Innovations in the Assessment of Skeletal Muscle Health: A Glimpse into the Future.

Skeletal muscle is the largest organ system in the human body and plays critical roles in athletic performance, mobility, and disease pathogenesis. Despite growing recognition of its importance by major health organizations, significant knowledge gaps remain regarding skeletal muscle health and its crosstalk with nearly every physiological system. Relevant public health challenges like pain, injury, obesity, and sarcopenia underscore the need to accurately assess skeletal muscle health and function. Feasible, non-invasive techniques that reliably evaluate metrics including muscle pain, dynamic structure, contractility, circulatory function, body composition, and emerging biomarkers are imperative to unraveling the complexities of skeletal muscle. Our concise review highlights innovative or overlooked approaches for comprehensively assessing skeletal muscle in vivo. We summarize recent advances in leveraging dynamic ultrasound imaging, muscle echogenicity, tensiomyography, blood flow restriction protocols, molecular techniques, body composition, and pain assessments to gain novel insight into muscle physiology from cellular to whole-body perspectives. Continued development of precise, non-invasive tools to investigate skeletal muscle are critical in informing impactful discoveries in exercise and rehabilitation science.

Citrullination Was Introduced into Animals by Horizontal Gene Transfer from Cyanobacteria.

Protein posttranslational modifications add great sophistication to biological systems. Citrullination, a key regulatory mechanism in human physiology and pathophysiology, is enigmatic from an evolutionary perspective. Although the citrullinating enzymes peptidylarginine deiminases (PADIs) are ubiquitous across vertebrates, they are absent from yeast, worms, and flies. Based on this distribution PADIs were proposed to have been horizontally transferred, but this has been contested. Here, we map the evolutionary trajectory of PADIs into the animal lineage. We present strong phylogenetic support for a clade encompassing animal and cyanobacterial PADIs that excludes fungal and other bacterial homologs. The animal and cyanobacterial PADI proteins share functionally relevant primary and tertiary synapomorphic sequences that are distinct from a second PADI type present in fungi and actinobacteria. Molecular clock calculations and sequence divergence analyses using the fossil record estimate the last common ancestor of the cyanobacterial and animal PADIs to be less than 1 billion years old. Additionally, under an assumption of vertical descent, PADI sequence change during this evolutionary time frame is anachronistically low, even when compared with products of likely endosymbiont gene transfer, mitochondrial proteins, and some of the most highly conserved sequences in life. The consilience of evidence indicates that PADIs were introduced from cyanobacteria into animals by horizontal gene transfer (HGT). The ancestral cyanobacterial PADI is enzymatically active and can citrullinate eukaryotic proteins, suggesting that the PADI HGT event introduced a new catalytic capability into the regulatory repertoire of animals. This study reveals the unusual evolution of a pleiotropic protein modification.

Alkaline nucleoplasm facilitates contractile gene expression in the mammalian heart.

Cardiac contractile strength is recognised as being highly pH-sensitive, but less is known about the influence of pH on cardiac gene expression, which may become relevant in response to changes in myocardial metabolism or vascularization during development or disease. We sought evidence for pH-responsive cardiac genes, and a physiological context for this form of transcriptional regulation. pHLIP, a peptide-based reporter of acidity, revealed a non-uniform pH landscape in early-postnatal myocardium, dissipating in later life. pH-responsive differentially expressed genes (pH-DEGs) were identified by transcriptomics of neonatal cardiomyocytes cultured over a range of pH. Enrichment analysis indicated "striated muscle contraction" as a pH-responsive biological process. Label-free proteomics verified fifty-four pH-responsive gene-products, including contractile elements and the adaptor protein CRIP2. Using transcriptional assays, acidity was found to reduce p300/CBP acetylase activity and, its a functional readout, inhibit myocardin, a co-activator of cardiac gene expression. In cultured myocytes, acid-inhibition of p300/CBP reduced H3K27 acetylation, as demonstrated by chromatin immunoprecipitation. H3K27ac levels were more strongly reduced at promoters of acid-downregulated DEGs, implicating an epigenetic mechanism of pH-sensitive gene expression. By tandem cytoplasmic/nuclear pH imaging, the cardiac nucleus was found to exercise a degree of control over its pH through Na+/H+ exchangers at the nuclear envelope. Thus, we describe how extracellular pH signals gain access to the nucleus and regulate the expression of a subset of cardiac genes, notably those coding for contractile proteins and CRIP2. Acting as a proxy of a well-perfused myocardium, alkaline conditions are permissive for expressing genes related to the contractile apparatus.

