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Case: An 18-year-old immunocompetent man presented with symptomatic lumbar canal stenosis, discharging sinuses, and cold abscess for 3 years treated with multiple incision drainage procedures with cottonoid packing antibiotic therapy. Radiographic imaging showed a soft tissue mass in the canal causing bony destruction. Postoperative histopathological examination showed an Aspergillus fungal ball. Patient showed improvement at 6-month follow-up with medical management. Conclusion: As far as we know, this is the first case report showing an aspergilloma involving the vertebral column. Inadequate antibiotic treatment and blind introduction of a foreign body into sinus tracts can lead to fungal infections mimicking tuberculosis, causing disastrous outcomes. Fungal cultures are recommended routinely. [ABSTRACT FROM AUTHOR]

Case: We present a 17-year-old male patient with an initially missed posterior sternoclavicular fracture dislocation who presented with symptoms related to thrombotic emboli arising from a pseudoaneurysm. He was treated 6 weeks after injury with a figure-of-eight tendon allograft repair with good clinical outcomes. Conclusion: This is a unique presentation that highlights the significant risk of a missed diagnosis, life-threatening complications that may ensue, and biomechanically superior surgical intervention. [ABSTRACT FROM AUTHOR]

Case: A 25-year-old right-hand dominant male police officer presented to the emergency department with a gunshot wound to his left shoulder. Magnetic resonance imaging demonstrated an osteochondral defect overlying the humeral head along the mid to lower aspect of the glenohumeral joint. A staged operation with shoulder arthroscopy followed by an osteochondral allograft (OCA) of the humeral head was performed. During his 6-month postoperative visit, he had returned to full work duty with no restrictions and reported that his pain was well controlled. Conclusion: Humeral head OCA transplantation may be an effective treatment option for traumatic osteochondral lesions of the glenohumeral joint. [ABSTRACT FROM AUTHOR]

Case: An overall healthy 48-year-old man suffered a left foot mangled crush injury resulting in a post-transmetatarsal amputation and subsequently developing a painful neuroma on the plantar surface of the foot. To avoid the zone of injury, targeted muscle reinnervation was used to treat the neuroma by coapting the tibial nerve to the motor point of the flexor hallucis longus (FHL) muscle. At 1-year follow-up, the patient reported no pain at rest, returned to work, and could ambulate with an orthosis for 30 minutes. Conclusion: Rare tibial nerve coaptations to the FHL could serve as a treatment option for patients with neuromas in traumatic postmetatarsal amputation. [ABSTRACT FROM AUTHOR]

Case: We report a unique case of dynamic scapular winging due to compression of the long thoracic nerve by a ventral scapular osteochondroma, representing a combination of mechanical and neural causes. Arthroscopic resection of the lesion was performed, which led to complete resolution of the symptoms. Conclusion: By reporting this case, we aimed to increase awareness of the importance of a correct etiological diagnosis of dynamic scapular winging, so that targeted treatment can be addressed. Arthroscopic resection seems ideal for this indication because it reduces the risk of complications and patient recovery time. [ABSTRACT FROM AUTHOR]

Case: A 48-year-old man presented to a Level 1 trauma center after a motor vehicle crash with a right irreducible posterior hip dislocation and ipsilateral fractures of the femoral head and segmental femur shaft. This injury was managed with open reduction and internal fixation and antegrade intramedullary nailing. Conclusion: This is the first report of a combined irreducible femoral head fracture-dislocation and a segmental femur fracture, a rare injury that requires a stepwise approach to operative management of each injury. Surgeons must recognize the clinical and radiographic findings associated with irreducible hip dislocations in the setting of ipsilateral fractures to the femoral head and shaft. [ABSTRACT FROM AUTHOR]

Case: We present a case of type II (intraosseous) entrapment of the median nerve in a patient who was diagnosed based on clinical examination and magnetic resonance imaging and who was treated with medial epicondyle osteotomy, neurolysis, and transposition of the nerve to its anatomical position within a month of injury. Our patient made a complete motor and sensory recovery at 5 months with complete functionality and grip strength. Conclusion: Median nerve entrapment after posterolateral elbow dislocation is a rare complication with roughly 40 cases reported in the literature. This case illustrates the importance of prompt diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Case: A 29-year-old man with hemophilia B presented with advanced arthropathy of the right knee, resulting in poor knee functional scores and difficulties in his livelihood. The patient underwent total knee replacement while receiving nonacog beta pegol factor IX by a multidisciplinary approach. Conclusion: Hemophilias commonly result in end-stage hemophilic arthropathy of the joints at a young age that may warrant joint replacement surgeries. This case report illustrates the surgical protocol of total knee arthroplasty in a patient who received a long-acting factor IX preparation. [ABSTRACT FROM AUTHOR]

Case: A 71-year-old man with castration-resistant Stage IVB prostate cancer developed symptomatic oligometastatic disease in the lumbar spine and bilateral proximal femurs. He was treated with a single-position L2-L4 kyphoplasty with concomitant prone left-sided femoral prophylactic cephalomedullary nailing. Six months later when he again lost the ability to ambulate, he was treated with a single-position L4-L5 laminectomy for an epidural tumor with prone right-sided femoral prophylactic cephalomedullary nailing. Conclusion: Single-position prone surgery of the spine and prone femoral nailing is feasible and improves on traditional multiposition approaches, eliminating the need to reposition or change tables during management. [ABSTRACT FROM AUTHOR]

Case: We present the case of a 59-year-old man who had MIS L4-5 decompression. He presented the next day with intractable back and leg pain. Magnetic resonance imaging revealed ventral displacement of the cauda equina and a subdural collection on the right L3/L4 nerve roots. Revision decompression revealed occult durotomy caudal and contralateral to the index decompression. Conclusion: Minimally invasive spine (MIS) surgery leverages shorter operative time and reduced postoperative pain. Yet, decreased exposure can make identification and management complications challenging. This report highlights occult durotomy and spinal subdural extra-arachnoid hygroma in patients with postoperative nerve compression after seemingly uncomplicated MISS. [ABSTRACT FROM AUTHOR]

Case: An 18-year-old male patient sustained a traumatic injury that resulted in the loss of approximately 50% of the radial head. Subsequently, reconstruction was performed by transplanting an osteochondral plug harvested from the lateral femoral condyle. At the 1-year postoperative follow-up, the patient was pain-free and had a good range of motion. Conclusion: Using a novel technique, an irreparable radial head fracture was reconstructed using an osteochondral plug from the lateral femoral condyle. Reconstruction with osteochondral plugs may be a treatment option for partial loss of the radial head. [ABSTRACT FROM AUTHOR]

Abnormal encoding of somatosensory modalities (ie, mechanical, cold, and heat) are a critical part of pathological pain states. Detailed phenotyping of patients' responses to these modalities have raised hopes that analgesic treatments could one day be tailored to a patient's phenotype. Such precise treatment would require a profound understanding of the underlying mechanisms of specific pain phenotypes at molecular, cellular, and circuitry levels. Although preclinical pain models have helped in that regard, the lack of a unified assay quantifying detailed mechanical, cold, and heat pain responses on the same scale precludes comparing how analgesic compounds act on different sensory phenotypes. The conflict avoidance assay is promising in that regard, but testing conditions require validation for its use with multiple modalities. In this study, we improve upon the conflict avoidance assay to provide a validated and detailed assessment of all 3 modalities within the same animal, in mice. We first optimized testing conditions to minimize the necessary amount of training and to reduce sex differences in performances. We then tested what range of stimuli produce dynamic stimulus-response relationships for different outcome measures in naive mice. We finally used this assay to show that nerve injury produces modality-specific sex differences in pain behavior. Our improved assay opens new avenues to study the basis of modality-specific abnormalities in pain behavior. [ABSTRACT FROM AUTHOR]

Case: A 24-year-old man with Klippel-Trenaunay syndrome (KTS) presented with severe knee osteoarthritis unresponsive to conservative measures. Owing to end-stage, debilitating arthritic symptoms, surgery was pursued. Careful preoperative, multidisciplinary planning/treatment included magnetic resonance imaging to characterize the venous malformations throughout the right lower extremity, preoperative sclerotherapy, sirolimus, and robotic-assisted cementless total knee arthroplasty (TKA). Conclusion: Cementless robotic-assisted TKA with selective patellar resurfacing can be a viable option for young KTS patients with severe osteoarthritis when a meticulous multidisciplinary approach, including sclerotherapy and advanced imaging, is undertaken to analyze vascular abnormalities, minimize surgical risks, preserve bone stock, and optimize outcomes. [ABSTRACT FROM AUTHOR]

