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Abstract Background Motor vehicle crashes are the second leading cause of injury death among adults aged 65 and older in the U.S., second only to falls. A common state-level approach to mitigating older adult crash risk is the implementation of driver license renewal policies which vary largely between states and data on their effectiveness in preventing crashes and injuries are limited. To fill this gap, the aim of this study is to examine the association between state driver license renewal policies and older driver crash and injury rates. Methods Historical crash data, license renewal policy data, and other relevant policy and demographic data were gathered from 13 U.S. states (CO, IL, IA, KS, MN, MO, NE, ND, OH, SD, UT, WI, WY) for years 2000 through 2019, inclusive. Main exposures included six license renewal policies: renewal period, in-person renewal frequency, vision testing, knowledge testing, on-road drive testing, and mandatory physician reporting. The primary outcomes were crash and injury rates per 100,000 population. Results The study population included 19,010,179 crash-involved drivers aged 40 and older. State policies became less restrictive in many states over the study period, even for drivers aged 75 and older, resulting in longer times between renewals and fewer in-person renewal requirements. Loosening of in-person renewal from every time to less than every time was associated with increased crash rates, among drivers aged 65 to 74 (RRcrash = 1.08, 95% CI: 1.01–1.16). A longer duration between in-person renewals was associated with increased injury rates among drivers 75 and older (RRinjury = 1.18, 95% CI: 1.00–1.39). Conclusions Generally, state policies became less restrictive and resulted in longer required intervals between license renewal. Loosening of driver license renewal policies was associated with increased crash and injury rates. However, safety benefits of restrictive older driver licensing policies should be carefully weighed against costs to older adult well-being and quality of life following licensure loss. Additional methods to assess fitness to drive are necessary to identify the mechanisms behind the increased rates.

Axonal regeneration following surgical nerve repair is slow and often incomplete, resulting in poor functional recovery which sometimes contributes to lifelong disability. Currently, there are no FDA-approved therapies available to promote nerve regeneration. Tacrolimus accelerates axonal regeneration, but systemic side effects presently outweigh its potential benefits for peripheral nerve surgery. The authors describe herein a biodegradable polyurethane-based drug delivery system for the sustained local release of tacrolimus at the nerve repair site, with suitable properties for scalable production and clinical application, aiming to promote nerve regeneration and functional recovery with minimal systemic drug exposure. Tacrolimus is encapsulated into co-axially electrospun polycarbonate-urethane nanofibers to generate an implantable nerve wrap that releases therapeutic doses of bioactive tacrolimus over 31 days. Size and drug loading are adjustable for applications in small and large caliber nerves, and the wrap degrades within 120 days into biocompatible byproducts. Tacrolimus released from the nerve wrap promotes axon elongation in vitro and accelerates nerve regeneration and functional recovery in preclinical nerve repair models while off-target systemic drug exposure is reduced by 80% compared with systemic delivery. Given its surgical suitability and preclinical efficacy and safety, this system may provide a readily translatable approach to support axonal regeneration and recovery in patients undergoing nerve surgery.

Abstract Background The U.S.-Mexico “border wall” between El Paso, Texas and Ciudad Juárez, Mexico was raised and extended beginning in 2018 in accordance with Presidential Executive Order 13,767. We hypothesized that these changes resulted in increased incidence and severity of injuries of individuals attempting to cross the border wall in the El Paso region. Methods A retrospective cohort review was conducted of University Medical Center of El Paso Trauma Registry charts from 2001 to 2022. Year of injury, gender, age, Injury Severity Score, hospital length-of-stay, ICU length-of-stay, ventilator days, and survival were analyzed by Chi-square analysis with Fisher’s exact test for categorical variables and Independent Samples T-test for continuous variables. An independent samples Mann Whitney U Test was used to compare border wall fall injuries before and after 2018. Results Of the 842 patients reviewed, 69 patients presented before 2018 and 773 presented from 2018 to 2022. Statistically significant differences were identified in the mean Injury Severity Score which increased from 6.3 (SD ± 3.8) to 8.3 (SD ± 5.5, p

Deaths related to opioid overdoses continue to climb, and there remains a need for innovative strategies to address this ongoing crisis. Harm reduction (HR), a nonjudgmental philosophy aimed at reducing consequences associated with drug use and other potentially unsafe behavior, has emerged as a compassionate and effective approach. Harm reduction further emphasizes overdose prevention and fosters a shift in perspective that recognizes substance use disorder as a disease and not a moral failing. The tenets of HR collectively advocate for the well-being of individuals who use substances and support any positive change as defined by the individual. Given the high rate of morbidity and mortality associated with substance misuse and barriers or ambivalence to receiving treatment, awareness of and advocacy for HR practice is essential. This manuscript aims to describe evidence-based HR interventions, provide a foundation for the implementation of services, and further promote the importance of providing humanistic care without judgment. As valued members of the multidisciplinary treatment team, Board-Certified Psychiatric Pharmacists should implement and engage in HR services in the settings where people with substance use disorders receive care.

Reporting interventions thoroughly and consistently in the literature allows for study reproducibility or implementation of the intervention into practice. Although there is currently no standard for describing Board-Certified Psychiatric Pharmacist (BCPP) interventions in the published literature, there are multiple checklists or guides that have been developed for reporting clinical interventions, including the template for intervention description and replication and the pharmacist patient care intervention reporting (PaCIR) checklist, that seek to improve the quality of reporting interventions in the literature. The purpose of this paper is to describe a proposed guide for reporting BCPP interventions in the literature by expanding the PaCIR checklist. Authors use a logic model developed by the American Association of Psychiatric Pharmacists to ensure all elements of the process are addressed in the expanded guide.

IntroductionBrain cross-sectional images, tractography, and segmentation are valuable resources for neuroanatomical education and research but are also crucial for neurosurgical planning that may improve outcomes in cerebellar and brainstem interventions. Although ultrahigh-resolution 7-Tesla (7T) magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) reveal such structural brain details in living or fresh unpreserved brain tissue, imaging standard formalin-preserved cadaveric brain specimens often used for neurosurgical anatomic studies has proven difficult. This study sought to develop a practical protocol to provide anatomic information and tractography results of an ex vivo human brainstem-cerebellum specimen.Materials and methodsA protocol was developed for specimen preparation and 7T MRI with image postprocessing on a combined brainstem-cerebellum specimen obtained from an 85-year-old male cadaver with a postmortem interval of 1 week that was stored in formalin for 6 months. Anatomic image series were acquired for detailed views and diffusion tractography to map neural pathways and segment major anatomic structures within the brainstem and cerebellum.ResultsComplex white matter tracts were visualized with high-precision segmentation of crucial brainstem structures, delineating the brainstem-cerebellum and mesencephalic-dentate connectivity, including the Guillain-Mollaret triangle. Tractography and fractional anisotropy mapping revealed the complexities of white matter fiber pathways, including the superior, middle, and inferior cerebellar peduncles and visible decussating fibers. 3-dimensional (3D) reconstruction and quantitative and qualitative analyses verified the anatomical precision of the imaging relative to a standard brain space.DiscussionThis novel imaging protocol successfully captured the intricate 3D architecture of the brainstem-cerebellum network. The protocol, unique in several respects (including tissue preservation and rehydration times, choice of solutions, preferred sequences, voxel sizes, and diffusion directions) aimed to balance high resolution and practical scan times. This approach provided detailed neuroanatomical imaging while avoiding impractically long scan times. The extended postmortem and fixation intervals did not compromise the diffusion imaging quality. Moreover, the combination of time efficiency and ultrahigh-resolution imaging results makes this protocol a strong candidate for optimal use in detailed neuroanatomical studies, particularly in presurgical trajectory planning.

