Citations

Abstract Spinal cord disease is important in most people with multiple sclerosis, but assessment remains less emphasized in patient care, basic and clinical research and therapeutic trials. The North American Imaging in Multiple Sclerosis Spinal Cord Interest Group was formed to determine and present the contemporary landscape of multiple sclerosis spinal cord evaluation, further existing and advanced spinal cord imaging techniques, and foster collaborative work. Important themes arose: (i) multiple sclerosis spinal cord lesions (differential diagnosis, association with clinical course); (ii) spinal cord radiological–pathological associations; (iii) ‘critical’ spinal cord lesions; (iv) multiple sclerosis topographical model; (v) spinal cord atrophy; and (vi) automated and special imaging techniques. Distinguishing multiple sclerosis from other myelopathic aetiology is increasingly refined by imaging and serological studies. Post-mortem spinal cord findings and MRI pathological correlative studies demonstrate MRI’s high sensitivity in detecting microstructural demyelination and axonal loss. Spinal leptomeninges include immune inflammatory infiltrates, some in B-cell lymphoid-like structures. ‘Critical’ demyelinating lesions along spinal cord corticospinal tracts are anatomically consistent with and may be disproportionately associated with motor progression. Multiple sclerosis topographical model implicates the spinal cord as an area where threshold impairment associates with multiple sclerosis disability. Progressive spinal cord atrophy and ‘silent’ multiple sclerosis progression may be emerging as an important multiple sclerosis prognostic biomarker. Manual atrophy assessment is complicated by rater bias, while automation (e.g. Spinal Cord Toolbox), and artificial intelligence may reduce this. Collaborative research by the North American Imaging in Multiple Sclerosis and similar groups with experts combining distinct strengths is key to advancing assessment and treatment of people with multiple sclerosis spinal cord disease.

AbstractBackgroundThe clinical relevance of cardiac troponin (cTn) elevation in takotsubo syndrome (TTS) remains uncertain. The present study sought to investigate the role of cardiac troponin (cTn) elevations in mortality prediction of patients with Takotsubo syndrome (TTS).MethodsPatients enrolled in the International Takotsubo (InterTAK) Registry from January 2011 to February 2020 with available data on peak cTn levels were included in the analysis. Peak cTn levels during the index hospitalization were used to define clinically relevant myocardial injury. The threshold at which clinically relevant myocardial injury drives mortality at 1 year was identified using restricted cubic spline analysis.ResultsOut of 2′938 patients, 222 (7.6%) patients died during 1‐year follow‐up. A more than 28.8‐fold increase of cTn above the upper reference limit was identified as threshold for clinically relevant myocardial injury. The presence of clinically relevant myocardial injury was significantly associated with an increased risk of mortality at 5 years (adjusted HR 1.58, 95% CI 1.18–2.12, p =.002). Clinically relevant myocardial injury was related to an increased 5‐year mortality risk in patients with apical TTS (adjusted HR 1.57, 95% CI 1.21–2.03, p =.001), in presence of physical stressors (adjusted HR 1.60, 95% CI 1.22–2.11, p =.001), and in absence of emotional stressors (adjusted HR 1.49, 95% CI, 1.17–1.89, p =.001).ConclusionThis study for the first time determined a troponin threshold for the identification of TTS patients at excess risk of mortality. These findings advance risk stratification in TTS and assist in identifying patients in need for close monitoring and follow‐up.

