Associations of Mortality Outcomes With Employment Status at Discharge From VA Vocational Rehabilitation Service Programs.

OBJECTIVE: The authors evaluated associations between employment at discharge from Veterans Health Administration Vocational Rehabilitation Service (VR) programs and suicide and other causes of death. METHODS: For veterans receiving VR between October 1, 2005, and September 30, 2014 (N=78,293), proportional hazards analyses were used to test associations of employment with suicide, drug overdose, and external and natural cause mortality rates over 1 and 5 years postdischarge and through December 31, 2019. The analyses were adjusted for clinical and sociodemographic characteristics and propensity for employment. RESULTS: Of the veterans, 94.1% had a psychiatric diagnosis, and 35.5% were employed at VR discharge. In proportional hazards analyses, employment was associated with lower mortality rates through 1 year (suicide, hazard ratio [HR]=0.54; overdose, HR=0.70; external causes, HR=0.62; and natural causes, HR=0.51) and 5 years postdischarge (overdose, HR=0.72; external causes, HR=0.81; and natural causes, HR=0.72). Through December 31, 2019, employment was associated with lower risks for overdose (HR=0.80) and death by external (HR=0.81) and natural (HR=0.80) causes. CONCLUSIONS: Employment at VR discharge was associated with lower mortality risk among veterans with psychiatric diagnoses.

A Case of Metastatic Chromophobe Renal Cell Carcinoma Masked as Suspected Hepatic Abscesses.

Background: Characterizing multiple hepatic lesions on cross-sectional imaging, particularly differentiating abscesses from metastatic lesions, can be challenging. Case Presentation: A male aged 53 years with a history of chromophobe renal cell carcinoma presented with fevers and abdominal pain and was found to have multiple hepatic lesions concerning for hepatic abscesses. The lesions initially evaded diagnosis on imaging, laboratory tests, and biopsy, but ultimately were determined to be a rare case of metastatic chromophobe renal cell carcinoma of the liver. Conclusions: The finding of multiple new liver lesions on imaging during a febrile illness is concerning for hepatic abscess or malignancy, which can be difficult to diagnose with imaging alone. Differentiation between infectious and neoplastic etiologies may require additional imaging and/or tissue sampling.

Implementing and evaluating a veterans crisis line quality improvement initiative: The safety planning pilot program.

The Veterans Crisis Line (VCL) is part of the U.S. Department of Veterans Affairs' suicide prevention mission. In 2021, VCL assessed the impact of a pilot implementation project of conducting six-part safety plans (SPs) instead of VCL's usual risk mitigation plan. VCL responders offered to complete six-part SPs with eligible callers. Parametric and nonparametric methods compared call characteristics and Veteran Health Administration (VHA) utilization of eligible callers, by SP completion. We forecasted the operational impact of VCL-wide implementation. 27.37% (N = 448/1,637) of calls to designated responders were eligible for SPs. Of those, 27.23% (N = 122/448) completed SPs. Common barriers were call interruptions and the veteran declining. Among veteran callers who use VHA, SP completers were more likely to accept clinical referrals and had more outpatient mental health appointments before and after their VCL call. Calls involving SPs had a call plus documentation time 175% longer than eligible calls without SPs (87.78 vs. 49.66 min). If SPs were implemented VCL-wide, this would require 3-5(4.12%) more responders per hour to maintain current VCL call answer speed. SPs are adaptable to VCL; however, implementation presents logistical barriers. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Walking net V ˙ O2 rises with advancing age in older women: where to go from here?

