Citations

Abstract Introduction Cannabidiol has been shown to exert significant anti-inflammatory effects and has demonstrated efficacy in murine models of autoimmune myocarditis, pericarditis, and heart failure. The ARCHER Study assessed whether a pharmaceutically produced cannabidiol formulation showed beneficial effects on cardiac magnetic resonance (CMR) endpoints known to predict prognosis in this patient population. Methods In a multicentre international double-blind placebo-controlled phase 2 study, we randomly assigned 109 patients within 10 days of CMR confirmed diagnosis of acute myocarditis to 12 weeks of pharmaceutically produced oral cannabidiol (active) or placebo. Dose was titrated up to 10 mg/kg of body weight twice daily. Primary endpoints were the difference in extracellular volume (ECV) and global longitudinal strain (GLS) measured by CMR at week 12. Other CMR endpoints included left-ventricular ejection fraction (LVEF), LV mass, intracellular volume (ICV), LV end-diastolic and end-systolic volumes (LVEDV, LVESV), and left-atrial end-systolic volume (LAESV). Results All randomized patients (56 active/53 placebo) completed the study with no loss to follow-up. Study drug appeared safe and well tolerated. Baseline mean ECV 38.9 ± 10.9 ml, GLS −15.3 ± 3.6%, and LVEF 60.6 ± 9.9% were consistent with mild to moderate myocarditis and predominantly intact LV function. Week 12 mean ECV was 33.6 ml in the active group and 37.3 ml in the placebo group, a difference of −3.7 ml, confidence interval (CI): −7.4 to 0.1; P = .0538; GLS was −16.0% in the active group and −15.9% in the placebo group, difference of −0.1, CI: −1.2 to 1.1; P = .90. Left ventricular mass was significantly reduced in the active group at 121.1 g compared to placebo 130.3 g, a difference of −9.2, CI: −16.4 to −2.1; P = .0117. In terms of remodelling, LAESV was significantly reduced in the active group (−8.1 ml; P = .0376) while the reduction in LVEDV failed to reach significance (−7.4 ml; P = .098). Conclusion In mild-to-moderate acute myocarditis, treatment with pharmaceutically manufactured cannabidiol was not associated with a statistically significant change in myocardial ECV or GLS, although a trend towards reduction in ECV was observed. In addition, improvement in other potential markers of myocardial recovery, including a significant reduction in LV mass, was seen in the active treatment group. Further investigation of the therapeutic potential of this therapy in inflammatory cardiac conditions is warranted.

Abstract Background Reference sets are needed to evaluate performance of multi-cancer detection (MCD) assays. The National Cancer Institute funded the Alliance reference set study to assess MCDs for use in future trials. Methods Individuals with cancer and controls were recruited; blood specimens were collected prior to cancer treatment. A performance evaluation study was designed utilizing reference set samples. Companies (n = 6) were selected to participate based on review of performance data and ability to utilize the blood collection tube. Companies received samples from cancer types their assay was designed to detect (“targeted”), plus additional “non-targeted” and control samples. Companies reported positive/negative calls, risk scores, and tissue-of-origin (TOO) predictions. Sensitivity was computed for early (I-II) and late (III-IV) stage cases, based on positive/negative calls (SEPN) and at fixed 98% specificity (SE98). Specificity and TOO accuracy were computed. Results Five hundred and forty nine cases (encompassing 13 cancer types) and 413 controls from the reference set were included in the study. Companies assessed samples from median 6 (range 5-9) targeted cancer types and median 8 (range: 7-11) overall cancer types. Median (range) specificity was 92.3% (76.5%-98.5%). Median (range) SEPN was 32% (25%-42%) for early stage and 73% (48%-89%) for late stage; while median (range) SE98 was 19% (8%-35%) for early stage and 66% (13%-79%) for late stage. Median sensitivity for non-targeted types was 40% (early stage) and 52% (late stage). Median (range) TOO accuracy (primary predicted site) was 75% (64%-78%). Conclusions Sensitivity and specificity varied widely across assays with early-stage sensitivity substantially lower than late-stage sensitivity. Clinical Trial Registration Number ClinicalTrials.gov identifier NCT05334069.

