Interpersonal Coordination between Female Soccer Players: Leader-Follower Roles within a Collision-Avoidance Task.

Background/Purpose: Return to sport decision-making may be improved by assessing an athlete's ability to coordinate movement with opponents in sport. The purpose was to investigate whether previous injuries associated with female soccer players' interpersonal coordination during a collision avoidance task. The authors hypothesized that external perturbations would disrupt the strength and stability of coordinated movement, and that individuals with a history of injury would be less likely to recover coordinated movement. Study Design: Cross-Sectional. Methods: Nine female athletes with a history of lower extremity injuries and nine without injuries were paired into dyads. Each dyad completed twenty trials of an externally paced collision-avoidance agility task with an unanticipated perturbation. Participant trajectories were digitized and analyzed using cross-recurrence quantification analysis (CRQA) to determine the strength and stability of interpersonal coordination dynamics. Trials in which participants with injury history assumed leader or follower roles within each dyad were then used to study how dyadic coordination varied across task stages (early, perturbation, and late) using linear mixed effect models. Cohen's d effect sizes were calculated to demonstrate magnitude of differences. In exploratory analysis, psychological readiness (i.e., self-reported knee functioning, fear of injury, and risk-taking propensity) was evaluated for their association with leader-follower status. Results: Perturbation disrupted the strength (R2=0.65, p<0.001, early=49.7±1.7, perturbation=41.1±1.7, d=0.39) and stability (R2=0.71, p < 0.001, early=65.0±1.6, perturbation=58.0±1.7, d=0.38) of interpersonal coordination regardless of leader-follower status. Individuals with injury history failed to restore coordination after the perturbation compared to control participants (injury=44.2.0±2.1, control=50.8±2.6, d=0.39). Neither demographic nor psychological measures were associated with leader-follower roles (B=0.039, p=0.224). Conclusion: Individuals with a history of lower extremity injury may have a diminished ability to adapt interpersonal coordination to perturbations, possibly contributing to a higher risk of re-injury. Level of Evidence: 3.

The fatty liver disease-causing protein PNPLA3-I148M alters lipid droplet-Golgi dynamics.

Nonalcoholic fatty liver disease, recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD), is a progressive metabolic disorder that begins with aberrant triglyceride accumulation in the liver and can lead to cirrhosis and cancer. A common variant in the gene PNPLA3, encoding the protein PNPLA3-I148M, is the strongest known genetic risk factor for MASLD. Despite its discovery 20 y ago, the function of PNPLA3, and now the role of PNPLA3-I148M, remain unclear. In this study, we sought to dissect the biogenesis of PNPLA3 and PNPLA3-I148M and characterize changes induced by endogenous expression of the disease-causing variant. Contrary to bioinformatic predictions and prior studies with overexpressed proteins, we demonstrate here that PNPLA3 and PNPLA3-I148M are not endoplasmic reticulum-resident transmembrane proteins. To identify their intracellular associations, we generated a paired set of isogenic human hepatoma cells expressing PNPLA3 and PNPLA3-I148M at endogenous levels. Both proteins were enriched in lipid droplet, Golgi, and endosomal fractions. Purified PNPLA3 and PNPLA3-I148M proteins associated with phosphoinositides commonly found in these compartments. Despite a similar fractionation pattern as the wild-type variant, PNPLA3-I148M induced morphological changes in the Golgi apparatus, including increased lipid droplet-Golgi contact sites, which were also observed in I148M-expressing primary human patient hepatocytes. In addition to lipid droplet accumulation, PNPLA3-I148M expression caused significant proteomic and transcriptomic changes that resembled all stages of liver disease. Cumulatively, we validate an endogenous human cellular system for investigating PNPLA3-I148M biology and identify the Golgi apparatus as a central hub of PNPLA3-I148M-driven cellular change.

Engagement in Meaningful Activity Mediates the Relationship Between Stressful Life Events and Functional Resilience.

