Sensitivity of Mesoscale Modeling of Smoke Direct Radiative Effect to the Emission Inventory: a Case Study in Northern Sub-Saharan African Region

An ensemble approach is used to examine the sensitivity of smoke loading and smoke direct radiative effect in the atmosphere to uncertainties in smoke emission estimates. Seven different fire emission inventories are applied independently to WRF-Chem model (v3.5) with the same model configuration (excluding dust and other emission sources) over the northern sub-Saharan African (NSSA) biomass-burning region. Results for November and February 2010 are analyzed, respectively representing the start and end of the biomass burning season in the study region. For February 2010, estimates of total smoke emission vary by a factor of 12, but only differences by factors of 7 or less are found in the simulated regional (15degW-42degE, 13degS-17degN) and monthly averages of column PM(sub 2.5) loading, surface PM(sub 2.5) concentration, aerosol optical depth (AOD), smoke radiative forcing at the top-of-atmosphere and at the surface, and air temperature at 2 m and at 700 hPa. The smaller differences in these simulated variables may reflect the atmospheric diffusion and deposition effects to dampen the large difference in smoke emissions that are highly concentrated in areas much smaller than the regional domain of the study. Indeed, at the local scale, large differences (up to a factor of 33) persist in simulated smoke-related variables and radiative effects including semi-direct effect. Similar results are also found for November 2010, despite differences in meteorology and fire activity. Hence, biomass burning emission uncertainties have a large influence on the reliability of model simulations of atmospheric aerosol loading, transport, and radiative impacts, and this influence is largest at local and hourly-to-daily scales. Accurate quantification of smoke effects on regional climate and air quality requires further reduction of emission uncertainties, particularly for regions of high fire concentrations such as NSSA

Sensitivity of Mesoscale Modeling of Smoke Direct Radiative Effect to the Emission Inventory: A Case Study in Northern Sub-Saharan African Region

An ensemble approach is used to examine the sensitivity of smoke loading and smoke direct radiative effect in the atmosphere to uncertainties in smoke emission estimates. Seven different fire emission inventories are applied independently to WRF-Chem model (v3.5) with the same model configuration (excluding dust and other emission sources) over the northern sub-Saharan African (NSSA) biomass-burning region. Results for November and February 2010 are analyzed, respectively representing the start and end of the biomass burning season in the study region. For February 2010, estimates of total smoke emission vary by a factor of 12, but only differences by factors of 7 or less are found in the simulated regional (15°W–42°E, 13°S–17°N) and monthly averages of column PM2.5 loading, surface PM2.5 concentration, aerosol optical depth (AOD), smoke radiative forcing at the top-of-atmosphere and at the surface, and air temperature at 2 m and at 700 hPa. The smaller differences in these simulated variables may reflect the atmospheric diffusion and deposition effects to dampen the large difference in smoke emissions that are highly concentrated in areas much smaller than the regional domain of the study. Indeed, at the local scale, large differences (up to a factor of 33) persist in simulated smoke-related variables and radiative effects including semi-direct effect. Similar results are also found for November 2010, despite differences in meteorology and fire activity. Hence, biomass burning emission uncertainties have a large influence on the reliability of model simulations of atmospheric aerosol loading, transport, and radiative impacts, and this influence is largest at local and hourly-to-daily scales. Accurate quantification of smoke effects on regional climate and air quality requires further reduction of emission uncertainties, particularly for regions of high fire concentrations such as NSSA

The DANTE trial protocol: a randomised phase III trial to evaluate the Duration of ANti-PD-1 monoclonal antibody Treatment in patients with metastatic mElanoma.

BACKGROUND: Immunotherapy is revolutionising the treatment of patients diagnosed with melanoma and other cancers. The first immune checkpoint inhibitor, ipilimumab (targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)), showed a survival advantage over standard chemotherapy. Subsequently the anti-programmed cell death protein 1 (PD-1) antibodies, nivolumab and pembrolizumab were shown to be more effective than ipilimumab. Ipilimumab combined with nivolumab gives an incremental gain in overall survival compared with nivolumab alone but increases the risk of severe, potentially life-threatening toxicities. In contrast to ipilimumab monotherapy, anti-PD-1 antibodies are licensed to be continued until disease progression. Follow-up of patients recruited to the first trials evaluating 2 years of pembrolizumab showed that three-quarters of responding patients continue responding after stopping treatment. Suggestive of early response, we hypothesised that continuing anti-PD-1 treatment beyond 1 year in progression-free patients may be unnecessary and so designed the DANTE trial. METHODS: DANTE is a multicentre, randomised, phase III, non-inferiority trial to evaluate the duration of anti-PD-1 therapy in patients with metastatic (unresectable stage III and stage IV) melanoma. It uses a two-stage recruitment strategy, registering patients before they complete 1 year of first-line anti-PD-1 +/- CTLA-4 therapy and randomising eligible patients who have received 12 months of treatment and are progression-free at 1 year. At randomisation, 1208 patients are assigned (1:1) to either 1) continue anti-PD-1 treatment until disease progression/ unacceptable toxicity/ for at least 2 years in the absence of disease progression/ unacceptable toxicity or 2) to stop treatment. Randomisation stratifies for baseline prognostic factors. The primary outcome is progression-free survival at 3, 6, 9 and 12 months and then, 6-monthly for up to 4-years. Secondary outcomes collected at all timepoints include overall survival, response-rate and duration and safety, with quality of life and cost-effectiveness outcomes collected 3-monthly for up to 18-months. Sub-studies include a qualitative analysis of patient acceptance of randomisation and sample collection to inform future translational studies into response/ toxicity biomarkers. DISCUSSION: DANTE is a unique prospective trial investigating the optimal duration of anti-PD-1 therapy in metastatic melanoma patients. Outcomes will inform future use of these high burden drugs. TRIAL REGISTRATION: ISRCTN15837212 , 31 July 2018

