Background: We evaluated vorasidenib (VOR), a dual inhibitor of mIDH1/2, in patients with mIDH1/2 glioma (Phase 3; NCT04164901). Methods: Patients with residual/recurrent grade 2 mIDH1/2 oligodendroglioma or astrocytoma were enrolled (age ≥12; Karnofsky Performance Score ≥80; measurable non-enhancing disease; surgery as only prior treatment; not in immediate need of chemoradiotherapy). Patients were stratified by 1p19q status and baseline tumor size and randomized 1:1 to VOR 40 mg or placebo (PBO) daily in 28-day cycles. Endpoints included imaging-based progression-free survival (PFS), time to next intervention (TTNI), tumor growth rate (TGR), health-related quality of life (HRQoL), neurocognition and seizure activity. Results: 331 patients were randomized (VOR, 168; PBO, 163). The median age was 40.0 years. 172 and 159 patients had histologically confirmed oligodendroglioma and astrocytoma, respectively. Treatment with VOR significantly improved PFS and TTNI. Median PFS: VOR, 27.7 mos; PBO, 11.1 mos (P=0.000000067). Median TTNI: VOR, not reached; PBO, 17.8 mos (P=0.000000019). Treatment with VOR resulted in shrinkage of tumor volume. Post-treatment TGR: VOR, -2.5% (95% CI: -4.7, -0.2); PBO, 13.9% (95% CI: 11.1, 16.8). HRQoL and neurocognition were preserved and seizure control was maintained. VOR had a manageable safety profile. Conclusions: VOR was effective in mIDH1/2 diffuse glioma not in immediate need of chemoradiotherapy.

Background: Duchenne muscular dystrophy (DMD) is caused by DMD gene mutations. Delandistrogene moxeparvovec is an investigational gene transfer therapy, developed to address the underlying cause of DMD. We report findings from Part 1 (52 weeks) of the two-part EMBARK trial (NCT05096221). Methods: Key inclusion criteria: Ambulatory patients aged ≥4-<8 years with a confirmed DMD mutation within exons 18–79 (inclusive); North Star Ambulatory Assessment (NSAA) score >16 and <29 at screening. Eligible patients were randomized 1:1 to intravenous delandistrogene moxeparvovec (1.33×1014 vg/kg) or placebo. The primary endpoint was change from baseline in NSAA total score to Week 52. Results: At Week 52 (n=125), the primary endpoint did not reach statistical significance, although there was a nominal difference in change from baseline in NSAA total score in the delandistrogene moxeparvovec (2.6, n=63) versus placebo groups (1.9, n=61). Key secondary endpoints (time to rise, micro-dystrophin expression, 10-meter walk/run) demonstrated treatment benefit in both age groups (4-5 and 6-7 years; p<0.05).There were no new safety signals, reinforcing the favorable and manageable safety profile observed to date. Conclusions: Based on the totality of functional assessments including the timed function tests, treatment with delandistrogene moxeparvovec indicates beneficial modification of disease trajectory.

Dobbs v. Jackson Women’s Health continues a trajectory of U.S. Supreme Court jurisprudence that undermines the normative foundation of public health — the idea that the state is obligated to provide a robust set of supports for healthcare services and the underlying social determinants of health. Dobbs furthers a longstanding ideology of individual responsibility in public health, neglecting collective responsibility for better health outcomes. Such an ideology on individual responsibility not only enables a shrinking of public health infrastructure for reproductive health, it facilitates the rise of reproductive coercion and a criminal legal response to pregnancy and abortion. This commentary situates Dobbs in the context of a long historical shift in public health that increasingly places burdens on individuals for their own reproductive health care, moving away from the possibility of a robust state public health infrastructure.

Thin spray-on liners (TSLs) have been found to be effective for structurally supporting the walls of mining tunnels and thus reducing the occurrence of rock bursts, an effect primarily due to the penetration of cracks by the liner. Surface tension effects are thus important. However, TSLs are also used to simply stabilize rock surfaces, for example, to prevent rock fall, and in this context crack penetration is desirable but not necessary, and the tensile and shearing strength and adhesive properties of the liner determine its effectiveness. We examine the effectiveness of nonpenetrating TSLs in a global lined tunnel and in a local rock support context. In the tunnel context, we examine the effect of the liner on the stress distribution in a tunnel subjected to a geological or mining event. We show that the liner has little effect on stresses in the surrounding rock and that tensile stresses in the rock surface are transmitted across the liner, so that failure is likely to be due to liner rupture or detachment from the surface. In the local rock support context, loose rock movements are shown to be better achieved using a liner with small Young’s modulus, but high rupture strength.

Double-masking may be used to reduce the transmission of a virus. If additionally the masks are compressible, with different permeabilities and behaviour under compression, then it may be possible to design a mask that allows for easy breathing under normal breathing conditions, but is relatively impermeable under coughing or sneezing conditions. Such a mask could be both comfortable to wear and effective. We obtain analytical solutions for the steady-state flow-through behaviour of such a double mask under flow-out conditions. The results show that the reduction in permeability required to produce a relatively impermeable mask under high flux expulsion (sneezing) conditions could be achieved using either a single filter compressible mask or two filters with different poroelastic parameters. The parameters can be more easily adjusted using a double mask. For both single- and double-mask cases, there is an abrupt cut off, whereby through-flux levels reduce from a maximum value to zero as pressure drop levels increase beyond a critical value. Additionally, in the double-mask case, there exists a second steady-state solution for particular parameter ranges. This second solution is unlikely to occur under normal circumstances.

We previously reported that African (Loxodonta africana) and Asian (Elephas maximus) female elephants in European zoos have shorter adult lifespans than protected conspecifics in range countries. This effect was the cause of greatest concern in Asian elephants, and risk factors within this species included being zoo-born, transferred between zoos, and possibly removed early from the mother. Here, we investigate these risk factors further; assess fecundity and sustainability in European zoos; and propose testable hypotheses as to the causes of these animals’ problems. Although imported wild-born Asian elephants live longer than zoo-born conspecifics, being imported when juvenile or adult appears no more protective than being imported in infancy, suggesting that the benefits of being wild- rather than zoo-born are conferred early in life. Zoo-born Asian neonates are significantly heavier than those born to working animals in range countries, with a possible tendency to be fatter. In zoos, African elephants have tended to be removed from their mothers at older ages than young Asians, and were also transferred between zoos significantly less often: factors that could possibly underlie this species’ lower calf losses and improving adult survivorship in Europe. Both species have low fecundity in European zoos compared to in situ populations, and are not self-sustaining, declining at approximately 10% per annum if reliant on captive-bred females under historically prevailing conditions. Data from other species suggest that stress and/or obesity are parsimonious explanations for the suite of problems seen. We recommend specific screens for testing these hypotheses, and for potentially identifying vulnerable individuals within the extant zoo populations.