Resilience during stressful life events is a priority for administering the most client-centered care as possible. Occupational therapy practitioners have the unique opportunity to support resilience through promoting meaningful participation. The current study aims to understand the associations between meaningful activity engagement, resilience, and stressful life events. We specifically focused on answering if meaningful participation mediates the relationship between stressful life events and resilience. 492 participants from a non-clinical convenience sample of Amazon's MTurk completed the study. Participants completed an online survey and reported their experiences of stressful life events, resilience, well-being, and meaningful participation. We used SPSS and PROCESS to analyze our data. Stressful event severity and resilience were inversely related. When accounting for the effect of meaningful participation, the relationship became non-significant, indicating evidence of mediation. Implications: Focusing on measuring meaningful participation may be worth studying in further research.

Engagement in Meaningful Activity Mediates the Relationship between Stressful Life Events and Functional ResilienceSupporting recovery both psychologically and physically after a stressful life event is an important aspect of providing client-centered care. By supporting patients' and clients' engagement in meaningful participation, therapists can promote resilient outcomes for all patients and clients. The current study explored the relationship between resilience and meaningful activity participation during stressful life events. The sample was comprised of a convenience sample of 492 participants who were recruited from the online crowdsourcing platform MTurk. The results of the study include that when the stressful life experience was more severe for an individual, they reported lower resilience scores. When meaningful activity participation was accounted for, the relationship between stressful life event severity and resilience became non-existent. The results of the study suggest the importance of using and measuring meaningful activity when supporting recovery after an stressful and adverse life event.

Structure-Activity Relationships of Natural and Semisynthetic Plecomacrolides Suggest Distinct Pathways for HIV-1 Immune Evasion and Vacuolar ATPase-Dependent Lysosomal Acidification.

The human immunodeficiency virus (HIV)-encoded accessory protein Nef enhances pathogenicity by reducing major histocompatibility complex I (MHC-I) cell surface expression, protecting HIV-infected cells from immune recognition. Nef-dependent downmodulation of MHC-I can be reversed by subnanomolar concentrations of concanamycin A (1), a well-known inhibitor of vacuolar ATPase, at concentrations below those that interfere with lysosomal acidification or degradation. We conducted a structure-activity relationship study that assessed 76 compounds for Nef inhibition, 24 and 72 h viability, and lysosomal neutralization in Nef-expressing primary T cells. This analysis demonstrated that the most potent compounds were natural concanamycins and their derivatives. Comparison against a set of new, semisynthetic concanamycins revealed that substituents at C-8 and acylation of C-9 significantly affected Nef potency, target cell viability, and lysosomal neutralization. These findings provide important progress toward understanding the mechanism of action of these compounds and the identification of an advanced lead anti-HIV Nef inhibitory compound.

Revealing the dynamics and mechanisms of bacterial interactions in cheese production with metabolic modelling.

Cheese taste and flavour properties result from complex metabolic processes occurring in microbial communities. A deeper understanding of such mechanisms makes it possible to improve both industrial production processes and end-product quality through the design of microbial consortia. In this work, we caracterise the metabolism of a three-species community consisting of Lactococcus lactis, Lactobacillus plantarum and Propionibacterium freudenreichii during a seven-week cheese production process. Using genome-scale metabolic models and omics data integration, we modeled and calibrated individual dynamics using monoculture experiments, and coupled these models to capture the metabolism of the community. This model accurately predicts the dynamics of the community, enlightening the contribution of each microbial species to organoleptic compound production. Further metabolic exploration revealed additional possible interactions between the bacterial species. This work provides a methodological framework for the prediction of community-wide metabolism and highlights the added value of dynamic metabolic modeling for the comprehension of fermented food processes.

A Portable, Neurostimulation-Integrated, Force Measurement Platform for the Clinical Assessment of Plantarflexor Central Drive.

