Adult-Onset Ataxia with Neuropathy and White Matter Abnormalities Due to a Novel SAMD9L Variant

Variants in tumor suppressor genes and in genes encoding DNA repairing proteins are associated with syndromes conferring neurologic features and increased risk for malignancy. The best example for these conditions is ataxia-telangiectasia (AT). A more rare and recent disease is an ataxia-pancytopenia syndrome (ATXPC) associated with heterozygous gain-of-function variants in the tumor suppressor gene SAMD9L (MIM 159550). Here, we describe a patient with a complex cerebellar syndrome associated with a novel SAMD9L pathogenic variant.publishedVersio

Comprehensive genetic and epigenetic analysis of sporadic meningioma for macro-mutations on 22q and micro-mutations within the NF2 locus

BACKGROUND: Meningiomas are the most common intracranial neoplasias, representing a clinically and histopathologically heterogeneous group of tumors. The neurofibromatosis type 2 (NF2) tumor suppressor is the only gene known to be frequently involved in early development of meningiomas. The objective of this study was to identify genetic and/or epigenetic factors contributing to the development of these tumors. A large set of sporadic meningiomas were analyzed for presence of 22q macro-mutations using array-CGH in order to identify tumors carrying gene dosage aberrations not encompassing NF2. The NF2 locus was also comprehensively studied for point mutations within coding and conserved non-coding sequences. Furthermore, CpG methylation within the NF2 promoter region was thoroughly analyzed. RESULTS: Monosomy 22 was the predominant finding, detected in 47% of meningiomas. Thirteen percent of the tumors contained interstitial/terminal deletions and gains, present singly or in combinations. We defined at least two minimal overlapping regions outside the NF2 locus that are small enough (~550 kb and ~250 kb) to allow analysis of a limited number of candidate genes. Bialleinactivationo the NF2 gne was detected in 36% of meningiomas. Among the monosomy 22 cases, no additional NF2 mutations could be identified in 35% (17 out of 49) of tumors. Furthermore, the majority of tumors (9 out of 12) with interstitial/terminal deletions did not have any detectable NF2 mutations. Methylation within the NF2 promoter region was only identified at a single CpG site in one tumor sample. CONCLUSION: We confirmed previous findings of pronounced differences in mutation frequency between different histopathological subtypes. There is a higher frequency of biallelic NF2 inactivation in fibroblastic (52%) compared to meningothelial (18%) tumors. The presence of macro-mutations on 22q also shows marked differences between fibroblastic (86%) and meningothelial (39%) subtypes. Thus, inactivation of NF2, often combined with the presence of macro-mutation on 22q, is likely not as important for the development of the meningothelial subtype, as opposed to the fibroblastic form. Analysis of 40 CpG sites distributed within 750 bp of the promoter region suggests that NF2 promoter methylation does not play a major role in meningioma development

A list of tools is NOT enough! Professionals’ advice on how to implement a Core Outcome Set in practice

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What is important to people living with dementia?:the ‘long-list’ of outcome items in the development of a core outcome set for use in the evaluation of non-pharmacological community-based health and social care interventions

BackgroundCore outcome sets (COS) prioritise outcomes based on their importance to key stakeholders, reduce reporting bias and increase comparability across studies. The first phase of a COS study is to form a ‘long-list’ of outcomes. Key stakeholders then decide on their importance. COS reporting is described as suboptimal and this first phase is often under-reported. Our objective was to develop a ‘long-list’ of outcome items for non-pharmacological interventions for people with dementia living at home. MethodsThree iterative phases were conducted. First, people living with dementia, care partners, health and social care professionals, policymakers and researchers (n = 55) took part in interviews or focus groups and were asked which outcomes were important. Second, existing dementia trials were identified from the ALOIS database. 248 of 1009 pharmacological studies met the inclusion criteria. Primary and secondary outcomes were extracted from a 50% random sample (n = 124) along with eight key reviews/qualitative papers and 38 policy documents. Third, extracted outcome items were translated onto an existing qualitative framework and mapped into domains. The research team removed areas of duplication and refined the ‘long-list’ in eight workshops. ResultsOne hundred seventy outcome items were extracted from the qualitative data and literature. The 170 outcome items were consolidated to 54 in four domains (Self-Managing Dementia Symptoms, Quality of Life, Friendly Neighbourhood & Home, Independence). ConclusionsThis paper presents a transparent blueprint for ‘long-list’ development. Though a useful resource in their own right, the 54 outcome items will be distilled further in a modified Delphi survey and consensus meeting to identify core outcomes

The energy and mass balance of Peruvian glaciers

Peruvian glaciers are important contributors to dry season runoff for agriculture and hydropower, but they are at risk of disappearing due to climate change. We applied a physically based, energy balance melt model at five on-glacier sites within the Peruvian Cordilleras Blanca and Vilcanota. Net shortwave radiation dominates the energy balance, and despite this flux being higher in the dry season, melt rates are lower due to losses from net longwave radiation and the latent heat flux. The sensible heat flux is a relatively small contributor to melt energy. At three of the sites the wet season snowpack was discontinuous, forming and melting within a daily to weekly timescale, and resulting in highly variable melt rates closely related to precipitation dynamics. Cold air temperatures due to a strong La Niña year at Shallap Glacier (Cordillera Blanca) resulted in a continuous wet season snowpack, significantly reducing wet season ablation. Sublimation was most important at the highest site in the accumulation zone of the Quelccaya Ice Cap (Cordillera Vilcanota), accounting for 81% of ablation, compared to 2%–4% for the other sites. Air temperature and precipitation inputs were perturbed to investigate the climate sensitivity of the five glaciers. At the lower sites warmer air temperatures resulted in a switch from snowfall to rain, so that ablation was increased via the decrease in albedo and increase in net shortwave radiation. At the top of Quelccaya Ice Cap warming caused melting to replace sublimation so that ablation increased nonlinearly with air temperature

