α1-Antitrypsin Binds to the Glucocorticoid Receptor with Anti-Inflammatory and Antimycobacterial Significance in Macrophages.

α1-Antitrypsin (AAT), a serine protease inhibitor, is the third most abundant protein in plasma. Although the best-known function of AAT is irreversible inhibition of elastase, AAT is an acute-phase reactant and is increasingly recognized to have a panoply of other functions, including as an anti-inflammatory mediator and a host-protective molecule against various pathogens. Although a canonical receptor for AAT has not been identified, AAT can be internalized into the cytoplasm and is known to affect gene regulation. Because AAT has anti-inflammatory properties, we examined whether AAT binds the cytoplasmic glucocorticoid receptor (GR) in human macrophages. We report the finding that AAT binds to GR using several approaches, including coimmunoprecipitation, mass spectrometry, and microscale thermophoresis. We also performed in silico molecular modeling and found that binding between AAT and GR has a plausible stereochemical basis. The significance of this interaction in macrophages is evinced by AAT inhibition of LPS-induced NF-κB activation and IL-8 production as well as AAT induction of angiopoietin-like 4 protein, which are, in part, dependent on GR. Furthermore, this AAT-GR interaction contributes to a host-protective role against mycobacteria in macrophages. In summary, this study identifies a new mechanism for the gene regulation, anti-inflammatory, and host-defense properties of AAT.

Patients Who Have Prior Solid Organ Transplants Have Increased Risk of 10-Year Periprosthetic Joint Infection Revision Following Primary Total Knee Arthroplasty: A Propensity-Matched Analysis.

BACKGROUND: Total knee arthroplasty (TKA) for solid organ transplant (SOT) patients is becoming more prominent as life expectancy in this population increases. However, data on long-term (10 year) implant survivorship in this cohort are sparse. The purpose of this study was to compare 90-day, 2-year, 5-year, and 10-year implant survivability following primary TKA in patients who did and did not have prior SOT. METHODS: The PearlDiver database was utilized to query patients who underwent unilateral elective TKA with at least 2 years of active follow-up. These patients were stratified into those who had a SOT before TKA and those who did not. The SOT cohort was propensity-matched to control patients based on age, sex, Charlson Comorbidity Index, and obesity in a 1:2 ratio. Cumulative incidence rates and hazard ratios (HRs) were compared between the SOT, matched, and unmatched cohorts. RESULTS: No difference was observed in 10-year cumulative incidence and risk of all-cause revision surgery in TKA patients with prior SOT when compared to matched and unmatched controls. Compared to the matched control, the SOT cohort had no difference in the risk of revision when stratified by indication and timing. However, when compared to the unmatched control, patients who had prior SOT had a higher risk for revision due to periprosthetic joint infection at 10 years (HR: 1.80; 95% confidence interval: 1.17 to 2.76) as well as all-cause revision within 90 days after TKA (HR: 1.93; 95% confidence interval: 1.10 to 3.36). CONCLUSIONS: Prior SOT patients have higher rates of all-cause revision within 90 days and periprosthetic joint infection within 10 years when compared to the general population, likely associated with the elevated number of comorbidities in SOT patients and not the transplant itself. Therefore, these patients should be monitored in the preoperative and early postoperative settings to optimize their known comorbidities.

A Review of Bicarbonate Use in Common Clinical Scenarios.

BACKGROUND: The use of sodium bicarbonate to treat metabolic acidosis is intuitive, yet data suggest that not all patients benefit from this therapy. OBJECTIVE: In this narrative review, we describe the physiology behind commonly encountered nontoxicologic causes of metabolic acidosis, highlight potential harm from the indiscriminate administration of sodium bicarbonate in certain scenarios, and provide evidence-based recommendations to assist emergency physicians in the rational use of sodium bicarbonate. DISCUSSION: Sodium bicarbonate can be administered as a hypertonic push, as a resuscitation fluid, or as an infusion. Lactic acidosis and cardiac arrest are two common scenarios where there is limited benefit to routine use of sodium bicarbonate, although certain circumstances, such as patients with concomitant acute kidney injury and lactic acidosis may benefit from sodium bicarbonate. Patients with cardiac arrest secondary to sodium channel blockade or hyperkalemia also benefit from sodium bicarbonate therapy. Recent data suggest that the use of sodium bicarbonate in diabetic ketoacidosis does not confer improved patient outcomes and may cause harm in pediatric patients. Available evidence suggests that alkalinization of urine in rhabdomyolysis does not improve patient-centered outcomes. Finally, patients with a nongap acidosis benefit from sodium bicarbonate supplementation. CONCLUSIONS: Empiric use of sodium bicarbonate in patients with nontoxicologic causes of metabolic acidosis is not warranted and likely does not improve patient-centered outcomes, except in select scenarios. Emergency physicians should reserve use of this medication to conditions with clear benefit to patients.

