Differences in thick filament activation in fast rodent skeletal muscle and slow porcine cardiac muscle.

There is a growing appreciation that regulation of muscle contraction requires both thin filament and thick filament activation in order to fully activate the sarcomere. The prevailing mechano-sensing model for thick filament activation was derived from experiments on fast-twitch muscle. We address the question whether, or to what extent, this mechanism can be extrapolated to the slow muscle in the hearts of large mammals, including humans. We investigated the similarities and differences in structural signatures of thick filament activation in porcine myocardium as compared to fast rat extensor digitorum longus (EDL) skeletal muscle under relaxed conditions and sub-maximal contraction using small angle X-ray diffraction. Thick and thin filaments were found to adopt different structural configurations under relaxing conditions, and myosin heads showed different changes in configuration upon sub-maximal activation, when comparing the two muscle types. Titin was found to have an X-ray diffraction signature distinct from those of the overall thick filament backbone, and its spacing change appeared to be positively correlated to the force exerted on the thick filament. Structural changes in fast EDL muscle were found to be consistent with the mechano-sensing model. In porcine myocardium, however, the structural basis of mechano-sensing is blunted suggesting the need for additional activation mechanism(s) in slow cardiac muscle. These differences in thick filament regulation can be related to their different physiological roles where fast muscle is optimized for rapid, burst-like, contractions, and the slow cardiac muscle in large mammalian hearts adopts a more finely tuned, graded response to allow for their substantial functional reserve. KEY POINTS: Both thin filament and thick filament activation are required to fully activate the sarcomere. Thick and thin filaments adopt different structural configurations under relaxing conditions, and myosin heads show different changes in configuration upon sub-maximal activation in fast extensor digitorum longus muscle and slow porcine cardiac muscle. Titin has an X-ray diffraction signature distinct from those of the overall thick filament backbone and this titin reflection spacing change appeared to be directly proportional to the force exerted on the thick filament. Mechano-sensing is blunted in porcine myocardium suggesting the need for additional activation mechanism(s) in slow cardiac muscle. Fast skeletal muscle is optimized for rapid, burst-like contractions, and the slow cardiac muscle in large mammalian hearts adopts a more finely tuned graded response to allow for their substantial functional reserve.

Chemical Flexibility of Atomically Precise Metal Clusters.

Ligand-protected metal clusters possess hybrid properties that seamlessly combine an inorganic core with an organic ligand shell, imparting them exceptional chemical flexibility and unlocking remarkable application potential in diverse fields. Leveraging chemical flexibility to expand the library of available materials and stimulate the development of new functionalities is becoming an increasingly pressing requirement. This Review focuses on the origin of chemical flexibility from the structural analysis, including intra-cluster bonding, inter-cluster interactions, cluster-environments interactions, metal-to-ligand ratios, and thermodynamic effects. In the introduction, we briefly outline the development of metal clusters and explain the differences and commonalities of M(I)/M(I/0) coinage metal clusters. Additionally, we distinguish the bonding characteristics of metal atoms in the inorganic core, which give rise to their distinct chemical flexibility. Section 2 delves into the structural analysis, bonding categories, and thermodynamic theories related to metal clusters. In the following sections 3 to 7, we primarily elucidate the mechanisms that trigger chemical flexibility, the dynamic processes in transformation, the resultant alterations in structure, and the ensuing modifications in physical-chemical properties. Section 8 presents the notable applications that have emerged from utilizing metal clusters and their assemblies. Finally, in section 9, we discuss future challenges and opportunities within this area.

Clinical outcomes with utilization of high-potency topical steroids in patients with lichen sclerosus-associated vulvar cancer.

