Racial and ethnic differences in self-reported barriers to substance use treatment among emergency department patients.

BACKGROUND AND OBJECTIVES: As overdose rates rise among non-White Americans, understanding barriers to substance use disorder (SUD) treatment access by race and ethnicity is important. This study explores self-reported barriers to SUD treatment by race and ethnicity in emergency department (ED) populations. METHODS: We conducted a secondary, exploratory analysis of a randomized trial of patients not seeking SUD treatment who endorsed active drug use at six academic EDs. Responses to the Barriers to Treatment Inventory were compared by race, ethnicity, and drug severity, using χ2 tests (N = 858), followed by adjusted logistic regression models. RESULTS: Absence of a perceived drug problem (39% non-Hispanic Black, 38% Hispanic, 50% non-Hispanic White; p ≤ .001) was the most prevalent barrier to SUD treatment. Non-Hispanic Black participants were less likely to state that they could handle their drug use on their own (OR = 0.69, CI = 0.50-0.95), and were more likely to report disliking personal questions than non-Hispanic White participants (OR = 1.49, CI = 1.07-2.09). Non-Hispanic Black participants were less likely than Hispanic participants to agree that treatment availability (OR = 0.46, CI = 0.28-0.76) and family disapproval (OR = 0.38, CI = 0.16-0.91) were treatment barriers. DISCUSSION AND CONCLUSIONS: Screening and counseling may help address the barrier, common to all groups, that drug use was not seen as problematic. Expanding access to diverse treatment options may also address the range of barriers reported by our study population. SCIENTIFIC SIGNIFICANCE: Our study is one of the first in the U.S. to examine both individual and structural barriers to accessing treatment and to examine the association with drug use severity by race/ethnicity.

Feasibility of Wearable Sensors to Assess Cognitive Load During Clinical Performance: Lessons Learned and Blueprint for Success.

INTRODUCTION: Cognitive load (CogL) is increasingly recognized as an important resource underlying operative performance. Current innovations in surgery aim to develop objective performance metrics via physiological monitoring from wearable digital sensors. Surgeons have access to consumer technology that could measure CogL but need guidance regarding device selection and implementation. To realize the benefits of surgical performance improvement these methods must be feasible, incorporating human factors usability and design principles. This paper aims to evaluate the feasibility of using wearable sensors to assess CogL, identify the benefits and challenges of implementing devices, and develop guidance for surgeons planning to implement wearable devices in their research or practice. METHODS: We examined the feasibility of wearable sensors from a series of empirical studies that measured aspects of clinical performance relating to CogL. Across four studies, 84 participants and five sensors were involved in the following clinical settings: (i) real intraoperative surgery; (ii) simulated laparoscopic surgery; and (iii) medical team performance outside the hospital. RESULTS: Wearable devices worn on the wrist and chest were found to be comfortable. After a learning curve, electrodermal activity data were easily and reliably collected. Devices using photoplethysmography to determine heart rate variability were significantly limited by movement artifact. There was variable success with electroencephalography devices regarding connectivity, comfort, and usability. CONCLUSIONS: It is feasible to use wearable sensors across various clinical settings, including surgery. There are some limitations, and their implementation is context and device dependent. To scale sensor use in clinical research, surgeons must embrace human factors principles to optimize wearability, usability, reliability, and data security.

Using viral diversity to identify HIV-1 variants under HLA-dependent selection in a systematic viral genome-wide screen.

The pathogenesis of HIV-1 infection is governed by a highly dynamic, time-dependent interaction between the host and the viral genome. In this study, we developed a novel systematic approach to assess the host-virus interaction, using average pairwise viral diversity as a proxy for time since infection, and applied this method to nearly whole viral genome sequences (n = 4,464), human leukocyte antigen (HLA) genotyping data (n = 1,044), and viral RNA load (VL) measurements during the untreated chronic phase (n = 829) of Swiss HIV Cohort Study participants. Our systematic genome-wide screen revealed for 98 HLA/viral-variant pairs a signature of immune-driven selection in the form of an HLA-dependent effect of infection time on the presence of HIV amino acid variants. Of these pairs, 12 were found to have an effect on VL. Furthermore, 28/58 pairs were validated by time-to-event analyses and 48/92 by computational HLA-epitope predictions. Our diversity-based approach allows a powerful and systematic investigation of the interaction between the virus and cellular immunity, revealing a notable subset of such interaction effects. From an evolutionary perspective, these observations underscore the complexity of HLA-mediated selection pressures on the virus that shape viral evolution and pathogenesis.

Loss of RREB1 reduces adipogenesis and improves insulin sensitivity in mouse and human adipocytes.

