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An exaggerated mean arterial blood pressure (MAP) response to exercise in patients with peripheral artery disease (PAD), likely driven by inflammation and oxidative stress and, perhaps, required to achieve an adequate blood flow response, is well described. However, the blood flow response to exercise in patients with PAD actually remains equivocal. Therefore, eight patients with PAD and eight healthy controls completed 3 min of plantar flexion exercise at both an absolute work rate (WR) (2.7 W, to evaluate blood flow) and a relative intensity (40%WRmax, to evaluate MAP). The exercise-induced change in popliteal artery blood flow (BF, Ultrasound Doppler), MAP (Finapress), and vascular conductance (VC) were quantified. In addition, resting markers of inflammation and oxidative stress were measured in plasma and muscle biopsies. Exercise-induced ΔBF, assessed at 2.7 W, was lower in PAD compared with controls (PAD: 251 ± 150 vs. Controls: 545 ± 187 mL/min, P < 0.001), whereas ΔMAP, assessed at 40%WRmax, was greater for PAD (PAD: 23 ± 14 vs. Controls: 11 ± 6 mmHg, P = 0.028). The exercise-induced ΔVC was lower for PAD during both the absolute WR (PAD: 1.9 ± 1.6 vs. Controls: 4.7 ± 1.9 mL/min/mmHg) and relative intensity exercise (PAD: 1.9 ± 1.8 vs. Controls: 5.0 ± 2.2 mL/min/mmHg) trials (both, P < 0.01). Inflammatory and oxidative stress markers, including plasma interleukin-6 and muscle protein carbonyls, were elevated in PAD (both, P < 0.05), and significantly correlated with the hemodynamic changes during exercise ( r = −0.57 to −0.78, P < 0.05). Thus, despite an exaggerated ΔMAP response, patients with PAD exhibit an impaired exercise-induced ΔBF and ΔVC, and both inflammation and oxidative stress likely play a role in this attenuated hemodynamic response.

SNPs associated with human stroke risk have been identified in the intergenic region between Forkhead family transcription factors FOXF2 and FOXQ1 , but we lack a mechanism for the association. FoxF2 is expressed in vascular mural pericytes and is important for maintaining pericyte number and stabilizing small vessels in zebrafish. The stroke-associated SNPs are located in a previously unknown transcriptional enhancer for FOXF2 , functional in human cells and zebrafish. We identify critical enhancer regions for FOXF2 gene expression, including binding sites occupied by transcription factors ETS1, RBPJ, and CTCF. rs74564934, a stroke-associated SNP adjacent to the ETS1 binding site, decreases enhancer function, as does mutation of RPBJ sites. rs74564934 is significantly associated with the increased risk of any stroke, ischemic stroke, small vessel stroke, and elevated white matter hyperintensity burden in humans. Foxf2 has a conserved function cross-species and is expressed in vascular mural pericytes of the vessel wall. Thus, stroke-associated SNPs modulate enhancer activity and expression of a regulator of vascular stabilization, FOXF2 , thereby modulating stroke risk.

Reductions in skeletal muscle mass and function are often reported in patients with cancer-associated weight loss and are associated with reduced quality of life, impaired treatment tolerance, and increased mortality. Although cellular changes, including altered mitochondrial function, have been reported in animals, such changes have been incompletely characterized in humans with cancer. Whole body and skeletal muscle physical function, skeletal muscle mitochondrial function, and whole body protein turnover were assessed in eight patients with cancer-associated weight loss (10.1 ± 4.2% body weight over 6–12 mo) and 19 age-, sex-, and body mass index (BMI)-matched healthy controls to characterize skeletal muscle changes at the whole body, muscle, and cellular level. Potential pathways involved in cancer-induced alterations in metabolism and mitochondrial function were explored by interrogating skeletal muscle and plasma metabolomes. Despite similar lean mass compared with control participants, patients with cancer exhibited reduced habitual physical activity (57% fewer daily steps), cardiorespiratory fitness [22% lower V̇o(2peak) (mL/kg/min)] and leg strength (35% lower isokinetic knee extensor strength), and greater leg neuromuscular fatigue (36% greater decline in knee extensor torque). Concomitant with these functional declines, patients with cancer had lower mitochondrial oxidative capacity [25% lower State 3 O(2) flux (pmol/s/mg tissue)] and ATP production [23% lower State 3 ATP production (pmol/s/mg tissue)] and alterations in phospholipid metabolite profiles indicative of mitochondrial abnormalities. Whole body protein turnover was unchanged. These findings demonstrate mitochondrial abnormalities concomitant with whole body and skeletal muscle functional derangements associated with human cancer, supporting future work studying the role of mitochondria in the muscle deficits associated with cancer. NEW & NOTEWORTHY To our knowledge, this is the first study to suggest that skeletal muscle mitochondrial deficits are associated with cancer-associated weight loss in humans. Mitochondrial deficits were concurrent with reductions in whole body and skeletal muscle functional capacity. Whether mitochondrial deficits are causal or secondary to cancer-associated weight loss and functional deficits remains to be determined, but this study supports further exploration of mitochondria as a driver of cancer-associated losses in muscle mass and function.

Recently it was documented that fatiguing, high-intensity exercise resulted in a significant attenuation in maximal skeletal muscle mitochondrial respiratory capacity, potentially due to the intramuscular metabolic perturbation elicited by such intense exercise. With the utilization of intrathecal fentanyl to attenuate afferent feedback from group III/IV muscle afferents, permitting increased muscle activation and greater intramuscular metabolic disturbance, this study aimed to better elucidate the role of metabolic perturbation on mitochondrial respiratory function. Eight young, healthy males performed high-intensity cycle exercise in control (CTRL) and fentanyl-treated (FENT) conditions. Liquid chromatography-mass spectrometry and high-resolution respirometry were used to assess metabolites and mitochondrial respiratory function, respectively, pre- and postexercise in muscle biopsies from the vastus lateralis. Compared with CTRL, FENT yielded a significantly greater exercise-induced metabolic perturbation (PCr: −67% vs. −82%, Pi: 353% vs. 534%, pH: −0.22 vs. −0.31, lactate: 820% vs. 1,160%). Somewhat surprisingly, despite this greater metabolic perturbation in FENT compared with CTRL, with the only exception of respiratory control ratio (RCR) (−3% and −36%) for which the impact of FENT was significantly greater, the degree of attenuated mitochondrial respiratory capacity postexercise was not different between CTRL and FENT, respectively, as assessed by maximal respiratory flux through complex I (−15% and −33%), complex II (−36% and −23%), complex I + II (−31% and −20%), and state 3CI+CII control ratio (−24% and −39%). Although a basement effect cannot be ruled out, this failure of an augmented metabolic perturbation to extensively further attenuate mitochondrial function questions the direct role of high-intensity exercise-induced metabolite accumulation in this postexercise response.