OBJECTIVES: To evaluate the impact of high-potency topical steroid use on risk of recurrence of lichen sclerosus-associated vulvar cancer. METHODS: This is a retrospective cohort study evaluating patients with lichen sclerosus (LS)- associated vulvar squamous cell cancer (VSCC). Demographic and clinical outcome data were compared between two comparison groups: patients who received steroids, mainly clobetasol, and patients who did not receive steroids following treatment of LS-related vulvar cancer. Categorical variables were compared using Fisher's exact test or chi-square test. Continuous variables were compared using a two-sided student's t-test. Time to recurrence (TTR) and overall survival (OS) were analyzed using Kaplan-Meier survival plot and compared using Mantel-Cox log rank test. Cox proportional hazard regression models were conducted to generate hazard ratios for both TTR and OS. A p value of <0.05 was considered statistically significant. RESULTS: A total of 49 patients were included, with 36 patients receiving steroid treatment and 13 patients in the expectant management group. The median age of diagnosis was 68. The average BMI was 31.7 +/- 7.0. The median length of follow up was 41 months. The majority of patients were diagnosed with stage I VSCC. There was no difference in demographics or oncologic management of vulvar cancer between the two cohorts. Overall recurrence was decreased among patients who received steroid treatment when compared to patients who did not, 12 patients (33.3%) versus 9 patients (69.2%) respectively (p = 0.048). CONCLUSIONS: High-potency topical steroid use following treatment of lichen sclerosus-associated vulvar squamous cell carcinoma is associated with decreased risk of recurrence and prolonged median time to recurrence.

Relative Cost and Infectious Days Averted Associated With Rapid Gonorrhea and Chlamydia Testing Among Men Who Have Sex With Men.

BACKGROUND: Standard-of-care nucleic acid amplification tests (routine NAATs) for Neisseria gonorrhoeae (GC) and Chlamydia trachomatis (CT) can take several days to result and therefore delay treatment. Rapid point-of-care GC/CT NAAT (rapid NAAT) could reduce the time to treatment and therefore onward transmission. This study evaluated the incremental cost per infectious day averted and overall cost of implementation associated with rapid compared with routine NAAT. METHODS: Prospective sexually transmitted infection (STI) treatment data from men who have sex with men and transgender women in San Diego who received rapid NAAT between November 2018 and February 2021 were evaluated. Historical time from testing to treatment for routine NAAT was abstracted from the literature. Costs per test for rapid and routine NAAT were calculated using a micro-costing approach. The incremental cost per infectious day averted comparing rapid to routine NAAT and the costs of rapid GC/CT NAAT implementation in San Diego Public Health STI clinics were calculated. RESULTS: Overall, 2333 individuals underwent rapid NAAT with a median time from sample collection to treatment of 2 days compared with 7 to 14 days for routine NAAT equating to a reduction of 5 to 12 days. The cost of rapid and routine GC/CT NAAT was $57.86 and $18.38 per test, respectively, with a cost-effectiveness of between $2.43 and $5.82 per infectious day averted. The incremental cost of rapid NAAT improved when at least 2000 tests were performed annually. CONCLUSIONS: Although rapid GC/CT NAAT is more expensive than routine testing, the reduction of infectious days between testing and treatment may reduce transmission and provide improved STI treatment services to patients.

Age and gender profiles of HIV infection burden and viraemia: novel metrics for HIV epidemic control in African populations with high antiretroviral therapy coverage.

Introduction: To prioritize and tailor interventions for ending AIDS by 2030 in Africa, it is important to characterize the population groups in which HIV viraemia is concentrating. Methods: We analysed HIV testing and viral load data collected between 2013-2019 from the open, population-based Rakai Community Cohort Study (RCCS) in Uganda, to estimate HIV seroprevalence and population viral suppression over time by gender, one-year age bands and residence in inland and fishing communities. All estimates were standardized to the underlying source population using census data. We then assessed 95-95-95 targets in their ability to identify the populations in which viraemia concentrates. Results: Following the implementation of Universal Test and Treat, the proportion of individuals with viraemia decreased from 4.9% (4.6%-5.3%) in 2013 to 1.9% (1.7%-2.2%) in 2019 in inland communities and from 19.1% (18.0%-20.4%) in 2013 to 4.7% (4.0%-5.5%) in 2019 in fishing communities. Viraemia did not concentrate in the age and gender groups furthest from achieving 95-95-95 targets. Instead, in both inland and fishing communities, women aged 25-29 and men aged 30-34 were the 5-year age groups that contributed most to population-level viraemia in 2019, despite these groups being close to or had already achieved 95-95-95 targets. Conclusions: The 95-95-95 targets provide a useful benchmark for monitoring progress towards HIV epidemic control, but do not contextualize underlying population structures and so may direct interventions towards groups that represent a marginal fraction of the population with viraemia.