The menopausal transition accelerates neuromuscular ageing in females compared to males. Males and females experience different trajectories of neuromuscular function across the lifespan, with females demonstrating accelerated deconditioning in later life. We hypothesize that the menopause is a critical period in the female lifespan, during which the dramatic reduction in sex hormone concentrations negatively impacts synaptic input to the motoneuron pool, as well as motor unit discharge properties. [ABSTRACT FROM AUTHOR]

Case: A 69-year-old man underwent a C3-4 anterior cervical discectomy and fusion and developed postoperative hypoglossal and glossopharyngeal palsies that resolved with symptomatic treatment. Conclusion: Cranial nerve palsy is a rare and possibly under-reported injury after higher-level cervical spine surgery. Conscientious positioning and awareness of these nerves during surgical exposure are crucial to minimizing cranial nerve palsies. Proper workup to identify these palsies and differentiate them from other complications is necessary to guide proper treatment. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to examine adherence to the weekly physical activity guidelines (≥150 min of aerobic activities at moderate-to-vigorous intensity and two or more sessions of strength training (yes or no)) and health outcomes during the COVID-19 pandemic for men living with obesity, 46 wk after being offered an online muscle-strengthening circuit program for 12 wk. Methods: Sixty men (age ≥19 yr) living with obesity (body fat percentage ≥25%) were randomly assigned to the intervention group (n = 30) or the control condition (n = 30) for 12 wk. The intervention group was offered an online circuit training, three sessions perweek, whereas the control group received a website helping themto reach the physical activity guidelines. Adherence to the weekly physical activity guidelines was evaluated 46 wk after enrolling in the program using a heart rate tracker (Fitbit Charge 3) and an exercise log. Health outcomes (e.g., anthropometrics, body composition) were measured at baseline and after 12, 24, and 46 wk. Results: The intervention group had higher adherence to physical activity guidelines at 46 wk (36.8%) than the control group (5.3%; P = 0.02). However, no difference in health outcomes was observed between participants in the intervention group compared with the control group after 12, 24, and 46 wk. Conclusions: Increasing adherence to exercise in men living with obesity is challenging. The proposed program increased adherence to the physical activity guidelines after about a year for men living with obesity; however, more studies are needed to understand how to improve health outcomes when following an online delivery exercise program in this population. [ABSTRACT FROM AUTHOR]

Case: A 16-year-old male patient presented with isolated bilateral sacroiliac (SI) joint dislocation. In this report, we discuss the presentation and focus on strategies for operative reduction and fixation for this rare injury. Conclusion: In conclusion, we present a case of a bilateral ligamentous SI joint dislocation in an adolescent. The patient was reduced in the supine position with a sacral bump and bilateral traction with direct and indirect reduction aids inserted through a lateral window. Bilateral SI screws stabilized the pelvis, facilitating uncomplicated healing. [ABSTRACT FROM AUTHOR]

Case: We present a 12-year-old boy with partial delamination of the patellar tendon in the coronal plane and bipolar avulsion fracture of the tibial tubercle and patella after a planting injury while skateboarding. Pediatric patellar tendon rupture with associated bipolar avulsion fractures is rare. Furthermore, to the best of our knowledge, a delamination injury pattern of the patellar tendon has not been described. Conclusion: This type of extensor mechanism injury has not been reported in the literature. Repair with Krackow sutures and suture-bone tunnel technique, with consideration of the proximal tibial physis, is a safe and effective way to fix this unique pathology. [ABSTRACT FROM AUTHOR]

Case: An 82-year-old man sustained a periprosthetic fracture after IlluminOss photodynamic bone stabilization system (PBSS) stabilization for an impending pathologic fracture. Nonoperative management was unsuccessful, and he subsequently underwent operative fixation, which featured lag screw fixation of the spiral distal humeral shaft fracture and osteotomy followed by plate fixation of the pathologic humeral shaft fracture. Conclusion: This is the first article to report this complication with IlluminOss PBSS stabilization and details regarding revision surgery. [ABSTRACT FROM AUTHOR]

Case: A 50-year-old healthy man with normal kidney function underwent surgery for fracture-related infection. Unfortunately, the patient received 2.5 times the intended dose of tobramycin pellets in the medullary cavity and developed acute kidney failure. Given the intraosseous administration of tobramycin, the drug displayed an absorption-dependent pharmacokinetics and multiple treatments with hemodialysis were needed. However, the patient had a complete recovery, and the kidney function remained normal at the 2-year follow-up. Conclusion: Tobramycin pellets are nephrotoxic in supratherapeutic doses; however, it was reversible in this case. Owing to the intraosseous administration, multiple treatments with hemodialysis were required. [ABSTRACT FROM AUTHOR]

Case: A 66-year-old man presented with new left hip pain after total hip arthroplasty 21 years earlier. Computed tomography imaging revealed massive osteolysis involving the ileum behind the well-fixed acetabular component. The patient was indicated for head and liner exchange with grafting of the osteolytic lesion. Surgery was complicated by cardiopulmonary arrest after injection of a bone graft substitute into the lesion. Despite resuscitation attempts, the patient died. Conclusion: Embolism is a rare complication of bone graft substitute injection for pelvic osteolysis. This material can extravasate from bone and deposit in the pulmonary and cerebral microcirculation. [ABSTRACT FROM AUTHOR]

Case: A 17-year-old adolescent boy complained of plantar pain at the first metatarsal 2 months after a catfish spine injury. Imaging was consistent with a retained foreign body, and surrounding osteolysis was concerning for osteomyelitis. He underwent surgical debridement and was found to have inflammation and necrosis, apparently caused by catfish spine venom. Conclusion: Although osteolytic lesions are commonly attributed to infection or tumor, in the situation of venomous injuries, osteolysis can be a sequela of the severe local inflammatory reaction due to the toxins. Debridement is vital to remove the offending agent and the local toxins from the venom. [ABSTRACT FROM AUTHOR]

Case: A 76-year-old fisherman with a history of diabetes mellitus, coronary artery bypass grafting, and a previous ipsilateral elbow wound presented with a 1-year history of hand pain and swelling. Anti-inflammatories and antibiotics were administered without improvement. Magnetic resonance imaging and ultrasound demonstrated flexor tenosynovitis. Intraoperative cultures revealed Mycobacterium chimaera. The treatment course included 2 tenosynovectomies and a 1-year course of triple antimycobacterial therapy. Conclusion: Nontuberculous mycobacteria infections should be considered in cases of indolent tenosynovitis. M. chimaera should be considered in patients with a history of cardiopulmonary bypass given its association with cardiopulmonary heater-cooler units. [ABSTRACT FROM AUTHOR]

Case: A case of Francisella tularensis finger proximal interphalangeal joint septic arthritis secondary to feral cat bite is presented. The patient underwent operative debridement on presentation. On postoperative day 5, a gram-negative rod resembling F. tularensis was identified. The patient received 4 weeks of gentamicin for culture-confirmed ulceroglandular tularemia. At the final follow-up, the infection had resolved, and full function of the digit had been regained. Conclusion: Francisella tularensis septic arthritis secondary to a feral cat bite is exceedingly rare but should be considered in the appropriate clinical context. Proper identification and treatment with antibiotics is essential for a positive outcome. [ABSTRACT FROM AUTHOR]

Case: A 22-year-old man presented with long-standing, progressive neck pain of unknown etiology. Investigation revealed a cervical spine osteoid osteoma affecting the right C4-5 facet joint. He underwent minimally invasive en bloc resection with O-arm–assisted 3-dimensional navigation without introducing iatrogenic spinal instability. Symptoms resolved after surgery, without recurrence or instability at the 2-year follow-up. Conclusion: Cervical spine osteoid osteoma is a tumor that presents diagnostic and therapeutic challenges. Achieving precise, complete resection of the tumor with a minimally invasive approach while avoiding spinal instrumentation and arthrodesis is paramount to excellent surgical outcomes. [ABSTRACT FROM AUTHOR]

Background and Objectives: In recent years, researchers have sought to address the challenges of obtaining informed consent for participation in acute stroke trials. We studied outcomes related to the use of deferral of consent in the phase 3 Alteplase Compared to Tenecteplase (AcT) trial., Methods: As part of our protocol, we captured methods of consent, participant withdrawals, door-to-randomization times, and door-to-needle times. Participants at 3 sites were invited to complete a survey of attitudes regarding consent for AcT and for acute stroke trials generally., Results: The AcT trial enrolled 1,600 participants from 22 centers across Canada of whom 1,537 were enrolled through deferral of consent (96.0%) and 63 (4.0%) were enrolled by prospective verbal consent followed by written informed consent. Of those enrolled by deferral of consent, 95% (1,454/1,537) consented to ongoing participation. Door-to-randomization times were similar regardless of method of consent, with an overall median of 30 minutes (interquartile range [IQR] 22-42): 29 minutes (IQR 22-42) in the deferral of consent group vs 32 minutes (IQR 25-44) in the prospective consent group ( p = 0.1602). Survey respondents overwhelming agreed or strongly agreed with the use of deferral of consent in AcT (86%) and in any acute stroke trial (76%)., Discussion: Deferral of consent was broadly acceptable to participants in the AcT trial as demonstrated by low rates of withdrawal and by survey results. Door-to-randomization times using deferral of consent in AcT were short, although a system of prospective verbal consent used at 1 center took only slightly longer. These results support the importance of innovation around consent for acute stroke trials.

