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Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed treatment for individuals experiencing major depressive disorder (MDD). The therapeutic mechanisms that take place before, during, or after SSRIs bind the serotonin transporter (SERT) are poorly understood, partially because no studies exist of the cellular and subcellular pharmacokinetic properties of SSRIs in living cells. We studied escitalopram and fluoxetine using new intensity- based drug-sensing fluorescent reporters (“iDrugSnFRs”) targeted to the plasma membrane (PM), cytoplasm, or endoplasmic reticulum (ER) of cultured neurons and mammalian cell lines. We also employed chemical detection of drug within cells and phospholipid membranes. The drugs attain equilibrium in neuronal cytoplasm and ER, at approximately the same concentration as the externally applied solution, with time constants of a few s (escitalopram) or 200-300 s (fluoxetine). Simultaneously, the drugs accumulate within lipid membranes by ≥ 18-fold (escitalopram) or 180-fold (fluoxetine), and possibly by much larger factors. Both drugs leave cytoplasm, lumen, and membranes just as quickly during washout. We synthesized membrane-impermeant quaternary amine derivatives of the two SSRIs. The quaternary derivatives are substantially excluded from membrane, cytoplasm, and ER for > 2.4 h. They inhibit SERT transport-associated currents 6- or 11-fold less potently than the SSRIs (escitalopram or fluoxetine derivative, respectively), providing useful probes for distinguishing compartmentalized SSRI effects. Although our measurements are orders of magnitude faster than the “therapeutic lag” of SSRIs, these data suggest that SSRI-SERT interactions within organelles or membranes may play roles during either the therapeutic effects or the “antidepressant discontinuation syndrome”.SIGNIFICANCE STATEMENTSelective serotonin reuptake inhibitors stabilize mood in several disorders. In general, these drugs bind to the serotonin (5-hydroxytryptamine) transporter (SERT), which clears serotonin from CNS and peripheral tissues. SERT ligands are effective and relatively safe; primary care practitioners often prescribe them. However, they have several side effects and require 2 to 6 weeks of continuous administration until they act effectively. How they work remains perplexing, contrasting with earlier assumptions that the therapeutic mechanism involves SERT inhibition followed by increased extracellular serotonin levels. This study establishes that two SERT ligands, fluoxetine and escitalopram, enter neurons within minutes, while simultaneously accumulating in many membranes. Such knowledge will motivate future research, hopefully revealing where and how SERT ligands “engage” their therapeutic target(s).

Background Clozapine clinics can facilitate greater access to clozapine, but there is a paucity of data on their structure in the US. Methods A 23-item survey was administered to participants recruited from the SMI Adviser Clozapine Center of Excellence listserv to understand characteristics of clozapine clinics. Results Clozapine clinics (N = 32) had a median caseload of 45 (IQR = 21–88) patients and utilized a median of 5 (IQR = 4–6) interdisciplinary roles. The most common roles included psychiatrists (100%), pharmacists (65.6%), nurses (65.6%), psychiatric nurse practitioners (53.1%), and case managers (53.1%). The majority of clinics outreached to patients who were overdue for labs (78.1%) and had access to on-site phlebotomy (62.5%). Less than half had on call services (46.9%). Conclusions In this first systematic description of clozapine clinics in the US, there was variation in the size, staffing, and services offered. These findings may serve as a window into configurations of clozapine teams.

The need for huge data sets represents a bottleneck for the application of artificial intelligence. Substantially fewer annotated target lesions than normal tissues for comparison present an additional problem in the field of pathology. Organic brains overcome these limitations by utilizing large numbers of specialized neural nets arranged in both linear and parallel fashion, with each solving a restricted classification problem. They rely on local Hebbian error corrections as compared to the nonlocal back-propagation used in most artificial neural nets, and leverage reinforcement. For these reasons, even toddlers are able to classify objects after only a few examples. Rather than provide an overview of current AI research in pathology, this review focuses on general strategies for overcoming the data bottleneck. These include transfer learning, zero-shot learning, Siamese networks, one-class models, generative networks, and reinforcement learning. Neither an extensive mathematic background nor advanced programing skills are needed to make these subjects accessible to pathologists. However, some familiarity with the basic principles of deep learning, briefly reviewed here, is expected to be useful in understanding both the current limitations of machine learning and determining ways to address them.