Intensive longitudinal assessment following index trauma to predict development of PTSD using machine learning.

There are significant challenges to identifying which individuals require intervention following exposure to trauma, and a need for strategies to identify and provide individuals at risk for developing PTSD with timely interventions. The present study seeks to identify a minimal set of trauma-related symptoms, assessed during the weeks following traumatic exposure, that can accurately predict PTSD. Participants were 2185 adults (Mean age=36.4 years; 64% women; 50% Black) presenting for emergency care following traumatic exposure. Participants received a 'flash survey' with 6-8 varying symptoms (from a pool of 26 trauma symptoms) several times per week for eight weeks following the trauma exposure (each symptom assessed ∼6 times). Features (mean, sd, last, worst, peak-end scores) from the repeatedly assessed symptoms were included as candidate variables in a CART machine learning analysis to develop a pragmatic predictive algorithm. PTSD (PCL-5 ≥38) was present for 669 (31%) participants at the 8-week follow-up. A classification tree with three splits, based on mean scores of nervousness, rehashing, and fatigue, predicted PTSD with an Area Under the Curve of 0.836. Findings suggest feasibility for a 3-item assessment protocol, delivered once per week, following traumatic exposure to assess and potentially facilitate follow-up care for those at risk.

Feasibility study of the application of magnetic resonance elastography (MRE) to measure oral posture related changes in stiffness of zygomaticus major muscle.

PURPOSE: Development of a technique for measuring the mechanical properties of zygomaticus major (ZM) may aid advances in clinical treatments for correcting abnormal oral posture. The objective of this work was to demonstrate the feasibility of measuring the stiffness of ZM using an MR elastography technique that incorporates a custom local driver and a phase-gradient (PG) inversion. METHODS: 2D MRE investigations were performed for 3 healthy subjects using a vibration frequency of 90 Hz to test the prediction that the stiffness of ZM would be greater in the mouth-open compared to the mouth-closed position. MRE wave images were acquired along the long axis of ZM and processed using a 2D spatial-temporal directional filter applied in the direction of wave propagation along the long axis of the muscle. Stiffness measurements were obtained by applying the PG technique to a 1D-profile drawn in the phase image of the first harmonic of the wave images and a one-tailed paired t-test was used to compare the ZM stiffness between the two mouth postures for each participant (p < 0.05). RESULTS: The mean stiffness and standard deviation (SD) of ZM across the three participants in the mouth-closed and mouth-open postures was 6.75 kPa (SD 3.36 kPa) and 15.5 kPa (SD 5.15 kPa), respectively. Changes of ZM stiffness were significantly greater in the mouth-open than the mouth-closed posture (p = 0.038). CONCLUSION: The feasibility of using the PG MRE technique to measure stiffness changes in a small muscle such as ZM for different mouth postures has been demonstrated. Further investigations are required in a larger cohort of participants to investigate the sensitivity and reproducibility of the technique for potential clinical application as well as in health and beauty related studies.

Assessing deep learning reconstruction for faster prostate MRI: visual vs. diagnostic performance metrics.

