Structural and genetic diversity in the secreted mucins MUC5AC and MUC5B.

The secreted mucins MUC5AC and MUC5B are large glycoproteins that play critical defensive roles in pathogen entrapment and mucociliary clearance. Their respective genes contain polymorphic and degenerate protein-coding variable number tandem repeats (VNTRs) that make the loci difficult to investigate with short reads. We characterize the structural diversity of MUC5AC and MUC5B by long-read sequencing and assembly of 206 human and 20 nonhuman primate (NHP) haplotypes. We find that human MUC5B is largely invariant (5,761-5,762 amino acids [aa]); however, seven haplotypes have expanded VNTRs (6,291-7,019 aa). In contrast, 30 allelic variants of MUC5AC encode 16 distinct proteins (5,249-6,325 aa) with cysteine-rich domain and VNTR copy-number variation. We group MUC5AC alleles into three phylogenetic clades: H1 (46%, ∼5,654 aa), H2 (33%, ∼5,742 aa), and H3 (7%, ∼6,325 aa). The two most common human MUC5AC variants are smaller than NHP gene models, suggesting a reduction in protein length during recent human evolution. Linkage disequilibrium and Tajima's D analyses reveal that East Asians carry exceptionally large blocks with an excess of rare variation (p < 0.05) at MUC5AC. To validate this result, we use Locityper for genotyping MUC5AC haplogroups in 2,600 unrelated samples from the 1000 Genomes Project. We observe a signature of positive selection in H1 among East Asians and a depletion of the likely ancestral haplogroup (H3). In Europeans, H3 alleles show an excess of common variation and deviate from Hardy-Weinberg equilibrium (p < 0.05), consistent with heterozygote advantage and balancing selection. This study provides a generalizable strategy to characterize complex protein-coding VNTRs for improved disease associations.

Design and Rationale of the V-Wave Shunt MitraClip Study.

BACKGROUND: Patients heart failure (HF) and moderate-to-severe mitral regurgitation (MR) with residual elevations in left atrial pressure (LAP) following MitraClip may remain symptomatic and suffer subsequent HF readmissions. The V-Wave Interatrial Shunt System is a permanent interatrial septal implant that shunts blood from the left to right atrium and serves to continuously unload the left atrium. Though the V-Wave shunt has previously been studied in HF patients, the safety and feasibility of its deployment at the time of the MitraClip procedure is unknown. STUDY DESIGN: The V-Wave Shunt MitraClip Study (NCT04729933) is an early feasibility study which aims to demonstrate the safety and efficacy of implantation of the V-Wave shunt device at the time of MitraClip procedure. Patients with moderate-to-severe secondary MR with LVEF 20-50% and NYHA functional class III/IV symptoms despite optimal medical therapy, residual mean left atrial pressure ≥ 20 mmHg after MitraClip, and mean left atrial pressure - right atrial pressure difference ≥ 5 mmHg are included. The primary safety endpoint is a composite outcome of all-cause death, stroke, myocardial infarction device embolization, cardiac tamponade, or device-related re-intervention or surgery at 30-days. Patients will be followed out to 5 years. Enrollment is ongoing, with 30-day results expected by the end of 2024. CONCLUSIONS: The V-Wave Shunt Mitraclip study aims to demonstrate the safety and efficacy of the implantation of the V-Wave interatrial shunt device at the time of index MitraClip placement which may serve as an adjunctive method by which continuous left atrial unloading may be achieved.

Heterogeneous treatment effects of sodium-glucose cotransporter 2 inhibitors on risk of dementia in people with type 2 diabetes: A population-based cohort study.

