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Orofacial clefts (OFCs), which include non-syndromic cleft lip with or without cleft palate (CL/P), are among the most common birth defects in humans, affecting approximately 1 in 700 newborns. CL/P is phenotypically heterogeneous and has a complex etiology caused by genetic and environmental factors. Previous genome-wide association studies (GWASs) have identified at least 15 risk loci for CL/P. As these loci do not account for all of the genetic variance of CL/P, we hypothesized the existence of additional risk loci. We conducted a multiethnic GWAS in 6480 participants (823 unrelated cases, 1700 unrelated controls and 1319 case-parent trios) with European, Asian, African and Central and South American ancestry. Our GWAS revealed novel associations on 2p24 near FAM49A, a gene of unknown function (P = 4.22 × 10-8), and 19q13 near RHPN2, a gene involved in organizing the actin cytoskeleton (P = 4.17 × 10-8). Other regions reaching genome-wide significance were 1p36 (PAX7), 1p22 (ARHGAP29), 1q32 (IRF6), 8q24 and 17p13 (NTN1), all reported in previous GWASs. Stratification by ancestry group revealed a novel association with a region on 17q23 (P = 2.92 × 10-8) among individuals with European ancestry. This region included several promising candidates including TANC2, an oncogene required for development, and DCAF7, a scaffolding protein required for craniofacial development. In the Central and South American ancestry group, significant associations with loci previously identified in Asian or European ancestry groups reflected their admixed ancestry. In summary, we have identified novel CL/P risk loci and suggest new genes involved in craniofacial development, confirming the highly heterogeneous etiology of OFCs. Orofacial clefts (OFCs), which include non-syndromic cleft lip with or without cleft palate (CL/P), are among the most common birth defects in humans, affecting approximately 1 in 700 newborns. CL/P is phenotypically heterogeneous and has a complex etiology caused by genetic and environmental factors. Previous genome-wide association studies (GWASs) have identified at least 15 risk loci for CL/P. As these loci do not account for all of the genetic variance of CL/P, we hypothesized the existence of additional risk loci. We conducted a multiethnic GWAS in 6480 participants (823 unrelated cases, 1700 unrelated controls and 1319 case-parent trios) with European, Asian, African and Central and South American ancestry. Our GWAS revealed novel associations on 2p24 near FAM49A, a gene of unknown function (P = 4.22 × 10(-8)), and 19q13 near RHPN2, a gene involved in organizing the actin cytoskeleton (P = 4.17 × 10(-8)). Other regions reaching genome-wide significance were 1p36 (PAX7), 1p22 (ARHGAP29), 1q32 (IRF6), 8q24 and 17p13 (NTN1), all reported in previous GWASs. Stratification by ancestry group revealed a novel association with a region on 17q23 (P = 2.92 × 10(-8)) among individuals with European ancestry. This region included several promising candidates including TANC2, an oncogene required for development, and DCAF7, a scaffolding protein required for craniofacial development. In the Central and South American ancestry group, significant associations with loci previously identified in Asian or European ancestry groups reflected their admixed ancestry. In summary, we have identified novel CL/P risk loci and suggest new genes involved in craniofacial development, confirming the highly heterogeneous etiology of OFCs.

