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Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified > 300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alíeles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection.

Vascular Effects of Improving Metabolic Control With Metformin or Rosiglitazone in Type 2 Diabetes Andrea Natali , MD 1 , Stephanie Baldeweg , MD 2 , Elena Toschi , MD 1 , Brunella Capaldo , MD 3 , Daniele Barbaro , MD 4 , Amalia Gastaldelli , PHD 1 , John S. Yudkin , MD 2 and Ele Ferrannini , MD 1 1 Department of Internal Medicine and C.N.R. Institute of Clinical Physiology, University of Pisa, Pisa, Italy 2 Department of Medicine, University College, London, U.K. 3 Department of Internal Medicine, “Federico II” University, Naples, Italy 4 Livorno General Hospital, Livorno, Italy Address correspondence and reprint requests to Dr. Andrea Natali, Department of Internal Medicine, Via Roma, 67, 56100 Pisa, Italy. E-mail: anatali{at}ifc.cnr.it Abstract OBJECTIVE —The aim of this study was to test whether vascular reactivity is modified by improving metabolic control and peripheral insulin resistance in type 2 diabetes. RESEARCH DESIGN AND METHODS —In a randomized, double-blind design, we assigned 74 type 2 diabetic patients to rosiglitazone (8 mg/day), metformin (1,500 mg/day), or placebo treatment for 16 weeks and measured insulin sensitivity (euglycemic insulin clamp), ambulatory blood pressure, and forearm blood flow response to 1 ) intra-arterial acetylcholine (ACh), 2 ) intra-arterial nitroprusside, 3 ) the clamp, and 4 ) blockade of nitric oxide (NO) synthase. RESULTS —Compared with 25 nondiabetic subjects, patients had reduced insulin sensitivity (30 ± 1 vs. 41 ± 3 μmol · min −1 · kg fat-free mass −1 ; P < 0.001) and reduced maximal response to ACh (586 ± 42 vs. 883 ± 81%; P < 0.001). Relative to placebo, 16 weeks of rosiglitazone and metformin similarly reduced fasting glucose (−2.3 ± 0.5 and −2.3 ± 0.5 mmol/l) and HbA 1c (−1.2 ± 0.3 and −1.6 ± 0.3%). Insulin sensitivity increased with rosiglitazone (+6 ± 3 μmol · min −1 · kg fat-free mass −1 ; P < 0.01) but not with metformin or placebo. Ambulatory diastolic blood pressure fell consistently (−2 ± 1 mmHg; P < 0.05) only in the rosiglitazone group. Nitroprusside dose response, clamp-induced vasodilatation, and NO blockade were not affected by either treatment. In contrast, the slope of the ACh dose response improved with rosiglitazone (+40% versus baseline, P < 0.05, +70% versus placebo, P < 0.005) but did not change with either metformin or placebo. This improvement in endothelium-dependent vasodilatation was accompanied by decrements in circulating levels of free fatty acids and tumor necrosis factor-α. CONCLUSIONS —At equivalent glycemic control, rosiglitazone, but not metformin, improves endothelium dependent vasodilatation and insulin sensitivity in type 2 diabetes. ABPM, ambulatory blood pressure monitoring ACh, acetylcholine eNOS, endothelial nitric oxide synthase EGP, endogenous glucose production FBF, forearm blood flow l-NMMA, NG-monomethyl-l-arginine NEFA, nonesterified fatty acid SNP, sodium nitroprusside TNF-α, tumor necrosis factor-α Footnotes A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. Accepted March 1, 2004. Received November 7, 2003. DIABETES CARE

Three patients with AIDS who were taking 3′-azido-3′-deoxythymidine (AZT) developed cutaneous abscesses from which Mycobacterium avium-Mycobacterium intracellulare was isolated. Culture of multiple blood samples and bone marrow aspirate from all three patients revealed that the infection was not disseminated. This is a rare form of presentation for this infection in AIDS patients. We speculate that the antiviral drug AZT was responsible for the localization of disease.

The purpose of this dissertation is to develop and empirically test a theoretical model of international school headship transitions in order to identify potential sources of unwanted turnover. Anecdotal evidence from the past two decades suggests that the short tenure of international school heads (average = 3.7 years, Benson, 2011) is unwanted by international schools, a result of up to 70% of heads either volunteering to leave their schools prematurely, being fired, or failing to have their contracts renewed. This qualitative multi-case study dissertation analyzes the experiences of twelve second-year international school heads guided by the use of a theoretical framework grounded in the literatures of leadership and governance in international schools, non-profit organizations, U.S. school districts, and charter schools in order to determine the factors that heads identify as affecting their transitions to work and life abroad. Findings from this study suggest that the headship transition process proceeds in three phases, with heads identifying specific factors affecting transition experiences at each respective phase. Organizational recruitment and selection, contract negotiation, and personal motivation affect heads during the acceptance phase, or the period between the job search and formally accepting an offered contract to become a head of school. Work transition supports (realistic job previews), relocation supports (i.e. locating housing and medical care), and work role spillover (i.e. exiting one job while preparing to entry another) impacts heads during the anticipation stage between hire and their first day on the job. Managing board relations, personal/familial satisfaction in living abroad, and unforeseen incidents (i.e. illness or civil strife) affects heads during the adjustment phase in the first year on the job. This dissertation contributes to the limited literature concerning leadership and governance in international schools while extending the more robust education leadership and expatriate adjustment literatures.