INTRODUCTION: Sodium-glucose cotransporter 2 (SGLT2) inhibitors exhibit potential benefits in reducing dementia risk, yet the optimal beneficiary subgroups remain uncertain. METHODS: Individuals with type 2 diabetes (T2D) initiating either SGLT2 inhibitor or sulfonylurea were identified from OneFlorida+ Clinical Research Network (2016-2022). A doubly robust learning was deployed to estimate risk difference (RD) and 95% confidence interval (CI) of all-cause dementia. RESULTS: Among 35,458 individuals with T2D, 1.8% in the SGLT2 inhibitor group and 4.7% in the sulfonylurea group developed all-cause dementia over a 3.2-year follow-up, yielding a lower risk for SGLT2 inhibitors (RD, -2.5%; 95% CI, -3.0% to -2.1%). Hispanic ethnicity and chronic kidney disease were identified as the two important variables to define four subgroups in which RD ranged from -4.3% (-5.5 to -3.2) to -0.9% (-1.9 to 0.2). DISCUSSION: Compared to sulfonylureas, SGLT2 inhibitors were associated with a reduced risk of all-cause dementia, but the association varied among different subgroups. HIGHLIGHTS: New users of sodium-glucose cotransporter 2 (SGLT2) inhibitors were significantly associated with a lower risk of all-cause dementia as compared to those of sulfonylureas. The association varied among different subgroups defined by Hispanic ethnicity and chronic kidney disease. A significantly lower risk of Alzheimer's disease and vascular dementia was observed among new users of SGLT2 inhibitors compared to those of sulfonylureas.

Serologic extracellular matrix remodeling markers are related to fibrosis stage and prognosis in a phase 2b trial of simtuzumab in patients with primary sclerosing cholangitis.

BACKGROUND: Novel noninvasive predictors of disease severity and prognosis in primary sclerosing cholangitis (PSC) are needed. This study evaluated the ability of extracellular matrix remodeling markers to diagnose fibrosis stage and predict PSC-related fibrosis progression and clinical events. METHODS: Liver histology and serum markers of collagen formation (propeptide of type III collagen [Pro-C3], propeptide of type IV collagen, propeptide of type V collagen), collagen degradation (type III collagen matrix metalloproteinase degradation product and type IV collagen matrix metalloproteinase degradation product), and fibrosis (enhanced liver fibrosis [ELF] score and its components [metalloproteinase-1, type III procollagen, hyaluronic acid]) were assessed in samples from baseline to week 96 in patients with PSC enrolled in a study evaluating simtuzumab (NCT01672853). Diagnostic performance for advanced fibrosis (Ishak stages 3-6) and cirrhosis (Ishak stages 5-6) was evaluated by logistic regression and AUROC. Prognostic performance for PSC-related clinical events and fibrosis progression was assessed by AUROC and Wilcoxon rank-sum test. RESULTS: Among 234 patients, 51% had advanced fibrosis and 11% had cirrhosis at baseline. Baseline Pro-C3 and ELF score and its components provided moderate diagnostic ability for discrimination of advanced fibrosis (AUROC 0.73-0.78) and cirrhosis (AUROC 0.73-0.81). Baseline Pro-C3, ELF score, and type III procollagen provided a moderate prognosis for PSC-related clinical events (AUROC 0.70-0.71). Among patients without cirrhosis at baseline, median changes in Pro-C3 and ELF score to week 96 were higher in those with than without progression to cirrhosis (both p < 0.001). CONCLUSIONS: Pro-C3 correlated with fibrosis stage, and Pro-C3 and ELF score provided discrimination of advanced fibrosis and cirrhosis and predicted PSC-related events and fibrosis progression. The results support the clinical utility of Pro-C3 and ELF score for staging and as prognostic markers in PSC.

Cancers with epidemiologic signatures of viral oncogenicity among immunocompromised populations in the United States.

BACKGROUND: Immunosuppressed individuals have elevated risk of virus-related cancers. Identifying cancers with elevated risk in people with HIV (PWH) and solid organ transplant recipients (SOTRs), two immunosuppressed populations, may help identify novel etiologic relationships with infectious agents. METHODS: We utilized two linkages of population-based cancer registries with HIV and transplant registries in the United States. Cancer entities were systematically classified based on site and histology codes. Standardized incidence ratios (SIRs) were used to compare risk in PWH and SOTRs with the general population. For selected cancer entities, incidence rate ratios (IRRs) were calculated for indicators of immunosuppression within each population. FINDINGS: We identified 38,047 cancer cases in SOTRs and 53,592 in PWH, yielding overall SIRs of 1.66 (95%CI = 1.65-1.68) and 1.49 (95%CI = 1.47-1.50), respectively. Forty-three cancer entities met selection criteria, including conjunctival squamous cell carcinoma (SCC) (PWH SIR = 7.1, 95%CI = 5.5-9.2; SOTRs SIR = 9.4; 95%CI = 6.8-12.6). Sebaceous adenocarcinoma was elevated in SOTRs (SIR = 16.2; 95%CI = 14.0-18.6) and, among SOTRs, associated with greater risk in lung/heart transplant recipients compared to recipients of other organs (IRR = 2.3; 95%CI = 1.7-3.2). Salivary gland tumors, malignant fibrous histiocytoma (MFH), and intrahepatic cholangiocarcinoma showed elevated risk in SOTRs (SIR = 3.9; SIR = 4.7; and SIR = 3.2, respectively) but not in PWH. However, risks for these cancers were elevated following an AIDS diagnosis among PWH (IRR = 2.4; IRR = 4.3; and IRR = 2.0, respectively). INTERPRETATION: Elevated SIRs among SOTRs and PWH, and associations with immunosuppression within these populations, suggest novel infectious causes for several cancers including conjunctival SCC, sebaceous adenocarcinoma, salivary gland tumors, MFH, and intrahepatic cholangiocarcinoma.