Abstract Background Angiolipomas have been well described in patients with HIV exposed to protease inhibitors with possible resolution after switching to non-nucleoside reverse transcriptase inhibitor-based regimens. Resolution of symptoms have occurred with switches to non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens; however, little is known regarding the development of angiolipomas when switching from NNRTI- to modern, integrase strand transfer inhibitor-based regimens. We describe a patient who underwent switch therapy from tenofovir disoproxil fumarate/emtricitabine/efavirenz (TDF/FTC/EFV) to tenofovir alafenamide/FTC/bictegravir (TAF/FTC/BIC) who later developed angiolipomas. Case Presentation A 55-year-old male had been on TDF/FTC/EFV for 8 years before switching to TAF/FTC/BIC. Nineteen months after antiretroviral switch, the patient presented with multiple lesions in the upper extremities and abdomen. Diagnostic biopsies revealed non-encapsulated angiolipomas and HHV-8 and non-alcoholic fatty liver disease was ruled out. New lesions continued to appear 29 months after ART switch, after which now lesions appeared and prior lesions remained stable with no increase in size noted. No surgical intervention or change in antiretroviral therapy was needed. Conclusions Angiogenesis may have been suppressed with TDF/FTC/EFV treatment, however when switched to TAF/FTC/BIC, promoted the growth of angiolipomas. Clinicians should be aware of the impact of switching to modern ART therapies resulting in possible adipogenesis.

Abstract Substantial literature documents the impact of mass traumatic events on post-traumatic stress disorder (PTSD) in populations. However, the trajectory of PTSD in the US population during the pandemic and the association between assets, Covid-19 related stressors, and PTSD over time remains unclear. The Covid-19 and Life Stressors Impact on Mental Health and Well-Being (CLIMB) is a nationally representative, longitudinal panel of US adults in Spring 2020 (N = 1270), 2021 (N = 1182), and 2022 (N = 1091). Using the four-item PC-PTSD-4, we assessed the prevalence of probable PTSD in the US population over three years. Using generalized estimating equations (GEE) and logistic regression at each wave, we estimated associations of demographics, assets, and stressors with probable PTSD. Here we report that the overall prevalence of PTSD decreases from 22.2% in 2020 to 16.8% in 2022 (p = 0.02). Persons with household incomes below $20,000 report higher prevalence of probable PTSD compared to other income groups. The GEE model shows higher odds of probable PTSD among persons with household incomes below $20,000 (OR = 2.17 (95%CI: 1.35,3.50)) relative to $75,000 or more; and high stressor scores (OR = 2.33 (95%CI: 1.72,3.15)) compared to low stressor scores. High stressor scores are associated with higher odds of probable PTSD in 2020 (OR = 2.69 (95%CI: 1.56,4.66)), 2021 (OR = 4.58 (95%CI: 2.52,8.30)), and 2022 (OR = 3.89 (95%CI: 2.05,7.38)) compared to low stressor scores. This analysis highlights the pandemic’s prolonged influence on population mental health, particularly among persons with fewer economic assets and those experiencing more pandemic-related stressors. Reducing mental health disparities requires interventions to address inequities.

Introduction Pharmacists focusing on psychotropic medication management and practicing across a wide variety of healthcare settings have significantly improved patient-level outcomes. The Systematic Literature Review Committee of the American Association of Psychiatric Pharmacists was tasked with compiling a comprehensive database of primary literature highlighting the impact of psychiatric pharmacists on patient-level outcomes. Methods A systematic search of literature published from January 1, 1961, to December 31, 2022, was conducted using PubMed and search terms based on a prior American Association of Psychiatric Pharmacists literature review. Publications describing patient-level outcome results associated with pharmacist provision of care in psychiatric/neurologic settings and/or in relation to psychotropic medications were included. The search excluded articles for which there was no pharmacist intervention, no psychiatric disorder treatment, no clinical outcomes, no original research, no access to full text, and/or no English-language version. Results A total of 4270 articles were reviewed via PubMed, with 4072 articles excluded based on title, abstract, and/or full text in the initial pass and 208 articles selected for inclusion. A secondary full-text review excluded 11 additional articles, and 5 excluded articles were ultimately included based on a secondary review, for a final total of 202 articles meeting the inclusion criteria. A comprehensive database of these articles was compiled, including details on their study designs and outcomes. Discussion The articles included in the final database had a wide range of heterogeneity. While the overall impact of psychiatric pharmacists was positive, the study variability highlights the need for future publications to have more consistent, standardized outcomes with stronger study designs.

This work investigates and analyzes collaborative beamforming for a Swarm-enabled distributed sensing project. It investigates the use of a three-dimensional, randomly populated, and uniformly-distributed array in three configurations: spherical, cylindrical, and cubical. These topologies uniquely act like a practical bound to contain the elements in swarm-type applications. In addition, these topologies provide mathematical simplicity toward understanding the fundamental research problem of both surface and underwater swarm-based UUV sensor networks, and their constraints to implementing a physical system in a volumetric setting. Therefore, statistical, ensemble, mean-valued average beampatterns scanned at the meridian elevation plane are analyzed in closed form using a large population of one million elements densely populated amongst geometrical bounds. This large density profile applies the law of large numbers in which numerical beampatterns converge to their expected (mean) patterns. Faithful agreement of the solution is shown to validate the distributed array pattern behavior. Finally, additional simulations are provided in this work using a cylindrical manifold that comprises ten, fifty, and one hundred isotropic radiators to determine the feasibility of a small element population.

Abstract The continued emergence of highly pathogenic viruses, which either thwart immune- and small molecule-based therapies or lack interventions entirely, mandates alternative approaches, particularly for prompt and facile pre- and post-exposure prophylaxis. Many highly pathogenic viruses, including coronaviruses, employ the six-helix bundle heptad repeat membrane fusion mechanism to achieve infection. Although heptad-repeat-2 decoys can inhibit viral entry by blocking six-helix bundle assembly, the biophysical and pharmacologic liabilities of peptides have hindered their clinical development. Here, we develop a chemically stapled lipopeptide inhibitor of SARS-CoV-2 as proof-of-concept for the platform. We show that our lead compound blocks infection by a spectrum of SARS-CoV-2 variants, exhibits mucosal persistence upon nasal administration, demonstrates enhanced stability compared to prior analogs, and mitigates infection in hamsters. We further demonstrate that our stapled lipopeptide platform yields nanomolar inhibitors of respiratory syncytial, Ebola, and Nipah viruses by targeting heptad-repeat-1 domains, which exhibit strikingly low mutation rates, enabling on-demand therapeutic intervention to combat viral outbreaks.

