Incorporating temporal information during feature engineering bolsters emulation of spatio-temporal emergence.

MOTIVATION: Emergent biological dynamics derive from the evolution of lower-level spatial and temporal processes. A long-standing challenge for scientists and engineers is identifying simple low-level rules that give rise to complex higher-level dynamics. High-resolution biological data acquisition enables this identification and has evolved at a rapid pace for both experimental and computational approaches. Simultaneously harnessing the resolution and managing the expense of emerging technologies-e.g. live cell imaging, scRNAseq, agent-based models-requires a deeper understanding of how spatial and temporal axes impact biological systems. Effective emulation is a promising solution to manage the expense of increasingly complex high-resolution computational models. In this research, we focus on the emulation of a tumor microenvironment agent-based model to examine the relationship between spatial and temporal environment features, and emergent tumor properties. RESULTS: Despite significant feature engineering, we find limited predictive capacity of tumor properties from initial system representations. However, incorporating temporal information derived from intermediate simulation states dramatically improves the predictive performance of machine learning models. We train a deep-learning emulator on intermediate simulation states and observe promising enhancements over emulators trained solely on initial conditions. Our results underscore the importance of incorporating temporal information in the evaluation of spatio-temporal emergent behavior. Nevertheless, the emulators exhibit inconsistent performance, suggesting that the underlying model characterizes unique cell populations dynamics that are not easily replaced. AVAILABILITY AND IMPLEMENTATION: All source codes for the agent-based model, emulation, and analyses are publicly available at the corresponding DOIs: 10.5281/zenodo.10622155, 10.5281/zenodo.10611675, 10.5281/zenodo.10621244, respectively.

Model design choices impact biological insight: Unpacking the broad landscape of spatial-temporal model development decisions.

Computational models enable scientists to understand observed dynamics, uncover rules underlying behaviors, predict experimental outcomes, and generate new hypotheses. There are countless modeling approaches that can be used to characterize biological systems, further multiplied when accounting for the variety of model design choices. Many studies focus on the impact of model parameters on model output and performance; fewer studies investigate the impact of model design choices on biological insight. Here we demonstrate why model design choices should be deliberate and intentional in context of the specific research system and question. In this study, we analyze agnostic and broadly applicable modeling choices at three levels-system, cell, and environment-within the same agent-based modeling framework to interrogate their impact on temporal, spatial, and single-cell emergent dynamics. We identify key considerations when making these modeling choices, including the (i) differences between qualitative vs. quantitative results driven by choices in system representation, (ii) impact of cell-to-cell variability choices on cell-level and temporal trends, and (iii) relationship between emergent outcomes and choices of nutrient dynamics in the environment. This generalizable investigation can help guide the choices made when developing biological models that aim to characterize spatial-temporal dynamics.

Electrochemical Doping of Two-Dimensional Superatomic Materials.

We report an electrochemical method for doping two-dimensional (2D) superatomic semiconductor Re6Se8Cl2 that significantly improves the material's electrical transport while retaining the in-plane and stacking structures. The electrochemical reduction induces the complete dissociation of chloride anions from the surface of each superatomic nanosheet. After the material is dehalogenated, we observe the electrical conductivity (σ) increases by two orders of magnitude while the 3D electron carrier density (n3D) increases by three orders of magnitude. In addition, the thermal activation energy (Ea) and electron mobility (µe) decrease. We conclude that we have achieved effective electron-doping in 2D superatomic Re6Se8Cl2, which significantly improves the electrical transport properties. Our work sets the foundation for electrochemically doping and tuning the transport properties of other 2D superatomic materials.

Use of Impedance Planimetry in the Diagnosis of Gastric Sleeve Stenosis: The Establishment of New Benchmark Values.