PURPOSE: Walking net V ˙ O2 tends to increase with advancing age; however, factors contributing to this relationship have not been widely described. The implications of such findings could inform targeted strategies to promote independent mobility in older adults. Herein, we evaluated the relationship between net V ˙ O2 and age at two submaximal workloads while exploring potential moderators of this relationship. METHODS: Secondary analyses were performed on 35 older (65 ± 3 years) women who completed a battery of physical assessments including fixed-speed, non-graded and graded (+ 2.5%) treadmill walking with indirect calorimetry to determine net V ˙ O2. Maximal oxygen uptake ( V ˙ O2max), knee extensor maximal isometric voluntary contraction (MVC), peak rate of torque development (RTD), and plantar flexor range-of-motion (PFROM) were also measured. RESULTS: Bivariate correlations showed non-graded (r = 0.403, p = 0.017) and graded (r = 0.413, p = 0.014) net V ˙ O2 were positively related to age. Notably, these relationships strengthened after adjusting for V ˙ O2max. Regression modeling showed age, RTD:MVC ratio (composite of muscle performance), and PFROM together explained 49% and 34% of the variance in non-graded and graded net V ˙ O2, respectively. Further analyses suggested knee extensor MVC moderates the relationship between non-graded net V ˙ O2 and age, accounting for 9% of the variance [ΔR2 = 0.090, F (1,31) = 4.13, p = 0.05]. CONCLUSION: These data support the premise that, in older women, walking net V ˙ O2 rises with advancing age, and additionally, the RTD:MVC ratio and PFROM are independent correlates of non-graded net V ˙ O2. Exercise interventions with a high degree of training specificity including explosive, velocity-based elements may promote independent mobility in older women.

Combination therapy of itraconazole and an acylhydrazone derivative (D13) for the treatment of sporotrichosis in cats.

Acylhydrazone (AH) derivatives represent a novel category of anti-fungal medications that exhibit potent activity against Sporothrix sp., both in vitro and in a murine model of sporotrichosis. In this study, we demonstrated the anti-fungal efficacy of the AH derivative D13 [4-bromo-N'-(3,5-dibromo-2-hydroxybenzylidene)-benzohydrazide] against both planktonic cells and biofilms formed by Sporothrix brasiliensis. In a clinical study, the effect of D13 was then tested in combination with itraconazole (ITC), with or without potassium iodide, in 10 cats with sporotrichosis refractory to the treatment of standard of care with ITC. Improvement or total clinical cure was achieved in five cases after 12 weeks of treatment. Minimal abnormal laboratory findings, e.g., elevation of alanine aminotransferase, were observed in four cats during the combination treatment and returned to normal level within a week after the treatment was ended. Although highly encouraging, a larger and randomized controlled study is required to evaluate the effectiveness and the safety of this new and exciting drug combination using ITC and D13 for the treatment of feline sporotrichosis. IMPORTANCE: This paper reports the first veterinary clinical study of an acylhydrazone anti-fungal (D13) combined with itraconazole against a dimorphic fungal infection, sporotrichosis, which is highly endemic in South America in animals and humans. Overall, the results show that the combination treatment was efficacious in ~50% of the infected animals. In addition, D13 was well tolerated during the course of the study. Thus, these results warrant the continuation of the research and development of this new class of anti-fungals.

Impact of Implementation Facilitation on the REACH VET Clinical Program for Veterans at Risk for Suicide.

OBJECTIVE: In 2017, the Veterans Health Administration (VHA) implemented a national suicide prevention program, called Recovery Engagement and Coordination for Health-Veterans Enhanced Treatment (REACH VET), that uses a predictive algorithm to identify, attempt to reach, assess, and care for patients at the highest risk for suicide. The authors aimed to evaluate whether facilitation enhanced implementation of REACH VET at VHA facilities not meeting target completion rates. METHODS: In this hybrid effectiveness-implementation type 2 program evaluation, a quasi-experimental pre-post design was used to assess changes in implementation outcome measures evaluated 6 months before and 6 months after onset of facilitation of REACH VET implementation at 23 VHA facilities. Measures included percentages of patients with documented coordinator and provider acknowledgment of receipt, care evaluation, and outreach attempt. Generalized estimating equations were used to compare differences in REACH VET outcome measures before and after facilitation. Qualitative interviews were conducted with personnel and were explored via template analysis. RESULTS: Time had a significant effect in all outcomes models (p<0.001). An effect of facilitation was significant only for the outcome of attempted outreach. Patients identified by REACH VET had significantly higher odds of having a documented outreach attempt after facilitation of REACH VET implementation, compared with before facilitation. Site personnel felt supported and reported that the external facilitators were helpful and responsive. CONCLUSIONS: Facilitation of REACH VET implementation was associated with an improvement in outreach attempts to veterans identified as being at increased risk for suicide. Outreach is critical for engaging veterans in care.

Impact of the Communities That HEAL Intervention on Buprenorphine-Waivered Practitioners and Buprenorphine Prescribing: A Prespecified Secondary Analysis of the HCS Randomized Clinical Trial.