Cilofexor in Patients with Compensated Cirrhosis Due to Primary Sclerosing Cholangitis: an Open-label Phase 1B Study.

OBJECTIVES: This proof-of-concept, open-label phase 1b study evaluated the safety and efficacy of cilofexor, a potent selective farnesoid X receptor agonist, in patients with compensated cirrhosis due to primary sclerosing cholangitis (PSC). METHODS: Escalating doses of cilofexor (30 mg [weeks 1-4], 60 mg [weeks 5-8], 100 mg [weeks 9-12]) were administered orally once daily over 12 weeks. The primary endpoint was safety. Exploratory measures included cholestasis and fibrosis markers, and pharmacodynamic biomarkers of bile acid homeostasis. RESULTS: Eleven patients were enrolled (median age: 48 years; 55% men). The most common treatment-emergent adverse events (TEAEs) were pruritus (8/11 [72.7%]), fatigue, headache, nausea, and upper respiratory tract infection (2/11 [18.2%] each). Seven patients experienced a pruritus TEAE (one grade 3) considered drug related. One patient temporarily discontinued cilofexor owing to peripheral edema. There were no deaths, serious TEAEs, or TEAEs leading to permanent discontinuation. Median changes (interquartile ranges) from baseline to week 12 (predose, fasting) were -24.8% (-35.7, -7.4) for alanine transaminase, -13.0% (-21.9, -8.6) for alkaline phosphatase, -43.5% (-52.1, -30.8) for gamma-glutamyl transferase, -12.7% (-25.0, 0.0) for total bilirubin, and -21.2% (-40.0, 0.0) for direct bilirubin. Least-squares mean percentage change (95% confidence interval) from baseline to week 12 at trough was -55.3% (-70.8, -31.6) for C4 and -60.5% (-81.8, -14.2) for cholic acid. Fasting fibroblast growth factor 19 levels transiently increased after cilofexor administration. CONCLUSIONS: Escalating doses of cilofexor over 12 weeks were well tolerated and improved cholestasis markers in patients with compensated cirrhosis due to PSC (NCT04060147).

Muscle-to-Bone Ratio in NCAA Division I Collegiate Football Players by Position.

ABSTRACT: Dengel, DR, Studee, HR, Juckett, WT, Bosch, TA, Carbuhn, AF, Stanforth, PR, and Evanoff, NG. Muscle-to-bone ratio in NCAA division I collegiate football players by position. J Strength Cond Res XX(X): 000-000, 2024-The purpose of this study was to compare the muscle-to-bone ratio (MBR) in National Collegiate Athletic Association Division I football players (collegiate football players [CFP]) to healthy, age-matched controls. In addition, we examined MBR in CFP by position. A total of 553 CFP and 261 controls had their total and regional lean mass (LM), fat mass (FM), and bone mineral content (BMC) determined by dual x-ray absorptiometry (DXA). College football players were categorized by positions defined as offensive linemen (OL), defensive linemen (DL), tight end, linebacker (LB), running back (RB), punter or kicker, quarterback (QB), defensive back (DB), and wide receiver (WR). There were significant differences between CFP and controls for total LM (80.1 ± 10.0 vs. 56.9 ± 7.8 kg), FM (22.2 ± 12.5 vs. 15.2 ± 7.1 kg), and BMC (4.3 ± 0.5 vs. 3.1 ± 0.5 kg). Although there were significant differences in body composition between CFP and controls, there was no significant differences in total MBR between CFP and controls (18.6 ± 1.4 vs. 18.8 ± 1.7). Regionally, CFP had significantly lower trunk MBR than controls (26.7 ± 2.7 vs. 28.7 ± 4.2), but no difference was seen in leg or arm MBR. Positional differences in CFP were noted as total MBR being significantly higher in DL (19.0 ± 1.4) than in DB (18.1 ± 1.3), WR (18.1 ± 1.3), and LB (18.2 ± 1.3). OL had a significantly higher total MBR (19.2 ± 1.3) than DB (18.1 ± 1.3), LB (18.2 ± 1.3), QB (18.1 ± 1.0), and WR (18.1 ± 1.3). In addition, RB had significantly higher total MBR (18.8 ± 1.3) than DB (18.1 ± 1.3) and WR (18.1 ± 1.3). This study may provide athletes and training staff with normative values when evaluating total and regional MBR with DXA.

