Inflammatory response after prehospital high-dose glucocorticoid to patients resuscitated from out-of-hospital cardiac arrest: a sub-study of the STEROHCA trial.

BACKGROUND: The post-cardiac arrest syndrome (PCAS) after out-of-hospital cardiac arrest (OHCA) is characterized by a series of pathological events, including inflammation. In the randomized "STERoid for OHCA" (STEROHCA) trial, prehospital high-dose glucocorticoid decreased interleukin (IL) 6 and C-reactive protein levels following resuscitated OHCA. The aim of this predefined sub-study was to assess the inflammatory response the first three days of admission. METHODS: The STEROHCA trial enrolled 137 OHCA patients randomized to either a single prehospital injection of methylprednisolone 250 mg or placebo. Inflammatory markers, including pro- and anti-inflammatory cytokines, were analyzed in plasma samples, from 0-, 24-, 48-, and 72 hours post-admission. Mixed-model analyses were applied using log-transformed data to assess group differences. RESULTS: The 137 patients included in this sub-study had a median age of 67 years (57 to 74), and the 180-day survival rates were 75% (n=51/68) and 64% (n=44/69) in the glucocorticoid and placebo group, respectively. A total of 130 (95%) patients had at least one plasma sample available. The anti-inflammatory cytokine IL-10 was increased at hospital admission in the glucocorticoid group (ratio 2.74 (1.49-5.05), p=0.006), but the intervention showed the strongest effect after 24 hours, decreasing pro-inflammatory levels of IL-6 (ratio 0.06 (0.03-0.10), p<0.001), IL-8 (ratio 0.53 (0.38-0.75), p<0.001), macrophage chemokine protein-1 (MCP-1, ratio 0.02 (0.13-0.31), p<0.001), macrophage inflammatory protein-1-beta (MIP-1b, ratio 0.28 (0.18-0.45), p<0.001), and tumor necrosis factor-α (TNF-α, ratio 0.6 (0.4-0.8), p=0.01). CONCLUSION: Administering high-dose glucocorticoid treatment promptly after resuscitation from OHCA influenced the inflammatory response with a reduction in several systemic proinflammatory cytokines after 24 hours. Trial registration EudraCT number: 2020-000855-11; submitted March 30, 2020. URL: https://www. CLINICALTRIALS: gov; Unique Identifier: NCT04624776.

Infection prophylaxis among patients with antineutrophil cytoplasmic antibody (ANCA) vasculitis: a scoping review.

Severe infections associated with the use of strong immunosuppressive medication are a leading cause of morbidity and mortality in patients with ANCA vasculitis (AV). While guidelines conditionally recommend trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis for Pneumocystis jirovecii pneumonia in AV patients, robust evidence on prophylaxis strategies is lacking. This scoping review aimed to assess the existing evidence on infection prophylaxis in AV patients, identify knowledge gaps, and guide future study design. A comprehensive search of six databases and relevant references identified original studies in English from January 1, 2000, to July 31, 2020. Inclusion criteria encompassed studies evaluating the impact of any antimicrobial prophylaxis strategy on infection-related outcomes in AV patients receiving immunosuppressive treatment. Studies were screened by four researchers using a blinded approach. Data was extracted by two reviewers, with differences resolved via consensus in consultation with a third reviewer. Nineteen studies met inclusion criteria, including two randomized trials and 17 cohort studies, with TMP-SMX being the most commonly assessed prophylactic strategy. The studies varied in sample sizes, outcomes measured, prophylactic strategies employed, and proportion of patients who received the regimen. Most cohort studies included no or limited control of potential confounding factors. This scoping review suggests significant variation in AV patients' receipt of TMP-SMX and alternative infection prophylaxis approaches. Observational studies using large secondary healthcare databases with rigorous designs are needed to provide high-quality evidence of the real-world effectiveness of antimicrobial prophylactic regimens, to improve clinical decision-making and quality of care for AV patients receiving immunosuppressive treatment.

