an online questionnaire reporting their height, weight, and demographic/lifestyle characteristics. Medical conditions for 6 mo before questionnaire completion were obtained from a comprehensive military electronic medical surveillance system and grouped into 39 CDMCs covering both broad (largely systemic) and specific medical conditions. BMI was calculated as weight/height2 (kg/m2). The prevalence of CDMCs was compared among normal weight (<25.0 kg/m2), overweight (25.0-29.9 kg/m2), and obese (≥30 kg/m2) SMs. RESULTS: After multivariable adjustment for demographic/lifestyle characteristics, higher BMI was associated with higher odds of a diagnosed medical condition in 30 of 39 CDMCs, with all 30 displaying dose-response relationships. The 5 major CDMCs with the largest odds ratios comparing obese to normal weight were endocrine/nutritional/metabolic diseases (OR=2.67, 95%CI=2.24-3.15), nervous system diseases (odds ratio [OR]=2.59, 95%CI=2.32-2.90), circulatory system diseases (OR=2.56, 95%CI=2.15-3.06), musculoskeletal system diseases (OR=1.92, 95%CI=1.76-2.09), and mental/behavioral disorders (OR=1.69, 95%CI=1.51-1.90). Compared with normal weight SMs, overweight or obese SMs had a higher number of CDMCs (1.8±1.9 vs. 2.0±2.0 and 2.5±2.3, mean ± standard deviation, respectively, P<0.01). CONCLUSIONS: In a young, physically active population, higher BMI was associated with a host of medical conditions, even after adjustment for demographic/lifestyle characteristics. The US Department of Defense should improve nutrition education and modify other factors that contribute to overweight and obesity. This study demonstrates that the medical burden of obesity is substantial in overweight and obese SMs.

Inhibition of Retinoic Acid Signaling in Proximal Tubular Epithelial cells Protects against Acute Kidney Injury by Enhancing Kim-1-dependent Efferocytosis.

Retinoic acid receptor (RAR) signaling is essential for mammalian kidney development, but in the adult kidney is restricted to occasional collecting duct epithelial cells. We now show there is widespread reactivation of RAR signaling in proximal tubular epithelial cells (PTECs) in human sepsis-associated acute kidney injury (AKI), and in mouse models of AKI. Genetic inhibition of RAR signaling in PTECs protects against experimental AKI but is associated with increased expression of the PTEC injury marker, Kim-1. However, Kim-1 is also expressed by de-differentiated, proliferating PTECs, and protects against injury by increasing apoptotic cell clearance, or efferocytosis. We show that the protective effect of inhibiting PTEC RAR signaling is mediated by increased Kim-1 dependent efferocytosis, and that this is associated with de-differentiation, proliferation, and metabolic reprogramming of PTECs. These data demonstrate a novel functional role that reactivation of RAR signaling plays in regulating PTEC differentiation and function in human and experimental AKI.

Leveraging Electronic Health Record Technology and Team Care to Address Medication Adherence: Protocol for a Cluster Randomized Controlled Trial.

BACKGROUND: Low medication adherence is a common cause of high blood pressure but is often unrecognized in clinical practice. Electronic data linkages between electronic health records (EHRs) and pharmacies offer the opportunity to identify low medication adherence, which can be used for interventions at the point of care. We developed a multicomponent intervention that uses linked EHR and pharmacy data to automatically identify patients with elevated blood pressure and low medication adherence. The intervention then combines team-based care with EHR-based workflows to address medication nonadherence. OBJECTIVE: This study aims to describe the design of the Leveraging EHR Technology and Team Care to Address Medication Adherence (TEAMLET) trial, which tests the effectiveness of a multicomponent intervention that leverages EHR-based data and team-based care on medication adherence among patients with hypertension. METHODS: TEAMLET is a pragmatic, cluster randomized controlled trial in which 10 primary care practices will be randomized 1:1 to the multicomponent intervention or usual care. We will include all patients with hypertension and low medication adherence who are seen at enrolled practices. The primary outcome is medication adherence, as measured by the proportion of days covered, and the secondary outcome is clinic systolic blood pressure. We will also assess intervention implementation, including adoption, acceptability, fidelity, cost, and sustainability. RESULTS: As of May 2023, we have randomized 10 primary care practices into the study, with 5 practices assigned to each arm of the trial. The enrollment for the study commenced on October 5, 2022, and the trial is currently ongoing. We anticipate patient recruitment to go through the fall of 2023 and the primary outcomes to be assessed in the fall of 2024. CONCLUSIONS: The TEAMLET trial will evaluate the effectiveness of a multicomponent intervention that leverages EHR-based data and team-based care on medication adherence. If successful, the intervention could offer a scalable approach to address inadequate blood pressure control among millions of patients with hypertension. TRIAL REGISTRATION: ClinicalTrials.gov NCT05349422; https://clinicaltrials.gov/ct2/show/NCT05349422. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/47930.