Impact of Frailty on Surgical Outcomes of Patients With Cushing Disease Using the Multicenter Registry of Adenomas of the Pituitary and Related Disorders Registry.

BACKGROUND AND OBJECTIVES: Despite growing interest in how patient frailty affects outcomes (eg, in neuro-oncology), its role after transsphenoidal surgery for Cushing disease (CD) remains unclear. We evaluated the effect of frailty on CD outcomes using the Registry of Adenomas of the Pituitary and Related Disorders (RAPID) data set from a collaboration of US academic pituitary centers. METHODS: Data on consecutive surgically treated patients with CD (2011-2023) were compiled using the 11-factor modified frailty index. Patients were classified as fit (score, 0-1), managing well (score, 2-3), and mildly frail (score, 4-5). Univariable and multivariable analyses were conducted to examine outcomes. RESULTS: Data were analyzed for 318 patients (193 fit, 113 managing well, 12 mildly frail). Compared with fit and managing well patients, mildly frail patients were older (mean ± SD 39.7 ± 14.2 and 48.9 ± 12.2 vs 49.4 ± 8.9 years, P < .001) but did not different by sex, race, and other factors. They had significantly longer hospitalizations (3.7 ± 2.0 and 4.5 ± 3.5 vs 5.3 ± 3.5 days, P = .02), even after multivariable analysis (ß = 1.01, P = .007) adjusted for known predictors of prolonged hospitalization (age, Knosp grade, surgeon experience, American Society of Anesthesiologists grade, complications, frailty). Patients with mild frailty were more commonly discharged to skilled nursing facilities (0.5% [1/192] and 4.5% [5/112] vs 25% [3/12], P < .001). Most patients underwent gross total resection (84.4% [163/193] and 79.6% [90/113] vs 83% [10/12]). No difference in overall complications was observed; however, venous thromboembolism was more common in mildly frail (8%, 1/12) than in fit (0.5%, 1/193) and managing well (2.7%, 3/113) patients (P = .04). No difference was found in 90-day readmission rates. CONCLUSION: These results demonstrate that mild frailty predicts CD surgical outcomes and may inform preoperative risk stratification. Frailty-influenced outcomes other than age and tumor characteristics may be useful for prognostication. Future studies can help identify strategies to reduce disease burden for frail patients with hypercortisolemia.

Climatically robust multiscale species distribution models to support pronghorn recovery in California.

We combined two climate-based distribution models with three finer-scale suitability models to identify habitat for pronghorn recovery in California now and into the future. We used a consensus approach to identify areas of suitable climate now and future for pronghorn in California. We compared the results of climate models from two separate hypotheses about their historical ecology in the state. Under the migration hypothesis, pronghorn were expected to be limited climatically by extreme cold in winter and extreme heat in summer; under the niche reduction hypothesis, historical pronghorn of distribution would have better represented the climatic limitations of the species. We combined occurrences from GPS collars distributed across three populations of pronghorn in the state to create three distinct habitat suitability models: (1) an ensemble model using random forests, Maxent, classification and regression Trees, and a generalized linear model; (2) a step selection function; and (3) an expert-driven model. We evaluated consensus among both the climate models and the suitability models to prioritize areas for, and evaluate the prospects of, pronghorn recovery. Climate suitability for pronghorn in the future depends heavily on model assumptions. Under the migration hypothesis, our model predicted that there will be no suitable climate in California in the future. Under the niche reduction hypothesis, by contrast, suitable climate will expand. Habitat suitability also depended on the methods used, but areas of consensus among all three models exist in large patches throughout the state. Identifying habitat for a species which has undergone extreme range collapse, and which has very fine scale habitat needs, presents novel challenges for spatial ecologists. Our multimethod, multihypothesis approach can allow habitat modelers to identify areas of consensus and, perhaps more importantly, fill critical knowledge gaps that could resolve disagreements among the models. For pronghorn, a better understanding of their upper thermal tolerances and whether historical populations migrated will be crucial to their potential recovery in California and throughout the arid Southwest.