Background Central nervous system complications are reported in an increasing number of patients with Coronavirus Disease 2019 (COVID-19). COVID-19-related Guillain-Barre syndrome (GBS) is of particular importance given its association with higher mortality rates and prolonged respiratory failure. Review summary We conducted a systematic review of published cases for COVID-19-related GBS, and provide a summary of clinical management strategies for these cases. Sixty-three studies, including 86 patients, were included. Seventy-six cases with reported outcome data were eligible for the outcome analysis. Ninety-nine percent of patients were diagnosed with COVID-19 before diagnosis of GBS (median: 14 d prior, interquartile range: 7 to 20). Intravenous immunotherapy (intravenous immunoglobulin: 0.4 g/kg/d for 5 d) was the most frequently used treatment approach. The review indicated that the outcome was not favorable in 26% of cases (persistent neurological deficits). A mortality rate of 3.5% was observed in patients with COVID-19-related GBS. Conclusions Although evidence to support specific treatments is lacking, clinicians should consider the benefits of immunotherapy and plasma exchange in addition to the standard antimicrobial and supportive therapies for patients who meet the diagnostic criteria for acute sensory and motor polyradiculoneuritis. Intravenous immunoglobulin treatment alone is not shown to result in improved outcomes or mortality. More extensive studies aimed at exploring the neurological manifestations and complications of COVID-19 and distinctive treatment options for COVID-19-related GBS are warranted.

Objective Mindfulness has received attention in smoking cessation research, yet the mechanisms by which mindfulness may promote smoking cessation are not well understood. Mindfulness training may help individuals increase awareness and respond skillfully to processes that contribute to smoking, such as affective states and craving. This study used experience sampling (ES) to test how awareness was related to craving, positive and negative affect and smoking, in the moment, among smokers in treatment for smoking cessation. Method Participants (N = 228) were part of a clinical trial evaluating Craving to Quit, a smartphone app for mindfulness training for smoking cessation, compared to an app delivering only ES. All participants were asked to complete 22 days of ES, with up to 6 ES surveys per day, measuring awareness, craving, positive and negative affect and smoking. Data were analyzed using multilevel linear modeling. Results Both at the within and between-person level, higher awareness was associated with higher positive affect, lower craving and lower negative affect. Lower within-person craving was associated with lower smoking. Within-person awareness, positive and negative affect were not significantly associated with smoking. At the between-person level, higher awareness and higher positive affect, and lower negative affect and lower craving were associated with lower smoking. Conclusions Awareness of current experience was related to key psychological variables linked to behavior change in smoking cessation, namely positive and negative affect and craving, among smokers trying to quit. Future studies should test whether learning to increase awareness, such as through mindfulness training, may benefit smokers in treatment. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Obesity is associated with several skeletal muscle impairments which can be improved through an aerobic exercise prescription. The possibility that exercise responsiveness is diminished in people with obesity has been suggested but not well-studied. The purpose of this study was to investigate how obesity influences acute exercise responsiveness in skeletal muscle and circulating amino metabolites. Non-obese (NO; n = 19; 10F/9M; BMI = 25.1 ± 2.8 kg/m

Mindfulness is a two-component skill that includes mindful awareness (attentional monitoring of present moment experience) and mindful acceptance (adopting an attitude of acceptance toward this experience). Although mindfulness-based interventions (MBIs) are efficacious for many conditions, there is a lack of research on MBIs for eating disorders (EDs). We propose that MBIs may be promising for EDs given their potential to mobilize not one, but multiple associative-learning change mechanisms in EDs-defined as adaptive processes of change involving one of two forms of associative-learning: Pavlovian and operant learning. We hypothesize how MBIs-via increasing either mindful awareness or mindful acceptance-may mobilize up to eight associative-learning change mechanisms, two involving Pavlovian learning, and six involving operant learning. We also elaborate on similarities and differences between MBIs and CBT approaches for EDs, as well as opportunities for synergy. Finally, we present recommendations for future research related to the development and evaluation of novel MBI interventions for EDs and the testing of mechanisms and patient-treatment matching hypotheses.

Recognition of pathogen-or-damage-associated molecular patterns is critical to inflammation. However, most pathogen-or-damage-associated molecular patterns exist within intact microbes/cells and are typically part of non-diffusible, stable macromolecules that are not optimally immunostimulatory or available for immune detection. Partial digestion of microbes/cells following phagocytosis potentially generates new diffusible pathogen-or-damage-associated molecular patterns, however, our current understanding of phagosomal biology would have these molecules sequestered and destroyed within phagolysosomes. Here, we show the controlled release of partially-digested, soluble material from phagolysosomes of macrophages through transient, iterative fusion-fission events between mature phagolysosomes and the plasma membrane, a process we term eructophagy. Eructophagy is most active in proinflammatory macrophages and further induced by toll like receptor engagement. Eructophagy is mediated by genes encoding proteins required for autophagy and can activate vicinal cells by release of phagolysosomally-processed, partially-digested pathogen associated molecular patterns. We propose that eructophagy allows macrophages to amplify local inflammation through the processing and dissemination of pathogen-or-damage-associated molecular patterns.

The transient receptor potential cation channel 5 (TRPC5) plays an important role in numerous cellular processes. Due to this, it has gained considerable attention over the past few years as a potential therapeutic target. Recently, TRPC5 has been shown to be involved in the regulation of podocyte survival, indicating a potential treatment option for chronic kidney disease. In addition, a recent study has shown TRPC5 to be expressed in human sensory neurons and suggests that TRPC5 inhibition could be an effective treatment for spontaneous and tactile pain. To understand these processes more fully, potent and selective tool compounds are needed. Herein we report further exploration of the 2-aminobenzimidazole scaffold as a potent TRPC5 inhibitor, culminating in the discovery of 16 f as a potent and selective TRPC5 inhibitor.

OBJECTIVE. The health benefits of exercise are well documented, but several exercise response parameters are attenuated in individuals with obesity. The goal of this pilot study was to identify molecular mechanisms that may influence exercise response with obesity. METHODS. We performed a multi-omics comparison of the transcriptome, proteome and phosphoproteome in muscle from a preliminary cohort of lean (N=4) and people with obesity (N=4) before and after a single bout of 30 minutes of unilateral cycling at 70% VO(2)peak. Mass spectrometry and RNA sequencing were used to interrogate the proteome, phosphoproteome, and transcriptome from muscle biopsy tissue. RESULTS. The main findings are that individuals with obesity exhibited transcriptional and proteomic signatures consistent with reduced mitochondrial function, protein synthesis, and glycogen synthesis. Furthermore, individuals with obesity demonstrated markedly different transcriptional, proteomic, and phosphoproteomic responses to exercise, particularly biosynthetic pathways of glycogen synthesis and protein synthesis. We identified protein kinase CK2 and GSK3β signaling as exercise responsive pathways that were notably altered by obesity. CONCLUSIONS. Opportunities to enhance exercise responsiveness by targeting specific molecular pathways that are disrupted in skeletal muscle from individuals with obesity awaits a better understanding of the precise molecular mechanisms that may limit exercise response pathways in obesity.

Intracranial aneurysms (IA) occur in 3–5% of the general population and may require surgical or endovascular obliteration if the patient is symptomatic or has an increased risk of rupture. These procedures carry an inherent risk of neurological complications, and the outcome can be influenced by the physiological and pharmacological effects of the administered anesthetics. Despite the critical role of anesthetic agents, however, there are no current studies to systematically assess the intraoperative anesthetic risks, benefits, and outcome effects in this population. In this systematic review of the literature, we carefully examine the existing evidence on the risks and benefits of common anesthetic agents during IA obliteration, their physiological and clinical characteristics, and effects on neurological outcome. The initial search strategy captured a total of 287 published studies. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, 28 studies were included in the final report. Our data showed that both volatile and intravenous anesthetics are commonly employed, without evidence that either is superior. Although no specific anesthetic regimens are promoted, their unique neurological, cardiovascular, and physiological properties may be critical to the outcome in vulnerable patients. In particular, patients at risk for perioperative ischemia may benefit from timely administration of anesthetic agents with neuroprotective properties and optimization of their physiological parameters. Further studies are warranted to examine if these anesthetic regimens can reduce the risk of neurological injury and improve the overall outcome in these patients.