Background/Objectives: To evaluate risk factors for postoperative neurological deficits following cervical endoscopic unilateral laminotomy for bilateral decompression (CE-ULBD) and to determine whether intraoperative neurophysiological monitoring (IONM) can predict neurological compromise. Methods: A multicenter retrospective review was performed on 42 CE-ULBD procedures conducted between 2016 and 2024; 33 cases met the inclusion criteria with available imaging and electromyography data. Demographic, operative, and neurophysiological variables were analyzed. Preoperative stenosis severity was graded using the Kang MRI system. Intraoperative IONM data, including electromyography firing and motor evoked potential (MEP) changes, were correlated with new postoperative weakness. Results: The cohort (69.1% male, mean age 70.2 ± 1.7 years, mean BMI 29.6 ± 1.1) included 56 decompressed levels. The most common operative levels were C3-4 (37%) and C4-5 (24%). Postoperative weakness occurred in four patients (12.1%), all of whom had severe (Grade 3) preoperative stenosis. Among these, 50% exhibited preoperative weakness. Neuromonitoring changes correlated significantly with postoperative weakness (Fisher’s Exact, p < 0.001); 100% of patients with new post-operative weakness had sustained MEP decrease at the time of closure. Conclusions: Patients with severe cervical stenosis and preoperative weakness are at heightened risk of postoperative neurological deficits following CE-ULBD. Elevated epidural pressure from continuous irrigation in a constricted canal may exacerbate cord compression, particularly in those with preexisting myelopathy. IONM changes strongly correlate with new deficits and may exacerbate cord compression, particularly in those with preexisting myelopathy, and may serve as an early warning system for impending neurological injury. Surgeons should exercise caution and maintain low irrigation pressures in patients with severe stenosis undergoing endoscopic cervical decompression.

Objectives Ultrasound‐guided percutaneous needle fenestration (UPNF) and percutaneous needle tenotomy (UPNT) are minimally invasive procedures commonly used to treat chronic tendinopathies. However, these techniques can be painful, potentially limiting patient tolerance, satisfaction, and procedural feasibility. Although local anesthetics (LAs) provide analgesia, their potential inhibitory effects on tenocyte activity and the efficacy of orthobiologics raise concerns regarding their impact on tendon healing. The objectives of this study is to propose a practical, anatomy‐based approach for the use of ultrasound‐guided peripheral nerve blocks (USG‐PNBs) as a strategy to reduce pain and improve patient comfort during UPNF and UPNT, with or without orthobiologic adjuncts. Methods We reviewed commonly affected anatomical sites in chronic tendinopathies and identified corresponding peripheral nerve targets that can be reliably and safely blocked under ultrasound guidance. For each condition, we outline appropriate nerve block techniques, anatomical landmarks, and recommended patient positioning to optimize procedural analgesia. Results A set of targeted USG‐PNBs was defined for commonly treated tendinopathies, including supraspinatus tendinopathy, lateral and medial epicondylitis, gluteus medius and/or minimus tendinopathy, patellar tendinopathy, Achilles tendinopathy, and plantar fasciopathy. Conclusion Ultrasound‐guided peripheral nerve blocks represent a practical and effective approach to manage pain during percutaneous procedures for chronic tendinopathies. By reducing procedural discomfort and avoiding the potential drawbacks of peritendinous LAs, these techniques may enhance patient tolerance, procedural success, and overall clinical outcomes.

Aims Total elbow arthroplasty (TEA) has shown favourable outcomes in the management of severely comminuted distal humeral fractures in low-demand elderly patients, leading to its increased use in recent years. Less is known about the outcomes of TEA when used for the failure of either internal fixation or conservative management, particularly whether not performing TEA acutely influences the options for further management if fixation fails. This systematic review aimed to assess the clinical and functional outcomes following TEA when used for the post-traumatic sequelae of a distal humeral fracture, and to compare these outcomes with those in patients with a distal humeral fracture who undergo TEA acutely. Methods MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Scopus databases were searched from January 2000 to September 2024 for studies reporting complications, reoperations, the range of motion of the elbow, or functional outcomes following the use of TEA in the management of the post-traumatic sequelae of distal humeral fractures, including those due to failed fixation, nonunion, and post-traumatic arthritis. Demographic and clinical data were collected, descriptive statistics were summarized, and meta-analyses were undertaken to compare the outcomes between salvage and acute TEA. Results A total of 16 studies were included, with a total of 380 patients who underwent salvage TEA and 251 who underwent TEA as the initial management. Salvage TEA was associated with a significantly higher overall risk of complications (odds ratio (OR) 2.5 (95% CI 1.0 to 5.9)), though the rate of reoperations did not differ from those who underwent TEA acutely (OR 1.4 (95% CI 0.8 to 2.4)). Pooled analyses revealed a similar postoperative range of flexion (mean difference (MD) -2.4° (95% CI -9.1 to 4.3)) and extension of the elbow (MD 1.1° (95% CI -2.3 to 4.5)) and pronation (MD 0.0° (95% CI -1.1 to 1.1)) and supination (MD -0.0° (95% CI -1.0 to 0.9)) of the forearm. However, salvage TEA showed significantly inferior functional outcomes, as assessed by the Mayo Elbow Performance Score (MD 9.7 (95% CI -18.8 to -0.6)). Conclusion These findings indicate that salvage TEA represents a viable option for the management of post-traumatic sequelae following the teatment of a distal humeral fracture, although patients who underwent salvage TEA had a significantly increased rate of complications and significantly inferior functional outcomes compared with those who underwent TEA acutely. Cite this article: Bone Joint J 2026;108-B(1):21–29.

