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.

The present study aims to investigate the efficacy of intravenously injected mesenchymal stem cells (MSCs) in treating neuropathic pain either before or after its induction by a chronic constriction injury (CCI) model. Rats were divided into four groups: control group, neuropathic group, and treated groups (pre and postinduction) with i.v. mononuclear cells (106 cell/mL). For these rats, experimental testing for both thermal and mechanical hyperalgesia was evaluated. The cerebral cortex of the rats was dissected, and immunohistochemical analysis using anti-proliferating cell nuclear antigen (PCNA), CD117, nestin, and glial fibrillary acidic protein was performed. Our results showed that a single injection of MSCs (either preemptive/or post-CCI) produced equipotent effects on allodynia, mechanical hyperalgesia, and thermal response. Immunohistochemical analysis showed that the stem cells have reached the cerebral cortex. The injected group with MSCs before CCI showing few stem cells expressed PCNA, CD117, and nestin in the cerebral cortex. The group injected with MSCs after CCI, showing numerous recently proliferated CD117-, nestin-, PCNA-positive stem cells in the cerebral cortex. In conclusion, our findings demonstrate that the most probable effect of i.v. stem cells is the central anti-inflammatory effect, which opens concerns about how stem cells circulating in systemic administration to reach the site of injury.

Pomegranate peels (PP) and mango leaves (ML) were analysed for nutrients and tannin contents. In an in vitro test, ten diets were prepared; six contained 2, 4 and 6% of PP or ML, three diets supplemented with mixed levels of PP and ML (1 + 1%, 2 + 2% and 3 + 3%) and control diet free of them. Gas was measured after 3, 6, 12, 24, 48 and 72 h of incubation. Methane and rumen parameters were estimated. In an in vivo experiment, 40 Ossimi lambs were divided into four groups; the first was control, other groups (T1, T2 and T3) fed diets containing 6% PP, 6% ML or mix levels (3% PP + 3%ML), respectively, for 2 months. Results showed that PP and ML were rich in tannins. In the in vitro test, a maximum reduction in gas, methane and NH3-N was in 6% PP, 6% ML and mixed levels (3% PP + 3% ML). In the in vivo experiment, there were no differences in growth and digestibility of DM and nutrients between treatment groups. Only a lowered DM intake and protein digestibility in lambs fed 6% PP. Gas and methane emission was decreased significantly in lambs fed 6% PP, compared to other groups. TVFAs and NH3-N were decreased for treatment groups. Also, all treatments did not show any pathological changes in liver function or on oxidative stress markers. In conclusion, PP and ML can be used in sheep diets at inclusion levels of 6% and mixture without detrimental effects on general health of Ossimi lambs.

Functional circuits of the human brain emerge and change dramatically over the second half of gestation. It is possible that variation in neural functional system connectivity in utero predicts individual differences in infant behavioral development, but this possibility has yet to be examined. The current study examines the association between fetal sensorimotor brain system functional connectivity and infant postnatal motor ability. Resting-state functional connectivity data was obtained in 96 healthy human fetuses during the second and third trimesters of pregnancy. Infant motor ability was measured 7 months after birth using the Bayley Scales of Infant Development. Increased connectivity between the emerging motor network and regions of the prefrontal cortex, temporal lobes, posterior cingulate, and supplementary motor regions was observed in infants that showed more mature motor functions. In addition, females demonstrated stronger fetal-brain to infant-behavior associations. These observations extend prior longitudinal research back into prenatal brain development and raise exciting new ideas about the advent of risk and the ontogeny of early sex differences.