Aims: Vericiguat reduced the primary composite outcome of cardiovascular death or heart failure (HF) hospitalization in patients with worsening HF with reduced ejection fraction (HFrEF) and a lower limit of baseline estimated glomerular filtration rate (eGFR) of 15 mL/min/1.73 m2. We evaluated the relationship between the efficacy of vericiguat and baseline and subsequent changes in renal function.Methods and results: In VICTORIA, core laboratory serum creatinine was measured at baseline (n = 4956) and weeks 16, 32, and 48. Worsening renal function (WRF), defined as an increase ≥0.3 mg/dL in creatinine from baseline to week 16, was assessed via a Cox model with respect to subsequent primary events. Mean age was 69 years, 24% were female, and mean baseline eGFR was 61 mL/min/1.73 m2. During 48 weeks of treatment, the trajectories in eGFR and creatinine with vericiguat were similar to placebo (P = 0.50 and 0.18). The beneficial effects of vericiguat on the primary outcome were not influenced by baseline eGFR (interaction P = 0.48). WRF occurred in 15% of patients and was associated with worse outcomes (adjusted hazard ratio 1.28, 95% confidence interval 1.11–1.47; P < 0.001), but the beneficial effects of vericiguat on the primary outcome were similar in patients with or without WRF (interaction P = 0.76).Conclusion: Renal function trajectories were similar between vericiguat- and placebo-treated patients and the beneficial effects of vericiguat on the primary outcome were consistent across the full range of eGFR and irrespective of WRF.

The strong spin-orbit interaction in the organic-inorganic perovskites tied to the incorporation of heavy elements (e.g., Pb and I) makes these materials interesting for applications in spintronics. In conjunction with a lack of inversion symmetry associated with distortions of the metal-halide octahedra, surfaces and interfaces, or the application of a bias, the Rashba effect (used in spin field-effect transistors and spin filters) has been predicted to be much larger in these materials than in traditional III-V semiconductors such as GaAs. Evidence of strong Rashba coupling has been observed in both 3D (bulk) and 2D perovskites, with the relative role of bulk and surface Rashba contributions in the former case under active debate. The varying size of the reported spin splittings points to the need for more experimental studies of Rashba effects in the organic-inorganic perovskite family of materials. Here, we apply time-resolved circular dichroism techniques to the study of carrier spin dynamics in a 2D perovskite thin film [(BA)2MAPb2I7; BA = CH3(CH2)3NH3, MA = CH3NH3]. Our findings confirm the presence of a Rashba spin splitting via the dominance of precessional spin relaxation induced by the Rashba effective magnetic field (also known as D’yakonov Perel spin relaxation). The size of the Rashba spin splitting in our system was extracted from simulations of the measured spin dynamics incorporating LO-phonon and electron-electron scattering, yielding a value of 10 meV at an electron energy of 50 meV above the band gap, representing a 20 times larger value than in GaAs quantum wells.