OBJECTIVE: Deep learning (DL) MRI reconstruction enables fast scan acquisition with good visual quality, but the diagnostic impact is often not assessed because of large reader study requirements. This study used existing diagnostic DL to assess the diagnostic quality of reconstructed images. MATERIALS AND METHODS: A retrospective multisite study of 1535 patients assessed biparametric prostate MRI between 2016 and 2020. Likely clinically significant prostate cancer (csPCa) lesions (PI-RADS ≥ 4) were delineated by expert radiologists. T2-weighted scans were retrospectively undersampled, simulating accelerated protocols. DL reconstruction (DLRecon) and diagnostic DL detection (DLDetect) were developed. The effect on the partial area under (pAUC), the Free-Response Operating Characteristic (FROC) curve, and the structural similarity (SSIM) were compared as metrics for diagnostic and visual quality, respectively. DLDetect was validated with a reader concordance analysis. Statistical analysis included Wilcoxon, permutation, and Cohen's kappa tests for visual quality, diagnostic performance, and reader concordance. RESULTS: DLRecon improved visual quality at 4- and 8-fold (R4, R8) subsampling rates, with SSIM (range: -1 to 1) improved to 0.78 ± 0.02 (p < 0.001) and 0.67 ± 0.03 (p < 0.001) from 0.68 ± 0.03 and 0.51 ± 0.03, respectively. However, diagnostic performance at R4 showed a pAUC FROC of 1.33 (CI 1.28-1.39) for DL and 1.29 (CI 1.23-1.35) for naive reconstructions, both significantly lower than fully sampled pAUC of 1.58 (DL: p = 0.024, naïve: p = 0.02). Similar trends were noted for R8. CONCLUSION: DL reconstruction produces visually appealing images but may reduce diagnostic accuracy. Incorporating diagnostic AI into the assessment framework offers a clinically relevant metric essential for adopting reconstruction models into clinical practice. CLINICAL RELEVANCE STATEMENT: In clinical settings, caution is warranted when using DL reconstruction for MRI scans. While it recovered visual quality, it failed to match the prostate cancer detection rates observed in scans not subjected to acceleration and DL reconstruction.

Managing STEMIs without a Catheterization Lab: A Simulated Scenario to Improve Emergency Clinician Recognition and Execution of Thrombolysis in the Setting of Rural STEMI Management.

Audience: The targeted audience for this simulation is Emergency Medicine (EM) residents. Medical students, advanced practice providers, and staff physicians could all also find educational merit in this scenario. Background: Cardiovascular disease is the leading cause of death in the United States according to the CDC.1 Coronary artery disease caused 375,000 deaths 2021 alone, and about 5% of all adult patients have a prior history of coronary artery disease.2 Furthermore, chest pain itself is a common chief complaint encountered in the ED, with nearly 8 million visits annually occurring throughout the United States, with 10-20% of those patients ultimately being diagnosed with an acute coronary syndrome3, including ST-elevation myocardial infarction (STEMI). Given this, it is essential that EM residents are well prepared to care for all patients presenting with chest pain, regardless of the acute care or emergency setting.Throughout their training, most EM residents typically learn and evaluate patients at a large tertiary or quaternary medical center with 24-hour catheterization laboratory availability. For patients presenting with electrocardiogram (EKG) findings consistent with STEMI, the standard of care is for the patient to undergo cardiac catheterization and stent placement within 90 minutes of arrival. Unfortunately, only half of patients living in rural areas have a cardiac catheterization-capable facility available to them within a 60-minute driving radius, making it difficult for those patients to undergo cardiac catheterization within the desired time frame.4 These patients remain candidates for thrombolytic therapy, but given infrequent opportunities to learn about and deploy thrombolytic agents during residency training, graduating EM residents may be unfamiliar with indications, dosing, and contraindications before they begin practice. Furthermore, the recent EM workforce data suggests that although there may be an oversupply of 8,000 emergency physicians by 2030, robust practice opportunities for emergency physicians remain in rural settings.5 Although historically EM graduates have not selected rural areas for practice, with only approximately 8% of emergency physicians practicing in rural areas,6 it is likely that given the opportunities present and perceived saturation in many non-rural settings, more EM graduates will pursue practice in a rural setting. With these changing practice dynamics in mind, this simulation provides the opportunity for residents and medical students to experience the management of a STEMI in the rural setting, with a focus upon the indications, contraindications, dosing, and disposition of a patient receiving thrombolytics. Educational Objectives: By the end of this simulation, learners will be able to:Diagnose ST elevation myocardial infarction accurately and initiate thrombolysis in the rural setting without timely access to cardiac catheterization.Engage the simulated patient in a shared decision-making conversation, clearly outlying the benefits and risks of thrombolysis.Identify the indications and contraindications for thrombolysis in ST elevation myocardial infarction.Arrange for transfer to a tertiary care center following completion of thrombolysis. Educational Methods: This scenario is a simulated encounter in a rural emergency department setting requiring the diagnosis of a STEMI, a discussion with the patient regarding the risks and benefits of thrombolysis prior to administration, administration of thrombolysis, and transfer of patient to a higher level of care. Research Methods: The educational content of this simulation as a teaching instrument was evaluated by the learner utilizing an internally developed survey after case completion. This survey was reviewed for precision of language and assessment of learning objectives by our simulation faculty and other members of our West Virginia University Emergency Medicine Department of Medical Education. The learner was asked to specify any prior experience with rural STEMI management as well as quantify via a five-point Likert Scale, where 1 = very uncomfortable and 5 = very comfortable, their level of comfort with thrombolysis before and after the scenario as well as their comfort with having a shared decision-making conversation with patients with regards to thrombolysis. Learners were also asked to rank the helpfulness of this simulation in preparing them for administering thrombolytics for STEMI in a rural setting on a five-point Likert scale, where 1 = not helpful and 5 =very helpful. An open response section was also provided to allow learners the opportunity to comment directly on any aspect of the simulation. Results: Data was collected anonymously from 16 PGY1-3 resident learners via surveys with a 100% response rate. Overall, the feedback received regarding the simulation was positive. There was a low average comfort level with administering thrombolytics and having a shared decision-making conversation regarding administering thrombolytics. There was a high average rating of the helpfulness of this simulation in preparing residents for this conversation as well as managing STEMIs in a rural setting. Subjective comments regarding the simulation were universally positive. Discussion: The management of STEMI in the rural emergency department differs significantly from the environment in which many EM residents train. As a leading cause of death in the United States, STEMI management is a vital component of EM resident education. Although the concept of thrombolysis in the rural setting is discussed, the opportunity for real-world experience in its execution is often limited despite many graduates ultimately working in rural emergency departments. This simulation sought to provide a realistic patient encounter to promote familiarity and comfort in the identification, patient discussion and execution of thrombolysis in the treatment of a STEMI. The educational content was shown to be effective via learner survey completion.