OBJECTIVE Many patients recruited in the Treatment of Brain Arteriovenous Malformations Study (TOBAS) are managed conservatively. The aim of this study was to monitor what happened to those patients. METHODS TOBAS comprises two randomized controlled trials and multiple prospective registries. All patients with brain arteriovenous malformations (AVMs) can participate. This report concerns patients selected for conservative management. The primary trial outcome measure is related death or dependency (modified Rankin Scale [mRS] score > 2) at 10 years. Secondary outcomes include intracranial hemorrhages, nonhemorrhagic neurological events, and serious adverse events (SAEs). For this report, outcome results are presented using patient-years, Kaplan-Meier survival curves, and Cox log-rank tests. There was no blinding. RESULTS From June 2014 to May 2021, 1010 patients were recruited, of whom 498 (49%) were proposed the prospective observation registry. After exclusions, 434 (87%) patients remained for analysis. The majority of patients had unruptured AVMs (378/434 [87%]), of which 195 (52%) were low grade (Spetzler-Martin grade I or II). During a mean follow-up period of 3.2 years (total 1368 patient-years), the primary outcome occurred in 23 of 434 (5%) patients, corresponding to an incidence of 1.7 (95% CI 1.1–2.5) per 100 patient-years. For unruptured AVMs the incidence was 1.1 (95% CI 0.7–1.9) per 100 patient-years, and for low-grade unruptured AVMs it was 0.6 (95% CI 0.2–1.7) per 100 patient-years. Poor outcomes were more frequent in patients with a history of rupture (HR 5.6 [95% CI 2.4–13.0], p < 0.001), infratentorial AVMs (HR 2.9 [95% CI 1.1–7.3], p = 0.027), and age ≥ 55 years (HR 3.2 [95% CI 1.4–7.6], p = 0.007). Major intracranial hemorrhage occurred in 35 of 434 (8%) patients (incidence of 2.6 [95% CI 1.9–3.6] per 100 patient-years; 2.0 [95% CI 1.3–2.9] per 100 patient-years for unruptured AVMs and 1.3 [95% CI 0.6–2.6] per 100 patient-years for low-grade unruptured AVMs). Major AVM hemorrhages were more frequent in ruptured (HR 4.4 [95% CI 2.1–8.9], p < 0.001), large (HR 2.6 [95% CI 1.1–6.6], p = 0.039), and high-grade (HR 2.5 [95% CI 1.2–5.3], p = 0.013) AVMs and those with deep venous drainage (HR 2.1 [95% CI 1.1–4.2], p = 0.032). SAEs occurred in 48 of 434 (11%) patients (incidence of 3.6 [95% CI 2.7–4.8] per 100 patient-years). For unruptured AVMs the incidence was 2.8 (95% CI 2.0–4.0) per 100 patient-years, and for low-grade unruptured AVMs it was 1.8 (95% CI 1.0–3.2) per 100 patient-years. CONCLUSIONS Nearly half of TOBAS participants were observed. Rates of untoward neurological events were within expected boundaries.

Abstract Accumulating evidence suggests dysregulated immune checkpoint (IC) signaling can exacerbate COVID-19 severity, but the role of these molecules in the pathogenesis of fatal COVID-19-related diffuse alveolar damage (DAD) remains elusive. Understanding how IC proteins influence acute lung injury due to COVID-19 can provide insights into potential therapeutic strategies to modulate immune responses and improve patient outcomes. Here, in a single-center autopsy cohort, we determined the cellular localization of ICs in lung tissue from cases of fatal COVID-19, DAD-comparators, and non-fibrotic controls by using immunohistochemistry, and investigated their association with clinical outcomes. We expanded our findings by performing analyses of publicly available single-cell RNA sequencing datasets from patients with fatal COVID-19 and non-fibrotic controls. We demonstrated the presence of protein-protein interaction networks of ICs in the lung cellular niche by performing transcriptomic profiling of lung tissue-derived RNA counts from patients with fatal COVID-19. Further, we leveraged data from the largest international, multi-center COVID-19 autopsy cohort and validated that, among patients with fatal COVID-19, those with higher PD-L1/CD274 expression in lung endothelial cells had more rapid clinical deterioration. Lastly, in a cohort of individuals with early COVID-19, IC plasma protein levels were elevated in those with persistent SARS-CoV-2 RNAemia and adverse clinical outcomes. Collectively, our data provide unique pathological insights into the role of IC dysregulation and differential disease severity in COVID-19.

