The relationship between self-reported falls and fracture risk was estimated in an international meta-analysis of individual-level data from 46 prospective cohorts. Previous falls were associated with an increased fracture risk in women and men and should be considered as an additional risk factor in the FRAX® algorithm. Previous falls are a well-documented risk factor for subsequent fracture but have not yet been incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between previous falls and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD). The resource comprised 906,359 women and men (66.9
Aged hematopoietic stem cells (HSCs) expand in clusters over time, while reducing their regenerative capacity and their ability to preserve the homeostasis of the hematopoietic system. The expression of Notch ligands in the bone marrow (BM) niche is essential for hematopoiesis. However, the impact of Notch signaling on adult HSC function and its involvement in HSC aging remains controversial. Here, we show that Notch activation in young HSCs is not homogeneous, and it is triggered by sinusoidal expression of the Notch ligand Jagged2 (Jag2). Sinusoidal Jag2 deletion in young mice recapitulates the decrease in Notch activity observed in aged HSCs and alters HSC divisional symmetry and fate priming, promoting myeloid-biased HSCs (My-HSCs) expansion. Mechanistically, our data reveals that upon decreasing sinusoidal Jag2 expression, HSCs themselves upregulate Jag2, which cis-inhibits Notch signaling, resulting in the expansion of My-HSCs and in reduced hematopoietic regeneration. Collectively, these findings identify the crosstalk between BM niche-driven and HSC intrinsic features in regulating HSC fate priming and regenerative potential and reveal an extrinsic Notch trans-activation to intrinsic cis-inhibition switch underlying HSC aging.
LINKER-MM1 (NCT03761108) is a Phase 1/2 study of linvoseltamab, a human BCMA×CD3 bispecific antibody for patients with relapsed/refractory multiple myeloma (RRMM) who are triple-class exposed (TCE) with ≥ 3 prior lines of therapy (3L+), or triple-class refractory (TCR). To contextualize efficacy data from LINKER-MM1, the Phase 2 linvoseltamab 200 mg cohort (N = 105) was compared with an international external control arm (ECA) comprising 203 patients from participating International Myeloma Working Group sites who met LINKER-MM1 eligibility criteria based on chart reviews. The ECA reflected real-world standard-of-care (RW SOC). An independent data review committee assessed data relevance, quality, and cohort comparability, while a separate independent central review committee evaluated response data. Inverse probability of treatment weighting was used to balance baseline characteristics between the linvoseltamab arm and the ECA. Linvoseltamab had a higher objective response rate (weighted odds ratio 3.0 [95% confidence interval (CI): 1.9-4.1]) and longer median progression-free survival (weighted hazard ratio [wHR] 0.33 [95% CI: 0.28-0.40]), time to next treatment (wHR 0.34 [95% CI: 0.29-0.44]), and overall survival (wHR 0.72 [95% CI: 0.58-0.98]) than RW SOC. These findings highlight linvoseltamab's potential as an effective treatment for 3L+ and TCE/TCR RRMM.
In this meta-analysis of international cohorts, current smoking is confirmed as a significant BMD-independent predictor of future fracture with a stronger relationship in men than in women. A causative and reversible effect of smoking on fracture risk is suggested by past smoking having a significantly lower risk than current smoking. In this meta-analysis of international cohorts, the aim was to examine the relationship of current and past smoking with fracture risk to provide an update for future iterations of the FRAX tool. The risk of fracture associated with current and past smoking was estimated using an extended Poisson model applied separately to each of 58 prospective international cohort studies. Covariates included current time since start of follow up, current age, and in an additional model, BMD at the femoral neck. The results of the different studies were merged by using inverse-variance weighted β-coefficients. This analysis included a total of 1,691,024 participants (61.2
Since 2022, intra-articular (IA) and periarticular (PA) administrations of glucocorticoids (GC) have been prohibited in sports during competitions. The aim of this study was to evaluate plasma and urinary concentrations of betamethasone (BET) and triamcinolone acetonide (TA) following IA and PA administrations, in order to verify the suitability of the minimum reporting levels (MRL) and washout periods established by WADA and to assess their systemic effects. Urine and plasma samples were collected after IA or PA administration in patients or athletes receiving GC treatment. For BET, 12 participants received IA, and 20 received PA injections; for TA, eight participants received IA, and six received PA administrations. Sample analysis was performed using validated LC-MS/MS methods. The elimination profiles of BET after both IA and PA administrations were comparable, with high concentrations observed during the first postadministration day followed by a progressive decline. Similar plasma concentrations were obtained after both routes, with a similar effect on cortisol levels, indicating a clear systemic effect. For TA, different excretion patterns were observed depending on the administration route. After IA injections, TA displayed a profile similar to that of BET. In contrast, following PA administration, TA concentrations in urine and plasma were lower and remained relatively constant over several days. The degree and duration of cortisol suppression after PA administration varied among participants, with some showing a short effect. The results obtained support the MRL for IA and PA administrations defined by WADA. However, the washout period for BET is recommended to be increased to 5 days.