Integrated genomics approaches identify transcriptional mediators and epigenetic responses to Afghan desert particulate matter in small airway epithelial cells.

Military Deployment to Southwest Asia and Afghanistan and exposure to toxic airborne particulates have been associated with an increased risk of developing respiratory disease, collectively termed deployment-related respiratory diseases (DRRDs). Our knowledge about how particulates mediate respiratory disease is limited, precluding the appropriate recognition or management. Central to this limitation is the lack of understanding of how exposures translate into dysregulated cell identity with dysregulated transcriptional programs. The small airway epithelium is involved in both the pathobiology of DRRD and fine particulate matter deposition. To characterize small airway epithelial cell epigenetic and transcriptional responses to Afghan desert particulate matter (APM) and investigate the functional interactions of transcription factors that mediate these responses, we applied two genomics assays, the assay for transposase accessible chromatin with sequencing (ATAC-seq) and Precision Run-on sequencing (PRO-seq). We identified activity changes in a series of transcriptional pathways as candidate regulators of susceptibility to subsequent insults, including signal-dependent pathways, such as loss of cytochrome P450 or P53/P63, and lineage-determining transcription factors, such as GRHL2 loss or TEAD3 activation. We further demonstrated that TEAD3 activation was unique to APM exposure despite similar inflammatory responses when compared with wood smoke particle exposure and that P53/P63 program loss was uniquely positioned at the intersection of signal-dependent and lineage-determining transcriptional programs. Our results establish the utility of an integrated genomics approach in characterizing responses to exposures and identifying genomic targets for the advanced investigation of the pathogenesis of DRRD.

Deconvolution of multiplexed transcriptional responses to wood smoke particles defines rapid aryl hydrocarbon receptor signaling dynamics.

The heterogeneity of respirable particulates and compounds complicates our understanding of transcriptional responses to air pollution. Here, we address this by applying precision nuclear run-on sequencing and the assay for transposase-accessible chromatin sequencing to measure nascent transcription and chromatin accessibility in airway epithelial cells after wood smoke particle (WSP) exposure. We used transcription factor enrichment analysis to identify temporally distinct roles for ternary response factor-serum response factor complexes, the aryl hydrocarbon receptor (AHR), and NFκB in regulating transcriptional changes induced by WSP. Transcription of canonical targets of the AHR, such as CYP1A1 and AHRR, was robustly increased after just 30 min of WSP exposure, and we discovered novel AHR-regulated pathways and targets including the DNA methyltransferase, DNMT3L. Transcription of these genes and associated enhancers rapidly returned to near baseline by 120 min after exposure. The kinetics of AHR- and NFκB-regulated responses to WSP were distinguishable based on the timing of both transcriptional responses and chromatin remodeling, with induction of several cytokines implicated in maintaining NFκB-mediated responses through 120 min of exposure. In aggregate, our data establish a direct and primary role for AHR in mediating airway epithelial responses to WSP and identify crosstalk between AHR and NFκB signaling in controlling proinflammatory gene expression. This work also defines an integrated genomics-based strategy for deconvoluting multiplexed transcriptional responses to heterogeneous environmental exposures.

Nascent transcript analysis of glucocorticoid crosstalk with TNF defines primary and cooperative inflammatory repression.

