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Mutations in UBQLN2 cause amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerations. However, the mechanism by which the UBQLN2 mutations cause disease remains unclear. Alterations in proteins involved in autophagy are prominent in neuronal tissue of human ALS UBQLN2 patients and in a transgenic P497S UBQLN2 mouse model of ALS/FTD, suggesting a pathogenic link. Here, we show UBQLN2 functions in autophagy and that ALS/FTD mutant proteins compromise this function. Inactivation of UBQLN2 expression in HeLa cells reduced autophagic flux and autophagosome acidification. The defect in acidification was rescued by reexpression of wild type (WT) UBQLN2 but not by any of the five different UBQLN2 ALS/FTD mutants tested. Proteomic analysis and immunoblot studies revealed P497S mutant mice and UBQLN2 knockout HeLa and NSC34 cells have reduced expression of ATP6v1g1, a critical subunit of the vacuolar ATPase (V-ATPase) pump. Knockout of UBQLN2 expression in HeLa cells decreased turnover of ATP6v1g1, while overexpression of WT UBQLN2 increased biogenesis of ATP6v1g1 compared with P497S mutant UBQLN2 protein. In vitro interaction studies showed that ATP6v1g1 binds more strongly to WT UBQLN2 than to ALS/FTD mutant UBQLN2 proteins. Intriguingly, overexpression of ATP6v1g1 in UBQLN2 knockout HeLa cells increased autophagosome acidification, suggesting a therapeutic approach to overcome the acidification defect. Taken together, our findings suggest that UBQLN2 mutations drive pathogenesis through a dominant-negative loss-of-function mechanism in autophagy and that UBQLN2 functions as an important regulator of the expression and stability of ATP6v1g1. These findings may have important implications for devising therapies to treat UBQLN2-linked ALS/FTD.

The bluegill sunfish Lepomis macrochirus and the closely related redear sunfish Lepomis microlophus have important ecological and recreational value and are widely used for research and aquaculture. While both species have been introduced outside of their native ranges, only the bluegill is considered invasive. Here, we report de novo transcriptome assemblies for these fish as a resource for sunfish biology. Comparative analyses of the transcriptomes revealed an unexpected, bluegill-specific expansion in the HSP70 and HSP90 molecular chaperone gene families. These expansions were not unique to the bluegill as expansions in HSP70s and HSP90s were identified in the genomes of other teleost fish using the NCBI RefSeq database. To determine whether gene family expansions are specific for thermal stress responses, GST and SOD gene families that are associated with oxidative stress responses were also analyzed. Species-specific expansions were also observed for these gene families in distinct fish species. Validating our approach, previously described expansions in the MHC gene family were also identified. Intriguingly, the number of HSP70 paralogs was positively correlated with thermotolerance range for each species, suggesting that these expansions can impact organismal physiology. Furthermore, fish that are considered invasive contained a higher average number of HSP70 paralogs than non-invasive fish. Invasive fish also had higher average numbers of HSP90, MHC and GST paralogs, but not SOD paralogs. Taken together, we propose that expansions in key cellular stress response gene families represent novel genetic signatures that correlate with invasive potential.

Omega-3 polyunsaturated fatty acids (n-3 PUFAs), obtained from diet and dietary supplements, have been tested in clinical trials for the prevention or treatment of several diseases. n-3 PUFAs exert their effects by activation of free fatty acid (FFA) receptors. FFA1 receptor, expressed in the pancreas and brain, is activated by medium- to long-chain fatty acids. Despite some beneficial effects on cognition, the effects of n-3 PUFAs on the blood–brain barrier (BBB) are not clearly understood. We examined the effects of FFA1 activation on BBB permeability in vitro, using rat brain microvascular endothelial cells (RBMVEC), and in vivo, by assessing Evans Blue extravasation and by performing live imaging of brain microcirculation in adult rats. AMG837, a synthetic FFA1 agonist, produced a dose-dependent decrease in RBMVEC monolayer resistance assessed with Electric Cell–Substrate Impedance Sensing (ECIS); the effect was attenuated by the FFA1 antagonist, GW1100. Immunofluorescence studies revealed that AMG837 produced a disruption in tight and adherens junction proteins. AMG837 increased Evans Blue content in the rat brain in a dose-dependent manner. Live imaging studies of rat brain microcirculation with miniaturized fluorescence microscopy (miniscope) showed that AMG837 increased extravasation of sodium fluorescein. Taken together, our results demonstrate that FFA1 receptor activation reduced RBMVEC barrier function and produced a transient increase in BBB permeability.

Lay Summary We demonstrate low rates of breakthrough coronavirus disease 2019 (COVID-19) infection and mild course of illness following severe acute respiratory syndrome coronavirus 2 vaccination in a large cohort of inflammatory bowel disease patients. Residence in southern United States and lower median anti-receptor binding antibody level were associated with development of COVID-19.