Abstract Objective The presence of comorbidities can substantially affect patients’ quality of life, but data regarding their impact on idiopathic inflammatory myopathies (IIMs) are limited. Methods We examined the prevalence of comorbidities in IIM patients, other autoimmune rheumatic diseases (oAIRDs) and healthy controls (HCs), using data from the self-reported COVAD-2 survey. We defined basic multimorbidity (BM) as the presence of ≥2 non-rheumatic chronic conditions and complex multimorbidity (CM) as the presence of ≥3 non-rheumatic chronic conditions affecting ≥3 organ systems. Hierarchical clustering on principal components was performed for grouping. Results Among the COVAD respondents, 1558 IIMs, 4591 oAIRDs and 3652 HCs were analysed. IIMs exhibited a high burden of comorbidities (odds ratio [OR]: 1.62 vs oAIRDs and 2.95 vs HCs, P &lt; 0.01), BM (OR: 1.66 vs oAIRDs and 3.52 vs HCs, P &lt; 0.01), CM (OR: 1.69 vs AIRDs and 6.23 vs HCs, P &lt; 0.01) and mental health disorders (MHDs) (OR: 1.33 vs oAIRDs and 2.63 vs HCs, P &lt; 0.01). Among the IIM patients, those with comorbidities or MHDs had lower PROMIS Global Physical (PGP), PROMIS Global Mental (PGM), and PROMIS Physical Function (SF10) scores, and higher fatigue (F4a) scores (all P &lt; 0.001). PGP, PGM, SF10a and F4a were influenced by age, active disease, BM and MHDs. Four distinct clusters were identified among the IIMs according to comorbidities and PROMIS scores. Conclusion Patients with IIMs have a higher burden of comorbidities that influence physical and mental health, identifiable as clinical clusters for optimized and holistic management approaches.

Introduction: Syphilis is an ancient STI causing a new worldwide outbreak in general and in Lebanon specifically. Methods: We conducted a retrospective chart review to assess the rate of syphilis increase in an infectious diseases clinic in Lebanon from 2006 to 2023. We studied the epidemiology of these cases, stage and treatment response and their association to HIV infection and its control. Results: There was an 862% increase in syphilis cases from 2006 to 2019.Most of our cases were middle aged men living with HIV. Most of them had well-controlled HIV infection with good CD4 counts. Most of the diagnosed cases of syphilis were primary and secondary, responding to penicillin G. Discussion: Our data mostly parallels international data, except for gender distribution. Despite successful treatment of most cases in our clinic, the alarming rise of new cases highlights the urgent need for public health measures to mitigate this epidemic. Conclusion: Inclusive awareness is needed to stop syphilis spread in Lebanon, and more screening is key in identifying new cases early for a successful eradication.

Abstract Background and Aims Severe tricuspid regurgitation is associated with increased mortality rates, but benefit of its correction and ideal timing are not clearly determined. This study aimed to identify patient subsets who might benefit from the surgery. Methods In TRIGISTRY, an international cohort study of consecutive patients with severe isolated functional tricuspid regurgitation (33 centres, 10 countries), survival rates up to 10 years were compared between patients who underwent isolated tricuspid valve surgery (repair or replacement) and those conservatively managed, overall and according to TRI-SCORE category (low: ≤3, intermediate: 4–5, and high: ≥6). Results One thousand and two hundred seventeen were managed conservatively, and 551 underwent isolated tricuspid valve surgery (200 repairs and 351 replacements). TRI-SCORE distribution was 33% low, 32% intermediate, and 35% high. At 10 years, survival rates were similar between surgical and conservative management [41% vs. 36%; hazard ratio (HR) .97; 95% confidence interval (CI) .88–1.08, P = .57]. Surgery improved survival compared with conservative management in the low TRI-SCORE category (72% vs. 44%; HR .27; 95% CI .20–.37, P &lt; .0001), but not in the intermediate (36% vs. 37%; HR 1.17; 95%CI .98–1.40, P = .09) or high categories (20% vs. 24%; HR 1.06; 95% CI .91–1.25, P = .45). Both repair and replacement improved survival in the low TRI-SCORE category (84% and 61% vs. 44%; HR .11; 95% CI .06–.19, P &lt; .0001, and HR .65; 95% CI .47–.90, P = .009). Repair showed benefit in the intermediate category (59% vs. 37%; HR .49; 95% CI .35–.68, P &lt; .0001) while replacement was possibly harmful (25% vs. 37%; HR 1.43; 95% CI 1.18–1.72, P = .0002). Conclusions Higher survival rates were observed with repair than replacement and benefit of intervention declined as TRI-SCORE increased with no benefit of any type of surgery in the high TRI-SCORE category. These results emphasize the importance of timely intervention and patient selection to achieve the best outcomes and the need for randomized controlled trials.