Predictors of Durable Remission After Successful Surgery for Cushing Disease: Results From the Multicenter RAPID Registry.

BACKGROUND AND OBJECTIVE: Cushing disease (CD) affects mortality and quality of life along with limited long-term remission, underscoring the need to better identify recurrence risk. The identification of surgical or imaging predictors for CD remission after transsphenoidal surgery has yielded some inconsistent results and has been limited by single-center, single-surgeon, or meta-analyses studies. We sought to evaluate the multicenter Registry of Adenomas of the Pituitary and Related Disorders (RAPID) database of academic US pituitary centers to assess whether robust nonhormonal recurrence predictors could be elucidated. METHODS: Patients with treated CD from 2011 to 2023 were included. The perioperative and long-term characteristics of CD patients with and without recurrence were assessed using univariable and multivariable analyses. RESULTS: Of 383 patients with CD from 26 surgeons achieving postoperative remission, 288 (75.2%) maintained remission at last follow-up while 95 (24.8%) showed recurrence (median time to recurrence 9.99 ± 1.34 years). Patients with recurrence required longer postoperative hospital stays (5 ± 3 vs 4 ± 2 days, P = .002), had larger average tumor volumes (1.76 ± 2.53 cm3 vs 0.49 ± 1.17 cm3, P = .0001), and more often previously failed prior treatment (31.1% vs 14.9%, P = .001) mostly being prior surgery. Multivariable hazard prediction models for tumor recurrence found younger age (odds ratio [OR] = 0.95, P = .002) and Knosp grade of 0 (OR = 0.09, reference Knosp grade 4, P = .03) to be protective against recurrence. Comparison of Knosp grade 0 to 2 vs 3 to 4 showed that lower grades had reduced risk of recurrence (OR = 0.27, P = .04). Other factors such as length of stay, surgeon experience, prior tumor treatment, and Knosp grades 1, 2, or 3 failed to reach levels of statistical significance in multivariable analysis. CONCLUSION: This multicenter study centers suggests that the strongest predictors of recurrence include tumor size/invasion and age. This insight can help with patient counseling and prognostication. Long-term follow-up is necessary for patients, and early treatment of small tumors may improve outcomes.

Physician-directed patient self-management in heart failure using left atrial pressure: Interim insights from the VECTOR-HF I and IIa studies.

AIMS: Haemodynamic monitoring using implantable pressure sensors reduces the risk of heart failure (HF) hospitalizations. Patient self-management (PSM) of haemodynamics in HF has the potential to personalize treatment, increase adherence, and reduce the risk of worsening HF, while lowering clinicians' burden. METHODS AND RESULTS: The VECTOR-HF I and IIa studies are prospective, single-arm, open-label clinical trials assessing safety, usability and performance of left atrial pressure (LAP)-guided HF management using PSM in New York Heart Association class II and III HF patients. Physician-prescribed LAP thresholds trigger patient self-adjustment of diuretics. Primary endpoints include the ability to perform LAP measurements and transmit data to the healthcare provider (HCP) interface and the patient guidance application, and safety outcomes. This is an interim analysis of 13 patients using the PSM approach. Over 12 months, no procedure- or device-related major adverse cardiovascular or neurological events were observed, and there were no failures to obtain measurements from the sensor and transmit the data to the HCP interface and the patient guidance application. Patient adherence was 91.4%. Using PSM, annualized HF hospitalization rate significantly decreased compared to a similar period prior to PSM utilization (0 admissions vs. 0.69 admissions over 11.84 months, p = 0.004). At 6 months, 6-min walk test distance and the Kansas City Cardiomyopathy Questionnaire overall summary score demonstrated significant improvement. CONCLUSIONS: Interim findings suggest that PSM using a LAP monitoring system is feasible and safe. PSM is associated with high patient adherence, potentially improving HF patients' functional status, quality of life, and limiting HF hospitalizations.