Cartography of teneurin and latrophilin expression reveals spatiotemporal axis heterogeneity in the mouse hippocampus during development.

Synaptic adhesion molecules (SAMs) are evolutionarily conserved proteins that play an important role in the form and function of neuronal synapses. Teneurins (Tenms) and latrophilins (Lphns) are well-known cell adhesion molecules that form a transsynaptic complex. Recent studies suggest that Tenm3 and Lphn2 (gene symbol Adgrl2) are involved in hippocampal circuit assembly via their topographical expression. However, it is not known whether other teneurins and latrophilins display similar topographically restricted expression patterns during embryonic and postnatal development. Here, we reveal the cartography of all teneurin (Tenm1-4) and latrophilin (Lphn1-3 [Adgrl1-3]) paralog expression in the mouse hippocampus across prenatal and postnatal development as monitored by large-scale single-molecule RNA in situ hybridization mapping. Our results identify a striking heterogeneity in teneurin and latrophilin expression along the spatiotemporal axis of the hippocampus. Tenm2 and Tenm4 expression levels peak at the neonatal stage when compared to Tenm1 and Tenm3, while Tenm1 expression is restricted to the postnatal pyramidal cell layer. Tenm4 expression in the dentate gyrus (DG) exhibits an opposing topographical expression pattern in the embryonic and neonatal hippocampus. Our findings were validated by analyses of multiple RNA-seq datasets at bulk, single-cell, and spatial levels. Thus, our study presents a comprehensive spatiotemporal map of Tenm and Lphn expression in the hippocampus, showcasing their diverse expression patterns across developmental stages in distinct spatial axes.

Excited-State Identification of a Nickel-Bipyridine Photocatalyst by Time-Resolved X-ray Absorption Spectroscopy.

