Excess androgen production in subcutaneous adipose tissue of women with polycystic ovarian syndrome

© 2019 Society for Endocrinology Published by Bioscientifica Ltd. The purpose of this study was to investigate androgen production and the role of insulin and LH in its regulation in subcutaneous adipose tissue (SAT) of women with polycystic ovarian syndrome (PCOS). Protein and mRNA expression of androgen synthesis enzymes (cytochrome P450 17A1 (CYP17A1) and aldo-keto reductase 1C3 (AKR1C3)) were measured in SAT biopsies from women with PCOS, diagnosed according to the Rotterdam criteria (n = 15) and healthy controls (n = 15). Cultured mature adipocytes (differentiated from SAT biopsies) were treated with insulin ± phosphoinositol-3-kinase inhibitor (LY294002) or LH ± insulin. CYP17A1 and AKR1C3 mRNA expression and testosterone concentrations were measured in treated and untreated adipocyte cultures. AKR1C3 mRNA was significantly (P < 0.001) greater in PCOS vs non-PCOS SAT, but CYP17A1 was not significantly different between the two groups. AKR1C3 and CYP17A1 protein expression was not significantly different in PCOS vs non-PCOS SAT. In untreated adipocyte cultures, CYP17A1, AKR1C3 and testosterone levels were significantly higher in the PCOS vs the non-PCOS groups. Addition of insulin increased AKR1C3 mRNA and testosterone levels, but not CYP17A1 mRNA in non-PCOS with no effect on PCOS adipocytes. The stimulatory effects of insulin were not inhibited by LY294002. Addition of LH increased CYP17A1, AKR1C3 and testosterone in non-PCOS adipocytes with no effect in PCOS adipocytes. In conclusion, SAT of women with PCOS produces excess androgen, which may contribute to PCOS-related hyperandrogenaemia. This SAT androgen excess is independent of obesity and is not directly stimulated by inulin or LH

Identifying key health system components associated with improved outcomes to inform the reconfiguration of services for adults with rare autoimmune rheumatic diseases : a mixed methods study.

Open Access via the Elsevier agreementPeer reviewe

Identifying key health system components associated with improved outcomes to inform the reconfiguration of services for adults with rare autoimmune rheumatic diseases: a mixed methods study

Background Adults with rare autoimmune rheumatic diseases face unique challenges and struggles to navigate health-care systems designed to manage common conditions. Evidence to inform an optimal service framework for their care is scarce. Using systemic vasculitis as an exemplar, we aimed to identify and explain the key service components underpinning effective care for rare diseases. Methods In this mixed-methods study, data were collected as part of a survey of vasculitis service providers across the UK and Ireland, interviews with patients, and from organisational case studies to identify key service components that enable good care. The association between these components and patient outcomes (eg, serious infections, mortality) and provider outcomes (eg, emergency hospital admissions) were examined in a population-based data linkage study using routine health-care data obtained from patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis from national health datasets in Scotland. We did univariable and multivariable analyses using Bayesian poisson and negative binomial regression to estimate incident rate ratios (IRRs), and Cox proportional hazards models to estimate hazard ratios (HRs). People with lived experiences were involved in the research and writing process. Findings Good care was characterised by service components that supported timely access to services, integrated care, and expertise. In 1420 patients with ANCA-associated vasculitis identified from national health datasets, service-reported average waiting times for new patients of less than 1 week were associated with fewer serious infections (IRR 0·70 [95% credibility interval 0·55–0·88]) and fewer emergency hospital admissions (0·78 [0·68–0·92]). Nurse-led advice lines were associated with fewer serious infections (0·76 [0·58–0·93]) and fewer emergency hospital admissions (0·85 [0·74–0·96]). Average waiting times for new patients of less than 1 week were also associated with reduced mortality (HR 0·59 [95% credibility interval 0·37–0·93]). Cohorted clinics, nurse-led clinics, and specialist vasculitis multi-disciplinary team meetings were associated with fewer serious infections (IRR 0·75 [0·59–0·96] for cohorted clinics; 0·65 [0·39–0·84] for nurse-led clinics; 0·72 [0·57–0·90] for specialist vasculitis multi-disciplinary team meetings) and emergency hospital admissions (0·81 [0·71–0·91]; 0·75 [0·65–0·94]; 0·86 [0·75–0·96]). Key components were characterised by their ability to overcome professional tensions between specialties. Interpretation Key service components associated with important health outcomes and underpinning factors were identified to inform initiatives to improve the design, delivery, and effectiveness of health-care models for rare autoimmune rheumatic diseases