OBJECTIVE: Four decades ago the “controlled drinking” controversy roiled the alcohol field. Data have subsequently accumulated indicating that non-abstinent alcohol use disorder (AUD) recovery is achievable, but questions remain whether it is sustainable long-term. This study examined whether non-abstinent recovery at three years following AUD treatment is associated with better functioning at 10 years following treatment. METHODS: Data were from the 10-year follow-up of Project MATCH (New Mexico site only, n=146; 30.1% female, 58.6% non-White). Recovery was defined by latent profile analyses based on psychosocial functioning and alcohol consumption three years following treatment. Drinking practices and consequences, depression, purpose in life, and anger were assessed 10 years following treatment. Distal outcome analyses examined differences in drinking and functional outcomes at 10 years as a function of the 3-year latent profiles. Analyses were pre-registered at https://osf.io/3hbxr. RESULTS: Four latent profiles identified at three years following treatment (i.e., low functioning frequent heavy drinkers, low functioning infrequent heavy drinkers, high functioning heavy drinkers, and high functioning infrequent non-heavy drinkers) were significantly associated with outcomes ten years following treatment. The two high functioning profiles at three years had the highest level of psychological functioning at ten years post-treatment, regardless of alcohol consumption level. Abstinence at three years did not predict better psychological functioning at ten years. CONCLUSIONS: Non-abstinent AUD recovery is possible and is sustainable for up to 10 years following treatment. The current findings align with recent proposals to move beyond relying on alcohol consumption as a central defining feature of AUD recovery.

The allostatic model of addiction suggests that negative affect, such as depressive symptoms, mediates the effect of stress on outcomes among individuals with substance use disorders. However, few longitudinal treatment studies have demonstrated this effect. We analyzed data from a 12-week randomized trial of galantamine and/or computerized cognitive-behavioral therapy (CBT4CBT) for individuals (N = 120) with cocaine use disorder in methadone treatment for opioid use disorder. We evaluated baseline perceived stress as a predictor of end-of-treatment (EOT) substance use outcomes, and EOT perceived stress as a predictor of month 6 posttreatment outcomes. We conducted mediation models with intervening depressive symptoms as a mediator. We also explored whether CBT4CBT moderated the effects of perceived stress. Baseline perceived stress did not predict EOT outcomes (i.e., total effect). However, in mediation models, we found indirect effects of baseline perceived stress on EOT cocaine and illicit opioid use, via midtreatment depressive symptoms. EOT perceived stress had significant total effects on month 6 cocaine and illicit opioid use, and an indirect effect on month 6 illicit opioid use (but not cocaine use), via month 3 depressive symptoms. Alternative models with depressive symptoms as the predictor and perceived stress as a mediator revealed no indirect effects. The addition of CBT4CBT to standard methadone treatment did not moderate total or indirect effects of perceived stress on substance use. Depressive symptoms may play a mediating role in the prospective indirect effect of perceived stress on substance use outcomes, particularly illicit opioid use. Further research is needed on therapies targeting stress. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

PURPOSE: Prostate specific membrane antigen targeted (18)F-DCFPyL positron emission tomography/computerized tomography may offer superior image quality and sensitivity for the detection of biochemically recurrent prostate cancer. We examined the association of Gleason sum, serum prostate specific antigen and prostate specific antigen doubling time with any detectable and pelvic confined disease in patients with biochemically recurrent prostate cancer. MATERIALS AND METHODS: Data from 108 patients with biochemically recurrent prostate cancer after radical prostatectomy who underwent prostate specific membrane antigen targeted (18)F-DCFPyL positron emission tomography/computerized tomography were analyzed. Data were collected on positive positron emission tomography findings as well as pelvic confined disease. Associations between Gleason sum, prostate specific antigen and prostate specific antigen doubling time were retrospectively explored. RESULTS: Serum prostate specific antigen was associated with positive prostate specific membrane antigen targeted imaging as continuous (OR 3.08, 95% CI 1.60–7.95, p=0.005) and categorical values (ie prostate specific antigen greater than 2.0 to 5.0 vs 0.5 ng/ml or less, OR 16.92, 95% CI 3.13–315.81, p=0.008). No relationship between Gleason sum or prostate specific antigen doubling time with overall positive imaging was observed. Patients with a prostate specific antigen greater than 2.0 to 5.0 ng/ml were significantly less likely to be diagnosed with pelvic confined disease compared with the 0.5 ng/ml or less subgroup (OR 0.21, 95% CI 0.06–0.69, p=0.013). A prostate specific antigen doubling time of 9 months or more (OR 4.20, 95% CI 1.57–11.89, p=0.005) or prostate specific antigen doubling time of 12 months or more (OR 3.03, 95% CI 1.12–8.76, p=0.033) was significantly associated with pelvic confined disease. No relationship between Gleason sum and pelvic confined disease was observed. CONCLUSIONS: Absolute prostate specific antigen was positively associated with the presence of findings on prostate specific membrane antigen targeted imaging and negatively associated with pelvic confined disease. Prostate specific antigen doubling time did not predict for overall disease detection, but long prostate specific antigen doubling times were associated with pelvic confined prostate cancer.

Schizophrenia is an idiopathic disorder that affects approximately 1% of the human population, and presents with persistent delusions, hallucinations, and disorganized behaviors. Antipsychotics are the standard pharmacological treatment for schizophrenia, but are frequently discontinued by patients due to inefficacy and/or side effects. Chronic treatment with the typical antipsychotic haloperidol causes tardive dyskinesia (TD), which manifests as involuntary and often irreversible orofacial movements in around 30% of patients. Mice treated with haloperidol develop many of the features of TD, including jaw tremors, tongue protrusions, and vacuous chewing movements (VCMs). In this study, we used genetically diverse Collaborative Cross (CC) recombinant inbred inter-cross (RIX) mice to elucidate the genetic basis of antipsychotic-induced adverse drug reactions (ADRs). We performed a battery of behavioral tests in 840 mice from 73 RIX lines (derived from 62 CC strains) treated with haloperidol or placebo in order to monitor the development of ADRs. We used linear mixed models to test for strain and treatment effects. We observed highly significant strain effects for almost all behavioral measurements investigated (P < 0.001). Further, we observed strong strain-by-treatment interactions for most phenotypes, particularly for changes in distance traveled, vertical activity, and extrapyramidal symptoms (EPS). Estimates of overall heritability ranged from 0.21 (change in body weight) to 0.4 (VCMs and change in distance traveled) while the portion attributable to the interactions of treatment and strain ranged from 0.01 (for change in body weight) to 0.15 (for change in EPS). Interestingly, close to 30% of RIX mice exhibited VCMs, a sensitivity to haloperidol exposure, approximately similar to the rate of TD in humans chronically exposed to haloperidol. Understanding the genetic basis for the susceptibility to antipsychotic ADRs may be possible in mouse, and extrapolation to humans could lead to safer therapeutic approaches for schizophrenia.