Photoassisted catalysis using Ni complexes is an emerging field for cross-coupling reactions in organic synthesis. However, the mechanism by which light enables and enhances the reactivity of these complexes often remains elusive. Although optical techniques have been widely used to study the ground and excited states of photocatalysts, they lack the specificity to interrogate the electronic and structural changes at specific atoms. Herein, we report metal-specific studies using transient Ni L- and K-edge X-ray absorption spectroscopy of a prototypical Ni photocatalyst, (dtbbpy)Ni(o-tol)Cl (dtb = 4,4'-di-tert-butyl, bpy = bipyridine, o-tol = ortho-tolyl), in solution. We unambiguously confirm via direct experimental evidence that the long-lived (∼5 ns) excited state is a tetrahedral metal-centered triplet state. These results demonstrate the power of ultrafast X-ray spectroscopies to unambiguously elucidate the nature of excited states in important transition-metal-based photocatalytic systems.

Bridge-to-transplant temporary mechanical circulatory support and risk of allosensitization.

INTRODUCTION: Since the 2018 change in the US adult heart allocation policy, more patients are bridged-to-transplant on temporary mechanical circulatory support (tMCS). Previous studies indicate that durable left ventricular assist devices (LVAD) may lead to allosensitization. The goal of this study was to assess whether tMCS implantation is associated with changes in sensitization. METHODS: We included patients evaluated for heart transplants between 2015 and 2022 who had alloantibody measured before and after MCS implantation. Allosensitization was defined as development of new alloantibodies after tMCS implant. RESULTS: A total of 41 patients received tMCS before transplant. Nine (22.0%) patients developed alloantibodies following tMCS implantation: 3 (12.0%) in the intra-aortic balloon pump group (n = 25), 2 (28.6%) in the microaxial percutaneous LVAD group (n = 7), and 4 (44.4%) in the veno-arterial extra-corporeal membrane oxygenation group (n = 9)-p = .039. Sensitized patients were younger (44.7 ± 11.6 years vs. 54.3 ± 12.5 years, p = .044), were more likely to be sensitized at baseline - 3 of 9 (33.3%) compared to 2 out of 32 (6.3%) (p = .028) and received more transfusions with red blood cells (6 (66.6%) vs. 8 (25%), p = .02) and platelets (6 (66.6%) vs. 5 (15.6%), p = .002). There was no significant difference in tMCS median duration of support (4 [3,15] days vs. 8.5 [5,14.5] days, p = .57). Importantly, out of the 11 patients who received a durable LVAD after tMCS, 5 (45.5%) became sensitized, compared to 4 out of 30 patients (13.3%) who only had tMCS-p = .028. CONCLUSIONS: Our findings suggest that patients bridged-to-transplant with tMCS, without significant blood product transfusions and a subsequent durable LVAD implant, have a low risk of allosensitization. Further studies are needed to confirm our findings and determine whether risk of sensitization varies by type of tMCS and duration of support.

Increasing intra- and inter-subtype HIV diversity despite declining HIV incidence in Uganda.

HIV incidence has been declining in Africa with scale-up of HIV interventions. However, there is limited data on HIV evolutionary trends in African populations with waning epidemics. We evaluated changes in HIV viral diversity and genetic divergence in southern Uganda over a twenty-five-year period spanning the introduction and scale-up of HIV prevention and treatment programs using HIV sequence and survey data from the Rakai Community Cohort Study, an open longitudinal population-based HIV surveillance cohort. Gag (p24) and env (gp41) HIV data were generated from persons living with HIV (PLHIV) in 31 inland semi-urban trading and agrarian communities (1994 to 2018) and four hyperendemic Lake Victoria fishing communities (2011 to 2018) under continuous surveillance. HIV subtype was assigned using the Recombination Identification Program with phylogenetic confirmation. Inter-subtype diversity was estimated using the Shannon diversity index and intra-subtype diversity with the nucleotide diversity and pairwise TN93 genetic distance. Genetic divergence was measured using root-to-tip distance and pairwise TN93 genetic distance analyses. Evolutionary dynamics were assessed among demographic and behavioral sub-groups, including by migration status. 9,931 HIV sequences were available from 4,999 PLHIV, including 3,060 and 1,939 persons residing in inland and fishing communities, respectively. In inland communities, subtype A1 viruses proportionately increased from 14.3% in 1995 to 25.9% in 2017 (p<0.001), while those of subtype D declined from 73.2% in 1995 to 28.2% in 2017 (p<0.001). The proportion of viruses classified as recombinants significantly increased by more than four-fold. Inter-subtype HIV diversity has generally increased. While p24 intra-subtype genetic diversity and divergence leveled off after 2014, diversity and divergence of gp41 increased through 2017. Inter- and intra-subtype viral diversity increased across all population sub-groups, including among individuals with no recent migration history or extra-community sexual partners. This study provides insights into population-level HIV evolutionary dynamics in declining African HIV epidemics following the scale-up of HIV prevention and treatment programs. Continued molecular surveillance may provide a better understanding of the dynamics driving population HIV evolution and yield important insights for epidemic control and vaccine development.