INTRODUCTION: Gastric sleeve stenosis (GSS) is an increasingly common adverse event following sleeve gastrectomy for which objective diagnostic criteria are lacking. Impedance planimetry measurements show promise in characterizing GSS, though normal and abnormal benchmark values have never been established. METHODS: This was a retrospective analysis of upper endoscopies performed with impedance planimetry for suspected GSS. A bariatric endoscopist, blind to impedance planimetry measurements, assessed gastric sleeve anatomy and graded GSS severity. Impedance planimetry of diameter and distensibility index (DI) were obtained using 3 different balloon volumes (30, 40, and 50 mL). RESULTS: A total of 110 upper endoscopies were included. Distribution of GSS was graded as none, mild, moderate, and severe in 19 (17%), 27 (25%), 34 (31%), and 30 (27%) procedures, respectively. In normal gastric sleeve anatomy, mean (±SD) diameter and DI measurements using consecutive balloon volumes ranged from 19.1 (±5.5) to 23.2 (±1.7) and 16.8 (±4.9) to 23.1 (±10.9), respectively. In severe GSS, mean diameter and DI measurements ranged from 10.3 (±3.0) to 16.6 (±2.1) and 7.5 (±2.4) to 7.7 (±2.4), respectively. When stratified by severity, impedance planimetry measurements of diameter and DI were significantly lower with each subsequent increase in GSS grade regardless of balloon fill volumes ( P ≤ 0.001). DISCUSSION: Impedance planimetry measurements provide objective assessment in the diagnosis of GSS and correlate with luminal narrowing. A diameter ≥20 mm and a DI ≥15 mm 2 /mm Hg, as measured by impedance planimetry, are predictive of normal gastric sleeve anatomy. This study provides new benchmark values for the diagnosis and severity of GSS.

Ultrasound for acute pyelonephritis: a systematic review and meta-analysis.

BACKGROUND: There is little consensus regarding the indications and utility of urinary tract imaging and type of imaging to perform in patients presenting with acute pyelonephritis (APN). AIMS: The aims of this systematic review were to, among patients with APN, (i) identify the proportion of patients investigated with ultrasound (US), (ii) identify the proportion of abnormal US and (iii) identify the proportion of patients with a change in management resulting from abnormal US. METHODS: A comprehensive search covered two electronic databases (Medline and EMBASE), with selection of studies performed independently by two investigators. Inclusion criteria were English language APN diagnosis and quantification of patients assessed with US or abnormal US results. Quality appraisal used the Newcastle-Ottawa instrument. RESULTS: There were 35 studies included. The proportion of patients assessed with US was reported in 16 manuscripts and ranged from 20% to 94%, with significant heterogeneity and publication bias. The proportion of abnormal US was reported in 31 manuscripts and ranged from 7% to 79%. The proportion of abnormal US leading to change in management was reported in five studies and ranged from 7% to 59%. There was marked heterogeneity among studies included in all three subgroups. CONCLUSIONS: Patients with APN are commonly investigated with US, but only a small proportion have abnormalities and appear to be associated with changes in clinical management. The use of routine US for APN is therefore questioned. The identification of clinical variables for appropriate selection of patients to investigate with US requires further research.

Coupling between magnetic order and charge transport in a two-dimensional magnetic semiconductor.

Semiconductors, featuring tunable electrical transport, and magnets, featuring tunable spin configurations, form the basis of many information technologies. A long-standing challenge has been to realize materials that integrate and connect these two distinct properties. Two-dimensional (2D) materials offer a platform to realize this concept, but known 2D magnetic semiconductors are electrically insulating in their magnetic phase. Here we demonstrate tunable electron transport within the magnetic phase of the 2D semiconductor CrSBr and reveal strong coupling between its magnetic order and charge transport. This provides an opportunity to characterize the layer-dependent magnetic order of CrSBr down to the monolayer via magnetotransport. Exploiting the sensitivity of magnetoresistance to magnetic order, we uncover a second regime characterized by coupling between charge carriers and magnetic defects. The magnetoresistance within this regime can be dynamically and reversibly tuned by varying the carrier concentration using an electrostatic gate, providing a mechanism for controlling charge transport in 2D magnets.

The 2022 top 10 list of endoscopy topics in medical publishing: an annual review by the American Society for Gastrointestinal Endoscopy Editorial Board.