AbstractFrom the first cases in 2019, COVID-19 infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have resulted in over 6 million human deaths in a worldwide pandemic. SARS-CoV-2 is commonly spread from human to human through close contact and is capable of infecting both humans and animals. Worldwide, there have been over 675 animal outbreaks reported that resulted in over 2000 animal infections including domestic and wild animals. As the role of animal infections in the transmission, pathogenesis, and evolution of SARS-CoV-2 is still unfolding, accurate and reliable animal diagnostic tests are critical to aid in managing both human and animal health. This review highlights key animal samples and the three main diagnostic approaches used for animal testing: PCR, serology, and Next Generation Sequencing. Diagnostic results help inform (often difficult) clinical decision-making, but also possible ways to mitigate spread among pets, food supplies, or wildlife. A One Health approach has been key to monitoring the SARS-CoV-2 pandemic, as consistent human-animal interactions can lead to novel variants. Having multiple animal diagnostic tests for SARS-CoV-2 available is critical to ensure human, animal, and environmental health.

Abstract Cellular phenotypes and functional responses are modulated by the signals present in their microenvironment, including extracellular matrix (ECM) proteins, tissue mechanical properties, soluble signals and nutrients, and cell–cell interactions. To better recapitulate and analyze these complex signals within the framework of more physiologically relevant culture models, high throughput culture platforms can be transformative. High throughput methodologies enable scientists to extract increasingly robust and broad datasets from individual experiments, screen large numbers of conditions for potential hits, better qualify and predict responses for preclinical applications, and reduce reliance on animal studies. High throughput cell culture systems require uniformity, assay miniaturization, specific target identification, and process simplification. In this review, we detail the various techniques that researchers have used to face these challenges and explore cellular responses in a high throughput manner. We highlight several common approaches including two‐dimensional multiwell microplates, microarrays, and microfluidic cell culture systems as well as unencapsulated and encapsulated three‐dimensional high throughput cell culture systems, featuring multiwell microplates, micromolds, microwells, microarrays, granular hydrogels, and cell‐encapsulated microgels. We also discuss current applications of these high throughput technologies, namely stem cell sourcing, drug discovery and predictive toxicology, and personalized medicine, along with emerging opportunities and future impact areas.

Abstract Nonalcoholic fatty liver disease affects 30% of the United States population and its progression can lead to nonalcoholic steatohepatitis (NASH), and increased risks for cirrhosis and hepatocellular carcinoma. NASH is characterized by a highly heterogeneous liver microenvironment created by the fibrotic activity of hepatic stellate cells (HSCs). While HSCs have been widely studied in 2D, further advancements in physiologically relevant 3D culture platforms for the in vitro modeling of these heterogeneous environments are needed. In this study, the use of stiffness‐variable, extracellular matrix (ECM) protein‐conjugated polyethylene glycol microgels as 3D cell culture scaffolds to modulate HSC activation is demonstrated. These microgels as a high throughput ECM screening system to identify HSC matrix remodeling and metabolic activities in distinct heterogeneous microenvironmental conditions are further employed. The 6 kPa fibronectin microgels are shown to significantly increase HSC matrix remodeling and metabolic activities in single or multiple‐component microenvironments. Overall, heterogeneous microenvironments consisting of multiple distinct ECM microgels promoted a decrease in HSC matrix remodeling and metabolic activities compared to homogeneous microenvironments. The study envisions this ECM screening platform being adapted to a broad number of cell types to aid the identification of ECM microenvironments that best recapitulate the desired phenotype, differentiation, or drug efficacy.

Abstract Background By analyzing how health care leaders in the United States view mobile health programs and their impact on the organization’s bottom line, this study equips those who currently operate or plan to deploy mobile clinics with a business case framework. Our aim is to understand health care leaders’ perspectives about business-related incentives and disincentives for mobile healthcare. Methods We conducted 25 semi-structured key informant interviews with U.S. health care leaders to explore their views and experiences related to mobile health care. We used deductive and inductive thematic analysis to identify patterns in the data. An advisory group with expertise in mobile health, health management, and health care finance informed data collection and analysis. Results In addition to improving health outcomes, mobile clinics can bolster business objectives of health care organizations including those related to budget, business strategy, organizational culture, and health equity. We created a conceptual framework that demonstrates how these factors, supported by community engagement and data, come together to form a business case for mobile health care. Discussion Our study demonstrates that mobile clinics can contribute to health care organizations’ business goals by aligning with broader organizational strategies. The conceptual model provides a guide for aligning mobile clinics’ work with business priorities of organizations and funders. Conclusions By understanding how health care leaders reconcile the business pressures they face with opportunities to advance health equity using mobile clinics, we can better support the strategic and sustainable expansion of the mobile health sector.

The regenerative capacity of the peripheral nervous system is limited, and peripheral nerve injuries often result in incomplete healing and poor outcomes even after repair. Transection injuries that induce a nerve gap necessitate microsurgical intervention; however, even the current gold standard of repair, autologous nerve graft, frequently results in poor functional recovery. Several interventions have been developed to augment the surgical repair of peripheral nerves, and the application of functional biomaterials, local delivery of bioactive substances, electrical stimulation, and allografts are among the most promising approaches to enhance innate healing across a nerve gap. Biocompatible polymers with optimized degradation rates, topographic features, and other functions provided by their composition have been incorporated into novel nerve conduits (NCs). Many of these allow for the delivery of drugs, neurotrophic factors, and whole cells locally to nerve repair sites, mitigating adverse effects that limit their systemic use. The electrical stimulation of repaired nerves in the perioperative period has shown benefits to healing and recovery in human trials, and novel biomaterials to enhance these effects show promise in preclinical models. The use of acellular nerve allografts (ANAs) circumvents the morbidity of donor nerve harvest necessitated by the use of autografts, and improvements in tissue-processing techniques may allow for more readily available and cost-effective options. Each of these interventions aid in neural regeneration after repair when applied independently, and their differing forms, benefits, and methods of application present ample opportunity for synergistic effects when applied in combination.

Many quiescent galaxies discovered in the early Universe by JWST raise fundamental questions on when and how these galaxies became and stayed quenched. Making use of the latest version of the semianalytic model GAEA that provides good agreement with the observed quenched fractions up to z ∼ 3, we make predictions for the expected fractions of quiescent galaxies up to z ∼ 7 and analyze the main quenching mechanism. We find that in a simulated box of 685 Mpc on a side, the first quenched massive ( M _⋆ ∼ 10 ^11 M _⊙ ), Milky Way–mass, and low-mass ( M _⋆ ∼ 10 ^9.5 M _⊙ ) galaxies appear at z ∼ 4.5, z ∼ 6.2, and before z = 7, respectively. Most quenched galaxies identified at early redshifts remain quenched for more than 1 Gyr. Independently of galaxy stellar mass, the dominant quenching mechanism at high redshift is accretion disk feedback (quasar winds) from a central massive black hole, which is triggered by mergers in massive and Milky Way–mass galaxies and by disk instabilities in low-mass galaxies. Environmental stripping becomes increasingly more important at lower redshift.

