HumanIslets: An integrated platform for human islet data access and analysis.

Comprehensive molecular and cellular phenotyping of human islets can enable deep mechanistic insights for diabetes research. We established the Human Islet Data Analysis and Sharing (HI-DAS) consortium to advance goals in accessibility, usability, and integration of data from human islets isolated from donors with and without diabetes at the Alberta Diabetes Institute (ADI) IsletCore. Here we introduce HumanIslets.com , an open resource for the research community. This platform, which presently includes data on 547 human islet donors, allows users to access linked datasets describing molecular profiles, islet function and donor phenotypes, and to perform various statistical and functional analyses at the donor, islet and single-cell levels. As an example of the analytic capacity of this resource we show a dissociation between cell culture effects on transcript and protein expression, and an approach to correct for exocrine contamination found in hand-picked islets. Finally, we provide an example workflow and visualization that highlights links between type 2 diabetes status, SERCA3b Ca 2+ -ATPase levels at the transcript and protein level, insulin secretion and islet cell phenotypes. HumanIslets.com provides a growing and adaptable set of resources and tools to support the metabolism and diabetes research community.

Revision Rotator Cuff Repair Versus Primary Repair: An Assessment of Longitudinal Outcomes Outcomes in Revision Rotator Cuff Repair.

BACKGROUND: Information about outcomes after revision rotator cuff repair (RCR) is limited. A more thorough investigation of pain, range of motion (ROM), strength, and functional outcomes is needed. Comparing outcomes between primary and revision rotator cuff repair patients can help surgeons guide patient expectations of the revision procedure. The aim of this study was to compare the outcomes of a revision repair group to a control group of primary RCR patients. We expect revision RCR patients to have worse clinical outcomes than primary RCR patients. METHODS: A retrospective review of patients who underwent primary or revision RCR between 2012 to 2020 was performed. The case group included 104 revision patients, and the control group included 414 primary RCR patients. Patient visual analog score (VAS) for pain, ROM, strength, Simple Shoulder Test (SST), American Shoulder and Elbow Surgeons (ASES), and Constant-Murley scores were collected at baseline, 12 months, 24 months, and final follow-up. RESULTS: The average final follow-up was 43.9 months for primary patients and 63.8 months for revision patients. 352 primary patients and 55 revision patients had a final follow-up of 2 or more years. By final follow-up, primary patients had less pain than revision patients (Δ of 2.11, P < .0001), but both groups improved overall. Primary patients had significant improvements in forward flexion, external rotation, internal rotation, and abduction at 2 years that were lost by final follow-up, but revision patients did not experience any long-term improvement in ROM. These differences in ROM between groups were not significant. Supraspinatus strength in the revision group did not improve nor decline by final follow-up. By final follow-up, both primary and revision patients had improved SST and ASES scores from baseline. Primary patient ASES scores were 17.9 points higher (P < .0001) than revision patients by final follow-up, and there was no difference between groups in SST scores at this time. CONCLUSION: Revision RCR significantly improves patient pain, SST score, and ASES score at 4 years. Revision patients should not expect to see the improvements in range of motion that may occur after primary repair.

Non-benzodiazepine Hypnotics and Police-Reported Motor Vehicle Crash Risk among Older Adults: A Sequential Target Trial Emulation.

Non-benzodiazepine hypnotics ( "Z-drugs") are prescribed for insomnia, but might increase risk of motor vehicle crash (MVC) among older adults through prolonged drowsiness and delayed reaction times. We estimated the effect of initiating Z-drug treatment on the 12-week risk of MVC in a sequential target trial emulation. After linking New Jersey driver licensing and police-reported MVC data to Medicare claims, we emulated a new target trial each week (July 1, 2007 - October 7, 2017) in which Medicare fee-for-service beneficiaries were classified as Z-drug-treated or untreated at baseline and followed for an MVC. We used inverse probability of treatment and censoring weighted pooled logistic regression models to estimate risk ratios (RR) and risk differences with 95% bootstrap confidence limits (CLs). There were 257,554 person-trials, of which 103,371 were Z-drug-treated and 154,183 untreated, giving rise to 976 and 1,249 MVCs, respectively. The intention-to-treat RR was 1.06 (95%CLs 0.95, 1.16). For the per-protocol estimand, there were 800 MVCs and 1,241 MVCs among treated and untreated person-trials, respectively, suggesting a reduced MVC risk (RR 0.83 [95%CLs 0.74, 0.92]) with sustained Z-drug treatment. Z-drugs should be prescribed to older patients judiciously but not withheld entirely over concerns about MVC risk.

