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The article presents a study which examines the attitudes of medical care professionals toward young people who engage in self-harm. The study involved sixty registered nurses (RNs) and nursing aides (NAs) employed at forensic units and at a young offenders institure in Great Britain. Key findings indicated that 22 percent of respondents were noted to express sympathy and empathy to self-harming clients.

The article reports on the results of research which was conducted in to compare the views of nurses and patients regarding the administration of medication on acute psychiatric wards. Researchers found that that noisy and busy environments and overworked nurses can have an effect upon the their perspective, if not their performance. and that patients were happy with the way that staff engaged with and felt that nurses provide a good service for which they are grateful.

Brief structured clinical interviews are a key component of the Department of Defense postdeployment health reassessment program. Such interviews are critical for recommending individuals for follow-up assessment and care. To standardize the interview process, U.S. Army Medical Research Unit-Europe developed a structured interview guide, designed in response to both clinical requirements and research findings. The guide includes sections on depression, suicidality, post-traumatic stress disorder, anger, relationship problems, alcohol problems, and sleep problems. In addition, there is an open-ended section on other problems and a section for case dispositions. Data from a 2005 blinded validation study with soldiers returning from a 1-year-long combat deployment are included to demonstrate the utility of the structured interview. Guidelines and implementation considerations for the use of the structured interview are discussed. [ABSTRACT FROM AUTHOR]

A persistent cause for concern among hospital patients is that they often feel that they have not been given sufficient information about their condition. The desire for more information, lack of understanding and a memory of the message, and failure to provide it, all point to the need for provision of information in print.The two aims of the project were to improve communication between health care professionals and neurosurgical patients, as well as the improvement of information resources through the development of patient information brochures. The Delphi consensus model was used to identify educational needs of patients and suitable topics for brochure development in consultation with patients and health care professionals regarding appropriate content. Principles of preparing and writing well-designed patient materials were also reviewed to enhance the probability that the patient information brochures would be readable and understood.Subsequently, a set of neurosurgical patient information brochures was developed incorporating extensive multi-disciplinary consultation. These were introduced throughout the neurosurgical service leading to improved communication and positive patient experiences. [ABSTRACT FROM AUTHOR]

Fall related injury in acute care facilities is a significant safety concern. Through processes of incident monitoring and clinical review it was identified that a high number of falls with negative consequences were occurring on the neurosurgical ward when compared to other surgical wards within our acute care hospital, hence a multidisciplinary team was formed to address this issue. The aims were to decrease the incidence of high-risk patient falls by 50% in 6 months and eventually to zero. The team organised, categorised and prioritised data and suggested falls could be prevented and hence decreased by cohorting high-risk patients together into a 'High Risk Falls Room'. A four-bedded room, within a 30-bed unit, was allocated as the gender neutral 'High Risk Falls Room'. Assistants in Nursing (AIN) were staffed to act as sitters 24 hours a day, 7 days a week Data was analysed and results presented monthly to the Surgical Quality Management Group and Neurosurgical Mortality and Morbidity (M&M) group. Six months after the introduction of the high risk falls room, the incidence of falls decreased from the baseline of 6.5 falls per month (range 5-8 falls), to just 1 fall, and within 9 months the team had achieved a zero falls incident rate. Using this model, standards and benchmarking can be set and falls incidence decreased to improve patient outcomes. [ABSTRACT FROM AUTHOR]

This study examined the validity of psychological measures used in screening for the U.S. Army with 885 soldiers before a 6-month peacekeeping rotation in Kosovo. Content validity and construct validity were assessed by evaluating the clinical domains, comparing clinician assessments of functioning, and assessing risk factors for screening positive. Construct validity and content validity were demonstrated. Risks, benefits, and future directions of the Army's psychological screening research program are discussed. [ABSTRACT FROM AUTHOR]

Toxic epidermal necrolysis (TEN) is a rare disorder characterised by a blistering and peeling of the top layer of skin. Internationally, the average incidence of TEN is 0.5-1.4 cases per million population per year and mortality is estimated to be 25-70%. It is important for nursing and medical staff to be aware of the signs and symptoms of TEN, as early intervention is essential. This rare condition is explored by outlining the case of a 36 year old woman admitted to hospital with a head injury who died due to the development of TEN caused by a reaction to phenytoin. The causes, clinical features, diagnosis, treatment and complications of TEN are discussed in relation to this case study, and important issues highlighted. [ABSTRACT FROM AUTHOR]

Virtual behavioral health (VBH) services are used frequently to address the high demand for behavioral health (BH) services in the military. Few studies have investigated the relationship between the use of VBH services and BH outcomes or preferences for the use of VBH technologies. In this article, we evaluated BH interviews conducted via video teleconferencing (VTC) or face-to-face in terms of BH symptoms, satisfaction rates, stigma, barriers to care, and preferences for future use of BH care. Soldiers (n = 307) from the headquarters element of an operational unit were surveyed 4 months following a 12-month deployment to Iraq. There were no significant differences in satisfaction rates based on interview modality, but significantly more soldiers preferred face-to-face interviews over VTC interviews in the future. Soldiers who preferred face-to-face interviews also reported higher levels of anxiety and depression symptoms than those who preferred VTC interviews. No significant age differences were found in terms of interview modality satisfaction or preference. Soldiers with greater deployment experience were more likely to report that they would not like using VTC if seeking BH care in the future than soldiers with less deployment experience. These findings highlight the importance of promoting choice in type of BH interview modality. [ABSTRACT FROM AUTHOR]