The V2475F CPVT1 mutation yields distinct RyR2 channel populations that differ in their responses to cytosolic Ca2+ and Mg2.

Catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1) is a lethal genetic disease causing arrhythmias and sudden cardiac death in children and young adults and is linked to mutations in the cardiac ryanodine receptor (RyR2). The effects of CPVT1 mutations on RyR2 ion-channel function are often investigated using purified recombinant RyR2 channels homozygous for the mutation. However, CPVT1 patients are heterozygous for the disease, so this approach does not reveal the true changes to RyR2 function across the entire RyR2 population of channels in the heart. We therefore investigated the native cardiac RyR2 single-channel abnormalities in mice heterozygous for the CPVT1 mutation, V2475F(+/-)-RyR2, and applied molecular modelling techniques to investigate the possible structural changes that could initiate any altered function. We observed that increased sensitivity of cardiac V2475F(+/-)-RyR2 channels to both activating and inactivating levels of cytosolic Ca2+ , plus attenuation of Mg2+ inhibition, were the most marked changes. Severity of abnormality was not uniform across all channels, giving rise to multiple sub-populations with differing functional characteristics. For example, 46% of V2475F(+/-)-RyR2 channels exhibited reduced Mg2+ inhibition and 23% were actually activated by Mg2+ . Using homology modelling, we discovered that V2475 is situated at a hinge between two regions of the RyR2 helical domain 1 (HD1). Our model proposes that detrimental functional changes to RyR2 arise because mutation at this critical site reduces the angle between these regions. Our results demonstrate the necessity of characterising the total heterozygous population of CPVT1-mutated channels in order to understand CPVT1 phenotypes in patients. KEY POINTS: RyR2 mutations can cause type-1 catecholaminergic polymorphic ventricular tachycardia (CPVT1), a lethal, autosomal-dominant arrhythmic disease. However, the changes in RyR2 ion-channel function that result from the many different patient mutations are rarely investigated in detail and often only recombinant RyR2, homozygous for the mutation, is studied. As CPVT1 is a heterozygous disease and the tetrameric RyR2 channels expressed in the heart will contain varying numbers of mutated monomers, we have investigated the range of RyR2 single-channel abnormalities found in the hearts of mice heterozygous for the CPVT1 mutation, V2475F(+/-)-RyR2. Specific alterations to ligand regulation of V2475F(+/-)-RyR2 were observed. Multiple sub-populations of channels exhibited varying degrees of abnormality. In particular, an increased sensitivity to activating and inactivating cytosolic [Ca2+ ], and reduced sensitivity to Mg2+ inhibition were evident. Our results provide mechanistic insight into the changes to RyR2 gating that destabilise sarcoplasmic reticulum Ca2+ -release causing life-threatening arrhythmias in V2475F(+/-)-CPVT1 patients.

Quantitative RyR1 reduction and loss of calcium sensitivity of RyR1Q1970fsX16+A4329D cause cores and loss of muscle strength.

Recessive ryanodine receptor 1 (RYR1) mutations cause congenital myopathies including multiminicore disease (MmD), congenital fiber-type disproportion and centronuclear myopathy. We created a mouse model knocked-in for the Q1970fsX16+A4329D RYR1 mutations, which are isogenic with those identified in a severely affected child with MmD. During the first 20 weeks after birth the body weight and the spontaneous running distance of the mutant mice were 20% and 50% lower compared to wild-type littermates. Skeletal muscles from mutant mice contained 'cores' characterized by severe myofibrillar disorganization associated with misplacement of mitochondria. Furthermore, their muscles developed less force and had smaller electrically evoked calcium transients. Mutant RyR1 channels incorporated into lipid bilayers were less sensitive to calcium and caffeine, but no change in single-channel conductance was observed. Our results demonstrate that the phenotype of the RyR1Q1970fsX16+A4329D compound heterozygous mice recapitulates the clinical picture of multiminicore patients and provide evidence of the molecular mechanisms responsible for skeletal muscle defects.

Demographic, Behavioral, and Proximal Risk Factors for Gambling Disorder in the US Military.