Comorbidity is common with posttraumatic stress disorder, and alcohol use disorder (AUD) is among the most common co-occurring disorders. When viewed through the lens of avoidance behaviors, AUD can shape an individual's response to distressing trauma reminders by dulling the emotional response and promoting disengagement from the traumatic memory. Over time, this response strengthens posttraumatic distress by reinforcing the belief that traumatic memories and their emotional responses are themselves dangerous and intolerable. In turn, this belief may impede treatment progress. Concurrent trauma-focused therapy and AUD treatment can serve to establish more adaptive coping strategies. Reducing reliance on alcohol for coping while engaging safely and effectively with trauma memories allows the individual to process the memories, build tolerance to emotional distress, and ultimately reframe maladaptive trauma-related beliefs and decrease the intensity of reactions. This case presents concurrent psychopharmacology and cognitive processing therapy for co-occurring posttraumatic stress disorder and AUD. We explore how alcohol use, and emotional avoidance more broadly, become targets for change.

Circulating tumor cells (CTCs) captured from the blood of cancer patients may serve as a surrogate source of tumor material that can be obtained via a venipuncture (also known as a liquid biopsy) and used to better understand tumor characteristics. However, the only FDA-cleared CTC assay has been limited to the enumeration of surface marker–defined cells and not further characterization of the CTCs. In this study, we tested the ability of a semi-automated device capable of capturing and harvesting CTCs from peripheral blood based on cell size and deformability, agnostic of cell-surface markers (the Parsortix® PC1 System), to yield CTCs for evaluation by downstream techniques commonly available in clinical laboratories. The data generated from this study were used to support a De Novo request (DEN200062) for the classification of this device, which the FDA recently granted. As part of a multicenter clinical trial, peripheral blood samples from 216 patients with metastatic breast cancer (MBC) and 205 healthy volunteers were subjected to CTC enrichment. A board-certified pathologist enumerated the CTCs from each participant by cytologic evaluation of Wright-Giemsa-stained slides. As proof of principle, cells harvested from a concurrent parallel sample provided by each participant were evaluated using one of three additional evaluation techniques: molecular profiling by qRT-PCR, RNA sequencing, or cytogenetic analysis of HER2 amplification by FISH. The study demonstrated that the Parsortix® PC1 System can effectively capture and harvest CTCs from the peripheral blood of MBC patients and that the harvested cells can be evaluated using orthogonal methodologies such as gene expression and/or Fluorescence In Situ Hybridization (FISH).

The purpose of education and training in dermatology ranges from increasing knowledge and skills to improving confidence or enhancing patient outcomes. Specification of the purpose of the education and training is vital so that evaluation can be aligned to purpose, and thus provide evidence on effectiveness. Further, the quality and quality improvement of education and training can be enhanced by a careful specification of how they are expected to achieve their purpose. Multiple theories and methods can be used to evaluate both the process and the outcome of education and training. In this paper, we summarize some of these and focus particularly on the use of behavioural science to evaluate education and training. We illustrate these theories and methods with an example in dermatology.

PURPOSE To quantitatively evaluate through automated simulations the clinical significance of potential high-dose rate (HDR) prostate brachytherapy (HDRPB) physics errors selected from our internal failure-modes and effect analysis (FMEA). METHODS AND MATERIALS A list of failure modes was compiled and scored independently by 8 brachytherapy physicists on a one-to-ten scale for severity (S), occurrence (O), and detectability (D), with risk priority number (RPN) = SxOxD. Variability of RPNs across observers (standard deviation/average) was calculated. Six idealized HDRPB plans were generated, and error simulations were performed: single (N = 1722) and systematic (N = 126) catheter shifts (craniocaudal; -1cm:1 cm); single catheter digitization errors (tip and connector needle-tips displaced independently in random directions; 0.1 cm:0.5 cm; N = 44,318); and swaps (two catheters swapped during digitization or connection; N = 528). The deviations due to each error in prostate D90%, urethra D20%, and rectum D1cm3 were analyzed using two thresholds: 5–20% (possible clinical impact) and >20% (potentially reportable events). RESULTS Twenty-nine relevant failure modes were described. Overall, RPNs ranged from 6 to 108 (average ± 1 standard deviation, 46 ± 23), with responder variability ranging from 19% to 184% (average 75% ± 30%). Potentially reportable events were observed in the simulations for systematic shifts >0.4 cm for prostate and digitization errors >0.3 cm for the urethra and >0.4 cm for rectum. Possible clinical impact was observed for catheter swaps (all organs), systematic shifts >0.2 cm for prostate and >0.4 cm for rectum, and digitization errors >0.2 cm for prostate and >0.1 cm for urethra and rectum. CONCLUSIONS A high variability in RPN scores was observed. Systematic simulations can provide insight in the severity scoring of multiple failure modes, supplementing typical FMEA approaches.

Today’s workforce is dependent on teams. Organizations are interested in positively influencing antecedents to team effectiveness such as team composition. While many factors have been studied thoroughly concerning team composition and effectiveness, team roles have not received comparable attention. Team roles refer to groups of generalizable, goal-directed behaviors that support team performance. Current team role assessments are reliant on surveys and peer ratings. To explore avenues that would enable comparisons between survey-based measures of team roles with benchmarks of observable behavior, we developed a behavior observation tool based on a team role taxonomy known as Team Role Experience and Orientation (TREO). We present the first iteration of this tool based on our review of team role literature, results of an inter-rater reliability assessment, and discuss its potential impact concerning future research and organizational utility. More work is needed to develop a construct-valid behavioral team role assessment.

Shared decision making in mental health is a priority for stakeholders, but faces significant implementation barriers, particularly in settings intended to serve people with serious mental illnesses (SMI). As a result, current levels of shared decision making are low. We highlight these barriers and propose that a novel paradigm, collaborative decision making, will offer conceptual and practical solutions at the systemic and patient/clinician level. Collaborative decision making is tailored for populations like people with SMI and other groups who experience chronic and complex symptoms, along with power imbalances within health systems. Advancing from shared decision making to collaborative decision making clarifies the mission of the model: to facilitate an empowering and recovery-oriented decision-making process that assigns equal power and responsibility to patients and clinicians; to improve alignment of treatment decisions with patient values and priorities; to increase patient trust and confidence in clinicians and the treatment process; and, in the end, to improve treatment engagement, satisfaction, and outcomes. The primary purpose of collaborative decision making is to increase values-aligned care, therefore prioritizing inclusion of patient values, including cultural values and quality of life-related outcomes. Given the broad and constantly changing context of treatment and care for many people with SMI (and also other groups), this model is dynamic and continuously evolving, ready for use across diverse contexts. Implementation of collaborative decision making includes increasing patient knowledge but also patient power, comfort, and confidence. It is one tool to reshape patient-clinician and patient-system relationships and to increase access to value-aligned care for people with SMI and other groups.

Background Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that lacks targeted therapies. Patients with TNBC have a very poor prognosis because the disease often metastasizes. New treatment approaches addressing drivers of metastasis and tumor growth are crucial to improving patient outcomes. Developing targeted gene therapy is thus a high priority for TNBC patients. PEA15 (phosphoprotein enriched in astrocytes, 15 kDa) is known to bind to ERK, preventing ERK from being translocated to the nucleus and hence blocking its activity. The biological function of PEA15 is tightly regulated by its phosphorylation at Ser104 and Ser116. However, the function and impact of phosphorylation status of PEA15 in the regulation of TNBC metastasis and in epithelial-to-mesenchymal transition (EMT) are not well understood. Methods We established stable cell lines overexpressing nonphosphorylatable (PEA15-AA) and phospho-mimetic (PEA15-DD) mutants. To dissect specific cellular mechanisms regulated by PEA15 phosphorylation status, we performed RT-PCR immune and metastasis arrays. In vivo mouse models were used to determine the effects of PEA15 phosphorylation on tumor growth and metastasis. Results We found that the nonphosphorylatable mutant PEA15-AA prevented formation of mammospheres and expression of EMT markers in vitro and decreased tumor growth and lung metastasis in in vivo experiments when compared to control, PEA15-WT and phosphomimetic PEA15-DD. However, phosphomimetic mutant PEA15-DD promoted migration, mesenchymal marker expression, tumorigenesis, and lung metastasis in the mouse model. PEA15-AA-mediated inhibition of breast cancer cell migratory capacity and tumorigenesis was the partial result of decreased expression of interleukin-8 (IL-8). Further, we identified that expression of IL-8 was possibly mediated through one of the ERK downstream molecules, Ets-1. Conclusions Our results show that PEA15 phosphorylation status serves as an important regulator for PEA15’s dual role as an oncogene or tumor suppressor and support the potential of PEA15-AA as a therapeutic strategy for treatment of TNBC.

Laminin-α4 (LAMA4) is an extracellular matrix protein implicated in the regulation of adipocyte differentiation and function. Prior research describes a role for LAMA4 in modulating adipocyte thermogenesis and uncoupling protein-1 (UCP1) expression in white adipose; however, the mechanisms involved are poorly understood. Here, we describe that Lama4 knockout mice (Lama4−/−) exhibit heightened mitochondrial biogenesis and peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1) expression in subcutaneous white adipose tissue (sWAT). Furthermore, the acute silencing of LAMA4 with small interfering RNA in primary murine adipocytes was sufficient to upregulate the expression of thermogenic markers UCP1 and PR domain containing 16 (PRDM16). Silencing also resulted in an upregulation of PGC1-α and adenosine 5′-monophosphate–activated protein kinase (AMPK)-α expression. Subsequently, we show that integrin-linked kinase (ILK) is downregulated in the sWAT of Lama4−/− mice, and its silencing in adipocytes similarly resulted in elevated expression of UCP1 and AMPKα. Last, we demonstrate that treatment of human induced pluripotent stem cell–derived thermogenic adipocytes with LAMA4 (LN411) inhibited the expression of thermogenic markers and AMPKα. Overall, our results indicate that LAMA4 negatively regulates a thermogenic phenotype and pathways involving mitochondrial biogenesis in adipocytes through the suppression of AMPKα.

