Citations

Abstract The recent FDA approval of the first T-cell receptor–engineered (TCR) T-cell cancer therapy has solidified the treatment as a viable therapeutic strategy. However, only a fraction of patients who received this treatment achieved substantial and long-lasting responses, highlighting the need to understand the molecular underpinnings of these responses and develop more effective strategies to improve this therapy. Previous research has demonstrated that the activation of myeloid differentiation primary response 88 (MyD88) signaling in tumor-specific T cells functions as a robust costimulatory signaling pathway that promotes effective antitumor T-cell responses. In this study, we developed a strategy for improving TCR T-cell therapies by creating a synthetic TCR in which the intracellular domain of CD3ζ and a modified MyD88 are appended to the β-chain of a tumor-reactive TCR. The β:CD3ζ:MyD88 TCR activated MyD88 signaling in a tumor antigen/TCR-specific manner, and β:CD3ζ:MyD88 TCR T cells exhibited enhanced functionality and a reduced propensity to become exhausted. Furthermore, MyD88 signaling promoted T-cell persistence and expansion in vitro. In vivo, tumor-infiltrating β:CD3ζ:MyD88 TCR T cells skewed the immunosuppressive tumor microenvironment toward a less immunosuppressive state. Finally, β:CD3ζ:MyD88 TCR T cells substantially delayed tumor growth kinetics in a melanoma model. These findings introduce an approach for improving TCR-dependent T-cell responses by directly appending signaling domains to the full-length TCR and exemplify the utility of activating MyD88 signaling in tumor-specific T cells. Significance: A chimeric β:CD3ζ:MyD88 TCR reduces exhaustion and improves antitumor T-cell responses, overcoming the limited efficacy of current TCR-engineered T-cell cancer therapies.

Background: Frequent pivoting, rotation, and deep hip flexion place football players at high risk for femoroacetabular impingement (FAI), a leading cause of hip pain in this population. Previous studies have primarily focused on professional National Football League athletes undergoing mixed surgical techniques, including labral debridement. Limited data exist on outcomes in younger, amateur players treated with labral repair. Purpose: To report return to sport (RTS) rates and functional outcomes at a minimum 5-year follow-up in primarily active high school and college football players undergoing primary hip arthroscopy with labral repair for FAI. Study Design: Case series, Level of evidence, 4. Methods: All football players who underwent primary hip arthroscopy with labral repair for FAI between 2010 and 2019 were identified from an institutional database. Collected data included descriptive data, radiographic parameters, surgical details, and reoperations. At a minimum 5-year follow-up, RTS outcomes and patient-reported outcome measures (PROMs), such as the Modified Harris Hip Score (mHHS) and Hip Outcome Score (HOS), were evaluated. Results: A total of 36 hips in 27 male athletes (mean age, 18 years; body mass index, 28.1 kg/m 2 ) were included. The majority of athletes competed at the high school (70%) or collegiate level (26%). Mean preoperative radiographic measurements were as follows: lateral center-edge angle, 31.6°; Tönnis angle, 4.1°; and alpha angle, 61.4°. Femoroplasty and acetabuloplasty were performed in 100% and 86% of cases, respectively. Also, 84% of players returned to football, all at the same or higher level than before surgery. At a mean follow-up of 9.8 years, all PROMs improved significantly from baseline ( P < .002). Outcome scores at follow-up were as follows: mHHS 90.5; HOS-Activities of Daily Living, 94.5; HOS-Sports-Specific Subscale, 91.1; and visual analog scale (VAS) pain with use, 2.3/10; VAS pain at rest, 1.3/10; and surgical satisfaction, 8.5/10. No patients required revision surgery. However, 2 patients (7%) underwent reoperations—including 1 for heterotopic ossification excision and 1 for periacetabular osteotomy. Conclusion: American football players who underwent primary hip arthroscopy with labral repair for FAI achieved excellent long-term outcomes, with high RTS rates at the same or higher levels, and improvements in PROMs and patient satisfaction. Despite favorable outcomes, nonmedical factors, such as graduation, may influence RTS in competitive athletes, particularly at the high school and collegiate levels.