BACKGROUND AND OBJECTIVES: To estimate the diagnostic prevalence and incidence of gambling disorder among United States service members and to identify associated risk factors, including demographics, history of mental illness or substance misuse, and proximity to legalized gambling vicinities. METHODS: Gambling disorder cases comprised active component Service members who received a pathological or problem gambling diagnosis between October 1, 2005 and September 30, 2015. There were 901 cases (392 incidents) during the study period. Controls were matched on the case military entrance date (N = 43,564). Geospatial distance between gambling venue and military treatment facilities were calculated, then multivariable logistic regression and survival analyses were conducted. RESULTS: The 10-year prevalence of gambling disorder was 6.6 per 100,000. Men were 3.5 times more likely than women to receive a gambling disorder diagnosis. Other risk factors included age over 24, Asian or Black race, formerly married, and enlisted rank. The odds of gambling disorder increased with duration and proximity to gambling venues, ranging from 2.0 to 3.9. Service members with prior substance misuse or mental health conditions were 3.9 times and 6.3 times more likely to receive a disordered gambling diagnosis than those without substance misuse or mental illness history, respectively. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: The results of this study reveal that proximity to gambling venues and slot machines on bases, as well as a history of substance misuse or mental disorders, are important risk factors for gambling disorder in the US military. Department of Defense screening policies that focus on high-risk populations are appropriate. (Am J Addict 2021;00:00-00).

Inter- and intra-tumoural heterogeneity in cancer-associated fibroblasts of human pancreatic ductal adenocarcinoma.

Cancer-associated fibroblasts (CAF) are orchestrators of the pancreatic ductal adenocarcinoma (PDAC) microenvironment. Stromal heterogeneity may explain differential pathophysiological roles of the stroma (pro- versus anti-tumoural) in PDAC. We hypothesised that multiple CAF functional subtypes exist in PDAC, that contribute to stromal heterogeneity through interactions with cancer cells. Using molecular and functional analysis of patient-derived CAF primary cultures, we demonstrated that human PDAC-derived CAFs display a high level of inter- and intra-tumour heterogeneity. We identified at least four subtypes of CAFs based on transcriptomic analysis, and propose a classification for human PDAC-derived CAFs (pCAFassigner). Multiple CAF subtypes co-existed in individual patient samples. The presence of these CAF subtypes in bulk tumours was confirmed using publicly available gene expression profiles, and immunostainings of CAF subtype markers. Each subtype displayed specific phenotypic features (matrix- and immune-related signatures, vimentin and α-smooth muscle actin expression, proliferation rate), and was associated with an assessable prognostic impact. A prolonged exposure of non-tumoural pancreatic stellate cells to conditioned media from cancer cell lines (cancer education experiment) induced a CAF-like phenotype, including loss of capacity to revert to quiescence and an increase in the expression of genes related to CAF subtypes B and C. This classification demonstrates molecular and functional inter- and intra-tumoural heterogeneity of CAFs in human PDAC. Our subtypes overlap with those identified from single-cell analyses in other cancers, and pave the way for the development of therapies targeting specific CAF subpopulations in PDAC. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Typologies of Combat Exposure and Their Effects on Posttraumatic Stress Disorder and Depression Symptoms.

The present study identified distinct classes of U.S. military service members based on their combat experiences and examined mental health outcomes and longitudinal growth curves of posttraumatic stress disorder (PTSD) and depression symptoms associated with each class. Participants were 551 active duty service members who screened positive for PTSD and/or depression based on DSM-IV-TR criteria. All participants completed the Combat Experiences Scale at baseline as well as PTSD and depression measures at baseline and at 3-, 6-, and 12-month follow-ups. A latent class analysis identified four classes of service members based on their combat experiences: limited exposure, medical exposure, unit exposure, and personal exposure. Service members in the personal exposure class were characterized by a distinct mental health profile: They reported a higher level of PTSD symptoms at baseline and a higher prevalence of traumatic brain injury and PTSD diagnoses during the course of the study. The limited exposure class was more likely to receive diagnoses of depression and adjustment disorders. All classes except the medical exposure class demonstrated a slight decrease in PTSD and depression symptoms over time. However, participants in the limited exposure class had a larger decrease in PTSD and depression symptoms earlier in care but did not demonstrate superior long-term symptom improvements at 12 months compared to the other groups. These results inform PTSD development models and have implications for the screening and clinical management of combat-exposed service members.