Importance: Buprenorphine significantly reduces opioid-related overdose mortality. From 2002 to 2022, the Drug Addiction Treatment Act of 2000 (DATA 2000) required qualified practitioners to receive a waiver from the Drug Enforcement Agency to prescribe buprenorphine for treatment of opioid use disorder. During this period, waiver uptake among practitioners was modest; subsequent changes need to be examined. Objective: To determine whether the Communities That HEAL (CTH) intervention increased the rate of practitioners with DATA 2000 waivers and buprenorphine prescribing. Design, Setting, and Participants: This prespecified secondary analysis of the HEALing Communities Study, a multisite, 2-arm, parallel, community-level, cluster randomized, open, wait-list-controlled comparison clinical trial was designed to assess the effectiveness of the CTH intervention and was conducted between January 1, 2020, to December 31, 2023, in 67 communities in Kentucky, Massachusetts, New York, and Ohio, accounting for approximately 8.2 million adults. The participants in this trial were communities consisting of counties (n = 48) and municipalities (n = 19). Trial arm randomization was conducted using a covariate constrained randomization procedure stratified by state. Each state was balanced by community characteristics including urban/rural classification, fatal opioid overdose rate, and community population. Thirty-four communities were randomized to the intervention and 33 to wait-list control arms. Data analysis was conducted between March 20 and September 29, 2023, with a focus on the comparison period from July 1, 2021, to June 30, 2022. Intervention: Waiver trainings and other educational trainings were offered or supported by the HEALing Communities Study research sites in each state to help build practitioner capacity. Main Outcomes and Measures: The rate of practitioners with a DATA 2000 waiver (overall, and stratified by 30-, 100-, and 275-patient limits) per 100 000 adult residents aged 18 years or older during July 1, 2021, to June 30, 2022, were compared between the intervention and wait-list control communities. The rate of buprenorphine prescribing among those waivered practitioners was also compared between the intervention and wait-list control communities. Intention-to-treat and per-protocol analyses were performed. Results: A total of 8 166 963 individuals aged 18 years or older were residents of the 67 communities studied. There was no evidence of an effect of the CTH intervention on the adjusted rate of practitioners with a DATA 2000 waiver (adjusted relative rate [ARR], 1.04; 95% CI, 0.94-1.14) or the adjusted rate of practitioners with a DATA 2000 waiver who actively prescribed buprenorphine (ARR, 0.97; 95% CI, 0.86-1.10). Conclusions and Relevance: In this randomized clinical trial, the CTH intervention was not associated with increases in the rate of practitioners with a DATA 2000 waiver or buprenorphine prescribing among those waivered practitioners. Supporting practitioners to prescribe buprenorphine remains a critical yet challenging step in the continuum of care to treat opioid use disorder. Trial Registration: ClinicalTrials.gov Identifier: NCT04111939.

Impact of Primary Care-Mental Health Care Integration on Mental Health Care Engagement Across Racial and Ethnic Groups.

OBJECTIVE: Receiving mental health services as part of primary care in the Veterans Health Administration (VHA) might increase engagement in specialty mental health care. The authors reexamined the association between primary care-mental health integration (PCMHI) and continued engagement in specialty mental health care for VHA patients and assessed differences by race and ethnicity. METHODS: The study included 437,051 primary care patients with a first in-person specialty mental health encounter in 2015-2016 (no specialty mental health encounters in prior 12 months), including 46,417 patients with new PCMHI encounters in the year before the first specialty mental health encounter. Multivariable logistic regression assessed odds of follow-up specialty mental health care within 3 months of the first specialty mental health encounter. The dependent variable was care engagement (attending a second specialty mental health appointment); independent variables were whether patients were seen by PCMHI on the same day as the primary care appointment ("same-day access"), the time between PCMHI and first specialty mental health appointments, and race and ethnicity. RESULTS: PCMHI was associated with increased engagement in specialty mental health care for all patients, with a greater likelihood of engagement among non-Hispanic White patients. Same-day access to PCMHI was positively associated with care engagement, with no significant differences by race or ethnicity. PCMHI care within 3 months before a first specialty mental health encounter was associated with greater care engagement. CONCLUSIONS: PCMHI, especially same-day access to PCMHI care, may boost engagement in mental health care, although the study design precluded conclusions regarding causal relationships.