Classical Wolf-Rayet (WR) stars mark an important stage in the late evolution of massive stars. As hydrogen-poor massive stars, these objects have lost their outer layers, while still losing further mass through strong winds indicated by their prominent emission line spectra. Wolf-Rayet stars have been detected in a variety of different galaxies. Their strong winds are a major ingredient of stellar evolution and population synthesis models. Yet, a coherent theoretical picture of their strong mass-loss is only starting to emerge. In particular, the occurrence of WR stars as a function of metallicity (Z) is still far from being understood. To uncover the nature of the complex and dense winds of Wolf-Rayet stars, we employ a new generation of model atmospheres including a consistent solution of the wind hydrodynamics in an expanding non-LTE situation. With this technique, we can dissect the ingredients driving the wind and predict the resulting mass-loss for hydrogen-depleted massive stars. Our modelling efforts reveal a complex picture with strong, non-linear dependencies on the luminosity-to-mass ratio and Z with a steep, but not totally abrupt onset for WR-type winds in helium stars. With our findings, we provide a theoretical motivation for a population of helium stars at low Z, which cannot be detected via WR-type spectral features. Our study of massive He-star atmosphere models yields the very first mass-loss recipe derived from first principles in this regime. Implementing our first findings in stellar evolution models, we demonstrate how traditional approaches tend to overpredict WR-type mass loss in the young Universe., 6 pages, 3 figures, to appear in the proceedings of IAUS 366 "The Origin of Outflows in Evolved Stars"

International audience

Stars strongly impact their environment, and shape structures on all scales throughout the universe, in a process known as “feedback.” Due to the complexity of both stellar evolution and the physics of larger astrophysical structures, there remain many unanswered questions about how feedback operates and what we can learn about stars by studying their imprint on the wider universe. In this white paper, we summarize discussions from the Lorentz Center meeting “Bringing Stellar Evolution and Feedback Together” in 2022 April and identify key areas where further dialog can bring about radical changes in how we view the relationship between stars and the universe they live in.

Background: Data on the performance of newer biologics in patients with fistulizing Crohn’s disease (CD) are limited. Objective: Our study’s objective was to evaluate the response to ustekinumab (UST) and vedolizumab (VDZ) in patients with fistulizing CD. Design: Retrospective cohort. Methods: We used natural language processing of electronic medical record data to identify a retrospective cohort of individuals with fistulizing CD at a single academic tertiary-care referral center and then performed a chart review. Individuals were eligible for inclusion if a fistula was present at the time of UST or VDZ initiation. Outcomes included medication discontinuation, surgical intervention, development of a new fistula, and fistula closure. Groups were compared with unadjusted analyses and competing risk analyses using multi-state survival models. Results: In all, 68 patients were included (48 UST and 20 VDZ). Most patients had one fistula (79%) and had prior anti-tumor necrosis factor-α treatment (98% in UST group, 80% in VDZ group, p = 0.01). VDZ was significantly more likely to be discontinued than UST ( p Conclusion: In individuals with fistulizing CD, our data suggest that UST has better clinical utility than VDZ based on lower rates of discontinuation, though the sample size is small. These findings highlight the importance of further research on the treatment of perianal fistulizing Crohn’s disease.

Substandard and falsified medicines are often reported jointly, making it difficult to recognize variations in medicine quality. This study characterized medicine quality based on active pharmaceutical ingredient (API) amounts reported among substandard and falsified essential medicines in low- and middle-income countries (LMICs). A systematic review and meta-analysis was conducted using PubMed, supplemented by results from a previous systematic review, and the Medicine Quality Scientific Literature Surveyor. Study quality was assessed using the Medicine Quality Assessment Reporting Guidelines (MEDQUARG). Random-effects models were used to estimate the prevalence of medicines with N = 9,724), 25.9% (95% CI: 19.3–32.6%) reported having

Background Highly connected individuals disseminate information effectively within their social network. To apply this concept to inflammatory bowel disease (IBD) care and lay the foundation for network interventions to disseminate high-quality treatment, we assessed the need for improving the IBD practices of highly connected clinicians. We aimed to examine whether highly connected clinicians who treat IBD patients were more likely to provide high-quality treatment than less connected clinicians. Methods We used network analysis to examine connections among clinicians who shared patients with IBD in the Veterans Health Administration between 2015–2018. We created a network comprised of clinicians connected by shared patients. We quantified clinician connections using degree centrality (number of clinicians with whom a clinician shares patients), closeness centrality (reach via shared contacts to other clinicians), and betweenness centrality (degree to which a clinician connects clinicians not otherwise connected). Using weighted linear regression, we examined associations between each measure of connection and two IBD quality indicators: low prolonged steroids use, and high steroid-sparing therapy use. Results We identified 62,971 patients with IBD and linked them to 1,655 gastroenterologists and 7,852 primary care providers. Clinicians with more connections (degree) were more likely to exhibit high-quality treatment (less prolonged steroids beta -0.0268, 95%CI -0.0427, -0.0110, more steroid-sparing therapy beta 0.0967, 95%CI 0.0128, 0.1805). Clinicians who connect otherwise unconnected clinicians (betweenness) displayed more prolonged steroids use (beta 0.0003, 95%CI 0.0001, 0.0006). The presence of variation is more relevant than its magnitude. Conclusions Clinicians with a high number of connections provided more high-quality IBD treatments than less connected clinicians, and may be well-positioned for interventions to disseminate high-quality IBD care. However, clinicians who connect clinicians who are otherwise unconnected are more likely to display low-quality IBD treatment. Efforts to improve their quality are needed prior to leveraging their position to disseminate high-quality care.