Caloric restriction extends healthy lifespan in multiple species 1 . Intermittent fasting, an alternative form of dietary restriction, is potentially more sustainable in humans, but its effectiveness remains largely unexplored 2-8 . Identifying the most efficacious forms of dietary restriction is key for developing interventions to improve human health and longevity 9 . Here we performed an extensive assessment of graded levels of caloric restriction (20% and 40%) and intermittent fasting (1 and 2 days fasting per week) on the health and survival of 960 genetically diverse female mice. We show that caloric restriction and intermittent fasting both resulted in lifespan extension in proportion to the degree of restriction. Lifespan was heritable and genetics had a larger influence on lifespan than dietary restriction. The strongest trait associations with lifespan included retention of body weight through periods of handling-an indicator of stress resilience, high lymphocyte proportion, low red blood cell distribution width and high adiposity in late life. Health effects differed between interventions and exhibited inconsistent relationships with lifespan extension. 40% caloric restriction had the strongest lifespan extension effect but led to a loss of lean mass and changes in the immune repertoire that could confer susceptibility to infections. Intermittent fasting did not extend the lifespan of mice with high pre-intervention body weight, and two-day intermittent fasting was associated with disruption of erythroid cell populations. Metabolic responses to dietary restriction, including reduced adiposity and lower fasting glucose, were not associated with increased lifespan, suggesting that dietary restriction does more than just counteract the negative effects of obesity. Our findings indicate that improving health and extending lifespan are not synonymous and raise questions about which end points are the most relevant for evaluating aging interventions in preclinical models and clinical trials., (© 2024. The Author(s).)

Dystroglycan is a cell adhesion molecule that localizes to synapses throughout the nervous system. While Dystroglycan is required to maintain inhibitory synapses from cerebellar molecular layer interneurons (MLIs) onto Purkinje cells (PCs) whether initial synaptogenesis during development is dependent on Dystroglycan has not been examined. We show that conditional deletion of Dystroglycan from Purkinje cells prior to synaptogenesis results in impaired MLI:PC synapse formation and function due to reduced presynaptic inputs and abnormal postsynaptic GABA A receptor clustering. Using genetic manipulations that disrupt glycosylation of Dystroglycan or truncate its cytoplasmic domain, we show that Dystroglycan's role in synapse function requires both extracellular and intracellular interactions, whereas synapse formation requires only extracellular interactions. Together, these findings provide molecular insight into the mechanism of inhibitory synapse formation and maintenance in cerebellar cortex., Competing Interests: Competing interests: The authors declare that they have no competing interests.

Abstract: Student mental health nurses have greater patient contact than registered nurses, and this is appreciated by patients. This phenomenological study explored the impact of patients and student mental health nurses' time shared on forensic units for men carrying a personality disorder diagnosis. Phenomenology was the underpinning philosophy of this research. Patients and student mental health nurses in forensic hospitals participated in unstructured hermeneutic interviews. The time students and patients shared together was considered a gift, enabling them to feel that they were "just people" and valued, strongly impacting on their sense of person. The impact the students have on patients' quality of life is meaningful. When the students and patients connected, it had powerful implications for their sense of humanness and value, highlighting the reciprocal impact they each have on another and the importance of having student nurse clinical placements in forensic wards and facilities.Implications for Clinical Forensic Nursing Practice: This article offers a unique contribution to forensic practice by exploring the experiences of the time patients and students share together in forensic units. Students, who often have the greatest contact with patients, represent the present and future of nursing, and their time is appreciated by patients. Previous research focuses on attitudes and therapeutic relationships, rather than the impact of shared contact. In addition to this, patients in forensic services with personality disorder diagnoses can be the most stigmatized group in mental health care, and exploration of their experiences is lacking. These experiences must be shared., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 International Association of Forensic Nurses.)

Introduction: Competency in diversity, equity, and inclusion skills is critical for graduate medical education program coordinators. Coordinators contribute to high-level personnel and program management while also providing informal social support to residents. However, little has been reported about program coordinator learning needs, interest, and self-reported skills and attitudes regarding diversity, equity, and inclusion initiatives in graduate medical education. This study sought to describe the characteristics, job tasks, attitudes, and learning needs of program coordinators attending a professional development session about diversity, equity, and inclusion., Methods: Participants registered for a September 2022 program coordinator professional development workshop on diversity, equity, inclusion, and bias were invited to complete an electronic needs assessment prior to the workshop. Items were based on expert opinion and literature review. We performed descriptive and comparative analysis., Results: The response rate was 54% (106/198); 90% (94/104) of respondents identified as female; 42% (44/104) identified as an underrepresented minority. Fifty-seven percent (63/104) received mandatory training on bias while 13% (14/104) were previously trained on bias at a conference specific to the role of a coordinator. Eighty-nine percent (86/104) of coordinators reported having contact with applicants during recruiting; 67% (63/104) offer informal resident evaluations. Most participants agreed it is the coordinator's professional responsibility to confront colleagues who display signs of discrimination toward women (66%; 62/104) or based on cultural/ethnic identity (65%; 61/104)., Conclusions: Program coordinators report visible and impactful roles in the residency leadership and management team. Few coordinators have received diversity, equity, and inclusion training related to their complex work in graduate medical education. Future graduate medical education diversity, equity, inclusion, and bias competency programs should specifically include program coordinators., (© 2024 by the Society of Teachers of Family Medicine.)

Background: Merkel cell carcinoma (MCC) is an aggressive cancer with often poor outcomes. Limited biomarkers exist for predicting clinical outcomes. The Merkel cell polyomavirus (MCPyV) serum antibody test (AMERK) has shown potential for indicating better recurrence-free survival in a single-institution study. The study aimed to evaluate the link between initial AMERK serostatus and survival. Secondary objectives included examining the relationship between initial AMERK titer levels and tumor burden., Methods: A retrospective cohort study across two institutions analyzed patients tested with AMERK within 90 days of MCC diagnosis. Regression models assessed the association of survival outcomes with serostatus, considering various factors. The relationship between AMERK titer and tumor burden indicators was evaluated using ANOVA. Significance testing was exploratory, without a fixed significance level., Results: Of 261 MCC patients tested, 49.4% were initially seropositive (titer ≥75). Multivariable analysis showed that seropositivity improved recurrence, event-free, overall, and MCC-specific survival rates. Strong associations were found between initial AMERK titer and clinical, tumor, and nodal stages, tumor size, and disease extent. Notably, improved survival with seropositivity was observed only in patients with localized disease at initial presentation., Conclusion: Circulating antibodies to MCPyV oncoproteins, as indicated by the AMERK test, are linked with better survival in MCC patients with localized disease at presentation. This could enhance patient risk profiling and treatment personalization. The study's retrospective nature and exploratory analysis are key limitations., Plain Language Summary: Merkel cell carcinoma (MCC) is a potentially aggressive skin cancer, and tools to predict patient outcomes are limited. A blood test called anti-Merkel cell panel (AMERK), which checks for specific antibodies related to this cancer, might give us some clues. In this study, we looked at 261 MCC patients who took the AMERK test within 90 days of diagnosis. We found that patients with an initial positive AMERK result tended to have better outcomes, especially if their cancer was in the early stages. However, it is important to note that this study has limitations, including using retrospective data and exploratory analyses., (© 2024 American Cancer Society.)