Spanish Abstracts by Asociación Chilena de Estrés Traumático (ACET) Tipologías de Exposición a Combate y sus Efectos en el Trastorno de Estrés Postraumático y Síntomas Depresivos. EXPERIENCIAS TRAUMÁTICAS DE COMBATE, TEPT Y DEPRESIÓN El presente estudio identificó clases distintivas de miembros del servicio militar de los EEUU basados en sus experiencias de combate y examinó los resultados en salud mental y las curvas de crecimiento longitudinal del Trastorno de Estrés Postraumático (TEPT) y síntomas depresivos asociados con cada clase. Los participantes fueron 551 miembros en servicio activo que resultaron positivo para TEPT y/o depresión basado en los criterios DSM-IV-R. Todos los participantes completaron la Escala de Experiencias de Combate así como también medidas de TEPT y Depresión, al inicio y a los 3, 6 y 12 meses de seguimiento. Un análisis de grupos latente identificó cuatro clases de miembros del servicio basados en sus experiencias de combate: exposición limitada, exposición médica, exposición de la unidad, y exposición personal. Los miembros del servicio en el grupo de exposición personal se caracterizaron por un perfil distintivo de salud mental: Ellos reportaron, al inicio, niveles más altos de síntomas de TEPT y prevalencias más altas de diagnósticos de lesión traumática cerebral y TEPT durante el curso del estudio. El grupo de exposición limitada tuvo mayor probabilidad de recibir los diagnósticos de depresión y trastorno de adaptación. Todos los grupos, excepto el grupo de exposición médica, demostraron una leve disminución en los síntomas de TEPT y depresión con el tiempo. Sin embargo, los participantes en el grupo de exposición limitada tuvieron una disminución mayor en síntomas de TEPT y depresión al inicio de la atención, pero no demostraron una mejoría mayor de los síntomas a largo plazo a los 12 meses en comparación con los otros grupos. Estos resultados sirven de base para los modelos de desarrollo de TEPT y tienen implicaciones para la detección y manejo clínico de los miembros en servicio expuestos a combate.

Identifying research gaps in substance use disorder: A systematic methodology and prioritized list.

Background: This paper presents a new methodology for identifying and prioritizing research gaps, contributing to the nascent literature on systematic ways to identify research gaps. Objectives: The goal of this paper is to report on a gaps analysis of substance use disorder (SUD) research. Based on input from Military Health System stakeholders, we selected the following subtopics as priorities: alcohol use disorder (AUD) and comorbid conditions, prescription opioids, and novel synthetic drugs (NSDs), including synthetic cannabinoids, synthetic cathinones, novel synthetic opioids, and e-cigarette use. Methods: Statements of research needs were extracted from authoritative source reports. A work group of 13 subject matter experts then supplemented, consolidated, and refined the statements. Support for each statement was rated based on predetermined metrics to produce a list of high-priority potential research gaps. Work group members searched both published and ongoing research literature to determine whether these potential gaps were sufficiently addressed in the literature. Finally, to prioritize the gaps, work group members rated them on a set of metrics. Results: The work group reduced 175 statements of research needs to a list of 18 final prioritized gaps: nine for AUD, four for prescription opioids, and five for NSDs. For each topic, we present a prioritized list of gaps. Conclusions: This paper describes a method to identify and prioritize research gaps relevant to military and civilian research and presents the prioritized SUD gaps. Our methodology and findings can inform policy makers, researchers, and funding agencies as they consider investments in future research.

Dampened activity of ryanodine receptor channels in mutant skeletal muscle lacking TRIC-A.

KEY POINTS: The role of trimeric intracellular cation (TRIC) channels is not known, although evidence suggests they may regulate ryanodine receptors (RyR) via multiple mechanisms. We therefore investigated whether Tric-a gene knockout (KO) alters the single-channel function of skeletal RyR (RyR1). We find that RyR1 from Tric-a KO mice are more sensitive to inhibition by divalent cations, although they respond normally to cytosolic Ca2+ , ATP, caffeine and luminal Ca2+ . In the presence of Mg2+ , ATP cannot effectively activate RyR1 from Tric-a KO mice. Additionally, RyR1 from Tric-a KO mice are not activated by protein kinase A phosphorylation, demonstrating a defect in the ability of ß-adrenergic stimulation to regulate sarcoplasmic reticulum (SR) Ca2+ -release. The defective RyR1 gating that we describe probably contributes significantly to the impaired SR Ca2+ -release observed in skeletal muscle from Tric-a KO mice, further highlighting the importance of TRIC-A for normal physiological regulation of SR Ca2+ -release in skeletal muscle. ABSTRACT: The type A trimeric intracellular cation channel (TRIC-A) is a major component of the nuclear and sarcoplasmic reticulum (SR) membranes of cardiac and skeletal muscle, and is localized closely with ryanodine receptor (RyR) channels in the SR terminal cisternae. The skeletal muscle of Tric-a knockout (KO) mice is characterized by Ca2+ overloaded and swollen SR and by changes in the properties of SR Ca2+ release. We therefore investigated whether RyR1 gating behaviour is modified in the SR from Tric-a KO mice by incorporating native RyR1 into planar phospholipid bilayers under voltage-clamp conditions. We find that RyR1 channels from Tric-a KO mice respond normally to cytosolic Ca2+ , ATP, adenine, caffeine and to luminal Ca2+ . However, the channels are more sensitive to the inactivating effects of divalent cations, thus, in the presence of Mg2+ , ATP is inadequate as an activator. Additionally, channels are not characteristically activated by protein kinase A even though the phosphorylation levels of Ser2844 are similar to controls. The results of the present study suggest that TRIC-A functions as an excitatory modulator of RyR1 channels within the SR terminal cisternae. Importantly, this regulatory action of TRIC-A appears to be independent of (although additive to) any indirect consequences to RyR1 activity that arise as a result of K+ fluxes across the SR via TRIC-A.

