Combined clinical, structural, and cellular studies discriminate pathogenic and benign TRPV4 variants.

Dominant mutations in the calcium-permeable ion channel TRPV4 (transient receptor potential vanilloid 4) cause diverse and largely distinct channelopathies, including inherited forms of neuromuscular disease, skeletal dysplasias, and arthropathy. Pathogenic TRPV4 mutations cause gain of ion channel function and toxicity that can be rescued by small molecule TRPV4 antagonists in cellular and animal models, suggesting that TRPV4 antagonism could be therapeutic for patients. Numerous variants in TRPV4 have been detected with targeted and whole exome/genome sequencing, but for the vast majority, their pathogenicity remains unclear. Here, we used a combination of clinical information and experimental structure-function analyses to evaluate 30 TRPV4 variants across various functional protein domains. We report clinical features of seven patients with TRPV4 variants of unknown significance and provide extensive functional characterization of these and an additional 17 variants, including structural position, ion channel function, subcellular localization, expression level, cytotoxicity, and protein-protein interactions. We find that gain-of-function mutations within the TRPV4 intracellular ankyrin repeat domain target charged amino acid residues important for RhoA interaction, whereas ankyrin repeat domain residues outside of the RhoA interface have normal or reduced ion channel activity. We further identify a cluster of gain-of-function variants within the intracellular intrinsically disordered region that may cause toxicity via altered interactions with membrane lipids. In contrast, assessed variants in the transmembrane domain and other regions of the intrinsically disordered region do not cause gain of function and are likely benign. Clinical features associated with gain of function and cytotoxicity include congenital onset of disease, vocal cord weakness, and motor predominant disease, whereas patients with likely benign variants often demonstrated late-onset and sensory-predominant disease. These results provide a framework for assessing additional TRPV4 variants with respect to likely pathogenicity, which will yield critical information to inform patient selection for future clinical trials for TRPV4 channelopathies.

Surgical Management of Hook of Hamate Fractures: A Systematic Review of Outcomes.

Purpose: This review aimed to compare the postoperative outcomes of open reduction internal fixation (ORIF) versus excision in the surgical treatment of hook of hamate fractures. Methods: A systematic review of PubMed and EMBASE databases from 1954 to 2023 was performed using the search term "hook of hamate fracture" to identify all publications regarding the use of ORIF or excision in the treatment of hook of hamate fractures. Outcomes included a return to sport, pain, ulnar nerve dysfunction, flexor tendon dysfunction, union rate, wrist range of motion (ROM; % of contralateral hand), grip strength (% of contralateral hand), and quick disabilities of arm, shoulder, and hand scores. Results: Twenty-seven of the 705 total screened articles were included. Excision of the hook of hamate (n = 779) resulted in a shorter return to sport time (6 vs 7.8 weeks), lower rates of postoperative pain (6.1% vs 33.3%), higher rates of ulnar nerve sensory dysfunction (4.2% vs 0%), and higher rates of ulnar nerve motor dysfunction (1.5% vs 0%) relative to ORIF (n = 51). Chronic fractures had a longer return to sport time (7.2 vs 5.7 weeks) relative to nonchronic injuries. Conclusions: Both surgical procedures appear to yield acceptable outcomes in the treatment of hook of hamate fractures. However, based on the sparsity of available data, we are unable to determine a consistent difference between hook of hamate excision and ORIF. Clinical relevance: To our knowledge, no current consensus on the optimal surgical treatment for hook of hamate fractures exists. Our findings emphasize the need for a large prospective cohort study using standardized outcomes to provide strong evidence as to whether surgical excision or ORIF yields greater outcomes in the treatment of hook of hamate fractures.

Characterization of adverse events in injured patients at risk of hemorrhagic shock: a secondary analysis of three harmonized prehospital randomized clinical trials.