Background Inflammatory bowel disease is associated with an increased risk of skin cancer. The aims of this study were to determine whether IBD susceptibility variants are also associated with skin cancer susceptibility and if such risk is augmented by use of immune-suppressive therapy. Methods The discovery cohort included participants in the UK Biobank. The validation cohort included participants in the Michigan Genomics Initiative. The primary outcome of interest was skin cancer, subgrouped into nonmelanoma skin cancers (NMSC) and melanoma skin cancers (MSC). Multivariable logistic regression with matched controls (3 controls:1 case) was performed to identify genomic predictors of skin malignancy in the discovery cohort. Variants with P Results The discovery cohort included 10,247 cases of NMSC and 1883 cases of MSC. The validation cohort included 7334 cases of NMSC and 3304 cases of MSC. Twenty-nine variants were associated with risk of NMSC in the discovery cohort, of which 5 replicated in the validation cohort (increased risk, rs7773324-A [DUSP22; IRF4], rs2476601-G [PTPN22], rs1847472-C [BACH2], rs72810983-A [CPEB4]; decreased risk, rs6088765-G [PROCR; MMP24]). Twelve variants were associated with risk of MSC in the discovery cohort, of which 4 were replicated in the validation cohort (increased risk, rs61839660-T [IL2RA]; decreased risk, rs17391694-C [GIPC2; MGC27382], rs6088765-G [PROCR; MMP24], and rs1728785-C [ZFP90]). No effect modification was observed. Conclusions The results of this study highlight shared genetic susceptibility across IBD and skin cancer, with increased risk of NMSC in those who carry risk variants in IRF4, PTPN22, CPEB4, and BACH2 and increased risk of MSC in those who carry a risk variant in IL2RA.

Ubiquilin (UBQLN) proteins are a dynamic and versatile family of proteins found in all eukaryotes that function in the regulation of proteostasis. Besides their canonical function as shuttle factors in delivering misfolded proteins to the proteasome and autophagy systems for degradation, there is emerging evidence that UBQLN proteins play broader roles in proteostasis. New information suggests the proteins function as chaperones in protein folding, protecting proteins prior to membrane insertion, and as guardians for mitochondrial protein import. In this review, we describe the evidence for these different roles, highlighting how different domains of the proteins impart these functions. We also describe how changes in the structure and phase separation properties of UBQLNs may regulate their activity and function. Finally, we discuss the pathogenic mechanisms by which mutations in UBQLN2 cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We describe the animal model systems made for different UBQLN2 mutations and how lessons learnt from these systems provide fundamental insight into the molecular mechanisms by which UBQLN2 mutations drive disease pathogenesis through disturbances in proteostasis.

peer-reviewed Objective Increased fetal size is associated with shoulder dystocia during labor and subsequent need for assisted delivery. We sought to investigate if increased fetal adiposity diagnosed sonographically in late pregnancy is associated with increased risk of operative delivery. Methods This secondary analysis of the Genesis Study recruited 2392 nulliparous women with singleton pregnancy in cephalic presentation, in a prospective, multicenter study, to examine prenatal and intrapartum predictors of Cesarean delivery. Participants underwent ultrasound and clinical evaluation between 39 + 0 and 40 + 6 weeks' gestation. Data on fetal biometry were not revealed to patients or to their managing clinicians. A fetal adiposity composite of fetal thigh adiposity and fetal abdominal wall thickness was compiled for each infant in order to determine whether fetal adiposity > 90th centile was associated with an increased risk of Cesarean or operative vaginal delivery. Results After exclusions, data were available for 2330 patients. Patients with a fetal adiposity composite > 90th centile had a higher maternal body mass index (BMI) (25 ± 5 kg/m2 vs 24 ± 4 kg/m2; P = 0.005), birth weight (3872 ± 417 g vs 3585 ± 401 g; P 90th centile were more likely to require Cesarean delivery than were those with adiposity composite ≤ 90th centile (P 90th centile remained a risk factor for Cesarean delivery (P 90th centile was more predictive of the need for unplanned Cesarean delivery than was an estimated fetal weight > 90th centile (odds ratio, 2.20 (95% CI, 1.65–2.94; P 90th centile was not associated with an increased likelihood of operative vaginal delivery when compared with having an adiposity composite ≤ 90th centile (P = 0.37). Conclusions Fetuses with increased adipose deposition are more likely to require Cesarean delivery than are those without increased adiposity. Consideration should, therefore, be given to adding fetal thigh adiposity and abdominal wall thickness to fetal sonographic assessment in late pregnancy. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd. ACCEPTED peer-reviewed