Division-Independent Differentiation of Muscle Stem Cells During a Growth Stimulus.

Adult muscle stem cells (MuSCs) are known to replicate upon activation before differentiating and fusing to regenerate myofibers. It is unclear whether MuSC differentiation is intrinsically linked to cell division, which has implications for stem cell population maintenance. We use single-cell RNA-sequencing to identify transcriptionally diverse subpopulations of MuSCs after 5 days of a growth stimulus in adult muscle. Trajectory inference in combination with a novel mouse model for tracking MuSC-derived myonuclei and in vivo labeling of DNA replication revealed an MuSC population that exhibited division-independent differentiation and fusion. These findings demonstrate that in response to a growth stimulus in the presence of intact myofibers, MuSC division is not obligatory.

Inhibition of p53-MDM2 binding reduces senescent cell abundance and improves the adaptive responses of skeletal muscle from aged mice.

Skeletal muscle adaptation to external stimuli, such as regeneration following injury and hypertrophy in response to resistance exercise, are blunted with advanced age. The accumulation of senescent cells, along with defects in myogenic progenitor cell (MPC) proliferation, have been strongly linked as contributing factors to age-associated impairment in muscle adaptation. p53 plays an integral role in all these processes, as upregulation of p53 causes apoptosis in senescent cells and prevents mitotic catastrophe in MPCs from old mice. The goal of this study was to determine if a novel pharmaceutical agent (BI01), which functions by upregulating p53 through inhibition of binding to MDM2, the primary p53 regulatory protein, improves muscle regeneration and hypertrophy in old mice. BI01 effectively reduced the number of senescent cells in vitro but had no effect on MPC survival or proliferation at a comparable dose. Following repeated oral gavage with 2 mg/kg of BI01 (OS) or vehicle (OV), old mice (24 months) underwent unilateral BaCl2 injury in the tibialis anterior (TA) muscle, with PBS injections serving as controls. After 7 days, satellite cell number was higher in the TA of OS compared to OV mice, as was the expression of genes involved in ATP production. By 35 days, old mice treated with BI01 displayed reduced senescent cell burden, enhanced regeneration (higher muscle mass and fiber cross-sectional area) and restoration of muscle function relative to OV mice. To examine the impact of 2 mg/kg BI01 on muscle hypertrophy, the plantaris muscle was subjected to 28 days of mechanical overload (MOV) in OS and OV mice. In response to MOV, OS mice had larger plantaris muscles and muscle fibers than OV mice, particularly type 2b + x fibers, associated with reduced senescent cells. Together our data show that BI01 is an effective senolytic agent that may also augment muscle metabolism to enhance muscle regeneration and hypertrophy in old mice.

Design of aided augmentative and alternative communication systems for children with vision impairment: psychoacoustic perspectives.

Children with complex communication needs often have multiple disabilities including visual impairments that impact their ability to interact with aided augmentative and alternative communication (AAC) systems. Just as the field benefited from a consideration of visual cognitive neuroscience in construction of visual displays, an exploration of psychoacoustics can potentially assist in maximizing the possibilities within AAC systems when the visual channel is either (a) not the primary sensory mode, or (b) is one that can be augmented to ultimately benefit AAC outcomes. The purpose of this paper is to highlight background information about psychoacoustics and present possible future directions for the design of aided AAC system technologies for children with visual impairments who rely on auditory information to learn and utilize AAC.

ApoE isoform does not influence skeletal muscle regeneration in adult mice.