Plantarflexor central drive is a promising biomarker of neuromotor impairment; however, routine clinical assessment is hindered by the unavailability of force measurement systems with integrated neurostimulation capabilities. In this study, we evaluate the accuracy of a portable, neurostimulation-integrated, plantarflexor force measurement system we developed to facilitate the assessment of plantarflexor neuromotor function in clinical settings. Two experiments were conducted with the Central Drive System (CEDRS). To evaluate accuracy, experiment #1 included 16 neurotypical adults and used intra-class correlation (ICC2,1) to test agreement of plantarflexor strength capacity measured with CEDRS versus a stationary dynamometer. To evaluate validity, experiment #2 added 26 individuals with post-stroke hemiparesis and used one-way ANOVAs to test for between-limb differences in CEDRS' measurements of plantarflexor neuromotor function, comparing neurotypical, non-paretic, and paretic limb measurements. The association between paretic plantarflexor neuromotor function and walking function outcomes derived from the six-minute walk test (6MWT) were also evaluated. CEDRS' measurements of plantarflexor neuromotor function showed high agreement with measurements made by the stationary dynamometer (ICC = 0.83, p < 0.001). CEDRS' measurements also showed the expected between-limb differences (p's < 0.001) in maximum voluntary strength (Neurotypical: 76.21 ± 13.84 ft-lbs., Non-paretic: 56.93 ± 17.75 ft-lbs., and Paretic: 31.51 ± 14.08 ft-lbs.), strength capacity (Neurotypical: 76.47 ± 13.59 ft-lbs., Non-paretic: 64.08 ± 14.50 ft-lbs., and Paretic: 44.55 ± 14.23 ft-lbs.), and central drive (Neurotypical: 88.73 ± 1.71%, Non-paretic: 73.66% ± 17.74%, and Paretic: 52.04% ± 20.22%). CEDRS-measured plantarflexor central drive was moderately correlated with 6MWT total distance (r = 0.69, p < 0.001) and distance-induced changes in speed (r = 0.61, p = 0.002). CEDRS is a clinician-operated, portable, neurostimulation-integrated force measurement platform that produces accurate measurements of plantarflexor neuromotor function that are associated with post-stroke walking ability.

Community-scale models of microbiomes: Articulating metabolic modelling and metagenome sequencing.

Building models is essential for understanding the functions and dynamics of microbial communities. Metabolic models built on genome-scale metabolic network reconstructions (GENREs) are especially relevant as a means to decipher the complex interactions occurring among species. Model reconstruction increasingly relies on metagenomics, which permits direct characterisation of naturally occurring communities that may contain organisms that cannot be isolated or cultured. In this review, we provide an overview of the field of metabolic modelling and its increasing reliance on and synergy with metagenomics and bioinformatics. We survey the means of assigning functions and reconstructing metabolic networks from (meta-)genomes, and present the variety and mathematical fundamentals of metabolic models that foster the understanding of microbial dynamics. We emphasise the characterisation of interactions and the scaling of model construction to large communities, two important bottlenecks in the applicability of these models. We give an overview of the current state of the art in metagenome sequencing and bioinformatics analysis, focusing on the reconstruction of genomes in microbial communities. Metagenomics benefits tremendously from third-generation sequencing, and we discuss the opportunities of long-read sequencing, strain-level characterisation and eukaryotic metagenomics. We aim at providing algorithmic and mathematical support, together with tool and application resources, that permit bridging the gap between metagenomics and metabolic modelling.

Corticomuscular cross-recurrence analysis reveals between-limb differences in motor control among individuals with ACL reconstruction.

Surgical reconstruction of the anterior cruciate ligament (ACL) and subsequent physical therapy can help athletes return to competition; however, re-injury rates remain disproportionately high due, in part, to lingering biomechanical and neurological factors that are not fully addressed during rehabilitation. Prior reports indicate that individuals exhibit altered electrical activity in both brain and muscle after ACL reconstruction (ACLR). In this investigation, we aimed to extend existing approaches by introducing a novel non-linear analysis of corticomuscular dynamics, which does not assume oscillatory coupling between brain and muscle: Corticomuscular cross-recurrence analysis (CM-cRQA). Our findings indicate that corticomuscular dynamics vary significantly between involved (injured) and uninvolved legs of participants with ACLR during voluntary isometric contractions between the brain and both the vastus medialis and lateralis. This finding points to a potential lingering neural deficit underlying re-injury for athletes after surgical reconstruction, namely the dynamical structure of neuromuscular (brain to quad muscle) coordination, which is significantly asymmetric, between limbs, in those who have ACLR.