Background and Objectives: The 21-point Brain Care Score (BCS) is an index that ranks behaviors and clinical measurements with the aim of encouraging lifestyle adjustments to lower the incidence of age-related brain disease, including stroke, late-life depression (LLD), and dementia. A higher BCS at baseline is associated with a lower risk of these outcomes. We aimed to investigate whether the associations between BCS and stroke, LLD, and dementia risks are independent of genetic predisposition for these conditions and quantify the effect of healthy lifestyle across genetic risk distributions for these outcomes., Methods: Using the UK Biobank (UKB) prospective cohort study, we computed baseline BCSs and polygenic scores to estimate genetic predisposition for stroke and LLD and APOE ε allele status to stratify dementia risk. As for outcomes again in UKB, we measured incidence of stroke, LLD, and dementia. We used multivariate Cox proportional hazard models to assess associations between BCS, genetic predisposition, and these outcomes. We also conducted stratified and interaction analyses to estimate the incidence of these outcomes across quartiles of genetic risk and BCS., Results: We included 368,340 UKB participants (median age 58 years (interquartile range 51-63 years), 46.3% male). Independent of genetic risk, a 5-point increase in BCS corresponded to lowered hazards of stroke (hazard ratio [HR] 0.70, 95% CI 0.68-0.73), LLD (HR 0.65, 95% CI 0.63-0.67), and dementia (HR 0.82, 95% CI 0.78-0.85). Incidences of all 3 outcomes were higher among participants with high genetic risk of these outcomes. However, these increased risks were offset for individuals with a higher BCS (incidence rates per 1,000 person-years were 2.76 vs 1.19 for stroke, 7.34 vs 4.46 for LLD, and 3.64 vs 2.05 for dementia, when comparing low and high BCS)., Discussion: Across different genetic predispositions for stroke, LLD, and dementia, healthier lifestyle behaviors are protective for brain health, demonstrating the nondeterminism of genetic risk. Furthermore, differences in BCS behave as aggregate risk estimators of all 3 outcomes. Further work is needed to prospectively investigate the utility and performance of the BCS as a targeted intervention in populations at elevated genetic risk of age-related brain disease.

Background and Objectives: Epidemiologic studies suggest increasing incidence and prevalence of myasthenia gravis (MG) among the elderly population outside the United States. We aimed to provide an estimation of MG incidence and prevalence and their trend among the Medicare Fee-For-Service (FFS)-covered elderly US population., Methods: We performed a retrospective longitudinal study using Medicare claims data (2006-2019). Study-eligible beneficiaries were aged 65 years and older, had at least 1 month of FFS Part A/B coverage, and were without any health maintenance organization insurance coverage. Study-eligible beneficiaries were aggregated into 2-year periods from 2006-2007 through 2018-2019. MG cases were ascertained using a validated algorithm of 2 MG claims within each 2-year period, from 2 outpatient office visits or a combination of 1 inpatient admission and 1 outpatient office visit, separated by ≥ 28 days. Period prevalence was calculated from MG-ascertained cases divided by FFS Part A/B beneficiaries and reported as cases per 100,000 population. Incident cases were determined among MG prevalent cases if the initial MG claim occurred in that period after a full calendar year since coverage initiation. Incidence was calculated as case counts per 100,000 at-risk beneficiary person-years (PYs) in each period excluding 2006-2007. Trends of prevalence and incidence over time were examined with Poisson regression. All-cause mortality of each 2-year period was calculated., Results: The period prevalence of MG increased from 81 to 119 per 100,000 FFS A/B population from 2006-2007 to 2018-2019 ( p < 0.001). Increasing trends of prevalence were observed in all sex (male/female), age (65-69/70-74/75-79/80+), race/ethnic (African American/Asian/Hispanics of any race/non-Hispanic White/other), and census region (Northeast/Midwest/South/West) subgroups. MG incidence increased from 12.2 to 13.3 per 100,000 PYs from 2008-2009 to 2018-2019 ( p < 0.05). Increasing incidence trends were significant in the following subgroups: men and women; all age groups except 75-79 years; White non-Hispanic race; Northeast, Midwest, and South census regions. All-cause mortality among MG beneficiaries was stable from 6.26 deaths per 100 PYs in 2006-2007 to 5.67 in 2018-2019 ( p = 0.18)., Discussion: Increasing trends in MG prevalence and incidence in the elderly US population, with variation in rates of certain subgroups, are confirmed in this 14-year period.

Background and Objectives: Disentangling brain aging from disease-related neurodegeneration in patients with multiple sclerosis (PwMS) is increasingly topical. The brain-age paradigm offers a window into this problem but may miss disease-specific effects. In this study, we investigated whether a disease-specific model might complement the brain-age gap (BAG) by capturing aspects unique to MS., Methods: In this retrospective study, we collected 3D T1-weighted brain MRI scans of PwMS to build (1) a cross-sectional multicentric cohort for age and disease duration (DD) modeling and (2) a longitudinal single-center cohort of patients with early MS as a clinical use case. We trained and evaluated a 3D DenseNet architecture to predict DD from minimally preprocessed images while age predictions were obtained with the DeepBrainNet model. The brain-predicted DD gap (the difference between predicted and actual duration) was proposed as a DD-adjusted global measure of MS-specific brain damage. Model predictions were scrutinized to assess the influence of lesions and brain volumes while the DD gap was biologically and clinically validated within a linear model framework assessing its relationship with BAG and physical disability measured with the Expanded Disability Status Scale (EDSS)., Results: We gathered MRI scans of 4,392 PwMS (69.7% female, age: 42.8 ± 10.6 years, DD: 11.4 ± 9.3 years) from 15 centers while the early MS cohort included 749 sessions from 252 patients (64.7% female, age: 34.5 ± 8.3 years, DD: 0.7 ± 1.2 years). Our model predicted DD better than chance (mean absolute error = 5.63 years, R 2 = 0.34) and was nearly orthogonal to the brain-age model (correlation between DD and BAGs: r = 0.06 [0.00-0.13], p = 0.07). Predictions were influenced by distributed variations in brain volume and, unlike brain-predicted age, were sensitive to MS lesions (difference between unfilled and filled scans: 0.55 years [0.51-0.59], p < 0.001). DD gap significantly explained EDSS changes ( B = 0.060 [0.038-0.082], p < 0.001), adding to BAG (Δ R 2 = 0.012, p < 0.001). Longitudinally, increasing DD gap was associated with greater annualized EDSS change ( r = 0.50 [0.39-0.60], p < 0.001), with an incremental contribution in explaining disability worsening compared with changes in BAG alone (Δ R 2 = 0.064, p < 0.001)., Discussion: The brain-predicted DD gap is sensitive to MS-related lesions and brain atrophy, adds to the brain-age paradigm in explaining physical disability both cross-sectionally and longitudinally, and may be used as an MS-specific biomarker of disease severity and progression.