Quantifying the controls of Peruvian glacier response to climate

Peruvian glaciers are important contributors to dry season runoff for agriculture and hydropower, but they are at risk of disappearing due to climate warming. Their energy balance and ablation characteristics have previously been studied only for individual glaciers, with no comparisons between regions. We applied the physically-based, energy balance melt component of the model Tethys-Chloris at five on-glacier meteorological stations: three in the Cordillera Blanca near Huaraz (with glaciers above ~4300 m a.s.l.), and two in the Cordillera Vilcanota east of Cusco (with glaciers above ~ 4800 m). The climate of these regions is strongly seasonal, with an austral summer wet season and winter dry season. Our results revealed that at most sites the energy available for melt is greatest in the wet season. This is a consequence of the dry season energy losses from the latent heat flux and net longwave radiation which counter-balance the high dry season net shortwave radiation, which otherwise dominates the energy balance. The sensible heat flux is a relatively small contributor to melt energy in both seasons. Comparison of the five sites suggests that there is more energy available for melt at a given elevation in the Cordillera Vilcanota compared to the Cordillera Blanca. At three of the sites the wet season snowpack was discontinuous, forming and melting within a daily to weekly timescale. Albedo and melt are thus highly variable in the wet season and closely related to the precipitation dynamics. At the highest site, in the accumulation zone of the Quelccaya Ice Cap, 81% of ablation was from sublimation. Sublimation was less important at the lower sites, but it reduces dry season melt. Correlation of the NOAA Oceanic El Niño Index (ONI) to the outputs of the two sites with the longest records revealed that the warmer wet season temperatures characteristic of a positive ONI were associated with a decreased albedo, greater net shortwave radiation, a more positive sensible heat flux and increased melt rates. Air temperature and precipitation inputs were also perturbed at all five sites to understand their sensitivity to climate change. Enhanced mass loss was predicted with a static increase of 2°C or more, even with a +30% precipitation increase, with the lower elevation Cordillera Blanca sites at risk of the greatest mass loss due to warming

Sex differences in cerebral venous sinus thrombosis after adenoviral vaccination against COVID-19

Introduction: Cerebral venous sinus thrombosis associated with vaccine-induced immune thrombotic thrombocytopenia (CVST-VITT) is a severe disease with high mortality. There are few data on sex differences in CVST-VITT. The aim of our study was to investigate the differences in presentation, treatment, clinical course, complications, and outcome of CVST-VITT between women and men. Patients and methods: We used data from an ongoing international registry on CVST-VITT. VITT was diagnosed according to the Pavord criteria. We compared the characteristics of CVST-VITT in women and men. Results: Of 133 patients with possible, probable, or definite CVST-VITT, 102 (77%) were women. Women were slightly younger [median age 42 (IQR 28–54) vs 45 (28–56)], presented more often with coma (26% vs 10%) and had a lower platelet count at presentation [median (IQR) 50x109/L (28–79) vs 68 (30–125)] than men. The nadir platelet count was lower in women [median (IQR) 34 (19–62) vs 53 (20–92)]. More women received endovascular treatment than men (15% vs 6%). Rates of treatment with intravenous immunoglobulins were similar (63% vs 66%), as were new venous thromboembolic events (14% vs 14%) and major bleeding complications (30% vs 20%). Rates of good functional outcome (modified Rankin Scale 0-2, 42% vs 45%) and in-hospital death (39% vs 41%) did not differ. Discussion and conclusions: Three quarters of CVST-VITT patients in this study were women. Women were more severely affected at presentation, but clinical course and outcome did not differ between women and men. VITT-specific treatments were overall similar, but more women received endovascular treatment.</p

Sex differences in cerebral venous sinus thrombosis after adenoviral vaccination against COVID-19

Introduction: Cerebral venous sinus thrombosis associated with vaccine-induced immune thrombotic thrombocytopenia (CVST-VITT) is a severe disease with high mortality. There are few data on sex differences in CVST-VITT. The aim of our study was to investigate the differences in presentation, treatment, clinical course, complications, and outcome of CVST-VITT between women and men. Patients and methods: We used data from an ongoing international registry on CVST-VITT. VITT was diagnosed according to the Pavord criteria. We compared the characteristics of CVST-VITT in women and men. Results: Of 133 patients with possible, probable, or definite CVST-VITT, 102 (77%) were women. Women were slightly younger [median age 42 (IQR 28–54) vs 45 (28–56)], presented more often with coma (26% vs 10%) and had a lower platelet count at presentation [median (IQR) 50x109/L (28–79) vs 68 (30–125)] than men. The nadir platelet count was lower in women [median (IQR) 34 (19–62) vs 53 (20–92)]. More women received endovascular treatment than men (15% vs 6%). Rates of treatment with intravenous immunoglobulins were similar (63% vs 66%), as were new venous thromboembolic events (14% vs 14%) and major bleeding complications (30% vs 20%). Rates of good functional outcome (modified Rankin Scale 0-2, 42% vs 45%) and in-hospital death (39% vs 41%) did not differ. Discussion and conclusions: Three quarters of CVST-VITT patients in this study were women. Women were more severely affected at presentation, but clinical course and outcome did not differ between women and men. VITT-specific treatments were overall similar, but more women received endovascular treatment.</p

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe