Membrane phospholipids control gating of the mechanosensitive potassium leak channel TREK1

Tandem pore domain (K2P) potassium channels modulate resting membrane potentials and shape cellular excitability. For the mechanosensitive subfamily of K2Ps, the composition of phospholipids within the bilayer strongly influences channel activity. To examine the molecular details of K2P lipid modulation, we solved cryo-EM structures of the TREK1 K2P channel bound to either the anionic lipid phosphatidic acid (PA) or the zwitterionic lipid phosphatidylethanolamine (PE). At the extracellular face of TREK1, a PA lipid inserts its hydrocarbon tail into a pocket behind the selectivity filter, causing a structural rearrangement that recapitulates mutations and pharmacology known to activate TREK1. At the cytoplasmic face, PA and PE lipids compete to modulate the conformation of the TREK1 TM4 gating helix. Our findings demonstrate two distinct pathways by which anionic lipids enhance TREK1 activity and provide a framework for a model that integrates lipid gating with the effects of other mechanosensitive K2P modulators

Discontinuation and nonpublication of clinical trials in orthopaedic oncology

Abstract Background Despite the pivotal role of clinical trials in advancing orthopaedic oncology knowledge and treatment strategies, the persistent issues of trial discontinuation and nonpublication are significant problems. This study conducted an analysis examining clinical trial discontinuation rates, associations between intervention types and discontinuation/nonpublication, and the role of funding, enrollment size, and their implications for trial success and completion. Methods This study, conducted on May 1, 2023, utilized a cross-sectional design to comprehensively analyze phase 3 and 4 randomized controlled trials within the realm of orthopaedic oncology. We specifically incorporated Phase 3 and 4 trials as they are designed to evaluate prolonged outcomes in human subjects and are more likely to reach publication. Study characteristics of interest included the intervention utilized in the clinical trial, presence of funding, whether the trial was published, completed, and trial enrollment size. The investigation involved an examination of ClinicalTrials.gov, a prominent online repository of clinical trial data managed by the National Library of Medicine of the USA. Descriptive statistics and multivariate logistic regressions were used to determine statistical significance. Results Among the cohort of 130 trials, 19.2% were prematurely discontinued. Completion rates varied based on intervention type; 111 pharmaceutical trials demonstrated a completion rate of 83.8%, whereas 19 non-pharmaceutical trials exhibited a completion rate of 8.0% (P < .001). Surgical trials, totaling 10, showed a completion rate of 90%. The overall trial publication rate was 86.15%, with pharmaceutical interventions achieving a publication rate of 91.96%. Larger-scale trials (≥ 261 participants) emerged as a protective factor against both discontinuation (Adjusted Odds Ratio [AOR]: 0.85, 95% Confidence Interval [CI] 0.42–0.95) and nonpublication (AOR: 0.19, 95% CI 0.13–.47), compared to smaller-scale trials. Conclusion This study accentuates the heightened vulnerability of non-pharmaceutical interventions and trials exhibiting lower rates of enrollment to the issues of discontinuation and nonpublication. Moving forward, the advancement of clinical trials necessitates a concerted effort to enhance trial methodologies, especially concerning nonpharmaceutical interventions, along with a meticulous refinement of participant enrollment criteria

Gender Disparities in Endowed Professorships Within Orthopaedic Surgery.

Background Orthopaedic surgery has the lowest number of full-time faculty positions held by women, at 19%, with endowed chairs among the most coveted and advantageous. We examined the characteristics of endowed professors from the US top 100 orthopaedic academic centers and highest-funded musculoskeletal (MSK)&nbsp;researchers to determine if gender is associated with endowed professorship. Additionally, we sought to determine if&nbsp;gender is associated with increased NIH funding for top-performing musculoskeletal researchers.&nbsp; Methods Our primary study group included the top 100 orthopaedic academic centers defined by US News World Report and Doximitys rankings. Our secondary study group examined the top MSK researchers, defined as principal investigators, who received &gt;$400,000 in annual NIH funding from 2018 to 2021. Orthopaedic departments included MSK researchers and subspecialties within orthopaedics and medicine. Publicly available sources were used to compile institutional, gender, H-index, citation number, and subspecialty data on endowed professors; statistical comparisons were calculated. Results Within the top 100 orthopaedic academic departments, 4674 faculty were identified. Seven hundred and thirty-three (15.68%) were identified as women, 3941 as men (84.32%). One hundred and ninety-four held endowed professorships; 13 were awarded to women (6.7%), and 185 (95.3%) were awarded to men, with a significant odds ratio (OR) of 2.95, favoring men. For MSK researchers, the OR increases to 11.4. Arthroplasty and sports had the highest numbers of endowments. Significant differences in H-index, publications, and graduation year were identified between men and women for top MSK researchers and orthopaedic-trained surgeons; however, these differences disappeared when considering heterogenous orthopaedic departments that included medicine subspecialties, plastic surgery, hand surgery, and neurosurgery. Additional gender differences were observed in endowment names, with awards commemorating 51.5% men, 7.2% women, and 34% families or groups. Conclusion Gender inequities at the endowment level are substantial, and there are very few women in musculoskeletal medicine to achieve endowments. Differences in H-index, publications, and graduation year between men and women MSK researchers and orthopaedic-trained surgeons, but not combined orthopaedic, PM&amp;R, and medical subspecialty departments, suggest unique challenges in orthopaedic surgery environments and histories that may contribute to endowment disparity. Gender was not found to be associated with funding bias for top-performing musculoskeletal researchers

Discontinuation and nonpublication of clinical trials in orthopaedic oncology.