The glucocorticoid receptor (NR3C1, also known as GR) binds to specific DNA sequences and directly induces transcription of anti-inflammatory genes that contribute to cytokine repression, frequently in cooperation with NF-kB. Whether inflammatory repression also occurs through local interactions between GR and inflammatory gene regulatory elements has been controversial. Here, using global run-on sequencing (GRO-seq) in human airway epithelial cells, we show that glucocorticoid signaling represses transcription within 10 min. Many repressed regulatory regions reside within "hyper-ChIPable" genomic regions that are subject to dynamic, yet nonspecific, interactions with some antibodies. When this artifact was accounted for, we determined that transcriptional repression does not require local GR occupancy. Instead, widespread transcriptional induction through canonical GR binding sites is associated with reciprocal repression of distal TNF-regulated enhancers through a chromatin-dependent process, as evidenced by chromatin accessibility and motif displacement analysis. Simultaneously, transcriptional induction of key anti-inflammatory effectors is decoupled from primary repression through cooperation between GR and NF-kB at a subset of regulatory regions. Thus, glucocorticoids exert bimodal restraints on inflammation characterized by rapid primary transcriptional repression without local GR occupancy and secondary anti-inflammatory effects resulting from transcriptional cooperation between GR and NF-kB.

Dispelling myths and misconceptions about the treatment of acute hyperkalemia.

Hyperkalemia represents a widespread and potentially lethal condition that affects millions of people across their lives. Despite the prevalence and severity of the condition, there are no consensus guidelines on the treatment of hyperkalemia or even a standard definition. Herein, we provide a succinct review of what we believe to be the most significant misconceptions encountered in the emergency care of hyperkalemia, examine current available literature, and discuss practical points on several modalities of hyperkalemia treatment. Additionally, we review the pathophysiology of the electrocardiographic effects of hyperkalemia and how intravenous calcium preparations can antagonize these effects. We conclude each section with recommendations to aid emergency physicians in making safe and efficacious choices for the treatment of acute hyperkalemia.

Prospective correlation between the patient microbiome with response to and development of immune-mediated adverse effects to immunotherapy in lung cancer.

BACKGROUND: Though the gut microbiome has been associated with efficacy of immunotherapy (ICI) in certain cancers, similar findings have not been identified for microbiomes from other body sites and their correlation to treatment response and immune related adverse events (irAEs) in lung cancer (LC) patients receiving ICIs. METHODS: We designed a prospective cohort study conducted from 2018 to 2020 at a single-center academic institution to assess for correlations between the microbiome in various body sites with treatment response and development of irAEs in LC patients treated with ICIs. Patients must have had measurable disease, ECOG 0-2, and good organ function to be included. Data was collected for analysis from January 2019 to October 2020. Patients with histopathologically confirmed, advanced/metastatic LC planned to undergo immunotherapy-based treatment were enrolled between September 2018 and June 2019. Nasal, buccal and gut microbiome samples were obtained prior to initiation of immunotherapy +/- chemotherapy, at development of adverse events (irAEs), and at improvement of irAEs to grade 1 or less. RESULTS: Thirty-seven patients were enrolled, and 34 patients were evaluable for this report. 32 healthy controls (HC) from the same geographic region were included to compare baseline gut microbiota. Compared to HC, LC gut microbiota exhibited significantly lower α-diversity. The gut microbiome of patients who did not suffer irAEs were found to have relative enrichment of Bifidobacterium (p = 0.001) and Desulfovibrio (p = 0.0002). Responders to combined chemoimmunotherapy exhibited increased Clostridiales (p = 0.018) but reduced Rikenellaceae (p = 0.016). In responders to chemoimmunotherapy we also observed enrichment of Finegoldia in nasal microbiome, and increased Megasphaera but reduced Actinobacillus in buccal samples. Longitudinal samples exhibited a trend of α-diversity and certain microbial changes during the development and resolution of irAEs. CONCLUSIONS: This pilot study identifies significant differences in the gut microbiome between HC and LC patients, and their correlation to treatment response and irAEs in LC. In addition, it suggests potential predictive utility in nasal and buccal microbiomes, warranting further validation with a larger cohort and mechanistic dissection using preclinical models. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03688347 . Retrospectively registered 09/28/2018.

