Formative evaluation of an emergency department clinical decision support system for agitation symptoms: a study protocol.

INTRODUCTION: The burden of mental health-related visits to emergency departments (EDs) is growing, and agitation episodes are prevalent with such visits. Best practice guidance from experts recommends early assessment of at-risk populations and pre-emptive intervention using de-escalation techniques to prevent agitation. Time pressure, fluctuating work demands, and other systems-related factors pose challenges to efficient decision-making and adoption of best practice recommendations during an unfolding behavioural crisis. As such, we propose to design, develop and evaluate a computerised clinical decision support (CDS) system, Early Detection and Treatment to Reduce Events with Agitation Tool (ED-TREAT). We aim to identify patients at risk of agitation and guide ED clinicians through appropriate risk assessment and timely interventions to prevent agitation with a goal of minimising restraint use and improving patient experience and outcomes. METHODS AND ANALYSIS: This study describes the formative evaluation of the health record embedded CDS tool. Under aim 1, the study will collect qualitative data to design and develop ED-TREAT using a contextual design approach and an iterative user-centred design process. Participants will include potential CDS users, that is, ED physicians, nurses, technicians, as well as patients with lived experience of restraint use for behavioural crisis management during an ED visit. We will use purposive sampling to ensure the full spectrum of perspectives until we reach thematic saturation. Next, under aim 2, the study will conduct a pilot, randomised controlled trial of ED-TREAT at two adult ED sites in a regional health system in the Northeast USA to evaluate the feasibility, fidelity and bedside acceptability of ED-TREAT. We aim to recruit a total of at least 26 eligible subjects under the pilot trial. ETHICS AND DISSEMINATION: Ethical approval by the Yale University Human Investigation Committee was obtained in 2021 (HIC# 2000030893 and 2000030906). All participants will provide informed verbal consent prior to being enrolled in the study. Results will be disseminated through publications in open-access, peer-reviewed journals, via scientific presentations or through direct email notifications. TRIAL REGISTRATION NUMBER: NCT04959279; Pre-results.

Intravascular Lymphoma as a Cause of Recurrent Strokes - Case Report and Review of the Literature.

Background: Intravascular lymphoma is an uncommon cause of ischemic strokes. Because of its rarity and atypical pattern, most diagnoses are made post-mortem. Case study: We present a case of a 68-year-old male with multiple cardiovascular risk factors and recent SARS-CoV-2 infection who presented with recurrent strokes. Because of his stroke risk factors, he was initially managed with a sequentially escalating antithrombotic regimen. A malignant process was low on the differential at this point given his lack of systemic symptoms. When he continued to have new strokes despite these measures, including a spinal cord infarct, a broad workup was sent including for hypercoagulable states, vasculitis, and intravascular lymphoma. Eventually, a skin biopsy of a cherry angioma returned positive for lymphoma cells. He was treated with methotrexate followed by chemotherapy and rituximab. Unfortunately, he did not improve and was made comfort measures only by his family. Conclusion: This case illustrates the importance of considering intravascular lymphoma as a potential etiology of recurrent strokes, as early diagnosis and treatment are important for preventing irreversible neurological damage.

Monkeypox outbreak, vaccination, and treatment implications for the dermatologic patient: Review and interim guidance from the Medical Dermatology Society.

Rapid human-to-human transmission of monkeypox has created a public health emergency requiring prompt, multidisciplinary attention. Dermatologists are at the forefront of diagnosis due to the disease-defining skin lesions. Moreover, patients with pre-existing skin disease and those who are on immunosuppressive medications for skin disease may be at increased risk of severe infection. In this review, a panel of authors with expertise in complex medical dermatology and managing patients on immunosuppression reviews the literature and provides initial guidance for diagnosis and management in dermatology practices. Though there are knowledge gaps due to a lack of controlled studies, we support use of replication-deficit vaccines in all dermatologic patients who meet qualifying risk or exposure criteria. We offer strategies to optimize vaccine efficacy in patients with immunosuppression. We discuss alternative post-exposure treatments and their safety profiles. Finally, we outline supportive care recommendations for cutaneous manifestations of monkeypox. Large scale epidemiologic investigations and clinical trials will ultimately revise and extend our guidance.

Effectiveness of matching human leukocyte antigens (HLA) in corneal transplantation: a systematic review protocol.