Differences in Patient Secure Message Volume Among Otolaryngologists: A Retrospective Cohort Study.

OBJECTIVE: To identify differences in inbox and secure message burden among otolaryngologists based on demographics and subspecialty over 4 years. METHODS: Inbox data were queried from January 2019 until December 2022. Otolaryngologists were categorized into cohorts by area of practice and gender. All inbox tasks, secure messages, and clinical encounters were collected and compared by gender, practice type, and years in practice. Means were compared using t-tests and chi-squared tests. RESULTS: Of the 128 physicians, 45.7% were comprehensive otolaryngologists and 61.3% were male. The most common subspecialties were facial plastics (15.6%), oncology (8.6%), and otology (7.8%). Otolaryngologists had an average of 143.5 inbox tasks per month, with 97.2 (67.7%) of them being secure messages, resulting in an average of 1.14 inbox tasks and 0.80 secure messages per clinical encounter. The ratio of secure messages per clinical encounter was consistent across all specialties except oncology (1.10, P = .003). Otology (0.86, P = .032) and facial plastics (0.95, P = .028) had significantly lower ratios of inbox tasks to clinical encounters when compared to their colleagues, while oncology had a higher ratio (1.70, P < .001). No significant differences in inbox burden were observed between genders, years in practice, or languages spoken. Secure messages steadily increased over the study period. CONCLUSION: Inbox burden for otolaryngologists primarily stems from patient secure messages and varies across subspecialties. Considerations should be made to the inbox burden of head and neck oncologists. The implementation of support systems for inbox management could improve the imbalance between clinical and non-clinical responsibilities in otolaryngology. LEVEL OF EVIDENCE: Level III, Retrospective Cohort Study.

Circulating KRAS G12D but not G12V is associated with survival in metastatic pancreatic ductal adenocarcinoma.

While high circulating tumor DNA (ctDNA) levels are associated with poor survival for multiple cancers, variant-specific differences in the association of ctDNA levels and survival have not been examined. Here we investigate KRAS ctDNA (ctKRAS) variant-specific associations with overall and progression-free survival (OS/PFS) in first-line metastatic pancreatic ductal adenocarcinoma (mPDAC) for patients receiving chemoimmunotherapy ("PRINCE", NCT03214250), and an independent cohort receiving standard of care (SOC) chemotherapy. For PRINCE, higher baseline plasma levels are associated with worse OS for ctKRAS G12D (log-rank p = 0.0010) but not G12V (p = 0.7101), even with adjustment for clinical covariates. Early, on-therapy clearance of G12D (p = 0.0002), but not G12V (p = 0.4058), strongly associates with OS for PRINCE. Similar results are obtained for the SOC cohort, and for PFS in both cohorts. These results suggest ctKRAS G12D but not G12V as a promising prognostic biomarker for mPDAC and that G12D clearance could also serve as an early biomarker of response.

Relevance of Age and Hypertension for Blood-Pressure Targets in Comatose Survivors of Cardiac Arrest - A BOX-trial sub study.

BACKGROUND: To assess whether the optimal mean arterial blood pressure (MAP) target after out-of-hospital cardiac arrest (OHCA) is influenced by age and a history of arterial hypertension. METHODS: Post-hoc analysis of data from the Blood Pressure and Oxygenation Targets in Post Resuscitation Care (BOX) trial. The trial included 789 comatose patients randomized to a MAP target of 63mmHg or 77mmHg. The primary outcome of this sub-study was one-year all-cause mortality. Cox proportional-hazards regression and restricted cubic splines were used to examine whether prevalent hypertension and age modified the effect of low versus high MAP target on all-cause mortality. RESULTS: Of the 789 patients randomized, 393 were assigned to a high MAP target, and 396 to a low MAP target. Groups were well balanced for mean age (high MAP target 63±13 years versus low 62±14 years) and hypertension (45% versus 47% respectively). At one year, the primary outcome occurred in 143 patients (36%) with high MAP target and 138 (35%) with low MAP target. The risk of the primary outcome increased linearly with increasing age (P<0.001). The effect of a high versus low MAP target on the primary outcome was modified by age when tested continuously, potentially favoring low MAP target in younger patients (P for interaction=0.03). Prevalent hypertension did not modify the effect of a high versus low MAP target on the primary outcome (P for interaction=0.67). CONCLUSIONS: Among patients resuscitated after OHCA, older patients and those with a history of hypertension did not benefit from a higher MAP target.