There are multiple independent genetic signals at the Ras-responsive element binding protein 1 ( RREB1 ) locus associated with type 2 diabetes risk, fasting glucose, ectopic fat, height, and bone mineral density. We have previously shown that loss of RREB1 in pancreatic beta cells reduces insulin content and impairs islet cell development and function. However, RREB1 is a widely expressed transcription factor and the metabolic impact of RREB1 loss in vivo remains unknown. Here, we show that male and female global heterozygous knockout ( Rreb1 +/- ) mice have reduced body length, weight, and fat mass on high-fat diet. Rreb1 +/- mice have sex- and diet-specific decreases in adipose tissue and adipocyte size; male mice on high-fat diet had larger gonadal adipocytes, while males on standard chow and females on high-fat diet had smaller, more insulin sensitive subcutaneous adipocytes. Mouse and human precursor cells lacking RREB1 have decreased adipogenic gene expression and activated transcription of genes associated with osteoblast differentiation, which was associated with Rreb1 +/- mice having increased bone mineral density in vivo . Finally, human carriers of RREB1 T2D protective alleles have smaller adipocytes, consistent with RREB1 loss-of-function reducing diabetes risk.

A causal machine-learning framework for studying policy impact on air pollution: A case-study in COVID-19 lockdowns.

When studying the impact of policy interventions or natural experiments on air pollution, such as new environmental policies and opening or closing an industrial facility, careful statistical analysis is needed to separate causal changes from other confounding factors. Using COVID-19 lockdowns as a case-study, we present a comprehensive framework for estimating and validating causal changes from such perturbations. We propose using flexible machine learning-based comparative interrupted time series (CITS) models for estimating such a causal effect. We outline the assumptions required to identify causal effects, showing that many common methods rely on strong assumptions that are relaxed by machine learning models. For empirical validation, we also propose a simple diagnostic criterion, guarding against false effects in baseline years when there was no intervention. The framework is applied to study the impact of COVID-19 lockdowns on NO2 in the eastern US. The machine learning approaches guard against false effects better than common methods and suggest decreases in NO2 in Boston, New York City, Baltimore, and Washington D.C. The study showcases the importance of our validation framework in selecting a suitable method and the utility of a machine learning based CITS model for studying causal changes in air pollution time series.

Yersinia pestis and pneumonic plague: Insight into how a lethal pathogen interfaces with innate immune populations in the lung to cause severe disease.

Yersinia pestis is the causative agent of bubonic, septicemic and pneumonic plague. The historical importance and potential of plague to re-emerge as a threat worldwide are indisputable. The most severe manifestion of plague is pneumonic plague, which results in disease that is 100% lethal without treatment. Y. pestis suppresses host immune responses early in the lung to establish infection. The later stages of infection see the rapid onset of hyperinflammatory responses that prove lethal. The study of Y. pestis host/pathogen interactions have largely been investigated during bubonic plague and with attenuated strains in cell culture models. There remains a somewhat limited understanding of the interactions between virulent Y. pestis and immune populations in the lung that drive severe disease. In this review we give a broad overview of the progression of pneumonic plague and highlighting how Y. pestis interfaces with host innate immune populations in the lung to cause lethal disease.

Polyploidy of MDA-MB-231 cells drives increased extravasation with enhanced cell-matrix adhesion.

Metastasis, the leading cause of cancer-related deaths, involves a complex cascade of events, including extravasation. Despite extensive research into metastasis, the mechanisms underlying extravasation remain unclear. Molecular targeted therapies have advanced cancer treatment, yet their efficacy is limited, prompting exploration into novel therapeutic targets. Here, we showed the association of polyploidy in MDA-MB-231 breast cancer cells and their extravasation, using microfluidic systems to reproduce the in vivo microvascular environment. We observed enhanced extravasation in polyploid cells alongside upregulated expression of genes involved in cell-substrate adhesion and cell mechanical dynamics. These findings offer insights into the relationship between polyploidy and extravasation, highlighting potential targets for cancer therapy.

Self-reported neurocognitive complaints in the Swiss HIV Cohort Study: a viral genome-wide association study.