The prevalence of depression in U.S. adults during the COVID-19 pandemic has been high overall and particularly high among persons with fewer assets. Building on previous work on assets and mental health, we document the burden of depression in groups based on income and savings during the first two years of the COVID-19 pandemic. Using a nationally representative, longitudinal panel study of U.S. adults (N = 1,271) collected in April-May 2020 (T1), April-May 2021 (T2), and April-May 2022 (T3), we estimated the adjusted odds of reporting probable depression at any time during the COVID-19 pandemic with generalized estimating equations (GEE). We explored probable depression-defined as a score of ≥10 on the Patient Health Questionnaire-9 (PHQ-9)-by four asset groups, defined by median income (≥$65,000) and savings (≥$20,000) categories. The prevalence of probable depression was consistently high in Spring 2020, Spring 2021, and Spring 2022 with 27.9% of U.S. adults reporting probable depression in Spring 2022. We found that there were four distinct asset groups that experienced different depression trajectories over the COVID-19 pandemic. Low income-low savings asset groups had the highest level of probable depression across time, reporting 3.7 times the odds (95% CI: 2.6, 5.3) of probable depression at any time relative to high income-high savings asset groups. While probable depression stayed relatively stable across time for most groups, the low income-low savings group reported significantly higher levels of probable depression at T2, compared to T1, and the high income-low savings group reported significantly higher levels of probable depression at T3 than T1. The weighted average of probable depression across time was 42.9% for low income-low savings groups, 24.3% for high income-low savings groups, 19.4% for low income-high savings groups, and 14.0% for high income-high savings groups. Efforts to ameliorate both savings and income may be necessary to mitigate the mental health consequences of pandemics.

ObjectivePosttraumatic Stress Disorder (PTSD) affects millions of people worldwide. While the relationship between direct exposure to traumatic events and PTSD is well-established, the influence of indirect trauma exposure on PTSD remains unclear. It is similarly unclear what role cumulative exposure to direct and indirect traumas play in the risk of PTSD.MethodsThe study uses data from the Houston Trauma and Recovery Study, conducted on 2020-2021, and involved a random sampling of 1,167 individuals residing in Houston during Hurricane Harvey in 2017. Participants were asked about their experiences related to both Hurricane Harvey and the subsequent COVID-19 pandemic. Exposures were categorized as direct or indirect traumas, in line with the criteria delineated in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Cumulative exposures were also calculated.ResultsAmong participants, 12.6% were experiencing current PTSD. There were significant associations between both direct [OR = 3.18, 95% CI 1.85, 5.46] and indirect [OR = 1.91, 95% CI 1.05, 3.46] traumas related to Harvey, as well as direct [OR = 2.13, 95% CI 1.20, 3.77] and indirect [OR = 1.69, 95% CI 0.93, 3.09] traumas due to COVID and the risk of PTSD in fully adjusted models. Further, significant associations were found between the cumulative exposure to traumas from both Hurricane Harvey and COVID-19 and the risk of PTSD, considering both direct [OR = 2.53, 95% CI 1.36, 4.70] and indirect exposures [OR = 2.79, 95% CI 1.47, 5.28].ConclusionsOur study offers support for connections between exposure to both direct and indirect traumas stemming from large-scale disasters and PTSD. Moreover, we show that cumulative exposures to multiple large-scale events increase the risk of PTSD. This highlights the importance of the consideration of a range of exposures as risks for PTSD, particularly in a time of compounding disasters and broad population exposures to these events.

Abstract Antimicrobial resistance (AMR) monitoring for public health is relying more on whole genome sequencing to characterize and compare resistant strains. This requires new approaches to describe and track AMR that take full advantage of the detailed data provided by genomic technologies. The plasmid-mediated transfer of AMR genes is a primary concern for AMR monitoring because plasmid rearrangement events can integrate new AMR genes into the plasmid backbone or promote hybridization of multiple plasmids. To better monitor plasmid evolution and dissemination, we developed the Lociq subtyping method to classify plasmids by variations in the sequence and arrangement of core plasmid genetic elements. Subtyping with Lociq provides an alpha-numeric nomenclature that can be used to denominate plasmid population diversity and characterize the relevant features of individual plasmids. Here we demonstrate how Lociq generates typing schema to track and characterize the origin, evolution and epidemiology of multidrug resistant plasmids.

Abstract Background Generalizable population-based studies are unable to account for individual tumor heterogeneity that contributes to variability in a patient’s response to physician-chosen therapy. Although molecular characterization of tumors has advanced precision medicine, in early-stage and locally advanced breast cancer patients, predicting a patient’s response to neoadjuvant therapy (NAT) remains a gap in current clinical practice. Here, we perform a study in an independent cohort of early-stage and locally advanced breast cancer patients to forecast tumor response to NAT and assess the stability of a previously validated biophysical simulation platform. Methods A single-blinded study was performed using a retrospective database from a single institution (9/2014–12/2020). Patients included: ≥ 18 years with breast cancer who completed NAT, with pre-treatment dynamic contrast enhanced magnetic resonance imaging. Demographics, chemotherapy, baseline (pre-treatment) MRI and pathologic data were input into the TumorScope Predict (TS) biophysical simulation platform to generate predictions. Primary outcomes included predictions of pathological complete response (pCR) versus residual disease (RD) and final volume for each tumor. For validation, post-NAT predicted pCR and tumor volumes were compared to actual pathological assessment and MRI-assessed volumes. Predicted pCR was pre-defined as residual tumor volume ≤ 0.01 cm3 (≥ 99.9% reduction). Results The cohort consisted of eighty patients; 36 Caucasian and 40 African American. Most tumors were high-grade (54.4% grade 3) invasive ductal carcinomas (90.0%). Receptor subtypes included hormone receptor positive (HR+)/human epidermal growth factor receptor 2 positive (HER2+, 30%), HR+/HER2− (35%), HR−/HER2+ (12.5%) and triple negative breast cancer (TNBC, 22.5%). Simulated tumor volume was significantly correlated with post-treatment radiographic MRI calculated volumes (r = 0.53, p = 1.3 × 10–7, mean absolute error of 6.57%). TS prediction of pCR compared favorably to pathological assessment (pCR: TS n = 28; Path n = 27; RD: TS n = 52; Path n = 53), for an overall accuracy of 91.2% (95% CI: 82.8% – 96.4%; Clopper–Pearson interval). Five-year risk of recurrence demonstrated similar prognostic performance between TS predictions (Hazard ratio (HR): − 1.99; 95% CI [− 3.96, − 0.02]; p = 0.043) and clinically assessed pCR (HR: − 1.76; 95% CI [− 3.75, 0.23]; p = 0.054). Conclusion We demonstrated TS ability to simulate and model tumor in vivo conditions in silico and forecast volume response to NAT across breast tumor subtypes.

Abstract Terrestrial open water evaporation is difficult to measure both in situ and remotely yet is critical for understanding changes in reservoirs, lakes, and inland seas from human management and climatically altered hydrological cycling. Multiple satellite missions and data systems (e.g., ECOSTRESS, OpenET) now operationally produce evapotranspiration (ET), but the open water evaporation data produced over millions of water bodies are algorithmically produced differently than the main ET data and are often overlooked in evaluation. Here, we evaluated the open water evaporation algorithm, AquaSEBS, used by ECOSTRESS and OpenET against 19 in situ open water evaporation sites from around the world using MODIS and Landsat data, making this one of the largest open water evaporation validations to date. Overall, our remotely sensed open water evaporation retrieval captured some variability and magnitude in the in situ data when controlling for high wind events (instantaneous: r2 = 0.71; bias = 13% of mean; RMSE = 38% of mean). Much of the instantaneous uncertainty was due to high wind events (u > mean daily 7.5 m·s−1) when the open water evaporation process shifts from radiatively-controlled to atmospherically-controlled; not accounting for high wind events decreases instantaneous accuracy significantly (r2 = 0.47; bias = 36% of mean; RMSE = 62% of mean). However, this sensitivity minimizes with temporal integration (e.g., daily RMSE = 1.2–1.5 mm·day−1). To benchmark AquaSEBS, we ran a suite of 11 machine learning models, but found that they did not significantly improve on the process-based formulation of AquaSEBS suggesting that the remaining error is from a combination of the in situ evaporation measurements, forcing data, and/or scaling mismatch; the machine learning models were able to predict error well in and of itself (r2 = 0.74). Our results provide confidence in the remotely sensed open water evaporation data, though not without uncertainty, and a foundation by which current and future missions may build such operational data.