Background: The reporting of adverse events (AEs) is required and well defined in the execution of clinical trials, but is poorly characterized particularly in prehospital trials focusing on traumatic injury. In the setting of prehospital traumatic injury trials, no literature currently exists analyzing the clinical implications of AEs and their associations with mortality and morbidity. We sought to analyze AEs from three prehospital hemorrhagic shock trials and characterize their time course, incidence, severity, associated clinical outcomes, and relatedness. Methods: We performed a secondary analysis of three prehospital randomized clinical trials. We analyzed AEs at both the patient level as well as the individual AE level. We categorized patients who had no AEs, a single documented AE and those with multiple events (>1 AE). We characterized AE timing, severity, relatedness and attributable mortality outcomes. Results: We included 1490 patients from the three harmonized clinical trials, with 299 (20.1%) individual patients having at least a single AE documented with 529 AEs documented overall as a proportion of patients had multiple events. Over 44% of patients had a death-related misclassified AE. Patients with at least a single documented AE had a significantly higher 28-day mortality (log-rank χ2=81.27, p<0.001) compared with those without an AE documented. Patients with a single AE had a significant higher mortality than those with multiple AEs, potentially due to survival bias (log-rank χ2=11.80, p=0.006). When relatedness of each individual AE was characterized, over 97% of AEs were classified as 'definitely not related' or 'probably not related' to the intervention. Conclusions: AEs in hemorrhagic shock trials are common, occur early and are associated with mortality and survival bias. The potential for inaccurate reporting exists, and education and training remain essential for appropriate treatment arm comparison. The current results have important relevance to injury-related clinical trials. Trial registration numbers: NCT01818427, NCT02086500 and NCT03477006. Level of evidence: II.

Prehospital tranexamic acid is associated with a survival benefit without an increase in complications: results of two harmonized randomized clinical trials.

INTRODUCTION: Recent randomized clinical trials have demonstrated that prehospital tranexamic acid (TXA) administration following injury is safe and improves survival. However, the effect of prehospital TXA on adverse events, transfusion requirements and any dose response relationships require further elucidation. METHODS: A secondary analysis was performed using harmonized data from two large, double-blinded, randomized prehospital TXA trials. Outcomes, including 28-day mortality, pertinent adverse events and 24-hour red cell transfusion requirements were compared between TXA and placebo groups. Regression analyses were utilized to determine the independent associations of TXA after adjusting for study enrollment, injury characteristics and shock severity across a broad spectrum of injured patients. Dose response relationships were similarly characterized based upon grams of prehospital TXA administered. RESULTS: A total of 1744 patients had data available for secondary analysis and were included in the current harmonized secondary analysis. The study cohort had an overall mortality of 11.2% and a median injury severity score of 16 (IQR: 5-26). TXA was independently associated with a lower risk of 28-day mortality (HR: 0.72, 95% CI 0.54, 0.96, p = 0.03). Prehospital TXA also demonstrated an independent 22% lower risk of mortality for every gram of prehospital TXA administered (HR: 0.78, 95% CI 0.63, 0.96, p = 0.02). Multivariable linear regression verified that patients who received TXA were independently associated with lower 24-hour red cell transfusion requirements (ß: -0.31, 95% CI -0.61, -0.01, p = 0.04) with a dose-response relationship (ß: -0.24, 95% CI -0.45, -0.02, p = 0.03). There was no independent association of prehospital TXA administration on VTE, seizure, or stroke. CONCLUSIONS: In this secondary analysis of harmonized data from two large randomized interventional trials, prehospital TXA administration across a broad spectrum of injured patients is safe. Prehospital TXA is associated with a significant 28-day survival benefit, lower red cell transfusion requirements at 24 hours and demonstrates a dose-response relationship. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Adjuvant Stereotactic Radiosurgery for Clear Cell Meningiomas.