Cosmochemical and spectroscopic properties of Northwest Africa 7325 - A consortium study

This work is part of a project to build an infrared database in order to link IR data of planetary materials (and therefore possible Mercury material) with remote sensing observations of Mercury, which will probably be obtained by the MERTIS instrument on the forthcoming BepiColombo mission.The unique achondrite Northwest Africa (NWA) 7325, which has previously been suggested to represent the first sample from Mercury, was investigated by optical and electron microscopy, and infrared and Raman spectroscopy. In addition, the oxygen, strontium, xenon, and argon isotopes were measured and the abundance of selected trace elements determined. The meteorite is a cumulate rock with subchondritic abundances of HFSE and REE and elevated Sr contents, which underwent a second heating and partial remelting process. Oxygen isotope measurements show that NWA 7325 plots in the ureilite field, close to the ALM-A trachyandesitic fragment found in the unique Almahata Sitta meteorite breccia. On the other hand, mineralogical investigations of the pyroxenes in NWA 7325 provide evidence for similarities to the lodranites and acapulcoites. Furthermore, the rock is weakly shocked and argon isotope data record ancient (~4.5 Ga) plateau ages that have not been reset. The sample records a cosmogenic exposure age of ~19 Ma. Systematics of Rb-Sr indicate an extreme early volatile depletion of the precursor material, similar to many other achondrite groups. However, despite its compositional similarities to other meteorite groups, our results suggest that this meteorite is unique and unrelated to any other known achondrite group. An origin for NWA 7325 as a sample from the planet Mercury is not supported by the results of our investigation. In particular, the evidence from infrared spectroscopy indicates that a direct relationship between NWA 7325 and the planet Mercury can be ruled out: no acceptable spectral match between laboratory analyses and remote sensing observations from Mercury has been obtained. However, we demonstrate that infrared spectroscopy is a rapid and nondestructive method to characterize mineral phases and thus an excellent tool for planetary surface characterization in space missions

Early treatment outcomes and HIV status of patients with extensively drug-resistant tuberculosis in South Africa: a retrospective cohort study

SummaryBackgroundData from Kwazulu Natal, South Africa, suggest that almost all patients with extensively drug-resistant (XDR) tuberculosis are HIV-positive, with a fatal outcome. Since, there are few data for the treatment-related outcomes of XDR tuberculosis in settings with a high HIV prevalence, we investigated the associations of these diseases in such settings to formulate recommendations for control programmes.MethodsIn a retrospective cohort study, we analysed the case records of patients (>16 years old) with XDR tuberculosis (culture-proven at diagnosis) between August, 2002, and February, 2008, at four designated provincial treatment facilities in South Africa. We used Cox proportional hazards regression models to assess risk factors associated with the outcomes—mortality and culture conversion.Findings195 of 227 patients were analysed. 21 died before initiation of any treatment, and 174 patients (82 with HIV infection) were treated. 62 (36%) of these patients died during follow-up. The number of deaths was not significantly different in patients with or without HIV infection: 34 (41%) of 82 versus 28 (30%) of 92 (p=0·13). Treatment with moxifloxacin (hazard ratio 0·11, 95% CI 0·01–0·82; p=0·03), previous culture-proven multidrug-resistant tuberculosis (5·21, 1·93–14·1; p=0·001), and number of drugs used in a regimen (0·59, 0·45–0·78, p<0·0001) were independent predictors of death. Fewer deaths occurred in patients with HIV infection given highly active antiretroviral therapy than in those who were not (0·38, 0·18–0·80; p=0·01). 33 (19%) of 174 patients showed culture conversion, of which 23 (70%) converted within 6 months of initiation of treatment.InterpretationIn South Africa, patients with XDR tuberculosis, a substantial proportion of whom are not infected with HIV, have poor management outcomes. Nevertheless, survival in patients with HIV infection is better than previously reported. The priorities for the country are still prevention of XDR tuberculosis, and early detection and management of multidrug-resistant and XDR tuberculosis through strengthened programmes and laboratory capacity.FundingSouth African Medical Research Council, European Union Framework 7 program, and European Developing Countries Clinical Trials Partnership