And labor came to us: making use of an opportune workforce - enhancing migrant integration into British economy

This article considers the opportunities presented by the availability of migrant labor in the U.K. employment market and its utilization. The research found that despite their qualifications, migrant labor is underutilized, thereby resulting in a readily available workforce being shunned and excluded from participative integration. This raises economic and ethical questions whose exploration revealed structural barriers (individually, communally, and institutionally) that impeded migrants’ fulfillment of citizenship obligations to host communities and U.K. businesses. The article’s key contribution is to highlight a skills mismatch and the persistent absence of institutional, communal, and strategic frameworks to support migrants’ integration

Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.

Neðst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinn View/OpenLoss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ~150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.US National Institutes of Health (NIH) Training 5-T32-GM007748-33 Doris Duke Charitable Foundation 2006087 Fulbright Diabetes UK Fellowship BDA 11/0004348 Broad Institute from Pfizer, Inc. NIH U01 DK085501 U01 DK085524 U01 DK085545 U01 DK085584 Swedish Research Council Dnr 521-2010-3490 Dnr 349-2006-237 European Research Council (ERC) GENETARGET T2D GA269045 ENGAGE 2007-201413 CEED3 2008-223211 Sigrid Juselius Foundation Folkh lsan Research Foundation ERC AdG 293574 Research Council of Norway 197064/V50 KG Jebsen Foundation University of Bergen Western Norway Health Authority Lundbeck Foundation Novo Nordisk Foundation Wellcome Trust WT098017 WT064890 WT090532 WT090367 WT098381 Uppsala University Swedish Research Council and the Swedish Heart- Lung Foundation Academy of Finland 124243 102318 123885 139635 Finnish Heart Foundation Finnish Diabetes Foundation, Tekes 1510/31/06 Commission of the European Community HEALTH-F2-2007-201681 Ministry of Education and Culture of Finland European Commission Framework Programme 6 Integrated Project LSHM-CT-2004-005272 City of Kuopio and Social Insurance Institution of Finland Finnish Foundation for Cardiovascular Disease NIH/NIDDK U01-DK085545 National Heart, Lung, and Blood Institute (NHLBI) National Institute on Minority Health and Health Disparities N01 HC-95170 N01 HC-95171 N01 HC-95172 European Union Seventh Framework Programme, DIAPREPP Swedish Child Diabetes Foundation (Barndiabetesfonden) 5U01DK085526 DK088389 U54HG003067 R01DK072193 R01DK062370 Z01HG000024info:eu-repo/grantAgreement/EC/FP7/20201

HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer

BACKGROUND: Oestrogen receptor positive/ human epidermal growth factor receptor positive (ER+/HER2+) breast cancers (BCs) are less responsive to endocrine therapy than ER+/HER2- tumours. Mechanisms underpinning the differential behaviour of ER+HER2+ tumours are poorly characterised. Our aim was to identify biomarkers of response to 2 weeks’ presurgical AI treatment in ER+/HER2+ BCs. METHODS: All available ER+/HER2+ BC baseline tumours (n=342) in the POETIC trial were gene expression profiled using BC360™ (NanoString) covering intrinsic subtypes and 46 key biological signatures. Early response to AI was assessed by changes in Ki67 expression and residual Ki67 at 2 weeks (Ki672wk). Time-To-Recurrence (TTR) was estimated using Kaplan-Meier methods and Cox models adjusted for standard clinicopathological variables. New molecular subgroups (MS) were identified using consensus clustering. FINDINGS: HER2-enriched (HER2-E) subtype BCs (44.7% of the total) showed poorer Ki67 response and higher Ki672wk (p<0.0001) than non-HER2-E BCs. High expression of ERBB2 expression, homologous recombination deficiency (HRD) and TP53 mutational score were associated with poor response and immune-related signatures with High Ki672wk. Five new MS that were associated with differential response to AI were identified. HER2-E had significantly poorer TTR compared to Luminal BCs (HR 2.55, 95% CI 1.14–5.69; p=0.0222). The new MS were independent predictors of TTR, adding significant value beyond intrinsic subtypes. INTERPRETATION: Our results show HER2-E as a standardised biomarker associated with poor response to AI and worse outcome in ER+/HER2+. HRD, TP53 mutational score and immune-tumour tolerance are predictive biomarkers for poor response to AI. Lastly, novel MS identify additional non-HER2-E tumours not responding to AI with an increased risk of relapse