Anti-stromal treatment together with chemotherapy targets multiple signalling pathways in pancreatic adenocarcinoma.

Stromal targeting for pancreatic ductal adenocarcinoma (PDAC) is rapidly becoming an attractive option, due to the lack of efficacy of standard chemotherapy and increased knowledge about PDAC stroma. We postulated that the addition of stromal therapy may enhance the anti-tumour efficacy of chemotherapy. Gemcitabine and all-trans retinoic acid (ATRA) were combined in a clinically applicable regimen, to target cancer cells and pancreatic stellate cells (PSCs) respectively, in 3D organotypic culture models and genetically engineered mice (LSL-Kras(G12D) (/+) ;LSL-Trp53(R172H) (/+) ;Pdx-1-Cre: KPC mice) representing the spectrum of PDAC. In two distinct sets of organotypic models as well as KPC mice, we demonstrate a reduction in cancer cell proliferation and invasion together with enhanced cancer cell apoptosis when ATRA is combined with gemcitabine, compared to vehicle or either agent alone. Simultaneously, PSC activity (as measured by deposition of extracellular matrix proteins such as collagen and fibronectin) and PSC invasive ability were both diminished in response to combination therapy. These effects were mediated through a range of signalling cascades (Wnt, hedgehog, retinoid, and FGF) in cancer as well as stellate cells, affecting epithelial cellular functions such as epithelial-mesenchymal transition, cellular polarity, and lumen formation. At the tissue level, this resulted in enhanced tumour necrosis, increased vascularity, and diminished hypoxia. Consequently, there was an overall reduction in tumour size. The enhanced effect of stromal co-targeting (ATRA) alongside chemotherapy (gemcitabine) appears to be mediated by dampening multiple signalling cascades in the tumour-stroma cross-talk, rather than ablating stroma or targeting a single pathway. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

"Figuring out your place at a school like this:" Intersectionality and sense of belonging among STEM and non-STEM college students.

BACKGROUND: Students' sense of belonging in college-an individual's feelings of contentment, mattering, importance, and "finding one's place" in a social setting-can influence choice of major and career trajectory. We contribute to the belongingness literature through a mixed methods intersectional study of students attending a STEM-focused public university we call Meadow State University (MSU). We assess the potential for students' intersecting social identities to differentially influence their experiences with intersectional oppression-subjection to multiple systems of oppression due to simultaneous membership in more than one marginalized group-that, in turn, may influence their college pathways. In addition, we explore whether intersectional differences affect sense of belonging differently in STEM and non-STEM majors. We employ a mixed-methods approach, informed by critical quantitative methods and in-depth interviews. We utilize quantitative institutional data measuring college satisfaction, expressed as "willingness to return" to the same university, for over 3,000 students during two academic years (2013-14 and 2016-17). Survey data explores college satisfaction as an indicator of intersectional differences in student experiences. Then, we analyze 37 in-depth interviews, collected between 2014-2016 at the same institution, to further contextualize the intersectional variation suggested by survey results. RESULTS: Willingness to return is influenced by major, as well as academic, social, and campus belonging. Moreover, the extent to which these factors affected outcomes additionally varied by race/ethnicity, gender, family income, other background factors, and the ways these factors may intersect. Important components of academic belonging included faculty-student interactions, perceptions of academic support, and a privileging of STEM degree programs and students over non-STEM students and their degree programs at MSU. Faculty responsiveness and high impact practices like internships played an important role, particularly in STEM programs. Taken together, our findings demonstrate that, particularly for students of color and those subject to intersectional oppression due to multiple marginalized identities, satisfaction with academics did not always outweigh deficiencies in other areas of campus life shaping belongingness. CONCLUSIONS: Our mixed-methods approach contributes insights into how and why students' background, individual choices, and institutional practices concurrently-and intersectionally-influence their ability to form a sense of belonging on campus. Structural changes are required to end practices that support intersecting systems of oppression by favoring White, upper-income men as the "default" STEM students in the U.S. Our research supports growing evidence that institutions must actively build models of inclusion for underrepresented and marginalized groups that address inequitable and unjust practices, providing transformative mentoring and educational guidance that attends to intersectional oppression, in order to effectively support the next generation of women and scholars of color.