Objective:Job loss is common in multiple sclerosis (MS) and frequently associated with depression, fatigue, and cognitive dysfunction. Identifying these modifiable risk factors and providing “at-risk” women with a neuropsychologically-based intervention may improve employment outcomes. Our study seeks to investigate the utility of a neuropsychologically-based intervention with varying levels of treatment and follow-up, and evaluate treatment and employment outcomes among groups.Method:In this longitudinal, quasi-randomized controlled trial, employed women with MS meeting criteria on screening measures were considered “at-risk” for job instability and randomized to one of two neuropsychological testing interventions (standard-care group received testing and phone feedback of results and recommendations; experimental group received testing and in-person feedback with subsequent care-coordinator calls from a nurse to help coordinate recommendation completion). Participants who did not meet criteria were considered “low-risk” and only followed over time.Results:56 women in the treatment groups (standard-care = 23; experimental = 33) and 63 women in the follow-only group were analyzed at 1 year. Rates of decreased employment were similar between standard-care (17.4%) and experimental (21.2%) groups (OR = .782, 95% CI .200–3.057). However, the experimental group completed significantly more treatment recommendations, t(53) = −3.237, p = .002. Rates of decreased employment were also similar between the “low-risk” (17.5%) and “at-risk” groups (19.6%), (OR = .721, 95% CI .285–1.826).Conclusion:Employment outcomes were similar at 1 year between treatment groups receiving differing levels of a neuropsychologically-based intervention, however treatment adherence significantly improved in the experimental group. Treatment groups also had similar employment outcomes as compared to a “low-risk,” no intervention group, suggesting that engaging in either neuropsychological intervention may have impacted job stability.

Brown adipose tissue (BAT) is a key thermogenic organ whose expression of uncoupling protein 1 (UCP1) and ability to maintain body temperature in response to acute cold exposure require histone deacetylase 3 (HDAC3). HDAC3 exists in tight association with nuclear receptor corepressors (NCoRs) NCoR1 and NCoR2 (also known as silencing mediator of retinoid and thyroid receptors [SMRT]), but the functions of NCoR1/2 in BAT have not been established. Here we report that as expected, genetic loss of NCoR1/2 in BAT (NCoR1/2 BAT-dKO) leads to loss of HDAC3 activity. In addition, HDAC3 is no longer bound at its physiological genomic sites in the absence of NCoR1/2, leading to a shared deregulation of BAT lipid metabolism between NCoR1/2 BAT-dKO and HDAC3 BAT-KO mice. Despite these commonalities, loss of NCoR1/2 in BAT does not phenocopy the cold sensitivity observed in HDAC3 BAT-KO, nor does loss of either corepressor alone. Instead, BAT lacking NCoR1/2 is inflamed, particularly with respect to the interleukin-17 axis that increases thermogenic capacity by enhancing innervation. Integration of BAT RNA sequencing and chromatin immunoprecipitation sequencing data revealed that NCoR1/2 directly regulateMmp9, which integrates extracellular matrix remodeling and inflammation. These findings reveal pleiotropic functions of the NCoR/HDAC3 corepressor complex in BAT, such that HDAC3-independent suppression of BAT inflammation counterbalances stimulation of HDAC3 activity in the control of thermogenesis.

The variability of age at first marriage has implications for the destandardization of life course and the deinstitutionalization of marriage institution in recent decades. Previous studies, based on Western societies, suggest a more dispersed variability in recent cohorts. However, despite the rise in women’s education, the universal ideology of formal marriage, the powerful link between formal marriage and childbearing, and collectivism in East Asian societies may constrain variability in marriage timing. Also, women with different levels of education experience different life course sequences and interactions with marriage, leading to heterogeneous changes in the variability. Using the Women’s Marriage, Fertility, and Employment Survey in Taiwan, this article presents a representative case of changing marriage and childbearing behaviors in East Asia. Our results show that the variability among women without a high school degree has become more dispersed in more recent birth cohorts. In contrast, variability of age at first marriage among highly educated women has remained consistent. The educational differences became more salient in recent cohorts, especially in women born after 1960. Our findings contribute to the literature on how the life course and the institution of marriage have diverged across education levels over birth cohorts in East Asia.