In the year 2019, we identified and screened over 400 peer-reviewed publications on pancreatic transplantation, over 200 on intestinal transplantation, and over 1900 on kidney transplantation. The liver transplantation section focuses on and features selected articles among 70 clinical trials published in 2019. This review highlights noteworthy literature pertinent to anesthesiologists and critical care physicians caring for patients undergoing abdominal organ transplantation. We explore a broad range of topics, including risks for and prediction of perioperative complications, updated indications for transplantation, recommendations on perioperative management, including Enhanced Recovery After Surgery programs, and topics relevant to optimization of patient and graft outcomes and survival.

Ventricular arrhythmias are associated with neurological impairment and could represent a source of cerebral hypoperfusion. In the present study, data from healthy individuals (n = 11), patients with ischaemic heart disease (IHD; ejection fraction40%; n = 9) and patients with heart failure with reduced ejection fraction (HFrEF; EF = 31 (5)%, n = 11), as well as data from swine surgeries, where spontaneous ventricular arrhythmias were observed during cerebrovascular examination (transcranial Doppler ultrasound in humans and laser Doppler in swine) were analysed retrospectively to investigate the effect of arrhythmia on cerebral microvascular haemodynamics. A subset of participants also completed the Montreal Cognitive Assessment (MoCA). Middle cerebral artery mean blood velocity (MCA

As a result of the COVID-19 pandemic, nations across the globe have responded by attempting to understand how the virus was spreading in their communities, in order to isolate cases, reduce morbidity and mortality, and avoid overwhelming healthcare facilities. In this article, we describe the global response to tracking the virus and discuss new technological advances in molecular testing that have been deployed and developed to track and mitigate COVID-19. We also discuss how the successes and failures observed in the COVID-19 pandemic can be extrapolated to improve our ability to respond to the next pandemic.

Nociceptors, the high-threshold primary sensory neurons that trigger pain, interact with immune cells in the periphery to modulate innate immune responses. Whether they also participate in adaptive and humoral immunity is, however, not known. In this study, we probed if nociceptors have a role in distinct airway and skin models of allergic inflammation. In both models, the genetic ablation and pharmacological silencing of nociceptors substantially reduced inflammatory cell infiltration to the affected tissue. Moreover, we also found a profound and specific deficit in IgE production in these models of allergic inflammation. Mechanistically, we discovered that the nociceptor-released neuropeptide substance P helped trigger the formation of antibody-secreting cells and their release of IgE. Our findings suggest that nociceptors, in addition to their contributions to innate immunity, play a key role in modulating the adaptive immune response, particularly B cell antibody class switching to IgE.

The dopamine receptor 4 (D4R) is highly expressed in both motor, associative and limbic subdivisions of the coritico-basal ganglia network. Due to the distribution in the brain, there is mounting evidence pointing to a role for the D4R in the modulation of this network and its subsequent involvement in L-DOPA induced dyskinesias in Parkinson’s disease. As part of our continued effort in the discovery of novel D4R antagonists, we report the discovery and characterization of a new 3- or 4-benzyloxypiperidine scaffold as D4R antagonists. We report several D4R selective compounds (>30-fold vs. other dopamine receptor subtypes) with improved in vitro and in vivo stability over previously reported D4R antagonists.

Rift Valley fever virus (RVFV) is a mosquito-transmitted virus from the Bunyaviridae family that causes high rates of mortality and morbidity in humans and ruminant animals. Previous studies indicated that DEAD-box helicase 17 (DDX17) restricts RVFV replication by recognizing two primary non-coding RNAs in the S-segment of the genome: the intergenic region (IGR) and 5&prime, non-coding region (NCR). However, we lack molecular insights into the direct binding of DDX17 with RVFV non-coding RNAs and information on the unwinding of both non-coding RNAs by DDX17. Therefore, we performed an extensive biophysical analysis of the DDX17 helicase domain (DDX17135&ndash, 555) and RVFV non-coding RNAs, IGR and 5&rsquo, NCR. The homogeneity studies using analytical ultracentrifugation indicated that DDX17135&ndash, 555, IGR, and 5&rsquo, NCR are pure. Next, we performed small-angle X-ray scattering (SAXS) experiments, which suggested that DDX17 and both RNAs are homogenous as well. SAXS analysis also demonstrated that DDX17 is globular to an extent, whereas the RNAs adopt an extended conformation in solution. Subsequently, microscale thermophoresis (MST) experiments were performed to investigate the direct binding of DDX17 to the non-coding RNAs. The MST experiments demonstrated that DDX17 binds with the IGR and 5&rsquo, NCR with a dissociation constant of 5.77 &plusmn, 0.15 &micro, M and 9.85 &plusmn, 0.11 &micro, M, respectively. As DDX17135&ndash, 555 is an RNA helicase, we next determined if it could unwind IGR and NCR. We developed a helicase assay using MST and fluorescently-labeled oligos, which suggested DDX17135&ndash, 555 can unwind both RNAs. Overall, our study provides direct evidence of DDX17135&ndash, 555 interacting with and unwinding RVFV non-coding regions.

G protein–gated inwardly rectifying K(+) (GIRK) channels are critical mediators of excitability in the heart and brain. Enhanced GIRK-channel activity has been implicated in the pathogenesis of supraventricular arrhythmias, including atrial fibrillation. The lack of selective pharmacological tools has impeded efforts to investigate the therapeutic potential of cardiac GIRK–channel interventions in arrhythmias. Here, we characterize a recently identified GIRK-channel inhibitor, VU0468554. Using whole-cell electrophysiological approaches and primary cultures of sinoatrial nodal cells and hippocampal neurons, we show that VU0468554 more effectively inhibits the cardiac GIRK channel than the neuronal GIRK channel. Concentration-response experiments suggest that VU0468554 inhibits Gβγ-activated GIRK channels in noncompetitive and potentially uncompetitive fashion. In contrast, VU0468554 competitively inhibits GIRK-channel activation by ML297, a GIRK-channel activator containing the same chemical scaffold as VU0468554. In the isolated heart model, VU0468554 partially reversed carbachol-induced bradycardia in hearts from wild-type mice but not Girk4(–/–) mice. Collectively, these data suggest that VU0468554 represents a promising new pharmacological tool for targeting cardiac GIRK channels with therapeutic implications for relevant cardiac arrhythmias. SIGNIFICANCE STATEMENT: Although cardiac GIRK–channel inhibition shows promise for the treatment of supraventricular arrhythmias, the absence of subtype-selective channel inhibitors has hindered exploration into this therapeutic strategy. This study utilizes whole-cell patch-clamp electrophysiology to characterize the new GIRK-channel inhibitor VU0468554 in human embryonic kidney 293T cells and primary cultures. We report that VU0468554 exhibits a favorable pharmacodynamic profile for cardiac over neuronal GIRK channels and partially reverses GIRK-mediated bradycardia in the isolated mouse heart model.

Heart failure with reduced ejection fraction is associated with increased exercise intolerance, morbidity, and mortality. Importantly, exercise intolerance in heart failure with reduced ejection fraction is a key factor limiting patient quality of life and survival. Exercise intolerance in heart failure with reduced ejection fraction stems from a multi-organ failure to maintain homeostasis at rest and during exercise, including the heart, skeletal muscle, and autonomic nervous system, lending itself to a system constantly trying to "catch-up". Hemodynamic control during exercise is regulated primarily by the autonomic nervous system, whose operation, in turn, is partly regulated via reflexive information from exercise-stimulated receptors throughout the body (e.g., arterial baroreflex, central and peripheral chemoreceptors, and the muscle metabo- and mechanoreflexes). Persons with heart failure with reduced ejection fraction exhibit malfunctioning autonomic reflexes, which lead to exaggerated sympathoexcitation and attenuated parasympathetic tone. Chronic elevation of sympathetic activity is associated with increased morbidity and mortality. In this review, we provide an overview of how each main exercise-related autonomic reflex is changed in heart failure with reduced ejection fraction, and the role of exercise training in attenuating or reversing the counterproductive changes.