Objectives: The objective of this study was to estimate the incidence, timing, and type of new cancer diagnosis among patients with cryptogenic stroke., Methods: We used data from the ARCADIA trial, which enrolled patients with cryptogenic stroke and atrial cardiopathy. Participants were prospectively followed, and serious adverse events were assessed every 3 months or sooner if investigators were alerted between visits to an event. Kaplan-Meier statistics were used to estimate the cumulative incidence of a cancer diagnosis within the first year after randomization., Results: Among 878 participants without baseline history of cancer, 13 (1.5%) were diagnosed with incident cancer in the year after randomization, comprising 12 solid cancers (3 prostate, 2 breast, 2 gastrointestinal, and 5 other primary sites) and 1 hematologic cancer (non-Hodgkin lymphoma). The cumulative incidences of a cancer diagnosis were 0% at 3 months, 0.6% (95% CI 0.2%-1.5%) at 6 months, and 2.0% (95 CI 1.1%-3.4%) at 1 year. The median time from index stroke to cancer diagnosis was 261 days (interquartile range 183-358)., Discussion: In a multicenter cryptogenic stroke cohort with prospective follow-up, the 1-year cumulative incidence of a cancer diagnosis was 2%. This rate may be an underestimation because of the clinical trial population and exclusion of cancers diagnosed immediately after stroke., Trial Registration Information: ClinicalTrials.gov Identifier: NCT03192215. Registered June 20, 2017. First patient enrolled February 1, 2018.

Background and Objectives: Although most spontaneous intracerebral hemorrhages (ICHs) are due to cerebral small vessel diseases (SVDs), between 1 in 7 and 1 in 10 are due to a macrovascular cause. Rapid diagnosis has important therapeutic and prognostic implications but sometimes requires digital subtraction angiography (DSA), an invasive procedure which cannot be performed in all patients. MRI provides optimal sensitivity for markers of SVD but was not included in previous risk stratification scores. We aimed to create and validate a risk stratification score for macrovascular causes of ICH including MRI findings to guide diagnosis and further investigations., Methods: We pooled data from 2 large observational study cohorts (London/United Kingdom and Graz/Austria) of consecutive patients with ICH who had brain MRI and at least 1 angiographic modality within 90 days of symptom onset. The primary outcome was a macrovascular cause of ICH (arteriovenous malformation/dural arteriovenous fistula, aneurysm, cavernoma, or cerebral venous thrombosis), with the diagnosis based on neurovascular multidisciplinary meetings. Using lasso logistic regression, we built the MRI Assessment of the Causes of intRacerebral haemOrrhage (MACRO) score to assess the probability of a macrovascular cause. We performed internal validation using bootstrapping and external validation in an independent cohort (Bern/Switzerland)., Results: We included 1,043 patients with ICH (mean age 66 years, 42% female), 78 of whom had a macrovascular cause (7.5%). The final score includes age (0-39, 40-69, or ≥70), location of ICH (lobar, deep, or infratentorial), and SVD markers on MRI (≥1 microbleed, ≥1 lacune, presence of cortical superficial siderosis, or white matter hyperintensities using the Fazekas scale). The MACRO score showed an optimism-adjusted c -statistic of 0.90 (95% CI 0.88-0.93), superior to existing CT-based scores ( p < 0.001). In external validation, the c -statistic was 0.87 (95% CI 0.80-0.94). MACRO scores ≥6 (59.5% of patients) indicated a very low risk of a macrovascular cause (0.2%), while scores ≤2 (9% of patients) indicated a high risk (48.9%)., Discussion: The MRI-based MACRO score shows excellent performance in predicting the likelihood of macrovascular causes of spontaneous intracerebral hemorrhage, making it useful in guiding further investigations. Important limitations include the observational study design and the performance of DSA in a minority of patients.

Background and Objectives: Cerebral amyloid angiopathy (CAA) is common in older adults and is associated with dementia. Less is known whether this association is mediated by Alzheimer disease (AD) neuropathologic changes, the examination of which was the objective of this study., Methods: This was a retrospective cross-sectional examination of the Kaiser Permanente Washington database of the Adult Changes in Thought (ACT) autopsy cohort with information on CAA, dementia, the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) (amyloid neuritic plaques), and Braak (tau neurofibrillary tangles). CAA was diagnosed by immunohistochemistry and dementia by ACT Consensus Diagnostic Conference. AD neuropathology was categorized by CERAD scores and Braak stages. Multivariable logistic regression models were used to estimate odds ratios (ORs) and 95% CIs of the associations of CAA with dementia, adjusting for age at death and sex, and with additional adjustments separately for CERAD scores (moderate-severe vs mild-absent), Braak stages (V-VI vs 0-IV), APOE ε4, and stroke. Formal mediation analyses were conducted to estimate age-sex-adjusted OR (95% CI) for natural indirect effects (NIEs) of CERAD scores and Braak stages., Results: The 848 participants had a mean age of 86.7 ± 4.6 years at death, and 57.6% were female. CAA was present in 322 participants (38.0%), of whom 152, 145, and 25 had mild, moderate, and severe CAA, respectively. Dementia was present in 384 participants (45.3%), of whom 317 had AD. Dementia was more common in those with CAA than without (53.7% vs 40.1%; age-sex-adjusted OR 1.57, 95% CI 1.18-2.10). This association remained significant after separate adjustment for other covariates but lost significance when adjusted for CERAD scores (OR 1.27, 95% CI 0.93-1.71) and Braak stages (OR 0.96, 95% CI 0.69-1.33). Findings from our formal mediation analyses show that ORs (95% CIs) for NIE of CERAD scores and Braak stages were 1.25 (1.13-1.37) and 1.63 (1.38-1.88), respectively, and CERAD scores and Braak stages mediated 53% and 111% of the total association, respectively., Discussion: We observed a significant association between CAA and dementia that disappeared when adjusted for CERAD or Braak stages. Findings from our mediation analyses suggest that the CAA-dementia association may be potentially mediated by AD neuropathologic changes. This hypothesis needs to be tested in future mechanistic studies in AD accounting for unmeasured confounders.

Objectives: To describe a novel subtype of autoimmune myopathy, immune-mediated megaconial myopathy (IMMM), myopathologically characterized by giant mitochondria (megaconia)., Methods: In this case series, we reviewed the Mayo Clinic Muscle Pathology database, between 2018 and 2023, to identify patients with megaconial pathology, subacute progressive weakness, and hyperCKemia, clinically resembling myositis. We recruited 1 patient from another institute, who had similar clinicopathologic features., Results: Five patients were identified. Age at onset of weakness ranged from 19 to 45.5 years. All patients had proximal weakness, elevated creatine kinase levels (1,214 to 5,920 U/L), negative myositis antibodies, necrotizing myopathology, and nonnecrotic myofibers harboring giant mitochondria. Immunohistochemical studies conducted in 4 patients showed sarcolemmal MHC-1 and C5b9 immunoreactivities. Megaconial pathology was considered pathognomonic of congenital muscular dystrophy due to biallelic pathogenic variants in CHKB . Sequencing of CHKB in 4/5 patients was unrevealing. Immunomodulatory therapy improved weakness and hyperCKemia in 4 treated patients. Of interest, all patients had coexisting pancreatic diseases (3 cystic fibrosis-related exocrine pancreatic insufficiency, 1 pancreatic cancer, and 1 pancreatitis)., Discussion: In addition to incurable CHKB -congenital muscular dystrophy, giant mitochondria can also occur in this new subtype of treatable autoimmune myopathy, IMMM. The association between IMMM and pancreatic disorders remains to be elucidated.

Background and Objectives: All 4 previous nationwide surveys of multiple sclerosis (MS) in Japan were conducted before the discovery of anti-aquaporin-4 (AQP4) antibodies; thus, neuromyelitis optica spectrum disorder (NMOSD) was included in MS, as optic-spinal MS. We aimed to clarify the epidemiologic features and trends of MS and NMOSD in Japan separately using a fifth nationwide survey., Methods: The primary survey, in which a questionnaire was sent to 3,799 selected departments (including neurology/internal medicine, pediatrics, and ophthalmology), explored the estimated number and prevalence of patients with MS or NMOSD in 2017, and the secondary survey collected detailed characteristics of the patients using a second questionnaire., Results: The response rates for the primary and secondary surveys were 60.1% and 53.9%, respectively. The estimated total number of patients with MS or NMOSD was 24,800, 2.5-fold higher than that in the fourth survey in 2003. The crude prevalence was 19.6 per 100,000 patients (14.2 for MS and 5.4 for NMOSD), compared with 7.7 per 100,000 patients in the fourth survey. Patients with MS showed milder disability (median Expanded Disability Status Scale [EDSS] score: 2.0 [interquartile range 1.0-4.5] vs 2.5 [1.0-6.0]), decreased secondary progression (8.5% vs 15.2%), and increased usage of disease-modifying drugs (63.7% vs 37.2%) compared with those with conventional MS in the fourth survey. The proportions of oligoclonal bands and Barkhof criteria fulfillment on MRI, which are features of classical MS, increased with advancing year of birth. Patients with NMOSD also showed less disability and shorter disease duration than patients with optic-spinal MS in the fourth survey (EDSS score: 3.5 [2.0-5.5] vs 3.8 [2.0-6.0]; disease duration: 8.0 [3.9-14.8] vs 10.0 [5.0-16.0]). Among patients with NMOSD, disability was exacerbated by a history of longitudinally extensive spinal cord lesions and anti-AQP4 antibody positivity, which both decreased with advancing year of birth., Discussion: The prevalences of MS (particularly with classical features) and NMOSD have been increasing in Japan, suggesting the contribution of environmental factors. However, disabilities in patients with MS and NMOSD have been mitigated. Extensive usage of various disease-modifying drugs could be a factor contributing to this disability mitigation in MS.