Exercise induced hypoalgesia during different intensities of a dynamic resistance exercise: A randomized controlled trial.

INTRODUCTION: Exercise produces an immediate lessening of pain sensitivity (Exercise-Induced Hypoalgesia (EIH)) in healthy individuals at local and distant sites, possibly through a shared mechanism with conditioned pain modulation (CPM). Dynamic resistance exercise is a recommended type of exercise to reduce pain, yet limited research has examined the effects of intensity on EIH during this type of exercise. Therefore, the primary purpose of this study is to compare changes in PPT at a local and distant site during a leg extension exercise at a high intensity, a low intensity, or a quiet rest condition. A secondary purpose is to examine if CPM changes after each intervention. The final purpose is to examine if baseline pain sensitivity measures are correlated with response to each intervention. METHODS: In a randomized controlled trial of 60 healthy participants, participants completed baseline pain sensitivity testing (heat pain threshold, temporal summation, a cold pressor test as measure of CPM) and were randomly assigned to complete a knee extension exercise at: 1) high intensity (75% of a 1 Repetition Maximum (RM), 2) low intensity (30% 1RM), or 3) Quiet Rest. PPT was measured between each set at a local (quadriceps) and distant (trapezius) site during the intervention. CPM was then repeated after the intervention. To test the first purpose of the study, a three-way ANOVA examined for time x site x intervention interaction effects. To examine for changes in CPM by group, a mixed-model ANOVA was performed. Finally, a Pearson Correlation examined the association between baseline pain sensitivity and response to each intervention. RESULTS: Time x site x intervention interaction effects were not significant (F(5.3, 150.97) = 0.87, p = 0.51, partial eta2 = 0.03). CPM did not significantly change after the interventions (time x intervention F(1,38) = 0.81, p = 0.37, partial eta2 = 0.02. EIH effects at the quadriceps displayed a significant, positive moderate association with baseline HPT applied over the trapezius (r = 0.61, p<0.01) and TS (r = 0.46, p = 0.04). DISCUSSION: In healthy participants, PPT and CPM did not significantly differ after a leg extension exercise performed at a high intensity, low intensity, or quiet rest condition. It is possible pre-intervention CPM testing with a noxious stimuli may have impaired inhibitory effects frequently observed during exercise but future research would need to examine this hypothesis.

Biopsychosocial contributors to irritability in individuals with shoulder or low back pain.

OBJECTIVES: Irritability is a foundational clinical reasoning concept in rehabilitation to evaluate reactivity of the examination and treatment. While originally theorized to reflect tissue damage, a large body of evidence supports pain is a biopsychosocial experience impacted by pain sensitivity and psychological factors. Therefore, the purpose of this study was to examine biopsychosocial contributors to irritability. METHODS: 40 patients with shoulder (n = 20) and low back (n = 20) pain underwent Quantitative Sensory Testing (QST) (Pressure Pain Threshold, Heat Pain Threshold, Conditioned Pain Modulation, Temporal Summation), completed pain-related psychological questionnaires, an Exercise-Induced Hypoalgesia protocol, and standardized irritability assessment based on Clinical Practice Guidelines. Participants were then categorized as irritable or not irritable based on Maitland's criteria and by irritability level based on Clinical Practice Guidelines. An independent samples t-test examined for differences in QST and psychological factors by irritability category. A MANOVA examined for differences in QST and psychological factors by irritability level (high, moderate, low). RESULTS: Significantly lower heat and pressure pain thresholds at multiple locations (p < 0.05), as well as less efficient conditioned pain modulation (p = 0.02), were demonstrated in individuals categorized as irritable. Heat and pressure pain thresholds were also significantly lower in patients with high irritability compared to other levels. Significantly higher depression and anger, as well as lower self-efficacy, were reported in individuals with an irritable presentation. DISCUSSION/CONCLUSION: Biopsychosocial factors, including widespread hyperalgesia and elevated psychological factors, may contribute to an irritable presentation.