Two types of engineered T cells have been successfully used to treat patients with cancer, one with an antigen recognition domain derived from antibodies [chimeric antigen receptors (CARs)] and the other derived from T cell receptors (TCRs). CARs use high-affinity antigen-binding domains and costimulatory domains to induce T cell activation but can only react against target cells with relatively high amounts of antigen. TCRs have a much lower affinity for their antigens but can react against target cells displaying only a few antigen molecules. Here, we describe a new type of receptor, called a Co-STAR (for costimulatory synthetic TCR and antigen receptor), that combines aspects of both CARs and TCRs. In Co-STARs, the antigen-recognizing components of TCRs are replaced by high-affinity antibody fragments, and costimulation is provided by two modules that drive NF-κB signaling (MyD88 and CD40). Using a TCR-mimic antibody fragment that targets a recurrent p53 neoantigen presented in a common human leukocyte antigen (HLA) allele, we demonstrate that T cells equipped with Co-STARs can kill cancer cells bearing low densities of antigen better than T cells engineered with conventional CARs and patient-derived TCRs in vitro. In mouse models, we show that Co-STARs mediate more robust T cell expansion and more durable tumor regressions than TCRs similarly modified with MyD88 and CD40 costimulation. Our data suggest that Co-STARs may have utility for other peptide-HLA antigens in cancer and other targets where antigen density may limit the efficacy of engineered T cells.

The Cre-lox system is an indispensable tool in neuroscience research for targeting gene deletions to specific cellular populations. Here we assess the utility of several transgenic Cre lines, along with a viral approach, for targeting cerebellar Purkinje cells (PCs) in mice. Using a combination of a fluorescent reporter line ( Ai14 ) to indicate Cre -mediated recombination and a floxed Dystroglycan line ( Dag1 flox ), we show that reporter expression does not always align precisely with loss of protein. The commonly used Pcp2 Cre line exhibits a gradual mosaic pattern of Cre recombination in PCs from Postnatal Day 7 (P7) to P14, while loss of Dag1 protein is not complete until P30. Ptf1a Cre drives recombination in precursor cells that give rise to GABAergic neurons in the embryonic cerebellum, including PCs and molecular layer interneurons. However, due to its transient expression in precursors, Ptf1a Cre results in stochastic loss of Dag1 protein in these neurons. Nestin Cre , which is often described as a "pan-neuronal" Cre line for the central nervous system, does not drive Cre -mediated recombination in PCs. We identify a Calb1 Cre line that drives efficient and complete recombination in embryonic PCs, resulting in loss of Dag1 protein before the period of synaptogenesis. AAV8 -mediated delivery of Cre at P0 results in gradual transduction of PCs during the second postnatal week, with loss of Dag1 protein not reaching appreciable levels until P35. These results characterize several tools for targeting conditional deletions in cerebellar PCs at different developmental stages and illustrate the importance of validating the loss of protein following recombination., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Jahncke and Wright.)

The greatest challenge in cancer therapy is to eradicate cancer cells with minimal damage to normal cells. Targeted therapy has been developed to meet that challenge, showing a substantially increased therapeutic index compared with conventional cancer therapies. Antibodies are important members of the family of targeted therapeutic agents because of their extraordinarily high specificity to the target antigens. Therapeutic antibodies use a range of mechanisms that directly or indirectly kill the cancer cells. Early antibodies were developed to directly antagonize targets on cancer cells. This was followed by advancements in linker technologies that allowed the production of antibody-drug conjugates (ADCs) that guide cytotoxic payloads to the cancer cells. Improvement in our understanding of the biology of T cells led to the production of immune checkpoint-inhibiting antibodies that indirectly kill the cancer cells through activation of the T cells. Even more recently, bispecific antibodies were synthetically designed to redirect the T cells of a patient to kill the cancer cells. In this Review, we summarize the different approaches used by therapeutic antibodies to target cancer cells. We discuss their mechanisms of action, the structural basis for target specificity, clinical applications and the ongoing research to improve efficacy and reduce toxicity., (© 2024. Springer Nature Limited.)