BACKGROUND: Corneal transplantation is the most frequently performed transplantation in the UK. Despite this, the therapeutic value of matching human leukocyte antigen (HLA) subtypes for transplanted corneas remains controversial. Ocular immune privilege was originally deemed to render matching unnecessary; however, more recently, matching has demonstrated improved outcomes including graft success, amongst others. This systematic review aims to evaluate the effectiveness of major and minor antigen matching on graft outcomes in corneal transplantation. METHODS: Standard systematic review methodology will be used to identify, select and extract data from observational studies and clinical trials assessing the effects of HLA matching on corneal graft outcomes. Bibliographic databases (Cochrane Library, EMBASE, MEDLINE, Web of Science, Scopus), clinical trial registers, abstract and conference proceedings, in addition to dissertation, thesis and grey literature will be searched. Neither date of publication nor language will be restricted, and non-English articles will be translated where necessary. The primary outcome will be to assess corneal graft success for different degrees of HLA matching/mismatching. The precise end outcome measure varies amongst studies and includes graft rejection, immunoreaction, failure and survival. Therefore, data will be extracted across all relevant outcome parameters and grouped for subsequent statistical tests. Risk of bias assessment will be completed, appropriate to each study design. Study selection, data extraction and risk of bias assessment will be independently completed by two reviewers. Data will be tabulated, and a narrative synthesis presented. Meta-analysis will be performed where there is sufficient homogeneity between studies to warrant its effective completion. Subgroup and sensitivity analysis will be undertaken if appropriate. DISCUSSION: Many studies have investigated the effectiveness of HLA matching for corneal transplantation. A systematic review is needed to collate and analyse this evidence. Findings of this systematic review may form the basis of evidence-based recommendations on pre-operative HLA typing and matching of corneal grafts for transplantation. SYSTEMATIC REVIEW REGISTRATION: PROSPERO reference CRD42020198882.

Using Visual Arts Education in Dermatology to Benefit Resident Wellness and Clinical Communication.

Introduction: Art education interventions improve observation skills among dermatology residents, but there is limited data regarding their benefits to wellness and clinical communication. Methods: Residents in the Stanford dermatology residency program participated in an arts-based education session, repeated in the fall of 2018 and 2019, that included a rotation of observational exercises adapted from the Artful Thinking program through Harvard Project Zero. The 2018 session featured exercises on identification and understanding of visual observation, while the 2019 session featured exercises on perspectives and objectivity of visual observation. Participants completed preintervention, postintervention, and 3-month follow-up surveys in fall 2018 and a postintervention survey in fall 2019. Results: Twenty-one residents participated in the 2018 education session and produced an adequate response rate (62%-90%) across surveys. At 3 months, five of 13 residents (39%) reported new use of art for mindfulness and stress reduction, 12 of 13 (92%) could recall an example of use of observation to improve patient communication, and four of 13 (31%) confirmed and described adjustments to their handoff technique. In 2019, 13 out of 18 participants (72%) completed the postintervention survey. Responses reinforced themes from the prior iteration but focused on perspective, objectivity, context, and uncertainty in observations. Respondents also identified additional arenas of communication to benefit from these observational techniques. Discussion: Dermatology residents increased use of art for personal wellness and adjusted clinical communication strategies after a single arts-based education session. Annual repetition with novel exercises maintained engagement and yielded additional participant insights.

Theoretical Study on Tuning Band Gap and Electronic Properties of Atomically Thin Nanostructured MoS2/Metal Cluster Heterostructures.

Nano-heterostructures have attracted immense attention recently due to their remarkable interfacial properties determined by the heterointerface of different nanostructures. Here, using first-principles density functional theory (DFT) calculations, we examine what range the variable electronic properties such as the electronic band gap can be tuned by combining two dissimilar nanostructures consisting of atomically thin nanostructured MoS2 clusters with small silver and gold nanoparticles (Ag/Au NPs). Most interestingly, our calculations show that the electronic band gap of the nanostructured MoS2 cluster can be tuned from 2.48 to 1.58 and 1.61 eV, by the formation of heterostructures with silver and gold metal nanoclusters, respectively. This band gap is ideal for various applications ranging from flexible nanoelectronics to nanophotonics applications. Furthermore, the adsorption of H2 molecules on both nano-heterostructures is investigated, and the computed binding energies are found to be within the desirable range. The reported theoretical results provide inspiration for engineering various optoelectronic applications for nanostructured MoS2-based heterostructures.

Depression and Anxiety Subgroups Across Alcohol Use Disorder and Substance Use in a National Epidemiologic Study.