The mosquito continues to be the most lethal animal to humans due to the devastating diseases that it carries and transmits. Controlling mosquito-borne diseases relies heavily on vector management using neurotoxic insecticides with limited modes of action. This has led to the emergence of resistance to pyrethroids and other neurotoxic insecticides in mosquitoes, which has reduced the efficacy of chemical control agents. Moreover, many neurotoxic insecticides are not selective for mosquitoes and negatively impact beneficial insects such as honeybees. Developing new mosquitocides with novel mechanisms of action is a clear unmet medical need; this review covers the efforts made toward this end by targeting the renal inward rectifier potassium channel (Kir) of the mosquito.

Background. Healthcare-associated infections (HAIs) are a persistent clinical challenge caused primarily by bacteria on the skin. Proper utilization of optimized antiseptic skin preparation solutions helps reduce the prevalence and impact of HAIs by decreasing patient skin microorganisms preoperatively. The purpose of this study was to evaluate the efficacy of two antimicrobial solutions containing iodine and isopropyl alcohol (IPA): Povidone iodine (PVP-I) with IPA (i.e., PVP-I+IPA, PurPrep™) and Iodine Povacrylex+IPA (DuraPrep™). Methods. The antimicrobial activity of the test solutions was evaluated in vitro by determinations of minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) against 1105 diverse microbial isolates and a time-kill assay to evaluate efficacy against 120 strains of Gram-positive and Gram-negative bacteria and yeasts. Peel tests were performed between skin samples treated with test solutions and representative drape/dressing materials to determine effects of test solutions on the biomechanical adhesion properties. Finally, an Institutional Review Board (IRB)-approved, randomized, controlled, single-center, partially blinded in vivo study was performed to assess the immediate and persistent antimicrobial activity of the test solutions on the abdomen and groin. Results. Both PVP-I+IPA and Iodine Povacrylex+IPA solutions demonstrated broad-spectrum antimicrobial activity with MIC and MBC at less than 1% of the full-strength concentration of each product against a wide variety of microorganisms. In the time-kill tests, both solutions were able to successfully reduce all microbial populations by 99.99% (i.e., 4log10) at the contact times of 30 seconds, 2 minutes and 10 minutes. The two solutions showed relatively similar adhesion results when tested with three representative operating room materials. Both PVP-I+IPA and Iodine Povacrylex+IPA met the expected Food and Drug Administration (FDA) efficacy requirements at 10 minutes and 6 hours post-treatment for both anatomical sites (i.e., groin and abdomen) in the clinical study, with no safety issues or adverse events. Conclusions. Analysis of the in vitro antimicrobial activity, biomechanical adhesive strength, and in vivo efficacy of PVP-I+IPA demonstrated similar results compared to Iodine Povacrylex+IPA. Both products were efficacious at reducing or eliminating a wide range of clinically-relevant microorganisms in lab-based and clinical settings, supporting their use as antiseptic skin preparation solutions to reduce bacteria on the skin that can cause infection.

Heart failure with preserved ejection fraction (HFpEF) is the fastest growing form of heart failure in the United States. The cardinal feature of HFpEF is reduced exercise tolerance (peak oxygen uptake, (Equation is included in full-text article.)O2peak) secondary to impaired cardiac, vascular, and skeletal muscle function. There are currently no evidence-based drug therapies to improve clinical outcomes in patients with HFpEF. In contrast, exercise training is a proven effective intervention for improving (Equation is included in full-text article.)O2peak, aerobic endurance, and quality of life in HFpEF patients. This brief review discusses the pathophysiology of exercise intolerance and the role of exercise training to improve (Equation is included in full-text article.)O2peak in clinically stable HFpEF patients. It also discusses the mechanisms responsible for the exercise training-mediated improvements in (Equation is included in full-text article.)O2peak in HFpEF. Finally, it provides evidence-based exercise prescription guidelines for cardiac rehabilitation specialists to assist them with safely implementing exercise-based cardiac rehabilitation programs for HFpEF patients.

Case Presentation An 80-year-old man was admitted to our hospital with 24 hours of epigastric pain. The pain was described as sharp, episodic, nonradiating, and without an identifiable provoking factor. Associated symptoms included nausea and nonbloody vomiting. He denied dyspnea, angina, fevers, chills, dysphagia, diarrhea, melena, or hematochezia. He had taken less than 2 g of acetaminophen earlier in the day without symptomatic relief. He had a 30-pack-year smoking history but quit over 25 years ago. He did not drink alcohol or use illicit drugs. He had a medical history of end-stage renal disease, for which he had undergone hemodialysis; hypertension; metastatic prostate cancer, for which he had received androgen deprivation therapy; and abdominal aortic aneurysm. His surgical history included a remote endovascular repair of the abdominal aortic aneurysm. His medications included amlodipine, losartan, carvedilol, sevelamer, and leuprolide.

This study applied a dyadic approach to condom-use research. Partners from 124 heterosexual couples independently completed a questionnaire assessing condom-related attitudes, subjective norms, perceived behavioral control, and intentions to use condoms. Results demonstrate the superiority of a dyadic approach to understanding couples’ condom-use intentions and behavior over traditional, individual-level approaches. The addition of partner effects to the model, via the actor–partner interdependence model, resulted in an increase in the variance accounted for in condom-use intentions and this dyadic model showed better fit compared to the individual-level model. The results suggest that consideration of relationship partners plays an important role in the prediction of safer sex intentions.

Sarcopenia is linked with impaired adaptive responses to exercise in aging skeletal muscle. The unfolded protein response (UPR) is an important intramyocellular molecular response pathway that is activated by exercise. The influence of age on skeletal muscle adaptive UPR in response to exercise, and the relationship to other key exercise-responsive regulatory pathways is not well-understood. We evaluated age-related changes in transcriptional markers of UPR activation following a single bout of resistance exercise in 12 young (27 ± 5yrs) and 12 older (75 ± 5yrs) healthy men and women. At baseline, there were modest differences in expression of UPR-related genes in young and older adults. Following exercise, transcriptional markers of UPR pathway activation were attenuated in older adults compared to young based on specific salient UPR-related genes and gene set enrichment analysis. The coordination of post-exercise transcriptional patterns between the UPR pathway, p53/p21 axis of autophagy, and satellite cell differentiation were less evident in older compared to young adults. In conclusion, transcriptomic analysis revealed an age-related decline in the adaptive UPR transcriptional response following a single bout of exercise that could contribute to impaired exercise responsiveness with age.