Molecular detection of pre-ribosomal RNAs of Mycobacterium bovis bacille Calmette-Guérin and Mycobacterium tuberculosis to enhance pre-clinical tuberculosis drug and vaccine development.

Efforts are underway globally to develop effective vaccines and drugs against M. tuberculosis (Mtb) to reduce the morbidity and mortality of tuberculosis. Improving detection of slow-growing mycobacteria could simplify and accelerate efficacy studies of vaccines and drugs in animal models and human clinical trials. Here, a real-time reverse transcription PCR (RT-PCR) assay was developed to detect pre-ribosomal RNA (pre-rRNA) of Mycobacterium bovis bacille Calmette-Guérin (BCG) and Mtb. This pre-rRNA biomarker is indicative of bacterial viability. In two different mouse models, the presence of pre-rRNA from BCG and Mtb in ex vivo tissues showed excellent agreement with slower culture-based colony-forming unit assays. The addition of a brief nutritional stimulation prior to molecular viability testing further differentiated viable but dormant mycobacteria from dead mycobacteria. This research has set the stage to evaluate pre-rRNA as a BCG and/or Mtb infection biomarker in future drug and vaccine clinical studies.

The fatty liver disease-causing protein PNPLA3-I148M alters lipid droplet-Golgi dynamics.

Non-alcoholic fatty liver disease (NAFLD), recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD), is a progressive metabolic disorder that begins with aberrant triglyceride accumulation in the liver and can lead to cirrhosis and cancer. A common variant in the gene PNPLA3, encoding the protein PNPLA3-I148M, is the strongest known genetic risk factor for MASLD to date. Despite its discovery twenty years ago, the function of PNPLA3, and now the role of PNPLA3-I148M, remain unclear. In this study, we sought to dissect the biogenesis of PNPLA3 and PNPLA3-I148M and characterize changes induced by endogenous expression of the disease-causing variant. Contrary to bioinformatic predictions and prior studies with overexpressed proteins, we demonstrate here that PNPLA3 and PNPLA3-I148M are not endoplasmic reticulum-resident transmembrane proteins. To identify their intracellular associations, we generated a paired set of isogenic human hepatoma cells expressing PNPLA3 and PNPLA3-I148M at endogenous levels. Both proteins were enriched in lipid droplet, Golgi, and endosomal fractions. Purified PNPLA3 and PNPLA3-I148M proteins associated with phosphoinositides commonly found in these compartments. Despite a similar fractionation pattern as the wild-type variant, PNPLA3-I148M induced morphological changes in the Golgi apparatus, including increased lipid droplet-Golgi contact sites, which were also observed in I148M-expressing primary human patient hepatocytes. In addition to lipid droplet accumulation, PNPLA3-I148M expression caused significant proteomic and transcriptomic changes that resembled all stages of liver disease. Cumulatively, we validate an endogenous human cellular system for investigating PNPLA3-I148M biology and identify the Golgi apparatus as a central hub of PNPLA3-I148M-driven cellular change.

Neural drive and motor unit characteristics after anterior cruciate ligament reconstruction: implications for quadriceps weakness.