What Is the Best Evidence to Guide Management of Acute Achilles Tendon Ruptures? A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Uncertainty exists regarding the best treatment for acute Achilles tendon ruptures. Simultaneous comparison of the multiple treatment options using traditional study designs is problematic; multiarm clinical trials often are logistically constrained to small sample sizes, and traditional meta-analyses are limited to comparisons of only two treatments that have been compared in head-to-head trials. Network meta-analyses allow for simultaneous comparison of all existing treatments utilizing both direct (head-to-head comparison) and indirect (not previously compared head-to-head) evidence. QUESTIONS/PURPOSES: We performed a network meta-analysis of randomized controlled trials (RCTs) to answer the following questions: Considering open repair, minimally invasive surgery (MIS) repair, functional rehabilitation, or primary immobilization for acute Achilles tendon ruptures, (1) which intervention is associated with the lowest risk of rerupture? (2) Which intervention is associated with the lowest risk of complications resulting in surgery? METHODS: This study was conducted with methods guided by the Cochrane Handbook for Systematic Reviews of Interventions and is reported in adherence with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension statement for incorporating network meta-analysis. Five databases and grey literature sources (such as major orthopaedic meeting presentation lists) were searched from inception to September 30, 2019. Included studies were RCTs comparing treatment of acute Achilles tendon ruptures using two or more of the following interventions: primary immobilization, functional rehabilitation, open surgical repair, or MIS repair. We excluded studies enrolling patients with chronic ruptures, reruptures, and preexisting Achilles tendinopathy as well as studies with more than 20% loss to follow-up or less than 6 months of follow-up. Nineteen RCTs (1316 patients) were included in the final analysis. The mean number of patients per study treatment arm was 35 ± 16, mean age was 41 ± 5 years, mean sex composition was 80% ± 10% males, and mean follow-up was 22 ± 12 months. The four treatment groups were compared for the main outcomes of rerupture and complications resulting in operation. The analysis was conducted using random-effects Bayesian network meta-analysis with vague priors. Evidence quality was evaluated using Grades of Recommendation, Assessment, Development, and Evaluation methodology. We found risk of selection, attrition, and reporting bias to be low across treatments, and we found the risk of performance and detection bias to be high. Overall risk of bias between treatments appeared similar. RESULTS: We found that treatment with primary immobilization had a greater risk of rerupture than open surgery (odds ratio 4.06 [95% credible interval {CrI} 1.47 to 11.88]; p < 0.05). There were no other differences between treatments for risk of rerupture. Minimally invasive surgery was ranked first for fewest complications resulting in surgery and was associated with a lower risk of complications resulting in surgery than functional rehabilitation (OR 0.16 [95% CrI 0.02 to 0.90]; p < 0.05), open surgery (OR 0.22 [95% CrI 0.04 to 0.93]; p < 0.05), and primary immobilization (OR < 0.01 [95% CrI < 0.01 to 0.01]; p < 0.05). Risk of complications resulting in surgery was no different between primary immobilization and open surgery (OR 1.46 [95% CrI 0.35 to 5.36]). Data for patient-reported outcome scores and return to activity were inappropriate for pooling secondary to considerable clinical heterogeneity and imprecision associated with small sample sizes. CONCLUSION: Faced with acute Achilles tendon rupture, patients should be counseled that, based on the best-available evidence, the risk of rerupture likely is no different across contemporary treatments. Considering the possibly lower risk of complications resulting in surgery associated with MIS repair, patients and surgeons must balance any benefit with the potential risks of MIS techniques. As treatments continue to evolve, consistent reporting of validated patient-reported outcome measures is critically important to facilitate analysis with existing RCT evidence. Infrequent but serious complications such as rerupture and deep infection should be further explored to determine whether meaningful differences exist in specific patient populations. LEVEL OF EVIDENCE: Level I, therapeutic study.

All-epiphyseal anterior cruciate ligament reconstruction produces good functional outcomes and low complication rates in pediatric patients: a systematic review.