Summary Background Etrolizumab is a gut-targeted anti-β7 integrin monoclonal antibody. In an earlier phase 2 induction study, etrolizumab significantly improved clinical remission relative to placebo in patients with moderately to severely active ulcerative colitis. The HIBISCUS studies aimed to compare the efficacy and safety of etrolizumab to adalimumab and placebo for induction of remission in patients with moderately to severely active ulcerative colitis. Methods HIBISCUS I and HIBISCUS II were identically designed, multicentre, phase 3, randomised, double-blind, placebo-controlled and active-controlled studies of etrolizumab, adalimumab, and placebo in adult (18–80 years) patients with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6–12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) who were naive to tumour necrosis factor inhibitors. All patients had an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. In both studies, patients were randomly assigned (2:2:1) to receive subcutaneous etrolizumab 105 mg once every 4 weeks; subcutaneous adalimumab 160 mg on day 1, 80 mg at week 2, and 40 mg at weeks 4, 6, and 8; or placebo. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants, and baseline disease activity. All patients and study site personnel were masked to treatment assignment. The primary endpoint was induction of remission at week 10 (defined as MCS of 2 or lower, with individual subscores of 1 or lower, and rectal bleeding subscore of 0) with etrolizumab compared with placebo. Pooled analyses of both studies comparing etrolizumab and adalimumab were examined for several clinical and endoscopic endpoints. Efficacy was analysed using a modified intent-to-treat population, defined as all randomly assigned patients who received at least one dose of study drug. These trials are registered with ClinicalTrials.gov , NCT02163759 (HIBISCUS I), NCT02171429 (HIBISCUS II). Findings Between Nov 4, 2014, and May 25, 2020, each study screened 652 patients (HIBISCUS I) and 613 patients (HIBISCUS II). Each study enrolled and randomly assigned 358 patients (HIBISCUS I etrolizumab n=144, adalimumab n=142, placebo n=72; HIBISCUS II etrolizumab n=143; adalimumab n=143; placebo n=72). In HIBISCUS I, 28 (19·4%) of 144 patients in the etrolizumab group and five (6·9%) of 72 patients in the placebo group were in remission at week 10, with an adjusted treatment difference of 12·3% (95% CI 1·6 to 20·6; p=0·017) in favour of etrolizumab. In HIBISCUS II, 26 (18·2%) of 143 patients in the etrolizumab group and eight (11·1%) of 72 patients in the placebo group were in remission at week 10, with an adjusted treatment difference of 7·2% (95% CI –3·8 to 16·1; p=0·17). In the pooled analysis, etrolizumab was not superior to adalimumab for induction of remission, endoscopic improvement, clinical response, histological remission, or endoscopic remission; however, similar numerical results were observed in both groups. In HIBISCUS I, 50 (35%) of 144 patients in the etrolizumab group reported any adverse event, compared with 61 (43%) of 142 in the adalimumab group and 26 (36%) of 72 in the placebo group. In HIBISCUS II, 63 (44%) of 143 patients in the etrolizumab group reported any adverse event, as did 62 (43%) of 143 in the adalimumab group and 33 (46%) in the placebo group. The most common adverse event in all groups was ulcerative colitis flare. The incidence of serious adverse events in the pooled patient population was similar for etrolizumab (15 [5%] of 287) and placebo (seven [5%] of 144) and lower for adalimumab (six [2%] of 285). Two patients in the etrolizumab group died; neither death was deemed to be treatment related. Interpretation Etrolizumab was superior to placebo for induction of remission in HIBISCUS I, but not in HIBISCUS II. Etrolizumab was well tolerated in both studies. Funding F Hoffmann-La Roche.

Substandard and falsified antimalarials contribute to the global malaria burden by increasing the risk of treatment failures, adverse events, unnecessary health expenditures, and avertable deaths. Yet no study has examined this impact in Western Francophone Africa to date. In Benin, where malaria remains endemic and is the leading cause of mortality among children under age five, there is a lack of robust data to combat the issue effectively and inform policy decisions. We adapted the Substandard and Falsified Antimalarial Research Impact (SAFARI) model to assess the health and economic impact of poor-quality antimalarials in this population. The model simulated population characteristics, malaria infection, care-seeking behavior, disease progression, treatment outcomes, and associated costs of malaria. We estimated approximately 1.8 million cases of malaria in Benin among children under age five, which cost $177 million (95% CI: $176 – $178 million) in treatment costs and productivity losses annually. Substandard and falsified antimalarials were responsible for 2.8% (n=165) of deaths and nearly $4.9 million in annual costs. Moreover, we found that replacing all antimalarials with quality-assured artemisinin combination therapies (ACTs) could result in $13.6 million in cost-savings, and increasing pediatric malaria care-seeking by 20% could bring $19.4 million in cost-savings. These results highlight the value of improving access to quality-assured ACTs for malaria treatment and increasing care-seeking in Benin. Policymakers and key stakeholders should use these findings to advocate for increased access to quality-assured antimalarials, inform policies and interventions to improve healthcare access and quality, and reduce the burden of malaria.

We unveil the stellar wind driven shell of the luminous massive star-forming region of RCW 49 using SOFIA FEEDBACK observations of the [CII] 158 $\mu$m line. The complementary dataset of the $^{12}$CO and $^{13}$CO J = 3 - 2 transitions is observed by the APEX telescope and probes the dense gas toward RCW 49. Using the spatial and spectral resolution provided by the SOFIA and APEX telescopes, we disentangle the shell from a complex set of individual components of gas centered around RCW 49. We find that the shell of radius ~ 6 pc is expanding at a velocity of 13 km s$^{-1}$ toward the observer. Comparing our observed data with the ancillary data at X-Ray, infrared, sub-millimeter and radio wavelengths, we investigate the morphology of the region. The shell has a well defined eastern arc, while the western side is blown open and is venting plasma further into the west. Though the stellar cluster, which is ~ 2 Myr old gave rise to the shell, it only gained momentum relatively recently as we calculate the shell's expansion lifetime ~ 0.27 Myr, making the Wolf-Rayet star WR20a a likely candidate responsible for the shell's re-acceleration., Comment: 31 pages, 17 figures

Low-temperature pavement performance is important in freezing areas in northern climates. While agencies and contractors pursue efforts to add recycled asphalt materials (RAMs) into the mi...

UBQLN2 mutations cause amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD), but the pathogenic mechanisms by which they cause disease remain unclear. Proteomic profiling identified ‘mitochondrial proteins’ as comprising the largest category of protein changes in the spinal cord (SC) of the P497S UBQLN2 mouse model of ALS/FTD. Immunoblots confirmed P497S animals have global changes in proteins predictive of a severe decline in mitochondrial health, including oxidative phosphorylation (OXPHOS), mitochondrial protein import and network dynamics. Functional studies confirmed mitochondria purified from the SC of P497S animals have age-dependent decline in nearly all steps of OXPHOS. Mitochondria cristae deformities were evident in spinal motor neurons of aged P497S animals. Knockout (KO) of UBQLN2 in HeLa cells resulted in changes in mitochondrial proteins and OXPHOS activity similar to those seen in the SC. KO of UBQLN2 also compromised targeting and processing of the mitochondrial import factor, TIMM44, resulting in accumulation in abnormal foci. The functional OXPHOS deficits and TIMM44-targeting defects were rescued by reexpression of WT UBQLN2 but not by ALS/FTD mutant UBQLN2 proteins. In vitro binding assays revealed ALS/FTD mutant UBQLN2 proteins bind weaker with TIMM44 than WT UBQLN2 protein, suggesting that the loss of UBQLN2 binding may underlie the import and/or delivery defect of TIMM44 to mitochondria. Our studies indicate a potential key pathogenic disturbance in mitochondrial health caused by UBQLN2 mutations.

International audience; Aims: Revealing the 3D dynamics of H II region bubbles and their associated molecular clouds and H I envelopes is important for developing an understanding of the longstanding problem as to how stellar feedback affects the density structure and kinematics of the different phases of the interstellar medium. Methods: We employed observations of the H II region RCW 120 in the [C II] 158 μm line, observed within the Stratospheric Observatory for Infrared Astronomy (SOFIA) legacy program FEEDBACK, and in the 12CO and 13CO (3 →2) lines, obtained with the Atacama Pathfinder Experiment (APEX) to derive the physical properties of the gas in the photodissociation region (PDR) and in the molecular cloud. We used high angular resolution H I data from the Southern Galactic Plane Survey to quantify the physical properties of the cold atomic gas through H I self-absorption. The high spectral resolution of the heterodyne observations turns out to be essential in order to analyze the physical conditions, geometry, and overall structure of the sources. Two types of radiative transfer models were used to fit the observed [C II] and CO spectra. A line profile analysis with the 1D non-LTE radiative transfer code SimLine proves that the CO emission cannot stem from a spherically symmetric molecular cloud configuration. With a two-layer multicomponent model, we then quantified the amount of warm background and cold foreground gas. To fully exploit the spectral-spatial information in the CO spectra, a Gaussian mixture model was introduced that allows for grouping spectra into clusters with similar properties. Results: The CO emission arises mostly from a limb-brightened, warm molecular ring, or more specifically a torus when extrapolated in 3D. There is a deficit of CO emission along the line-of-sight toward the center of the H II region which indicates that the H II region is associated with a flattened molecular cloud. Self-absorption in the CO line may hide signatures of infalling and expanding molecular gas. The [C II] emission arises from an expanding [C II] bubble and from the PDRs in the ring/torus. A significant part of [C II] emission is absorbed in a cool (~60-100 K), low-density (−3) atomic foreground layer with a thickness of a few parsec. Conclusions: We propose that the RCW 120 H II region formed in a flattened, filamentary, or sheet-like, molecular cloud and is now bursting out of its parental cloud. The compressed surrounding molecular layer formed a torus around the spherically expanding H II bubble. This scenario can possibly be generalized for other H II bubbles and would explain the observed "flat" structure of molecular clouds associated with H II bubbles. We suggest that the [C II] absorption observed in many star-forming regions is at least partly caused by low-density, cool, H I -envelopes surrounding the molecular clouds. The 12CO and 13CO (3 →2) data shown in Fig. 4 are only available at the CDS via anonymous ftp to cdsarc.u-strasbg.fr (ftp://130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/cat/J/A+A/659/A36 The [C II] data are provided at the NASA/IPAC Infrared science archive at https://irsa.ipac.caltech.edu/Missions/sofia.html