Distinct Plasma Metabolomic and Gut Microbiome Profiles after Gestational Diabetes Mellitus Diet Treatment: Implications for Personalized Dietary Interventions.

Gestational diabetes mellitus (GDM) triggers alterations in the maternal microbiome. Alongside metabolic shifts, microbial products may impact clinical factors and influence pregnancy outcomes. We investigated maternal microbiome-metabolomic changes, including over 600 metabolites from a subset of the "Choosing Healthy Options in Carbohydrate Energy" (CHOICE) study. Women diagnosed with GDM were randomized to a diet higher in complex carbohydrates (CHOICE, n = 18, 60% complex carbohydrate/25% fat/15% protein) or a conventional GDM diet (CONV, n = 16, 40% carbohydrate/45% fat/15% protein). All meals were provided. Diets were eucaloric, and fiber content was similar. CHOICE was associated with increases in trimethylamine N-oxide, indoxyl sulfate, and several triglycerides, while CONV was associated with hippuric acid, betaine, and indole propionic acid, suggestive of a healthier metabolome. Conversely, the microbiome of CHOICE participants was enriched with carbohydrate metabolizing genes and beneficial taxa such as Bifidobacterium adolescentis, while CONV was associated with inflammatory pathways including antimicrobial resistance and lipopolysaccharide biosynthesis. We also identified latent metabolic groups not associated with diet: a metabolome associated with less of a decrease in fasting glucose, and another associated with relatively higher fasting triglycerides. Our results suggest that GDM diets produce specific microbial and metabolic responses during pregnancy, while host factors also play a role in triglycerides and glucose metabolism.

CCAR1 promotes DNA repair via alternative splicing.

DNA repair is directly performed by hundreds of core factors and indirectly regulated by thousands of others. We massively expanded a CRISPR inhibition and Cas9-editing screening system to discover factors indirectly modulating homology-directed repair (HDR) in the context of ∼18,000 individual gene knockdowns. We focused on CCAR1, a poorly understood gene that we found the depletion of reduced both HDR and interstrand crosslink repair, phenocopying the loss of the Fanconi anemia pathway. CCAR1 loss abrogated FANCA protein without substantial reduction in the level of its mRNA or that of other FA genes. We instead found that CCAR1 prevents inclusion of a poison exon in FANCA. Transcriptomic analysis revealed that the CCAR1 splicing modulatory activity is not limited to FANCA, and it instead regulates widespread changes in alternative splicing that would damage coding sequences in mouse and human cells. CCAR1 therefore has an unanticipated function as a splicing fidelity factor.

Revisiting reactive oxygen species production in hypoxia.

Cellular responses to hypoxia are crucial in various physiological and pathophysiological contexts and have thus been extensively studied. This has led to a comprehensive understanding of the transcriptional response to hypoxia, which is regulated by hypoxia-inducible factors (HIFs). However, the detailed molecular mechanisms of HIF regulation in hypoxia remain incompletely understood. In particular, there is controversy surrounding the production of mitochondrial reactive oxygen species (ROS) in hypoxia and how this affects the stabilization and activity of HIFs. This review examines this controversy and attempts to shed light on its origin. We discuss the role of physioxia versus normoxia as baseline conditions that can affect the subsequent cellular response to hypoxia and highlight the paucity of data on pericellular oxygen levels in most experiments, leading to variable levels of hypoxia that might progress to anoxia over time. We analyze the different outcomes reported in isolated mitochondria, versus intact cells or whole organisms, and evaluate the reliability of various ROS-detecting tools. Finally, we examine the cell-type and context specificity of oxygen's various effects. We conclude that while recent evidence suggests that the effect of hypoxia on ROS production is highly dependent on the cell type and the duration of exposure, efforts should be made to conduct experiments under carefully controlled, physiological microenvironmental conditions in order to rule out potential artifacts and improve reproducibility in research.

