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Objective The prevailing approaches to selecting multiple sclerosis (MS) disease modifying therapies (DMTs) have contributed to exponential increases in societal expenditures and out‐of‐pocket expenses, without compelling evidence of improved outcomes. Guidance is lacking regarding when and in whom the benefits of preventing MS‐related disability likely outweighs the risks of highly effective DMTs (HET) and when it is appropriate to consider DMT costs. Our objective was to develop a standardized approach to improve the quality, affordability and equity of MS care. Methods MS experts partnered with health plan pharmacists to develop an ethical, risk‐stratified, cost‐sensitive treatment algorithm. We developed a risk‐stratification schema to classify patients with relapsing forms of MS as high, intermediate or low risk of disability based on the best available evidence and, when the evidence was poor or lacking, by consensus. DMTs are grouped as highly, modestly or low/uncertain effectiveness and preferentially ranked within groups by safety based on pre‐specified criteria. We reviewed FDA documents and the published literature. When efficacy and safety are equivalent, the lower cost DMT is preferred. Results Assignment to the high‐risk group prompts treatment with preferred HETs early in the disease course. For persons in the intermediate‐ or low‐risk groups with cost or health care access barriers, we incorporated induction therapy with an affordable B‐cell depleting agent. Based on more favorable safety profiles, our preferred approach prioritizes use of rituximab and natalizumab among HETs and interferon‐betas or glatiramer acetate among modestly effective agents. Interpretation The risk‐stratified treatment approach we recommend provides clear, measurable guidance in whom and when to prescribe HETs, when to prioritize lower cost DMTs and how to accommodate persons with MS with cost or other barriers to DMT use. It can be adapted to other cost structures and updated quickly as new information emerges. We recommend that physician groups partner with health insurance plans to adapt our approach to their settings, particularly in the United States. Future studies are needed to resolve the considerable uncertainty about how much variability in prognosis specific risk factors explain.

Purpose Integrating genomic sequencing in clinical care requires standardization of variant interpretation practices. The Clinical Genome Resource has established expert panels to adapt the American College of Medical Genetics and Genomics/Association for Molecular Pathology classification framework for specific genes and diseases. The Cardiomyopathy Expert Panel selected MYH7 , a key contributor to inherited cardiomyopathies, as a pilot gene to develop a broadly applicable approach. Methods Expert revisions were tested with 60 variants using a structured double review by pairs of clinical and diagnostic laboratory experts. Final consensus rules were established via iterative discussions. Results Adjustments represented disease-/gene-informed specifications (12) or strength adjustments of existing rules (5). Nine rules were deemed not applicable. Key specifications included quantitative frameworks for minor allele frequency thresholds, the use of segregation data, and a semiquantitative approach to counting multiple independent variant occurrences where fully controlled case-control studies are lacking. Initial inter-expert classification concordance was 93%. Internal data from participating diagnostic laboratories changed the classification of 20% of the variants ( n  = 12), highlighting the critical importance of data sharing. Conclusion These adapted rules provide increased specificity for use in MYH7 -associated disorders in combination with expert review and clinical judgment and serve as a stepping stone for genes and disorders with similar genetic and clinical characteristics.

BackgroundBicuspid aortic valve (BAV) is the most common congenital heart defect in adults, often leading to complications such as thoracic aortic aneurysms and aortic stenosis. While BAV is frequently associated with 22q11.2 deletion syndrome (22q11.2DS), the contribution of rare copy number variants (CNVs) in this region to non-syndromic BAV is less clear. This study is aimed to assess the role of rare 22q11.2 CNVs in patients with early-onset BAV (EBAV) and to determine whether these variants are linked to an increased risk of complications.MethodsWhole genome microarray genotyping was conducted on 272 patients with BAV with early onset valve or aortic disease (EBAV) and 272 biological relatives. CNVs were detected using three independent algorithms, focusing on the 22q11.2 region (18–24 Mb). CNV burden in the EBAV cohort was compared with unselected European ancestry controls.ResultsRare duplications and deletions within the 22q11.2 region, particularly involving genes associated with cardiac development, were identified in 7.4% of EBAV probands. These CNVs were significantly enriched compared with the general population and segregated with BAV in families. Individuals carrying rare 22q11.2 CNVs had a higher prevalence of psychiatric diagnoses and learning difficulties, although they did not exhibit the typical features of 22q11.2DS. Importantly, these CNVs were associated with early onset or complex BAV cases, underscoring their potential clinical relevance.ConclusionsRare 22q11.2 CNVs play a role in non-syndromic BAV, particularly in cases with early onset or complex presentations. CNV screening could be considered as part of risk stratification for patients with BAV, helping to predict complications and guide management.Trial registration number NCT01823432.

Bicuspid aortic valve (BAV), the most common congenital heart defect, is a major cause of aortic valve disease requiring valve interventions and thoracic aortic aneurysms predisposing to acute aortic dissections. The spectrum of BAV ranges from early onset valve and aortic complications (EBAV) to sporadic late onset disease. Rare genomic copy number variants (CNVs) have previously been implicated in the development of BAV and thoracic aortic aneurysms. We determined the frequency and gene content of rare CNVs in EBAV probands (n = 272) using genome-wide SNP microarray analysis and three complementary CNV detection algorithms (cnvPartition, PennCNV, and QuantiSNP). Unselected control genotypes from the Database of Genotypes and Phenotypes were analyzed using identical methods. We filtered the data to select large genic CNVs that were detected by multiple algorithms. Findings were replicated in a BAV cohort with late onset sporadic disease (n = 5040). We identified 3 large and rare (< 1,1000 in controls) CNVs in EBAV probands. The burden of CNVs intersecting with genes known to cause BAV when mutated was increased in case-control analysis. CNVs intersecting with GATA4 and DSCAM were enriched in cases, recurrent in other datasets, and segregated with disease in families. In total, we identified potentially pathogenic CNVs in 9% of EBAV cases, implicating alterations of candidate genes at these loci in the pathogenesis of BAV.

We conducted a retrospective cohort study in Kaiser Permanente Southern California from 1 January 2020 to 30 September 2020. We found that rituximab‐treated persons with multiple sclerosis (pwMS, n = 1895) were more likely be hospitalized (n = 8, 33.3%), but not die (n = 0) from COVID‐19, compared to the 4.81 million non‐MS population (5.8% and 1.4%, respectively). Time in months (adjusted OR = 0.32, 95% CI = 0.15–0.69, p = 0.0033) and receiving 1000 mg compared to lower doses at last infusion (adjusted OR = 6.28, 95% CI = 1.38–28.5, p = 0.0173) were independent predictors of COVID‐19 severity. Rituximab‐treated pwMS should be counseled to take extra precautions in the 5 months following each infusion. Using extended dosing intervals and lower doses could be considered.

The information technology (IT) boom dramatically boosted the rapid growth of the U.S. economy during the 1990s, contributing 1.4 percentage points of the 4.6 percent national average real gross domestic product growth from 1996 to 2000. As the IT boom went bust in 2001, however, the IT sector's influence on the economy dwindled.

Het Vlaams Indicatorenboek 2019 is een uitgave van het Expertisecentrum O&O Monitoring van de Vlaamse Gemeenschap in opdracht van de Vlaamse minister van Werk, Economie, Innovatie, en Sport en van de Vlaamse minister van Onderwijs