Introduction: Despite the high prevalence of those with mental illnesses, there is a critical shortage of psychiatric providers in the United States. Psychiatric pharmacists are valuable members of the health care team who meet patient care needs, especially those practicing with prescriptive authority (PA). Methods: A cross-sectional electronic survey was administered to Board Certified Psychiatric Pharmacists (BCPPs) and non-BCPP members of the College of Psychiatric and Neurologic Pharmacists. The objective of this study was to compare demographic and practice characteristics between respondents with and without PA. Results: Of the 334 respondents, 155 (46.4%) reported having PA. Those with PA, including those with Veterans Affairs (VA) affiliated PA, had fewer mean number of years of licensure than those without PA (P =.008 and P =.007, respectively). The majority with PA practiced in outpatient settings (53.5%). Respondents with PA (including those with VA-affiliated PA) were more likely to have their positions funded by practice sites (P

Small mammals, particularly rodents, are often important seed-dispersal agents in Neotropical forests. Directional seed dispersal into tree-fall gaps may enhance seedling survival of light-demanding species and thus influence forest regeneration. To examine this proposition, we tracked seeds of a light-demanding palm (Attalea butyracea), with a focus on spiny rats (Proechimys semispinosus), the most-likely seed-removal agents. We established seed-removal stations at three distances relative to 28 gaps (gap center, gap edge, and intact forest 10 m from a gap edge) in a lowland forest in Central Panama. We placed five fresh fruits (with their seed) in semi-permeable exclosures to exclude larger mammals at each station and tracked the directions in which seeds were moved and deposited intact. More seeds were moved toward or into gaps when removed from gap center or edge stations; however, seeds dispersed from intact forest stations showed no such directionality. Small mammals may have dispersed seeds into and within tree-fall gaps because they favored caching seeds in areas that offered increased cover, which is typical of gaps, and consequently protection from predation. The lack of directional dispersal from intact forest stations may have been because spiny rats were able to find sufficient cover in the young intact forest that was closer than the gaps. In older forest, the contrast between intact forest and gaps may be greater, resulting in directed dispersal into gaps.

Abstract Effective regeneration after peripheral nerve injury requires macrophage recruitment. We investigated the activation of remodeling pathways within the macrophage population when repair is delayed and identified alteration of key upstream regulators of the inflammatory response. We then targeted one of these regulators, using exogenous IL10 to manipulate the response to injury at the repair site. We demonstrate that this approach alters macrophage polarization, promotes macrophage recruitment, axon extension, neuromuscular junction formation, and increases the number of regenerating motor units reaching their target. We also demonstrate that this approach can rescue the effects of delayed nerve graft.

Introduction: The social determinants of health (SDoH) shape both the risk of mental disorders and access to treatment. There is ample evidence detailing the decline in mental health during the Covid-19 pandemic. However, there is a gap in our understanding of the association between disruptions to SDoH and adverse psychological indicators in different contexts. Methods: Data were collected through a multi-country, random, anonymous, opt-in, cross-sectional online survey in eight geographically diverse countries—Brazil, China, Germany, Egypt, India, Indonesia, Nigeria, and the United States. We documented the relationship between experiencing self/family job loss, financial problems, and food/supplies shortages and adverse mental health indicators—depression symptoms and probable posttraumatic stress disorder (PTSD). Results: Almost one-third of respondents who experienced at least one disruption had depression symptoms (32.3%, 95% CI: 30.3%–34.4%). This was consistent across countries, except Indonesia. Reporting at least one Covid-19 related SDoH disruption had 1.26 (95% CI: 1.14-1.39) times the risk of depression symptoms compared to respondents reporting no Covid-19 related SDoH disruptions. Across countries, experiencing at least one Covid-19 related SDoH disruption had significantly increased risk of depression symptoms, except for China, Egypt, and Indonesia. The prevalence of probable PTSD among respondents who reported at least one SDoH disruption was 8.4% (95% CI: 7.3%–9.5%). The prevalence was comparably elevated within countries, except for China. Reporting at least one SDoH disruption was associated with greater odds of probable PTSD in the overall adjusted model (OR=2.87, 95% CI: 2.31-3.59) and in the models for countries except for China and Indonesia. Conclusion: Disruptions to SDoH due to the pandemic were associated with an elevated burden of symptoms of depression and probable PTSD across geographically diverse countries, with a few exceptions particularly in China. This highlights the need to account for the broader consequences of mitigation policies that potentially have an impact on the health of populations.

Background:. The use of sensory nerve transfers to the anesthetic cornea has transformed the treatment of neurotrophic keratopathy by restoring ocular surface sensation and activating dysfunctional epithelial repair mechanisms. However, despite numerous reports on surgical techniques, there is a scarcity of information on the interdisciplinary management, preoperative assessment, and surgical decision-making, which are equally critical to treatment success. Methods:. This Special Topic presents a standardized, interdisciplinary preoperative workup based on our 10-year experience with corneal neurotization in 32 eyes of patients with neurotrophic keratopathy. Results:. Our assessment includes a medical history review, ophthalmic evaluation, and systematic facial sensory donor nerve mapping for light touch and pain modalities. This approach enables evidence-based patient selection, optimal surgery timing, and suitable donor nerve identification, including backup options. Conclusions:. Based on a decade-long experience, this special topic highlights the importance of interdisciplinary collaboration and provides a practical roadmap for optimizing patient selection and surgical decision-making in patients undergoing corneal neurotization.

The measurement of corneal sensation allows clinicians to assess the status of corneal innervation and serves as a crucial indicator of corneal disease and eye health. Many devices are available to assess corneal sensation, including the Cochet–Bonnet aesthesiometer, the Belmonte Aesthesiometer, the Swiss Liquid Jet Aesthesiometer, and the newly introduced Corneal Esthesiometer Brill. Increasing the clinical use of in vivo confocal microscopy and optical coherence tomography will allow for greater insight into the diagnosis, classification, and monitoring of ocular surface diseases such as neurotrophic keratopathy; however, formal esthesiometric measurement remains necessary to assess the functional status of corneal nerves. These aesthesiometers vary widely in their mode of corneal stimulus generation and their relative accessibility, precision, and ease of clinical use. The development of future devices to optimize these characteristics, as well as further comparative studies between device types should enable more accurate and precise diagnosis and treatment of corneal innervation deficits. The purpose of this narrative review is to describe the advancements in the use of aesthesiometers since their introduction to clinical practice, compare currently available devices for assessing corneal innervation and their relative limitations, and discuss how the assessment of corneal innervation is crucial to understanding and treating pathologies of the ocular surface.

Integrating cellular microarrays, experimental and computational data for liver progenitor cell differentiation patterning, the interplay between Notch signaling and cellular mechanics is assessed.