Background: Functional hypothalamic amenorrhea (FHA) is a common form of secondary amenorrhea caused partly by undernutrition relative to demand. Objective: To compare the dietary nutritional intake between women with FHA and eumenorrheic controls and evaluate micronutrient profiles. Methods: This cross-sectional study included 30 women with FHA and 29 eumenorrheic controls not on hormones. FHA was defined as ≥3 consecutive months of amenorrhea, estradiol of <50 pg/mL, and FSH and LH of <10 mIU/L, excluding other etiologies. A 3-day food diary was collected for dietary analysis, excluding dietary supplements using ESHA Research Food Processor. Results: The mean age of women with FHA and controls was 26.4 years ± 6.2 versus 30.3 years ± 3.7 ( p = 0.002), with no differences in BMI ( p = 0.16) or the waist-to-hip ratio ( p = 0.71). Women with FHA and controls consumed comparable median calorie intake (1784 kcal [1465, 2011] vs. 1732 kcal [1578, 1982], p = 0.62), with no differences in self-reported exercise patterns. Women with FHA consumed more dietary protein (84.2g [74, 112] vs. 74 g [59, 92], p = 0.001) and dietary fiber (30.1 g [22, 43] vs. 17.3 g [15, 23], p = 0.02) versus controls, respectively. When expressed as a percentage of estimated average requirements (% estimated average requirement), women with FHA had higher intakes of vitamin A (105% [45, 219] vs. 43% [21, 86], p = 0.005), vitamin C (201% [139, 351] vs. 107% [75, 190], p = 0.004), and iron (169% [146, 220] vs. 120% [99, 192], p = 0.027) compared with controls. Conclusions: Women with FHA had similar caloric intake to eumenorrheic controls but consumed more dietary protein, fiber, vitamin A, vitamin C, and iron. Future studies should examine the nutritional profiles of women with FHA in relation to long-term health consequences such as bone and vascular health.

Background: Long COVID, the chronic sequela of SARS-CoV-2 infection, has affected millions of people worldwide. However, its pathogenesis and treatment remain unknown. To address this critical gap, the National Institutes of Health (NIH) developed the Researching COVID to Enhance Recovery (RECOVER) Initiative that included the Viral Persistence and Reactivation, and Immune Dysregulation (RECOVER-VITAL) study as one of the first of five NIH-sponsored, integrated platform protocols to support the rigorous and rapid investigation of potential interventions for Long COVID. Methods: Experts across academia, the NIH, and the community of patients and caregivers were brought together to design the RECOVER-VITAL protocol. We present the challenges and rationale underpinning critical components of this protocol and provide evidence for use of the platform for efficient execution of current and future Long COVID clinical trials. Facets of the RECOVER-VITAL protocol, including inclusion criteria, intervention groups, study procedures, investigation of biomarkers, and endpoints, were carefully crafted to advance the current and future science and operations of Long COVID clinical trials, particularly in the absence of existing data. The initial trial within the RECOVER-VITAL platform evaluated two durations of an antiviral drug, nirmatrelvir/ritonavir, to test the proposed etiology of viral persistence on the Long COVID symptom clusters of autonomic dysfunction, cognitive dysfunction, and exercise intolerance. The primary outcome measures were patient-reported, and secondary outcomes included performance-based measures for each of the symptom clusters of interest. Conclusions: The RECOVER-VITAL platform protocol has substantial implications for the design and conduct of future Long COVID clinical trials.

Asthma is a heterogeneous chronic respiratory disease driven by diverse inflammatory pathways that vary across patients. The recognition of distinct molecular endotypes has led to the development of targeted biologic therapies that have transformed the management of moderate-to-severe asthma. However, selecting the most appropriate biologic therapy for each patient remains challenging. Health providers often rely on trial-and-error approaches that may delay disease control, increase costs, and expose patients to unnecessary side effects. Biomarkers are key to precision asthma care, as they provide objective measures of underlying disease mechanisms. Established biomarkers such as blood eosinophil count, fractional exhaled nitric oxide, and serum total immunoglobulin E are important for identifying type 2-high asthma. Sputum biomarkers offer direct insight into airway inflammation, but their use is limited by technical complexity and availability across centers. Emerging biomarkers, including proteomic, transcriptomic, metabolomic, and genomic biomarkers, show promise in further refining biologic therapy selection. In addition, digital biomarkers derived from electronic health records, wearable devices, and artificial intelligence-based algorithms offer new opportunities to capture real-world changes in disease and treatment response. Non-medical drivers of health, particularly socioeconomic factors, are increasingly recognized as modifiers of biologic effectiveness and may also be helpful in selecting biologic therapies. This review summarizes the existing evidence on established and emerging biomarkers used to guide biologic therapy selection in asthma. Integrating multiple biomarkers will be essential to improve biological selection, monitor response, and ultimately achieve the goal of remission in asthma.

Abstract The transition from internship to residency represents an important period for trainees. However, little is known about self-assessed preparedness among physiatry trainees. This national cross-sectional exploratory survey of United States postgraduate year 2–4 physiatry residents aimed to examine self-reported preparedness at the start of postgraduate year 2. A total of 109 postgraduate year 2–4 residents completed this survey, with 57.8% (63/109) reporting feeling prepared to assume patient care responsibilities at the start of postgraduate year 2 and 42.2% (46/109) reporting feeling unprepared to do so. Specific internship experiences (e.g., developing comfort handling overnight calls and rapid responses), but not type of intern year (e.g., transitional year, preliminary internal medicine or surgery year, intern year included in a categorical physiatry residency program) may be associated with self-reported clinical preparedness. Further research is warranted to explore in more detail factors identified as potentially associated with self-assessed clinical preparedness, as well as opportunities to identify and address physiatry trainee needs.

