Citations

AbstractThe sliding filament theory explains skeletal muscle fibre force change as a function of length based on the overlap of actin and myosin filaments. Although this length‐tension (LT) relationship has been well investigated in animal models, it is not known whether this microscopic sarcomere LT property can be scaled up five orders of magnitude to explain the LT behaviour of a long human muscle such as the gracilis. The goal of this study is to validate the sarcomere LT curve in humans based on human filament length combined with in vivo experimental data. Intraoperative measurements of maximal tetanic force and muscle‐tendon unit length at four different joint configurations (JC) were obtained from 19 patients undergoing free functioning muscle transfer surgery. With physiologically measured fibre length and estimated sarcomere shortening resulting from tendon compliance, we show that 79.7% variance in isometric force data is explained by a simple human sarcomere LT model. This study demonstrates that the human whole muscle LT relationship can be modelled by the sliding filament theory given patient‐specific fibre length, filament length, tendon compliance and sarcomere shortening. imageKey points Whole human gracilis muscle isometric length‐tension relationships were measured in the operating room. Grouped whole muscle raw length‐tension curves showed no obvious form. The width of each experimental length‐tension curve was highly variable across subjects and used to predict fibre length (serial sarcomere number). After whole muscle length‐tension curves were normalized to each patient's serial sarcomere number, the whole human muscle length‐tension curve was well predicted by the sliding filament theory.

Abstract Rationale: The US prison population carries a high burden of chronic disease and disability, with older adults constituting the fastest growing subpopulation. When medical needs exceed a prison's healthcare service capabilities, incarcerated patients are transported to clinics and hospitals in surrounding communities. The influence of prison policies on off-site medical care of incarcerated patients is poorly understood. This study aims to identify and classify correctional policies regulating the care of incarcerated patients in community hospitals. Methods: Between 6/2024-10/2024 we searched the Internet for policies from states’ Departments of Corrections (DOC) pertaining to healthcare of incarcerated patients. We compiled, reconciled and organized those policies according to date, jurisdiction and relevance to hospital care. We then developed a preliminary thematic coding scheme and, using mixed inductive and deductive content analysis, two coders independently applied our codebook to each policy. Any coding discrepancies were resolved by consensus, and when necessary, with adjudication by a third team member. Results: Forty-eight state DOCs and the District of Columbia (totaling 49 “states”) have publicly available policies pertaining to healthcare. Among these, 20/49 (41%) have policies pertaining to the protection of bodily privacy during healthcare encounters. Separately, 31 (63%) have policies regarding the confidentiality of incarcerated patients’ medical encounters and records. Thirty-four (69%) maintain policies regarding incarcerated individuals’ right to select and consent to treatment. Thirty-three (67%) include language about the right to refuse treatment. Twenty-six states (53%) direct that incarcerated individuals be informed of their right to access healthcare either in writing (22/49; 45%), verbally (20/49; 41%), or through posted signage (5/49; 10%). Twenty-one states (43%) address shackling during off-site medical care, but only 15 (31%) address responding to requests from off-site clinicians to minimize or remove patients’ restraints. Just 4/49 states (8%) use person-centered language (avoiding terms like “offender” and “inmate”). Policy excerpts addressing key domains are depicted in the Table. Conclusions: Correctional policies regarding the care of incarcerated patients in community hospitals vary significantly in scope and content across states. While incarcerated people have a Constitutionally protected right to accept or refuse healthcare, including making their own treatment decisions, many state policies do not explicitly mandate how these disclosures must be communicated to patients or their healthcare providers. These silences, when combined with security measures like shackling and the ubiquitous presence of officers, countermand person-centered care and undermine the ability of hospital healthcare professionals to uphold the rights and dignity of incarcerated patients.