Objectives: To observe medication cost trends for 5 common neurologic conditions., Methods: We quantified annual out-of-pocket (OOP) and total medication costs for patients seen by a neurologist with epilepsy, multiple sclerosis (MS), Parkinson disease (PD), peripheral neuropathy (PN), and dementia/Alzheimer's disease in a commercial claims database cross-sectionally from 2012 to 2021., Results: We identified 186,144 patients with epilepsy, 54,676 with MS, 45,909 with PD, 169,127 with PN, and 60,861 with dementia/Alzheimer. OOP costs for MS medications increased each year, by 217% on average. Branded epilepsy medications had higher OOP costs than generics. Decreases ranging from 48% to 80% in annual OOP costs of duloxetine, pregabalin, rasagiline, rivastigmine, and memantine were observed in the years after generic introduction., Discussion: Preferentially selecting generic medications reduces OOP costs, other than for MS where costs continue to increase. Policy solutions, such as cost caps, are needed.

Background and Objectives: Isolated REM sleep behavior disorder (iRBD) is strongly associated with synucleinopathies. Previous iRBD cohort studies have primarily focused on older (>50 years), male-predominant cohorts. Risk of phenoconversion in women and younger adults remains unclear. The study aimed to determine clinical features associated with conversion to a defined neurodegenerative disorder in women and men with iRBD., Methods: One hundred eighty-six women and 186 men with iRBD were matched by polysomnography month. Baseline clinical variables and subsequent neurodegenerative outcomes were abstracted by chart review. Kaplan-Meier curves assessed conversion rates. Cox proportional hazards modeling evaluated factors associated with phenoconversion risk., Results: Age at iRBD diagnosis was younger in women compared with men (54.9 vs 62.5 years, p < 0.01). Forty-eight patients (12.9%), including 18 women (9.7%) and 30 men (16.1%), phenoconverted during a median follow-up of 6.0 years. Conversion rates were lower in antidepressant users and patients with chronic pain or psychiatric comorbidity while rates were higher in those with vascular comorbidity. Only age at diagnosis (HR 1.09, 95% CI 1.06-1.13) was associated with phenoconversion after adjusting for RBD symptom duration; sex; antidepressant use; and psychiatric, chronic pain, and vascular comorbidities., Discussion: Age at diagnosis was independently associated with phenoconversion risk in women and men with iRBD.

Background and Objectives: The incidence of stroke among young adults was rising globally, but the death burden of stroke in young adults in China is lacking. We aimed to examine the temporal trends in mortality and years of life lost (YLLs) caused by stroke among young adults from 2005 to 2020 across China., Methods: Based on the data from the National Mortality Surveillance System in China, we estimated the number and age-standardized rate of mortality and YLLs due to stroke and its subtypes among young adults aged 15-49 years during 2005-2020, for both China and its 31 mainland provinces., Results: During 2005-2020, the age-standardized mortality rate of stroke among young adults aged 15-49 years in China decreased by 21.0%, from 5.9/100,000 to 4.7/100,000, and the YLL rate decreased from 286.9/100,000 to 229.5/100,000. The age-standardized mortality rate among young adults due to intracerebral hemorrhage (ICH) showed a significant downward trend with a decrease of 26.3% while that of ischemic stroke (IS) and subarachnoid hemorrhage (SAH) decreased by 4.5% and 0.6%, respectively. In 2020, the mortality rate of ICH was 3.5 times higher than that of IS (3.3/100,000 vs 0.9/100,000) among young adults in China. The male/female ratio of age-standardized mortality rate of stroke in young adults increased from 2.0 in 2005 to 3.1 in 2020. The age-standardized mortality rate of IS and SAH in young men increased by 11.0% and 2.5%, respectively. In 2020, Tibet (18.4/100,000), Jilin (10.4/100,000), and Qinghai (8.3/100,000) were the top 3 provinces holding the highest age-standardized mortality rate due to stroke among young adults. Tibet was found to have the highest mortality rate due to ICH and SAH while that of IS was higher in northeast China., Discussion: In China, the death burden caused by ICH among young adults was substantially higher than that of IS. The increasing death burden of IS and SAH among young men requires special attention. Evidence-based intervention strategies are needed to improve the outcomes of stroke and alleviate the death burden due to stroke among young adults in Chinese population.

Background and Objectives: Recent technological advances have enabled visualizing in vivo a subset of chronic active brain lesions in persons with multiple sclerosis (pwMS), referred to as "paramagnetic rim lesions" (PRLs), with iron-sensitive MRI. PRLs predict future clinical disease progression, making them a promising clinical and translational imaging marker. However, it is unknown how disease progression is modified by PRL evolution (PRL disappearance, new PRL appearance). This is key to understanding MS pathophysiology and may help inform selection of sensitive endpoints for clinical trials targeting chronic active inflammation. To this end, we assessed the longitudinal associations between PRL disappearance and new PRL appearance and clinical disability progression and brain atrophy., Methods: PwMS and healthy controls (HCs) were included from a larger prospective, longitudinal cohort study at the University at Buffalo if they had available 3T MRI and clinical visits at baseline and follow-up timepoints. PwMS with sufficient clinical data for confirmed disability progression (CDP) analysis were included in a Disability Progression Cohort, and pwMS and HCs with brain volumetry data at baseline and follow-up were included in MS and HC Brain Atrophy cohorts. PRLs were assessed at baseline and follow-up and assigned as disappearing, newly appearing, or persisting at follow-up. Linear models were fit to compare annualized PRL disappearance rates or new PRL appearance (yes/no) with annualized rates of CDP and progression independent of relapse activity (PIRA) or with annualized rates of brain atrophy, adjusting for covariates including baseline PRL number and follow-up time. Statistical analyses were corrected for false discovery rate (FDR; i.e., q -value)., Results: In total, 160 pwMS (73.8% female; mean baseline age 46.6 ± 11.4 years; mean baseline disease duration 13.8 ± 10.6 years; median follow-up time 5.6 [interquartile range 5.2-7.8] years; 26.9% progressive MS) and 27 HCs (74.1% female; mean baseline age 43.9 ± 13.6 years; median follow-up time 5.4 [5.2-5.6] years) were enrolled. Greater PRL disappearance rates were associated with reduced rates of CDP (β mean = -0.262, 95% CI -0.475 to -0.049, q = 0.028) and PIRA (β mean = -0.283, 95% CI -0.492 to -0.073, q = 0.036), and new PRL appearance was associated with increased rates of PIRA (β mean = 0.223, 95% CI 0.049-0.398, q = 0.036). By contrast, no associations between new PRL appearance or PRL disappearance and brain volume changes survived FDR correction ( q > 0.05)., Discussion: Our results show that resolution of existing PRLs and lack of new PRLs are associated with improved clinical outcomes. These findings further motivate the need for novel therapies targeting microglia-mediated brain inflammation and adoption of clinical strategies to prevent appearance of new PRL.