It is well established that many tumor types possess defective autophagic pathways. Several studies have reported that the transmembrane, autophagic lipid scramblase ATG9B is altered in multiple cancers, suggesting that this dysregulation could contribute to oncogenesis. Therefore, the goal of this study was to define the cellular distribution of ATG9B in two different tumor cell types and to provide insights into its cellular function. Surprisingly, we found that ATG9B shows a modest association with autophagic structures and exhibits a unique and prominent localization to mitochondria, in contrast to its related form ATG9A. Upon expression of tagged ATG9B forms, this mitochondrial distribution was accompanied by aberrant changes in mitochondrial morphology as well as a reduction in the mitochondrial membrane potential and the release of mtDNA. Few indicators for ATG9B-dependent mitophagy were noted. Instead, ATG9B overexpression led to pronounced apoptotic cell death as assessed by a variety of indicators. Further, we find that the N-terminal sequence of ATG9B acts as a mitochondrial targeting domain and that expression of this peptide alone can induce apoptotic cell death. These findings provide new insights into a putative cellular localization and function for ATG9B.

Background: Acute traumatic patellar dislocations may cause intra-articular derangements of the knee in the setting of acute and chronic instability which may not always be appropriately identified on magnetic resonance imaging (MRI). Purpose: To determine the rates of coexisting intra-articular pathology in patients with patellar instability requiring medial patellofemoral ligament (MPFL) reconstruction and to report discrepancies between preoperative magnetic resonance imaging (MRI) findings and diagnostic arthroscopy results. Study Design: Cohort study (Diagnosis); Level of evidence, 3. Methods: Patients who underwent MPFL reconstruction at a single institution between 2010 and 2023 were identified. Operative reports and preoperative MRIs were reviewed. Records without full MRI reports as read by a radiologist or cases in which a diagnostic arthroscopy was not conducted were excluded. Intra-articular pathologies noted on MRI and confirmed by arthroscopy were documented. MRI findings were considered to be discordant from arthroscopic findings if a lesion was identified on diagnostic arthroscopy that was not present in the full MRI report and that lesion resulted in additional surgical procedures. Results: There were 331 arthroscopic procedures conducted within the study population of 508 patients who underwent diagnostic arthroscopy at the time of their patellar stabilization procedures. These procedures included 180 loose body removals, 95 osteochondral lesions treated via a variety of interventions including open reduction and internal fixation (26 cases), particulated allograft chondral grafting (30 cases), osteochondral allograft transplantation (9 cases), and microfracture (30 cases), and 39 meniscal tears resulting in 33 partial meniscectomies and 6 meniscal repairs. Among these 508 patients, 105 (21%) demonstrated discordance of preoperative MRI and arthroscopic findings that necessitated additional procedures. This discordance was responsible for a total of 109 (33%) of the 331 arthroscopic procedures. These included 75 loose body removals, 2 osteochondral fracture fixation procedures, 2 microfractures for full-thickness cartilage loss, 16 partial meniscectomies, and 2 meniscal repairs, among others. Conclusion: Among patients undergoing patellar stabilization, 21% had intra-articular lesions not identified on preoperative MRI detected at the time of diagnostic arthroscopy that resulted in surgical intervention. This study, representing the largest cohort to date of patellar stabilization surgeries with both MRI and arthroscopy findings, underscores the importance of diagnostic arthroscopy for improving diagnostic accuracy and addressing associated intra-articular pathology.

Introduction: The Revised Cardiac Risk Index (RCRI) and the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) are well-recognized tools to predict 30-day postoperative cardiac events in noncardiac surgeries. However, their predictive accuracy is yet to be assessed in minimally invasive transurethral prostate surgery. We compared the RCRI- and NSQIP-predicted postoperative cardiac outcomes with the actual incidence of cardiac events after transurethral prostate surgery. Methods: We conducted a retrospective review of patients who underwent transurethral prostate surgery between July and December of 2022. We assessed for postoperative cardiac events within 30 days, as defined by the seminal cardiac VISION study. The RCRI and NSQIP cardiac event predictions were calculated. Fisher’s exact test was used for analysis. Results: We included 185 patients with an average age of 73 ± 8.4 (standard deviation) years, 86 of whom (46%) had transurethral resection of the prostate, and 99 underwent Holmium Laser Enucleation of the Prostate (54%). Myocardial injury after noncardiac surgery surveillance was needed for 34 patients (18.4%) as per standard practice. No patient had any intraoperative cardiac events. One patient experienced a nonfatal postoperative cardiac event (asystole) within hours of surgery. The 30-day cardiac event prediction by the RCRI was 4.8% of the patient cohort ( n ≈ 9), significantly higher than the observed incidence of 0.5% ( p = 0.0198). NSQIP predicted that 0.54% of the patient cohort ( n = 1) will have a cardiac complication within 30 days, which is not significantly different from the observed cardiac event incidence ( p = 1). Conclusion: The RCRI significantly overestimated the 30-day cardiac risk after transurethral prostate surgery, whereas NSQIP predictions and the observed rate of cardiac events were similar. Utilizing more representative predictive tools helps improve risk stratification and will allow patients and surgeons to make better-informed decisions.