A Brief Mind-body Intervention Is Feasible and May Prevent Persistent Pain After Acute Orthopaedic Traumas: A Randomized Controlled Trial.

BACKGROUND: Approximately 20% to 50% of patients develop persistent pain after traumatic orthopaedic injuries. Psychosocial factors are an important predictor of persistent pain; however, there are no evidence-based, mind-body interventions to prevent persistent pain for this patient population. QUESTIONS/PURPOSES: (1) Does the Toolkit for Optimal Recovery after Injury (TOR) achieve a priori feasibility benchmarks in a multisite randomized control trial (RCT)? (2) Does TOR demonstrate a preliminary effect in improving pain, as well as physical and emotional function? METHODS: This pilot RCT of TOR versus a minimally enhanced usual care comparison group (MEUC) was conducted among 195 adults with an acute orthopaedic traumatic injury at risk for persistent pain at four geographically diverse Level 1 trauma centers between October 2021 to August 2023. Fifty percent (97 of 195) of participants were randomized to TOR (mean age 43 ± 17 years; 67% [65 of 97] women) and 50% (98) to MEUC (mean age 45 ± 16 years; 67% [66 of 98] women). In TOR, 24% (23 of 97) of patients were lost to follow-up, whereas in the MEUC, 17% (17 of 98) were lost. At 4 weeks, 78% (76 of 97) of patients in TOR and 95% (93 of 98) in the MEUC completed the assessments; by 12 weeks, 76% (74 of 97) of patients in TOR and 83% (81 of 98) in the MEUC completed the assessments (all participants were still included in the analysis consistent with an intention-to-treat approach). The TOR has four weekly video-administered sessions that teach pain coping skills. The MEUC is an educational pamphlet. Both were delivered in addition to usual care. Primary outcomes were feasibility of recruitment (the percentage of patients who met study criteria and enrolled) and data collection, appropriateness of treatment (the percent of participants in TOR who score above the midpoint on the Credibility and Expectancy Scale), acceptability (the percentage of patients in TOR who attend at least three of four sessions), and treatment satisfaction (the percent of participants in TOR who score above the midpoint on the Client Satisfaction Scale). Secondary outcomes included additional feasibility (including collecting data on narcotics and rescue medications and adverse events), fidelity (whether the intervention was delivered as planned) and acceptability metrics (patients and staff), pain (numeric rating scale), physical function (Short Musculoskeletal Function Assessment questionnaire [SMFA], PROMIS), emotional function (PTSD [PTSD Checklist], depression [Center for Epidemiologic Study of Depression]), and intervention targets (pain catastrophizing, pain anxiety, coping, and mindfulness). Assessments occurred at baseline, 4 and 12 weeks. RESULTS: Several outcomes exceeded a priori benchmarks: feasibility of recruitment (89% [210 of 235] of eligible participants consented), appropriateness (TOR: 73% [66 of 90] scored > midpoint on the Credibility and Expectancy Scale), data collection (79% [154 of 195] completed all surveys), satisfaction (TOR: 99% [75 of 76] > midpoint on the Client Satisfaction Scale), and acceptability (TOR: 73% [71 of 97] attended all four sessions). Participation in TOR, compared with the MEUC, was associated with improvement from baseline to postintervention and from baseline to follow-up in physical function (SMFA, baseline to post: -7 [95% CI -11 to -4]; p < 0.001; baseline to follow-up: -6 [95% CI -11 to -1]; p = 0.02), PROMIS (PROMIS-PF, baseline to follow-up: 2 [95% CI 0 to 4]; p = 0.045), pain at rest (baseline to post: -1.2 [95% CI -1.7 to -0.6]; p < 0.001; baseline to follow-up: -1 [95% CI -1.7 to -0.3]; p = 0.003), activity (baseline to post: -0.7 [95% CI -1.3 to -0.1]; p = 0.03; baseline to follow-up: -0.8 [95% CI -1.6 to -0.1]; p = 0.04), depressive symptoms (baseline to post: -6 [95% CI -9 to -3]; p < 0.001; baseline to follow-up: -5 [95% CI -9 to -2]; p < 0.002), and posttraumatic symptoms (baseline to post: -4 [95% CI -7 to 0]; p = 0.03; baseline to follow-up: -5 [95% CI -9 to -1]; p = 0.01). Improvements were generally clinically important and sustained or continued through the 3 months of follow-up (that is, above the minimum clinically important different [MCID] of 7 for the SMFA, the MCID of 3.6 for PROMIS, the MCID of 2 for pain at rest and pain during activity, the MCID of more than 10% change in depressive symptoms, and the MCID of 10 for posttraumatic symptoms). There were treatment-dependent improvements in pain catastrophizing, pain anxiety, coping, and mindfulness. CONCLUSION: TOR was feasible and potentially efficacious in preventing persistent pain among patients with an acute orthopaedic traumatic injury. Using TOR in clinical practice may prevent persistent pain after orthopaedic traumatic injury. LEVEL OF EVIDENCE: Level I, therapeutic study.