Earlier work has shown that siRNA-mediated reduction of the SUPT4H or SUPT5H proteins, which interact to form the DSIF complex and facilitate transcript elongation by RNA polymerase II (RNAPII), can decrease expression of mutant gene alleles containing nucleotide repeat expansions differentially. Using luminescence and fluorescence assays, we identified chemical compounds that interfere with the SUPT4H-SUPT5H interaction and then investigated their effects on synthesis of mRNA and protein encoded by mutant alleles containing repeat expansions in the huntingtin gene ( HTT ), which causes the inherited neurodegenerative disorder, Huntington’s Disease (HD). Here we report that such chemical interference can differentially affect expression of HTT mutant alleles, and that a prototypical chemical, 6-azauridine (6-AZA), that targets the SUPT4H-SUPT5H interaction can modify the biological response to mutant HTT gene expression. Selective and dose-dependent effects of 6-AZA on expression of HTT alleles containing nucleotide repeat expansions were seen in multiple types of cells cultured in vitro, and in a Drosophila melanogaster animal model for HD. Lowering of mutant HD protein and mitigation of the Drosophila “rough eye” phenotype associated with degeneration of photoreceptor neurons in vivo were observed. Our findings indicate that chemical interference with DSIF complex formation can decrease biochemical and phenotypic effects of nucleotide repeat expansions.

The human skin xenograft model, in which human donor skin is transplanted onto an immunodeficient mouse host, is an important option for translational research in skin immunology. Murine and human skin differ substantially in anatomy and immune cell composition. Therefore, traditional mouse models have limitations for dermatological research and drug discovery. However, successful xenotransplants are technically challenging and require optimal specimen and mouse graft site preparation for graft and host survival. The present protocol provides an optimized technique for transplanting human skin onto mice and discusses necessary considerations for downstream experimental aims. This report describes the appropriate preparation of a human donor skin sample, assembly of a surgical setup, mouse and surgical site preparation, skin transplantation, and post-surgical monitoring. Adherence to these methods allows for maintenance of xenografts for over 6 weeks post-surgery. The techniques outlined below allow maximum grafting efficiency due to the development of engineering controls, sterile technique, and pre- and post-surgical conditioning. Appropriate performance of the xenograft model results in long-lived human skin graft samples for experimental characterization of human skin and preclinical testing of compounds in vivo.

Classic psychiatry patients are rare; real-world patients tend to have overlapping features of multiple disorders. Striving for diagnostic certainty, and treatments aimed at tentative diagnoses, often fail these patients. In such cases, tolerating diagnostic ambiguity and "treating the symptoms" can sometimes be transformative. An important symptom, often undertreated in a diagnosis-based approach, is rumination. We present a case study of a woman who, after 20 years of treatment failure, achieved significant symptom relief when her primary complaint-"labored thinking"-was targeted specifically. However, because no seriously ill person has only 1 symptom, 6 clinicians from different subdisciplines will discuss the patient's other issues, ones that an overfocus on rumination might leave out.

Introduction Timely matching of patients to beneficial targeted therapy is an unmet need in rheumatoid arthritis (RA). A molecular signature response classifier (MSRC) that predicts which patients with RA are unlikely to respond to tumor necrosis factor-α inhibitor (TNFi) therapy would have wide clinical utility. Methods The protein–protein interaction map specific to the rheumatoid arthritis pathophysiology and gene expression data in blood patient samples was used to discover a molecular signature of non-response to TNFi therapy. Inadequate response predictions were validated in blood samples from the CERTAIN cohort and a multicenter blinded prospective observational clinical study (NETWORK-004) among 391 targeted therapy-naïve and 113 TNFi-exposed patient samples. The primary endpoint evaluated the ability of the MSRC to identify patients who inadequately responded to TNFi therapy at 6 months according to ACR50. Additional endpoints evaluated the prediction of inadequate response at 3 and 6 months by ACR70, DAS28-CRP, and CDAI. Results The 23-feature molecular signature considers pathways upstream and downstream of TNFα involvement in RA pathophysiology. Predictive performance was consistent between the CERTAIN cohort and NETWORK-004 study. The NETWORK-004 study met primary and secondary endpoints. A molecular signature of non-response was detected in 45% of targeted therapy-naïve patients. The MSRC had an area under the curve (AUC) of 0.64 and patients were unlikely to adequately respond to TNFi therapy according to ACR50 at 6 months with an odds ratio of 4.1 (95% confidence interval 2.0–8.3, p value 0.0001). Odds ratios (3.4–8.8) were significant (p value, Plain Language Summary A blood-based molecular signature response classifier (MSRC) integrating next-generation RNA sequencing data with clinical features predicts the likelihood that a patient with rheumatoid arthritis will have an inadequate response to TNFi therapy. Treatment selection guided by test results, with likely inadequate responders appropriately redirected to a different therapy, could improve response rates to TNFi therapies, generate healthcare cost savings, and increase rheumatologists’ confidence in prescribing decisions and altered treatment choices. The MSRC described in this study predicts the likelihood of inadequate response to TNFi therapies among targeted therapy-naïve and TNFi-exposed patients in a multicenter, 24-week blinded prospective clinical study: NETWORK-004. Patients with a molecular signature of non-response are less likely to have an adequate response to TNFi therapies than those patients lacking the signature according to ACR50, ACR70, CDAI, and DAS28-CRP with significant odds ratios of 3.4–8.8 for targeted therapy-naïve patients and 3.3–26.6 for TNFi-exposed patients. This MSRC provides a solution to the long-standing need for precision medicine tools to predict drug response in rheumatoid arthritis—a heterogeneous and progressive disease with an abundance of therapeutic options. These data validate the performance of the MSRC in a blinded prospective clinical study of targeted therapy-naïve and TNFi therapy-exposed patients. Supplementary Information The online version contains supplementary material available at 10.1007/s40744-021-00330-y.