Abstract Introduction: The variety of pulmonary function tests (PFTs) offered in the pulmonary function lab (PFL) can confuse providers unfamiliar with the clinical role of the individual components of the PFT, potentially leading to repeat tests, diagnostic delays, patient burden, and reduced lab efficiency. We hypothesized that a symptom- and diagnosis-based ordering set will reduce the need for repeat testing visits. Methods: Baseline data (June 2022-June 2023) were first collected to establish PFL performance benchmarks and identify common reasons for incomplete or repeat PFL visits. We then implemented an electronic order set reflecting the clinical need of the PFT, based on symptoms, diagnoses, suspected diagnoses, or other common clinical indication in addition to a physician-supervised, results-driven protocol to allow de-escalation of testing when appropriate The pre-implementation data was compared to the post-implementation data (July 2023-June 2024), evaluating for its impact on PFL access, utilization of the specific PFT components (e.g. methacholine challenge test, MCT), and on diagnoses. Results: During the study period 52,292 PFTs were performed during the pre-implementation phase compared to 58,310 tests in the post-implementation phase. Following intervention, the need for a second PFL visit for the same clinical indication decreased from 26% to 13% (p<0.0001). The same day PFL capacity increased by 3-4 patients per day. 80% of primary care providers reported the new order design was more intuitive and easier to use. Among the specific components of the PFT, there was a significant increase in the number MCTs being performed, from 2.5% to 4%, (p<0.0001), with a change rate ranging between 26 – 81% / month. In a subset analysis of 57 consecutive patients having MCTs, the primary indications were evaluation for cough or wheezing (57.9%), initial asthma evaluation (22.8%), and specifically requested by the ordering provider (19.3%). MCT was not performed in 23% due to a low baseline lung function, difficulty with repeatable efforts, recent bronchodilator administration, or due to complicating comorbidities. Of the 39 tests completed, 89% were deemed appropriate, with 32% having positive results and 42% ultimately diagnosed with asthma. Conclusions: A symptom and/or diagnosis guided ordering set for pulmonary function testing appears to improve the efficiency of the PFL, while improving provider experience, PFL access, as well as on patient burden and diagnoses. Further research is needed to determine potential benefits for provider decision-making and patient outcomes.

Abstract Rationale: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer. They are also associated with life-threatening immune-related adverse events (irAEs), including the rare, poorly understood, and potentially fatal triad of myasthenia gravis, myocarditis, and myositis(triple M syndrome). We aimed to describe the management, intensive care unit (ICU)utilization, and outcomes of patients with irAEs with a specific focus on triple M syndrome. Methods: We conducted a retrospective chart review of patients with irAEs admitted to three quaternary care hospitals between December 2018 and 2023. We aimed to collect data on demographics, cancer type, treatment, ICU resource utilization, and outcomes including mortality. Results: Over this 5-year period, 140 patients were admitted for irAEs. Forty-nine percent were male, median age was 73 (IQR 64-80) years, 7% were of African American or Asian descent, and 32%required ICU admission. Median ICU and hospital length of stay (LOS) were 1.5 (IQR 0.7-2.9)and 7.2 (IQR 4.1-13.4) days, respectively. Among ICU patients, 14/140 (10%) had myositis,22/140 (16%) myocarditis, and 9/140 (6.4%) myasthenia gravis. Triple-M syndrome was diagnosed in 7/140 (5%) patients, including 3 with metastatic melanoma, 2 with genitourinary malignancies, 1 with metastatic lung and 1 with colon cancer. Four had received pembrolizumab and 3 nivolumab. Median ICU and hospital LOS were 3 (IQR 1-6) and 10 (IQR 8-21) days in this group. Three patients required mechanical ventilation, one required tracheostomy, and one required vasopressor support. Triple-M management included corticosteroids, IVIG, pyridostigmine, mycophenolate mofetil, and rituximab. Patients with triple-M syndrome were significantly older than other patients with ICI toxicity (P <0.009) and had higher mortality (57%vs 25%, p = 0.07). Patients discharged from the ICU had a median survival of 67 (IQR 26-201)days. Conclusions: Patients with irAEs frequently require ICU level of support with significant morbidity and mortality, especially with triple M syndrome. Clinicians should always consider the possibility of triple-M syndrome in patients with multiple irAEs as symptoms can be subtle and easily overlooked. Corticosteroids remain the primary treatment of irAEs and can be combined with other immunosuppressive agents such as infliximab, anti-thymocyte globulin, or pyridostigmine. Unfortunately, mortality due to triple-M syndrome remains high underscoring the importance of early recognition and prompt multidisciplinary management of these toxicities.

