This network meta-analysis involving 453 trials compares the benefits and harms of 21 antidiabetic interventions from 9 drug classes for adults with type 2 diabetes. Efficacy of the regimens appear... Background: Several pharmacologic options for type 2 diabetes are available. Purpose: To compare benefits and harms of glucose-lowering drugs in adults with type 2 diabetes. Data Sources: Several d...

Despite most monoclonal antibodies against Aβ in Alzheimer’s failed to demonstrate efficacy, the newest antibodies showed statistically significant clinical effects. We conducted a systematic review and meta-analysis to assess the efficacy, target engagement, and safety of anti-Aβ antibodies in sporadic AD including phase III RCTs published up to November 28, 2023. Antibodies as a drug class, attenuated worsening on the clinical scales CDR-SB and ADAS-Cog by very small effect sizes and reduced amyloid on PET by a very large effect size. Reduction of amyloid on PET was moderately correlated with CDR-SB and ADAS-Cog reductions. However, antibodies increased risk of ARIA-E and ARIA-H by a very large and moderate effect size, respectively. In subgroup analyses by individual drug, Donanemab and Lecanemab induced the largest benefits. In subgroup analyses by binding affinity, antibodies without binding to monomers were associated with the most favorable effects. Despite statistical significance for improvement on clinical measures, antibody effects were below the threshold of clinically meaningful change during the period they were studied. However, the newest antibodies demonstrably interfere with the underlying ΑD pathophysiology and therefore their benefit could be cumulative over time leading to larger clinical effects in subsequent years. PROSPERO registration no. CRD42022381334.

The premutation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene is characterized by an expansion of the CGG trinucleotide repeats (55 to 200 CGGs) in the 5’ untranslated region and increased levels of FMR1 mRNA. Molecular mechanisms leading to fragile X-premutation-associated conditions (FXPAC) include cotranscriptional R-loop formations, FMR1 mRNA toxicity through both RNA gelation into nuclear foci and sequestration of various CGG-repeat-binding proteins, and the repeat-associated non-AUG (RAN)-initiated translation of potentially toxic proteins. Such molecular mechanisms contribute to subsequent consequences, including mitochondrial dysfunction and neuronal death. Clinically, premutation carriers may exhibit a wide range of symptoms and phenotypes. Any of the problems associated with the premutation can appropriately be called FXPAC. Fragile X-associated tremor/ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI), and fragile X-associated neuropsychiatric disorders (FXAND) can fall under FXPAC. Understanding the molecular and clinical aspects of the premutation of the FMR1 gene is crucial for the accurate diagnosis, genetic counseling, and appropriate management of affected individuals and families. This paper summarizes all the known problems associated with the premutation and documents the presentations and discussions that occurred at the International Premutation Conference, which took place in New Zealand in 2023.