Background:. Sirenomelia is a rare congenital condition characterized by fusion of the lower limbs. Patients with sirenomelia generally do not survive long after birth because the condition is associated with multisystem organ dysfunction due to developmental anomalies. Considering the low incidence and few cases surviving the neonatal period, there is minimal understanding regarding the surgical management of sirenomelia. We present a unique case of an infant born with type 1 sirenomelia, absence of external genitalia, presence of a cloaca, absence of the bladder, and presence of an imperforate and vestigial anus, who not only survived the birth process, but, at the age of 11 months, was determined to be a candidate for surgical separation of the lower extremities. Methods:. This case was approached much like a dorsal rectangular flap syndactyly release. Large Z-plasty flaps were designed and raised, and the soft tissue within the skin bridge was meticulously dissected to preserve anatomy and to provide adequate skin flaps without perineal skin grafting. A quadrangular flap was designed to reconstruct the perineum and produce a neo-vulva using de-epithelialization. Results:. Successful lower extremity separation was achieved. There were no major postoperative complications. The patient progressed with lower extremity function, and eventually achieved independent ambulation. Conclusions:. Management of sirenomelia is incredibly challenging, and data to guide surgical management are limited. This report details our approach to a successful lower extremity separation, repair, and neo-vulvar reconstruction in a case of type I sirenomelia.

While issues of pollution, floods and drought in our rivers are widely studied, there is a hidden crisis with respect to the widespread global extraction of sand. Large volumes of sand are needed in the construction industry to make concrete. So far, calls for greater monitoring of sand mining activity have largely gone unmet. This is due to the fact mining is extensive, often hidden (e.g. underwater) and thus very difficult to properly assess. To meet this challenge, we use remote sensing methods to detect and monitor sand mining activities at the catchment scale, across the Ganges-Brahmaputra-Meghna River system (catchment size 1.72 million km ^2 ). Based on this analysis, here we show that mining activity is diverse and pervasive across the Ganges–Brahmaputra–Meghna Catchment system for our study period of 2016–2021, with rates of extraction increasing within some of the rivers. Results show the total estimate for sand extraction is ∼115 Mtyr ^−1 ± 20 Mtyr ^−1 , which is of a similar order of magnitude to the natural bedload flux of the catchment. While there are some limitations to deriving estimates based solely on imagery, this work highlights both the widespread spatial extent and large magnitude of sand mining for one of the world’s biggest catchments. Furthermore, given our estimated scale of sand extraction, it demonstrates the need to properly account for mining activities when considering delivery of sediment to deltas in terms of the management of these vulnerable systems in the face of rising sea-levels. Overall, this work stresses the urgent requirement for further similar studies of sand extraction in the world’s large rivers, which is vital to underpin sustainable management plans for the global sand commons.

High-velocity outflows are ubiquitous in compact, massive ( M _* ∼ 10 ^11 M _⊙ ), z ∼ 0.5 galaxies with extreme star formation surface densities (Σ _SFR ∼ 2000 M _⊙ yr ^−1 kpc ^−2 ). We have previously detected and characterized these outflows using Mg ii absorption lines. To probe their full extent, we present Keck/KCWI integral field spectroscopy of the [O ii ] and Mg ii emission nebulae surrounding all of the 12 galaxies in this study. We find that [O ii ] is more effective than Mg ii in tracing low surface brightness, extended emission in these galaxies. The [O ii ] nebulae are spatially extended beyond the stars, with radial extent R _90 between 10 and 40 kpc. The nebulae exhibit nongravitational motions, indicating galactic outflows with maximum blueshifted velocities ranging from −335 to −1920 km s ^−1 . The outflow kinematics correlate with the bursty star formation histories of these galaxies. Galaxies with the most recent bursts of star formation (within the last

Abstract Depression is a common mental disorder that may comprise distinct, underlying symptom patterns over time. Associations between stressful life events throughout the civilian lifecourse—including during childhood—and adult depression have been documented in many populations, but are less commonly assessed in military samples. We identified different trajectories of depression symptoms across four years in a military cohort using latent class growth analysis, and investigated the relationship between these trajectories and two domains of civilian life experiences: childhood adversity (e.g., being mistreated during childhood) and more proximal stressful experiences (e.g., divorce). A four-group depression model was identified, including a symptom-free group (62%), an increasing symptom group (13%), a decreasing symptom group (16%), and a “chronic” symptom group (9%). Compared to the symptom-free group, soldiers with childhood adversity were more likely to be in the chronic depression, decreasing, and increasing symptom groups. Time-varying adult stressors had the largest effect on depression symptoms for the increasing symptom group compared to other groups, particularly in the last two years of follow-up. This study indicates the importance of considering events from throughout the lifecourse—not only those from deployment—when studying the mental health of servicemembers.

Prew et al. uncovered a structural basis for human VLCAD deficiency that arises from point mutations within the enzyme’s membrane-binding region, which was shown to fold as a putative α-helical hairpin. Helix-breaking mutations selectively disrupt membrane interaction and thus homeostatic function.

Abstract The role of ER Ca2+ release via ryanodine receptors (RyR) in pancreatic β-cell function is not well defined. Deletion of RyR2 from the rat insulinoma INS-1 (RyR2KO) enhanced IP3 receptor activity stimulated by 7.5 mM glucose, coincident with reduced levels of the protein IP3 Receptor Binding protein released with Inositol 1,4,5 Trisphosphate (IRBIT). Insulin content, basal (2.5 mM glucose) and 7.5 mM glucose-stimulated insulin secretion were reduced in RyR2KO and IRBITKO cells compared to controls. INS2 mRNA levels were reduced in both RyR2KO and IRBITKO cells, but INS1 mRNA levels were specifically decreased in RyR2KO cells. Nuclear localization of S-adenosylhomocysteinase (AHCY) was increased in RyR2KO and IRBITKO cells. DNA methylation of the INS1 and INS2 gene promotor regions was very low, and not different among RyR2KO, IRBITKO, and controls, but exon 2 of the INS1 and INS2 genes was more extensively methylated in RyR2KO and IRBITKO cells. Exploratory proteomic analysis revealed that deletion of RyR2 or IRBIT resulted in differential regulation of 314 and 137 proteins, respectively, with 41 in common. These results suggest that RyR2 regulates IRBIT levels and activity in INS-1 cells, and together maintain insulin content and secretion, and regulate the proteome, perhaps via DNA methylation.

Abstract Diabetes is by far, the most common cause of neuropathy, inducing neurodegeneration of terminal sensory nerve fibers associated with loss of sensation, paresthesia, and persistent pain. Foretinib prevents die-back degeneration in cultured sensory and sympathetic neurons by rescuing mitochondrial activity and has been proven safe in prospective clinical trials. Here we aimed at investigating a potential neuroprotective effect of Foretinib in experimental diabetic neuropathy. A mouse model of streptozotocin induced diabetes was used that expresses yellow fluorescent protein (YFP) in peripheral nerve fibers under the thy-1 promoter. Streptozotocin-injected mice developed a stable diabetic state (blood glucose > 270 mg/dl), with a significant reduction of intraepidermal nerve fiber density by 25% at 5 weeks compared to the non-diabetic controls. When diabetic mice were treated with Foretinib, a significantly greater volume of the cutaneous nerve fibers (67.3%) in the plantar skin was preserved compared to vehicle treated (37.8%) and non-treated (44.9%) diabetic mice while proximal nerve fiber morphology was not affected. Our results indicate a neuroprotective effect of Foretinib on cutaneous nerve fibers in experimental diabetic neuropathy. As Foretinib treated mice showed greater weight loss compared to vehicle treated controls, future studies may define more sustainable treatment regimen and thereby may allow patients to take advantage of this neuroprotective drug in chronic neurodegenerative diseases like diabetic neuropathy.