BACKGROUND: Despite the pivotal role of clinical trials in advancing orthopaedic oncology knowledge and treatment strategies, the persistent issues of trial discontinuation and nonpublication are significant problems. This study conducted an analysis examining clinical trial discontinuation rates, associations between intervention types and discontinuation/nonpublication, and the role of funding, enrollment size, and their implications for trial success and completion. METHODS: This study, conducted on May 1, 2023, utilized a cross-sectional design to comprehensively analyze phase 3 and 4 randomized controlled trials within the realm of orthopaedic oncology. We specifically incorporated Phase 3 and 4 trials as they are designed to evaluate prolonged outcomes in human subjects and are more likely to reach publication. Study characteristics of interest included the intervention utilized in the clinical trial, presence of funding, whether the trial was published, completed, and trial enrollment size. The investigation involved an examination of ClinicalTrials.gov, a prominent online repository of clinical trial data managed by the National Library of Medicine of the USA. Descriptive statistics and multivariate logistic regressions were used to determine statistical significance. RESULTS: Among the cohort of 130 trials, 19.2% were prematurely discontinued. Completion rates varied based on intervention type; 111 pharmaceutical trials demonstrated a completion rate of 83.8%, whereas 19 non-pharmaceutical trials exhibited a completion rate of 8.0% (P &lt; .001). Surgical trials, totaling 10, showed a completion rate of 90%. The overall trial publication rate was 86.15%, with pharmaceutical interventions achieving a publication rate of 91.96%. Larger-scale trials (≥ 261 participants) emerged as a protective factor against both discontinuation (Adjusted Odds Ratio [AOR]: 0.85, 95% Confidence Interval [CI] 0.42-0.95) and nonpublication (AOR: 0.19, 95% CI 0.13-.47), compared to smaller-scale trials. CONCLUSION: This study accentuates the heightened vulnerability of non-pharmaceutical interventions and trials exhibiting lower rates of enrollment to the issues of discontinuation and nonpublication. Moving forward, the advancement of clinical trials necessitates a concerted effort to enhance trial methodologies, especially concerning nonpharmaceutical interventions, along with a meticulous refinement of participant enrollment criteria

Impact of social determinants of health on perioperative opioid utilization in patients with lumbar degeneration.

BackgroundSocial determinants of health (SDOH), have been demonstrated to significantly impact health outcomes in spine patients. There may be interaction between opioid use and these factors in spine surgical patients. We aimed to evaluate the social determinants of health (SDOH) which are associated with perioperative opioid use among lumbar spine patients.MethodsThis retrospective cohort study included patients undergoing spine surgery for lumbar degeneration in 2019. Opioid use was determined based on prescription records from the electronic medical records. Preoperative opioid users (OU) were compared with opioid-naïve patients regarding SDOH including demographics like age and race, and clinical data such as activity and tobacco use. Demographics and surgical data, including age, comorbidities, surgical invasiveness, and other variables were also collected from the records. Multivariate logistic regression was used for analysis of these factors.ResultsNinety-eight patients were opioid-naïve and 90 used opioids preoperatively. All OU had ≥3 months of use, had more prior spine surgeries (1.07 vs. 0.44, p&lt;.001) and more comorbidities including diabetes, hypertension, and depression (p=.021, 0.043, 0.017). Patients from lower community median income areas, unemployed, or with lower physical capacity (METS&lt;5) were more likely to use opioids preoperatively. Postoperative opioid use was strongly associated with preoperative opioid use, as well as alcohol use, and lower community median income. At one year postoperatively, OU had higher rates of opioid use [72.2% vs. 15.3%, p&lt;.001].ConclusionsUnemployment, low physical activity level, and lower community median income were associated with preoperative opioid use and longer-term opioid use postoperatively

Risk factors for extended length of stay and non-home discharge in adults treated with multi-level fusion for lumbar degenerative pathology and deformity