ABSTRACT Introduction Positron emission tomography (PET) myocardial flow reserve (MFR) is a robust indicator of coronary vascular health and a strong predictor of cardiovascular risk. Clinical guidelines typically use fixed MFR thresholds (e.g., <2.0) to stratify risk, yet this approach overlooks individual variation, particularly by age and sex. We aimed to establish age- and sex-adjusted MFR percentiles and to evaluate their prognostic and predictive performance for cardiovascular risk assessment, in comparison with conventional fixed-threshold MFR approach. Methods Using data from the REFINE PET registry (24,820 patients from 12 sites), we measured PET MFR and derived age- and sex-adjusted MFR reference percentiles using quantile regression in patients without known coronary artery disease. All patients were categorized into percentile-based quartile groups. The primary outcome for prognostic and prediction analyses was major adverse cardiovascular events (MACE), defined as all-cause mortality, myocardial infarction, or heart-failure hospitalization. Time-to-event associations were evaluated using covariate-adjusted survival models, with cumulative incidence and hazard ratios (HR) estimated at 1 and 5 years in the derivation dataset, an independent but similar validation dataset A, and a high-risk validation dataset B. Predictive performance for MACE was assessed using discrimination, calibration, and reclassification metrics, comparing percentile-based models with models using a fixed MFR threshold (<2.0). Results Among participants (mean age 66.5 years; median follow-up 3.6 years), age- and sex-adjusted MFR quartile groups were strong independent predictors of MACE, with adjusted HR increasing stepwise across quartile groups at both early and later follow-up. At 1 year, HR (95% CI) comparing the lowest to the highest quartile group were 4.06 (3.41–4.82) in the derivation cohort, 3.31 (2.32–4.71) in validation cohort A, and 2.35 (2.05–2.70) in validation cohort B. At 5 years, the corresponding HR were 2.18 (1.86–2.56), 1.77 (1.31–2.40), and 1.59 (1.36–1.86). Percentile-based models demonstrated consistently higher discrimination, better calibration, and greater net reclassification for MACE at both time points compared with fixed-threshold MFR models. Although 67.2% of patients had preserved MFR (>2.0), cardiovascular risk increased steadily across MFR percentiles even within this range. Conclusion Age- and sex-adjusted MFR percentiles provide a reliable, clinically actionable measure of vascular health, improving cardiovascular risk stratification by better capturing age- and sex-related heterogeneity in vascular risk. Compared with traditional fixed-threshold approaches, MFR percentiles demonstrate improved predictive performance for cardiovascular risk assessment across diverse patient populations. CLINICAL PERSPECTIVE What is new? In a large, multinational real-world registry of more than 24,000 patients undergoing PET MPI, we derived age- and sex-adjusted myocardial flow reserve (MFR) percentiles, establishing a lifespan-based reference framework with age-specific reference values. Age- and sex-adjusted MFR percentiles showed a strong, graded association with 1- and 5-year cardiovascular risk and demonstrated improved prognostic and predictive performance compared with fixed MFR thresholds and models without MFR across independent derivation and validation datasets, including a higher-risk cohort. Lower adjusted MFR percentiles were consistently associated with higher risk of major adverse cardiovascular events, including all-cause mortality, myocardial infarction, and heart-failure hospitalization. What are the clinical implications? Age- and sex-adjusted MFR percentiles provide a personalized, dynamic measure of coronary vascular health that improves cardiovascular risk stratification by accounting for age- and sex-related heterogeneity. A percentile-based approach may help clinicians better identify patients at elevated cardiovascular risk who may warrant closer monitoring or intensified preventive strategies, while avoiding unnecessary intervention in lower-risk individuals. By integrating macrovascular and microvascular dysfunction, age- and sex-adjusted MFR percentiles offer a clinically interpretable marker of vascular aging that may inform future research on aging biomarkers, novel therapeutics and cardiovascular risk assessment across the spectrum of atherosclerotic and microvascular disease.