American Heart Association Cardiogenic Shock Registry: Design and Implementation.

BACKGROUND: Cardiogenic shock is a morbid complication of heart disease that claims the lives of more than 1 in 3 patients presenting with this syndrome. Supporting a unique collaboration across clinical specialties, federal regulators, payors, and industry, the American Heart Association volunteers and staff have launched a quality improvement registry to better understand the clinical manifestations of shock phenotypes, and to benchmark the management patterns, and outcomes of patients presenting with cardiogenic shock to hospitals across the United States. METHODS: Participating hospitals will enroll consecutive hospitalized patients with cardiogenic shock, regardless of etiology or severity. Data are collected through individual reviews of medical records of sequential adult patients with cardiogenic shock. The electronic case record form was collaboratively designed with a core minimum data structure and aligned with Shock Academic Research Consortium definitions. This registry will allow participating health systems to evaluate patient-level data including diagnostic approaches, therapeutics, use of advanced monitoring and circulatory support, processes of care, complications, and in-hospital survival. Participating sites can leverage these data for onsite monitoring of outcomes and benchmarking versus other institutions. The registry was concomitantly designed to provide a high-quality longitudinal research infrastructure for pragmatic randomized trials as well as translational, clinical, and implementation research. An aggregate deidentified data set will be made available to the research community on the American Heart Association's Precision Medicine Platform. On March 31, 2022, the American Heart Association Cardiogenic Shock Registry received its first clinical records. At the time of this submission, 100 centers are participating. CONCLUSIONS: The American Heart Association Cardiogenic Shock Registry will serve as a resource using consistent data structure and definitions for the medical and research community to accelerate scientific advancement through shared learning and research resulting in improved quality of care and outcomes of shock patients.

Acridine photocatalysis enables tricomponent direct decarboxylative amine construction.

Amines are centrally important motifs in medicinal chemistry and biochemistry, and indispensable intermediates and linchpins in organic synthesis. Despite their cross-disciplinary prominence, synthetic access to amine continues to rely on two-electron approaches based on reductions and additions of organometallic reagents, limiting their accessible chemical space and necessitating stepwise preassembly of synthetic precursors. We report herein a homogeneous photocatalytic tricomponent decarboxylative radical-mediated amine construction that enables modular access to α-branched secondary amines directly from the broad and structurally diverse chemical space of carboxylic acids in a tricomponent reaction with aldehydes and aromatic amines. Our studies reveal the key role of acridine photocatalysis acting in concert with copper and Brønsted acid catalytic processes in facilitating the previously inaccessible homogeneous photocatalytic reaction and provide a streamlined segue to a wide range of amines and nonproteinogenic α-amino acids.

Robust variability of grid cell properties within individual grid modules enhances encoding of local space.

Although grid cells are one of the most well studied functional classes of neurons in the mammalian brain, the assumption that there is a single grid orientation and spacing per grid module has not been carefully tested. We investigate and analyze a recent large-scale recording of medial entorhinal cortex to characterize the presence and degree of heterogeneity of grid properties within individual modules. We find evidence for small, but robust, variability and hypothesize that this property of the grid code could enhance the ability of encoding local spatial information. Performing analysis on synthetic populations of grid cells, where we have complete control over the amount heterogeneity in grid properties, we demonstrate that variability, of a similar magnitude to the analyzed data, leads to significantly decreased decoding error, even when restricted to activity from a single module. Our results highlight how the heterogeneity of the neural response properties may benefit coding and opens new directions for theoretical and experimental analysis of grid cells.