Hemospray® (hemostatic powder TC-325) as monotherapy for acute gastrointestinal bleeding: a multicenter prospective study.

Background: Hemostatic powders are used as second-line treatment in acute gastrointestinal (GI) bleeding (AGIB). Increasing evidence supports the use of TC-325 as monotherapy in specific scenarios. This prospective, multicenter study evaluated the performance of TC-325 as monotherapy for AGIB. Methods: Eighteen centers across Europe and USA contributed to a registry between 2016 and 2022. Adults with AGIB were eligible, unless TC-325 was part of combined hemostasis. The primary endpoint was immediate hemostasis. Secondary outcomes were rebleeding and mortality. Associations with risk factors were investigated (statistical significance at P≤0.05). Results: One hundred ninety patients were included (age 51-81 years, male: female 2:1), with peptic ulcer (n=48), upper GI malignancy (n=79), post-endoscopic treatment hemorrhage (n=37), and lower GI lesions (n=26). The primary outcome was recorded in 96.3% (95% confidence interval [CI]: 92.6-98.5) with rebleeding in 17.4% (95%CI 11.9-24.1); 9.9% (95%CI 5.8-15.6) died within 7 days, and 21.7% (95%CI 15.6-28.9) within 30 days. Regarding peptic ulcer, immediate hemostasis was achieved in 88% (95%CI 75-95), while 26% (95%CI 13-43) rebled. Higher ASA score was associated with mortality (OR 23.5, 95%CI 1.60-345; P=0.02). Immediate hemostasis was achieved in 100% of cases with malignancy and post-intervention bleeding, with rebleeding in 17% and 3.1%, respectively. Twenty-six patients received TC-325 for lower GI bleeding, and in all but one the primary outcome was achieved. Conclusions: TC-325 monotherapy is safe and effective, especially in malignancy or post-endoscopic intervention bleeding. In patients with peptic ulcer, it could be helpful when the primary treatment is unfeasible, as bridge to definite therapy.

Effects of bench press technique variations on musculoskeletal shoulder loads and potential injury risk.

While shoulder injuries resulting from the bench press exercise are commonly reported, no biomechanical evidence for lowering injury risk is currently available. Therefore, the aim of the present study was to compare musculoskeletal shoulder loads and potential injury risk during several bench press variations. Ten experienced strength athletes performed 21 technical variations of the barbell bench press, including variations in grip width of 1,1.5 and 2 bi-acromial widths (BAW), shoulder abduction angles of 45°, 70° and 90°, and scapula poses including neutral, retracted, and released conditions. Motions and forces were recorded by an opto-electronic measurement system and an instrumented barbell. An OpenSim musculoskeletal shoulder model was employed to estimate joint reaction forces in the glenohumeral and acromioclavicular joints. Time-series of joint reaction forces were compared between techniques by statistical non-parametric mapping. Results showed that narrower grip widths of < 1.5 BAW decreased acromioclavicular compression (p < 0.05), which may decrease the risk for distal clavicular osteolysis. Moreover, scapula retraction, as well as a grip width of < 1.5 BAW (p < 0.05), decreased glenohumeral posterior shear force components and rotator cuff activity and may decrease the risk for glenohumeral instability and rotator cuff injuries. Furthermore, results showed that mediolaterally exerted barbell force components varied considerably between athletes and largely affected shoulder reaction forces. It can be concluded that the grip width, scapula pose and mediolateral exerted barbell forces during the bench press influence musculoskeletal shoulder loads and the potential injury risk. Results of this study can contribute to safer bench press training guidelines.