Background Precision medicine aims to identify those patients who will benefit the most from specific treatments. Recent work found large effects of naltrexone among “reward drinkers,” defined as individuals who drink primarily for the rewarding effects of alcohol. This study sought to replicate and extend these recent findings by examining whether the desire to drink mediated the effect of naltrexone among reward drinkers. Methods We conducted a secondary analysis of a 12‐week randomized clinical trial of daily or targeted naltrexone among problem drinkers (n = 163), with a focus on 86 individuals (n = 45 naltrexone and n = 41 placebo) who received daily medication. Interactive voice response technology was used to collect daily reports of drinking and desire to drink. Factor mixture models were used to derive reward and relief phenotypes. Moderation analyses were used to evaluate naltrexone effects, with phenotype as a moderator variable. Multilevel mediation tested average desire to drink as a mediator. Results Results indicated 4 phenotypes: low reward/low relief; low reward/high relief; high reward/low relief; and high reward/high relief. There was an interaction between the high reward/low relief subgroup (n = 10) and daily naltrexone versus placebo on drinks per drinking day (DPDD; p = 0.03), percent heavy drinking days (p = 0.004), and daily drinking (p = 0.02). As compared to placebo, individuals in the high reward/low relief phenotype who received daily naltrexone had significantly fewer DPDD (Cohen's d = 2.05) and had a lower proportion of heavy drinking days (Cohen's d = 1.75). As hypothesized, reductions in average desire to drink mediated the effect of naltrexone on average daily drinking among the high reward/low relief drinkers (moderated mediation effect: p = 0.029). Conclusions This theory‐driven study replicates the empirical finding that naltrexone is particularly efficacious among high reward/low relief drinkers. Our study brings the field a step closer to the potential of using a precision medicine approach to treating alcohol use disorder., In a post‐hoc precision medicine analysis of a 12‐week clinical trial, the current study examined the efficacy of naltrexone versus placebo for reward drinkers, individuals who drink primarily for the rewarding effects of alcohol and not for the relieving effects. As compared to placebo, reward drinkers who received naltrexone (50 mg/d) had significantly fewer drinks per drinking day (see Figure, Cohen's d = 2.05). Reductions in average desire to drink mediated the effect of naltrexone on average daily drinking among reward drinkers.

The host evolves redundant mechanisms to preserve physiological processing and homeostasis. These functions range from sensing internal and external threats, creating a memory of the insult and generating reflexes, which aim to resolve inflammation. Impairment in such functioning leads to chronic inflammatory diseases. By interacting through a common language of ligands and receptors, the immune and sensory nervous systems work in concert to accomplish such protective functions. Whilst this bidirectional communication helps to protect from danger, it can contribute to disease pathophysiology. Thus, the somatosensory nervous system is anatomically positioned within primary and secondary lymphoid tissues and mucosa to modulate immunity directly. Upstream of this interplay, neurons detect danger, which prompts the release of neuropeptides initiating (i) defensive reflexes (ranging from withdrawal response to coughing) and (ii) chemotaxis, adhesion and local infiltration of immune cells. The resulting outcome of such neuro-immune interplay is still ill-defined, but consensual findings start to emerge and support neuropeptides not only as blockers of TH 1-mediated immunity but also as drivers of TH 2 immune responses. However, the modalities detected by nociceptors revealed broader than mechanical pressure and temperature sensing and include signals as various as cytokines and pathogens to immunoglobulins and even microRNAs. Along these lines, we aggregated various dorsal root ganglion sensory neuron expression profiling datasets supporting such wide-ranging sensing capabilities to help identifying new danger detection modalities of these cells. Thus, revealing unexpected aspects of nociceptor neuron biology might prompt the identification of novel drivers of immunity, means to resolve inflammation and strategies to safeguard homeostasis.

To assess whether preoperative subpectoral tenderness in patients with rotator cuff tears was associated with arthroscopic findings of tendinopathy of the long head of the biceps, as well as whether they had resolution of their subpectoral tenderness postoperatively after tenodesis or tenotomy.Patients presenting between 2011 and 2016 undergoing arthroscopic rotator cuff repair were evaluated preoperatively with the subpectoral biceps test (SBT). This test is performed with the arm adducted and internally rotated to allow palpation of the biceps as it courses under the pectoralis major tendon. Preoperative SBT findings determined operative management with either tenodesis or tenotomy during rotator cuff repair. Patients were followed up postoperatively to assess resolution of subpectoral tenderness with a repeated SBT. Preoperative and postoperative Single Assessment Numeric Evaluation (SANE), American Shoulder and Elbow Surgeons, and Constant-Murley scores were recorded in all patients.A total of 128 patients were enrolled in the study, with a mean age of 58 years (range, 33-82 years). Patients with a positive preoperative SBT (n = 68) had significantly lower SANE and Constant-Murley scores preoperatively (P.01) than patients with a negative SBT (n = 60). All patients with a positive preoperative SBT underwent either tenodesis or tenotomy, with 94% of patients (n = 64) having resolution of subpectoral pain and tenderness at final follow-up. Intraoperatively, 93% of patients with a positive SBT showed gross pathologic changes in the tendon (fraying, erythema, tears, or subluxation) compared with only 65% of patients with negative preoperative examination findings (P.01). American Shoulder and Elbow Surgeons, Constant-Murley, and SANE scores were significantly increased postoperatively in all patients (P = .02).In this group of patients with rotator cuff tears surgically treated with concomitant biceps tenodesis or tenotomy, 94% had resolution of their subpectoral tenderness. A positive SBT was associated with gross pathologic changes of the biceps in 93% of patients.Level III, prospective comparative study.

OBJECTIVE: Abstinence outcomes are typically prioritized in the treatment of cocaine use disorder while ignoring patterns of low-frequency cocaine use. This study examined patterns of cocaine use frequency during treatment and evaluated how these patterns related to baseline characteristics and functioning outcomes 6 and 12 months after treatment. METHOD: We used a pooled dataset (N = 720) from seven randomized clinical trials for cocaine use disorder. The Addiction Severity Index (ASI) was used to assess functioning. Repeated-measures latent class analysis was used to derive patterns of cocaine use. RESULTS: Three patterns were identified: abstinence (10.6%), low-frequency use (approximately 1 day/week; 66.3%), and persistent frequent use (approximately 4 days/week; 23.1%). The low-frequency group was associated with male gender, younger age, and a criminal justice referral. The abstinent group had the highest alcohol problem severity score at baseline. At Month 6, the low-frequency group reported lower problem severity than the persistent frequent use group across multiple ASI areas, including the cocaine use as well as psychological, family, employment, and legal domains. At Month 12, the low-frequency group did not differ from the abstinent group in problem severity on any ASI domain and, relative to the persistent frequent use group, had lower cocaine use and employment problem severity. CONCLUSIONS: These findings highlight the importance of adopting a harm reduction approach and recognizing the potential clinical benefits associated with nonabstinent outcomes.

Exercise intolerance is a hallmark feature in heart failure with preserved ejection fraction (HFpEF). Prior heavy exercise (“priming exercise”) speeds pulmonary oxygen uptake (V̇o2p) kinetics in older adults through increased muscle oxygen delivery and/or alterations in mitochondrial metabolic activity. We tested the hypothesis that priming exercise would speed V̇o2pon-kinetics in patients with HFpEF because of acute improvements in muscle oxygen delivery. Seven patients with HFpEF performed three bouts of two exercise transitions: MOD1, rest to 4-min moderate-intensity cycling and MOD2, MOD1 preceded by heavy-intensity cycling. V̇o2p, heart rate (HR), total peripheral resistance (TPR), and vastus lateralis tissue oxygenation index (TOI; near-infrared spectroscopy) were measured, interpolated, time-aligned, and averaged. V̇o2pand HR were monoexponentially curve-fitted. TPR and TOI levels were analyzed as repeated measures between pretransition baseline, minimum value, and steady state. Significance was P < 0.05. Time constant (τ; tau) V̇o2p(MOD1 49 ± 16 s) was significantly faster after priming (41 ± 14 s; P = 0.002), and the effective HR τ was slower following priming (41 ± 27 vs. 51 ± 32 s; P = 0.025). TPR in both conditions decreased from baseline to minimum TPR ( P < 0.001), increased from minimum to steady state ( P = 0.041) but remained below baseline throughout ( P = 0.001). Priming increased baseline ( P = 0.003) and minimum TOI ( P = 0.002) and decreased the TOI muscle deoxygenation overshoot ( P = 0.041). Priming may speed the slow V̇o2pon-kinetics in HFpEF and increase muscle oxygen delivery (TOI) at the onset of and throughout exercise. Microvascular muscle oxygen delivery may limit exercise tolerance in HFpEF.