Introduction: A water extract of Centella asiatica (L.) Urban [Apiaceae] (CAW) has demonstrated cognitive-enhancing effects in mouse models of Alzheimer's disease and aging, the magnitude of which is influenced by whether CAW is delivered in the drinking water or the diet. These cognitive benefits are accompanied by improvements in oxidative stress and mitochondrial function in the brain, two pathways related to the neuroinflammatory response. The effect of CAW on neuroinflammation, however, has not been directly studied. Here, we investigated the effect of CAW on neuroinflammation in 5xFAD mice and compared plasma levels of CAW's active compounds following two modes of CAW administration., Methods: Eight-to-nine-month-old male and female 5xFAD mice and their wild-type littermates were administered CAW in their diet or drinking water (0 or 1,000 mg/kg/day) for five weeks. Immunohistochemistry was performed for β-amyloid (Aβ), glial fibrillary acidic protein (GFAP), and Griffonia simplicifolia lectin I (GSL I) in the cortex and hippocampus. Gene expression of inflammatory mediators (IL-6, TNFα, IL-1β, TREM2, AIF1, CX3CR1, CX3CL1, CD36, C3AR1, RAGE, CCR6, CD3E) was measured in the deep grey matter., Results: CAW decreased cortical Aβ plaque burden in female 5xFAD mice administered CAW in the drinking water but had no effect on Aβ plaques in other treatment groups. CAW did not impact elevated levels of GFAP or GSL I in 5xFAD mice, regardless of sex, brain region, or mode of CAW administration. In the deep grey matter, CAW increased C3AR1 expression in 5xFAD females administered CAW in the drinking water and decreased IL-1β expression in 5xFAD males administered CAW in the diet. CAW had no effect, however, on gene expression levels of any other inflammatory mediator in the deep grey, for either sex or mode of CAW administration. Mice administered CAW in the drinking water versus the diet had significantly higher plasma levels of CAW compounds., Discussion: CAW had little impact on the neuroinflammatory markers selected for evaluation in the present study, suggesting that the cognitive benefits of CAW may not be mediated by an anti-inflammatory effect or that additional molecular markers are needed to fully characterize the effect of CAW on neuroinflammation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Speers, Wright, Brandes, Kedjejian, Matthews, Caruso, Harris, Koike, Nguyen, Quinn, Soumyanath and Gray.)

NEDD4L is a HECT-type E3 ligase that catalyzes the addition of ubiquitin to intracellular substrates such as the cardiac voltage-gated sodium channel, Na V 1.5. The intramolecular interactions of NEDD4L regulate its enzymatic activity which is essential for proteostasis. For Na V 1.5, this process is critical as alterations in Na + current is involved in cardiac diseases including arrhythmias and heart failure. In this study, we perform extensive biochemical and functional analyses that implicate the C2 domain and the first WW-linker (1,2-linker) in the autoregulatory mechanism of NEDD4L. Through in vitro and electrophysiological experiments, the NEDD4L 1,2-linker was determined to be important in substrate ubiquitination of Na V 1.5. We establish the preferred sites of ubiquitination of NEDD4L to be in the second WW-linker (2,3-linker). Interestingly, NEDD4L ubiquitinates the cytoplasmic linker between the first and second transmembrane domains of the channel (DI-DII) of Na V 1.5. Moreover, we design a genetically encoded modulator of Nav1.5 that achieves Na + current reduction using the NEDD4L HECT domain as cargo of a Na V 1.5-binding nanobody. These investigations elucidate the mechanisms regulating the NEDD4 family and furnish a new molecular framework for understanding Na V 1.5 ubiquitination., Competing Interests: Conflict of interest The authors declare no conflicts of interest in regards to this manuscript. S. B. G. is a cofounder and equity holder in the company Advanced Molecular Sciences, LLC. S. B. G. has been or is a consultant for Scorpion Therapeutics and Xinthera. P. A. C. has been a consultant for Scorpion Therapeutics., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Social factors account for most health outcomes, underscoring the need to address social determinants of health (SDH) to eliminate health disparities. Our objectives are (1) to describe the scope of formal SDH curricula in family medicine residency, (2) to identify residency program characteristics associated with integrated core curriculum components to teach SDH, and (3) to identify barriers to addressing SDH in residency., Methods: We distributed a cross-sectional survey to all family medicine residency program directors (PDs) accredited by the Accreditation Council for Graduate Medical Education as identified by the Association of Family Medicine Residency Directors., Results: Of 624 eligible program directors, 279 completed the survey (45% response rate). Overall, 41.2% of respondents reported significant formal SDH training in their program. Though a majority (93.9%) agreed that screening for social needs should be a standard of care, most (58.9%) did not use standardized screening tools. The most common barriers to addressing SDH were lack of clinical resources (eg, social workers, legal advocates), lack of community resources (eg, food banks, substance use disorder treatment), and inadequate screening instruments or integration into the electronic medical record system. Availability of referral resources was associated with PDs' increased perception of resident SDH competency., Conclusions: Nearly all respondents agreed that screening for social needs should be a standard part of care; however, this vision is not yet realized. To better train the next generation of physicians to identify and meaningfully address social needs, additional research is needed. This research might include mixed-methods approaches that incorporate qualitative assessments to define best practices and patient-centered outcomes related to identifying and responding to SDH.

Dystroglycan (Dag1) is a transmembrane glycoprotein that links the extracellular matrix to the actin cytoskeleton. Mutations in Dag1 or the genes required for its glycosylation result in dystroglycanopathy, a type of congenital muscular dystrophy characterized by a wide range of phenotypes including muscle weakness, brain defects, and cognitive impairment. We investigated interneuron (IN) development, synaptic function, and associated seizure susceptibility in multiple mouse models that reflect the wide phenotypic range of dystroglycanopathy neuropathology. Mice that model severe dystroglycanopathy due to forebrain deletion of Dag1 or Pomt2 , which is required for Dystroglycan glycosylation, show significant impairment of CCK + /CB 1 R + IN development. CCK + /CB 1 R + IN axons failed to properly target the somatodendritic compartment of pyramidal neurons in the hippocampus, resulting in synaptic defects and increased seizure susceptibility. Mice lacking the intracellular domain of Dystroglycan have milder defects in CCK + /CB 1 R + IN axon targeting, but exhibit dramatic changes in inhibitory synaptic function, indicating a critical postsynaptic role of this domain. In contrast, CCK + /CB 1 R + IN synaptic function and seizure susceptibility was normal in mice that model mild dystroglycanopathy due to partially reduced Dystroglycan glycosylation. Collectively, these data show that inhibitory synaptic defects and elevated seizure susceptibility are hallmarks of severe dystroglycanopathy, and show that Dystroglycan plays an important role in organizing functional inhibitory synapse assembly., Competing Interests: JJ, DM, MK, ES, KW No competing interests declared