Early intermediates in bacterial RNA polymerase promoter melting visualized by time-resolved cryo-electron microscopy.

During formation of the transcription-competent open complex (RPo) by bacterial RNA polymerases (RNAPs), transient intermediates pile up before overcoming a rate-limiting step. Structural descriptions of these interconversions in real time are unavailable. To address this gap, here we use time-resolved cryogenic electron microscopy (cryo-EM) to capture four intermediates populated 120 ms or 500 ms after mixing Escherichia coli σ70-RNAP and the λPR promoter. Cryo-EM snapshots revealed that the upstream edge of the transcription bubble unpairs rapidly, followed by stepwise insertion of two conserved nontemplate strand (nt-strand) bases into RNAP pockets. As the nt-strand 'read-out' extends, the RNAP clamp closes, expelling an inhibitory σ70 domain from the active-site cleft. The template strand is fully unpaired by 120 ms but remains dynamic, indicating that yet unknown conformational changes complete RPo formation in subsequent steps. Given that these events likely describe DNA opening at many bacterial promoters, this study provides insights into how DNA sequence regulates steps of RPo formation.

Mechanisms of sensitivity and resistance to CDK4/CDK6 inhibitors in hormone receptor-positive breast cancer treatment.

Cell cycle dysregulation is a hallmark of cancer that promotes eccessive cell division. Cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6) are key molecules in the G1-to-S phase cell cycle transition and are crucial for the onset, survival, and progression of breast cancer (BC). Small-molecule CDK4/CDK6 inhibitors (CDK4/6i) block phosphorylation of tumor suppressor Rb and thus restrain susceptible BC cells in G1 phase. Three CDK4/6i are approved for the first-line treatment of patients with advanced/metastatic hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) BC in combination with endocrine therapy (ET). Though this has improved the clinical outcomes for survival of BC patients, there is no established standard next-line treatment to tackle drug resistance. Recent studies suggest that CDK4/6i can modulate other distinct effects in both BC and breast stromal compartments, which may provide new insights into aspects of their clinical activity. This review describes the biochemistry of the CDK4/6-Rb-E2F pathway in HR+ BC, then discusses how CDK4/6i can trigger other effects in BC/breast stromal compartments, and finally outlines the mechanisms of CDK4/6i resistance that have emerged in recent preclinical studies and clinical cohorts, emphasizing the impact of these findings on novel therapeutic opportunities in BC.

A Comprehensive, Multi-Faceted Strategy to Increase Pediatric Donor Heart Utilization.

BACKGROUND: Many hearts offered for pediatric heart transplantation (HT) are not placed. In 2016, we initiated a quality improvement endeavor to increase heart offer acceptance. This study assessed the effect of these interventions at our center. METHODS: Evaluation of pre-/post-implementation cohorts (1/1/2008-12/31/2016 vs. 1/1/2017- 7/1/2023) comparing donor heart utilization. Six interventions were iterated over time to increase offer acceptance ("extended criteria"): ABO-incompatible transplant, ex vivo perfusion for distanced donors, 3-dimensional total cardiac volume (TCV) assessment, acceptance of Hepatitis-C or SARS-COV-2 infected donors, and institutional culture change favoring consideration of donors previously considered unacceptable (Public Health Service Risk, long CPR duration, etc.). Outcomes studied included annual HT volume, median waitlist duration, sequence number at acceptance, and post-transplant clinical outcomes. RESULTS: From 1/2008-7/2023 annual transplant volume increased from 16/year to 25/year pre-/post-implementation. Three hundred-thirteen/389 (80%) listed patients were transplanted. Waitlist duration shortened post-implementation (P=0.01), as did the percentage of accepted heart offers utilizing at least one extended criterion (P<0.001). Institutional culture change and TCV assessment had the largest impact on donor heart utilization (P=0.04 &P<0.001). There was no difference in post-HT intubation or cardiovascular intensive care unit (CVICU) days (P= 0.05-0.9), though post-transplant hospitalization duration (P<0.001) increased. Post-transplant survival was unaffected by use of extended criteria hearts (P=0.3). CONCLUSIONS: We report increased donor heart offer acceptance resulting from a longitudinal, multi-faceted effort to increase organ offer utilization, with institutional culture change and TCV assessments having the greatest impact. Use of extended criteria hearts was not associated with inferior survival.