Abstract Background Gastrointestinal (GI) cancer remains a major global health challenge. This study provides updated 2022 estimates of GI cancer incidence and mortality worldwide, along with projections of incident cases and deaths through 2050 to inform cancer control strategies. Methods In this population‐based study, data from the GLOBOCAN 2022 database were used to examine incidence and deaths associated with GI cancer. By using global demographic projections, this study estimated the projected number of incident cases and deaths until the year 2050. Results By 2050, the global burden of GI cancer is projected to reach 9.06 million incident cases (+85%) and 6.42 million deaths (+93%) from 2022. Increases in incidence are projected for both females (+87%) and males (+83%), as are increases in mortality for both females (+97%) and males (+91%). Whereas the Western Pacific region will have the highest absolute burden, with 3.88 million new cases and 2.79 million deaths, the greatest relative increase is expected in Africa, with incidence and deaths rising by 157% and 160%, respectively. As measured by the Human Development Index (HDI), the steepest increases are projected in low (+151% incidence; +152% deaths) and medium (+112% incidence; +114% deaths) HDI countries. Overall, all GI cancer types are projected to increase, led by pancreatic cancer in incidence (+95%) and colorectal cancer in deaths (+103%). Conclusions GI cancer incidence and deaths are expected to nearly double by 2050, with increases across sexes, cancer types, and regions, especially in lower HDI countries.

Abstract Background TMEM106B encodes a lysosomal protein and is a genetic susceptibility factor for frontotemporal lobar degeneration (FTLD). Aptamer‐based proteomics quantifies TMEM106B protein levels in CSF. The associations of CSF TMEM106B with measures of disease severity have not been previously evaluated, and the value of CSF TMEM106B as a clinical biomarker is unknown. Method CSF TMEM106B and NfL protein levels were quantified with aptamer‐based proteomics in participants from two independent cohorts: sporadic FTLD with neuropathology‐confirmed FTLD‐tau and FTLD‐TDP, clinically diagnosed PSP‐Richardson Syndrome, and controls (UCSF MAC, n = 95; mean age = 69 ± 6 yrs; 48% female) and familial FTLD comprised of presymptomatic and symptomatic FTLD mutation carriers with family non‐carrier controls (ALLFTD, n = 179; mean age = 49 ± 13 yrs; 53% female). The association between biomarkers and diverse measures of disease severity, including the CDR®+NACC‐FTLD and CDR®+NACC‐FTLD sum of boxes, were determined with linear regressions or mixed linear models. Associations with brain volumes were determined within the framework of voxel‐based morphometry. Result In both cohorts, at baseline, CSF TMEM106B did not differ by sex, age, FTLD phenotype, or CSF NfL. CSF TMEM106B was lower in cases with worse disease severity (Figure 1) and in participants with the protective TMEM106B rs1990622 G/G genotype, regardless of pathological diagnosis or FTLD‐causing mutation. Low CSF TMEM106B was associated with more severe longitudinal worsening in FTLD disease severity (Figure 2), basic and instrumental function, global cognition, executive function, and depression scores. These associations were weaker than those of NfL. Low CSF TMEM106B was associated with low brain volumes in frontal, parietal, and temporal regions (FWE‐corrected p < 0.05) (Figure 3A). CSF NfL negatively correlated (FWE‐corrected p < 0.05) with brain volumes in frontotemporal regions (Figure 3B). Conclusion CSF TMEM106B concentrations are influenced by the TMEM106B rs1990622 genotype, and correlate with disease severity and brain volume in both genetic and sporadic FTLD. Lower levels of CSF TMEM106B correlate with more severe disease and brain atrophy. Disease severity is more strongly associated with CSF NfL, while brain volumes are more strongly associated with CSF TMEM106B. CSF TMEM106B may have value as a biomarker of neurodegeneration in FTLD.

