Publications by Year: 2026

CONTEXT: This review synthesizes current literature regarding metabolic aspects of athlete bone health and incorporates evidence-based recommendations into a clinician-friendly algorithm.

EVIDENCE ACQUISITION: Published manuscripts listed in PubMed between 1993 and 2024 were reviewed. Relevant terms including keywords and section titles of manuscripts were searched, and relevant studies identified.

STUDY DESIGN: Clinical review.

LEVEL OF EVIDENCE: Level 1-3.

RESULTS: A metabolic workup is often appropriate in the context of an athlete with bone stress injury (BSI) but varies based on clinical scenario. Evidence supports that all athletes with BSI be considered for a minimum workup including 25-hydroxyvitamin D (SORT A), complete blood count (CBC) (SORT B), and an iron panel with ferritin (SORT B). Athletes with features of low energy availability, including ≥2 Triad risk factors (low body mass index, abnormal uterine bleeding), or with multiple features of relative energy deficiency in sport require an initial strategy to correct energy availability (increased energy intake and/or decreased training load) and should be considered for dual-energy x-ray absorptiometry (DXA) (SORT A) and additional laboratory testing. If there is persistent clinical concern, a comprehensive laboratory evaluation should be considered, and varies based on athlete sex and clinical context. People with recurrent or multiple BSI or requiring surgical fixation also warrant detailed, stepwise testing for underlying causes (SORT C). A reasonable strategy starts with a focused workup for more common conditions (eg, CBC, complete metabolic panel, iron panel, 25-OH vitamin D, DXA) and may expand based on initial findings and clinical suspicion.

CONCLUSION: Existing evidence supports optimizing nutrition and further evaluation for factors influencing bone health for all athletes with BSI. More extensive workup is required in athletes with multiple features of low energy availability, multiple/recurrent BSI, BSI requiring surgical fixation, and signs/symptoms of an underlying medical disorder.Strength-of-Recommendation Taxonomy (SORT):A, B, C.

BackgroundAvailable evidence for many prescription drugs comes from clinical trials that often exclude older patients. Real-world evidence (RWE) generated post-approval can provide new evidence on effectiveness and safety for these populations. We sought to understand physicians' perceptions of clinical trial and RWE for prescribing decisions. To frame the study, we used examples of drugs for heart failure and anticoagulation, which are more like to be prescribed to older adults.MethodsWe conducted an interview study of 15 US physicians specializing in geriatrics, cardiology, or primary care and affiliated with academic medical centers. Interviews were coded using a qualitative thematic analysis approach to construct themes and identify patterns in responses.ResultsAll participants described limitations in current believed real-world evidence could help inform patient care and their practice. However, they had concerns about the data. If clinical trial and RWE findings diverged, all would need more information to determine which findings to follow.ConclusionsPhysicians who routinely prescribe to older patients are optimistically cautious about RWE for drugs but would rely on trusted sources, like professional society guidelines, for incorporating it into practice. Therefore, RWE researchers should identify opportunities to work alongside guideline developers and database editors on the practice-relevant interpretation and dissemination of the evidence.

OBJECTIVES: To comprehensively review the available literature on prehabilitation and rehabilitation exercise, nutrition, and psychological support interventions for patients with kidney cancer (KC), to summarise the clinically relevant efficacy and cost-effectiveness of interventions, to expose key knowledge gaps, and to inform future investigations and initiatives.

METHODS: This review was performed according to the per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Extension for Scoping Reviews Guidelines. We included randomised controlled trials (RCTs) assessing programmes of prehabilitation or rehabilitation, exercise, psychological support, or nutrition components in patients with KC or KC caregivers from January 2004 to March 2022. Statistically significant positive (SS+) and negative (SS-) results were summarised.

RESULTS: The systematic search yielded 10 968 records including 18 RCTs, involving 2774 unique subjects, 706 of whom were KC patients/survivors. None included caregivers or assessed cost-effectiveness. Two interventions were implemented before surgery, one was implemented prior to initiation of systemic therapy, eight were implemented during systemic or radiation therapy, three were implemented after treatment, while implementation time was not specified for four interventions.

CONCLUSION: Most (14/18) RCTs involving exercise, nutrition, psychological support, or prehabilitative or rehabilitative programmes for KC performed to date demonstrated SS+ results. The evidence was most robust regarding previously evaluated psychological support, especially mindfulness-based interventions (9/10 studies demonstrating SS+ improvement in primary outcomes), followed by therapeutically valid exercise with/without psychological support (5/8 RCTs demonstrated efficacy), then nutrition or pharmacological interventions (2/5 demonstrated efficacy). Level 1 evidence supports counselling patients and referral to mindfulness-based psychological therapy along with physical therapy or physical medicine and rehabilitation, as well as consideration of preoperative carbohydrate drinks. No studies have examined impact on caregivers, or cost-effectiveness, which are both critical areas for future study.