PurposeTo identify independent risk factors, including the Risk Assessment and Prediction Tool (RAPT) score, associated with extended length of stay (eLOS) and non-home discharge following elective multi-level instrumented spine fusion operations for diagnosis of adult spinal deformity (ASD) and lumbar degenerative pathology.MethodsAdults who underwent multi-level ([Formula: see text] segments) instrumented spine fusions for ASD and lumbar degenerative pathology at a single institution (2016-2021) were reviewed. Presence of a pre-operative RAPT score was used as an inclusion criterion. Excluded were patients who underwent non-elective operations, revisions, operations for trauma, malignancy, and/or infections. Outcomes were eLOS (&gt; 7&nbsp;days) and discharge location (home vs. non-home). Predictor variables included demographics, comorbidities, operative information, Surgical Invasiveness Index (SII), and RAPT score. Fisher's exact test was used for univariate analysis, and significant variables were implemented in multivariate binary logistic regression, with generation of 95% percent confidence intervals (CI), odds ratios (OR), and p-values.ResultsIncluded for analysis were 355 patients. Post-operatively, 36.6% (n = 130) had eLOS and 53.2% (n = 189) had a non-home discharge. Risk factors significant for a non-home discharge were older age (&gt; 70&nbsp;years), SII &gt; 36, pre-op RAPT &lt; 10, DMII, diagnosis of depression or anxiety, and eLOS. Risk factors significant for an eLOS were SII &gt; 20, RAPT &lt; 6, and an ASA score of 3.ConclusionThe RAPT score and SII were most important significant predictors of eLOS and non-home discharges following multi-level instrumented fusions for lumbar spinal pathology and deformity. Preoperative optimization of the RAPT's individual components may provide a useful strategy for decreasing LOS and modifying discharge disposition

Impact of social determinants of health on perioperative opioid utilization in patients with lumbar degeneration

Background: Social determinants of health (SDOH), have been demonstrated to significantly impact health outcomes in spine patients. There may be interaction between opioid use and these factors in spine surgical patients. We aimed to evaluate the social determinants of health (SDOH) which are associated with perioperative opioid use among lumbar spine patients. Methods: This retrospective cohort study included patients undergoing spine surgery for lumbar degeneration in 2019. Opioid use was determined based on prescription records from the electronic medical records. Preoperative opioid users (OU) were compared with opioid-naïve patients regarding SDOH including demographics like age and race, and clinical data such as activity and tobacco use. Demographics and surgical data, including age, comorbidities, surgical invasiveness, and other variables were also collected from the records. Multivariate logistic regression was used for analysis of these factors. Results: Ninety-eight patients were opioid-naïve and 90 used opioids preoperatively. All OU had ≥3 months of use, had more prior spine surgeries (1.07 vs. 0.44, p<.001) and more comorbidities including diabetes, hypertension, and depression (p=.021, 0.043, 0.017). Patients from lower community median income areas, unemployed, or with lower physical capacity (METS<5) were more likely to use opioids preoperatively. Postoperative opioid use was strongly associated with preoperative opioid use, as well as alcohol use, and lower community median income. At one year postoperatively, OU had higher rates of opioid use [72.2% vs. 15.3%, p<.001]. Conclusions: Unemployment, low physical activity level, and lower community median income were associated with preoperative opioid use and longer-term opioid use postoperatively

Preoperative medical assessment for adult spinal deformity surgery: a state-of-the-art review.

IntroductionThe purpose of this study is to provide a state-of-the-art review regarding risk factors for perioperative complications in adult spinal deformity (ASD) surgery. The review includes levels of evidence for risk factors associated with complications in ASD surgery.MethodsUsing the PubMed database, we searched for complications, risk factors, and adult spinal deformity. The included publications were assessed for level of evidence as described in clinical practice guidelines published by the North American Spine Society, with summary statements generated for each risk factor (Bono et al. in Spine J 9:1046-1051, 2009).ResultsFrailty had good evidence (Grade A) as a risk for complications in ASD patients. Fair evidence (Grade B) was assigned for bone quality, smoking, hyperglycemia and diabetes, nutritional status, immunosuppression/steroid use, cardiovascular disease, pulmonary disease, and renal disease. Indeterminate evidence (Grade I) was assigned for pre-operative cognitive function, mental health, social support, and opioid utilization.ConclusionsIdentification of risk factors for perioperative complications in ASD surgery is a priority for empowering informed choices for patients and surgeons and managing patient expectations. Risk factors with grade A and B evidence should be identified prior to elective surgery and modified to reduce the risk of perioperative complications

Patching a leak in an R1 university gateway STEM course.

A cognitively intensive companion service course has been introduced to the main fall general chemistry class at Cornell University. For years 2015 and 2016, priority students (those from groups under-represented and economically disadvantaged) show respectively improvement of +0.67 and +0.51 standard deviations in final course grade compared to priority students not in the program. Non-priority students show respectively a +0.66 and +0.62 standard deviation improvement. Progressive improvement (as measured by higher than expected Final Exam scores than what would have been expected solely from a given student's earlier Exam 1 score) demonstrates conclusively the service course's role in the enhanced outcomes. Progressive retention (as measured by the following year fall semester's organic chemistry exam scores compared to what would have been expected based on a given student's general chemistry final exam score) demonstrates that, on the average, the earlier observed progressive improvement is significantly retained in a chemistry course one year later. Preliminary retention statistics suggest a significant increase in first year to second year retention. A meta analysis of results from previously reported chemistry service courses indicate that such performance gains are difficult to achieve and hence common elements of the few effective programs may be of high value to the STEM education community