Purpose: The purpose of this investigation was to compare the quality of neural drive and recruited quadriceps motor units' (MU) action potential amplitude (MUAPAMP) and discharge rate (mean firing rate (MFR)) relative to recruitment threshold (RT) between individuals with anterior cruciate ligament reconstruction (ACLR) and controls. Methods: Fourteen individuals with ACLR and 13 matched controls performed trapezoidal knee extensor contractions at 30%, 50%, 70%, and 100% of their maximal voluntary isometric contraction (MVIC). Decomposition electromyography (dEMG) and torque were recorded concurrently. The Hoffmann reflex (H-reflex) and central activation ratio (CAR) were acquired bilaterally to detail the proportion of MU pool available and volitionally activated. We examined MUAPAMP-RT and MFR-RT relationships with linear regression and extracted the regression line slope, y-intercept, and RT range for each contraction. Linear mixed effect modelling used to analyze the effect of group and limb on regression line slope and RT range. Results: Individuals with ACLR demonstrated lower MVIC torque in the involved limb compared to uninvolved limb. There were no differences in H-reflex or CAR between groups or limbs. The ACLR involved limb demonstrated smaller mass-normalized RT range and slower MU firing rates at high contraction intensities (70% and 100% MVIC) compared to uninvolved and control limbs. The ACLR involved limb also demonstrated larger MU action potentials in the VM compared to the contralateral limb. These differences were largely attenuated with relative RT normalization. Conclusions: These results suggest that persistent strength deficits following ACLR may be attributable to a diminished quadriceps motor neuron pool and inability to upregulate the firing rate of recruited MUs.

Structure of a modular polyketide synthase reducing region.

The chemical scaffolds of numerous therapeutics are polyketide natural products, many formed by bacterial modular polyketide synthases (PKS). The large and flexible dimeric PKS modules have distinct extension and reducing regions. Structures are known for all individual enzyme domains and several extension regions. Here, we report the structure of the full reducing region from a modular PKS, the ketoreductase (KR), dehydratase (DH), and enoylreductase (ER) domains of module 5 of the juvenimicin PKS. The modular PKS-reducing region has a different architecture than the homologous fatty acid synthase (FAS) and iterative PKS systems in its arrangement of domains and dimer interface. The structure reveals a critical role for linker peptides in the domain interfaces, leading to discovery of key differences in KR domains dependent on module composition. Finally, our studies provide insight into the mechanism underlying modular PKS intermediate shuttling by carrier protein (ACP) domains.

Quantitative measurement of the requirement of diverse protein degradation pathways in MHC class I peptide presentation.

Peptides from degradation of intracellular proteins are continuously displayed by major histocompatibility complex (MHC) class I. To better understand origins of these peptides, we performed a comprehensive census of the class I peptide repertoire in the presence and absence of ubiquitin-proteasome system (UPS) activity upon developing optimized methodology to enrich for and quantify these peptides. Whereas most class I peptides are dependent on the UPS for their generation, a surprising 30%, enriched in peptides of mitochondrial origin, appears independent of the UPS. A further ~10% of peptides were found to be dependent on the proteasome but independent of ubiquitination for their generation. Notably, clinically achievable partial inhibition of the proteasome resulted in display of atypical peptides. Our results suggest that generation of MHC class I•peptide complexes is more complex than previously recognized, with UPS-dependent and UPS-independent components; paradoxically, alternative protein degradation pathways also generate class I peptides when canonical pathways are impaired.

Expression of Microcystis Biosynthetic Gene Clusters in Natural Populations Suggests Temporally Dynamic Synthesis of Novel and Known Secondary Metabolites in Western Lake Erie.

Microcystis spp. produce diverse secondary metabolites within freshwater cyanobacterial harmful algal blooms (cyanoHABs) around the world. In addition to the biosynthetic gene clusters (BGCs) encoding known compounds, Microcystis genomes harbor numerous BGCs of unknown function, indicating a poorly understood chemical repertoire. While recent studies show that Microcystis produces several metabolites in the lab and field, little work has focused on analyzing the abundance and expression of its broader suite of BGCs during cyanoHAB events. Here, we use metagenomic and metatranscriptomic approaches to track the relative abundance of Microcystis BGCs and their transcripts throughout the 2014 western Lake Erie cyanoHAB. The results indicate the presence of several transcriptionally active BGCs that are predicted to synthesize both known and novel secondary metabolites. The abundance and expression of these BGCs shifted throughout the bloom, with transcript abundance levels correlating with temperature, nitrate, and phosphorus concentrations and the abundance of co-occurring predatory and competitive eukaryotic microorganisms, suggesting the importance of both abiotic and biotic controls in regulating expression. This work highlights the need for understanding the chemical ecology and potential risks to human and environmental health posed by secondary metabolites that are produced but often unmonitored. It also indicates the prospects for identifying pharmaceutical-like molecules from cyanoHAB-derived BGCs. IMPORTANCE Microcystis spp. dominate cyanobacterial harmful algal blooms (cyanoHABs) worldwide and pose significant threats to water quality through the production of secondary metabolites, many of which are toxic. While the toxicity and biochemistry of microcystins and several other compounds have been studied, the broader suite of secondary metabolites produced by Microcystis remains poorly understood, leaving gaps in our understanding of their impacts on human and ecosystem health. We used community DNA and RNA sequences to track the diversity of genes encoding synthesis of secondary metabolites in natural Microcystis populations and assess patterns of transcription in western Lake Erie cyanoHABs. Our results reveal the presence of both known gene clusters that encode toxic secondary metabolites as well as novel ones that may encode cryptic compounds. This research highlights the need for targeted studies of the secondary metabolite diversity in western Lake Erie, a vital freshwater source to the United States and Canada.