Objective: The high prevalence of alcohol/substance use among individuals with psychiatric disorders elucidates the import of investigations into associations between types and severity of psychiatric symptoms and alcohol/substance use. This study examined the likelihood of alcohol use disorder and substance use among individuals with varying depression and anxiety symptoms and severity thereof. Differences across sex were also examined.Methods: Using data from the National Epidemiological Survey on Alcohol and Related Conditions, a nationally representative sample from the United States (N = 43,093), separate logistic regressions estimated the odds of lifetime alcohol use disorder, depressant, stimulant, hallucinogen, and comorbid substance use across psychiatric symptom clusters controlling for age, sex, and ethnicity.Results: Symptom severity was a more important correlate of alcohol use disorder and substance use than symptom type. In particular, the odds ratio of lifetime use of depressants, stimulants, hallucinogens, or any combination of these types of substances were higher for individuals with either severe depression or severe depression and anxiety relative to a healthy control. Moreover, the odds of having a diagnosis of lifetime alcohol use disorder were higher for individuals with severe symptoms of depression, anxiety, and both depression and anxiety, relative to healthy individuals. Those with mild depression were more likely to engage in substance use than individuals with anxiety alone. Patterns of association among males and females were highly consistent.Conclusions: The findings highlight an enhanced risk of alcohol and substance use among individuals with severe depression and/or anxiety symptoms above what is seen among individuals with less severe symptomatology. In addition, this study shows a unique risk posed by the presence of depression on substance use. This study offers a framework for future studies to examine the causal mechanisms explaining the connection between psychiatric symptoms and alcohol/substance use.

Rethinking Violence Prevention in Rural and Underserved Communities: How Veteran Peer Support Groups Help Participants Deal with Sequelae from Violent Traumatic Experiences.

PURPOSE: Access to mental health care and programs that address violence prevention can be a challenge for veterans residing in rural and underserved areas. A growing number of trauma-affected veterans are now returning to rural areas upon completion of military service. The Palo Alto VA Health Care System has piloted a program known as the Peer Support Program (PSP) where certified peer support specialists hold group sessions for their fellow veterans in remote, community-based outpatient clinics. METHODS: A total of 29 peer-support group participants and 1 certified peer specialist were interviewed. Semistructured interviews began with open-ended questions regarding participant firsthand experiences with the support group setting. These were followed by direct questions that addressed the role of the PSP, expectations for the PSP, as well as benefits and limitations of the program. We performed a domain analysis using the Spradley ethnographic method on 325 pages of compiled narrative data focusing on violence-related themes. FINDINGS: Four key themes emerged, including: 1) Violence in Military Training Not Acceptable in Civilian Life, 2) Peer Support Creates the Trust to Speak Freely, 3) Skills Are Taught to Defuse Violence, and 4) The Veteran Peer Support Specialist Relationship Is Multi-Dimensional. CONCLUSIONS: These emergent themes illustrate how trauma-focused assistance rendered by peer support specialists as part of an interdisciplinary mental health team can be implemented to benefit trauma-affected individuals and their communities in the prevention of future violence.

Peer support in an outpatient program for veterans with posttraumatic stress disorder: Translating participant experiences into a recovery model.

Veterans returning from recent conflicts present with increased rates of posttraumatic stress disorder (PTSD), and veterans from prior service eras continue to seek trauma-based services. Peer support for veterans with PTSD has the potential to resolve ongoing challenges in access and engagement in mental health care. Assessing the value of peer support services requires a thorough understanding of the expected role and the empirical mechanisms of peer support participation in PTSD recovery. To better understand these mechanisms, this study interviewed 29 veteran participants from an established peer support program (PSP), located in the Central Valley of the Veterans Affairs (VA) Palo Alto Health Care System (VAPAHCS) in Northern California. A domain analysis of narrative transcripts generated 34 codes through a grounded theory method. Codes were organized into the following thematic categories: the perceived role of the PSP, supportive experiences of the PSP, global gains from the PSP, and limitations to PSP and further mental health engagement. These results were synthesized into a theoretical model that identifies improved functioning and reduced distress as the expected outcomes of PSP-mediated recovery and illustrates the continuum from in-group experiences to these outcomes. Our results suggest that PSP-mediated recovery is defined as acceptance of PTSD into daily life and identity, rather than resolution of symptoms. This conceptualization has implications for peer support provider training, PSP integration into health care settings, and future outcome analyses on the effectiveness of PSPs. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Medical student INtervention to promote effective nicotine dependence and tobacco HEalthcare (MIND-THE-GAP): single-centre feasibility randomised trial results.

