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Spastic ataxias are rare neurogenetic disorders involving spinocerebellar and pyramidal tracts. Many genes are involved. Among them, CAPN1, when mutated, is responsible for a complex inherited form of spastic paraplegia (SPG76). We report the largest published series of 21 novel patients with nine new CAPN1 disease-causing variants and their clinical characteristics from two European university hospitals (Paris and Stockholm). After a formal clinical examination, causative variants were identified by next-generation sequencing and confirmed by Sanger sequencing. CAPN1 variants are a rare cause (~ 1.4%) of young-adult-onset spastic ataxia; however, together with all published cases, they allowed us to better describe the clinical and genetic spectra of this form. Truncating variants are the most frequent, and missense variants lead to earlier age at onset in favor of an additional deleterious effect. Cerebellar ataxia with cerebellar atrophy, dysarthria and lower limb weakness are often associated with spasticity. We also suggest that cognitive impairment and depression should be assessed specifically in the follow-up of SPG76 cases.

BackgroundEducational attainment is a critical social determinant of health that impacts the risk and severity of incident ischaemic stroke, but less is known of its impact on intracerebral haemorrhage (ICH). The objective of this study is to determine whether educational attainment is associated with ICH severity and short-term prognosis.MethodsSubjects were enrolled in a prospectively ascertained cohort with primary ICH from 1994 to 2020 at Massachusetts General Hospital. Educational attainment, medical history of ICH risk factors, ICH volume and ICH score were obtained on admission. The primary outcomes were ICH volume and the ICH score.ResultsOf 2539 eligible patients eligible, the median age of the sample was 74 (IQR 64–82) and 2159 (85%) had high school-only education. 1655 (65%) presented with an ICH volume less than or equal to 30 mL and 1744 (69%) presented with an ICH score less than 3. In multivariable logistic regression analyses controlling for age, income, employment history and prestroke diagnoses of hypertension and coronary artery disease, patients with high school-only education were more likely to have an ICH volume greater than 30 mL compared with college diplomates (OR 1.58, 95% CI 1.24 to 2.08) and more likely to have an ICH score of 3 or greater compared with college diplomates (OR 2.37, 95% CI 1.77 to 3.19).DiscussionPrestroke educational attainment is independently associated with ICH severity and short-term prognosis, with lower educational attainment associated with larger ICH volumes and higher ICH scores. Future studies should examine how educational attainment impacts exposure to traditional clinical risk factors.

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

Many patients with mild traumatic brain injury (mTBI) are at risk for mental health problems such as posttraumatic stress disorder (PTSD). The objective of this study was to determine whether the polygenic risk for PTSD (or for related mental health disorders or traits including major depressive disorder [MDD] and neuroticism [NEU]) was associated with an increased likelihood of PTSD in the aftermath of mTBI. We used data from individuals of European ancestry with mTBI enrolled in TRACK-TBI (n = 714), a prospective longitudinal study of level 1 trauma center patients. One hundred and sixteen mTBI patients (16.3%) had probable PTSD (PCL-5 score ≥33) at 6 months post-injury. We used summary statistics from recent GWAS studies of PTSD, MDD, and NEU to generate polygenic risk scores (PRS) for individuals in our sample. A multivariable model that included age, sex, pre-injury history of mental disorder, and cause of injury explained 7% of the variance in the PTSD outcome; the addition of the PTSD-PRS (and five ancestral principal components) significantly increased the variance explained to 11%. The adjusted odds of PTSD in the uppermost PTSD-PRS quintile was nearly four times higher (aOR = 3.71, 95% CI 1.80–7.65) than in the lowest PTSD-PRS quintile. There was no evidence of a statistically significant interaction between PTSD-PRS and prior history of mental disorder, indicating that PTSD-PRS had similar predictive utility among those with and without pre-injury psychiatric illness. When added to the model, neither MDD-PRS nor NEU-PRS were significantly associated with the PTSD outcome. These findings show that the risk for PTSD in the context of mTBI is, in part, genetically influenced. They also raise the possibility that an individual’s PRS could be clinically actionable if used—possibly with other non-genetic predictors—to signal the need for enhanced follow-up and early intervention; this precision medicine approach needs to be prospectively studied.