We developed an in-situ interprofessional simulation program to study system factors to establish a congenital cardiac arrest activation tree and test it using human factors engineering principles. We used the Systems Engineering Initiative for Patient Safety (SEIPS) 2.0 model to understand the structure, processes, and outcomes related to the congenital cardiac arrest activation tree (CCCAT) and discuss the Promoting Excellence and Reflective Learning in Simulation (PEARLS) for systems integration framework for our systems focused debriefing (SFD).

Limb immobilization causes local vasculature to experience detrimental adaptations. Simple strategies to increase blood flow (heating, fidgeting) successfully prevent acute (≤ 1 day) impairments; however, none have leveraged the hyperemic response over prolonged periods (weeks) mirroring injury rehabilitation. Throughout a 14-day unilateral limb immobilization, we sought to preserve vascular structure and responsiveness by repeatedly activating a reactive hyperemic response via blood flow restriction (BFR) and amplifying this stimulus by combining BFR with electric muscle stimulation (EMS). Young healthy adults (M:F = 14:17, age = 22.4 ± 3.7 years) were randomly assigned to control, BFR, or BFR + EMS groups. BFR and BFR + EMS groups were treated for 30 min twice daily (3 × 10 min ischemia–reperfusion cycles; 15% maximal voluntary contraction EMS), 5 days/week (20 total sessions). Before and after immobilization, artery diameter, flow-mediated dilation (FMD) and blood flow measures were collected in the superficial femoral artery (SFA). Following immobilization, there was less retrograde blood velocity (+ 1.8 ± 3.6 cm s−1, P = 0.01), but not retrograde shear (P = 0.097). All groups displayed reduced baseline and peak SFA diameter following immobilization (− 0.46 ± 0.41 mm and − 0.43 ± 0.39 mm, P

Introduction:As a result of COVID-19, several clinics have adopted telemedicine to safely deliver care. However, the introduction of a new technology into an already complex system creates ...

This article reviews several key aspects of the Theory of Active and Latent Failures, typically referred to as the Swiss cheese model of human error and accident causation. Although the Swiss cheese model has become well known in most safety circles, there are several aspects of its underlying theory that are often misunderstood. Some authors have dismissed the Swiss cheese model as an oversimplification of how accidents occur, whereas others have attempted to modify the model to make it better equipped to deal with the complexity of human error in health care. This narrative review aims to provide readers with a better understanding and greater appreciation of the Theory of Active and Latent Failures upon which the Swiss cheese model is based. The goal is to help patient safety professionals fully leverage the model and its associated tools when performing a root cause analysis as well as other patient safety activities.

Objective An escape room was used to study teamwork and its determinants, which have been found to relate to the quality and safety of patient care delivery. This pilot study aimed to explore the value of an escape room as a mechanism for improving cohesion among interdisciplinary healthcare teams. Methods This research was conducted at a nonprofit medical center in Southern California. All participants who work on a team were invited to participate. Authors employed an interrupted within-subjects design, with two pre- and post-escape room questionnaires related to two facets of group cohesion: (belonging – (PGC-B) and morale (PGC-M)). Participants rated their perceptions of group cohesion before, after, and one-month after the escape room. The main outcome measures included PGC-B/M. Results Sixty-two teams participated (n = 280 participants) of which 31 teams (50%) successfully “escaped” in the allotted 45 minutes. There was a statistically significant difference in PGC between the three time periods, F(4, 254) = 24.10, p 2 = .275. Results indicated significantly higher scores for PGC immediately after the escape room and at the one-month follow-up compared to baseline. Conclusions This work offers insights into the utility of using an escape room as a team building intervention in interprofessional healthcare teams. Considering the modifiability of escape rooms, they may function as valuable team building mechanisms in healthcare. More work is needed to determine how escape rooms compare to more traditional team building curriculums.