Introduction: Apolipoprotein E (ApoE) has been shown to be necessary for proper skeletal muscle regeneration. Consistent with this finding, single-cell RNA-sequencing analyses of skeletal muscle stem cells (MuSCs) revealed that Apoe is a top marker of quiescent MuSCs that is downregulated upon activation. The purpose of this study was to determine if muscle regeneration is altered in mice which harbor one of the three common human ApoE isoforms, referred to as ApoE2, E3 and E4. Methods: Histomorphometric analyses were employed to assess muscle regeneration in ApoE2, E3, and E4 mice after 14 days of recovery from barium chloride-induced muscle damage in vivo, and primary MuSCs were isolated to assess proliferation and differentiation of ApoE2, E3, and E4 MuSCs in vitro. Results: There was no difference in the basal skeletal muscle phenotype of ApoE isoforms as evaluated by section area, myofiber cross-sectional area (CSA), and myonuclear and MuSC abundance per fiber. Although there were no differences in fiber-type frequency in the soleus, Type IIa relative frequency was significantly lower in plantaris muscles of ApoE4 mice compared to ApoE3. Moreover, ApoE isoform did not influence muscle regeneration as assessed by fiber frequency, fiber CSA, and myonuclear and MuSC abundance. Finally, there were no differences in the proliferative capacity or myogenic differentiation potential of MuSCs between any ApoE isoform. Discussion: Collectively, these data indicate nominal effects of ApoE isoform on the ability of skeletal muscle to regenerate following injury or the in vitro MuSC phenotype.

Bleeding Gastrointestinal Stromal Tumor (GIST) Results in a Sticky Situation: The Good and Bad of Hemostatic Spray.

A 50-year-old female presented with symptomatic anemia and hematemesis due to a 3.3 cm gastric gastrointestinal stromal tumor (GIST), which was located in the fundus. Adequate endoscopic views were only achieved in the retroflexed position and attempts at hemostasis via endoscopic clips were unsuccessful. Subsequently, TC-325 hemostatic powder was sprayed on the bleeding lesion and given retroflexed positioning, the powder also coated the esophagogastroduodenoscopy (EGD) scope where it abutted the gastroesophageal junction (GEJ). Hemostasis was successful, but the scope was unable to be withdrawn due to adherence to the surrounding mucosa. With torque maneuvering and a moderate amount of withdrawal force, the scope was successfully freed. The patient was started on imatinib mesylate and did not experience further bleeding episodes. This case highlights the challenge of achieving hemostasis in a bleeding GIST, the beneficial role of hemostatic powder spray, and the need for caution when utilizing it in a retroflexed manner.

Acetate and succinate benefit host muscle energetics as exercise-associated post-biotics.

Recently, the gut microbiome has emerged as a potent modulator of exercise-induced systemic adaptation and appears to be crucial for mediating some of the benefits of exercise. This study builds upon previous evidence establishing a gut microbiome-skeletal muscle axis, identifying exercise-induced changes in microbiome composition. Metagenomics sequencing of fecal samples from non-exercise-trained controls or exercise-trained mice was conducted. Biodiversity indices indicated exercise training did not change alpha diversity. However, there were notable differences in beta-diversity between trained and untrained microbiomes. Exercise significantly increased the level of the bacterial species Muribaculaceae bacterium DSM 103720. Computation simulation of bacterial growth was used to predict metabolites that accumulate under in silico culture of exercise-responsive bacteria. We identified acetate and succinate as potential gut microbial metabolites that are produced by Muribaculaceae bacterium, which were then administered to mice during a period of mechanical overload-induced muscle hypertrophy. Although no differences were observed for the overall muscle growth response to succinate or acetate administration during the first 5 days of mechanical overload-induced hypertrophy, acetate and succinate increased skeletal muscle mitochondrial respiration. When given as post-biotics, succinate or acetate treatment may improve oxidative metabolism during muscle hypertrophy.

On-chip gain switched frequency comb generation using a two sectioned single cavity laser without additional optical injection.

A tunable comb source is demonstrated on a monolithically integrated photonic integrated circuit (PIC). The PIC is a two section device designed to produce a single mode tunable spectrum, and the comb is generated by gain switching one section of the two sectioned laser. The laser produces a single mode spectra with a tunable range of 1543 - 1565 nm, and combs were generated with a frequency range of 1 - 10 GHz without requiring additional optical injection to maintain the phase coherence.

Tunable, coherent optical comb source via on-chip bidirectional coupling.

A tunable comb source is demonstrated through gain switching on a three-sectioned photonic integrated circuit (PIC). The PIC consists of two mutually coupled lasers connected by a passive waveguide. One of these is a tunable, two-section, single mode laser. The second laser is a simple Fabry-Perot cavity laser which can be phase-locked with the single mode laser via bidirectional coupling. Frequency combs are produced by gain switching the Fabry-Perot laser by applying a high-power radio frequency signal. Combs are generated with line spacings ranging from 3.5 to 8 GHz. The on-chip bidirectional coupling causes the comb to also be generated in the two-section device. Despite the lack of on-chip optical isolation between the lasers, the resulting combs are stable. Numerical simulations using a delay-differential model reproduce the results and reveal the important role played by the short delay times inherent to on-chip integration in this stability.