People with HIV may report neurocognitive complaints, with or without associated neurocognitive impairment, varying between individuals and populations. While the HIV genome could play a major role, large systematic viral genome-wide screens to date are lacking. The Swiss HIV Cohort Study biannually enquires neurocognitive complaints. We quantified broad-sense heritability estimates using partial 'pol' sequences from the Swiss HIV Cohort Study resistance database and performed a viral near full-length genome-wide association study for the longitudinal area under the curve of neurocognitive complaints. We performed all analysis (i) restricted to HIV Subtype B and (ii) including all HIV subtypes. From 8547 people with HIV with neurocognitive complaints, we obtained 6966 partial 'pol' sequences and 2334 near full-length HIV sequences. Broad-sense heritability estimates for presence of memory loss complaints ranged between 1% and 17% (Subtype B restricted 1-22%) and increased with the stringency of the phylogenetic distance thresholds. The genome-wide association study revealed one amino acid (Env L641E), after adjusting for multiple testing, positively associated with memory loss complaints (P = 4.3 * 10-6). Other identified mutations, while insignificant after adjusting for multiple testing, were reported in other smaller studies (Tat T64N, Env *291S). We present the first HIV genome-wide association study analysis of neurocognitive complaints and report a first estimate for the heritability of neurocognitive complaints through HIV. Moreover, we could identify one mutation significantly associated with the presence of memory loss complaints. Our findings indicate that neurocognitive complaints are polygenetic and highlight advantages of a whole genome approach for pathogenicity determination.

Engineering microvascular networks using a KLF2 reporter to probe flow-dependent endothelial cell function.

Shear stress generated by the flow of blood in the vasculature is a potent regulator of endothelial cell function and vascular structure. While vascular responses to flow are complex and context-dependent, endothelial cell signaling in response to shear stress induced by laminar flows is coordinated by the transcription factor KLF2. The flow-dependent expression of KLF2 in endothelial cells is associated with a quiescent, anti-inflammatory phenotype and has been well characterized in two-dimensional systems but has not been studied in three-dimensional in vitro systems. Here we develop engineered microvascular networks (MVNs) that incorporate a KLF2-based endothelial cell flow sensor within a microfluidic chip, apply continuous flow using an attached microfluidic pump, and study the effects of this flow on vascular structure and function. We found that application of flow to MVNs for 48 h resulted in increased expression of the KLF2 reporter, larger vessel diameters, and decreased vascular branching and resistance. Notably, vessel diameters after the application of flow were independent of initial MVN morphologies. Finally, we found that MVNs exposed to flow have improved vascular barrier function and decreased platelet adhesion. MVNs with KLF2-based flow sensors represent a novel, powerful tool for evaluating the structural and functional effects of flow on engineered three-dimensional vascular systems.

How to grow crystals for X-ray crystallography.

Growing high-quality crystals remains a necessary part of crystallography and many other techniques. This article tabulates and describes several techniques and variations that will help individuals grow high-quality crystals in preparation for crystallographic techniques and other endeavors, such as form screening. The discussion is organized to focus on low-tech approaches available in any laboratory.

Personalized Vascularized Models of Breast Cancer Desmoplasia Reveal Biomechanical Determinants of Drug Delivery to the Tumor.

Desmoplasia in breast cancer leads to heterogeneity in physical properties of the tissue, resulting in disparities in drug delivery and treatment efficacy among patients, thus contributing to high disease mortality. Personalized in vitro breast cancer models hold great promise for high-throughput testing of therapeutic strategies to normalize the aberrant microenvironment in a patient-specific manner. Here, tumoroids assembled from breast cancer cell lines (MCF7, SKBR3, and MDA-MB-468) and patient-derived breast tumor cells (TCs) cultured in microphysiological systems including perfusable microvasculature reproduce key aspects of stromal and vascular dysfunction causing impaired drug delivery. Models containing SKBR3 and MDA-MB-468 tumoroids show higher stromal hyaluronic acid (HA) deposition, vascular permeability, interstitial fluid pressure (IFP), and degradation of vascular HA relative to models containing MCF7 tumoroids or models without tumoroids. Interleukin 8 (IL8) secretion is found responsible for vascular dysfunction and loss of vascular HA. Interventions targeting IL8 or stromal HA normalize vascular permeability, perfusion, and IFP, and ultimately enhance drug delivery and TC death in response to perfusion with trastuzumab and cetuximab. Similar responses are observed in patient-derived models. These microphysiological systems can thus be personalized by using patient-derived cells and can be applied to discover new molecular therapies for the normalization of the tumor microenvironment.

Loss of tolerance precedes triggering and lifelong persistence of pathogenic type I interferon autoantibodies.