The wake and sleep-modulating neurons of the lateral hypothalamic area demonstrate a differential pattern of degeneration in Alzheimer's disease.

Background: Sleep-wake dysfunction is an early and common event in Alzheimer's disease (AD). The lateral hypothalamic area (LHA) regulates the sleep and wake cycle through wake-promoting orexinergic and sleep-promoting melanin-concentrating hormone (MCH) neurons. These neurons share close anatomical proximity with functional reciprocity. This study investigated the pattern of neuronal loss (ORX and MCH) in the LHA in AD. Understanding the degeneration pattern of these neurons will be instrumental in designing potential therapeutics to slow down the disease progression and remediate the sleep-wake dysfunction in AD. Methods: Postmortem human brain tissue of subjects with AD (across progressive stages) and controls were examined using unbiased stereology. Neuronal counting was done using double immunohistochemistry with ORX, pTau (CP13), and MCH, pTau (CP13) labeled neurons on formalin-fixed, celloidin-embedded tissue. Results: We observed a progressive decline in orexinergic (ORX) neurons and a relative preservation of the melanin-concentrating hormone (MCH) neurons. The decline in ORX neurons was seen from BB 2 (56%, p=0.0634). By the late stage of the disease (BB 5-6), the decline in ORX neurons was 76% (p=0.0043). In contrast, the MCH neurons demonstrated an insignificant decline by BB 6 (25%, p=0.1313). Conclusions: Our data demonstrated very early substantial ORX neuronal loss in the LHA, while MCH neurons were resilient to AD pTau accumulation. Interventions capable of preventing ORX neuronal loss and inhibiting pTau accumulation in the LHA can reinstate sleep-wake dysfunction in AD and possibly prevent the progression of the disease.

A BIOCOMPATIBLE GLASS-ENCAPSULATED TRIAXIAL FORCE SENSOR FOR IMPLANTABLE TACTILE SENSING APPLICATIONS.

This paper reports a microfabricated triaxial capacitive force sensor. The sensor is fully encapsulated with inert and biocompatible glass (fused silica) material. The sensor comprises two glass plates, on which four capacitors are located. The sensor is intended for subdermal implantation in fingertips and palms and providing tactile sensing capabilities for patients with paralyzed hands. Additional electronic components, such as passives and IC chips, can also be integrated with the sensor in a hermetic glass package to achieve an implantable tactile sensing system. Through attachment to a human palm, the sensor has been shown to respond appropriately to typical hand actions, such as squeezing or picking up a bottle.

Visual Schema Displacement Therapy versus Eye Movement Desensitization and Reprocessing therapy versus waitlist in the treatment of post-traumatic stress disorder: results of a randomized clinical trial.