Using a systematic literature search of original articles published during 2022 in Gastrointestinal Endoscopy and other high-impact medical and gastroenterology journals, the 10-member Editorial Board of the American Society for Gastrointestinal Endoscopy composed a list of the 10 most significant topic areas in GI endoscopy during the study year. Each Editorial Board member was directed to consider 3 criteria in generating candidate lists-significance, novelty, and global impact on clinical practice-and subject matter consensus was facilitated by the Chair through electronic voting. The 10 identified areas collectively represent advances in the following endoscopic spheres: artificial intelligence, endoscopic submucosal dissection, Barrett's esophagus, interventional EUS, endoscopic resection techniques, pancreaticobiliary endoscopy, management of acute pancreatitis, endoscopic environmental sustainability, the NordICC trial, and spiral enteroscopy. Each board member was assigned a consensus topic area around which to summarize relevant important articles, thereby generating this précis of the "top 10" endoscopic advances of 2022.

Endoscopic severity of gastric sleeve stenosis can be quantified using impedance planimetry.

BACKGROUND: Gastric sleeve stenosis (GSS) is an adverse event following sleeve gastrectomy for which objective tools are needed for diagnosis and treatment. Endoscopic treatment with serial pneumatic balloon dilation may relieve symptoms and prevent the need for conversion to Roux-en-Y gastric bypass. Endoluminal functional impedance planimetry (EndoFLIP) is an endoscopic tool that measures luminal diameter and distensibility indices (DI) and could be used to characterize severity of GSS. METHODS: This was a retrospective analysis of a prospective database of patients referred for symptoms suggestive of GSS. Severity was determined at each endoscopy by a bariatric endoscopist blinded to EndoFLIP measurements. Successive pneumatic balloon dilations were performed until symptoms resolved; failure was defined as referral for conversion. EndoFLIP measurements of stenosis diameter and DI were obtained pre- and post-dilation. Primary outcomes were pre- and post-dilation luminal diameter and DI of GSS. Secondary outcomes were endoscopic severity of GSS, patient characteristics, and need for surgical revision. RESULTS: 26 patients were included; 23 (85%) were female. Mean age was 45.3 (± 9.9) years. Mean number of dilations was 2.4 (± 1.3) and 10 (38%) patients were referred for conversion. Mild, moderate, and severe GSS was found in 10 (38%), 6 (23%), and 10 (38%) patients, respectively. Moderate and severe GSS underwent more dilations (2.5 ± 1.0 and 3.2 ± 1.6) than mild GSS (1.8 ± 0.8) and were more likely to be referred for conversion. Both pre- and post-dilation diameters were significantly larger in mild versus moderate or severe GSS. Additionally, pre- and post-dilation DI at 30 ml were significantly higher for mild compared to moderate and severe GSS. DISCUSSION: EndoFLIP measurements correlate well with endoscopic assessment of GSS. While more data are needed to determine ideal balloon size and threshold measurements, our results suggest EndoFLIP may help expedite diagnosis and treatment of GSS.

Impact of parental status on US medical student specialty selection.

Medical training occurs during peak childbearing years for most medical students. Many factors influence specialty selection. The aims of this study were (i) to determine whether being a parent is a major deciding factor when picking a specialty and (ii) whether parents are more drawn to family-friendly specialties than non-parents. The authors performed a multicenter web-based survey study of medical students enrolled in Oregon Health and Science University, Dartmouth's Geisel School of Medicine, and University of Michigan Medical School. The 27-item instrument assessed parenthood status, specialty preference, specialty perceptions, and factors influencing specialty choice. A total of 537 out of 2236 (24.0%) students responded. Among respondents, 59 (10.9%) were current or expecting parents. The majority (359, 66.8%) were female and 24-35 years old (430, 80.1%). Of the students who were parents or expecting, 30 (50.9%) were female, and the majority (55, 93.2%) were partnered. Top specialties preferred by both parents and non-parents were family medicine, emergency medicine, obstetrics and gynecology (OB/GYN), internal medicine, psychiatry, and pediatrics. Specialties rated most family-friendly included family medicine, dermatology, pediatrics, psychiatry, radiology, emergency medicine, and pathology. The specialties rated least family-friendly were surgery, neurosurgery, orthopedic surgery, plastic surgery, and OB/GYN. These rankings were the same between groups. Passion for the field, culture of the specialty, and quality of life were the top three factors students considered when choosing a specialty. Being a parent or future parent ranked more highly for parents than non-parents, but was not in the top three factors for either group. US Medical School parents report that being a parent influenced their medical specialty choice "strongly" or "very strongly." However, being a parent was not weighed as heavily as passion for the field, culture of the specialty, and quality of life. These student-parents are entering perceived "non-family friendly" specialties at similar rates as their peers. US Medical school training and simultaneous parenting is daunting, yet student parents are putting their passion first when making a career choice. They must be supported.