Background The objective of this biomechanical study is to compare two variations of single-row knotless techniques (Knotless repair and Rip-stop Knotless repair) against a single-row double-loaded anchor (DL) repair, focused on evaluating contact pressure and contact area amongst three different single-row techniques for rotator cuff repairs. Methods A total of 24 fresh frozen human shoulders were tested. Specimens were randomly assigned into one of the three single-row (SR) repair groups: A Knotted single-row double-loaded anchor (DL) repair, a Knotless (K) repair, or a Knotless Rip-Stop (KRS) repair. The footprint was measured after complete detachment of the supraspinatus tendon from the greater tuberosity, introducing pressure sensors between bony footprint and detached rotator cuff, and finally reconstructing it. All specimens were mounted onto a servohydraulic test system to analyze contact variables at 0° and 30° of abduction with 0 N, 30 N and 50 N of tension. Results Groups did not differ significantly in their footprint sizes: DL group 359.75 ± 58.37 mm2, K group 386.5 ± 102.13 mm2, KRS group 415.87 ± 93.80 mm2 (p = 0.84); nor in bone mineral density: DL group 0.25 ± 0.14 g/cm2, K group 0.32 ± 0.19 g/cm2, KRS group 0.32 ± 0.13 g/cm2, (p = 0.75) or average age. The highest mean pressurized contact area measured for the K repair was 248.1 ± 50.9 mm2, which equals a reconstruction of 67.1 ± 19.3% at 0° abduction and a 50 N supraspinatus load. This reconstructed area was significantly greater compared with the DL repair 152.8 ± 73.1 mm2, reconstructing 42.0 ± 18.5% on average when under the same conditions (p = 0.04). The mean contact pressure did not significantly differ amongst groups (p = 1.0): DL group 30.8 ± 17.4 psi, K group 30.9 ± 17.4 psi and KRS group 30.0 ± 10.9 psi. Neither the 30° abduction angle nor the supraspinatus load had a significant influence on the contact pressure in our study. Conclusion Both single-row knotless techniques resulted in significantly higher footprint reconstruction, providing larger contact area and a more uniform pressure distribution when compared with the single-row Knotted techniques. The mean contact pressure did not differ among groups significantly. These knotless techniques may be an alternative if the surgeon decides to perform a single-row rotator cuff repair. Level of evidence Basic Science Study, Biomechanics.

The present study describes the discovery and characterization of a series of 5-aryl-2H-tetrazol-3-ylacetamides as G protein-gated inwardly-rectifying potassium (GIRK) channels activators. Working from an initial hit discovered during a high-throughput screening campaign, we identified a tetrazole scaffold that shifts away from the previously reported urea-based scaffolds while remaining effective GIRK1/2 channel activators. In addition, we evaluated the compounds in Tier 1 DMPK assays and have identified a (3-methyl-1H-pyrazol-1-yl)tetrahydrothiophene-1,1-dioxide head group that imparts interesting and unexpected microsomal stability compared to previously-reported pyrazole head groups.

Formation of a collagenous connective tissue scar that forms after penetrating injuries to the brain or spinal cord has been described and investigated for well over one hundred years. However, it was studied almost exclusively in the context of penetrating injuries that resulted in infiltration of meningeal fibroblasts, which raised doubts about translational applicability to most CNS injuries where the meninges remain intact. Recent studies demonstrating the perivascular niche as a source of fibroblasts have debunked the traditional view that a fibrotic scar only forms after penetrating lesions that tear the meninges. These studies have led to a renewed interest in CNS fibrosis not only in the context of axon regeneration after spinal cord injury, but also across a spectrum of CNS disorders. Arising with this renewed interest is some discrepancy about which perivascular cell gives rise to the fibrotic scar, but additional studies are beginning to provide some clarity. Although mechanistic studies on CNS fibrosis are still lacking, the similarities to fibrosis of other organs should provide important insight into how CNS fibrosis can be therapeutically targeted to promote functional recovery.

The wildland firefighter exposure and health effect (WFFEHE) study was a 2-year repeated-measures study to investigate occupational exposures and acute and subacute health effects among wildland firefighters. This manuscript describes the study rationale, design, methods, limitations, challenges, and lessons learned. The WFFEHE cohort included fire personnel ages 18–57 from six federal wildland firefighting crews in Colorado and Idaho during the 2018 and 2019 fire seasons. All wildland firefighters employed by the recruited crews were invited to participate in the study at preseason and postseason study intervals. In 2019, one of the crews also participated in a 3-day midseason study interval where workplace exposures and pre/postshift measurements were collected while at a wildland fire incident. Study components assessed cardiovascular health, pulmonary function and inflammation, kidney function, workplace exposures, and noise-induced hearing loss. Measurements included self-reported risk factors and symptoms collected through questionnaires; serum and urine biomarkers of exposure, effect, and inflammation; pulmonary function; platelet function and arterial stiffness; and audiometric testing. Throughout the study, 154 wildland firefighters participated in at least one study interval, while 144 participated in two or more study interval. This study was completed by the Centers for Disease Control and Prevention’s National Institute for Occupational Safety and Health through a collaborative effort with the U.S. Department of Agriculture Forest Service, Department of the Interior National Park Service, and Skidmore College. Conducting research in the wildfire environment came with many challenges including collecting study data with study participants with changing work schedules and conducting study protocols safely and operating laboratory equipment in remote field locations. Forthcoming WFFEHE study results will contribute to the scientific evidence regarding occupational risk factors and exposures that can impact wildland firefighter health over a season and across two wildland fire seasons. This research is anticipated to lead to the development of preventive measures and policies aimed at reducing risk for wildland firefighters and aid in identifying future research needs for the wildland fire community.

Background Assessment instruments commonly used in clinical trials to measure functional outcomes in substance users may lack sensitivity to detect change during treatment, potentially limiting findings regarding benefits of reduced drug use. This study evaluated the sensitivity of the Addiction Severity Index (ASI) to detect change in psychiatric functioning among cocaine users. Methods Data were pooled across five clinical trials for cocaine use disorder (N = 492) that included a 12-week treatment period and 6-month follow-up. Within-person cohen’s d′ was used to evaluate effect size of change on the Psychiatric Composite Score of the ASI (ASI-Psych) and Global Severity Index (GSI) of the Brief Symptom Inventory, as well as cocaine use. Results Effect sizes were larger for GSI than ASI-Psych from baseline to week 12 (GSI d′ = 0.59; ASI-Psych d′ = 0.16), and 6-month follow-up (GSI d′ = 0.48; ASI-Psych d′ = 0.10). For those with non-zero ASI-Psych at baseline (n = 252), medium effect sizes were found over the 12-week period (d′ = 0.53) and 6-month follow-up (d′ = 0.47). Effect sizes for change in days of cocaine use were most similar to GSI in either sample. Conclusions The ASI Psychiatric Composite Score may have limited sensitivity to detect change in psychiatric functioning among clinical trial participants who reduce cocaine use. It may be useful for detecting change amongst those reporting some psychiatric problems at the start of treatment. Future research should consider an instrument’s sensitivity to change when assessing the potential functional benefits of reducing cocaine use.