Precision medicine: Externally validated explainable AI support tool for predicting sustainability of infliximab and vedolizumab in ulcerative colitis.

OBJECTIVE: Drug sustainability (DS), a surrogate marker for drug efficacy, is important, especially when aiming for precision medicine. However, it lacks reliable prediction methods. AIMS: To develop and externally validate a web-based artificial intelligence(AI)-derived tool for predicting DS of infliximab and vedolizumab in patients with moderate-to-severe Ulcerative Colitis (UC). METHODS: Data from three Israeli centers included infliximab or vedolizumab patients treated for >54 weeks. Sustainability meant no corticosteroids, hospitalizations or surgeries. Machine learning techniques predicted >54-week and overall DS using baseline clinical data. RESULTS: The model was developed using data from 246 patients from Rabin Medical Center and externally validated on 67 patients from Rambam Health Care Campus and Sheba Medical Center. No significant difference in DS was observed across the datasets. Most patients were biologic-naïve and primarily treated with vedolizumab. The model performed well, with an area under the ROC curve of 0.86, and showed good accuracy (65.5 %-76.9 %) across the test sets. CONCLUSIONS: The study introduces a novel, AI-based tool for predicting >54-week DS of infliximab and vedolizumab in moderate-to-severe UC, using baseline parameters. This can aid clinical decision-making in the framework of precision medicine, promising to optimize disease management while maintaining physician autonomy.

Virus-blocking mosquitoes take flight in the fight against dengue.

Drone-based mosquito releases facilitate the introduction of dengue-blocking bacteria in wild mosquito populations.

Depressive symptoms predict cannabis vaping initiation among young adults.

BACKGROUND: Young adults in the United States, including college students, have the highest prevalence of cannabis use compared with other age groups. Although cannabis vaping is increasingly prevalent during young adulthood, little is known about factors contributing to the onset of cannabis vaping during this developmental period. METHODS: Participants were 3085 cannabis vaping naïve young adults aged 18-25 years (M = 20.60; SD = 1.80), initially recruited from 24 Texas colleges and participating in a multi-wave, longitudinal study. A survival analysis was conducted to determine if participants reporting elevated depressive symptoms had an increased risk of onset of cannabis vaping over six follow-up waves from fall 2015 to spring 2019 compared to their peers with lower levels of depressive symptoms. Socio-demographic characteristics, time-varying past 30 day substance use, and time-varying peer nicotine vaping were included as covariates in the model. RESULTS: Twenty-five percent of participants initiated cannabis vaping during the four-year study period, with stable initiation rates from 2015 to 2017 but doubling from 2017 to 2019. Analyses, both unadjusted and adjusted for study covariates, indicated that elevated depressive symptoms were significantly associated with an increased risk of cannabis vaping initiation. CONCLUSION: Findings indicate that initiation of cannabis vaping during young adulthood is common, and particularly more likely among those with greater depressive symptoms, thus underscoring the importance of prevention programs that include mental health support services tailored to young adults.

Utility of ultrasound in the diagnostic work-up of suspected pulmonary embolism: an open-label multicentre randomized controlled trial (the PRIME study).