BACKGROUND: Although brief cessation advice from healthcare professionals increases quit rates, smokers typically do not get this advice during hospitalisation, possibly due to resource issues, lack of training and professionals' own attitudes to providing such counselling. Medical students are a potentially untapped resource who could deliver cessation counselling, while upskilling themselves and changing their own attitudes to delivering such advice in the future; however, no studies have investigated this. We aimed to determine if brief student-led counselling could enhance motivation to quit and smoking cessation behaviours among hospitalised patients. METHODS: A mixed-methods, 2-arm pilot feasibility randomised controlled trial with qualitative process evaluation enrolled 67 hospitalised adult smokers, who were recruited and randomized to receive a brief medical student-delivered cessation intervention (n = 33) or usual care (n = 34); 61 medical students received standardised cessation training and 33 were randomly assigned to provide a brief in-hospital consultation and follow-up support by phone or in-person one week post-discharge. Telephone follow-up at 3- and 6-months assessed scores on the Motivation to Stop Smoking Scale (MTSS; primary outcome) and several other outcomes, including 7-day point prevalent abstinence, quit attempts, use of cessation medication, and ratings of student's knowledge and efficacy. Data were analysed as intention to treat (ITT) using penalised imputation, per protocol, and random effects repeated measures. Focus group interviews were conducted with students post-intervention to elicit their views on the training and intervention process. RESULTS: Analyses for primary and most secondary outcomes favoured the intervention group, although results were not statistically significant. Point prevalence abstinence rates were significantly higher for the intervention group during follow-up for all analyses except 6-month ITT analysis. Fidelity was variable. Patients rated students as being "very" knowledgeable about quitting and "somewhat" helpful. Qualitative results showed students were glad to deliver the intervention; were critical of current cessation care; felt constrained by their inability to prescribe cessation medications and wanted to include cessation and other behavioural counselling in their normal history taking. CONCLUSIONS: It appears feasible for medical students to be smoking cessation interventionists during their training, although their fidelity to the intervention requires further investigation. A definitive trial is needed to determine if medical students are effective cessation counsellors and if student-led intervention could be tailored for other health behaviours. TRIAL REGISTRATION: NCT02601599 (retrospectively registered 1 day after first participant recruited on November 3rd 2015).

Using thermal scanning assays to test protein-protein interactions of inner-ear cadherins.

Protein-protein interactions play a crucial role in biological processes such as cell-cell adhesion, immune system-pathogen interactions, and sensory perception. Understanding the structural determinants of protein-protein complex formation and obtaining quantitative estimates of their dissociation constant (KD) are essential for the study of these interactions and for the discovery of new therapeutics. At the same time, it is equally important to characterize protein-protein interactions in a high-throughput fashion. Here, we use a modified thermal scanning assay to test interactions of wild type (WT) and mutant variants of N-terminal fragments (EC1+2) of cadherin-23 and protocadherin-15, two proteins essential for inner-ear mechanotransduction. An environmentally sensitive fluorescent dye (SYPRO orange) is used to monitor melting temperature (Tm) shifts of protocadherin-15 EC1+2 (pcdh15) in the presence of increasing concentrations of cadherin-23 EC1+2 (cdh23). These Tm shifts are absent when we use proteins containing deafness-related missense mutations known to disrupt cdh23 binding to pcdh15, and are increased for some rationally designed mutants expected to enhance binding. In addition, surface plasmon resonance binding experiments were used to test if the Tm shifts correlated with changes in binding affinity. We used this approach to find a double mutation (cdh23(T15E)- pcdh15(G16D)) that enhances binding affinity of the cadherin complex by 1.98 kJ/mol, roughly two-fold that of the WT complex. We suggest that the thermal scanning methodology can be used in high-throughput format to quickly compare binding affinities (KD from nM up to 100 µM) for some heterodimeric protein complexes and to screen small molecule libraries to find protein-protein interaction inhibitors and enhancers.

Nkx2.5+ Cardiomyoblasts Contribute to Cardiomyogenesis in the Neonatal Heart.