Improving primary care access for rural women Veterans: the Boost Team.

Objectives: To improve healthcare access for rural cisgender women and gender diverse Veterans, we created the "Boost Team," a clinician-driven telehealth outreach service to connect this population to Veterans Health Administration (VHA) services. Methods: Between 9/2021 and 2/2022, we conducted a needs assessment in the Veterans Integrated Service Network (VISN) 21 and used those data to develop an outreach intervention. We piloted a clinician-led outreach intervention in 3/2022, and formally deployed an outreach team in 9/2022. Results: The needs assessment uncovered opportunities to educate Veterans, staff, and clinicians about available VHA women's health services, and a need for easily-accessible gender-sensitive services. During the pilot, 58% (7/12) rural cisgender women Veterans were successfully contacted, all reported positive experiences with the intervention. The formal outreach team launched in 9/2022 and consists of a nurse practitioner (NP), scheduler, Peer Support Specialist, and medical director. From 9/2022 to 12/2022 the Boost NP called 110 rural cisgender women and gender diverse Veterans and spoke to 65 (59%) of them. Common care needs identified and addressed included care coordination, new referrals, medication management, and diagnostics. Discussion: Data from Boost show that clinician-led outreach can engage rural cisgender women and gender diverse Veterans in VHA services, there is a desire for more gender-sensitive services, and there is a need for systems-level improvements to allow for improved care coordination and decreased leakage outside of VHA. Using robust strategies grounded in implementation sciences, we will continue conducting a program evaluation to study the impact of Boost and scale and expand the program.

Modulation of a critical period for motor development in Drosophila by BK potassium channels.

Critical periods are windows of heightened plasticity occurring during neurodevelopment. Alterations in neural activity during these periods can cause long-lasting changes in the structure, connectivity, and intrinsic excitability of neurons, which may contribute to the pathology of neurodevelopmental disorders. However, endogenous regulators of critical periods remain poorly defined. Here, we study this issue using a fruit fly (Drosophila) model of an early-onset movement disorder caused by BK potassium channel gain of function (BK GOF). Deploying a genetic method to place robust expression of GOF BK channels under spatiotemporal control, we show that adult-stage neuronal expression of GOF BK channels minimally disrupts fly movement. In contrast, limiting neuronal expression of GOF BK channels to a short window during late neurodevelopment profoundly impairs locomotion and limb kinematics in resulting adult flies. During this critical period, BK GOF perturbs synaptic localization of the active zone protein Bruchpilot and reduces excitatory neurotransmission. Conversely, enhancing neural activity specifically during development rescues motor defects in BK GOF flies. Collectively, our results reveal a critical developmental period for limb control in Drosophila that is influenced by BK channels and suggest that BK GOF causes movement disorders by disrupting activity-dependent aspects of synaptic development.

Through the Lens of Movement-Evoked Pain: A Theoretical Framework of the "Pain-Movement Interface" to Guide Research and Clinical Care for Musculoskeletal Pain Conditions.

Over 120 million Americans report experiencing pain in the past 3 months. Among these individuals, 50 million report chronic pain and 17 million report pain that limits daily life or work activities on most days (ie, high-impact chronic pain). Musculoskeletal pain conditions in particular are a major contributor to global disability, health care costs, and poor quality of life. Movement-evoked pain (MEP) is an important and distinct component of the musculoskeletal pain experience and represents an emerging area of study in pain and rehabilitation fields. This focus article proposes the "Pain-Movement Interface" as a theoretical framework of MEP that highlights the interface between MEP, pain interference, and activity engagement. The goal of the framework is to expand knowledge about MEP by guiding scientific inquiry into MEP-specific pathways to disability, high-risk clinical phenotypes, and underlying individual influences that may serve as treatment targets. This framework reinforces the dynamic nature of MEP within the context of activity engagement, participation in life and social roles, and the broader pain experience. Recommendations for MEP evaluation, encompassing the spectrum from high standardization to high patient specificity, and MEP-targeted treatments are provided. Overall, the proposed framework and recommendations reflect the current state of science in this emerging area of study and are intended to support future efforts to optimize musculoskeletal pain management and enhance patient outcomes. PERSPECTIVE: Movement-evoked pain (MEP) is a distinct component of the musculoskeletal pain experience and emerging research area. This article introduces the "Pain-Movement Interface" as a theoretical framework of MEP, highlighting the interface between MEP, pain interference, and activity engagement. Evaluating and treating MEP could improve rehabilitation approaches and enhance patient outcomes.