OBJECTIVE: Clear cell meningiomas (CCM) are an uncommon meningioma subtype marked by aggressive growth and high rates of recurrence despite initial resection. The present study evaluates the adjuvant benefit of stereotactic radiosurgery (SRS) for residual or recurrent tumors. METHODS: After review of our prospectively maintained database, we identified 6 patients (3 female) with histologically confirmed Grade 2 CCMs. The median age of the patients at the time of SRS was 45 years. Five patients had undergone prior gross total surgical resection and 1 patient had subtotal resection before SRS. The median SRS treatment volume was 4.7 cc and the median radiosurgical margin dose was 13 Gy (range: 10-15 Gy). RESULTS: The median follow-up time was 35.5 months (range 6-168 months). Three patients achieved tumor control after the first SRS procedure. Three patients experienced tumor progression at 4, 22, and 32 months after initial SRS. Tumor control was obtained in 2 of these patients after additional SRS. One patient with multiple SRS procedures had suspected adverse radiation effect that was successfully treated with corticosteroids followed by bevacizumab. CONCLUSIONS: Tumor control was maintained in 5 of 6 patients after one or more SRS procedures. SRS should be considered for early intervention after surgical resection of CCM. To maximize the tumor control rate, patients with diagnosed CCM should be treated more generously and higher margin dose should be prescribed. Patients with CCM should be counselled that more than one SRS may be necessary to provide sustained tumor control.

Missingness matters: a secondary analysis of thromboelastography measurements from a recent prehospital randomized tranexamic acid clinical trial.

Background: Tranexamic acid (TXA) has been hypothesized to mitigate coagulopathy in patients after traumatic injury. Despite previous prehospital clinical trials demonstrating a TXA survival benefit, none have demonstrated correlated changes in thromboelastography (TEG) parameters. We sought to analyze if missing TEG data contributed to this paucity of findings. Methods: We performed a secondary analysis of the Study of Tranexamic Acid During Air Medical and Ground Prehospital Transport Trial. We compared patients that received TEG (YES-TEG) and patients unable to be sampled (NO-TEG) to analyze subgroups in which to investigate TEG differences. TEG parameter differences across TXA intervention arms were assessed within subgroups disproportionately present in the NO-TEG relative to the YES-TEG cohort. Generalized linear models controlling for potential confounders were applied to findings with p<0.10 on univariate analysis. Results: NO-TEG patients had lower prehospital systolic blood pressure (SBP) (100 (78, 140) vs 125 (88, 147), p<0.01), lower prehospital Glascow Coma Score (14 (3, 15) vs 15 (12, 15), p<0.01), greater rates of prehospital intubation (39.4% vs 24.4%, p<0.01) and greater mortality at 30 days (36.4% vs 6.8%, p<0.01). NO-TEG patients had a greater international normalized ratio relative to the YES-TEG subgroup (1.2 (1.1, 1.5) vs 1.1 (1.0, 1.2), p=0.04). Within a severe prehospital shock cohort (SBP<70), TXA was associated with a significant decrease in clot lysis at 30 min on multivariate analysis (ß=-27.6, 95% CI (-51.3 to -3.9), p=0.02). Conclusions: Missing data, due to the logistical challenges of sampling certain severely injured patients, may be associated with a lack of TEG parameter changes on TXA administration in the primary analysis. Previous demonstration of TXA's survival benefit in patients with severe prehospital shock in tandem with the current findings supports the notion that TXA acts at least partially by improving clot integrity. Level of evidence: Level II.

Lung transplantation in HIV seropositive recipients: An analysis of the UNOS registry.

BACKGROUND: Experience with lung transplantation (LT) in patients with human immunodeficiency virus (HIV) is limited. Many studies have demonstrated the success of kidney and liver transplantation in HIV-seropositive (HIV+) patients. Our objective was to conduct a national registry analysis comparing LT outcomes in HIV+ to HIV-seronegative (HIV-) recipients. METHODS: The United Network for Organ Sharing database was queried to identify LTs performed in adult HIV+ patients between 2016 and 2023. Patients with unknown HIV status, multiorgan transplants, and redo transplants were excluded. The primary endpoints were mortality and graft rejection. Survival time was analyzed using Kaplan-Meier analysis. RESULTS: The study included 17 487 patients, 67 of whom were HIV+. HIV+ recipients were younger (59 vs. 62 years, p = .02), had higher pulmonary arterial pressure (28 vs. 25 mm Hg, p = .04), and higher lung allocation scores (47 vs. 41, p = .01) relative to HIV- recipients. There were no differences in graft/recipient survival time between groups. HIV+ recipients had higher rates of post-transplant dialysis (18% vs. 8.4%, p = .01), but otherwise had similar post-transplant outcomes to HIV-recipients. CONCLUSIONS: This national registry analysis suggests LT outcomes in HIV+ patients are not inferior to outcomes in HIV- patients and that well-selected HIV+ recipients can achieve comparable patient and graft survival rates relative to HIV- recipients.