During normal lifespan, the mammalian heart undergoes limited renewal of cardiomyocytes. While the exact mechanism for this renewal remains unclear, two possibilities have been proposed: differentiated myocyte replication and progenitor/immature cell differentiation. This study aimed to characterize a population of cardiomyocyte precursors in the neonatal heart and to determine their requirement for cardiac development. By tracking the expression of an embryonic Nkx2.5 cardiac enhancer, we identified cardiomyoblasts capable of differentiation into striated cardiomyocytes in vitro. Genome-wide expression profile of neonatal Nkx2.5+ cardiomyoblasts showed the absence of sarcomeric gene and the presence of cardiac transcription factors. To determine the lineage contribution of the Nkx2.5+ cardiomyoblasts, we generated a doxycycline suppressible Cre transgenic mouse under the regulation of the Nkx2.5 enhancer and showed that neonatal Nkx2.5+ cardiomyoblasts mature into cardiomyocytes in vivo. Ablation of neonatal cardiomyoblasts resulted in ventricular hypertrophy and dilation, supporting a functional requirement of the Nkx2.5+ cardiomyoblasts. This study provides direct lineage tracing evidence that a cardiomyoblast population contributes to cardiogenesis in the neonatal heart. The cell population identified here may serve as a promising therapeutic for pediatric cardiac regeneration.

High-throughput screening of tyrosine kinase inhibitor cardiotoxicity with human induced pluripotent stem cells.

Tyrosine kinase inhibitors (TKIs), despite their efficacy as anticancer therapeutics, are associated with cardiovascular side effects ranging from induced arrhythmias to heart failure. We used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), generated from 11 healthy individuals and 2 patients receiving cancer treatment, to screen U.S. Food and Drug Administration-approved TKIs for cardiotoxicities by measuring alterations in cardiomyocyte viability, contractility, electrophysiology, calcium handling, and signaling. With these data, we generated a "cardiac safety index" to reflect the cardiotoxicities of existing TKIs. TKIs with low cardiac safety indices exhibit cardiotoxicity in patients. We also derived endothelial cells (hiPSC-ECs) and cardiac fibroblasts (hiPSC-CFs) to examine cell type-specific cardiotoxicities. Using high-throughput screening, we determined that vascular endothelial growth factor receptor 2 (VEGFR2)/platelet-derived growth factor receptor (PDGFR)-inhibiting TKIs caused cardiotoxicity in hiPSC-CMs, hiPSC-ECs, and hiPSC-CFs. With phosphoprotein analysis, we determined that VEGFR2/PDGFR-inhibiting TKIs led to a compensatory increase in cardioprotective insulin and insulin-like growth factor (IGF) signaling in hiPSC-CMs. Up-regulating cardioprotective signaling with exogenous insulin or IGF1 improved hiPSC-CM viability during cotreatment with cardiotoxic VEGFR2/PDGFR-inhibiting TKIs. Thus, hiPSC-CMs can be used to screen for cardiovascular toxicities associated with anticancer TKIs, and the results correlate with clinical phenotypes. This approach provides unexpected insights, as illustrated by our finding that toxicity can be alleviated via cardioprotective insulin/IGF signaling.

A Neural Basis for Control of Cichlid Female Reproductive Behavior by Prostaglandin F2α.

In most species, females time reproduction to coincide with fertility. Thus, identifying factors that signal fertility to the brain can provide access to neural circuits that control sexual behaviors. In vertebrates, levels of key signaling molecules rise at the time of fertility to prime the brain for reproductive behavior [1-11], but how and where they regulate neural circuits is not known [12, 13]. Specifically, 17α,20ß-dihydroxyprogesterone (DHP) and prostaglandin F2α (PGF2α) levels rise in teleost fish around the time of ovulation [10, 14, 15]. In an African cichlid fish, Astatotilapia burtoni, fertile females select a mate and perform a stereotyped spawning routine, offering quantifiable behavioral outputs of neural circuits. We show that, within minutes, PGF2α injection activates a naturalistic pattern of sexual behavior in female A. burtoni. We also identify cells in the brain that transduce the prostaglandin signal to mate and show that the gonadal steroid DHP modulates mRNA levels of the putative receptor for PGF2α (Ptgfr). We use CRISPR/Cas9 to generate the first targeted gene mutation in A. burtoni and show that Ptgfr is necessary for the initiation of sexual behavior, uncoupling sexual behavior from reproductive status. Our findings are consistent with a model in which PGF2α communicates fertility status via Ptgfr to circuits in the brain that drive female sexual behavior. Our targeted genome modification in a cichlid fish shows that dissection of gene function can reveal basic control mechanisms for behaviors in this large family of species with diverse and fascinating social systems [16, 17].