Abstract Rationale Exertional dyspnea in children presents a complex diagnostic challenge, often requiring multiple evaluations to uncover underlying etiologies. Exercise testing is the standard for diagnosing exercise-induced bronchoconstriction (EIB) in children but requires significant resources. Fractional exhaled nitric oxide (FeNO), a marker of airway inflammation, has been proposed as an easier alternative to predict the need for exercise testing. The aim of this study is to evaluate the diagnostic utility of fractional exhaled nitric oxide (FeNO) as a non-invasive marker of bronchial hyperreactivity in pediatric patients with exertional dyspnea, by assessing its sensitivity, specificity, and predictive values in comparison to cardiopulmonary exercise testing (CPET), the gold standard for diagnosing exercise-induced bronchoconstriction (EIB). This study seeks to determine whether FeNO can reliably guide the need for CPET, potentially streamlining the diagnostic process in children with suspected EIB, while also identifying any limitations of FeNO as a standalone diagnostic tool. Methods In this retrospective study, we reviewed pediatric patients up to 18 years of age who presented with unexplained dyspnea and underwent both CPET and FeNO testing from July 2020 to February 2023. A post-exercise decline in FEV1% of ≥10% during CPET defined a positive result for EIB. For FeNO, a threshold of ≥25 parts per billion (ppb) was considered indicative of bronchial hyperreactivity. Diagnostic agreement between FeNO and CPET was analyzed using a 2x2 table, with CPET as the reference standard. Results Among 98 patients who completed CPET, the cohort had a mean age of 14 years (SD ± 2.42), mean BMI of 22.2 kg/m² (SD ± 5.25), and 71% were female. Of these, 40 patients also underwent FeNO testing. Compared to CPET, FeNO exhibited a sensitivity of 100%, a specificity of 2.6%, a positive predictive value of 5.1%, and a negative predictive value of 100% for identifying bronchial hyperreactivity in this setting. Conclusion FeNO testing shows high sensitivity but limited specificity for detecting bronchial hyperreactivity, effectively ruling out but not confirming it independently of CPET. These findings reinforce the essential role of CPET in diagnosing EIB and suggest that FeNO may serve best as an adjunctive tool, rather than a primary diagnostic measure, in evaluating children with exertional dyspnea. A limitation of this study is the reliance on a single FeNO threshold, which may not account for individual variability in bronchial inflammation responses.

Abstract Rationale Exertional dyspnea in children often necessitates a thorough evaluation to determine potential causes, with bronchial hyperresponsiveness (BHR) and exercise-induced bronchoconstriction (EIB) being among the most common. Cardiopulmonary exercise testing (CPET) is widely recognized as the gold standard for diagnosing EIB; however, it requires significant patient cooperation and specialized resources. The methacholine challenge test (MCT), a bronchial provocation test, is commonly employed to evaluate baseline airway hyperreactivity. Nonetheless, its reliability in predicting EIB in pediatric patients experiencing exertional dyspnea has not been well established. This study aims to evaluate the diagnostic accuracy of MCT compared to CPET in detecting BHR among pediatric patients with unexplained dyspnea. This assessment will help determine the potential of MCT as a complementary diagnostic tool for EIB. Methods We conducted a retrospective cohort study involving pediatric patients (up to 18 years of age) who underwent both CPET and MCT as part of their clinical evaluation for exertional dyspnea from July 2020 to February 2023. A reduction of ≥20% in FEV1% was considered a positive result for the methacholine challenge. In the CPET, a decrease of ≥10% in FEV1% post-exercise was indicative of EIB. The results from both tests were compiled in a 2x2 table, using MCT as the reference standard. Results Out of the 98 patients who underwent CPET, 53 also completed a methacholine challenge test. The mean age of participants was 14 years (SD ± 2.42), with a mean BMI of 22.2 kg/m² (SD ± 5.25), and 71% of the patients were female. Using CPET as the reference standard, the MCT demonstrated a sensitivity of 66.7%, specificity of 58%, positive predictive value of 8.7%, and a negative predictive value of 96.7% for identifying BHR in patients with exertional dyspnea. Conclusions MCT exhibited moderate sensitivity and specificity, and a high negative predictive value, indicating its effectiveness in ruling out BHR in children with exertional dyspnea. However, it is less reliable as a standalone diagnostic tool for EIB, and CPET remains essential for an accurate diagnosis of EIB in these patients.