Bomb radiocarbon evidence for strong global carbon uptake and turnover in terrestrial vegetation.

Vegetation and soils are taking up approximately 30% of anthropogenic carbon dioxide emissions because of small imbalances in large gross carbon exchanges from productivity and turnover that are poorly constrained. We combined a new budget of radiocarbon produced by nuclear bomb testing in the 1960s with model simulations to evaluate carbon cycling in terrestrial vegetation. We found that most state-of-the-art vegetation models used in the Coupled Model Intercomparison Project underestimated the radiocarbon accumulation in vegetation biomass. Our findings, combined with constraints on vegetation carbon stocks and productivity trends, imply that net primary productivity is likely at least 80 petagrams of carbon per year presently, compared with the 43 to 76 petagrams per year predicted by current models. Storage of anthropogenic carbon in terrestrial vegetation is likely more short-lived and vulnerable than previously predicted.

A multicentre prospective assessment of the utility of robotic assisted total hip arthroplasty with virtual range of motion on intraoperative implant positioning.

BACKGROUND: The growing adoption of robotic-assistance during total hip arthroplasty (THA) has provided novel means through which a patient's anatomy and dynamic spinopelvic relationship can be incorporated into surgical planning. However, the impact of enhanced technologies on intraoperative decision-making and changes to component positioning has not yet been described. METHODS: A multicentre, prospective study included 105 patients (52% women) patients who underwent robotic-assisted THA with the integration of software that incorporates a patient's pelvic tilt (PT) and virtual range-of-motion (VROM) for impingement modeling. The primary outcome of the study was the percentage of patients who underwent changes to the preoperative plan for cup position after incorporating the data from the software. RESULTS: Utilising the intraoperative VROM information, the preoperative plan for cup position was changed from the default (40° inclination and 20° anteversion) in 82/105 (78%) cases. When stratifying by spinopelvic mobility, 64% were considered normal (change ⩾ 10° and ⩽30°), 27% were stiff (change < 10°), and 9% were hypermobile (change > 30°). For all cohorts, the majority of cases (78%) deviated from the 40° inclination and 20° version target. When evaluating the proportion of cases within the Lewinnek and Callanan safe zones based on spinopelvic mobility, 19% of cases within the normal group were planned outside of both zones compared to 39% of stiff cases and 10% of hypermobile cases. CONCLUSIONS: Utilising the latest version of robotic-assisted THA software, the preoperative plan for cup position was changed in the vast majority (78%) of patients, causing substantial deviations from traditional, generic cup targets.

An Advanced Knee Simulator Model Can Reproducibly Be Used for Ligament Balancing Training during Total Knee Arthroplasty.

A critical and difficult aspect of total knee arthroplasty (TKA) is ligamentous balancing for which cadavers and models have played a large role in the education and training of new arthroplasty surgeons, although they both have several shortcomings including cost, scarcity, and dissimilarity to in vivo ligament properties. An advanced knee simulator (AKS) model based on computed tomography (CT) scans was developed in the setting of these challenges with cadavers and previous models. In this study, we compared the ligament balancing between AKS and human cadaveric knees to assess the validity of using the AKS for ligament balancing training during TKA. A CT scan of a TKA patient with varus deformity was used to design the AKS model with modular components, using three-dimensional printing. Three fellowship-trained arthroplasty surgeons used technology-assisted TKA procedure to plan and balance three cadaver knees and the AKS model. Medial and lateral laxity data were captured using manual varus and valgus stress assessments for cadavers and the model in an extension pose (10 degrees of flexion from terminal extension) and between 90 and 95 degrees for flexion. After preresection assessments, surgeons planned a balanced cruciate-retaining TKA. Following bony cuts and trialing, extension and flexion ligament laxity values were recorded in a similar manner. Descriptive statistics and Student's t-tests were performed to compare the cadavers and model with a p-value set at 0.05. Preresection medial/lateral laxity data for both extension and flexion were plotted and showed that the highest standard deviation (SD) for the cadavers was 0.67 mm, whereas the highest SD for the AKS was 1.25 mm. A similar plot for trialing demonstrated that the highest SD for the cadavers was 0.6 mm, whereas the highest SD for the AKS was 0.61 mm. The AKS trialing data were highly reproducible when compared with cadaveric data, demonstrating the value of the AKS model as a tool to teach ligament balancing for TKA and for future research endeavors.