PURPOSE: To assess the literature on indications, outcomes, and complications in pediatric patients undergoing all-epiphyseal (AE) anterior cruciate ligament reconstruction (ACLR). METHODS: PubMed, Medline, and Embase were searched for literature evaluating AE ACLR in pediatric patients. All included studies were assessed for quality using the Methodological Index for Non-Randomized Studies (MINORS). Descriptive statistics are presented where applicable. RESULTS: Overall, 17 studies comprising 545 patients, with a mean age of 12.0 ± 1.2 (range 8-19) met the inclusion criteria. The graft choices in this systematic review included hamstring tendon autografts (75.4%, n = 403), quadriceps tendon autograft (6.2%, n = 33), Achilles tendon allograft (3.6%, n = 19) and posterior tibialis tendon allograft in one patient (0.2%, n = 1). Time of return-to-sport ranged from 8 to 22 months. Postoperative subjective IKDC scores were above 90 points. The rate of return-to-sport after AE ACLR was 93.2% (n = 219/235) and 77.9% (n = 142/183) of patients returned to sport at pre-injury level. The overall complication rate was 9.8% (n = 53/545) with the most common complication being ACL re-rupture (5.0%; n = 27/545). Only 1.5% (n = 8/545) of patients demonstrated growth disturbances. CONCLUSION: Overall, the AE ACLR technique can achieve good postoperative functional outcomes while notably minimizing the incidence of primary issue of physeal disruption and potential associated leg-length discrepancies. AE ACLR should be considered in pediatric patients with at least 2 years of skeletal growth remaining based on radiographic bone age to minimize the impact of growth-related complications. LEVEL OF EVIDENCE: IV (Systematic Review of Level III and IV evidence).

Can Prehospital Personnel Accurately Triage Patients for Large Vessel Occlusion Strokes?

BACKGROUND: The Field Assessment Stroke Triage for Emergency Destination (FAST-ED) score was developed in the hospital setting to be used in the prehospital setting. It has been shown to have higher predictive value than comparable stroke scales, including the National Institutes of Health Stroke Scale, for identifying large vessel occlusion strokes. OBJECTIVE: We sought to determine whether prehospital FAST-ED scores are comparable with FAST-ED scores determined by emergency physicians. METHODS: Emergency Medical Services (EMS) personnel were trained to calculate a FAST-ED score for any patient suspected of having a stroke in the field. When the patient arrived at our ED, an emergency physician generated a FAST-ED score. RESULTS: One hundred and thirty-five patients were studied and large vessel occlusions were detected in 23.7%. There was no significant difference between median FAST-ED scores from EMS personnel (3; interquartile range [IQR] 1-5) and emergency physician (2; IQR 1-6). The difference between paired scores was not significantly different from 0 (median of paired differences was 0). In addition, prehospital FAST-ED scores were significantly and positively correlated with physician FAST-ED scores (r2 = 0.26). Comparable receiver operator curve area under the curve values were obtained for EMS FAST-ED (0.727; 95% confidence interval [CI] 0.638-0.816) and ED FAST-ED (0.769; 95% CI 0.669-0.868). CONCLUSIONS: The findings validate that prehospital FAST-ED scores are comparable in predictive value to FAST-ED scores calculated in the ED for prediction of large vessel occlusion strokes.

On the value of meta-research for early career researchers: A commentary.

Meta-research, also known as "research on research" is a field of study that investigates the methods, reporting, reproducibility, evaluation, and incentives along the research continuum. Meta-research literacy is imperative to ensure high quality, transparent and reproducible primary data or meta-research products. In this commentary, we propose that early career researchers should be trained in meta-research as a foundation to develop a deeper understanding of the research process and ability to appraise the research literature and design high-quality original studies, irrespective of their chosen field of study. We discuss the importance of meta-research and open science from the perspective of an early career trainee, highlighting essential areas for growth and obstacles one may encounter.

Sublingual Dermoid in an Adult Patient.

Dermoid cysts in the floor of the mouth are a relatively rare and unusual site of location anomalies presumed to be caused by entrapment of germinal epithelium along the lines of embryonic fusion. It presents as soft, non-painful, and slowly growing swelling along the lines of fusion during the closure of mandibular and hyoid branch arches. These cysts are developmental and histopathologically classified into three types: epidermoid, dermoid, and teratoid. We are reporting a rare case of a 32-year-old female who presented in the outpatient department with complaints of painless swelling over the floor of the mouth for two years, suggesting a benign sublingual mass. This case report underscores the importance of clinical presentation, diagnostic workup, and surgical approach in achieving successful outcomes for sublingual mass.

Mesenchymal stem cell based therapies for uveitis: a systematic review of preclinical studies.