Summary The migrated dip-angle domain provides a powerful opportunity to distinguish 4D noise from signal based on similarity filtering applied to data decomposed by position, frequency, and geological dip. However, 4D signal protection is problematic when the signal itself forms from differences between baseline and monitor. A set of dip-angle similarity filtering methods applied to towed streamer and OBN data from South Arne field show that 4D signal preservation is possible even with strong timeshift signals between baseline and monitor. Signal protection can be achieved with wrap-around timewarping applied within the filtering methods. A better approach detects lack of coherent signal rather than similarity of coherent signal when present. Using this method it is possible to attenuate significant levels of migration noise without appreciably altering the 4D signal. Dip-angle filtering with workflows that preserve surface offset also allow the similarity filtering to be combined with least-squares Kirchhoff migration using single-iteration migration deconvolution. Results show noise attenuation via similarity filtering complementing the illumination compensation achieved by the least-squares method.

We present a case of third trimester pregnancy complicated by SARS-CoV-2 infection and subsequent reduced fetal movements, resulting in emergency Caesarean delivery with demonstrable placental SARS-CoV-2 placentitis. We show through illustration of this case and literature review that SARS-Co-V-2 placentitis is an uncommon but readily recognisable complication of maternal SARS-CoV-2 infection that may be a marker of potential vertical transmission and that may have the capacity to cause fetal compromise through a direct injurious effect on the placenta., Highlights • We present a pregnancy complicated by SARS-CoV-2 infection and resultant placentitis. • 25% of the parenchyma comprised a deposition similar to perivillous fibrinoid. • Under microscopy, these areas were predominantly a histiocytic intervillositis. • Immunohistochemistry for SARS-CoV-2 showed extensive, strong positive staining. • Reported COVID-19 chronic intervillositis cases depict virus in syncytiotrophoblast.

The Humphreys-Davidson (HD) limit sets the boundary between evolutionary channels of massive stars that either end their lives as red supergiants (RSGs) or as the hotter blue supergiants (BSGs) and Wolf-Rayet stars. Mixing in the envelopes of massive stars close to their Eddington limit is crucial for investigating the upper luminosity limit of the coolest supergiants. We study the effects of excess mixing in superadiabatic layers that are dominated by radiation pressure, and we critically investigate the effects of mixing and mass loss on the evolution of RSGs with log (Teff/K) < 3.68 - as a function of metallicity. Using MESA, we produce grids of massive star models at three metallicities: Galactic (Zsol), LMC (1/2 Zsol) and SMC (1/5 Zsol), with both high and low amounts of overshooting to study the upper luminosity limit of RSGs. We systematically study the effects of excess mixing in the superadiabatic layers of post-main sequence massive stars, overshooting above the hydrogen core and yellow supergiant (YSG) mass-loss rates on the fraction of core helium burning time spent as a RSG. We find that the excess mixing in the superadiabatic layers is stronger at lower metallicities, as it depends on the opacities in the hydrogen bump at log (Teff/K) ~ 4, which become more pronounced at lower metallicity. This shifts the cutoff luminosities to lower values at lower metallicities, thus balancing the first-order effect of mass loss. The opposing effects of mass loss and excess envelope mixing during post-main sequence evolution of stars with higher overshooting potentially results in a metallicity-independent upper luminosity limit., Accepted for publication in MNRAS. 15 pages, 13 figures

In our previous studies, we have demonstrated the feasibility of characterizing intestinal inflammation and fibrosis using endoscopic photoacoustic imaging. Purposed at te clinical translation of the imaging technology, we developed a photoacoustic/ultrasound imaging probe by integrating a miniaturized ultrasound array and an angle-tipped optical fiber in a hydrostatic balloon catheter. When collapsed, the catheter probe may potentially be compatible with a clinical ileo-colonoscope. In addition, the flexible surface of the hydrostatic balloon allows for acoustic coupling at the uneven surfaces of the gas-filled intestine. Tissue phantom studies show that the catheter probe possesses an imaging penetration of at least 12 mm. Experiments with a rabbit model in vivo validated the probe in differentiating normal, acute and chronic conditions in intestinal obstruction.