Neurorehabilitation in a Pediatric Stroke Patient Supported on a CentriMag.

Patients supported on ventricular assist devices (VADs) benefit from rehabilitation while awaiting heart transplantation to recover from surgery, prevent deconditioning, and, in most cases, optimize transplant candidacy. With bleeding and neurological dysfunction as the most common VAD complications, the importance of rehabilitation dramatically increases when a patient on a VAD also suffers from a neurological injury. The rehabilitation needs for cardiac conditioning and neurological reeducation are not the same. Patients with severe neurological deficits require intense rehabilitation that often includes base-of-support challenges, usage of bolsters and balls, partial weight-bearing treadmill training, and assumption of various body positions in prone, kneeling, or quadruped for neuromotor reeducation. However, some devices are more conducive to rehabilitation than others. For children supported by the CentriMag in particular, rehabilitation is challenged by short cannula tubing, an external motor, a large interface, and an intensive care unit (ICU) admission. We report a safe and successful physical therapy course of a pediatric stroke patient with a diagnosis of Ebstein's anomaly supported by a CentriMag right VAD (RVAD) while awaiting heart transplant in the ICU.

Minimally invasive technique for acute fixation and subtalar fusion of displaced intra-articular calcaneus fractures.

Displaced intra-articular calcaneus fractures (DIACFs) are difficult injuries to treat and are often encountered by orthopedic surgeons. For DIACFs treated nonoperatively or with open reduction internal fixation (ORIF), a common complication is painful subtalar arthritis and the need for a secondary subtalar fusion, which prolongs the overall recovery time. One treatment option to address this sequela involves ORIF with subtalar fusion as the primary treatment. We describe a reproducible, minimally invasive surgical technique for primary ORIF with subtalar fusion when the calcaneal tuberosity is amendable to cannulated screw fixation to treat these complex calcaneal fractures. Our technique offers advantages compared to other techniques in that it avoids screw traffic, allows easy bony compression of the subtalar joint, and minimizes soft tissue damage via percutaneous screw fixation. Fourteen fractured calcanei in 12 patients underwent our technique and all achieved bony union with a median time to fusion of 107.5 days (range, 54-530 days). Eight patients returned to work with the remaining 4 patients having an unknown work status at last follow-up, although 2 of these 4 patients resumed normal activities. Only 1 patient experienced a complication, which was an infection after achieving bony union, and was treated with successful hardware removal and our infection protocol. Overall, we conclude our surgical technique offers a successful option in the treatment of DIACFs when the calcaneal tuberosity is amendable to cannulated screw fixation.

Absence of SARS-CoV-2 in wildlife of northeastern Minnesota and Isle Royale National Park.

AIMS: We investigated the presence of SARS-CoV-2 in free-ranging wildlife populations in Northeastern Minnesota on the Grand Portage Indian Reservation and Isle Royale National Park. METHODS AND RESULTS: One hundred twenty nasal samples were collected from white-tailed deer, moose, grey wolves and black bears monitored for conservation efforts during 2022-2023. Samples were tested for viral RNA by RT-qPCR using the CDC N1/N2 primer set. Our data indicate that no wildlife samples were positive for SARS-CoV-2 RNA. CONCLUSIONS: Continued surveillance is therefore crucial to better understand the changing landscape of zoonotic SARS-CoV-2 in the Upper Midwest.