Background The Centers for Medicare and Medicaid Services (CMS) penalizes hospitals for higher than expected 30-day mortality rates using methods without accounting for condition severity risk adjustment. For patients with stroke, CMS claims did not quantify stroke severity until recently, when the National Institutes of Health Stroke Scale (NIHSS) reporting began. Objective Examine the predictive ability of claim-based NIHSS to predict 30-day mortality and 30-day hospital readmission in patients with ischemic stroke. Design Retrospective cohort study of Medicare claims data. Patients Medicare beneficiaries with ischemic stroke (N=43,241) acute hospitalization between October 2016 and November 2017. Measurements All-cause 30-day mortality and 30-day hospital readmission. NIHSS score was derived from ICD-10 codes and stratified into the following: minor to moderate, moderate, moderate to severe, and severe categories. Results Among 43,241 patients with ischemic stroke with NIHSS from 2,659 US hospitals, 64.6% had minor to moderate stroke, 14.3% had moderate, 12.7% had moderate to severe, and 8.5% had a severe stroke,10.1% died within 30 days, 12.1% were readmitted within 30 days. The NIHSS exhibited stronger discriminant property (C-statistic 0.83, 95% CI: 0.82-0.84) for 30-day mortality compared to Elixhauser (0.74, 95% CI: 0.73-0.75). A monotonic increase in the adjusted 30-day mortality risk occurred relative to minor to moderate stroke category: hazard ratio [HR]=2.92 (95% CI=2.59-3.29) for moderate stroke, HR=5.49 (95% CI=4.90-6.15) for moderate to severe stroke, and HR=7.82 (95% CI=6.95-8.80) for severe stroke. After accounting for competing risk of mortality, there was a significantly higher readmission risk in the moderate stroke (HR=1.11, 95% CI=1.03-1.20), but significantly lower readmission risk in the severe stroke (HR=0.84, 95% CI=0.74-0.95) categories. Limitation Timing of NIHSS reporting during hospitalization is unknown. Conclusions Medicare claim-based NIHSS is significantly associated with 30-day mortality in Medicare patients with ischemic stroke and significantly improves discriminant property relative to the Elixhauser comorbidity index.

KEY POINTS Healthy older adults exhibit lower cardiorespiratory fitness ( VO2peak ) than young in the absence of any age-related difference in skeletal muscle mitochondrial capacity, suggesting central haemodynamics plays a larger role in age-related declines in VO2peak . Total physical activity did not differ by age, but moderate-to-vigorous physical activity was lower in older compared to young adults. Moderate-to-vigorous physical activity is associated with VO2peak and muscle oxidative capacity, but physical inactivity cannot entirely explain the age-related reduction in VO2peak . ABSTRACT Declining fitness ( VO2peak ) is a hallmark of ageing and believed to arise from decreased oxygen delivery and reduced muscle oxidative capacity. Physical activity is a modifiable lifestyle factor that is critical when evaluating the effects of age on parameters of fitness and energy metabolism. The objective was to evaluate the effects of age and sex on VO2peak , muscle mitochondrial physiology, and physical activity in young and older adults. An additional objective was to assess the contribution of skeletal muscle oxidative capacity to age-related reductions in VO2peak and determine if age-related variation in VO2peak and muscle oxidative capacity could be explained on the basis of physical activity levels. In 23 young and 52 older men and women measurements were made of VO2peak , mitochondrial physiology in permeabilized muscle fibres, and free-living physical activity by accelerometry. Regression analyses were used to evaluate associations between age and VO2peak , mitochondrial function, and physical activity. Significant age-related reductions were observed for VO2peak (P

AIMS Theory-driven, exploratory study to: (i) identify a reward drinking phenotype in young adults; (ii) evaluate this phenotype as a predictor of naltrexone response; and (iii) examine mechanisms of naltrexone in reward drinkers. DESIGN Secondary analysis of a randomized controlled trial. SETTING USA. PARTICIPANTS A total of 128 young adult (ages 18-25) heavy drinkers. INTERVENTIONS Naltrexone versus placebo. MEASUREMENTS Daily surveys assessed affect, urge, drinking, and context. The Drinking Motives Questionnaire was used to identify phenotypes based on reward (enhancement motives) and relief (coping motives) drinking. FINDINGS We identified three profiles: "Low reward/Low relief" (14.1%; low enhancement/low coping motives); "Reward drinkers" (62.2%; high enhancement/low coping motives); and "High reward/High relief" (22.7%; high enhancement/high coping motives). Among reward drinkers (versus low profile), naltrexone significantly reduced percent days drinking to intoxication (blood alcohol concentration [BAC] ≥0.08) (PDI) (d = 0.56; 95% CI [0.17, 0.96]) and percent high intensity drinking days (PHID) (8/10 drinks for women/men) (d = 0.32; 95% CI [0.01, 0.68]). Among the high reward/high relief profile drinkers (versus low profile), naltrexone reduced PHID (d = 0.69; 95% CI [0.02, 1.50]). Using profile-informed cutoffs and observed scores (for clinical applicability): (i) among cutoff-derived reward drinkers, we found a medium-to-large (d = 0.66; 95% CI [0.24, 1.16]) and small effect (d = 0.28; 95% CI [0.04, 0.72]) of naltrexone in reducing PDI and PHID, respectively; and (ii) among the cutoff-derived high reward/high relief subgroup, we found a medium-to-large effect (d = 0.63; 95% CI [0.05, 1.1]) of naltrexone in reducing PHID. Among reward drinkers (not other profiles), naltrexone reduced drinking on days a drinking event occurred by weakening the within-day association between positive affect and urges (P < 0.05). CONCLUSIONS Naltrexone has pronounced effects in reducing risky drinking among young adult reward drinkers (high reward/low relief) by reducing urges on days when individuals have higher positive affect and are exposed to a drinking event. Naltrexone also appears to reduce risky drinking among young adult high reward/high relief drinkers, but not via the same mechanism.

SARS-CoV-2 has highlighted the requirement for a drastic change in pandemic response. While cases continue to rise, there is an urgent need to deploy sensitive and rapid testing in order to identify potential outbreaks before there is an opportunity for further community spread. Currently, reverse transcription quantitative polymerase chain reaction (RT-qPCR) is considered the gold standard for diagnosing an active infection, using a nasopharyngeal swab; however, it can take days after symptoms develop to properly identify and trace the infection. While many civilian jobs can be performed remotely, the Department of Defense (DOD) is by nature a very fluid organization which requires in-person interaction and a physical presence to maintain effectiveness. In this commentary, we examine several current and emergent technologies and their ability to identify both active and previous SARS-CoV-2 infection, possibly in those without symptoms. Further, we will explore an ongoing study at the Air Force Research Laboratory, utilizing Reverse Transcription Loop-mediated isothermal amplification (RT-LAMP), next-generation sequencing, and the presence of SARS-CoV-2 antibodies through Lateral Flow Immunoassays. The ability to identify SARS-CoV-2 through volatile organic compound biomarker identification will also be explored. By exploring and validating multiple testing strategies, and contributing to Operation Warp Speed, the DOD is postured to respond to SARS-CoV-2, and future pandemics.