The HyGAL SOFIA legacy program surveys six hydride molecules -- ArH+, OH+, H2O+, SH, OH, and CH -- and two atomic constituents -- C+ and O -- within the diffuse interstellar medium (ISM) by means of absorption-line spectroscopy toward 25 bright Galactic background continuum sources. This detailed spectroscopic study is designed to exploit the unique value of specific hydrides as tracers and probes of different phases of the ISM, as demonstrated by recent studies with the Herschel Space Observatory. The observations performed under the HyGAL program will allow us to address several questions related to the lifecycle of molecular material in the ISM and the physical processes that impact its phase transition, such as: (1) What is the distribution function of the H2 fraction in the ISM? (2) How does the ionization rate due to low-energy cosmic-rays vary within the Galaxy? (3) What is the nature of interstellar turbulence, and what mechanisms lead to its dissipation? This overview discusses the observing strategy, synergies with ancillary and archival observations, the data reduction and analysis schemes adopted; and presents the first results obtained toward three of the survey targets, W3(OH), W3IRS5 and NGC7538IRS1. Robust measurements of the column densities of these hydrides -- obtained through widespread observations of absorption lines-- help address the questions raised, and there is a timely synergy between these observations and the development of theoretical models, particularly pertaining to the formation of H2 within the turbulent ISM. The provision of enhanced HyGAL data products will therefore serve as a legacy for future ISM studies., 33 pages, 17 figures, 7 tables. Accepted for publication in the Astrophysical Journal

At the end of its life, a very massive star is expected to collapse into a black hole. The recent detection of an 85 Msun black hole from the gravitational wave event GW 190521 appears to present a fundamental problem as to how such heavy black holes exist above the approximately 50 Msun pair-instability limit where stars are expected to be blown to pieces with no remnant left. Using MESA, we show that for stellar models with non-extreme assumptions, 90..100 Msun stars at reduced metallicity (Z/Zsun < 0.1) can produce blue supergiant progenitors with core masses sufficiently small to remain below the fundamental pair-instability limit, yet at the same time lose an amount of mass via stellar winds that is small enough to end up in the range of an "impossible" 85 Msun black hole. The two key points are the proper consideration of core overshooting and stellar wind physics with an improved scaling of mass loss with iron (Fe) contents characteristic for the host galaxy metallicity. Our modelling provides a robust scenario that not only doubles the maximum black hole mass set by pair instability, but also allows us to probe the maximum stellar black hole mass as a function of metallicity and Cosmic time in a physically sound framework., MNRAS Accepted. 9 pages, 3 figures. Prior Submission in September 2020 to Nature (see Research Square)

At the end of its life, a very massive star is expected to collapse into a black hole. The masses of these black holes are pivotal for our understanding of the evolution and fate of these stars, as well as for galaxy evolution and the build-up of black hole masses through Cosmic time. The recent detection of an 85 solar mass black hole from the gravitational wave event GW 190521 appears to present a fundamental problem as to how such heavy black holes exist above the approximately 50 solar mass pair-instability limit where stars are expected to be blown to pieces with no remnant left. Here we show that for stellar models at reduced heavy element content, 90-100 solar mass stars can produce core masses sufficiently small to remain below the fundamental pair-instability limit, yet at the same time lose an amount of mass small enough to end up in an 85 solar mass black hole. A key point is that the amount of mass-loss scales with the host galaxy heavy element fraction, and not with the total amount of element enrichment that occurs naturally during the life of massive stars. Our study shows how our Universe is capable of producing heavy black holes, which are important seeds for the production of supermassive black holes that regulate the evolution of galaxies. Our evolutionary channel to the formation of an 85 solar mass black hole is of fundamental relevance for the manner in which metals are released in the outflows and explosions of the most massive stars, which is shown to be a strong function of Cosmic time.

Background Many countries are striving to become malaria-free, but global reduction in case estimates has stagnated in recent years. Substandard and falsified medicines may contribute to this lack of progress. Zambia aims to eliminate their annual burden of 1.2 million pediatric malaria cases and 2500 child deaths due to malaria. We examined the health and economic impact of poor-quality antimalarials in Zambia. Methods An agent-based model, Substandard and Falsified Antimalarial Research Impact (SAFARI), was modified and applied to Zambia. The model was developed to simulate population characteristics, malaria incidence, patient care-seeking, disease progression, treatment outcomes, and associated costs of malaria for children under age five. Zambia-specific demographic, epidemiological, and cost inputs were extracted from the literature. Simulations were run to estimate the health and economic impact of poor-quality antimalarials, the effect of potential artemisinin resistance, and six additional malaria focused policy interventions. Results We simulated annual malaria cases among Zambian children under five. At baseline, we found 2610 deaths resulting in $141.5 million in annual economic burden of malaria. We estimated that elimination of substandard and falsified antimalarials would result in an 8.1% (n = 213) reduction in under-five deaths, prevent 937 hospitalizations, and realize $8.5 million in economic savings, annually. Potential artemisinin resistance could further increase deaths by 6.3% (n = 166) and cost an additional $9.7 million every year. Conclusions Eliminating substandard and falsified antimalarials is an important step towards a malaria-free Zambia. Beyond the dissemination of insecticide-treated bed nets, indoor residual spraying, and other malaria control measures, attention must also be paid to assure the quality of antimalarial treatments.