Preventing Sexual Violence: A Behavioral Problem Without a Behaviorally Informed Solution.

What solutions can we find in the research literature for preventing sexual violence, and what psychological theories have guided these efforts? We gather all primary prevention efforts to reduce sexual violence from 1985 to 2018 and provide a bird's-eye view of the literature. We first review predominant theoretical approaches to sexual-violence perpetration prevention by highlighting three interventions that exemplify the zeitgeist of primary prevention efforts at various points during this time period. We find a throughline in primary prevention interventions: They aim to change attitudes, beliefs, and knowledge (i.e., ideas) to reduce sexual-violence perpetration and victimization. Our meta-analysis of these studies tests the efficacy of this approach directly and finds that although many interventions are successful at changing ideas, behavior change does not follow. There is little to no relationship between changing attitudes, beliefs, and knowledge and reducing victimization or perpetration. We also observe trends over time, including a shift from targeting a reduction in perpetration to targeting an increase in bystander intervention. We conclude by highlighting promising new strategies for measuring victimization and perpetration and calling for interventions that are informed by theories of behavior change and that center sexually violent behavior as the key outcome of interest.

The single-cell opioid responses in the context of HIV (SCORCH) consortium.

Substance use disorders (SUD) and drug addiction are major threats to public health, impacting not only the millions of individuals struggling with SUD, but also surrounding families and communities. One of the seminal challenges in treating and studying addiction in human populations is the high prevalence of co-morbid conditions, including an increased risk of contracting a human immunodeficiency virus (HIV) infection. Of the ~15 million people who inject drugs globally, 17% are persons with HIV. Conversely, HIV is a risk factor for SUD because chronic pain syndromes, often encountered in persons with HIV, can lead to an increased use of opioid pain medications that in turn can increase the risk for opioid addiction. We hypothesize that SUD and HIV exert shared effects on brain cell types, including adaptations related to neuroplasticity, neurodegeneration, and neuroinflammation. Basic research is needed to refine our understanding of these affected cell types and adaptations. Studying the effects of SUD in the context of HIV at the single-cell level represents a compelling strategy to understand the reciprocal interactions among both conditions, made feasible by the availability of large, extensively-phenotyped human brain tissue collections that have been amassed by the Neuro-HIV research community. In addition, sophisticated animal models that have been developed for both conditions provide a means to precisely evaluate specific exposures and stages of disease. We propose that single-cell genomics is a uniquely powerful technology to characterize the effects of SUD and HIV in the brain, integrating data from human cohorts and animal models. We have formed the Single-Cell Opioid Responses in the Context of HIV (SCORCH) consortium to carry out this strategy.

Biological variation in cervical spinal cord MRI morphometry in healthy individuals and people with multiple sclerosis.

BACKGROUND AND PURPOSE: Conclusions from prior literature regarding the impact of sex, age, and height on spinal cord (SC) MRI morphometrics are conflicting, while the effect of body weight on SC morphometrics has been found to be nonsignificant. The purpose of this case-control study is to assess the associations between cervical SC MRI morphometric parameters and age, sex, height, and weight to establish their potential role as confounding variables in a clinical study of people with multiple sclerosis (MS) compared to a cohort of healthy volunteers. METHODS: Sixty-nine healthy volunteers and 31 people with MS underwent cervical SC MRI at 3 Tesla field strength. Images were centered at the C3/C4 intervertebral disc and processed using Spinal Cord Toolbox v.4.0.2. Mixed-effects linear regression models were used to evaluate the effects of biological variables and disease status on morphometric parameters. RESULTS: Sex, age, and height had significant effects on cord and gray matter (GM) cross-sectional area (CSA) as well as the GM:cord CSA ratio. There were no significant effects of body weight on morphometric parameters. The effect of MS disease duration on cord CSA in the C4 level was significant when controlling for all other variables. CONCLUSIONS: Studies of disease-related changes in SC morphometry should control for sex, age, and height to account for physiological variation.