Cell therapy has shown promising results for treating uveitis in preclinical studies. As the field continues to grow towards clinical translation, it is important to review and critically appraise existing studies. Herein, we analysed and critically appraised all preclinical studies using cell therapy or cell derived extracellular vesicles (EVs) for uveitis, and provided insight into mechanisms regulating ocular inflammation. We used PubMed, Medline, and Embase to search for preclinical studies examining stem cell therapy (e.g., mesenchymal stem cells [MSC]) and secreted EVs. All included studies were assessed for quality using the SYstematic Review Center for Laboratory animal Experimentation (SYRCLE) checklist. Sixteen preclinical studies from 2011 to 2022 were analysed and included in this review of which 75% (n = 12) focused only on cell therapy, 18.7% (n = 3) studies focused on EVs, and 6.3% (n = 1) study focused on both cells and EVs. MSCs were the most common type of cells used in preclinical studies (n = 15) and EVs were commonly isolated from MSCs (n = 3). Overall, both MSCs and EVs showed improvements in ocular inflammation (seen on fundoscopy/slit lamp and histology) and electroretinogram outcomes. Overall, MSC and MSC-derived EVs shown great potential as therapeutic agents for treating uveitis. Unfortunately, small sample size, risk of selection/performance bias, and lack of standardized cell harvesting or delivery protocols are some factors which limits clinical translation. Large scaled, randomized preclinical studies are required to understand the full potential of MSCs for treating uveitis.

How to optimize the systematic review process using AI tools.

Systematic reviews are a cornerstone for synthesizing the available evidence on a given topic. They simultaneously allow for gaps in the literature to be identified and provide direction for future research. However, due to the ever-increasing volume and complexity of the available literature, traditional methods for conducting systematic reviews are less efficient and more time-consuming. Numerous artificial intelligence (AI) tools are being released with the potential to optimize efficiency in academic writing and assist with various stages of the systematic review process including developing and refining search strategies, screening titles and abstracts for inclusion or exclusion criteria, extracting essential data from studies and summarizing findings. Therefore, in this article we provide an overview of the currently available tools and how they can be incorporated into the systematic review process to improve efficiency and quality of research synthesis. We emphasize that authors must report all AI tools that have been used at each stage to ensure replicability as part of reporting in methods.

Left atrial reservoir strain is a superior discriminator of cardioembolism in ischaemic stroke.

Aims: Echocardiographic measures of left heart size and function have long been associated with cardioembolic mechanisms of stroke development, however, the diagnostic performance and comparison of measures of atrial function in this context has not been well studied. We sought to evaluate the diagnostic performance of left atrial reservoir strain (LASr) in identification of cardioembolism in the ischaemic stroke population relative to traditional measures of left heart size and function. Methods and results: Consecutive patients admitted to our institution with ischaemic stroke or transient ischaemic attack were recruited and underwent comprehensive transthoracic echocardiography. Strokes were classified by aetiology with comparison undertaken between cardioembolic and non-cardioembolic types. Four hundred and eighteen consecutive stroke patients with a cardioembolic (n = 229) or non-cardioembolic (n = 189) stroke aetiology were analysed. LASr was impaired in cardioembolic compared with non-cardioembolic strokes (16.7 ± 8.2% vs. 26.0 ± 5.5%, P < 0.01) and provided greatest discrimination [area under the curve (AUC) 0.813, 95%CI 0.773-0.858] in differentiating stroke subtypes when compared with LVEF (AUC difference 0.150, P < 0.01), LAVI (AUC difference 0.083, P < 0.01), and E/e' (AUC difference 0.163, P < 0.01). Inclusion of LASr in a model with conventional left heart echocardiographic factors improved model performance with a net reclassification improvement of 1.083 (95%CI 0.945-1.220, P < 0.01). Further, a proposed user-defined model-based clinical algorithm with LASr demonstrated improved diagnostic accuracy of the identification of cardioembolic stroke subtypes which was best appreciated in patients without atrial fibrillation. Conclusion: LASr may provide enhanced diagnostic accuracy beyond conventional echocardiographic measures to discriminate cardioembolic from non-cardioembolic stroke mechanisms, in particular amongst those without comorbid atrial fibrillation.

Interventions to prevent and treat delirium: An umbrella review of randomized controlled trials.