Autoantibodies neutralizing type I interferons (IFN-Is) can underlie infection severity. Here, we trace the development of these autoantibodies at high-resolution using longitudinal samples from 1,876 well-treated individuals living with HIV over a 35-year period. Similar to general populations, ∼1.9% of individuals acquired anti-IFN-I autoantibodies as they aged (median onset ∼63 years). Once detected, anti-IFN-I autoantibodies persisted lifelong, and titers increased over decades. Individuals developed distinct neutralizing and non-neutralizing autoantibody repertoires at discrete times that selectively targeted combinations of IFNα, IFNß, and IFNω. Emergence of neutralizing anti-IFNα autoantibodies correlated with reduced baseline IFN-stimulated gene levels and was associated with subsequent susceptibility to severe COVID-19 several years later. Retrospective measurements revealed enrichment of pre-existing autoreactivity against other autoantigens in individuals who later developed anti-IFN-I autoantibodies, and there was evidence for prior viral infections or increased IFN at the time of anti-IFN-I autoantibody triggering. These analyses suggest that age-related loss of self-tolerance prior to IFN-I immune-triggering poses a risk of developing lifelong functional IFN-I deficiency.

Toward AI-driven neuroepigenetic imaging biomarker for alcohol use disorder: A proof-of-concept study.

Alcohol use disorder (AUD) is a disorder of clinical and public health significance requiring novel and improved therapeutic solutions. Both environmental and genetic factors play a significant role in its pathophysiology. However, the underlying epigenetic molecular mechanisms that link the gene-environment interaction in AUD remain largely unknown. In this proof-of-concept study, we showed, for the first time, the neuroepigenetic biomarker capability of non-invasive imaging of class I histone deacetylase (HDAC) epigenetic enzymes in the in vivo brain for classifying AUD patients from healthy controls using a machine learning approach in the context of precision diagnosis. Eleven AUD patients and 16 age- and sex-matched healthy controls completed a simultaneous positron emission tomography-magnetic resonance (PET/MR) scan with the HDAC-binding radiotracer [11C]Martinostat. Our results showed lower HDAC expression in the anterior cingulate region in AUD. Furthermore, by applying a genetic algorithm feature selection, we identified five particular brain regions whose combined [11C]Martinostat relative standard uptake value (SUVR) features could reliably classify AUD vs. controls. We validate their promising classification reliability using a support vector machine classifier. These findings inform the potential of in vivo HDAC imaging biomarkers coupled with machine learning tools in the objective diagnosis and molecular translation of AUD that could complement the current diagnostic and statistical manual of mental disorders (DSM)-based intervention to propel precision medicine forward.

A Novel, Multi-Modal, Intraoperative Cognitive Workload Assessment of Cardiac Surgery Team Members.

OBJECTIVE: We characterized cognitive workload (CWL) of cardiac surgery team members in a real-world setting during CABG using providers' heart rate variability (HRV) data as a surrogate measure of CWL. METHODS: HRV was collected from the surgeon, anesthesiologist, perfusionist, and scrub nurse. Audio/video was recorded during isolated, nonemergency CABG surgeries (N=27). Eight surgical phases were annotated by trained researchers and HRV was calculated for each phase. RESULTS: Significant differences in CWL were observed within a given role across surgical phases. Results are reported as (predicted probability (95% CI)). CWL was significantly higher for anesthesiologists during "Preparation and Induction" (0.57, (0.42, 0.71)) and "Anastomoses" (0.44, (0.30, 0.58)) compared to other phases, while the same held for nurses during "Opening" (0.51, 95 (0.37, 0.65)) and "Post-operative" (0.68, (0.42, 0.86)) phases. Additional significant differences were observed between roles within a given surgical phase. For example, surgeons had significantly higher CWL during "Anastomoses" (0.81, (0.69, 0.89)) compared to all other roles while the same was true of perfusionists during "Opening" (0.79, (0.66, 0.88)) and "Pre-bypass Preparation" (0.50, (0.36, 0.64)) phases. CONCLUSIONS: Our innovative analysis demonstrates that CWL fluctuates across surgical procedures by role and phase, which may reflect the distribution of primary tasks. This corroborates earlier findings from self-report measures. Data suggest that team-wide, peak CWL during a phase decreases from early phases of surgery through initiating bypass, rises during anastomosis, and decreases when terminating bypass. Knowledge of these trends could contribute to adopting behaviors to enhance team dynamics and performance.

Subthreshold activation of the melanocortin system causes generalized sensitization to anorectic agents in mice.