Background and Objectives: In 2020, the Association of Family Medicine Residency Directors (AFMRD) Diversity and Health Equity (DHE) Task Force developed and piloted a framework to measure diversity, equity, and inclusion (DEI) initiatives in medical residencies across five domains: curriculum, evaluation, institution, resident pathway, and faculty pathway. The objectives were (1) to measure DEI initiatives across multiple domains in family medicine residencies using the DEI milestones and (2) to obtain current national baseline data providing criteria against which to measure effectiveness of initiatives and create tailored benchmarks., Methods: We developed a cross-sectional survey of 12 quantitative residency characteristic items and the five DEI milestone ratings, and distributed the survey to program directors of family medicine residencies accredited by the Accreditation Council for Graduate Medical Education in the spring of 2022. We generated descriptive statistics, including item frequencies and cross-tabulations, and completed subgroup comparisons with analysis of variance., Results: We collected aggregate milestone data for 194 family medicine residencies of 588 eligible programs (33% response rate). Respondents represented 48 states and US territories: 107 community-based, university-affiliated; 48 community-based; 34 university-based; and 5 military/other programs. Overall, the curriculum milestone was rated the highest (mean=2.54, SD=1.03), whereas the faculty pathway (mean=1.94, SD=1.04) and resident pathway (mean=2.02, SD=1.06) milestones were rated lowest., Conclusions: DEI milestone data may support residency programs as they assess their institution's developmental progress across five key domains. Additionally, aggregate data may shed light on collective strengths and areas for improvement.

The identification of historical military remains by Unrecovered War Casualties-Army (UWC-A) currently relies on Y-chromosome Short Tandem Repeat (Y-STR) testing when maternal relatives are not available, or when a mitochondrial DNA match does not provide sufficient certainty of identification. However, common Y-STR profiles (using Yfiler™) between sets of remains or families often prevent identification. To resolve these cases, an investigation of additional Y-DNA markers is needed for their potential inclusion into the DNA identification strategy. The number of genetic transmissions between missing soldiers and their living relatives needs to be considered to avoid false exclusions between paternal relatives. Analysis of 236 World War I/II (WWI/II) era pairs of relatives identified up to seven genetic transmissions between WWII soldiers and their living relatives, and nine for WWI. Previous Y-STR meta-analyses were published approximately 10 years ago when rapidly mutating markers were relatively new. This paper reports a contemporary literature review and meta-analysis of 35 studies (which includes 23 studies not previously used in meta-analysis) and 23 commonly used Y-STR's mutation rates to inform the inclusion of additional loci to UWC-A's DNA identification strategy. Meta-analysis found mutation data for a given Y-STR locus could be pooled between studies and that the mutation rates were significantly different between some loci (at P  < 0.05). Based on this meta-analysis, we have identified two additional markers from PowerPlex® Y23 for potential inclusion in UWC-A's identification strategy. Further avenues for potential experimental exploration are discussed., Key Points: From 236 UWC-A pairs of relatives, we observed up to nine genetic transmissions between WWI soldiers and their living relatives, and seven for WWII.MedCalc® software for meta-analysis utilizing the Freeman-Tukey transformation was run, which analysed 35 published studies and 23 commonly used loci. Previous Y-STR mutation rate meta-analyses are now 10 years old; this paper includes 23 studies that were not included in previous meta-analyses.Through meta-analysis, we identify two markers from PowerPlex® Y23 for potential inclusion in UWC-A's historical remains identification strategy (alongside Yfiler™). We discuss potential next steps for experimental exploration of additional Y-DNA markers., (© The Author(s) 2024. Published by OUP on behalf of the Academy of Forensic Science.)

Microgreens, the immature plants harvested after a few weeks of growth, are perceived as a heathy, nutritious food ingredient but may be susceptible to colonisation by human pathogens including Shiga-toxigenic Escherichia coli (STEC). Some microgreen cultivars accumulate anthocyanins or secrete essential oils which, when extracted or purified, have been reported to inhibit bacterial growth. Therefore, the impact of anthocyanins on bacterial colonisation by STEC (Sakai) was compared for three species that have pigmented cultivars: basil (Ocimum basilicum L.), cabbage (Brassica oleracea L.) and mustard greens (Brassica juncea L.). Inoculation with low concentrations of STEC (Sakai) (3 log 10 colony forming units/ml (CFU/ml)) during seed germination resulted in extensive colonisation at the point of harvest, accumulating to ∼ 8 log 10  CFU/g FW in all cultivars. Bacterial colonies frequently aligned with anticlinal walls on the surface of epidermal cells of the cotyledons and, in basil, associated with peltate and capitate gland cells. Crude lysates of pigmented and non-pigmented basil cultivars had no impact on STEC (Sakai) growth rates, viability status or biofilm formation. Anthocyanins are located within plant vacuoles of these microgreen cultivars and did not affect colonisation by STEC (Sakai) and pigmentation therefore cannot be considered as a controlling factor in bacterial interactions., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Defensive responding is adaptive when it approximates the current threat but maladaptive when it exceeds the current threat. Here we asked if the substantia nigra, a region consistently implicated in reward, is necessary to show appropriate levels of defensive responding in Pavlovian fear discrimination. Rats received bilateral transduction of the caudal substantia nigra with halorhodopsin or a control fluorophore and bilateral ferrule implants. Rats then behaviorally discriminated cues predicting unique foot shock probabilities (danger, p = 1; uncertainty, p = .25; and safety, p = 0). Green-light illumination (532 nm) during cue presentation inflated defensive responding of halorhodopsin rats-measured by suppression of reward seeking-to uncertainty and safety beyond control levels. Green-light illumination outside of cue presentation had no impact on halorhodopsin or control rat responding. The results reveal caudal substantia nigra cue activity is necessary to inhibit defensive responding to nonthreatening and uncertain threat cues. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Introduction: End-of-Rotation Forms (EORFs) assess resident progress in graduate medical education and are a major component of Clinical Competency Committee (CCC) discussion. Single-institution studies suggest EORFs can detect deficiencies, but both grades and comments skew positive. In this study, we sought to determine whether the EORFs from three programs, including multiple specialties and institutions, produced useful information for residents, program directors, and CCCs., Methods: Evaluations from three programs were included (Program 1, Institution A, Internal Medicine: n = 38; Program 2, Institution A, Anesthesia: n = 9; Program 3, Institution B, Anesthesia: n = 11). Two independent researchers coded each written comment for relevance (specificity and actionability) and orientation (praise or critical) using a standardized rubric. Numeric scores were analyzed using descriptive statistics., Results: 4869 evaluations were collected from the programs. Of the 77,434 discrete numeric scores, 691 (0.89%) were considered "below expected level." 71.2% (2683/3767) of the total written comments were scored as irrelevant, while 3217 (85.4%) of total comments were scored positive and 550 (14.6%) were critical. When combined, 63.2% (n = 2379) of comments were scored positive and irrelevant while 6.5% (n = 246) were scored critical and relevant., Discussion: <1% of comments indicated below average performance; >70% of comments scored irrelevant. Critical, relevant comments were least frequently observed, consistent across all 3 programs. The low rate of constructive feedback and the high rate of irrelevant comments are inadequate for a CCC to make informed decisions. The consistency of these findings across programs, specialties, and institutions suggests both local and systemic changes should be considered., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2023 The Author(s).)