Introduction: The American Association of Psychiatric Pharmacists (AAPP) used multiple modalities to develop and refine 28 attribute statements to describe a best practice model for outpatient psychiatric pharmacists. Before addressing implementation, assessment, and field testing, it was necessary to finalize and confirm the statements and their supporting narratives among stakeholders. The objective of this project was to confirm the attribute statements and supporting justifications for a best practice model for outpatient psychiatric pharmacists providing direct patient care. Methods: The 4 phases that resulted in the 28 attribute statements and supporting narratives have been described and published elsewhere. As part of phase 5, the confirmation survey was distributed to pharmacists and resident members of AAPP in November 2021 for 3 weeks. Results: The survey respondents (n = 74; 6.1%) were licensed pharmacists for an average of 15.6 years (SD = 12.0) and had been practicing as psychiatric pharmacists for an average of 11.3 years (SD = 10.4). Slightly more than half (54.2%) of the respondents reported practicing in the outpatient setting and three-fourths (74.3%) were Board Certified Psychiatric Pharmacists. For each of the 28 statements, more than 90% of respondents either agreed or agreed with minimal reservations. Discussion: Given the high degree of agreement on the proposed practice model statements, they will be used as the basis for the outpatient psychiatric pharmacist best practice model. Next steps in developing this model include establishing implementation guidance, determining appropriate metrics for evaluation of these statements in practice, and establishing appropriate field-testing methods.

Introduction: A 2019 survey identified significant variability of practice characteristics among outpatient psychiatric pharmacists (OPPs). No published model establishes which attributes constitute best practice for OPPs. By developing a consensus for best practice model attributes, OPPs can work toward consistent, effective patient care. This project aimed to develop attribute statements for a best practice model for OPPs providing direct patient care. Methods: Board Certified Psychiatric Pharmacists and American Association of Psychiatric Pharmacists (AAPP) members were questioned using a 5-phase (P1-P5) survey and summit approach. The phases were: P1, broad ideation survey; P2, 10-person summit to develop draft statements; P3, survey of the draft statements for acceptance; P4, summit to resolve review feedback; and P5, survey of AAPP membership to confirm the finalized statements. Results: P1 survey results generated a list of 143 possible attributes that informed the P2 summit, which were refined to 28 statements. P3 survey results confirmed at least 70% agreement with each statement. The P4 summit evaluated all P3 survey results and made significant modifications to 4 statements. Informal feedback was sought with other stakeholders, and supporting narratives and references were developed to provide clarity regarding the intent of each statement. Finalized statements and supporting narratives were confirmed in the P5 survey. Discussion: The 28 attribute statements were developed over 18 months by gathering input and consensus through multiple modalities, including 3 surveys, 2 summit meetings, and numerous informal feedback requests. The agreement on the attribute statements was consistently high across all phases. The final attribute statements are presented elsewhere in this issue.

Introduction: Individuals with focal segmental glomerular sclerosis (FSGS) typically undergo kidney biopsy only once, which limits the ability to characterize kidney cell gene expression over time. Methods: We used single-cell RNA sequencing (scRNA-seq) to explore disease-related molecular signatures in urine cells from subjects with FSGS. We collected 17 urine samples from 12 FSGS subjects and captured these as 23 urine cell samples. The inflammatory signatures from renal epithelial and immune cells were evaluated in bulk gene expression data sets of FSGS and minimal change disease (MCD) (The Nephrotic Syndrome Study Network [NEPTUNE] study) and an immune single-cell data set from lupus nephritis (Accelerating Medicines Partnership). Results: We identified immune cells, predominantly monocytes, and renal epithelial cells in the urine. Further analysis revealed 2 monocyte subtypes consistent with M1 and M2 monocytes. Shed podocytes in the urine had high expression of marker genes for epithelial-to-mesenchymal transition (EMT). We selected the 16 most highly expressed genes from urine immune cells and 10 most highly expressed EMT genes from urine podocytes as immune signatures and EMT signatures, respectively. Using kidney biopsy transcriptomic data from NEPTUNE, we found that urine cell immune signature and EMT signature genes were more highly expressed in FSGS biopsies compared with MCD biopsies. Conclusion: The identification of monocyte subsets and podocyte expression signatures in the urine samples of subjects with FSGS suggests that urine cell profiling might serve as a diagnostic and prognostic tool in nephrotic syndrome. Furthermore, this approach may aid in the development of novel biomarkers and identifying personalized therapies targeting particular molecular pathways in immune cells and podocytes.

Morphological analyses are key outcome assessments for nerve regeneration studies but are historically limited to tissue sections. Novel optical tissue clearing techniques enabling three-dimensional imaging of entire organs at a subcellular resolution have revolutionized morphological studies of the brain. To extend their applicability to experimental nerve repair studies we adapted these techniques to nerves and their motor and sensory targets in rats. The solvent-based protocols rendered harvested peripheral nerves and their target organs transparent within 24 hours while preserving tissue architecture and fluorescence. The optical clearing was compatible with conventional laboratory techniques, including retrograde labeling studies, and computational image segmentation, providing fast and precise cell quantitation. Further, optically cleared organs enabled three-dimensional morphometry at an unprecedented scale including dermatome-wide innervation studies, tracing of intramuscular nerve branches or mapping of neurovascular networks. Given their wide-ranging applicability, rapid processing times, and low costs, tissue clearing techniques are likely to be a key technology for next-generation nerve repair studies. All procedures were approved by the Hospital for Sick Children’s Laboratory Animal Services Committee (49871/9) on November 9, 2019.

Abstract Protected areas are foundational to the conservation of biological diversity, and many scientists have called for increased protections in the face of the current extinction and climate‐change crises. Currently in the United States, the most recognized way to track the amount of protected land is the Gap Analysis Project classification system, which we argue is deficient in three ways: it does not, in a systematic way, specify the typical uses and constraints associated with each conservation designation; it is not fine‐tuned or nuanced enough to distinguish the levels of protection among designations within “protected” or “unprotected” areas that allow quite different human activities; and it largely ignores the durability of the designations, failing to account for an area's vulnerability to downsizing, downgrading, or degazetting. We propose a new classification system to address these deficiencies and demonstrate this method for several of the most common federal land designations in the United States.

Herein, complex motion in soft, fluid‐driven actuators composed of elastomer bladders arranged around a neutral plane and connected by slender tubes is demonstrated. Rather than relying on complex feedback control or multiple inputs, the motion is generated with a single pressure input, leveraging viscous flows within the actuator to produce nonuniform pressure between bladders. Using an accurate predictive model coupling with a large deformation Cosserat rod model and low‐Reynolds‐number flow, all dominating dynamic interactions including extension and curvature are captured with two governing equations. Given insights from this model, five design elements are described and demonstrated in practice. By choosing the relative timescales between the solid, fluid, and input pressure cycles, the tip of the actuator can obtain almost any desired trajectory and can be placed anywhere temporarily within its 2D workspace. Finally, the benefits of viscous‐driven soft actuators are showcased in a six‐legged untethered robot able to walk 0.05 body lengths per second. The foundation is laid for a new class of morphologically intelligent, soft robotic actuators that enables complex deformations and multifunctionality without explicit drivers; whereby generating nonuniform pressure distributions, their infinite degrees of freedom can be exploited.