AIMS: Radiofrequency ablation (RFA) is the gold standard for treating symptomatic osteoid osteoma (OO), yet risk factors for recurrence and complications remain poorly understood. This study aims to identify predictors of recurrence and local complications following RFA.

METHODS: A retrospective cohort study of OO patients treated with RFA at two academic medical centres between January 2010 and December 2024 was conducted. Primary outcomes were recurrence, defined as the return of symptoms with radiological confirmation, and post-procedural complications. Secondary outcomes included clinical success (complete pain resolution) and technical success (procedure done according to protocol). Descriptive, univariable, multivariable, and survival analyses were performed, with a sub-analysis of anterior tibial lesions.

RESULTS: A total of 272 patients were included. The median age was 20 years (IQR 16 to 26), and 189 of patients were male (69.5%). The most common locations for OO were the femur (41.9%, n = 114), tibia (26.5%, n = 72), and foot (11.4%, n = 31). The median tumour size was 7 mm (IQR 6 to 10) . Recurrence occurred in 5.5% (n = 15) of cases, with spinal location as a risk factor (odds ratio (OR) 6.22; p = 0.048). Complications were observed in 4% (n = 11) of patients, with increased risk in females (OR 5.17; p = 0.014) and those with tibial lesions (OR 13.23; p = 0.018). In tibial lesions, an anterior approach with the RFA probe was associated with a higher rate of wound infection (100% vs 0%; p = 0.028).

CONCLUSION: RFA is a highly effective treatment for OO, with low rates of recurrence and complications. The identified risk factors underscore the need for tailored treatment plans. Furthermore, the anterior tibial approach should consistently incorporate a soft-tissue buffer to minimize the risk of wound infection.

Posttraumatic stress disorder (PTSD) is associated with early onset of neurological conditions, but the mechanism by which PTSD relates to diseases of the central nervous system is unclear. One possibility is that PTSD perpetuates breakdown of the blood brain barrier (BBB), allowing for bidirectional passage of molecules across the periphery and central nervous system that promote neuropathology. Preclinical studies have implicated claudin-5 (CLDN5), a protein integral to the integrity of the BBB tight junctions, in the pathogenesis of depression. Based on this, we evaluated if trauma exposure and PTSD related to CLDN5 epigenetics in blood among 1311 trauma-exposed individuals (primarily Veterans) and in the brain tissue from 100 decedents. Three (out of 19) CLDN5 DNA methylation (DNAm) probes, cg00804504, cg17411190, and cg21872764, were significantly associated with trauma exposure or PTSD severity after multiple testing correction in blood. The latter two probes also showed association with PTSD diagnosis in ventromedial prefrontal cortex. The most strongly associated DNAm probe, cg21872764, also evidenced associations with the neuropathology biomarker neurofilament light in plasma. CLDN5 expression was strongly associated with estimated proportion of brain endothelial cells. The cross-sectional associations observed in this study highlight the importance of studying the link between traumatic stress and early onset of neuropathology. Future research is needed to test the mechanistic hypothesis that trauma exposure and chronic PTSD alter CLDN5 DNAm, lead to increased BBB permeability and allow for bidirectional passage of neuroinflammatory molecules across the BBB.

BACKGROUND: Low left ventricular ejection fraction (LEF) can progress undiagnosed. Artificial intelligence-based electrocardiogram (ECG-AI) screening may provide a scalable means to detect LEF.

OBJECTIVES: The purpose of this study was to validate a complete ECG-AI software as a medical device for LEF detection.

METHODS: Four geographically diverse sites in the United States identified patients with both ECGs and transthoracic echocardiograms performed within 30 days of each other in clinical practice. Data were electronically extracted to specific guidelines and transmitted to the coordinating center for analysis.

RESULTS: Records of 16,000 subjects were extracted, resulting in an evaluable set of 13,960 subjects (mean age 66 years; 52% male). The device demonstrated excellent discrimination (AUROC: 0.92 [95% CI: 0.91-0.93]) and was 84.5% (95% CI: 82.2%-86.6%) sensitive and 83.6% (95% CI: 82.9%-84.2%) specific for LEF. The overall prevalence of LEF in the study data set was 7.9%, with LEF among 1.6% of the ECG-AI negative and 30.5% of ECG-AI positive subjects, contributing to positive and negative predictive values of 30.5% (95% CI: 28.8%-32.1%) and 98.4% (95% CI: 98.2%-98.7%), respectively.