GIE Editorial Board Top 10: advances in GI endoscopy in 2021.

The 9-member Editorial Board of the American Society for Gastrointestinal Endoscopy performed a systematic literature search of original articles published during 2021 in Gastrointestinal Endoscopy and 10 other high-impact medical and gastroenterology journals on endoscopy-related topics. Votes from each editorial board member were tallied to identify a consensus list of the 10 most significant topic areas in GI endoscopy over the calendar year of study, with a focus on 3 criteria: significance, novelty, and global impact on clinical practice. The 10 areas identified collectively represent advances in the following endoscopic topics: colonoscopy optimization, bariatric endoscopy, endoscopic needle sampling and drainage, peroral endoscopic myotomy, endoscopic defect closure, meeting systemic challenges in endoscopic training and practice, endohepatology, FNA versus fine-needle biopsy sampling, endoscopic mucosal and submucosal procedures, and cold snare polypectomy. Each board member contributed a summary of important articles relevant to 1 to 2 of the consensus topic areas, leading to a collective summary that is presented in this document of the "top 10" endoscopic advances of 2021.

Quality of life instruments in atrial fibrillation: a systematic review of measurement properties.

OBJECTIVES: To identify the most frequently used atrial fibrillation-specific quality of life (QoL) instruments across atrial fibrillation (AF) ablation studies and to perform a systematic review of the most frequently used instrument's measurement properties. This study uses quality of life instruments as an overarching term for any patient reported outcome measure that assesses a person's health related well-being, functional status, and disease related symptoms. METHODS: A literature mapping exercise was undergone to identify the most frequently used AF-specific QoL instruments across AF ablation studies published from 2016 to 2021. A systematic review of the most frequently used AF QoL instruments identified from the mapping exercise was performed using the COSMIN guidelines for systematic reviews of patient-reported outcome measurements. A systematic search was conducted in Ovid MEDLINE, Ovid Embase, Ovid PsycINFO, EBSCO CINAHL, and Cochrane CENTRAL. The search used variations of the keywords "atrial fibrillation", "quality of life", and "catheter ablation". RESULTS: Forty-five instruments were identified via the literature mapping exercise. After excluding non-patient reported outcome instruments, non-AF specific instruments, and instruments appearing only once, six instruments were identified: AF Effect on QualiTy-of-Life (AFEQT), AF Severity Scale, Minnesota Living with Heart Failure Instrument, AF Quality of Life Instrument, Arrhythmia Specific instrument in Tachycardia and Arrhythmia (ASTA), and SCL (Arrhythmia Symptom Checklist, Frequency and Severity). A systematic review of these six AF-specific health related QoL instruments was performed. We screened 3221 articles and 17 studies were eligible for inclusion. Using the COSMIN guidelines, ASTA and AFEQT had the best ratings across measurement properties with both instruments having good ratings for instrument development and internal consistency. However, none of the 17 included articles assessed measurement error and cross-cultural validity. CONCLUSIONS: AFEQT and ASTA had the strongest measurement properties but not all measurement properties were assessed. Considering the large number of indeterminate and insufficient ratings, future research should focus on cross-cultural validation, measurement error, responsiveness, and interpretability. This review summarizes the current evidence for AF QoL instruments across AF ablation studies and outlines areas for future research.

Role of α-Catenin and its mechanosensing properties in regulating Hippo/YAP-dependent tissue growth.