Socioeconomic factors predict successful supervised exercise therapy completion.

OBJECTIVE: Supervised exercise therapy (SET) for patients with intermittent claudication (IC) can lower the risk of progression to chronic limb-threatening ischemia and amputation, while preserving and restoring functional status. Despite supporting evidence, it remains underutilized, and among those who initiate programs, attrition rates are extremely high. We hypothesize that socioeconomic factors may represent significant barriers to SET completion. METHODS: Patients with IC referred to SET at a multi-hospital, single-institution health care system (2018-2022) from a prospectively maintained database were retrospectively analyzed. Our primary endpoint was SET program completion and graduation, defined as completion of 36 sessions. Our secondary endpoints were vascular intervention within 1 year of referral and change in ankle-brachial index (ABI). Baseline demographics were assessed using standard statistical methods. Predictors of SET graduation were analyzed using multivariable logistic regression generating adjusted odds ratios (aORs) with 95% confidence intervals (CIs). Change in ABI was analyzed using t-test between subgroups. Reasons for attrition were tabulated. Patient Health Questionnaire-9 (PHQ-9), metabolic equivalent level, Vascular QOL, Duke Activity Status, and ABI were analyzed using paired t-tests across the entire cohort. RESULTS: Fifty-two patients met inclusion criteria: mean age 67.85 ± 10.69 years, 19 females (36.54%), mean baseline ABI of 0.77 ± 0.16. The co-pays for 100% of patients were fully covered by primary and secondary insurance plans. Twenty-one patients (40.38%) completed SET. On multivariable analysis, residence in a ZIP code with median household income <$47,000 (aOR, 0.10; 95% CI, 0.01-0.76; P = .03) and higher body mass index (aOR, 0.81; 95% CI, 0.67-0.99; P = .04) were significant barriers to SET graduation. There were no differences in ABI change or vascular intervention within 1 year between graduates and non-graduates. Non-graduates reported transportation challenges (25.00%), lack of motivation (20.83%), and illness/functional limitation (20.83%) as primary reasons for SET attrition. Metabolic Equivalent Level (P ≤ .01) and Duke Activity Status scores (P = .04) were significantly greater after participating in a SET program. CONCLUSIONS: Although SET participation improves lower extremity and functionality outcomes, only 40% of referred patients completed therapy in our cohort. Our findings suggest that both socioeconomic and functional factors influence the odds of completing SET programs, indicating a need for holistic pre-referral assessment to facilitate enhanced program accessibility for these populations.

Management of sarcomatoid Malignant pleural mesothelioma brain metastases with stereotactic radiosurgery: an Illustrative case.

Background: Malignant pleural mesothelioma (MPM) is a rare cancer of the respiratory system that rarely metastasizes to the brain. We report a case of sarcomatoid MPM (SMPM) managed with Stereotactic radiosurgery (SRS) to achieve intracranial tumor control and improve neurological symptoms.Illustrative case: This 67-year-old female patient underwent SRS twice in order to treat a total of 15 brain metastases. One-month follow-up imaging after the first SRS demonstrated local tumor response and seven tumors with symptomatic vasogenic edema that responded to initial corticosteroids followed by bevacizumab. At a three-month follow-up after the first procedure, eight new tumors were detected and required repeat SRS. Although sustained tumor control resulted in improved neurological function, the patient subsequently expired from systemic disease progression 12 months after initial diagnosis and six months after initial SRS for brain metastases despite the concurrent use of systemic immunotherapy and systemic chemotherapy.Conclusions: Although SRS provided overall tumor control of metastatic brain disease, further advances in systemic therapies will be needed to improve survival in this aggressive rare cancer.