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment

Safety, immunogenicity, and reactogenicity of BNT162b2 and mRNA-1273 COVID-19 vaccines given as fourth-dose boosters following two doses of ChAdOx1 nCoV-19 or BNT162b2 and a third dose of BNT162b2 (COV-BOOST): a multicentre, blinded, phase 2, randomised trial

Background Some high-income countries have deployed fourth doses of COVID-19 vaccines, but the clinical need, effectiveness, timing, and dose of a fourth dose remain uncertain. We aimed to investigate the safety, reactogenicity, and immunogenicity of fourth-dose boosters against COVID-19.Methods The COV-BOOST trial is a multicentre, blinded, phase 2, randomised controlled trial of seven COVID-19 vaccines given as third-dose boosters at 18 sites in the UK. This sub-study enrolled participants who had received BNT162b2 (Pfizer-BioNTech) as their third dose in COV-BOOST and randomly assigned them (1:1) to receive a fourth dose of either BNT162b2 (30 µg in 0·30 mL; full dose) or mRNA-1273 (Moderna; 50 µg in 0·25 mL; half dose) via intramuscular injection into the upper arm. The computer-generated randomisation list was created by the study statisticians with random block sizes of two or four. Participants and all study staff not delivering the vaccines were masked to treatment allocation. The coprimary outcomes were safety and reactogenicity, and immunogenicity (antispike protein IgG titres by ELISA and cellular immune response by ELISpot). We compared immunogenicity at 28 days after the third dose versus 14 days after the fourth dose and at day 0 versus day 14 relative to the fourth dose. Safety and reactogenicity were assessed in the per-protocol population, which comprised all participants who received a fourth-dose booster regardless of their SARS-CoV-2 serostatus. Immunogenicity was primarily analysed in a modified intention-to-treat population comprising seronegative participants who had received a fourth-dose booster and had available endpoint data. This trial is registered with ISRCTN, 73765130, and is ongoing.Findings Between Jan 11 and Jan 25, 2022, 166 participants were screened, randomly assigned, and received either full-dose BNT162b2 (n=83) or half-dose mRNA-1273 (n=83) as a fourth dose. The median age of these participants was 70·1 years (IQR 51·6–77·5) and 86 (52%) of 166 participants were female and 80 (48%) were male. The median interval between the third and fourth doses was 208·5 days (IQR 203·3–214·8). Pain was the most common local solicited adverse event and fatigue was the most common systemic solicited adverse event after BNT162b2 or mRNA-1273 booster doses. None of three serious adverse events reported after a fourth dose with BNT162b2 were related to the study vaccine. In the BNT162b2 group, geometric mean anti-spike protein IgG concentration at day 28 after the third dose was 23 325 ELISA laboratory units (ELU)/mL (95% CI 20 030–27 162), which increased to 37 460 ELU/mL (31 996–43 857) at day 14 after the fourth dose, representing a significant fold change (geometric mean 1·59, 95% CI 1·41–1·78). There was a significant increase in geometric mean anti-spike protein IgG concentration from 28 days after the third dose (25 317 ELU/mL, 95% CI 20 996–30 528) to 14 days after a fourth dose of mRNA-1273 (54 936 ELU/mL, 46 826–64 452), with a geometric mean fold change of 2·19 (1·90–2·52). The fold changes in anti-spike protein IgG titres from before (day 0) to after (day 14) the fourth dose were 12·19 (95% CI 10·37–14·32) and 15·90 (12·92–19·58) in the BNT162b2 and mRNA-1273 groups, respectively. T-cell responses were also boosted after the fourth dose (eg, the fold changes for the wild-type variant from before to after the fourth dose were 7·32 [95% CI 3·24–16·54] in the BNT162b2 group and 6·22 [3·90–9·92] in the mRNA-1273 group).Interpretation Fourth-dose COVID-19 mRNA booster vaccines are well tolerated and boost cellular and humoral immunity. Peak responses after the fourth dose were similar to, and possibly better than, peak responses after the third dose