α-catenin is a key protein of adherens junctions (AJs) with mechanosensory properties. It also acts as a tumor suppressor that limits tissue growth. Here we analyzed the function of Drosophila α-Catenin (α-Cat) in growth regulation of the wing epithelium. We found that different α-Cat levels led to a differential activation of Hippo/Yorkie or JNK signaling causing tissue overgrowth or degeneration, respectively. α-Cat can modulate Yorkie-dependent tissue growth through recruitment of Ajuba, a negative regulator of Hippo signaling to AJs but also through a mechanism independent of Ajuba recruitment to AJs. Both mechanosensory regions of α-Cat, the M region and the actin-binding domain (ABD), contribute to growth regulation. Whereas M is dispensable for α-Cat function in the wing, individual M domains (M1, M2, M3) have opposing effects on growth regulation. In particular, M1 limits Ajuba recruitment. Loss of M1 causes Ajuba hyper-recruitment to AJs, promoting tissue-tension independent overgrowth. Although M1 binds Vinculin, Vinculin is not responsible for this effect. Moreover, disruption of mechanosensing of the α-Cat ABD affects tissue growth, with enhanced actin interactions stabilizing junctions and leading to tissue overgrowth. Together, our findings indicate that α-Cat acts through multiple mechanisms to control tissue growth, including regulation of AJ stability, mechanosensitive Ajuba recruitment, and dynamic direct F-actin interactions.

Lateral entorhinal cortex supports the development of prefrontal network activity that bridges temporally discontiguous stimuli.

The lateral entorhinal cortex (LEC) is an essential component of the brain circuitry supporting long-term memory by serving as an interface between the hippocampus and neocortex. Dysfunction of the LEC affects sensory coding in the hippocampus, leading to a view that the LEC provides the hippocampus with highly processed sensory information. It remains unclear, however, how the LEC modulates neural processing in the neocortical regions. To address this point, we pharmacologically inactivated the LEC of male rats during a temporal associative learning task and examined its impact on local network activity in one of the LEC's efferent targets, the prelimbic region of the medial prefrontal cortex (mPFC). Rats were exposed to two neutral stimuli, one of which was paired with an aversive eyelid shock over a short temporal delay. The LEC inhibition reduced the expression of anticipatory blinking responses to the reinforced stimuli without increasing responses to nonreinforced stimuli. In control rats, both the reinforced and nonreinforced stimuli evoked a short-lived, wide-band increase in the prelimbic network activity. With learning, the initial increase of gamma-band activity started to extend into the interval between the reinforced neutral stimulus and the eyelid shock. LEC inhibition attenuated the learning-induced sustained activity, without affecting the initial transient activity. These results suggest that the integrity of LEC is necessary for the formation of temporal stimulus associations and its neural correlates in the mPFC. Given the minimal effects on the innate network responses to sensory stimuli, the LEC appears not to be the main source of sensory inputs to the mPFC; rather it may provide a framework that shapes the mPFC network response to behaviorally relevant cues.

Quantification of gastric sleeve stenosis using endoscopic parameters and image analysis.