Nintedanib for Systemic Sclerosis-Associated Interstitial Lung Disease

BACKGROUND: Interstitial lung disease (ILD) is a common manifestation of systemic sclerosis and a leading cause of systemic sclerosis-related death. Nintedanib, a tyrosine kinase inhibitor, has been shown to have antifibrotic and antiinflammatory effects in preclinical models of systemic sclerosis and ILD. METHODS: We conducted a randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of nintedanib in patients with ILD associated with systemic sclerosis. Patients who had systemic sclerosis with an onset of the first non-Raynaud's symptom within the past 7 years and a high-resolution computed tomographic scan that showed fibrosis affecting at least 10% of the lungs were randomly assigned, in a 1:1 ratio, to receive 150 mg of nintedanib, administered orally twice daily, or placebo. The primary end point was the annual rate of decline in forced vital capacity (FVC), assessed over a 52-week period. Key secondary end points were absolute changes from baseline in the modified Rodnan skin score and in the total score on the St. George's Respiratory Questionnaire (SGRQ) at week 52. RESULTS: A total of 576 patients received at least one dose of nintedanib or placebo; 51.9% had diffuse cutaneous systemic sclerosis, and 48.4% were receiving mycophenolate at baseline. In the primary end-point analysis, the adjusted annual rate of change in FVC was 1252.4 ml per year in the nintedanib group and 1293.3 ml per year in the placebo group (difference, 41.0 ml per year; 95% confidence interval [CI], 2.9 to 79.0; P=0.04). Sensitivity analyses based on multiple imputation for missing data yielded P values for the primary end point ranging from 0.06 to 0.10. The change from baseline in the modified Rodnan skin score and the total score on the SGRQ at week 52 did not differ significantly between the trial groups, with differences of 120.21 (95% CI, 120.94 to 0.53; P=0.58) and 1.69 (95% CI, 120.73 to 4.12 [not adjusted for multiple comparisons]), respectively. Diarrhea, the most common adverse event, was reported in 75.7% of the patients in the nintedanib group and in 31.6% of those in the placebo group. CONCLUSIONS: Among patients with ILD associated with systemic sclerosis, the annual rate of decline in FVC was lower with nintedanib than with placebo; no clinical benefit of nintedanib was observed for other manifestations of systemic sclerosis. The adverse-event profile of nintedanib observed in this trial was similar to that observed in patients with idiopathic pulmonary fibrosis; gastrointestinal adverse events, including diarrhea, were more common with nintedanib than with placebo

Genome-wide survey of SNP variation uncovers the genetic structure of cattle breeds

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Identifying the research, advocacy, policy and implementation needs for the prevention and management of respiratory syncytial virus lower respiratory tract infection in low- and middle-income countries

Introduction: The high burden of respiratory syncytial virus (RSV) infection in young children disproportionately occurs in low- and middle-income countries (LMICs). The PROUD (Preventing RespiratOry syncytial virUs in unDerdeveloped countries) Taskforce of 24 RSV worldwide experts assessed key needs for RSV prevention in LMICs, including vaccine and newer preventive measures. Methods: A global, survey-based study was undertaken in 2021. An online questionnaire was developed following three meetings of the Taskforce panellists wherein factors related to RSV infection, its prevention and management were identified using iterative questioning. Each factor was scored, by non-panellists interested in RSV, on a scale of zero (very-low-relevance) to 100 (very-high-relevance) within two scenarios: (1) Current and (2) Future expectations for RSV management. Results: Ninety questionnaires were completed: 70 by respondents (71.4% physicians; 27.1% researchers/scientists) from 16 LMICs and 20 from nine high-income (HI) countries (90.0% physicians; 5.0% researchers/scientists), as a reference group. Within LMICs, RSV awareness was perceived to be low, and management was not prioritised. Of the 100 factors scored, those related to improved diagnosis particularly access to affordable point-of-care diagnostics, disease burden data generation, clinical and general education, prompt access to new interventions, and engagement with policymakers/payers were identified of paramount importance. There was a strong need for clinical education and local data generation in the lowest economies, whereas upper-middle income countries were more closely aligned with HI countries in terms of current RSV service provision. Conclusion: Seven key actions for improving RSV prevention and management in LMICs are proposed