Background and Objectives: Intramuscular fat fraction (FF), assessed with quantitative MRI (qMRI), has emerged as one of the few responsive outcome measures in CMT1A patients. The main limitation for its use in future therapeutic trials is the time required for the manual segmentation of individual muscles. This study aimed to evaluate the accuracy and responsiveness of a fully automatic artificial intelligence (AI)-based segmentation pipeline to assess disease progression in a cohort of CMT1A patients over 1 year., Methods: Twenty CMT1A patients were included in this observational, prospective, longitudinal study. FF was measured twice a year apart using qMRI in the lower limbs. Individual muscle segmentation was performed fully automatically using a trained convolutional neural network with or without human quality check (QC). The corresponding results were compared with those obtained by fully manual (FM) segmentation using the Dice similarity coefficient (DSC). FF progression and its standardized response mean (SRM) were also computed in individual muscles over the single central slice and a 3D volume to define the most sensitive region of interest., Results: AI-based segmentation showed excellent DSC values (>0.90). Significant global FF progression was observed at thigh (+0.71% ± 1.28%; p = 0.016) and leg (+1.73% ± 2.88%, p = 0.007) levels, similarly to that calculated using the FM technique ( p = 0.363 and p = 0.634). FF progression of each individual muscle was comparable when computed from either the central slice or the 3D volume. The best SRM value (0.70) was obtained for the FF progression computed using the AI-based technique with human QC in the 3D volume at the leg level. The time required for fully automatic segmentation using AI with a QC was 10 hours for the entire data set compared with 90 hours for the FM., Discussion: qMRI combined with AI-based segmentation can be considered as a process ready for assessing longitudinal FF changes in CMT1A patients. Given the slow FF progression at a thigh level and the large heterogeneity between muscles and individuals, FF should be quantified from a 3D volume at the leg level for longitudinal analyses. A QC performed after the AI-based segmentation is still advised given the increased SRM value.

Background and Objectives: A quarter of ischemic strokes are of lacunar clinical subtype and have an underlying recent small subcortical infarct (RSSI), but their long-term outcomes remain poorly characterized. Hemosiderin deposits (HDs) have been noted in RSSIs at chronic stages and might mimic primary hemorrhage. We characterized HDs' morphology, frequency, and clinical relevance., Methods: Participants with RSSIs were identified from a prospective longitudinal study and evaluated on 3T MRI including susceptibility-weighted imaging (SWI) from stroke diagnosis to 12 months. We categorized HDs in RSSIs on SWI at all available time points into 4 types (spots, smudge, rim, cluster) and assessed their associations with demographic factors, stroke-related factors, and image markers with adjusted logistic regression., Results: HDs were observed in 43 (55.0%) of 108 participants within 3 months and 83 (76.9%) of 108 within 12 months after stroke onset. The mean time to first detection of HDs was 87 (interquartile range 53-164) days. A "rim" pattern (similar to late appearance of primary hemorrhage) occurred in at least 26.5% of RSSIs at all follow-up time points, mainly those located in the lentiform/internal capsule (50.0%) or thalamus (36.4%). Infarct volume (odds ratio [OR] 1.003, 95% CI 1.001-1.006; p = 0.004) and the total small vessel disease (SVD) score at baseline (OR 2.50, 95% CI 1.28-4.86, p = 0.007) independently predicted HDs at 12 months. HDs were positively associated with more lacunes (OR 1.60, 95% CI 1.13-2.26, p < 0.01), but not the Fazekas score, number of microbleeds, basal ganglia mineral deposit score, or clinical outcomes., Discussion: HDs occur commonly in RSSIs and may be associated with infarct volume and SVD score. Hemosiderin "rim" is common in RSSIs, urging caution to avoid mistaking ischemic RSSI for primary hemorrhage in subacute and chronic stages.

Objectives: To determine the association between early midlife sleep and advanced brain aging patterns in late midlife., Methods: Using the CARDIA study, we analyzed sleep data at baseline and 5 years later, focusing on short sleep duration, bad sleep quality (SQ), difficulty initiating and maintaining sleep (DIS and DMS), early morning awakening (EMA), and daytime sleepiness. These were categorized into 0-1, 2-3, and >3 poor sleep characteristics (PSC). Brain MRIs obtained 15 years later were used to determine brain age through a machine learning approach based on age-related atrophy., Results: This cohort study included 589 participants (mean age 40.4 ± 3.4 years, 53% women). At baseline, around 70% reported 0-1 PSC, 22% reported 2%-3%, and 8% reported >3 PSC. In multivariable linear regression analyses, participants with 2-3 or >3 PSC had 1.6-year (β = 1.61, 95% CI 0.28-2.93) and 2.6-year (β = 2.64, 95% CI 0.59-4.69) older brain age, respectively, compared with those with 0-1 PSC. Of the individual characteristics, bad SQ, DIS, DMS, and EMA were associated with greater brain age, especially when persistent over the 5-year follow-up., Discussion: Poor sleep was associated with advanced brain age in midlife, highlighting the importance of investigating early sleep interventions for preserving brain health.

Background and Objectives: Mounting evidence points to a strong connection between cardiovascular risk during middle age and brain health later in life. The American Heart Association's Life's Essential 8 (LE8) constitutes a research and public health construct capturing key determinants of cardiovascular health. However, the overall effect of the LE8 on global, clinically relevant metrics of brain health is still unknown. We tested the hypothesis that worse LE8 profiles are associated with higher composite risk of the most important clinical endpoints related to poor brain health., Methods: We conducted a two-stage (discovery and replication) prospective study using data from the UK Biobank (UKB) and All of Us (AoU), 2 large population studies in the United Kingdom and the United States, respectively. The primary exposure was the LE8 score, a validated tool that captures 8 modifiable cardiovascular risk factors (blood pressure, glucose, cholesterol, body mass index, smoking, physical activity, diet, and sleep duration), organized in 3 categories (optimal, intermediate, and poor). The primary outcome was a composite of stroke, dementia, or late-life depression. We evaluated associations using multivariable Cox proportional hazard models., Results: The discovery stage included 316,127 UKB participants (mean age 56, 52% female). Over a mean (SD) follow-up time of 4.9 (0.4) years, the unadjusted risk of the composite outcome was 0.7% (95% CI 0.61-0.74), 1.2% (95% CI 1.11-1.22), and 1.8% (95% CI 1.70-1.91) in participants with optimal, intermediate, and poor cardiovascular health, respectively ( p < 0.001). This association remained significant in multivariable Cox models (intermediate vs optimal cardiovascular health hazard ratio [HR], 1.37; 95% CI 1.24-1.52, and poor vs optimal cardiovascular health HR, 2.11; 95% CI 1.88-2.36, p trend <0.001). The replication stage included 68,407 AoU participants (mean age 56, 60% female). Over a mean (SD) follow-up time of 2.9 (1.41) years, the unadjusted risk of the composite outcome was 2.8% (95% CI 2.49-3.05), 6% (95% CI 5.76-6.22), and 9.7% (95% CI 9.24-10.24) in participants with optimal, intermediate, and poor cardiovascular health, respectively ( p < 0.001). This association remained significant in multivariable Cox models (intermediate vs optimal cardiovascular health, HR 1.35; 95% CI 1.21-1.51, and poor vs optimal cardiovascular health, HR 1.94; 95% CI 1.72-2.18; p trend <0.001)., Discussion: Among middle-aged adults enrolled in 2 large population studies, poor cardiovascular health profiles were associated with two-fold higher risk of developing a composite outcome that captures the most important diseases related to poor brain health. Because the evaluated risk factors are all modifiable, our findings highlight the potential brain health benefits of using the Life's Essential 8 to guide cardiovascular health optimization.

Background and Objectives: CT perfusion (CTP) maps can estimate the ischemic core in acute ischemic stroke based on distinctive cerebral blood flow thresholds. However, metabolic factors beyond perfusion influence the tissue tolerance to ischemia and the infarct growth rate. Underestimating the ischemic core volume (ICV) might result in overestimating the salvageable cerebral tissue and, consequently, overestimating the potential clinical benefits of reperfusion therapies. We aim to evaluate whether baseline hemoglobin and blood glucose levels influence the accuracy of baseline CTP ICV estimations., Methods: Large vessel occlusion stroke patients investigated with baseline CTP undergoing thrombectomy with near-complete reperfusion and without parenchymal hemorrhage from the ESCAPE-NA1 trial were included. Patients were subdivided into anemic (hemoglobin <130 g/L for men and <120 g/L for women) and nonanemic groups, and hyperglycemic (blood glucose level >7 mmol/L) and normoglycemic groups. Ischemic core underestimated volume (ICuV) was calculated: final infarct volume minus CTP-based ICV. The primary outcome was the presence of "perfusion scotoma" defined as ICuV ≥10 mL. Presence of "perfusion scotoma" and median ICuV were compared between anemic vs nonanemic and hyperglycemic vs normoglycemic patients using nonparametric tests and multivariable binary logistic regression with adjustment for baseline variables., Results: One hundred sixty-two of 1,105 (15%) patients were included (median age 70.5 [interquartile range (IQR) 61-80.4], 50.6% women). The median ICuV was 7.26 mL (IQR 0-25.63). Seventy-eight (48%) patients demonstrated perfusion scotoma. Forty-two (25.7%) patients were anemic, and 65 (40.1%) were hyperglycemic. In univariable analysis, the hyperglycemic group had a higher prevalence of perfusion scotoma (65% [n = 40] vs 39% [n = 38], p = 0.006) and larger ICuV (17.79 mL [IQR 1.57-42.75] vs 6 mL [-0.31 to 12.51], p = 0.003) compared to normoglycemic patients. No significant ICuV differences between patients with and without anemia were seen. Multivariable regression analysis revealed an association between perfusion scotoma and hyperglycemia, adjusted odds ratio (OR) 2.48 (95% CI 1.25-4.92), and between perfusion scotoma and blood glucose levels, adjusted OR 1.19 (95% CI 1.03-1.39) per 1 mmol/L increase., Discussion: In our study, CTP-based ischemic core underestimation was common and associated with higher baseline blood glucose levels. Individual metabolic factors beyond perfusion that critically influence the infarct growth rate should be considered when interpreting baseline CTP estimations of ischemic core.