The structural behaviour of a haüyne with a chemical composition of Na4.35Ca2.28K0.95[Al6Si6O24]- (SO4)2.03, at room pressure and from 33 to 1035°C on heating, was determined by using in situ synchrotron X-ray powder diffraction data (λ = 0.92249(5) Å). The satellite reflections in haüyne are lost at ∼400°C and a true substructure results because of this phase transition. There is a discontinuity in the a unit-cell parameter at ∼585°C. The α parameter increases rapidly and non-linearly to 585°C, but above 585°C, the expansion rate decreases. The percent volume change between 33 and 576°C is 2.0(3)%, and 0.6(3)% between 593 and 1035°C. Between 33 and 1035°C, the Al–O, Si–O and S–O distances are constant. Between 33 and 576°C, the angle of rotation of the AlO4 tetrahedron, jAl, changesfrom 11.5 to 5.8°, while the angle of rotation of the SiO4 tetrahedron, φSi, changesfrom 12.4 to 6.3°. The Al–O–Si bridging angle changesfrom 150.05(2) to 153.08(1)° from 33 to 576°C. Beyond 585°C, φAl and φSi angles remain nearly constant even though the maximum rotation of the tetrahedra is not achieved. Moreover, the Al–O–Si angle continues to increase at a slower rate from 585 to 1035°C by 1.05(2)°. From 33 to ∼585°C, the K atom position migrates at a slower rate than the Na and Ca atoms, and the structure expands at a high rate. Beyond 585°C, all the atomic positions of the interstitial cations (Na+, K+, Ca2+) remain nearly constant and the expansion of the structure is retarded.

Despite the profound health implications of Necator americanus infection in humans, many aspects of its interaction with the host immune system are poorly understood. Here we investigated the early events at the interface of N. americanus larvae (L3) and human dendritic cells (DCs). Our data show that co-culturing DCs and the larvae trigger ex-sheathing of hookworms rapidly where a majority of DCs are sequestered onto the larval sheath allowing the ex-sheathed larvae to migrate away unchallenged. Intriguingly, DCs show negligible interaction with the ex-sheathed larvae, alluding to differences between the surface chemistry of the larva and its sheath. Furthermore, blocking of two key C-type lectin receptors on DC surface (i.e. DC-SIGN and mannose receptor) resulted in inhibition of ex-sheathing process and DC sequestration, highlighting the importance of C-type lectins on DCs in the induction of the ex-sheathing. Analyses of DC phenotype and cytokine profile after co-culture with the N. americanus larvae showed an immature phenotype as evidenced by the low expression of the maturation markers and cytokines. These data provide new insights into early events at the interface of human DCs and N. americanus larvae and could explain how L3 evade immune recognition upon initial interaction with DCs.

Monitoring of nesting beaches is often the only feasible and low-cost approach for assessing sea turtle populations. We investigated spatio-temporal patterns of sea turtle nesting activity monitored over 17 successive years in the Lamu archipelago, Kenya. Community-based patrols were conducted on 26 stretches of beach clustered in five major locations. A total of 2,021 nests were recorded: 1,971 (97.5%) green turtle Chelonia mydas nests, 31 (1.5%) hawksbill Eretmochelys imbricata nests, 8 (0.4%) olive ridley Lepidochelys olivacea nests and 11 (0.5%) unidentified nests. Nesting occurred year-round, increasing during March–July, when 74% of nests were recorded. A stable trend in mean annual nesting densities was observed in all locations. Mean clutch sizes were 117.7 ± SE 1 eggs (range 20–189) for green turtles, 103 ± SE 6 eggs (range 37–150) for hawksbill turtles, and 103 ± SE 6 eggs (range 80–133) for olive ridley turtles. Curved carapace length for green turtles was 65–125 cm, and mean annual incubation duration was 55.5 ± SE 0.05 days. The mean incubation duration for green turtle nests differed significantly between months and seasons but not locations. The hatching success (pooled data) was 81.3% (n = 1,841) and was higher for in situ nests (81.0 ± SE 1.5%) compared to relocated nests (77.8 ± SE 1.4%). The results highlight the important contribution of community-based monitoring in Kenya to sustaining the sea turtle populations of the Western Indian Ocean region.