OBJECTIVES To use a human factors approach to conduct a needs assessment of patient preparedness, education, device usability, and satisfaction regarding all stages of sacral neuromodulation therapy and identify opportunities for improvement. Sacral neuromodulation, though minimally invasive, involves an initial testing phase that requires active patient participation. This process is relatively complex and, if a patient does not receive adequate preprocedure education, can be difficult to conceptualize. MATERIALS AND METHODS Candidates were recruited to participate before undergoing staged sacral neuromodulation. Ten patients were observed, and their experiences were evaluated at 4 phases: (1) date of test implant (Stage I), (2) 5 days following Stage I, (3) date of permanent implant (Stage II), and (4) 3 months following Stage II. Administered questionnaires focused on preoperative preparedness, postoperative satisfaction, and usability. RESULTS While every patient reported that their symptoms were at least “a little better” postoperatively, they generally had difficulty understanding the risks of the planned procedure, did not know what to expect postoperatively and were unsatisfied with the preoperative materials. Patients struggled with adjusting the settings for their implant devices and usability was considered “below average.” Despite overall objective success, 30% of patients indicated that they would not recommend this treatment to friends/family. CONCLUSION This pilot needs analysis demonstrates several opportunities for improvement in the experience of patients undergoing sacral neuromodulation. These findings highlight the opportunities for a multifaceted intervention to improve patient understanding through the testing phase.

ImportancePatients with recurrent or unresectable skin cancers have limited treatment options. Diffusing alpha-emitter radiation therapy (DaRT), a novel solid tumor management strategy using alpha-particle interstitial brachytherapy, may address this challenge.ObjectiveTo evaluate the feasibility and safety of using DaRT to manage recurrent or unresectable skin cancers.Design, Setting, and ParticipantsThis prospective cohort study of patients who received a 2-week to 3-week treatment course and were followed up for 24 weeks after treatment during 2021 and 2022 at 2 sites in the US. Patients with malignant skin tumors or soft tissue tumors were recruited if they had limited treatment options for tumors recurrent after prior surgery or external beam radiotherapy or unresectable tumors.InterventionPatients underwent DaRT to deliver a physical dose of 10 Gy (equivalent weighted dose of 200 CGE) to the tumor.Main Outcomes and MeasuresFeasibility of the DaRT procedure was evaluated based on the ability of investigators to successfully deliver radiation to the tumor. Patients were followed up for adverse events (AEs) for 24 weeks and for tumor response by physicians’ physical examination and imaging 12 weeks after device removal.ResultsThis study included 10 participants with recurrent or unresectable skin cancer (median [IQR] age, 72 [68-75] years; 6 males [60%]; 4 females [40%]). Six patients (60%) had recurrent disease, and 4 (40%) had tumors that were deemed unresectable. Tumors were located on the nose, chin, eyelid, scalp, neck, trunk, and extremities. Median (range) tumor volume before treatment was 2.1 cm3 (0.65-12.65 cm3). The mean (SD) prescription dose coverage of the gross tumor volume was 91% (2.8%) with all tumors having coverage of 85% or more. No device-related grade 3 AEs were noted. Common AEs were grade 1 to 2 erythema, edema, and pruritus. At 12 weeks following treatment, there was a 100% complete response rate. Nine of 10 complete responses (90%) were confirmed by CT imaging.Conclusions and RelevanceThis cohort study suggests the feasibility and preliminary safety of DaRT in the management of recurrent or unresectable skin cancers. The favorable safety profile and high response rates are promising. A US trial for marketing approval based on this pilot study is under way.Trial RegistrationClinicalTrials.gov Identifier: NCT04377360

Obesity and the metabolic disease epidemic has led to an increase in morbidity and mortality. A rise in adipose thermogenic capacity via activation of brown or beige fat is a potential treatment for metabolic diseases. However, an understanding of how local factors control adipocyte fate is limited. Mice with a null mutation in the laminin α4 (LAMA4) gene (KO) exhibit resistance to obesity and enhanced expression of thermogenic fat markers in white adipose tissue (WAT). In this study, changes in WAT extracellular matrix composition in the absence of LAMA4 were evaluated using liquid chromatography/tandem mass spectrometry. KO-mice showed lower levels of collagen 1A1 and 3A1, and integrins α7 (ITA7) and β1 (ITB1). ITA7-ITB1 and collagen 1A1-3A1 protein levels were lower in brown adipose tissue compared to WAT in wild-type mice. Immunohistochemical staining confirmed lower levels and different spatial distribution of ITA7 in KO-WAT. In culture studies, ITA7 and LAMA4 levels decreased following a 12-day differentiation of adipose-derived stem cells into beige fat, and knock-down of ITA7 during differentiation increased beiging. These results demonstrate that extracellular matrix interactions regulate adipocyte thermogenic capacity and that ITA7 plays a role in beige adipose formation. A better understanding of the mechanisms underlying these interactions can be used to improve systemic energy metabolism and glucose homeostasis.