BACKGROUND AND AIMS: Sleeve gastrectomy has quickly become the most commonly performed bariatric surgery. In light of its increasing popularity, the prevalence of gastric sleeve stenosis (GSS) continues to rise. Management with serial pneumatic dilation is highly successful but underused because of a lack of quantitative diagnostic criteria. We aimed to develop quantifiable endoscopic criteria to characterize GSS based on the (1) ratio of narrowest to widest gastric lumen diameter, (2) endoscope angulation/trajectory required for passage, and (3) presence of bilious fluid pooling in the proximal sleeve and compare it with endoluminal functional lumen imaging probe (EndoFLIP) diameter and distensibility indices (DIs) and endoscopic documentation of gastric lumen morphology. METHODS: We retrospectively reviewed a prospectively maintained database of patients undergoing endoscopy to assess for GSS. Endoscopic images were reviewed in a blinded fashion by 2 bariatric endoscopists. The narrowest and widest part of the gastric lumen diameters were noted on each image, in addition to a hypothetical trajectory required for endoscope passage. Using image processing software, we calculated the the ratio of diameters (ie, narrowest divided by widest) and angle of endoscope trajectory. The presence of bilious fluid pooling in the proximal gastric lumen was noted. These values were then compared with EndoFLIP parameters and endoscopic documentation of gastric lumen morphology. RESULTS: Thirty patients met inclusion criteria, and 26 (87%) were found to have a stenosis on endoscopy. Of those, 9 (35%) were characterized as mild, 11 (42%) as moderate, and 6 (23%) as severe. There was no difference in demographic information between patients with and without stenosis. In patients with stenosis, mean EndoFLIP diameters and DIs were 12.9 ± 3.9 mm and 11.0 ± 6.8 mm2/mm Hg, respectively. In patients without stenosis, mean EndoFLIP diameters and DIs were 19.9 ± 2.9 mm and 21.5 ± 1.0 mm2/mm Hg, respectively. Patients with stenosis had significantly lower diameter ratios compared with those without stenosis (.27 ± .14 vs .48 ± .77, P = .01). Diameter ratios were also inversely related to severity of sleeve stenosis (ß = -.08, P = .01). Patients with stenosis were also more likely to have fluid pooling (96.2% vs 25%, P < .001). There was no significant difference in the trajectory of endoscope passage between the 2 groups. CONCLUSIONS: Endoscopic criteria for diagnosis of GSS are lacking. Our data suggest the ratio between the narrowest and widest gastric lumen diameters and presence of pooled fluid is associated with diagnosis of stenosis by EndoFLIP and gastric lumen morphology. Future studies to validate these criteria are needed.

GIE Editorial Board top 10 topics: advances in GI endoscopy in 2020.

The American Society for Gastrointestinal Endoscopy's Gastrointestinal Endoscopy Editorial Board reviewed a systematic literature search of original endoscopy-related articles published during 2020 in Gastrointestinal Endoscopy and 10 other high-impact medical and gastroenterology journals. Votes from each individual board member were tallied to identify a consensus list of the 10 most significant topic areas in GI endoscopy over the calendar year of study using 4 criteria: significance, novelty, impact on national health, and impact on global health. The 10 areas identified were as follows: artificial intelligence in endoscopy, coronavirus disease 2019 and GI practice, third-space endoscopy, lumen-apposing metal stents, single-use duodenoscopes and other disposable equipment, endosonographic needle technology and techniques, endoscopic closure devices, advances in GI bleeding management, improvements in polypectomy techniques, and bariatric endoscopy. Each board member contributed a summary of important articles relevant to 1 to 2 topic areas, leading to a collective summary that is presented in this document of the "top 10" endoscopic advances of 2020.

Small bowel hemorrhage from check point inhibitor enteritis: a case report.

BACKGROUND: There is rising utilization of immune checkpoint inhibitors (ICI) for a growing number of metastatic malignancies. While gastrointestinal side effects of ICI are common, isolated ICI-induced enteritis leading to small bowel hemorrhage is rare. CASE PRESENTATION: A 71-year-old man with a previously resected right colon adenocarcinoma on atezolizumab and recently treated Clostridioides difficile presented with acute on chronic abdominal pain and non-bloody diarrhea. A CT scan revealed enteritis of the duodenum and jejunum without colitis. Initial endoscopic work-up revealed many clean-based non-bleeding duodenal ulcers to the third portion of the duodenum and normal rectosigmoid mucosa. The patient initially improved on steroids but was readmitted on day after discharge with hematochezia and hemorrhagic shock. Repeat CT showed improvement in enteritis; however, repeat push enteroscopy revealed multiple duodenal and jejunal ulcers, two with visible vessels requiring endoscopic intervention. He continued to have significant hemorrhage requiring transfusions despite IV methylprednisolone. Conventional angiogram revealed multiple sites of active extravasation, and he underwent small bowel resection and subsequent IR embolization due to persistent bleeding. He was then started on infliximab 10 mg/kg with resolution of his small bowel hemorrhage and diarrhea. CONCLUSIONS: Severe isolated ICI-enteritis is rare and can lead to clinically significant gastrointestinal hemorrhage. Patients with severe ICI-enteritis on endoscopy should be carefully monitored for steroid refractory disease for consideration of step-up therapy such as infliximab.