Background: BMP9 (bone morphogenetic protein 9) is a member of the TGF-β (transforming growth factor β) family of cytokines with pleiotropic effects on glucose metabolism, fibrosis, and lymphatic development. However, the role of BMP9 in myocardial infarction (MI) remains elusive., Methods: The expressional profiles of BMP9 in cardiac tissues and plasma samples of subjects with MI were determined by immunoassay or immunoblot. The role of BMP9 in MI was determined by evaluating the impact of BMP9 deficiency and replenishment with adeno-associated virus-mediated BMP9 expression or recombinant human BMP9 protein in mice., Results: We show that circulating BMP9 and its cardiac levels are markedly increased in humans and mice with MI and are negatively associated with cardiac function. It is important to note that BMP9 deficiency exacerbates left ventricular dysfunction, increases infarct size, and augments cardiac fibrosis in mice with MI. In contrast, replenishment of BMP9 significantly attenuates these adverse effects. We further demonstrate that BMP9 improves lymphatic drainage function, thereby leading to a decrease of cardiac edema. In addition, BMP9 increases the expression of mitochondrial DECR1 (2,4-dienoyl-CoA [coenzyme A] reductase 1), a rate-limiting enzyme involved in β-oxidation, which, in turn, promotes cardiac mitochondrial bioenergetics and mitigates MI-induced cardiomyocyte injury. Moreover, DECR1 deficiency exacerbates MI-induced cardiac damage in mice, whereas this adverse effect is restored by the treatment of adeno-associated virus-mediated DECR1. Consistently, DECR1 deletion abrogates the beneficial effect of BMP9 against MI-induced cardiomyopathy and cardiac damage in mice., Conclusions: These results suggest that BMP9 protects against MI by fine-tuning the multiorgan cross-talk among the liver, lymph, and the heart., Competing Interests: None.

Background: Endothelial cells (ECs) use glycolysis to produce energy. In preclinical models of peripheral arterial disease, further activation of EC glycolysis was ineffective or deleterious in promoting hypoxia-dependent angiogenesis, whereas pentose phosphate pathway activation was effective. Hexosamine biosynthesis pathway, pentose phosphate pathway, and glycolysis are closely linked. Glucosamine directly activates hexosamine biosynthesis pathway., Methods: Hind-limb ischemia in endothelial nitric oxide synthase knockout (eNOS -/- ) and BALB/c mice was used. Glucosamine (600 μg/g per day) was injected intraperitoneally. Blood flow recovery was assessed using laser Doppler perfusion imaging and angiogenesis was studied by CD31 immunostaining. In vitro, human umbilical vein ECs and mouse microvascular ECs with glucosamine, L-glucose, or vascular endothelial growth factor (VEGF 165 a) were tested under hypoxia and serum starvation. Cell Counting Kit-8, tube formation, intracellular reactive oxygen species, electric cell-substrate impedance sensing, and fluorescein isothiocyanate dextran permeability were assessed. Glycolysis and oxidative phosphorylation were assessed by seahorse assay. Gene expression was assessed using RNA sequencing, real-time quantitative polymerase chain reaction, and Western blot. Human muscle biopsies from patients with peripheral arterial disease were assessed for EC O-GlcNAcylation before and after supervised exercise versus standard medical care., Results: On day 3 after hind-limb ischemia, glucosamine-treated versus control eNOS -/- mice had less necrosis (n=4 or 5 per group). Beginning on day 7 after hind-limb ischemia, glucosamine-treated versus control BALB/c mice had higher blood flow, which persisted to day 21, when ischemic muscles showed greater CD31 staining per muscle fiber (n=8 per group). In vitro, glucosamine versus L-glucose ECs showed improved survival (n=6 per group) and tube formation (n=6 per group). RNA sequencing of glucosamine versus L-glucose ECs showed increased amino acid metabolism (n=3 per group). That resulted in increased oxidative phosphorylation (n=8-12 per group) and serine biosynthesis pathway without an increase in glycolysis or pentose phosphate pathway genes (n=6 per group). This was associated with better barrier function (n=6-8 per group) and less reactive oxygen species (n=7 or 8 per group) compared with activating glycolysis by VEGF 165 a. These effects were mediated by activating transcription factor 4, a driver of exercise-induced angiogenesis. In muscle biopsies from humans with peripheral arterial disease, EC/O-GlcNAcylation was increased by 12 weeks of supervised exercise versus standard medical care (n=6 per group)., Conclusions: In cells, mice, and humans, activation of hexosamine biosynthesis pathway by glucosamine in peripheral arterial disease induces an "exercise-like" angiogenesis and offers a promising novel therapeutic pathway to treat this challenging disorder., Competing Interests: None.

Background: The real incidence of atrial arrhythmia (AA) after patent foramen ovale (PFO) closure and whether this complication can be prevented remain unknown. We assessed whether flecainide is effective to prevent AA during the first 3 months after PFO closure, and whether 6 months of treatment with flecainide is more effective than 3 months to prevent AA after PFO closure., Methods: AFLOAT (Assessment of Flecainide to Lower the Patent Foramen Ovale Closure Risk of Atrial Fibrillation or Tachycardia Trial) is a prospective, multicentre, randomized, open-label, superiority trial with a blind evaluation of all the end points (PROBE [Prospective Randomized Open, Blinded End Point] design). Patients were randomized in a 1:1:1 ratio after PFO closure to receive flecainide (150 mg once daily in a sustained-release dose) for 3 months, flecainide (150 mg once daily in a sustained-release dose) for 6 months, or no additional treatment (standard of care) for 6 months. The primary end point was the percentage of patients with at least 1 episode of AA (≥30 seconds) recorded within 3 months after PFO closure on long-term monitoring with an insertable cardiac monitor. The secondary end point was the percentage of patients with at least 1 episode of AA (≥30 seconds) recorded with insertable cardiac monitor during the 3- to 6-month period after PFO closure., Results: A total of 186 patients were included (mean age, 54 years; 68.8% men) and AA (≥30 seconds) occurred in 53 patients (28.5%) during the 6-month follow-up; 86.8% of these AA events occurred in the first month after PFO closure. The primary outcome occurred in 33 of 123 (26.8%) and 16 of 63 (25.4%) patients receiving flecainide for at least 3 months or standard of care, respectively (risk difference, 1.4% [95% CI, -12.9% to 13.8%]; NS). The secondary end point occurred in 3 of 60 (5.0%), 4 of 63 (6.3%), and 5 of 63 (7.9%) patients receiving flecainide for 6 months, for 3 months, or standard of care, respectively (risk difference, -2.9% [95% CI, -12.7% to 6.9%], and risk difference, -1.6% [95% CI, -11.8% to 8.6%], respectively)., Conclusions: In the first 6 months after successful PFO closure, AA (≥30 seconds) occurred in 28.5% of cases, mostly in the first month after the procedure. Flecainide did not prevent AA after PFO closure., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05213104., Competing Interests: Dr Guedeney has received transportation assistance from Sanofi. Dr Laredo has received consultancy fees from Abbott and Biotronik. Dr Montalescot has received research grants to the institution or consulting and lecture fees from Abbott, Amgen, AstraZeneca, Ascendia, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Boston Scientific, Celecor, CSL Behring, Idorsia, Lilly, Novartis, Novo, Opalia, Pfizer, Quantum Genomics, Sanofi, and Terumo. Dr Silvain has received consulting fees or transportation assistance from AstraZeneca, Abbott Medical France, Bayer HealthCare, Abbott Medical France SAS, Biotronik, Boehringer Ingelheim France, CSL Behring SA, Gilead Science, Sanofi France, Terumo France, and Zoll; and is a stockholder in 4P-Pharma. Prof Hammoudi has received consulting and lecture fees from Abbott, Boehringer Ingelheim, Bayer, and Novartis. Dr Vicaut has received consulting fees from Abbott, Amgen, Bristol Myers Squibb, Celgene, LFB, Pfizer, and Sanofi. Dr Marijon received research grants from Abbott, Boston Scientific, and Medtronic. Dr Cayla received consulting fees from Edwards, Medtronic, and Microport CRM, and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Amgen, AstraZeneca, Abbott, Bayer, Biotronik, Bristol Myers Squibb, Edwards, Microport, Medtronic, Pfizer, and Sanofi-Aventis. The other authors report no relationships relevant to the contents of this article to disclose.