BACKGROUND: The introduction of new technology into the operating room (OR) can be beneficial for patients, but can also create new problems and complexities for physicians and staff. The observation of flow disruptions (FDs)—small deviations from the optimal course of care—can be used to understand how systems problems manifest. Prior studies showed that the docking process in robotic assisted surgery (RAS), which requires careful management of process, people, technology and working environment, might be a particularly challenging part of the operation. We sought to explore variation across multiple clinical sites and procedures; and to examine the sources of those disruptions. METHODS: Trained observers recorded FDs during 45 procedures across multiple specialties at three different hospitals. The rate of FDs was compared across surgical phases, sites, and types of procedure. A work-system flow of the RAS docking procedure was used to determine which steps were most disrupted. RESULTS: The docking process was significantly more disrupted than other procedural phases, with no effect of hospital site, and a potential interaction with procedure type. Particular challenges were encountered in room organization, retrieval of supplies, positioning the patient, and maneuvering the robot. CONCLUSIONS: Direct observation of surgical procedures can help to identify approaches to improve the design of technology and procedures, the training of staff, and configuration of the OR environment, with the eventual goal of improving safety, efficiency and teamwork in high technology surgery.

The General Medical Council (GMC) plans to introduce a national Medical Licensing Assessment (MLA) in 2024 for all UK medical students as part of their primary medical qualification, with dermatology specified in its assessment blueprint. We present an Update to the British Association of Dermatologists' Undergraduate Curriculum, aligned both to the MLA Content Map and the GMC Outcomes for Graduates 2018.

An accurate in vitro model of human adipose tissue could assist in the study of adipocyte function and allow for better tools for screening new therapeutic compounds. Cell culture models on two-dimensional surfaces fall short of mimicking the three-dimensional in vivo adipose environment, while three-dimensional culture models are often unable to support long-term cell culture due, in part, to insufficient mass transport. Microfluidic systems have been explored for adipose tissue models. However, current systems have primarily focused on 2D cultured adipocytes. In this work, a 3D human adipose microtissue was engineered within a microfluidic system. Human adipose-derived stem cells (ADSCs) were used as the cell source for generating differentiated adipocytes. The ADSCs differentiated within the microfluidic system formed a dense lipid-loaded mass with the expression of adipose tissue genetic markers. Engineered adipose tissue showed a decreased adiponectin secretion and increased free fatty acid secretion with increasing shear stress. Adipogenesis markers were downregulated with increasing shear stress. Overall, this microfluidic system enables the on-chip differentiation and development of a functional 3D human adipose microtissue supported by the interstitial flow. This system could potentially serve as a platform for in vitro drug testing for adipose tissue-related diseases.

Introduction/Objective The genetic etiology of autism spectrum disorders is only partially understood. Here we describe a 16-year-old male diagnosed with autism at two years of age. He has dysmorphic features, severe cognitive disability, and history of cryptorchidism. A review of systems was significant for slightly coarse features overall, with deep-set eyes, pinched nasal bridge with wide nasal tip, and widely spaced teeth. A large pectus excavatum deformity was also noted. Although the parent’s genetic testing concluded that this likely represents de novo mutation, it is worth mentioning that our patient has a 13-year-old female maternal first cousin with learning difficulties that were said to be less severe. There is no other family history of autism. Methods/Case Report Chromosome analysis showed an abnormal karyotype identifying a duplication of the short arm of chromosome 3 from p13 to p14.3, 46,XY,dup(3)(p13p14.3). Additional microarray testing confirmed this duplication and defined the size as 14.9 Mb. Regions of homozygosity of 29.8 Mb were also identified, representing about 1% of the autosomal genome. The duplicated area includes over 70 genes, thirteen of which are known Mendelian disease genes (IL17RD, HESX1, APPL1, FLNB, DNASEIL3, PDHB, ACOX2, ATXN7, SLC25A26, EOGT, LMOD3, MITF, and FOXP1). Duplications of 3p are extremely rare and can be de novo or inherited from a parent with a balanced translocation. Individuals with these better-described chromosome 3p duplications typically present with intellectual and developmental disabilities, such as autism, as 3p duplications typically present with intellectual and developmental disabilities, such as autism and distinctive dysmorphic features. This duplication has never been reported as a known syndrome and has minimal overlap with copy number variants (CNVs) among healthy individuals. Results (if a Case Study enter NA) NA Conclusion Autism spectrum disorders are largely characterized by speech, communication, and social impairment of varying degrees. Diagnosis is typically made on clinical grounds, but in 14-35% of cases, a genetic basis for the disorder, typically either due to a single gene disorder or a chromosomal deletion/duplication, may be found. This case report describes a rare finding of a 14.9 Mb interstitial duplication on chromosome 3p.