Background: Prevalence of pulmonary embolism (PE) in patients referred to diagnostic imaging is decreasing, indicating a need for improving patient selection. The aim of this study was to assess reduction in referral to diagnostic imaging by integrating a bespoke ultrasound protocol and describe associated failure rate and adverse events in patients with suspected PE. Methods: In a randomized open-label multicentre trial spanning June 18, 2021, through Feb 1, 2023, adult patients with suspected PE and 1) a Wells score of 0-6 and elevated age-adjusted D-dimer or 2) Wells score >6 were randomly assigned 1:1 to direct diagnostic imaging (controls) or focused lung, cardiac, and deep venous ultrasound by unblinded investigators. Ultrasound could: 1) dismiss PE if no signs of PE and low clinical suspicion or an alternate diagnosis, 2) confirm PE in case of visible venous thrombus, ≥2 subpleural infarctions, McConnell's, or D-sign, or 3) refer to diagnostic imaging if neither category was fulfilled or a patient with confirmed PE by ultrasound required admission. Primary endpoint was proportion of patients referred to diagnostic imaging. Outcome assessors were not blinded to group assignment. All included participants were included in safety analyses. The trial was registered at clinicaltrials.gov (NCT04882579). Findings: A total of 150 patients were recruited, of whom 73 were randomized to ultrasound. Among 77 controls referred to diagnostic imaging, 26 patients had PE confirmed. In the ultrasound group, 40 patients were referred to diagnostic imaging of whom 20 had PE, reducing referral for diagnostic imaging by 45.2% (95% CI: 34.3-56.6, p < 0.0001). Three further PEs were diagnosed by presence of a DVT. During 3-month follow-up, the number of patients who did not receive anticoagulation but was diagnosed with PE was two (4%; 95% CI: 1.1-13.5) and none (0%; 95% CI: 0.0-7.0) in the ultrasound and control group, respectively. Interpretation: Ultrasound substantially reduced referral to diagnostic imaging in suspected PE. Albeit with an unacceptable failure rate. Funding: University of Southern Denmark, Odense University Hospital, Master Carpenter Sophus Jacobsen and wife's foundation, Engineer K. A. Rhode and wife foundation.

Intramuscular Hamstring Stiffness Affects Anatomically Modeled Localized Muscle Strain During Passive Hip Flexion.

ABSTRACT: Rehbein, CO, McDougle, JM, Peñailillo, L, and Earp, JE. Intramuscular hamstring stiffness affects anatomically modeled localized muscle strain during passive hip flexion. J Strength Cond Res XX(X): 000-000, 2024-Hamstring strain injuries occur when localized tissue strain capacity is exceeded. Localized strain may be affected by intramuscular variation in stiffness, but research in this area is lacking. The purpose of this study was to determine the effects of intramuscular hamstring stiffness on localized muscle strain during passive hip flexion. Twenty-eight (age 25.0 ± 4.9 years) healthy women (n = 15) and men (n = 13) had biceps femoris, semitendinosus, and semimembranosus stiffness measured proximally, medially, and distally during passive hip flexion and extension using shear-wave elastography. Anthropometric and stiffness measurements were entered into an anatomical model of equivalent springs to estimate localized tissue strain and differentiate between the relative contribution to passive strain from each muscular region. In shortened and stretched positions, stiffness was lowest proximally for all muscles (Cohen's d = 0.66-0.79, p < 0.001). In addition, relative strain contribution was greater proximally (37.5-39.4%) compared with middle (31.74-32.2%) or distal (28.6-30.3%) regions (p < 0.001), with proximal contribution to strain increasing with greater hip flexion. Our results suggest that intramuscular variations in passive hamstring stiffness contribute to inhomogeneous strain throughout the muscle during passive hip flexion. Given the prevalence of proximal stretch-pattern strain injuries, variation in intramuscular stiffness may contribute to risk for such injuries.

Biopolymer-supramolecular polymer hybrids for photocatalytic hydrogen production.