White matter hyperintensity longitudinal morphometric analysis in association with Alzheimer disease.

INTRODUCTION: Vascular damage in Alzheimer's disease (AD) has shown conflicting findings particularly when analyzing longitudinal data. We introduce white matter hyperintensity (WMH) longitudinal morphometric analysis (WLMA) that quantifies WMH expansion as the distance from lesion voxels to a region of interest boundary. METHODS: WMH segmentation maps were derived from 270 longitudinal fluid-attenuated inversion recovery (FLAIR) ADNI images. WLMA was performed on five data-driven WMH patterns with distinct spatial distributions. Amyloid accumulation was evaluated with WMH expansion across the five WMH patterns. RESULTS: The preclinical group had significantly greater expansion in the posterior ventricular WM compared to controls. Amyloid significantly associated with frontal WMH expansion primarily within AD individuals. WLMA outperformed WMH volume changes for classifying AD from controls primarily in periventricular and posterior WMH. DISCUSSION: These data support the concept that localized WMH expansion continues to proliferate with amyloid accumulation throughout the entirety of the disease in distinct spatial locations.

Mechanisms of mechanical overload-induced skeletal muscle hypertrophy: current understanding and future directions.

Mechanisms underlying mechanical overload-induced skeletal muscle hypertrophy have been extensively researched since the landmark report by Morpurgo (1897) of "work-induced hypertrophy" in dogs that were treadmill trained. Much of the preclinical rodent and human resistance training research to date supports that involved mechanisms include enhanced mammalian/mechanistic target of rapamycin complex 1 (mTORC1) signaling, an expansion in translational capacity through ribosome biogenesis, increased satellite cell abundance and myonuclear accretion, and postexercise elevations in muscle protein synthesis rates. However, several lines of past and emerging evidence suggest that additional mechanisms that feed into or are independent of these processes are also involved. This review first provides a historical account of how mechanistic research into skeletal muscle hypertrophy has progressed. A comprehensive list of mechanisms associated with skeletal muscle hypertrophy is then outlined, and areas of disagreement involving these mechanisms are presented. Finally, future research directions involving many of the discussed mechanisms are proposed.

Correction: Aboriginal artefacts on the continental shelf reveal ancient drowned cultural landscapes in northwest Australia.

[This corrects the article DOI: 10.1371/journal.pone.0233912.].

Stochastic scanning events on the GCN4 mRNA 5' untranslated region generate cell-to-cell heterogeneity in the yeast nutritional stress response.

Gene expression stochasticity is inherent in the functional properties and evolution of biological systems, creating non-genetic cellular individuality and influencing multiple processes, including differentiation and stress responses. In a distinct form of non-transcriptional noise, we find that interactions of the yeast translation machinery with the GCN4 mRNA 5'UTR, which underpins starvation-induced regulation of this transcriptional activator gene, manifest stochastic variation across cellular populations. We use flow cytometry, fluorescence-activated cell sorting and microfluidics coupled to fluorescence microscopy to characterize the cell-to-cell heterogeneity of GCN4-5'UTR-mediated translation initiation. GCN4-5'UTR-mediated translation is generally not de-repressed under non-starvation conditions; however, a sub-population of cells consistently manifests a stochastically enhanced GCN4 translation (SETGCN4) state that depends on the integrity of the GCN4 uORFs. This sub-population is eliminated upon deletion of the Gcn2 kinase that phosphorylates eIF2α under nutrient-limitation conditions, or upon mutation to Ala of the Gcn2 kinase target site, eIF2α-Ser51. SETGCN4 cells isolated using cell sorting spontaneously regenerate the full bimodal population distribution upon further growth. Analysis of ADE8::ymRuby3/ GCN4::yEGFP cells reveals enhanced Gcn4-activated biosynthetic pathway activity in SETGCN4 cells under non-starvation conditions. Computational modeling interprets our experimental observations in terms of a novel translational noise mechanism underpinned by natural variations in Gcn2 kinase activity.