ABSTRACT Background Mood episodes in bipolar disorder (BD) follow a seasonal pattern in approximately 25% of patients. We aimed to examine the associations of specific seasonality patterns in BD with various clinical phenotypes and treatment‐related outcomes. Methods Patients from the Mayo Clinic Bipolar Disorder Biobank with available seasonality data were included in the study. Among those reporting any seasonality, participants were further categorized into four seasonality groups: fall/winter depression, spring/summer (hypo)mania, biphasic (fall/winter depression with spring/summer (hypo)mania), and equinoctial seasonality (any mood episode occurring in spring or fall). Regression models were used, treating seasonality patterns as the predictor of clinical phenotypes (BD subtype, early onset, history of psychosis, suicide attempt, rapid cycling), lifetime medication exposure (number of unique antidepressants, antipsychotics, and any psychotropics) and treatment response to mood stabilizers (Alda A score). Results Among 1702 patients with BD (61.5% female, mean age = 41.43 ± 14.73 years), 44.6% reported seasonal mood episodes. Individuals with any seasonality were more likely to have BD‐I (OR = 1.29, p = 0.024), early onset (OR = 1.29, p = 0.026), exposure to higher lifetime number of antipsychotics (IRR = 1.20, p < 0.001) and any psychotropics (IRR = 1.13, p < 0.001). Fall/winter depression was associated with a higher lifetime number of antidepressants (IRR = 1.18, p = 0.021), any psychotropics (IRR = 1.14, p = 0.013), worse response to lithium ( β = −0.82, p = 0.029) and all mood stabilizers ( β = −0.69, p = 0.014). Spring/summer (hypo)mania showed negative associations with rapid cycling (OR = 0.36, p < 0.001) and lifetime number of antidepressants (IRR = 0.70, p = 0.013). Equinoctial seasonality was linked to a history of psychosis (OR = 1.76, p = 0.004). Conclusion Seasonality in BD is associated with distinct clinical features and treatment‐related outcomes. Specific seasonality patterns, particularly fall/winter depression, may reflect a more complex and difficult‐to‐treat illness course. These findings highlight the need for research to better characterize seasonality subtypes beyond a binary “seasonal” vs. “non‐seasonal” classification and to explore how these patterns influence the illness course and management of BD.

Abstract Background Despite recent approval of monoclonal antibodies that reduce amyloid (Ab) accumulation, the development of disease‐modifying strategies targeting the underlying mechanisms of Alzheimer’s Disease (AD) are urgently needed. We identified mitochondrial complex I (mtCI) as a small‐molecule druggable target for AD. Using cryo‐EM, we previously demonstrated that the neuroprotective tool compound CP2 directly binds to the Q‐site of mtCI and weakly inhibits its activity. Method Rational design and extensive structure‐activity relationship studies using CP2 as a tool compound allowed the development of novel classes of partial mtCI inhibitors with high selectivity, specificity, safety, and improved drug‐like properties. Target engagement, selectivity, efficacy, safety and the direct binding to mtCI were demonstrated using multiple in vitro assays. Efficacy in vivo was established using APP/PS1 mice. The best new leads, C458 and C273, were evaluated as preclinical candidates. Result Like CP2, C458 and C273 weakly inhibit mtCI, leading to AMPK activation, which triggers a neuroprotective stress response. This response enhances oxidative stress protection, promotes autophagy, and increases mitochondrial biogenesis and turnover, ultimately protecting against Aβ toxicity. Pretreatment with the irreversible mtCI inhibitor rotenone (at non‐toxic concentrations) blocked C458 and C273 from binding to mtCI and abrogated their protection against Aβ toxicity. Both C458 and C273 exhibited excellent bioavailability, blood–brain barrier penetrance, and a clean safety profile in the CEREP 44 safety panel. Chronic administration of C458 (25 mg/kg/day in drinking water ad lib ) to APP/PS1 mice for 7 months preserved cognition, improved long‐term potentiation, reduced oxidative stress and inflammation, and enhanced mitochondrial biogenesis. Similarly, C273 (20, 50, or 80 mg/kg/day) administered to C57BL/6 mice for one month showed no detectable side effects or toxicity in the heart or liver. Conclusion Mechanistic studies revealed that C458 and C273 activate a mitochondrial stress response, augmenting mitochondrial biogenesis, antioxidant signaling, and autophagy, which collectively provided protection against Aβ toxicity in multiple in vitro and in vivo models of AD. These findings demonstrate that weak mtCI inhibition by novel compounds C458 and C273, with improved drug‐like properties, is neuroprotective. This supports the feasibility of developing safe and efficacious mtCI inhibitors as a disease‐modifying strategy for AD.