Solar generation of H2 is a promising strategy for dense energy storage. Supramolecular polymers composed of chromophore amphiphile monomers containing perylene monoimide (PMI) have been reported as crystalline light-harvesting assemblies for aqueous H2-evolving catalysts. Gelation of these supramolecular polymers with multivalent ions creates hydrogels with high diffusivity but insufficient mechanical stability and catalyst retention for reusability. We report here on using sodium alginate (SA) biopolymer to both induce supramolecular polymerization of PMI and co-immobilize them with catalysts in a robust hydrogel with high diffusivity that can also be 3D-printed. Faster mass transfer was achieved by controlling the material macrostructure by reducing gel diameter and microstructure by reducing biopolymer loading. Optimized gels produce H2 at rates rivaling solution-based PMI and generate H2 for up to 6 days. The PMI assemblies in the SA matrix create a percolation network capable of bulk-electron transfer under illumination. These PMI-SA materials were then 3D-printed on conductive substrates to create 3D hydrogel photoelectrodes with optimized porosity. The design of these versatile hybrid materials was bioinspired by the soft matter environment of natural photosynthetic systems and opens the opportunity to carry out light-to-fuel conversion within soft matter with arbitrary shapes and particular local environments.

Discordant effects of Janus kinases inhibition ex-vivo on inflammatory responses in colonic compared to ileal mucosa.

BACKGROUND & AIMS: Janus kinase (JAK) inhibitors are used for treating inflammatory bowel diseases (IBD). We aimed to identify molecular effects of JAK inhibition in human intestinal mucosa, considering IBD location and phenotype. METHODS: Colonic and ileal explants from patients with ulcerative colitis (UC), Crohn's disease (CD), and non-IBD controls (NC) were assessed for phosphorylated signal transducers and activators of transcription (p-STAT) levels and Inflammatory genes expression panel in response to ex-vivo JAK inhibitor (tofacitinib). Cytokine production by lamina propria lymphocytes in response to tofacitinib was assessed. Human intestinal organoids were used to investigate JAK inhibitors' effects on iNOS expression. RESULTS: Explants were collected from 68 patients (UC=20; CD=20; NC=28). p-STAT1\3\5 inhibition rates varied, being higher in colonic compared to ileal explants. p-STAT1\3 inhibition rates negatively correlated with CRP levels. While significant alterations in 120 of 255 inflammatory genes were observed in colonic explants, only 30 were observed in ileal NC explants. In colonic explants from UC, significant alterations were observed in 5 genes, including NOS2. JAK inhibition significantly decreased Th1\Th2\Th17-related cytokine production from lamina propria lymphocytes. Various JAK inhibitors reduced IFN-γ-induced increase in iNOS expression in organoids. CONCLUSIONS: Site-specific anti-inflammatory effect of JAK inhibition by tofacitinib was noticed, whereby the colon was more robustly affected than the ileum. Ex-vivo response to tofacitinib is individual. JAK inhibition may attenuate inflammation by decreasing iNOS expression. Ex-vivo mucosal platforms may be a valuable resource for studying personalized drug effects in patients with IBD.

Differential NEUROD1, ASCL1, and POU2F3 Expression Defines Molecular Subsets of Bladder Small Cell/Neuroendocrine Carcinoma With Prognostic Implications.