Task-specific resistance training adaptations in older adults: comparing traditional and functional exercise interventions.

Muscle strength declines ∼3% per year after the age of 70. Resistance training guidelines for older adults are often based on free-weight and machine exercises, which may be inaccessible and lack carryover to activities of daily living. We tested the hypothesis that resistance training adaptations in older adults are task-specific. Thirty adults (8 males, 22 females; mean age = 71 years) were randomly assigned to participate in 6 weeks of supervised, high-intensity resistance training (twice per week) utilizing free-weight and machine exercises (traditional) versus functional activities that were overloaded with a weighted vest (functional). Participants were thoroughly familiarized with the exercises and testing prior to beginning the study. Major outcome measures included assessments of functional performance, five-repetition maximum strength, isometric knee extensor force, and quadriceps muscle size. Physical activity and nutrition were monitored. The study results demonstrate that the magnitude of improvement within a given outcome was largely dependent on group assignment, with greater improvements in gait speed and the timed-up-and-go in the functional group, but 2-3× greater five repetition maximum strength improvements for the trap bar deadlift, leg press, and leg extension following traditional resistance training. Both groups showed improvements in isometric knee extensor force and muscle size, suggesting that some aspects of the observed adaptations were generic, rather than specific. Overall, these novel findings suggest that, among older adults, 1) resistance training adaptations exhibit a high degree of task specificity and 2) significant improvements in functional outcomes can be achieved with the use of a weighted vest.

The Association Between the Patient Self-Report Survey for the Assessment of Fibromyalgia with Pain Sensitivity and Psychological Factors in Individuals with Musculoskeletal Pain.

Purpose: The Patient Self-Report Survey for the Assessment of Fibromyalgia may potentially be a method for subgrouping patients with musculoskeletal pain who have a nociplastic pain presentation. Limited research has explored the convergent validity of this questionnaire against psychophysical measures of pain sensitivity and psychological factors in individuals with musculoskeletal pain. Therefore, the purpose of this study is to examine the strength of the association between total scores on the Patient Self-Report Survey for the Assessment of Fibromyalgia with clinical, pain sensitivity, and psychological factors. Patients and Methods: As a secondary analysis of a cross-sectional study, participants with shoulder (n = 20) or low back pain (n = 20) completed Quantitative Sensory Testing (QST), pain-related psychological questionnaires, and the Patient Self-Report Survey for the Assessment of Fibromyalgia. A Spearman correlation determined the association between total scores on the Patient Self Report Survey for the Assessment of Fibromyalgia with psychological factors and pain sensitivity behaviorally assessed with QST. Results: Negative psychological factors demonstrate moderate to strong positive associations with the Patient Self-Report Survey for the Assessment of Fibromyalgia (rho range = 0.36-0.80), suggesting greater negative psychological factors were observed in patients with higher severity of fibromyalgia symptoms. Pain sensitivity factors demonstrated weak to moderate negative associations with The Patient Self-Report Survey for the Assessment of Fibromyalgia (PPT rho range=-0.36- -0.41), suggesting that elevated pain sensitivity was observed in individuals with higher severity of nociplastic pain symptoms. Conclusion: Collectively, this supports the convergent validity of the Patient Self-Report Survey for the Assessment of Fibromyalgia with psychological and pain sensitivity factors in patients with musculoskeletal pain.

Novel methods of immunogenic antigen selection for serological diagnosis of Parelaphostrongylus tenuis infection.

This paper outlines methods used to identify novel antigens for use in the development of serological assays. Specifically, we applied these methods to a neurogenic parasitic nematode of cervids called Parelaphostrongylus tenuis. This parasite is of particular concern in both wild and domestic ungulates as it causes significant neurological signs and definitive diagnosis is only possible post-mortem, necessitating the development of serologic assays for antemortem diagnosis. Proteins extracted from P. tenuis organisms were affinity isolated using antibodies enriched from seropositive moose (Alces alces). The proteins were analyzed using mass spectrometry and liquid chromatography to obtain amino acid sequences that were then cross-referenced to open reading frames predicted from an assembled transcriptome. An antigen of interest was assessed for immunogenic epitopes and subsequently synthesized into 10-mer synthetic overlapping peptides representing these regions. These synthetic peptides were then assessed for reactivity against positive and negative moose sera and demonstrated potential use as a serological assay in diagnostic laboratories. Known negative moose sera revealed significantly lower optical density when compared to the positive samples (p < 0.05). This method serves as a pipeline for the construction of diagnostic assays of pathogens in both human and veterinary medicine.