Na V 1.7, the neuronal voltage-gated sodium channel isoform, plays an important role in the human body's ability to feel pain. Mutations within Na V 1.7 have been linked to pain-related syndromes, such as insensitivity to pain. To date, the regulation and internalization mechanisms of the Na V 1.7 channel are not well known at a biochemical level. In this study, we perform biochemical and biophysical analyses that establish that the HECT-type E3 ligase, NEDD4L, ubiquitinates the cytoplasmic C-terminal (CT) region of Na V 1.7. Through in vitro ubiquitination and mass spectrometry experiments, we identify, for the first time, the lysine residues of Na V 1.7 within the CT region that get ubiquitinated. Furthermore, binding studies with an NEDD4L E3 ligase modulator (ubiquitin variant) highlight the dynamic partnership between NEDD4L and Na V 1.7. These investigations provide a framework for understanding how NEDD4L-dependent regulation of the channel can influence the Na V 1.7 function., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Clinical workflows that prioritize repetitive patient intake screening to meet performance metrics may have unintended consequences. This retrospective analysis of electronic health record data from 24 Federally Qualified Health Centers assessed effectiveness and accuracy of the 2-item Patient Health Questionnaire (PHQ-2) for depression screening and Generalized Anxiety Disorder 2 (GAD-2) for anxiety screening from 2019 to 2021. Scores of over 91% of PHQ-2 and GAD-2 tests indicated low likelihood of depression or anxiety, which diverged markedly from published literature on screening outcomes. Visit-based screenings linked to performance metrics may not be delivering the intended value in a real-world setting and risk distracting clinical effort from other high value activities., (© 2023 Annals of Family Medicine, Inc.)

Introduction: Centella asiatica is an herbaceous plant reputed in Eastern medicine to improve memory. Preclinical studies have shown that C. asiatica aqueous extract (CAW) improves neuronal health, reduces oxidative stress, and positively impacts learning and cognition. This study aimed to develop and validate bioanalytical methods for detecting known bioactive compounds from C. asiatica in human biological matrices and apply them to a human pharmacokinetic trial in healthy older adults. Methods: High performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was used for detecting triterpenes and caffeoylquinic acids from C. asiatica , or their metabolites, in human plasma and urine. Validation parameters including linearity, precision, accuracy, recovery and thermal stability were evaluated. The method was applied to a Phase I, randomized, double-blind, crossover trial of two doses (2 or 4 g) of a standardized C. asiatica water extract product (CAP) in eight healthy older adults. Pharmacokinetic parameters were measured over a 12-h post administration period and acute safety was assessed. Results: The method satisfied US Food & Drug Administration criteria for linearity and recovery of the analytes of interest in human plasma and urine. The method also satisfied criteria for precision and accuracy at medium and high concentrations. Single administration of 2 and 4 g of CAP was well tolerated and safe in healthy older adults. The parent triterpene glycosides, asiaticoside and madecassoside, were not detected in plasma and in minimal amounts in urinary excretion analyses, while the aglycones, asiatic acid and madecassic acid, showed readily detectable pharmacokinetic profiles. Similarly, the di-caffeoylquinic acids and mono-caffeoylquinic acids were detected in low quantities, while their putative metabolites showed readily detectable pharmacokinetic profiles and urinary excretion. Discussion: This method was able to identify and calculate the concentration of triterpenes and caffeoylquinic acids from C. asiatica , or their metabolites, in human plasma and urine. The oral absorption of these key compounds from CAP, and its acute safety in healthy older adults, support the use of this C. asiatica product in future clinical trials., Competing Interests: AS is an ad hoc consultant for Oregon’s Wild Harvest. Services for clinical trial product manufacture provided by Ashland Laboratories and Oregon’s Wild Harvest were financed by the NIH grant R61AT009628 awarded to Oregon Health & Science University. The CAP products described in this study were made for research purposes only and not for commercial use. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wright, Bollen, David, Mepham, Alcázar Magaña, McClure, Maier, Quinn and Soumyanath.)

Specificity remains a major challenge to current therapeutic strategies for cancer. Mutation associated neoantigens (MANAs) are products of genetic alterations, making them highly specific therapeutic targets. MANAs are HLA-presented (pHLA) peptides derived from intracellular mutant proteins that are otherwise inaccessible to antibody-based therapeutics. Here, we describe the cryo-EM structure of an antibody-MANA pHLA complex. Specifically, we determine a TCR mimic (TCRm) antibody bound to its MANA target, the KRAS G12V peptide presented by HLA-A*03:01. Hydrophobic residues appear to account for the specificity of the mutant G12V residue. We also determine the structure of the wild-type G12 peptide bound to HLA-A*03:01, using X-ray crystallography. Based on these structures, we perform screens to validate the key residues required for peptide specificity. These experiments led us to a model for discrimination between the mutant and the wild-type peptides presented on HLA-A*03:01 based exclusively on hydrophobic interactions., (© 2023. Springer Nature Limited.)

