Citations

Purpose of review The increasing prevalence of hypertension, alongside the growing use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for conditions beyond type 2 diabetes, underscores the need for understanding if there is a role for these medications in blood pressure management. This review addresses the timely opportunity to assess how GLP-1 RAs could influence blood pressure control, potentially broadening therapeutic strategies for cardiovascular risk management. Recent findings Emerging literature indicates that GLP-1 RAs influence blood pressure through various mechanisms, such as sympathetic nervous modulation, vasodilation, and diuretic effects. Clinical trials demonstrate modest yet statistically significant reductions in systolic blood pressure (SBP), with less consistent effects on diastolic blood pressure (DBP). The advent of dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists presents enhanced possibilities for managing hypertension. Summary The implications of these findings suggest that GLP-1 RAs have potential as adjunctive therapies for hypertension, especially in patients already receiving these agents for other cardiometabolic conditions. The blood pressure-lowering effects, often independent of weight loss or glucose control, warrant further investigation to determine their precise role within hypertension treatment algorithms and encourage integration into clinical practice.

Background: Noninvasive tests (NITs) are used to risk-stratify metabolic dysfunction–associated steatotic liver disease. The aim was to survey global patterns of real-world use of NITs. Methods: A 38-item survey was designed by the Global NASH Council. Providers were asked about risks for advanced fibrosis, which NITs (cutoff values) they use to risk-stratify liver disease, monitor progression, and which professional guidelines they follow. Results: A total of 321 participants from 43 countries completed the survey (54% hepatologists, 28% gastroenterologists, and 18% other). Of the respondents, 85% would risk-stratify patients with type 2 diabetes, obesity (82%), or abnormal liver enzymes (73%). Among NITs to rule out significant or advanced fibrosis, transient elastography (TE) and fibrosis-4 (FIB-4) were most used, followed by NAFLD Fibrosis Score, Enhanced Liver Fibrosis, and magnetic resonance elastography. The cutoffs for ruling out significant fibrosis varied considerably between practices and from guidelines, with only 50% using TE <8 kPa, 65% using FIB-4 <1.30 for age <65, and 41% using FIB-4 <2.00 for age ≥65. Similar variability was found for ruling in advanced fibrosis, where thresholds of FIB-4 ≥2.67 and TE ≥10 kPa were used by 20% and 17%, respectively. To establish advanced fibrosis, 48% would use 2 NITs while 23% would consider 1 NIT, and 17% would confirm with liver biopsy. TE was used by >75% to monitor, and 66% would monitor (intermediate or high risk) annually. Finally, 65% follow professional guideline recommendations regarding NITs. Conclusions: In clinical practice, there is variability in NIT use and their thresholds. Additionally, there is suboptimal adherence to professional societies’ guidelines.

AbstractAlthough guidelines have historically recommended deferring decisions about learning genomic information for conditions not actionable in childhood until adulthood, youth have increasing access to personal genomic information through research, clinical, and direct‐to‐consumer testing. However, little is known about young people's reactions to, and perceived future utility of learning genomic information actionable in adulthood. We conducted qualitative interviews with 28 youth ages 15–22 without clinical indications for genetic screening who, through enrollment in a genomic decision‐making research study, learned they were carriers of an autosomal recessive condition, or anticipated being carriers but received negative results. Semi‐structured interviews occurred virtually between 3 and 16 months after the return of results. Interpretative description guided deductive and inductive coding of transcripts. Of the 28 participants, 21 received positive carrier results, and 7 received negative results. Although some carriers felt the result was unexpected, they expressed relief overall and did not feel worried about their result. Participants with negative results also felt relief about their results. All participants correctly described what a carrier result means, but some carriers could not remember the condition associated with their result. No participant regretted learning personal genomic information, and all reported their results helped them better understand risks to future children. Carriers who perceived the condition for which they were carriers as more severe and/or those familiar with the condition were more likely to remember their result and consider future reproductive options. Carriers also felt testing at their respective age allowed increased familiarity with results and more time to gather information and decide on the personal utility of the information. Our findings suggest early access to genomic information for some youth may allow integration of carrier information over time with minimal adverse effects. More research is needed to assess long‐term outcomes among carriers.