Dasatinib (SPRYCEL®) is the most potent BCR-ABL inhibitor and is 325-fold more potent than imatinib and 16-fold more potent than nilotinib in vitro against unmutated BCR-ABL. Previous studies have demonstrated the efficacy and safety of dasatinib 70 mg BID for patients with CML-AP who are intolerant or resistant to imatinib. In the phase III CA180-035 study, patients with CML-AP, blast phase CML, or Ph+ ALL were randomized to dasatinib 140 mg QD or 70 mg BID. The primary trial objective was to compare major hematologic response (MaHR) rates between the two schedules. Secondary objectives included a comparison of major cytogenetic response (MCyR) rates, time to and duration of responses, progression-free survival (PFS), overall survival (OS), and safety profiles between the two schedules. Previous analyses from this study have demonstrated that QD treatment is associated with equivalent efficacy and less frequent key adverse events (AEs) compared with BID treatment. Here, 2-year results from the subgroup with CML-AP (n=317) recruited from 97 international sites are reported. Among patients randomized to QD (n=158) or BID (n=159) treatment with dasatinib, rates of MaHR and MCyR were similar (MaHR: 66% vs 68%; MCyR: 39% vs 43%, respectively; Table). Excluding patients that were BCR-ABL positive, Ph negative (n=3), rates of MCyR were nearly identical. Most MaHRs were achieved within 4 months of therapy and most MCyRs were achieved within 6 months. Based on Kaplan-Meier analyses, an estimated 65% vs 60% of patients had maintained a durable MaHR in QD and BID groups, respectively, at 24 months. Estimated PFS rates were 51% vs 55% and OS rates were 63% vs 72%, respectively. Although dasatinib was generally well tolerated with both dose schedules, QD treatment was associated with an improved safety profile compared with BID treatment. Only small increases in AE rates were observed compared with 1-year data. Cytopenias were the most common AEs and for QD vs BID treatment, rates of grade 3/4 events were 59% vs 69% for neutropenia and 64% vs 67% for thrombocytopenia. Fewer drug-related fluid retention events (including pleural effusion, superficial edema, and peripheral edema) were reported in the QD (34%) vs BID (48%) group. In particular, significantly fewer patients experienced a pleural effusion with QD vs BID treatment (p<0.001, all grades). No grade 4 pleural effusions occurred. Pleural effusions were manageable and led to treatment discontinuation in only 5% (QD) and 9% (BID) of patients. Grade 3/4 nonhematologic AEs were reported in less than 7% of all QD and BID patients and included dyspnea (3% vs 7%) and diarrhea (3% in both groups). Median durations of dasatinib therapy were 15 months (QD) and 12 months (BID), and median values of mean daily doses were 138 mg and 110 mg, respectively. Fewer dose reductions (38% vs 50%) and interruptions (64% vs 74%) occurred in the QD group. At the time of analysis, 34% of the QD group and 35% of the BID group remained on study, with a median duration of therapy of 23 months in both groups. Overall, extended follow-up from the CA180-035 study confirms earlier findings and demonstrates that in patients with CML-AP with imatinib resistance or intolerance, dasatinib 140 mg QD has equivalent efficacy to dasatinib 70 mg BID but with an improved safety profile. Similar durable responses were observed with both schedules. Table | | Patients (%) | |:---------------------------------- | ------------ | ----------- | | | QD (n=158) | BID (n=159) | | MaHR | 66 | 68 | | MCyR | 39 | 43 | | MCyR (excluding BCR-ABL+ Ph−, n=3) | 38 | 43 | | 24-month PFS | 51 | 55 | | 24-month OS | 63 | 72 | | Neutropenia, grade 3/4 | 59 | 69 | | Thrombocytopenia, grade 3/4 | 64 | 67 | | Pleural effusion (drug-related) | | | | All grades | 20 | 39 | | Grade 3 | 7 | 6 | | Interruption | 38 | 50 | | Reduction | 64 | 74 |

Abstract To understand developmental milestones among young transgender women (YTW), we mapped age estimates per milestone by race/ethnicity and cohort age using baseline data from Project Lifeskills (n=298). Compared with older and white participants, younger black, Latina, Asian, and other/mixed race transgender (trans) women reported earlier experiences of sexual debut, transfeminine identity disclosure to others, sexual debut as trans, transfeminine identity expression in public, and integration of hormone use. Findings call for increased research and utilization of gender-affirmative interventions among YTW, with incorporation of nuanced, intersecting roles of race/ethnicity and cohort age across milestones.

Abstract Epigenetic alterations are a fundamental pathological hallmark of Alzheimer’s disease (AD). Herein, we uncover the unknown G9a modulation pathways involved in AD, showing the upregulation of G9a and H3K9me2 in the brains of AD patients. Likewise, treatment with a G9a inhibitor in SAMP8 mice reversed the high levels of H3K9me2 and rescued the cognitive decline. Interestingly, a transcriptional profile analysis revealed induction of neuronal plasticity and a reduction of oxidative stress and neuroinflammation; the latter being also validated in cell cultures. Furthermore, an exploratory H3K9me2 ChIP-seq analysis demonstrated that during G9a inhibition treatment, the H3K9me2 mark is enriched at the promoter of genes associated with neural functions. Lastly, we showed in Caenorhabditis elegans (C. elegans) AD transgenic strains, similar epigenetic modifications and modulated pathways were altered with increased β-amyloid levels, which were reverted by the set-25 (in C. elegans is similar to the mammalian G9a protein) knockout, including the cognitive impairment. Therefore, our findings confirm that RNAi suppression of set-25 or pharmacological G9a inhibition promotes a positive outcome in AD, being a promising therapeutic strategy.