A Novel Tool to Identify Bactericidal Compounds against Vulnerable Targets in Drug-Tolerant M. tuberculosis found in Caseum.

Caseous necrosis is a hallmark of tuberculosis (TB) pathology and creates a niche for drug-tolerant persisters within the host. Cavitary TB and high bacterial burden in caseum require longer treatment duration. An in vitro model that recapitulates the major features of Mycobacterium tuberculosis (Mtb) in caseum would accelerate the identification of compounds with treatment-shortening potential. We have developed a caseum surrogate model consisting of lysed and denatured foamy macrophages. Upon inoculation of Mtb from replicating cultures, the pathogen adapts to the lipid-rich matrix and gradually adopts a nonreplicating state. We determined that the lipid composition of ex vivo caseum and the surrogate matrix are similar. We also observed that Mtb in caseum surrogate accumulates intracellular lipophilic inclusions (ILI), a distinctive characteristic of quiescent and drug-tolerant Mtb. Expression profiling of a representative gene subset revealed common signatures between the models. Comparison of Mtb drug susceptibility in caseum and caseum surrogate revealed that both populations are similarly tolerant to a panel of TB drugs. By screening drug candidates in the surrogate model, we determined that the bedaquiline analogs TBAJ876 and TBAJ587, currently in clinical development, exhibit superior bactericidal against caseum-resident Mtb, both alone and as substitutions for bedaquiline in the bedaquiline-pretomanid-linezolid regimen approved for the treatment of multidrug-resistant TB. In summary, we have developed a physiologically relevant nonreplicating persistence model that reflects the distinct metabolic and drug-tolerant state of Mtb in caseum. IMPORTANCE M. tuberculosis (Mtb) within the caseous core of necrotic granulomas and cavities is extremely drug tolerant and presents a significant hurdle to treatment success and relapse prevention. Many in vitro models of nonreplicating persistence have been developed to characterize the physiologic and metabolic adaptations of Mtb and identify compounds active against this treatment-recalcitrant population. However, there is little consensus on their relevance to in vivo infection. Using lipid-laden macrophage lysates, we have designed and validated a surrogate matrix that closely mimics caseum and in which Mtb develops a phenotype similar to that of nonreplicating bacilli in vivo. The assay is well suited to screen for bactericidal compounds against caseum-resident Mtb in a medium-throughput format, allowing for reduced reliance on resource intensive animal models that present large necrotic lesions and cavities. Importantly, this approach will aid the identification of vulnerable targets in caseum Mtb and can accelerate the development of novel TB drugs with treatment-shortening potential.

Brain activation and single-limb balance following anterior cruciate ligament reconstruction.