Delirium is a common condition across different settings and populations. The interventions for preventing and managing this condition are still poorly known. The aim of this umbrella review is to synthesize and grade all preventative and therapeutic interventions for delirium. We searched five databases from database inception up to March 15th, 2023 and we included meta-analyses of randomized controlled trials (RCTs) to decrease the risk of/the severity of delirium. From 1959 records after deduplication, we included 59 systematic reviews with meta-analyses, providing 110 meta-analytic estimates across populations, interventions, outcomes, settings, and age groups (485 unique RCTs, 172,045 participants). In surgery setting, for preventing delirium, high GRADE evidence supported dexmedetomidine (RR=0.53; 95%CI: 0.46-0.67, k=13, N=3988) and comprehensive geriatric assessment (OR=0.46; 95%CI=0.32-0.67, k=3, N=496) in older adults, dexmedetomidine in adults (RR=0.33, 95%CI=0.24-0.45, k=7, N=1974), A2-adrenergic agonists after induction of anesthesia (OR= 0.28, 95%CI= 0.19-0.40, k=10, N=669) in children. High certainty evidence did not support melatonergic agents in older adults for delirium prevention. Moderate certainty supported the effect of dexmedetomidine in adults and children (k=4), various non-pharmacological interventions in adults and older people (k=4), second-generation antipsychotics in adults and mixed age groups (k=3), EEG-guided anesthesia in adults (k=2), mixed pharmacological interventions (k=1), five other specific pharmacological interventions in children (k=1 each). In conclusion, our work indicates that effective treatments to prevent delirium differ across populations, settings, and age groups. Results inform future guidelines to prevent or treat delirium, accounting for safety and costs of interventions. More research is needed in non-surgical settings.

Physical activity, suicidal ideation, suicide attempt and death among individuals with mental or other medical disorders: A systematic review of observational studies.

A growing body of research has demonstrated the potential role for physical activity as an intervention across mental and other medical disorders. However, the association between physical activity and suicidal ideation, attempts, and deaths has not been systematically appraised in clinical samples. We conducted a PRISMA 2020-compliant systematic review searching MEDLINE, EMBASE, and PsycINFO for observational studies investigating the influence of physical activity on suicidal behavior up to December 6, 2023. Of 116 eligible full-text studies, seven (n = 141691) were included. Depression was the most frequently studied mental condition (43%, k = 3), followed by chronic pain as the most common other medical condition (29%, k = 2). Two case-control studies examined suicide attempts and found an association between physical activity and a reduced frequency of such attempts. However, in studies examining suicidal ideation (k = 3) or suicide deaths (k = 2), no consistent associations with physical activity were observed. Overall, our systematic review found that physical activity may be linked to a lower frequency of suicide attempts in non-prospective studies involving individuals with mental disorders.

Pathogenesis of E-Cigarette Vaping Product Use-Associated Lung Injury (EVALI).

EVALI is an acute inflammatory disease in response to lung cell injury induced by electronic cigarettes and vaping devices (EV) frequently containing Vitamin E Acetate or tetrahydrocannabinol additives, in the context of risk factors such as microbial exposure. EVALI resembles a respiratory viral illness that may progress to acute respiratory failure and acute respiratory distress syndrome (ARDS) but can also affect extra pulmonary organs. Manifestations may be severe, leading to death or long-term morbidity and current treatments are largely supportive. While COVID-19 has demanded public and research attention, EVALI continues to affect young individuals and its better understanding via research remains a priority. Although clinical research led to improved recognition of triggers, clinical and pathological manifestations, and natural course of EVALI, important questions remain that require a better understanding of disease pathogenesis. Preclinical models utilizing laboratory animals and cell or tissue culture platforms provide insight into the physiologic and mechanistic consequences of acute and chronic EV exposure, including the characteristics of the respiratory dysfunction and inflammatory response. However, a key limitation in the field is the absence of an established animal model of EVALI. Important areas of research emphasis include identifying triggers and risk factors to understand why only certain vapers develop EVALI, the role of specific lung immune and structural cells in the pathogenesis of EVALI, and the most important molecular mediators and therapeutic targets in EVALI. © 2023 American Physiological Society. Compr Physiol 13:4617-4630, 2023.