AimsPrevious studies have highlighted differences in the risk of periprosthetic fractures (PPFs) in patients undergoing total hip arthroplasty with either a cemented taper slip (TS) stem or a composite beam (CB) stem. This biomechanical study explored the occurrence of PPF around these stems, and the protective effect of adding a 16-gauge prophylactic calcar or diaphyseal wire to the TS stems to increase the resistance to torque as a potential way to prevent these fractures.MethodsA total of 21 TS stems (eight alone, six with calcar wiring, and seven with diaphyseal wiring placed 2 cm distal to the lesser trochanter) and seven CB stems were cemented into standard sawbones. The peak torque at failure was measured using a servohydraulic test machine, and the fracture location was recorded. An a priori power analysis determined that seven specimens per group were needed to detect a 30 Nm difference with 90% power, assuming a 14.8 Nm SD in peak torque between groups. Comparisons were performed using paired t-tests.ResultsCB stems exhibited a significantly higher mean peak torque at failure (205.3 Nm (SD 26.9)) than TS stems (159.5 Nm (SD 17.4); p = 0.012), calcar-wired TS (148.2 Nm (SD 38.6); p = 0.031), and diaphyseal-wired TS (164.9 Nm (SD 21.5); p = 0.027). This study did not demonstrate that wired-TS stems had a higher peak torque at failure than non-wired TS stems. Additionally, calcar wiring was not found to be stronger than diaphyseal wiring (p = 0.400). Four CB fractures occurred distal to the stem, whereas all TS fractures occurred at the mid-stem, simulating a Vancouver type B fracture. Interestingly, adding the diaphyseal wire shifted the fracture location more distally in four of the seven stems (p = 0.070).ConclusionIn this model, CB stems had greater resistance to torque than TS stems, which may explain the lower risk of PPF. Adding calcar or diaphyseal wires to the TS stems resulted in no significant change in peak torque to fracture. CB cemented stems should be considered in patients at high risk of PPF.Cite this article: Bone Joint J 2025;107-B(5 Supple A):32–37.

ABSTRACT Intronic GGGGCC hexanucleotide repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Despite its intronic location, this repeat avidly supports synthesis of pathogenic dipeptide repeat (DPR) proteins via repeat-associated non-AUG (RAN) translation. However, the template RNA species that undergoes RAN translation endogenously remains unclear. Using long-read based 5’ RNA ligase-mediated rapid amplification of cDNA ends (5’ Repeat-RLM-RACE), we identified novel C9orf72 transcripts initiating within intron 1 in a C9BAC mouse model, patient-derived iNeurons, and iNeuron-derived polysomes. These cryptic m 7 G-capped mRNAs are at least partially polyadenylated and are more abundant than transcripts derived from intron retention or circular intron lariats. In RAN translation reporter assays, novel intronic template transcripts – even those with short (32 nucleotide) leaders – exhibited robust expression compared to exon-intron and repeat-containing lariat reporters. To assess endogenous lariat repeat RNA contributions to RAN translation, we enhanced endogenous lariat stability by knocking down the lariat debranching enzyme Dbr1. However, this modulation did not impact DPR production in patient-derived iNeurons. These findings identify cryptic, linear, m 7 G-capped intronic-initiating C9orf72 mRNAs as an endogenous template for RAN translation and DPR production, with implications for disease pathogenesis and therapeutic development. SIGNIFICANCE STATEMENT An intronic GGGGCC repeat expansion in C9orf72 supports an unusual translational initiation process known as repeat-associated non-AUG (RAN) translation to produce toxic dipeptide repeat (DPR) proteins that contribute to neurodegeneration in ALS and FTD. How an intronic repeat RNA engages with ribosomes to support such translation is unclear. Here we identify a series of novel mRNA transcripts that initiate within the repeat-containing intron to create linear m 7 G-capped templates for RAN translation from GGGGCC repeats. These cryptic mRNAs are present in patient iNeurons, engage with ribosomes, and robustly support RAN translation. This finding has important implications for both our understanding of the mechanism by which RAN translation occurs and on therapeutic development in this currently untreatable class of neurodegenerative disorders.