OBJECTIVE: To compare brain activity between individuals with anterior cruciate ligament reconstruction (ACLR) and controls during balance. To determine the influence of neuromodulatory interventions (external focus of attention [EF] and transcutaneous electrical nerve stimulation [TENS]) on cortical activity and balance performance. METHODS: Individuals with ACLR (n = 20) and controls (n = 20) performed a single-limb balance task under four conditions: internal focus (IF), object-based-EF, target-based-EF, and TENS. Electroencephalographic signals were decomposed, localized, and clustered to generate power spectral density in theta and alpha-2 frequency bands. RESULTS: Participants with ACLR had higher motor-planning (d = 0.5), lower sensory (d = 0.6), and lower motor activity (d = 0.4-0.8), while exhibiting faster sway velocity (d = 0.4) than controls across all conditions. Target-based-EF decreased motor-planning (d = 0.1-0.4) and increased visual (d = 0.2), bilateral sensory (d = 0.3-0.4), and bilateral motor (d = 0.4-0.5) activity in both groups compared to all other conditions. Neither EF conditions nor TENS changed balance performance. CONCLUSIONS: Individuals with ACLR exhibit lower sensory and motor processing, higher motor planning demands, and greater motor inhibition compared to controls, suggesting visual-dependence and less automatic balance control. Target-based-EF resulted in favorable reductions in motor-planning and increases in somatosensory and motor activity, transient effects in line with impairments after ACLR. SIGNIFICANCE: Sensorimotor neuroplasticity underlies balance deficits in individuals with ACLR. Neuromodulatory interventions such as focus of attention may induce favorable neuroplasticity along with performance benefits.

Mental health outcomes before psychotropic medications: a retrospective case series of one state hospital records from 1945 to 1954.

BACKGROUND: Current outcomes for mental illness are widely regarded as poor. Since the introduction of psychotropic medications in the mid 1950's, previous psychosocial practices were minimized in favor of medication focused treatment. The majority of large U.S. state hospitals have closed with records destroyed or in storage, inaccessible to researchers. This creates barriers to studying and comparing outcomes before and after this shift in treatment practices. AIMS: The study aim was to examine discharge outcomes in relation to length of stay and diagnosis in one U.S. state hospital. METHODS: This case series study examined 5618 medical records of participants admitted to one state hospital from 1945 to 1954, the decade prior to adoption of psychotropic medications. RESULTS: Of the 3332 individuals who left the facility, over half (59.87%) of first episode hospitalizations were discharged within 1 year, and 16.95% were hospitalized for more than 5 years. 46.17% of all admissions were discharged from hospital with no readmission. The most common diagnoses included schizophrenia, other forms of psychosis, and alcoholism. In the decade before the introduction of psychotropic medications, participants were often admitted for a single episode and returned to their homes within several years. CONCLUSIONS: Although limited to one site, findings suggest that discharge outcomes prior to psychotropic medication as a primary treatment for mental illness may be more positive than previously understood.

The human proton pump inhibitors inhibit Mycobacterium tuberculosis rifampicin efflux and macrophage-induced rifampicin tolerance.

Tuberculosis treatment requires months-long combination chemotherapy with multiple drugs, with shorter treatments leading to relapses. A major impediment to shortening treatment is that Mycobacterium tuberculosis becomes tolerant to the administered drugs, starting early after infection and within days of infecting macrophages. Multiple lines of evidence suggest that macrophage-induced drug tolerance is mediated by mycobacterial drug efflux pumps. Here, using assays to directly measure drug efflux, we find that M. tuberculosis transports the first-line antitubercular drug rifampicin through a proton gradient-dependent mechanism. We show that verapamil, a known efflux pump inhibitor, which inhibits macrophage-induced rifampicin tolerance, also inhibits M.tuberculosis rifampicin efflux. As with macrophage-induced tolerance, the calcium channel-inhibiting property of verapamil is not required for its inhibition of rifampicin efflux. By testing verapamil analogs, we show that verapamil directly inhibits M. tuberculosis drug efflux pumps through its human P-glycoprotein (PGP)-like inhibitory activity. Screening commonly used drugs with incidental PGP inhibitory activity, we find many inhibit rifampicin efflux, including the proton pump inhibitors (PPIs) such as omeprazole. Like verapamil, the PPIs inhibit macrophage-induced rifampicin tolerance as well as intramacrophage growth, which has also been linked to mycobacterial efflux pump activity. Our assays provide a facile screening platform for M. tuberculosis efflux pump inhibitors that inhibit in vivo drug tolerance and growth.