Barts Health NHS Trust is an NHS trust based in London, England. Established in 2012, it runs five hospitals throughout the City of London and East London, and is one of the largest NHS trusts in England.
Most effective information transmission in the human brain requires three fundamental elements, anatomical connectivity, functional connectivity and sufficiently low levels of information transmission error. It has been proposed that some of the major motor symptoms of Parkinson's disease (PD), such as slowness of movement, are a consequence of failure in the last of these. Here, this hypothesis is tested using a binary information transmission representation of human motor output based on basic features of motor physiology. When tested against experimental observations, it is demonstrated that the level of transmission error of motor code information predicts multiple behavioural and neurophysiological elements of the disorder as well as some of healthy movement. While some of these elements in people with PD have been attributed to impaired movement gain theories, and others have been unexplained, the ability of motor code transmission error to account for them all suggests it is a useful explanation of motor features in the disorder.
ImportanceThere is no international consensus on defining vitiligo severity or relapse. Current measures (such as body surface area) quantify depigmentation but do not fully capture the broader clinical and psychosocial effects of the disease.ObjectiveTo develop internationally agreed-upon definitions and criteria for vitiligo severity and relapse as part of the International Consensus on Definition of Severity and Relapse in Vitiligo study.Evidence ReviewThis global, mixed-methods consensus study used a multistep approach, including comprehensive literature review, qualitative study, 2 rounds of electronic Delphi surveys, and a final consensus meeting. To ensure adequate diversity and inclusivity and to capture a broad range of experiences, perspectives, social contexts, and representation, a recruitment framework (encompassing variation in age, sex, and skin phototypes) was predefined.FindingsIn total, 91 people from 5 continents expressed interest in participating. Experts (dermatologists, trialists, methodologists, nurses, psychologists, journal editors, and researchers) and people with vitiligo from diverse ethnic backgrounds and skin phototypes took part. During the first electronic Delphi survey round, 85 people participated and 81 participated in round 2 (response rate of 95% in each survey round). Consensus was reached that even though measurement of body surface area remains a necessary and adequate starting point for assessing vitiligo severity, this measure alone is insufficient to capture disease burden. The final consensus meeting included 44 participants (response rate of 54%). Twelve criteria for upgrading severity were recommended, encompassing both clinical aspects of vitiligo and its psychosocial effects. The major criteria for vitiligo include spread or active disease, involvement of highly visible or high-impact areas, psychological distress, stigmatization, lack of self-acceptance, and overall burden. The minor criteria for vitiligo include darker skin tones, younger age, involvement of scalp/facial hair, increased risk of sunburn, impact on career or school, and perceived loss of personal or cultural identity. No consensus was reached on the extent of pigment loss. Relapse was defined as loss of pigmentation in previously repigmented lesions (repigmentation had occurred either spontaneously or with treatment).Conclusion and RelevanceThis global, mixed-methods consensus study established internationally agreed-upon severity criteria for vitiligo. This consensus aims to bridge the gap between physician assessment and patient experience; improve the relevance and consistency of the severity classification in clinical care, research, and regulatory frameworks; and help close the remaining gaps in the diagnosis and classification of vitiligo. This consensus statement presents internationally agreed-upon definitions and criteria for vitiligo severity and relapse as part of the International Consensus on Definition of Severity and Relapse in Vitiligo study.
This prospective phase 2 multicentre non-randomised parallel arm study of haploidentical peripheral blood stem cell (PBSC) transplantation with post-transplant cyclophosphamide (PTCy) recruited 77 patients: 50 received reduced-intensity conditioning (RIC) with PTCy post stem cell infusion while 27 underwent myeloablative conditioning (MAC) with PTCy given after lymphocyte but prior to infusion of CD34 selected stem cells. The primary end-point 1-year overall survival (OS) was 86% for RIC and 78% for MAC, meeting the pre-specified targets for efficacy. At 4 years, OS was 63% for RIC and 60% for MAC with low non-relapse mortality of RIC 18% and MAC 4%. Engraftment was faster in the MAC arm (median time to neutrophil and platelet engraftment 11 and 15 days; 21 and 24 days in the RIC arm). The economic analysis showed that MAC had higher initial transplant costs, RIC incurred greater post-transplant monitoring costs, resulting in higher overall costs (RIC £156 711, MAC £131 092). Quality of life (QoL) outcomes in both indicated significant post-transplant declines at 3 months but returned to baseline by 12 months. This study confirms the long-term safety of using PBSC with PTCy in haploidentical transplants, with a good quality of life and reasonable costs.