Introduction: Visual Schema Displacement Therapy (VSDT) is a novel approach showing promise in mitigating distressing memories, akin to Eye Movement Desensitization and Reprocessing (EMDR). Objectives: This study aimed to determine the safety, feasibility, and effectiveness of VSDT in individuals with post-traumatic stress disorder (PTSD), comparing it to EMDR therapy and a waitlist control condition (WLCC). It was hypothesized that the application of VSDT would be safe and PTSD symptoms significantly be reduced from both baseline to post-treatment and from baseline to follow-up in the VSDT and EMDR therapy conditions. Furthermore, we expected both treatments to be significantly more effective than the waitlist control. Moreover, we hypothesized that VSDT and EMDR therapy would be associated with significant improvements in symptoms of depression and general psychopathology. Method: Forty-six adults with PTSD were randomly assigned to VSDT, EMDR therapy, or WLCC, receiving six 90-minute sessions. Assessments included the Clinician Administered PTSD Scale for the Diagnostic Statistical Manual (DSM)-5 (CAPS-5), PTSD Checklist for DSM-5 (PCL-5), Beck Depression Inventory-II (BDI-II) and Brief Symptom Inventory (BSI) before, during, and 3 months post-treatment. Results: Bayesian analysis found no differences between VSDT and EMDR in PTSD symptom reduction but both outperformed WLCC. EMDR was superior to the WLCC in reducing symptoms of depression and general psychopathology. At 3-month follow-up, 58.3% of the participants in the VSDT condition no longer met the PTSD diagnostic criteria (41.2% EMDR therapy and 15.4% WLCC) with no difference between the two therapy conditions. Self-reported PTSD symptom reduction was significant in VSDT (d = 1.38) and EMDR (d = 1.40) but modest in WLCC (d = 0.39). Dropout rate was 19.3%, with no adverse events. Conclusion: This study supports VSDT's efficacy in treating PTSD, offering a valuable therapeutic option comparable to EMDR, with significant reductions in PTSD symptoms and no difference with EMDR or the control condition for depressive symptoms and general psychopathology, and no reported adverse events.

The potential importance of the built-environment microbiome and its impact on human health.

There is increasing evidence that interactions between microbes and their hosts not only play a role in determining health and disease but also in emotions, thought, and behavior. Built environments greatly influence microbiome exposures because of their built-in highly specific microbiomes coproduced with myriad metaorganisms including humans, pets, plants, rodents, and insects. Seemingly static built structures host complex ecologies of microorganisms that are only starting to be mapped. These microbial ecologies of built environments are directly and interdependently affected by social, spatial, and technological norms. Advances in technology have made these organisms visible and forced the scientific community and architects to rethink gene-environment and microbe interactions respectively. Thus, built environment design must consider the microbiome, and research involving host-microbiome interaction must consider the built-environment. This paradigm shift becomes increasingly important as evidence grows that contemporary built environments are steadily reducing the microbial diversity essential for human health, well-being, and resilience while accelerating the symptoms of human chronic diseases including environmental allergies, and other more life-altering diseases. New models of design are required to balance maximizing exposure to microbial diversity while minimizing exposure to human-associated diseases. Sustained trans-disciplinary research across time (evolutionary, historical, and generational) and space (cultural and geographical) is needed to develop experimental design protocols that address multigenerational multispecies health and health equity in built environments.

Understanding therapeutic radiographers' confidence in assessing, managing & teaching radiation induced skin reactions (RISR): A national survey in the UK.

INTRODUCTION: The standard toxicity tools adopted for assessing Radiation Induced Skin Reactions (RISR) do not currently reflect how skin changes occur across all skin tones. A one size fits all approach is adopted currently for RISR assessment. The aim of this study was to understand what evidence-based practice and RISR tools are being used across the therapeutic radiography workforce and the levels of confidence in using these tools. METHODS: A survey using Likert scales to assess confidence in RISR assessment and management was made available to 77 departments in the UK between August-November 2021. Descriptive statistics were used to understand respondents' confidence in assessing, managing, and teaching RISR between white, brown, and black skin tones; Fisher's exact test was used to assess the significance of differences between groups. RESULTS: Complete responses were received from 406 therapeutic radiographers. Radiation Therapy Oncology Group (RTOG) was the most used RISR assessment tool (58% of respondents n = 237). Most respondents (74.2% n = 303) reported use of locally produced patient information on skin care, rather than the Society and College of Radiographers evidence-based patient leaflets. Confidence in assessing and managing RISR in white skin was higher than that in brown and black skin. Similarly, confidence was higher in teaching of appropriate RISR assessment and management in white skin tones when compared to brown and black skin. CONCLUSION: White skin tones appear to be more confidently assessed and managed for RISR along with taught appropriate assessment and management, than brown and black skin tones in the sample of the workforce that responded. IMPLICATIONS FOR PRACTICE: A greater understanding of the reasons for these differences is required but this study aims to instigate change and positive growth within this area.