We study stellar-halo formation using six Milky Way-mass galaxies in FIRE-2 cosmological zoom simulations. We find that $5-40\%$ of the outer ($50-300$ kpc) stellar halo in each system consists of $\textit{in-situ}$ stars that were born in outflows from the main galaxy. Outflow stars originate from gas accelerated by super-bubble winds, which can be compressed, cool, and form co-moving stars. The majority of these stars remain bound to the halo and fall back with orbital properties similar to the rest of the stellar halo at $z=0$.In the outer halo, outflow stars are more spatially homogeneous, metal rich, and alpha-element-enhanced than the accreted stellar halo. At the solar location, up to $\sim 10 \%$ of our kinematically-identified halo stars were born in outflows; the fraction rises to as high as $\sim 40\%$ for the most metal-rich local halo stars ([Fe/H] $> -0.5$). We conclude that the Milky Way stellar halo could contain local counterparts to stars that are observed to form in molecular outflows in distant galaxies. Searches for such a population may provide a new, near-field approach to constraining feedback and outflow physics. A stellar halo contribution from outflows is a phase-reversal of the classic halo formation scenario of Eggen, Lynden-Bell $\&$ Sandange, who suggested that halo stars formed in rapidly $\textit{infalling}$ gas clouds. Stellar outflows may be observable in direct imaging of external galaxies and could provide a source for metal-rich, extreme velocity stars in the Milky Way. 19 pages, 20 figures, submitted to MNRAS

Patient-reported outcomes (PROs) are increasingly emphasized as endpoints in clinical trials of ulcerative colitis (UC). However, the prognostic value of early improvement in PROs for long-term outcomes remains unclear.This was a post-hoc analysis of 611 vedolizumab-treated or adalimumab-treated patients in the VARSITY trial (Clinicaltrial.gov: NCT02497469). Stool frequency (SF) and rectal bleeding score (RBS) as reported in the Mayo score at post-induction (week 6 and 14) was assessed for their association with one-year endoscopic improvement (EI), defined as Mayo endoscopic subscore2; histo-endoscopic mucosal improvement (HEMI), defined as EI and Geboes highest grade3.2, clinical remission (CR), defined as total Mayo score ≤2; and PRO-2 remission, defined as RBS of 0 and SF ≤1. Multivariable logistic regression models adjusted for confounders assessed the relationships between post-induction PROs and outcomes of interest at one-year.Patients with severe SF at week 6 were significantly less likely to achieve one-year EI compared to those with non-severe SF [aOR 0.40 (95% CI: 0.24-0.68),Post-induction PROs strongly predict the odds of CR and EI in UC and simplified evaluations can be used to assess early response to UC therapies.

Abstract Docosahexaenoic acid (22:6n-3, DHA) is a structural fatty acid in biomembranes that is implicated in various aspects of human health. The intake of preformed dietary DHA by humans is largely dependent on marine sources such as fish which are subject to issues regarding sustainability and environmental contamination. Thraustochytrids have gained attention as a potential source of DHA for agricultural and aquacultural feedstocks, and human functional foods and nutraceuticals. In the present study, a dried and powdered strain of cultured Philippine thraustochytrids was examined for nutrient and fatty acid composition before and after sterilization by autoclave. Fatty acid determinations were completed by a conventional extraction plus transesterification method, direct transesterification using convectional heat and direct transesterification using microwave energy with DHA content ranging from 5.2 to 7.4 mg/g dried thraustochytrids. Fatty acid yields by extraction plus transesterification were 77–79% of the yields by direct transesterification. Interestingly, autoclaving had no effect on fatty acid estimates by extraction plus transesterification, but losses in long chain polyunsaturated fatty acids including DHA were observed with autoclaving and direct transesterification analyses. Thraustochytrids are a promising source of DHA, however, quantitation of fatty acids in microalgae is susceptible to sample processing and choice of analytical technique.