BACKGROUND AND AIMS:Immune checkpoint inhibitors (ICI) are associated with life-threatening myocarditis but milder presentations are increasingly recognized. The same autoimmune process that causes ICI myocarditis can manifest concurrent generalized myositis, myasthenia-like syndrome, and respiratory muscle failure. Prognostic factors for this 'cardiomyotoxicity' are lacking. The main aim of this study was to determine predictors and construct a risk score associated with negative outcomes in patients admitted for ICI myocarditis. METHODS:A multicentre registry collected data retrospectively from 17 countries between 2014 and 2023. A multivariable Cox regression model was used to determine risk factors for the primary composite outcome: time to severe arrhythmia, heart failure, respiratory muscle failure, and/or cardiomyotoxicity-related death. Covariates included demographics, comorbidities, cardiomuscular symptoms, diagnostics, and treatments. Time-dependent covariates were used, and missing data were imputed. A point-based prognostic risk score was derived and externally validated. RESULTS:In 748 patients (67% male, age 23-94 years), 30-day incidence of the primary composite outcome, cardiomyotoxic death, and overall death were 33%, 13%, and 17%, respectively. By multivariable analysis, the primary composite outcome was associated with active thymoma (hazard ratio [HR] 3.6, 95% confidence interval [CI] 1.7-7.7), presence of cardiomuscular symptoms (HR 2.6 [1.5-4.2]), low QRS voltage on presenting electrocardiogram (HR for ≤0.5 mV vs >1 mV 1.9 [1.1-3.1]), left ventricular ejection fraction (LVEF) < 50% (HR 1.7 [1.1-2.6]), and incremental troponin elevation (HR 1.8 [1.4-2.4], 2.9 [1.8-4.7], and 4.6 [2.3-9.3], for 20, 200, and 2000-fold above upper reference limit, respectively). A prognostic risk score developed using these parameters showed good performance; 30-day primary outcome incidence increased gradually from 4% (risk score = 0) to 81% (risk score ≥ 4). This risk score was externally validated in two independent French and US cohorts. This risk score was used prospectively in the external French cohort to identify low-risk patients who were managed with no immunosuppression resulting in no cardiomyotoxic events. CONCLUSIONS:ICI-associated myocarditis can manifest with high morbidity and mortality. Myocarditis severity is associated with magnitude of troponin, thymoma, low QRS voltage, depressed LVEF, and cardiomuscular symptoms. A risk score incorporating these features performed well. CLINICAL TRIAL REGISTRATION:NCT04294771 and NCT05454527.
ABSTRACT:Immunodeficiency-associated primary central nervous system lymphoma (ID-PCNSL) represents a clinicopathologically distinct PCNSL subtype, for which large studies and prognostic models are lacking. To address this gap, the International PCNSL Collaborative Group conducted a retrospective multicenter study, integrating clinical, radiological, and pathological data from 308 ID-PCNSL cases, diagnosed at 23 participating sites in 7 countries. Preexisting immunodeficiency included administration of immunosuppressants for transplantation (41.2%) or autoimmunity (36.7%) and HIV infection (21.7%). All tumors were diffuse large B-cell lymphomas, with Epstein-Barr virus (EBV) detected in 79.2%. Immune reconstitution together with rituximab and methotrexate-based chemotherapy was associated with the highest response rates and prolonged progression-free survival, irrespective of immunodeficiency subtype and EBV status. Survival outcomes were highly variable, with a 54-month median overall survival. Multivariable Cox regression identified age (per year increment; hazard ratio [HR], 1.05 (95% confidence interval [CI], 1.02-1.07); P< .001), Karnofsky performance status (KPS) <70 (HR, 3.10; 95% CI, 1.67-5.87; P< .001), and EBV positivity (HR, 3.26; 95% CI, 1.47-7.33; P = .004) as prognostic factors for overall survival. A prognostic score was developed based on the sum of these adverse variables (age >60 years, KPS <70, EBV positivity). Stratification by this score yielded median survival times of 135, 29, and 3 months in patients with up to 1, 2, and 3 unfavorable markers (P< .0001). It allowed improved prognostic stratification of ID-PCNSL as compared with the Memorial Sloan Kettering Cancer Center and International Extranodal Lymphoma Study Group models developed for immunocompetent PCNSL. Collectively, this large international cohort defines clinicobiological features of ID-PCNSL and introduces a prognostic system with potential to guide future management.