Small cell carcinomas (SMC) of the lung are now molecularly classified based on the expression of transcriptional regulators (NEUROD1, ASCL1, POU2F3, and YAP1) and DLL3, which has emerged as an investigational therapeutic target. PLCG2 has been shown to identify a distinct subpopulation of lung SMC with stem cell-like and prometastasis features and poor prognosis. We analyzed the expression of these novel neuroendocrine markers and their association with traditional neuroendocrine markers and patient outcomes in a cohort of bladder neuroendocrine carcinoma (NEC) consisting of 103 SMC and 19 large cell NEC (LCNEC) assembled in tissue microarrays. Coexpression patterns were assessed and integrated with detailed clinical annotation including overall (OS) and recurrence-free survival (RFS) and response to neoadjuvant/adjuvant chemotherapy. We identified 5 distinct molecular subtypes in bladder SMC based on the expression of ASCL1, NEUROD1, and POU2F3: ASCL1+/NEUROD1- (n = 33; 34%), ASCL1- /NEUROD1+ (n = 21; 21%), ASCL1+/NEUROD1+ (n = 17; 17%), POU2F3+ (n = 22, 22%), and ASCL1- /NEUROD1- /POU2F3- (n = 5, 5%). POU2F3+ tumors were mutually exclusive with those expressing ASCL1 and NEUROD1 and exhibited lower expression of traditional neuroendocrine markers. PLCG2 expression was noted in 33 tumors (32%) and was highly correlated with POU2F3 expression (P < .001). DLL3 expression was high in both SMC (n = 72, 82%) and LCNEC (n = 11, 85%). YAP1 expression was enriched in nonneuroendocrine components and negatively correlated with all neuroendocrine markers. In patients without metastatic disease who underwent radical cystectomy, PLCG2+ or POU2F3+ tumors had shorter RFS and OS (P < .05), but their expression was not associated with metastasis status or response to neoadjuvant/adjuvant chemotherapy. In conclusion, the NEC of the bladder can be divided into distinct molecular subtypes based on the expression of ASCL1, NEUROD1, and POU2F3. POU2F3-expressing tumors represent an ASCL1/NEUROD1-negative subset of bladder NEC characterized by lower expression of traditional neuroendocrine markers. Marker expression patterns were similar in SMC and LCNEC. Expression of PLCG2 and POU2F3 was associated with shorter RFS and OS. DLL3 was expressed at high levels in both SMC and LCNEC of the bladder, nominating it as a potential therapeutic target.

Developmental Programming of the Fetal Immune System by Maternal Western-Style Diet: Mechanisms and Implications for Disease Pathways in the Offspring.

Maternal obesity and over/undernutrition can have a long-lasting impact on offspring health during critical periods in the first 1000 days of life. Children born to mothers with obesity have reduced immune responses to stimuli which increase susceptibility to infections. Recently, maternal western-style diets (WSDs), high in fat and simple sugars, have been associated with skewing neonatal immune cell development, and recent evidence suggests that dysregulation of innate immunity in early life has long-term consequences on metabolic diseases and behavioral disorders in later life. Several factors contribute to abnormal innate immune tolerance or trained immunity, including changes in gut microbiota, metabolites, and epigenetic modifications. Critical knowledge gaps remain regarding the mechanisms whereby these factors impact fetal and postnatal immune cell development, especially in precursor stem cells in bone marrow and fetal liver. Components of the maternal microbiota that are transferred from mothers consuming a WSD to their offspring are understudied and identifying cause and effect on neonatal innate and adaptive immune development needs to be refined. Tools including single-cell RNA-sequencing, epigenetic analysis, and spatial location of specific immune cells in liver and bone marrow are critical for understanding immune system programming. Considering the vital role immune function plays in offspring health, it will be important to understand how maternal diets can control developmental programming of innate and adaptive immunity.

Concussion and the Sleeping Brain.

BACKGROUND: Emerging research has suggested sleep to be a modifier of the trajectory of concussion recovery in adolescent and adult populations. Despite the growing recognition of the relationship between sleep and concussion, the mechanisms and physiological processes governing this association have yet to be established. MAIN BODY: Following a concussion, a pathophysiologic cascade of events occurs, characterized by numerous factors including microglia activation, ionic imbalance, and release of excitatory neurotransmitters. Importantly, each of these factors plays a role in the regulation of the sleep-wake cycle. Therefore, dysregulation of sleep following injury may be a function of the diffuse disruption of cerebral functioning in the wake of both axonal damage and secondary physiological events. As the onset of sleep-related symptoms is highly variable following a concussion, clinicians should be aware of when and how these symptoms present. Post-injury changes in sleep have been reported in the acute, sub-acute, and chronic phases of recovery and can prolong symptom resolution, affect neurocognitive performance, and influence mood state. Though these changes support sleep as a modifier of recovery, limited guidance exists for clinicians or their patients in the management of sleep after concussion. This may be attributed to the fact that research has correlated sleep with concussion recovery but has failed to explain why the correlation exists. Sleep is a complex, multifactorial process and the changes seen in sleep that are seen following concussion are the result of interactions amongst numerous processes that regulate the sleep-wake cycle. SHORT CONCLUSION: The assessment and management of sleep by identifying and considering the biological, sociological, and psychological interactions of this multifactorial process will allow for clinicians to address the dynamic nature of changes in sleep following concussion.