Integrin Binding to the Trimeric Interface of CD40L Plays a Critical Role in CD40/CD40L Signaling.

CD40L plays a major role in immune response and is a major therapeutic target for inflammation. Integrin α5ß1 and CD40 simultaneously bind to CD40L. It is unclear if α5ß1 and CD40 work together in CD40/CD40L signaling or how α5ß1 binds to CD40L. In this article, we describe that the integrin-binding site of human CD40L is predicted to be located in the trimeric interface by docking simulation. Mutations in the predicted integrin-binding site markedly reduced the binding of α5ß1 to CD40L. Several CD40L mutants defective in integrin binding were defective in NF-κB activation and B cell activation and suppressed CD40L signaling induced by wild-type CD40L; however, they still bound to CD40. These findings suggest that integrin α5ß1 binds to monomeric CD40L through the binding site in the trimeric interface of CD40L, and this plays a critical role in CD40/CD40L signaling. Integrin αvß3, a widely distributed vascular integrin, bound to CD40L in a KGD-independent manner, suggesting that αvß3 is a new CD40L receptor. Several missense mutations in CD40L that induce immunodeficiency with hyper-IgM syndrome type 1 (HIGM1) are clustered in the integrin-binding site of the trimeric interface. These HIGM1 CD40L mutants were defective in binding to α5ß1 and αvß3 (but not to CD40), suggesting that the defect in integrin binding may be a causal factor of HIGM1. These findings suggest that α5ß1 and αvß3 bind to the overlapping binding site in the trimeric interface of monomeric CD40L and generate integrin-CD40L-CD40 ternary complex. CD40L mutants defective in integrins have potential as antagonists of CD40/CD40L signaling.

Upper gastrointestinal series after sleeve gastrectomy is unnecessary to evaluate for gastric sleeve stenosis.

BACKGROUND: There has been an increase in sleeve gastrectomy (SG) procedures being performed worldwide, and a paralleled rise in prevalence of gastric sleeve stenosis (GSS). Symptoms include dysphagia, reflux, and obstructive symptoms. Upper gastrointestinal series (UGIS) is commonly performed in the diagnostic algorithm prior to referral for endoscopic dilation; however, little is known about its utility in making a diagnosis. Our aim was to evaluate positive predictive value (PPV) and negative predictive value (NPV) of UGIS in detection of GSS. METHODS: We performed a retrospective analysis of a prospectively collected database at a tertiary center for patients referred with nausea/vomiting or obstructive symptoms following SG between 2017 and 2019. All patients underwent upper endoscopy (EGD) for evaluation of GSS. Serial balloon dilations were performed for GSS with increasing balloon size and/or filling pressure until symptom resolution or referral for surgical revision. Primary outcomes were PPV and NPV for UGIS in predicting GSS. Secondary outcomes included EGD findings and symptom response to dilation. RESULTS: Thirty consecutive patients were included in the analyses. The most common presenting symptoms were nausea (66.7%), vomiting (60.0%) reflux (66.7%), and abdominal pain (54.8%). Twenty-two (73.3%) patients underwent UGIS prior to EGD. On diagnostic EGD, 27 (87.1%) patients were diagnosed with GSS. The sensitivity and NPV of UGIS to detect GSS was 30.0%, and 12.5%, respectively. All 6 patients with GSS on UGIS also had GSS on endoscopic evaluation (specificity = 100%, PPV = 100%). Twenty-six (86.6%) patients had resolution of symptoms with a mean 1.97 ± 1.13 dilations. CONCLUSION: UGIS following SG has low NPV to evaluate for GSS. Independent of the UGIS findings, majority of patients found to have GSS on EGD had symptom improvement with dilations. The utility of UGIS is limited for diagnosing GSS and when suspicion for GSS is high, patients should be referred directly for EGD.

Geospatial indicators of exposure, sensitivity, and adaptive capacity to assess neighbourhood variation in vulnerability to climate change-related health hazards.