We have developed a cost-effective method to study the fate of stents, particularly flow diverter stents placed in the abdominal aorta, in a rat model. This technique utilizes (caudal) tail artery access,1–5 thereby avoiding the need for surgical exposure of the femoral or carotid arteries and reducing procedural invasiveness,6 7 aligning with the principles of refinement and reduction in animal research.7 This approach may be particularly beneficial for studies requiring multiple or iterative vascular access. The use of ultrasound guidance further reduces costs and infrastructure requirements by eliminating the need for specialized angiography suites.8 This makes this technique accessible to a broader range of research settings, promoting wider adoption and collaboration in the field of endovascular research. A detailed demonstration of this method is provided in the accompanying educational video (video 1). Video 1 -Technical video describing the tail artery access and flow diverter deployment using ultrasound guidance.

Objective To develop and validate classification criteria for pediatric chronic nonbacterial osteomyelitis (CNO) jointly supported by EULAR and the American College of Rheumatology (ACR). Methods This international initiative had 4 phases: (1) candidate items were proposed in a survey of pediatric rheumatologists, (2) criteria definition and reduction by Delphi and nominal group technique exercises, (3) criteria weighting using multicriteria decision analysis, and (4) refinement of weights and threshold score in a development cohort of 441 patients and validation in another cohort of 514 patients. Results The new EULAR/ACR classification criteria for CNO require typical radiographic or magnetic resonance imaging findings and bone pain as an obligatory entry criterion and exclusion criteria of malignancy, infection, vitamin C deficiency, and hypophosphatasia, followed by additive weighted criteria in 5 clinical (site of bone lesions, pattern of bone lesions, age at onset, coexisting conditions, fever) and 4 pathology/laboratory domains (bone biopsy findings if done, anemia, C‐reactive protein level, and erythrocyte sedimentation rate). A total score ≥55 is required for classification as CNO. The new criteria had a sensitivity of 82% and specificity of 98% in the validation cohort. Conclusion These new classification criteria for pediatric CNO developed with international input reflect current views about CNO, have high specificity and good sensitivity, and provide a key foundation for future CNO research.

PURPOSE Randomized clinical trials (RCTs) have shown progression-free survival (PFS) benefits of metastasis-directed therapy (MDT) without androgen deprivation therapy for oligometastatic castration-sensitive prostate cancer (omCSPC). Most patients with bone metastatic (BM) omCSPC recur with additional bone disease after MDT. We hypothesized the BM-targeting alpha-emitter radium-223 dichloride (Ra223) could target subclinical bone disease and delay progression. METHODS This is an investigator-initiated, multicenter, open-label phase II RCT. Eligible men with recurrent omCSPC with ≥one bone metastasis (≤three on conventional imaging and/or ≤five on molecular imaging) were randomly assigned (1:1) to stereotactic ablative radiation (SABR) MDT alone or SABR MDT with Ra223 (six cycles). Primary end point was composite PFS. RESULTS From August 9, 2019, to March 2, 2023, 64 patients were randomly assigned, 33 to SABR MDT and 31 to SABR MDT/Ra223 balancing for key covariates. Most SABR MDT/Ra223 patients (87%) received six cycles of Ra223. The median PFS was 11.8 months with SABR MDT and 10.5 months with SABR MDT/Ra223 (adjusted hazard ratio [aHR], 1.42 [95% CI, 0.79 to 2.56]; P = .24). Seven patients (11%) experienced grade 3 treatment-related adverse events (no grade 4 or 5), 2 of 33 (6%) with SABR and 5 of 30 (17%) with SABR MDT/Ra223. Patients with high-risk (HiRi) pathogenic mutations in ATM , BRCA1/2 , RB1 , or TP53 had worse PFS (HR, 5.95 [95% CI, 1.83 to 19.3]; P = .003). Greater T-cell receptor (TCR) unique productive rearrangements were prognostic for improved PFS independent of the treatment arm (aHR, 0.45 [95% CI, 0.21 to 0.96]; P = .04). CONCLUSION Adding Ra223 to SABR MDT in BM omCSPC does not delay progression of disease. We provide evidence for an HiRi mutational signature and TCR repertoire as prognostic biomarkers in omCSPC treated with SABR MDT, highlighting the importance of collecting biological correlates in RCTs for omCSPC.