The mature mammalian cortex is composed of 6 architecturally and functionally distinct layers. Two key steps in the assembly of this layered structure are the initial establishment of the glial scaffold and the subsequent migration of postmitotic neurons to their final position. These processes involve the precise and timely regulation of adhesion and detachment of neural cells from their substrates. Although much is known about the roles of adhesive substrates during neuronal migration and the formation of the glial scaffold, less is understood about how these signals are interpreted and integrated within these neural cells. Here, we provide in vivo evidence that Cas proteins, a family of cytoplasmic adaptors, serve a functional and redundant role during cortical lamination. Cas triple conditional knock-out (Cas TcKO) mice display severe cortical phenotypes that feature cobblestone malformations. Molecular epistasis and genetic experiments suggest that Cas proteins act downstream of transmembrane Dystroglycan and β1-Integrin in a radial glial cell-autonomous manner. Overall, these data establish a new and essential role for Cas adaptor proteins during the formation of cortical circuits and reveal a signaling axis controlling cortical scaffold formation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Wong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The mammalian somatosensory system is comprised of multiple neuronal populations that form specialized, highly organized sensory endings in the skin. The organization of somatosensory endings is essential to their functions, yet the mechanisms which regulate this organization remain unclear. Using a combination of genetic and molecular labeling approaches, we examined the development of mouse hair follicle-innervating low-threshold mechanoreceptors (LTMRs) and explored competition for innervation targets as a mechanism involved in the patterning of their receptive fields. We show that follicle innervating neurons are present in the skin at birth and that LTMR receptive fields gradually add follicle-innervating endings during the first two postnatal weeks. Using a constitutive Bax knockout to increase the number of neurons in adult animals, we show that two LTMR subtypes have differential responses to an increase in neuronal population size: Aδ-LTMR neurons shrink their receptive fields to accommodate the increased number of neurons innervating the skin, while C-LTMR neurons do not. Our findings suggest that competition for hair follicles to innervate plays a role in the patterning and organization of follicle-innervating LTMR neurons., (© 2023. The Author(s).)

Visual input to the hypothalamus from intrinsically photosensitive retinal ganglion cells (ipRGCs) influences several functions including circadian entrainment, body temperature, and sleep. ipRGCs also project to nuclei such as the supraoptic nucleus (SON), which is involved in systemic fluid homeostasis, maternal behavior, social behaviors, and appetite. However, little is known about the SON-projecting ipRGCs or their relationship to well-characterized ipRGC subtypes. Using a GlyT2 Cre mouse line, we show a subtype of ipRGCs restricted to the dorsal retina that selectively projects to the SON. These ipRGCs tile a dorsal region of the retina, forming a substrate for encoding ground luminance. Optogenetic activation of their axons demonstrates they release the neurotransmitter glutamate in multiple regions, including the suprachiasmatic nucleus (SCN) and SON. Our results challenge the idea that ipRGC dendrites overlap to optimize photon capture and suggests non-image forming vision operates to sample local regions of the visual field to influence diverse behaviors., (© 2023. The Author(s).)

Molecularly imprinted polymers (MIPs) for benzylpiperazine (BZP, 1 ), an illicit designer drug, were developed by using both self-assembly and semi-covalent approaches. From an array of potential functional monomers (FMs) and using a combination of pre-synthetic interaction studies (by molecular modelling and NMR analysis) and binding assays, the highest performing self-assembly 1 -MIPs were confirmed to result from methacrylic acid ( 7 ) as FM, ethylene glycol dimethacrylate (EGDMA) or trimethylolpropane trimethacrylate (TRIM) as crosslinkers and chloroform as the porogen and rebinding solvent at template (T): FM ratios of 1:1 and 1:2, giving imprinting factors (IF) 3 to 7. The semi-covalent 1 -MIPs were designed using benzylpiperazine (4-vinylphenyl) carbamate ( 16 ) as the template-monomer adduct in combination with either EDGMA or TRIM. Our comparative analysis showed the semi-covalent polymers to have a stronger affinity for 1 (significantly lower K d values and higher IFs) and faster uptake than the self-assembly systems. Both approaches have comparable cross-reactivity: marginal to low against cocaine ( 17 ) and morphine ( 18 ) and high against ephedrine ( 19 ) and phenylpiperazine ( 20 ). They also have comparable selectivity: highly selective towards 1 against 17 , moderate against 18 and non-selective against 19 . EGDMA-based self-assembly MIPs displayed a greater imprinting effect (higher IFs and NIP-to-MIP K d ratios) than TRIM-based MIPs, while the TRIM-based semi-covalent MIP outperformed its EGDMA-based equivalent. By virtue of its modest selectivity against the test illicit drugs, 1 -MIPs could potentially be used as a dummy MIP for the broad-based capture and enrichment of illicit drug blends for subsequent laboratory analysis.

The MID1 TRIM protein is important for ventral midline development in vertebrates, and mutations of its B-box1 domain result in several birth defects. The B-box1 domain of the human MID1 protein binds two zinc atoms and adopt a similar ββα-RING structure. This domain is required for the efficient ubiquitination of protein phosphatase 2A, alpha4, and fused kinase. Considering the structural similarity, the MID1 B-box1 domain exhibits mono-autoubiquitination activity, in contrast to poly-autoubiquitination observed for RING E3 ligases. To understand its mechanism of action, the interaction of the B-box1 domain with Ube2D1 (UbcH5a, E2), a preferred E2 ligase, is investigated. Using isothermal titration calorimetry, the MID1 RING and B-box1 domains were observed to have similar binding affinities with the Ube2D1 protein. However, NMR 15 N- 1 H Heteronuclear Single Quantum Coherence titration, 15 N relaxation data, and H igh A mbiguity D riven protein-protein DOCK ing (HADDOCK) calculations show the B-box1 domain binding on a surface distinct from where RING domains bind. The novel binding interaction shows the B-box1 domain partially overlapping the noncovalent Ube2D1 and a ubiquitin binding site that is necessary for poly-autoubiquitination activity. The B-box1 domain also displaces the ubiquitin from the Ube2D1 protein. These studies reveal a novel binding interaction between the zinc-binding ββα-fold B-box1 domain and the Ube2D enzyme family and that this difference in binding, compared to RING E3 ligases, provides a rationale for its auto-monoubiquitination E3 ligase activity.