Pseudomonas testosteroni has been largely overlooked as a potential pathogen in humans. Ten cases of infection due to P. testosteroni were identified at a single metropolitan hospital in Texas during a three-year period. The organism was most often found in association with anatomic abnormalities of the gastrointestinal tract (six of 10 cases); perforation of the appendix was the commonest abnormality (five cases). The infections were more often polymicrobial (seven cases) than monomicrobial (three cases) and usually involved other organisms that, like P. testosteroni, are of colonic origin. Eight additional cases of infection involving P. testosteroni were reported by other hospitals in Texas during the same period. The organism was isolated from the peritoneal cavity in five of these cases. The results of these surveys suggest that infections of humans with P. testosteroni, while not common, are not as rare as might be predicted on the basis of the number of cases reported in the literature.

Over the course of the COVID-19 pandemic, the care of patients with COVID-19 has changed and the use of extracorporeal membrane oxygenation (ECMO) has increased. We aimed to examine patient selection, treatments, outcomes, and ECMO centre characteristics over the course of the pandemic to date. We retrospectively analysed the Extracorporeal Life Support Organization Registry and COVID-19 Addendum to compare three groups of ECMO-supported patients with COVID-19 (aged ≥16 years). At early-adopting centres—ie, those using ECMO support for COVID-19 throughout 2020—we compared patients who started ECMO on or before May 1, 2020 (group A1), and between May 2 and Dec 31, 2020 (group A2). Late-adopting centres were those that provided ECMO for COVID-19 only after May 1, 2020 (group B). The primary outcome was in-hospital mortality in a time-to-event analysis assessed 90 days after ECMO initiation. A Cox proportional hazards model was fit to compare the patient and centre-level adjusted relative risk of mortality among the groups. In 2020, 4812 patients with COVID-19 received ECMO across 349 centres within 41 countries. For early-adopting centres, the cumulative incidence of in-hospital mortality 90 days after ECMO initiation was 36·9% (95% CI 34·1–39·7) in patients who started ECMO on or before May 1 (group A1) versus 51·9% (50·0–53·8) after May 1 (group A2); at late-adopting centres (group B), it was 58·9% (55·4–62·3). Relative to patients in group A2, group A1 patients had a lower adjusted relative risk of in-hospital mortality 90 days after ECMO (hazard ratio 0·82 [0·70−0·96]), whereas group B patients had a higher adjusted relative risk (1·42 [1·17−1·73]). Mortality after ECMO for patients with COVID-19 worsened during 2020. These findings inform the role of ECMO in COVID-19 for patients, clinicians, and policy makers. None.

Background There are several reports of extracorporeal membrane oxygenation (ECMO) use in patients with coronavirus disease 2019 (COVID-19) who develop severe acute respiratory distress syndrome (ARDS). We conducted a systematic review and meta-analysis to guide clinical decision-making and future research. Methods We searched MEDLINE, Embase, Cochrane and Scopus databases from 1 December 2019 to 10 January 2021 for observational studies or randomised clinical trials examining ECMO in adults with COVID-19 ARDS. We performed random-effects meta-analyses and meta-regression, assessed risk of bias using the Joanna Briggs Institute checklist and rated the certainty of evidence using the GRADE approach. Survival outcomes were presented as pooled proportions while continuous outcomes were presented as pooled means, both with corresponding 95% confidence intervals [CIs]. The primary outcome was in-hospital mortality. Secondary outcomes were duration of ECMO therapy and mechanical ventilation, weaning rate from ECMO and complications during ECMO. Results We included twenty-two observational studies with 1896 patients in the meta-analysis. Venovenous ECMO was the predominant mode used (98.6%). The pooled in-hospital mortality in COVID-19 patients (22 studies, 1896 patients) supported with ECMO was 37.1% (95% CI 32.3–42.0%, high certainty). Pooled mortality in the venovenous ECMO group was 35.7% (95% CI 30.7–40.7%, high certainty). Meta-regression found that age and ECMO duration were associated with increased mortality. Duration of ECMO support (18 studies, 1844 patients) was 15.1 days (95% CI 13.4–18.7). Weaning from ECMO (17 studies, 1412 patients) was accomplished in 67.6% (95% CI 50.5–82.7%) of patients. There were a total of 1583 ECMO complications reported (18 studies, 1721 patients) and renal complications were the most common. Conclusion The majority of patients received venovenous ECMO support for COVID-19-related ARDS. In-hospital mortality in patients receiving ECMO support for COVID-19 was 37.1% during the first year of the pandemic, similar to those with non-COVID-19-related ARDS. Increasing age was a risk factor for death. Venovenous ECMO appears to be an effective intervention in selected patients with COVID-19-related ARDS. PROSPERO CRD42020192627 .