Background: Microvascular angina is associated with dysregulation of the endothelin system and impairments in myocardial blood flow, exercise capacity, and health-related quality of life. The G allele of the noncoding single nucleotide polymorphism RS9349379 enhances expression of the endothelin-1 gene ( EDN1 ) in human vascular cells, potentially increasing circulating concentrations of Endothelin-1 (ET-1). Whether zibotentan, an oral ET-A receptor selective antagonist, is efficacious and safe for the treatment of microvascular angina is unknown., Methods: Patients with microvascular angina were enrolled in this double-blind, placebo-controlled, sequential crossover trial of zibotentan (10 mg daily for 12 weeks). The trial population was enriched to ensure a G allele frequency of 50% for the RS9349379 single nucleotide polymorphism. Participants and investigators were blinded to genotype. The primary outcome was treadmill exercise duration (seconds) using the Bruce protocol. The primary analysis estimated the mean within-participant difference in exercise duration after treatment with zibotentan versus placebo., Results: A total of 118 participants (mean±SD; years of age 63.5 [9.2]; 71 [60.2%] females; 25 [21.2%] with diabetes) were randomized. Among 103 participants with complete data, the mean exercise duration with zibotentan treatment compared with placebo was not different (between-treatment difference, -4.26 seconds [95% CI, -19.60 to 11.06] P =0.5871). Secondary outcomes showed no improvement with zibotentan. Zibotentan reduced blood pressure and increased plasma concentrations of ET-1. Adverse events were more common with zibotentan (60.2%) compared with placebo (14.4%; P <0.001)., Conclusions: Among patients with microvascular angina, short-term treatment with a relatively high dose (10 mg daily) of zibotentan was not beneficial. Target-related adverse effects were common., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04097314., Competing Interests: Dr Berry is employed by the University of Glasgow, which holds consultancy and research agreements with Abbott Vascular, AstraZeneca, Auxilius Pharma, Boehringer Ingelheim, Corflow, Coroventis, GlaxoSmithKline, HeartFlow, Menarini, Novartis, Siemens Healthcare, Somalogic, Xylocor and Valo Health. Dr Spyridopoulos receives research grants from Astra Zeneca, Cambridge, UK, and Kancera, Solna, Sweden. Dr Ford is a consultant/speaker/honorarium from Abbott Vascular, Boston Scientific, Boehringer Ingelheim, Biotronik, Bio-Excel, and Novartis. Dr Al-Lamee serves on advisory boards of Janssen Pharmaceuticals, Abbott, and Philips, and has received speaker honoraria from Abbott, Philips, Medtronic, Servier, Omniprex, and Menarini. These companies had no role in the design or conduct of the study or in the data collection or interpretation. Dr Davenport holds research grants from AstraZeneca and is a member of scientific advisory boards of Janssen, ENB Therapeutics, and Pharmazz. Drs Berry, Ford, and Davenport are named on a pending patent for the use of zibotentan for microvascular angina. The University of Glasgow holds the patent. None of the other authors have any relevant disclosures.

COVID-19 pandemic was accompanied by many healthcare-related issues. Concrete national data regarding the care performance of critical ill cases of COVID-19 does not exist in Korea. The current study aimed to describe the treatment outcome and healthcare resource utilization of critically ill COVID-19 patients. Our multicenter retrospective cohort study enrolled critically ill COVID-19 patients from 22 tertiary care hospitals in Korea. Inclusion criteria: (1) patients aged 19 years or older, (2) patients with laboratory-confirmed SARS-CoV-2 infection who received at least one of following initial treatments such as high-flow oxygen therapy (HFOT) or noninvasive ventilation (NIV) or invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation. During the study wave, a total of 1358 eligible participants were enrolled, with 21 institutions participating in the study. Among them, data from 1113 patients were available and analyzed. Of 921 (82.7%), 621 (55.8%) were supported by IMV. Of the 921 patients supported by HFOT or NIV, 438 (47.6%) recovered without IMV, 429 (46.6%) required IMV, and 54 died who DNR after NIV was applied. Prone position ventilation was administered to 163 (33.1%) patients with IMV and 25 (6.2%) patients with HFOT. Extracorporeal membrane oxygenation was administered to 128 (20.6%) patients treated with IMV. The overall mortality rate was 26.4%. In South Korea, mortality rates for patients with severe COVID-19 pneumonia have been shown substantial fatality, with the highest mortality rates observed in wave 3. The increased mortality rate in wave 3 could be associated with the rapid escalation of critically ill COVID-19 patients and the consequent saturation of intensive care unit capacities. Patients received NIV therapy and prone position ventilation more frequently in wave 3 as the number of cases increased., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

To investigate the value of circulating tumor cell (CTC) in cerebrospinal fluid (CSF) by Cyttel-Tech detection in patients with suspected leptomeningeal metastasis (LM) from malignant solid tumors. We collected CSF from 12 patients with suspected LM from malignant solid tumors at our hospital. Twelve milliliters (mL) of CSF were collected from each patient through the first lumbar puncture: 5 mL was for CTC detection by Cyttel-Tech method, 5 mL for CSF cytopathology examination, and 2 mL for cytology and biochemical analysis of the CSF. Additionally, all patients underwent cranial brain magnetic resonance imaging with both plain and contrast-enhanced scans. Among the 12 patients with suspected LM, CTC detection yielded a positivity rate of 11/12 (91.7%). The positivity rate for CSF cytopathology examination was 4/12 (33.3%). However, none of the patients showed positive findings on cranial brain magnetic resonance imaging with both plain and contrast-enhanced scans (0/12, 0%). The difference between CTC detection and cytopathology detection was statistically significant (P < .05). CTC detection may have a high positivity rate in diagnosing LM from malignant solid tumors. It potentially serves as a supplementary diagnostic method for patients with negative pathology results and be used for rapid and accurate adjunctive diagnosis of LM., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

To improve the management level of general anesthesia during bronchoscopy in the children with diffuse alveolar hemorrhage (DAH). A retrospective study was conducted in the children with DAH who had performed bronchoscopy under general anesthesia with spontaneous respiration by face mask ventilation initially from June 2021 to June 2022 in our hospital. (1) Thirty-four children who had underwent 38 bronchoscopy procedures were included. (2) General anesthesia induction was performed by bolus of propofol intravenous in all the procedures. For maintaining anesthesia, combination use of propofol and remifentanil intravenously infusion were given in 31 procedures (81.6%) and propofol intravenously infusion alone was given in the rest 7 procedures (18.4%). An intravenous bolus of ketamine or propofol was given as an anesthetic adjuvant in 21 procedures (55.3%). Thirty-five procedures (92.1%) were successfully completed under non-tracheal intubation ventilation, whereas the rest 3 procedures (7.9%) needed change to tracheal intubation ventilation. (3) Respiratory depression was found in 7 procedures (18.4%), laryngospasm was found in 2 procedure (2.6%), and bronchospasm was found in 17 procedures (44.7%). Intraoperative hypoxemia occurred in 16 procedures (42.1%). The incidence of intraoperative hypoxemia in the procedures at the active phage of disease was significantly higher compared to those at the remission phage of the disease (P < .05). Intraoperative hypercapnia also occurred in 16 procedures (42.1%). Two procedures (5.3%) were complicated by severe pulmonary hemorrhage. General anesthesia with spontaneous respiration by face mask ventilation is feasible and relatively safe for the children with DAH undergoing bronchoscopy, whereas the anesthetic protocol still needs to be improved., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)