Acute and Chronic Effects of Static Stretching on Intramuscular Hamstring Stiffness.

Passive hamstring stiffness varies proximo-distally, resulting in inhomogeneous tissue strain during stretching that may affect localized adaptations and risk of muscle injuries. The purpose of the present study was to determine the acute and chronic effects of static stretching (SS) on intramuscular hamstring stiffness. Thirty healthy active participants had acute changes in passive biceps femoris (BF), semimembranosus (SM), and semitendinosus (ST) stiffness measured at 25% (proximal), 50% (middle), and 75% (distal) muscle length, using shear-wave elastography, immediately after SS. Participants then completed 4 weeks of either a SS intervention (n = 15) or no intervention (CON, n = 15) with stiffness measured before and after the interventions. The acute and chronic effects of SS were compared between anatomical regions and between regions on the basis of their relative stiffness pre-intervention. Acutely, SS decreased stiffness throughout the BF and SM (p ≤ 0.05) but not the ST (p = 0.326). However, a regional effect of stretching was observed for SM and ST with greater reduction in stiffness occurring in stiffer muscular regions (p = 0.001-0.013). Chronically, SS increased BF and ST (p < 0.05), but not SM (p = 0.422) stiffness compared with CON, but no regional effect of stretching was observed in any muscle (p = 0.361-0.833). SS resulted in contrasting acute and chronic effects, acutely decreasing stiffness in stiffer regions while chronically increasing stiffness. These results indicate that the acute effects of SS vary along the muscle's length on the basis of the relative stiffness of the muscle and that acute changes in stiffness from SS are unrelated to chronic adaptations.

Feasibility and acceptability of patient- and clinician-level antithrombotic stewardship interventions to reduce gastrointestinal bleeding risk in patients using warfarin (Anticoagulation with Enhanced Gastrointestinal Safety): a factorial randomized controlled pilot trial.

Background: Overuse of antiplatelet therapy and underuse of gastroprotection contribute to preventable bleeding in patients taking anticoagulants. Objectives: (1) Determine the feasibility of a factorial trial testing patient activation and clinician outreach to reduce gastrointestinal (GI) bleeding risk in patients prescribed warfarin-antiplatelet therapy without proton pump inhibitor gastroprotection and (2) assess intervention acceptability. Methods: Pragmatic 2 × 2 factorial cluster-randomized controlled pilot comparing (1) a patient activation booklet vs usual care and (2) clinician notification vs clinician notification plus nurse facilitation was performed. The primary feasibility outcome was percentage of patients completing a structured telephone assessment after 5 weeks. Exploratory outcomes, including effectiveness, were evaluated using chart review, surveys, and semistructured interviews. Results: Among 47 eligible patients, 35/47 (74.5%; 95% CI, 58.6%-85.7%) met the feasibility outcome. In the subset confirmed to be high risk for upper GI bleeding, 11/29 (37.9%; 95% CI, 16.9%-64.7%) made a medication change, without differences between intervention arms. In interviews, few patients reported reviewing the activation booklet; barriers included underestimating GI bleeding risk, misunderstanding the booklet's purpose, and receiving excessive health communication materials. Clinicians responded to notification messages for 24/47 patients (51.1%; 95% CI, 26.4%-75.4%), which was lower for surgeons than nonsurgeons (22.7% vs 76.0%). Medical specialists but not surgeons viewed clinician notification as acceptable. Conclusion: The proposed trial design and outcome ascertainment strategy were feasible, but the patient activation intervention is unlikely to be effective as designed. While clinician notification appears promising, it may not be acceptable to surgeons, findings which support further refinement and testing of a clinician notification intervention.