Abstract Background and Aims Type 1 long QT syndrome (LQT1) is caused by pathogenic variants in the KCNQ1-encoded Kv7.1 potassium channels, which pathologically prolong ventricular action potential duration (APD). Herein, the pathologic phenotype in transgenic LQT1 rabbits is rescued using a novel KCNQ1 suppression-replacement (SupRep) gene therapy. Methods KCNQ1-SupRep gene therapy was developed by combining into a single construct a KCNQ1 shRNA (suppression) and an shRNA-immune KCNQ1 cDNA (replacement), packaged into adeno-associated virus serotype 9, and delivered in vivo via an intra-aortic root injection (1E10 vg/kg). To ascertain the efficacy of SupRep, 12-lead electrocardiograms were assessed in adult LQT1 and wild-type (WT) rabbits and patch-clamp experiments were performed on isolated ventricular cardiomyocytes. Results KCNQ1-SupRep treatment of LQT1 rabbits resulted in significant shortening of the pathologically prolonged QT index (QTi) towards WT levels. Ventricular cardiomyocytes isolated from treated LQT1 rabbits demonstrated pronounced shortening of APD compared to LQT1 controls, leading to levels similar to WT (LQT1-UT vs. LQT1-SupRep, P &lt; .0001, LQT1-SupRep vs. WT, P = ns). Under β-adrenergic stimulation with isoproterenol, SupRep-treated rabbits demonstrated a WT-like physiological QTi and APD90 behaviour. Conclusions This study provides the first animal-model, proof-of-concept gene therapy for correction of LQT1. In LQT1 rabbits, treatment with KCNQ1-SupRep gene therapy normalized the clinical QTi and cellular APD90 to near WT levels both at baseline and after isoproterenol. If similar QT/APD correction can be achieved with intravenous administration of KCNQ1-SupRep gene therapy in LQT1 rabbits, these encouraging data should compel continued development of this gene therapy for patients with LQT1.

Bi-allelic disruptive variants (nonsense, frameshift, and splicing variants) in KDM5B have been identified as causative for autosomal recessive intellectual developmental disorder type 65. In contrast, dominant variants, usually disruptive as well, have been more difficult to implicate in a specific phenotype, since some of them have been found in unaffected controls or relatives. Here, we describe individuals with likely pathogenic variants in KDM5B, including eight individuals with dominant missense variants. This study is a retrospective case series of 21 individuals with variants in KDM5B. We performed deep phenotyping and collected the clinical information and molecular data of these individuals’ family members. We compared the phenotypes according to variant type and to those previously described in the literature. The most common features were developmental delay, impaired intellectual development, behavioral problems, autistic behaviors, sleep disorders, facial dysmorphism, and overgrowth. DD, ASD behaviors, and sleep disorders were more common in individuals with dominant disruptive KDM5B variants, while individuals with dominant missense variants presented more frequently with renal and skin anomalies. This study extends our understanding of the KDM5B-related neurodevelopmental disorder and suggests the pathogenicity of certain dominant KDM5B missense variants.