CONCLUSIONS: External validation studies such as this one provide a rigorous framework to validate an algorithm's performance. This study demonstrated the algorithm's strong diagnostic accuracy over a geographically diverse, independent set of patients. In this generally unselected population, the algorithm produced a test negative result in 78% of the cases, suggesting potential utility as a rule-out strategy to defer echocardiography when other clinical findings are absent.

Histone deacetylase 6 (HDAC6) represents a compelling target in major depressive disorder (MDD) pathophysiology, yet in vivo investigation has been constrained by inadequate imaging capabilities. Here, we report the development and validation of [18F]PB200, a novel positron emission tomography (PET) radiotracer specifically targeting brain HDAC6. PB200 was engineered with nanomolar affinity, high HDAC6 selectivity, and excellent blood-brain barrier permeability. [18F]PB200 was successfully synthesized in a radiochemical yield of 13 ± 4 % and validated through in vitro autoradiography and in vivo PET imaging across rodent and non-human primate models. We subsequently employed [18F]PB200 alongside TSPO-targeted [18F]FEPPA PET imaging in a chronic unpredictable mild stress (CUMS) mouse model of depression. This dual-tracer approach, complemented by in vitro experiments, revealed significant HDAC6 upregulation occurring concurrently with enhanced neuroinflammatory markers, including microglial activation and elevated pro-inflammatory cytokines. Our findings provide the first in vivo molecular imaging evidence directly linking HDAC6 upregulation to depressive pathophysiology and associated neuroinflammation. This work illuminates the molecular relationship between depression and neuroinflammation while establishing [18F]PB200 as a valuable tool for evaluating HDAC6-targeted therapeutic interventions, potentially advancing precision diagnosis and treatment approaches for depression.

A European Respiratory Society research seminar entitled "Sleep Apnoea and Its Consequences: From Animal Models to Precision Medicine" was held in January 2024 in Lisbon, Portugal. It provided an in-depth analysis of the current landscape and future directions in OSA research, integrating recent findings from metabolomics, animal models, clinical predictors of cardiometabolic consequences of OSA, artificial intelligence (AI), and advances in diagnostic algorithms. This article presents a narrative review of the seminar's key discussions and conclusions. The limitations of current randomized controlled trials (RCTs) in assessing OSA treatment, such as low adherence and patient selection bias (e.g., absence of sleepiness or severe hypoxemia), were critically discussed. The expert panel recommended the use of real-world data, including patients commonly seen in clinical practice, and the use of digital tools for real-time monitoring of adherence and side effects. The concept of platform "disease-focused" trials was discussed as a more efficient and adaptable research design that could allow clinical trials to be more representative of the general OSA population and to compare CPAP with emerging treatments such as new drugs, devices and lifestyle interventions to gain a broader understanding of effective management strategies. The seminar concluded that a multifaceted approach to OSA research that leverages the strengths of animal models, advanced AI, metabolomics, and improved diagnostic algorithms is needed to gain deeper insights into the mechanisms of OSA and its treatment response. This new approach, coupled with new "platform" clinical trial designs, could contribute to improved outcomes in patients with OSA.

OBJECTIVE: To predict cartilage tumor malignancy from radiographic images combined with readily available non-imaging information based on a vision-language foundation model.

MATERIALS AND METHODS: This single-institution study assembled a dataset of 3336 radiographs from 455 patients with enchondroma or chondrosarcoma that was assembled from two sources: (1) patients with histopathology-confirmed diagnoses of enchondroma or chondrosarcoma, and (2) patients with imaging-stable enchondroma without biopsy, confirmed through long-term imaging follow-up. An adapted vision-language foundation model based on the pre-trained CLIP (Contrastive Language-Image Pretraining) architecture was fine-tuned with our proposed Medical Knowledge Adapters and evaluated using 10-fold patient-level cross-validation to predict cartilage tumor malignancy from plain radiographs and demographic information.

RESULTS AND CONCLUSION: Using radiographs alone, the model achieved an Areas Under the receiver operating characteristic Curve (AUC) of 0.91 ± 0.04. Incorporating demographics improved the AUC to 0.94 ± 0.02. Subgroup analysis demonstrated robust generalizability across tumor grades with an AUC of 0.91 ± 0.07 in distinguishing atypical cartilaginous tumors (ACT) previously known as low grade chondrosarcomas, and 0.95 ± 0.02 in differentiating high-grade chondrosarcomas from enchondromas. Within the clinically challenging extremity subgroup (enchondroma vs ACT/LGCS), the model achieved an AUC of 0.79 ± 0.14, reflecting diagnostic difficulty observed in clinical practice. This foundation model-based approach demonstrates strong performance using accessible data sources, offering a non-invasive, cost-efficient, and scalable solution for cartilage tumor assessment in musculoskeletal oncology.