The melanocortin-3 receptor (MC3R) regulates GABA release from agouti-related protein (AgRP) nerve terminals and thus tonically suppresses multiple circuits involved in feeding behavior and energy homeostasis. Here, we examined the role of the MC3R and the melanocortin system in regulating the response to various anorexigenic agents. The genetic deletion or pharmacological inhibition of the MC3R, or subthreshold doses of an MC4R agonist, improved the dose responsiveness to glucagon-like peptide 1 (GLP1) agonists, as assayed by inhibition of food intake and weight loss. An enhanced anorectic response to the acute satiety factors peptide YY (PYY3-36) and cholecystokinin (CCK) and the long-term adipostatic factor leptin demonstrated that increased sensitivity to anorectic agents was a generalized result of MC3R antagonism. We observed enhanced neuronal activation in multiple hypothalamic nuclei using Fos IHC following low-dose liraglutide in MC3R-KO mice (Mc3r-/-), supporting the hypothesis that the MC3R is a negative regulator of circuits that control multiple aspects of feeding behavior. The enhanced anorectic response in Mc3r-/- mice after administration of GLP1 analogs was also independent of the incretin effects and malaise induced by GLP1 receptor (GLP1R) analogs, suggesting that MC3R antagonists or MC4R agonists may have value in enhancing the dose-response range of obesity therapeutics.

Deep Learning Analysis of Surgical Video Recordings to Assess Nontechnical Skills.

Importance: Assessing nontechnical skills in operating rooms (ORs) is crucial for enhancing surgical performance and patient safety. However, automated and real-time evaluation of these skills remains challenging. Objective: To explore the feasibility of using motion features extracted from surgical video recordings to automatically assess nontechnical skills during cardiac surgical procedures. Design, Setting, and Participants: This cross-sectional study used video recordings of cardiac surgical procedures at a tertiary academic US hospital collected from January 2021 through May 2022. The OpenPose library was used to analyze videos to extract body pose estimations of team members and compute various team motion features. The Non-Technical Skills for Surgeons (NOTSS) assessment tool was employed for rating the OR team's nontechnical skills by 3 expert raters. Main Outcomes and Measures: NOTSS overall score, with motion features extracted from surgical videos as measures. Results: A total of 30 complete cardiac surgery procedures were included: 26 (86.6%) were on-pump coronary artery bypass graft procedures and 4 (13.4%) were aortic valve replacement or repair procedures. All patients were male, and the mean (SD) age was 72 (6.3) years. All surgical teams were composed of 4 key roles (attending surgeon, attending anesthesiologist, primary perfusionist, and scrub nurse) with additional supporting roles. NOTSS scores correlated significantly with trajectory (r = 0.51, P = .005), acceleration (r = 0.48, P = .008), and entropy (r = -0.52, P = .004) of team displacement. Multiple linear regression, adjusted for patient factors, showed average team trajectory (adjusted R2 = 0.335; coefficient, 10.51 [95% CI, 8.81-12.21]; P = .004) and team displacement entropy (adjusted R2 = 0.304; coefficient, -12.64 [95% CI, -20.54 to -4.74]; P = .003) were associated with NOTSS scores. Conclusions and Relevance: This study suggests a significant link between OR team movements and nontechnical skills ratings by NOTSS during cardiac surgical procedures, suggesting automated surgical video analysis could enhance nontechnical skills assessment. Further investigation across different hospitals and specialties is necessary to validate these findings.

The Role of Suprapubic Superficial Fascial System Reconstruction During Repair of Adult-Acquired Buried Penis.

BACKGROUND: Adult-Acquired Buried Penis is a disorder associated with systemic obesity that confers increased risks of malignancy, sexual dysfunction, urinary abnormalities, and psychological distress. Surgical correction improves patient-reported functional and psychological outcomes and often requires collaboration between plastic and urologic surgeons. To improve postoperative cosmetic outcomes and decrease wound complications following adult-acquired buried penis repair, we performed an anatomic and histologic study of the superficial fascial layers providing support to the external male genitalia and describe our approach for fascial reconstruction. METHODS: We characterized the superficial fascial anatomy in three patients undergoing adult-acquired buried penis repair, including two patients with Wisconsin Type II disease and one patient with Wisconsin Type IV disease. Gross specimens were sent from two patients histologic analysis using H&E and elastin-specific stains to characterize the identity of the superficial fibrofatty tissue. RESULTS: In all three patients, the fundiform ligament overlying the suspensory ligament was identified, isolated, and transected for removal with the suprapubic specimen. We found that reapproximation of this ligament following transection at the time of escutcheonectomy provided significant lift to the penis and genitals via improved support of dartos fascia. Histologic analysis of the superficial fibrofatty tissue located beneath the dermis revealed histologic similarities with the superficial fascial system described previously in abdominal and breast tissue. CONCLUSIONS: Reapproximation of the fundiform ligament and superficial fascial tissue following suprapubic/lower abdominal fat pad removal during adult-acquired buried penis may improve postoperative cosmesis by reducing strain on the dermal closure. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://www.springer.com/00266 .