Bacterial attachment on root surfaces is an important step preceding the colonization or internalization and subsequent infection of plants by pathogens. Unfortunately, bacterial attachment is not well understood because the phenomenon is difficult to observe. Here we assessed whether this limitation could be overcome using optical trapping approaches. We have developed a system based on counter-propagating beams and studied its ability to guide Pectobacterium atrosepticum (Pba) cells to different root cell types within the interstices of transparent soils. Bacterial cells were successfully trapped and guided to root hair cells, epidermal cells, border cells, and tissues damaged by laser ablation. Finally, we used the system to quantify the bacterial cell detachment rate of Pba cells on root surfaces following reversible attachment. Optical trapping techniques could greatly enhance our ability to deterministically characterize mechanisms linked to attachment and formation of biofilms in the rhizosphere., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Integrating social care into clinical care requires substantial resources. Use of existing data through a geographic information system (GIS) has the potential to support efficient and effective integration of social care into clinical settings. We conducted a scoping literature review characterizing its use in primary care settings to identify and address social risk factors., Methods: In December 2018, we searched 2 databases and extracted structured data for eligible articles that (1) described the use of GIS in clinical settings to identify and/or intervene on social risks, (2) were published between December 2013 and December 2018, and (3) were based in the United States. Additional studies were identified by examining references., Results: Of the 5,574 articles included for review, 18 met study eligibility criteria: 14 (78%) were descriptive studies, 3 (17%) tested an intervention, and 1 (6%) was a theoretical report. All studies used GIS to identify social risks (increase awareness); 3 studies (17%) described interventions to address social risks, primarily by identifying relevant community resources and aligning clinical services to patients' needs., Conclusions: Most studies describe associations between GIS and population health outcomes; however, there is a paucity of literature regarding GIS use to identify and address social risk factors in clinical settings. GIS technology may assist health systems seeking to address population health outcomes through alignment and advocacy; its current application in clinical care delivery is infrequent and largely limited to referring patients to local community resources., Competing Interests: Conflicts of interest: Dr Persell receives unrelated research support from Omron Healthcare Co. The other authors report no conflicts., (© 2023 Annals of Family Medicine, Inc.)

The therapeutic applications of antibodies are manifold and the emergence of SARS-CoV-2 provides a cogent example of the value of rapidly identifying biologically active antibodies. We describe an approach called SLISY (Sequencing-Linked ImmunoSorbent assaY) that in a single experiment can assess the binding specificity of millions of clones, be applied to any screen that links DNA sequence to a potential binding moiety, and requires only a single round of biopanning. We demonstrate this approach using an scFv library applied to cellular and protein targets to identify specific or broadly reacting antibodies. For a cellular target, we use paired HLA knockout cell lines to identify a panel of antibodies specific to HLA-A3. For a protein target, SLISY identifies 1279 clones that bound to the Receptor Binding Domain of the SARS-CoV-2 spike protein, with >40% of tested clones also neutralizing its interaction with ACE2 in in vitro assays. Using a multi-comparison SLISY against the Beta, Gamma, and Delta variants, we recovered clones that exhibited broad-spectrum neutralizing potential in vitro. By evaluating millions of scFvs simultaneously against multiple targets, SLISY allows the rapid identification of candidate scFvs with defined binding profiles facilitating the identification of antibodies with the desired biological activity., (© 2023. The Author(s).)

The glycoprotein dystroglycan was first identified in muscle, where it functions as part of the dystrophin glycoprotein complex to connect the extracellular matrix to the actin cytoskeleton. Mutations in genes involved in the glycosylation of dystroglycan cause a form of congenital muscular dystrophy termed dystroglycanopathy. In addition to its well-defined role in regulating muscle integrity, dystroglycan is essential for proper central and peripheral nervous system development. Patients with dystroglycanopathy can present with a wide range of neurological perturbations, but unraveling the complex role of Dag1 in the nervous system has proven to be a challenge. Over the past two decades, animal models of dystroglycanopathy have been an invaluable resource that has allowed researchers to elucidate dystroglycan's many roles in neural circuit development. In this review, we summarize the pathways involved in dystroglycan's glycosylation and its known interacting proteins, and discuss how it regulates neuronal migration, axon guidance, synapse formation, and its role in non-neuronal cells., (© 2022 American Association for Anatomy.)

The colonization of six edible plant species: alfalfa, broccoli, coriander, lettuce, parsley and rocket, by the human pathogen Shigatoxigenic Escherichia coli was investigated following two modes of artificial inoculation of seeds, by soaking or watering. The frequency and extent of colonization of cotyledons depended on the mode of inoculation, with three, rapidly germinating species being successfully colonized after overnight soaking, but slower germinating species requiring prolonged exposure to bacteria by watering of the surrounding growth media. Separate analysis of the cotyledons and leaves from individual plants highlighted that successful colonization of the true leaves was also species dependent. For three species, failure of transfer, or lack of nutrients or suitable microhabitat on the leaf surface resulted in infrequent bacterial colonization. Colonization of leaves was lower and generally in proportion to that in cotyledons, if present. The potential risks associated with consumption of leafy produce are discussed., (© 2022 The Authors. Environmental Microbiology Reports published by Society for Applied Microbiology and John Wiley & Sons Ltd.)