We present a comparison between lens cavity filters and atomic line filters, discussing their relative merits for applications in quantum optics. We describe the design, characterization and stabilization procedure of a lens cavity filter, which consists of a high-reflection coated commercially available plano-convex lens, and compare it to an ultra-narrow atomic band-pass filter utilizing the D$_{2}$ absorption line in atomic rubidium vapor. We find that the cavity filter peak transmission frequency and bandwidth can be chosen arbitrarily but the transmission frequency is subject to thermal drift and the cavity needs stabilization to better than a few mK, while the atomic filter is intrinsically stable and tied to an atomic resonance frequency such that it can be used in a non-laboratory environment., 10 pages, 5 figures

Contemporary approaches to monitoring quality of care in obstetrics often focus on comparing Cesarean Delivery rates. Varied rates can complicate interpretation of quality of care. We previously developed a risk prediction tool for nulliparous women who may require intrapartum Cesarean delivery which identified five key predictors. Our objective with this study was to ascertain if patient heterogeneity can account for much of the observed variation in Cesarean delivery rates, thereby enabling Cesarean delivery rates to be a better marker of quality of care.This is a secondary analysis of the Genesis study. This was a large prospective study of 2336 nulliparous singleton pregnancies recruited at seven hospitals. A heterogeneity score was calculated for each hospital. An adjusted Cesarean delivery rate was also calculated incorporating the heterogeneous risk score.A cut-off at the 90th percentile was determined for each predictive factor. Above the 90th percentile was considered to represent 'high risk' (with the exception of maternal height which identified those below the 10th percentile). The patient heterogeneous risk score was defined as the number of risk factors90th percentile (10th percentile for height). An unequal distribution of high-risk patients between centers was observed (p 0.001). The correlation between the Cesarean delivery rate and the patient heterogeneous risk score was high (0.76, p 0.05). When adjusted for patient heterogeneity, Cesarean delivery rates became closer aligned.Inter-institutional diversity is common. We suggest that crude comparison of Cesarean delivery rates between different hospitals as a marker of care quality is inappropriate. Allowing for marked differences in patient characteristics is essential for correct interpretation of such comparisons.

Current massive star evolution grids are not able to simultaneously reproduce the empirical upper luminosity limit of red supergiants, the Humphrey-Davidson (HD) limit at high and low metallicity. In this study, we provide a better understanding of what drives massive star evolution to blue and red supergiant phases, with the ultimate aim of reproducing the HD limit at varied metallicities (Z). For solar, LMC, and SMC Z, we develop eight grids of MESA models for the mass range 20-60M to probe the effect of semiconvection and overshooting. We compare rotating and non-rotating models with efficient (alpha_semi = 100) and inefficient semi-convection (alpha_semi = 0.1), with high and low core overshooting (alpha_ov of 0.1 or 0.5). The red and blue supergiant evolutionary phases are investigated by comparing the fraction of core He-burning lifetimes spent in each phase. We find that the extension of the convective core by overshooting alpha_ov = 0.5 has an effect on the post-MS evolution which can disable semiconvection leading to more RSGs, but a lack of BSGs. We therefore implement alpha_ov = 0.1 which switches on semiconvective mixing, though for standard alpha_semi = 1, would result in an HD limit which is higher than observed at low Z. Therefore, we need to implement very efficient semiconvection of alpha_semi = 100 which reproduces the HD limit at log L ~ 5.5 for the Magellanic Clouds while simultaneously reproducing the Galactic HD limit of log L ~ 5.8 naturally. The effect of semiconvection is not active at high Z due to the depletion of the envelope structure by strong mass loss such that semiconvective regions could not form. Z-dependent mass loss plays an indirect, yet decisive role in setting the HD limit as a function of Z. For a combination of efficient semiconvection and low overshooting with standard Z-dependent mass loss, we find a natural HD limit at all metallicities., 11pages, 7 figures, accepted for publication in A&A

ObjectiveTo assess the importance of ensuring medicine quality in order to achieve universal health coverage (UHC).MethodsWe developed a systems map connecting medicines quality assurance systems with UHC goals to illustrate the ensuing impact of quality-assured medicines in the implementation of UHC. The association between UHC and medicine quality was further examined in the context of essential medicines in low- and middle-income countries (LMICs) by analyzing data on reported prevalence of substandard and falsified essential medicines and established indicators for UHC. Finally, we examined the health and economic savings of improving antimalarial quality in four countries in sub-Saharan Africa: the Democratic Republic of the Congo (DRC), Nigeria, Uganda, and Zambia.FindingsA systems perspective demonstrates how quality assurance of medicines supports dimensions of UHC. Across 63 LMICs, the reported prevalence of substandard and falsified essential medicines was found to be negatively associated with both an indicator for coverage of essential services (p = 0.05) and with an indicator for government effectiveness (p = 0.04). We estimated that investing in improving the quality of antimalarials by 10% would result in annual savings of $8.3 million in Zambia, $14 million in Uganda, $79 million in two DRC regions, and $598 million in Nigeria, and was more impactful compared to other potential investments we examined. Costs of substandard and falsified antimalarials per malaria case ranged from $7 to $86, while costs per death due to poor-quality antimalarials ranged from $14,000 to $72,000.ConclusionMedicines quality assurance systems play a critical role in reaching UHC goals. By ensuring the quality of essential medicines, they help deliver effective treatments that lead to less illness and result in health care savings that can be reinvested towards UHC.