ABSTRACT Tuberculosis (TB) remains a leading cause of morbidity and mortality worldwide. To date, the mainstay of vaccination involves the use of Mycobacterium bovis bacillus Calmette-Guérin (BCG), a live-attenuated vaccine that confers protection against extrapulmonary disease in infants and children but not against lung disease. Thus, there is an urgent need for novel vaccines. Here, we show that a multicomponent acellular vaccine (TB-MAPS) induces robust antibody responses and long-lived systemic and tissue-resident memory Th1, Th17, and cytotoxic CD4+ and CD8+ T cells, and promotes trained innate immunity mediated by γδT and NKT cells in mice. When tested in a mouse aerosol infection model, TB-MAPS significantly reduced bacterial loads in the lungs and spleens to the same extent as BCG. When used in conjunction with BCG, TB-MAPS further enhanced BCG-mediated protection, especially in the lungs, further supporting this construct as a promising TB vaccine candidate. IMPORTANCE Tuberculosis (TB) remains a leading cause of morbidity and mortality worldwide. Here, we evaluate a novel vaccine which induces a broad immune response to Mycobacterium tuberculosis including robust antibody responses and long-lived systemic and tissue-resident memory Th1, Th17, and cytotoxic CD4+ and CD8+ T cells. When tested in a mouse aerosol infection model, this vaccine significantly reduced bacterial loads in the lungs and spleens to the same extent as BCG. When used in conjunction with BCG, TB-MAPS further enhanced BCG-mediated protection, especially in the lungs, further supporting this construct as a promising TB vaccine candidate.

Because of its importance to both carbon storage and biodiversity, old forest has regained currency as a focus of forest management and policy. However, absence of a systematic approach to classifying stages of forest development across all forest types precludes our understanding of the current distribution of the mature and old-growth forest estate. Here, we propose functional definitions of mature and old-growth forests consistent with theories of forest stand development and evaluate the implications for assessing their spatial distribution nationwide. Using plot data from a national forest inventory and assuming space-for-time substitution, we modeled forest carbon accumulation over time using saturating, non-linear growth models. We define the onset of old-growth characteristics as occurring at the age when the density of total forest carbon stored in live and dead biomass reaches 95% of the empirically derived maximum, and the mature forest stage as occurring between the peak average carbon increment and the age of onset of old growth. We fit models within unique forest type-groups and, where possible, accounted for differences in site productivity. Population-level estimates of the mature and old-growth forest estate were calculated using sample design-based estimators. Across forest type-groups, the age at onset of old growth varied from 34 to 577 years, and the onset of mature forest conditions ranged between 16 and 313 years. Within forest type-groups, the effect of site quality on the age at onset of mature and old-growth forest varied but generally supported our hypothesis that high site quality accelerates forest development and increases forest carbon storage in old forests. We classified 6.3% of current forested lands in the United States as old growth and almost one-third as mature. Of the current old-growth forest estate, approximately 46% is found on federal public lands, and 11% is currently in congressional reserves. We posit that continued improvements to modeling the dynamic process of forest development and integration with structural definitions of old growth will be needed to ensure targets for old-growth retention and development are achieved.

Background Ulnar nerve lesions proximal to the elbow can result in loss of intrinsic muscle function of the hand. The anterior interosseous nerve (AIN) to deep motor branch of the ulnar nerve (DBUN) transfer has been demonstrated to provide intrinsic muscle reinnervation, thereby preventing clawing and improving pinch and grip strength. The purpose of this study was to evaluate the efficacy of the AIN to DBUN transfer in restoring intrinsic muscle function for patients with traumatic ulnar nerve lesions. Methods We performed a prospective, multi-institutional study of outcomes following AIN to DBUN transfer for high ulnar nerve injuries. Twelve patients were identified, nine of which were enrolled in the study. The mean time from injury to surgery was 15 weeks. Results At final follow-up (mean postoperative follow-up 18 months + 15.5), clawing was observed in all nine patients with metacarpophalangeal joint hyperextension of the ring finger averaging 8.9 degrees (+ 10.8) and small finger averaging 14.6 degrees (+ 12.5). Grip strength of the affected hand was 27% of the unaffected extremity. Pinch strength of the affected hand was 29% of the unaffected extremity. None of our patients experienced claw prevention after either end-to-end (n = 4) or end-to-side (n = 5) AIN to DBUN transfer. Conclusion We conclude that, in traumatic high ulnar nerve injuries, the AIN to DBUN transfer does not provide adequate intrinsic muscle reinnervation to prevent clawing and normalize grip and pinch strength.

Background:. The brachial plexus consists of an intricate array of nerves originating from the C5–T1 ventral rami of the spinal cord. Their course is complex and can be substantially distorted after injury. Thus, dissection of the brachial plexus can be difficult. Here, we present a practical approach to the supraclavicular dissection of the brachial plexus, with emphasis on relevant anatomy and surgical landmarks. Methods:. This anatomical review was prepared using intraoperative surgical imaging. In addition, illustrations are used to display the images in schematic form. We present a stepwise surgical approach to the supraclavicular dissection of the brachial plexus. We highlight the differences between pre- and postganglionic nerve root injuries, and also relevant anatomical variants of the brachial plexus. Results:. Eleven steps are recommended to facilitate the supraclavicular approach to the brachial plexus. Conclusion:. The supraclavicular dissection of the brachial plexus is reliable with consistent landmarks and can be carried out in a stepwise fashion.

The ER Ca2+ channel ryanodine receptor 2 (RyR2) is required for maintenance of insulin content and glucose-stimulated insulin secretion, in part, via regulation of the protein IRBIT in the insulinoma cell line INS-1. Here, we examined store-operated and depolarization-dependent Ca2+entry using INS-1 cells in which either RyR2 or IRBIT were deleted. Store-operated Ca2+ entry (SOCE) stimulated with thapsigargin was reduced in RyR2KO cells compared to controls, but was unchanged in IRBITKO cells. STIM1 protein levels were not different between the three cell lines. Basal and stimulated (500 μM carbachol) phospholipase C (PLC) activity was also reduced specifically in RyR2KO cells. Insulin secretion stimulated by tolbutamide was reduced in RyR2KO and IRBITKO cells compared to controls, but was potentiated by an EPAC-selective cAMP analog in all three cell lines. Cellular PIP2 levels were increased and cortical f-actin levels were reduced in RyR2KO cells compared to controls. Whole-cell Cav channel current density was increased in RyR2KO cells compared to controls, and barium current was reduced by acute activation of the lipid phosphatase pseudojanin preferentially in RyR2KO cells over control INS-1 cells. Action potentials stimulated by 18 mM glucose were more frequent in RyR2KO cells compared to controls, and insensitive to the SK channel inhibitor apamin. Taken together, these results suggest that RyR2 plays a critical role in regulating PLC activity and PIP2 levels via regulation of SOCE. RyR2 also regulates β-cell electrical activity by controlling Cav current density and SK channel activation.