A Correction to this paper has been published: https://doi.org/10.1038/s41436-020-01064-y

Few data are available on the safety and efficacy of infliximab biosimilar CT-P13 in patients with ulcerative colitis and Crohn's disease.MethodsA prospective, multicenter, cohort study using a structured database.ResultsConsecutive patients (313 Crohn's disease and 234 ulcerative colitis) were enrolled from 31 referral centers; 311 patients were naive to anti–tumor necrosis factor alpha, 139 had a previous exposure to biologics, and the remaining 97 were switched to CT-P13 after a mean of 18 ± 14 infusions of infliximab. The mean follow-up was 4.3 ± 2.8 months, and the total follow-up time was 195 patient-years. After 2061 infusions, 66 serious adverse events were reported (12.1%), 38 (6.9%) of them were infusion-related reactions. The biosimilar had to be stopped in 29 (5.3%) cases for severe infusion reactions (8 naive, 19 previous exposed, and 2 switch), and in further 16 patients (2.9%) for other serious adverse events. Infusion reactions were significantly more frequent in patients pre-exposed to infliximab than to other anti–tumor necrosis factor alpha (incidence rate ratio = 2.82, 95% CI: 1.05–7.9). The efficacy of the biosimilar was evaluated in 434 patients who received treatment for at least 8 weeks, using time-to-event methods for censored observations: 35 patients were primary failures (8.1%). After further 8, 16, and 24 weeks, the efficacy estimations were 95.7%, 86.4%, and 73.7% for naive, 97.2%, 85.2%, and 62.2% for pre-exposed, and 94.5%, 90.8%, and 78.9% for switch, respectively (log-rank P = 0.64).ConclusionsAlthough no direct comparison was performed, preliminary data on efficacy and safety of CT-P13 were in line with those of infliximab.

Background: Dyslipidemias are a heterogeneous group of metabolic disorders mainly characterized by an increased risk of atherosclerotic cardiovascular disease (ASCVD) or other conditions, such as acute pancreatitis in hypertriglyceridemia. The aim of this study was to evaluate the effect of diet treatment and nutraceutical (NUTs) supplementation on the plasma lipid profile in outpatient dyslipidemic subjects, considering the influence of several factors (i.e., gender, age, body mass index, alcohol consumption, and smoking habits). Methods: 487 dyslipidemic patients spanning from 2015 to 2019 were treated with a Mediterranean diet or NUTs in a real-word setting and were retrospectively analyzed. General characteristics and lipid profile at baseline and after the follow-up period were evaluated. Results: Diet alone reduced total cholesterol (−19 mg/dL, −7.7%), LDL cholesterol (−18 mg/dL, −10.1%), and triglycerides (−20 mg/dL, −16.7%). Triglycerides (TG) decreased more in men, while women were associated with higher reduction of LDL cholesterol (LDL-C). Different types of NUTs further ameliorate lipid profiles when associated with diet. Nevertheless, most patients at low ASCVD risk (222 out of 262, 81.6%) did not achieve the 2019 ESC/EAS guidelines recommended LDL-C goals (i.e., LDL-C < 116 mg/dL). Conclusion: Lipid-lowering diet improves lipid profile, and NUTs can boost its efficacy, but taken together they are mainly unsatisfactory with respect to the targets imposed by 2019 EAS/ESC guidelines.

CAR− CD4+ T cell lymphopenia is an emerging issue following CAR‐T cell therapy. We analyzed the determinants of CD4+ T cell recovery and a possible association with survival in 31 consecutive patients treated with commercial CAR‐T for diffuse large B‐cell (DLBCL) or mantle cell lymphoma. Circulating immune subpopulations were characterized through multiparametric‐flow cytometry. Six‐month cumulative incidence of CAR− CD4+ T cell recovery (≥200 cells/μL) was 0.43 (95% confidence interval [CI]: 0.28–0.65). Among possible determinants of CD4+ T cell recovery, we recognized infusion of a 4‐1BB product (tisagenlecleucel, TSA) in comparison with a CD28 (axicabtagene/brexucabtagene, AXI/BRX) (hazard ratio [HR] [95% CI]: 5.79 [1.16–24.12] p = 0.016). Higher CD4+ T cell counts resulted with TSA at month‐1, ‐2 and ‐3. Moderate‐to‐severe infections were registered with prolonged CD4+ T cell lymphopenia. Early, month‐1 CD4+ T cell recovery was associated with a worse outcome in the DLBCL cohort, upheld in a multivariate regression model for overall survival (HR: 4.46 [95% CI: 1.12–17.71], p = 0.03). We conclude that a faster CAR− CD4+ T cell recovery is associated with TSA as compared to AXI/BRX. Month‐1 CAR− CD4+ T cell subset recovery could represent a “red flag” for CAR‐T cell therapy failure in DLBCL patients.