BACKGROUND: Although the frequency and magnitude of climate change-related health hazards (CCRHHs) are likely to increase, the population vulnerabilities and corresponding health impacts are dependent on a community's exposures, pre-existing sensitivities, and adaptive capacities in response to a hazard's impact. To evaluate spatial variability in relative vulnerability, we: 1) identified climate change-related risk factors at the dissemination area level; 2) created actionable health vulnerability index scores to map community risks to extreme heat, flooding, wildfire smoke, and ground-level ozone; and 3) spatially evaluated vulnerability patterns and priority areas of action to address inequity. METHODS: A systematic literature review was conducted to identify the determinants of health hazards among populations impacted by CCRHHs. Identified determinants were then grouped into categories of exposure, sensitivity, and adaptive capacity and aligned with available data. Data were aggregated to 4188 Census dissemination areas within two health authorities in British Columbia, Canada. A two-step principal component analysis (PCA) was then used to select and weight variables for each relative vulnerability score. In addition to an overall vulnerability score, exposure, adaptive capacity, and sensitivity sub-scores were computed for each hazard. Scores were then categorised into quintiles and mapped. RESULTS: Two hundred eighty-one epidemiological papers met the study criteria and were used to identify 36 determinant indicators that were operationalized across all hazards. For each hazard, 3 to 5 principal components explaining 72 to 94% of the total variance were retained. Sensitivity was weighted much higher for extreme heat, wildfire smoke and ground-level ozone, and adaptive capacity was highly weighted for flooding vulnerability. There was overall varied contribution of adaptive capacity (16-49%) across all hazards. Distinct spatial patterns were observed - for example, although patterns varied by hazard, vulnerability was generally higher in more deprived and more outlying neighbourhoods of the study region. CONCLUSIONS: The creation of hazard and category-specific vulnerability indices (exposure, adaptive capacity and sensitivity sub-scores) supports evidence-based approaches to prioritize public health responses to climate-related hazards and to reduce inequity by assessing relative differences in vulnerability along with absolute impacts. Future studies can build upon this methodology to further understand the spatial variation in vulnerability and to identify and prioritise actionable areas for adaptation.

A Machine Learning Approach to Passively Informed Prediction of Mental Health Risk in People with Diabetes: Retrospective Case-Control Analysis.

BACKGROUND: Proactive detection of mental health needs among people with diabetes mellitus could facilitate early intervention, improve overall health and quality of life, and reduce individual and societal health and economic burdens. Passive sensing and ecological momentary assessment are relatively newer methods that may be leveraged for such proactive detection. OBJECTIVE: The primary aim of this study was to conceptualize, develop, and evaluate a novel machine learning approach for predicting mental health risk in people with diabetes mellitus. METHODS: A retrospective study was designed to develop and evaluate a machine learning model, utilizing data collected from 142,432 individuals with diabetes enrolled in the Livongo for Diabetes program. First, participants' mental health statuses were verified using prescription and medical and pharmacy claims data. Next, four categories of passive sensing signals were extracted from the participants' behavior in the program, including demographics and glucometer, coaching, and event data. Data sets were then assembled to create participant-period instances, and descriptive analyses were conducted to understand the correlation between mental health status and passive sensing signals. Passive sensing signals were then entered into the model to train and test its performance. The model was evaluated based on seven measures: sensitivity, specificity, precision, area under the curve, F1 score, accuracy, and confusion matrix. SHapley Additive exPlanations (SHAP) values were computed to determine the importance of individual signals. RESULTS: In the training (and validation) and three subsequent test sets, the model achieved a confidence score greater than 0.5 for sensitivity, specificity, area under the curve, and accuracy. Signals identified as important by SHAP values included demographics such as race and gender, participant's emotional state during blood glucose checks, time of day of blood glucose checks, blood glucose values, and interaction with the Livongo mobile app and web platform. CONCLUSIONS: Results of this study demonstrate the utility of a passively informed mental health risk algorithm and invite further exploration to identify additional signals and determine when and where such algorithms should be deployed.