Ten Years of Experience Training Non-Physician Anesthesia Providers in Haiti.

Surgery is increasingly recognized as an effective means of treating a proportion of the global burden of disease, especially in resource-limited countries. Often non-physicians, such as nurses, provide the majority of anesthesia; however, their training and formal supervision is often of low priority or even non-existent. To increase the number of safe anesthesia providers in Haiti, Médecins Sans Frontières has trained nurse anesthetists (NAs) for over 10 years. This article describes the challenges, outcomes, and future directions of this training program. From 1998 to 2008, 24 students graduated. Nineteen (79%) continue to work as NAs in Haiti and 5 (21%) have emigrated. In 2008, NAs were critical in providing anesthesia during a post-hurricane emergency where they performed 330 procedures. Mortality was 0.3% and not associated with lack of anesthesiologist supervision. The completion rate of this training program was high and the majority of graduates continue to work as nurse anesthetists in Haiti. Successful training requires a setting with a sufficient volume and diversity of operations, appropriate anesthesia equipment, a structured and comprehensive training program, and recognition of the training program by the national ministry of health and relevant professional bodies. Preliminary outcomes support findings elsewhere that NAs can be a safe and effective alternative where anesthesiologists are scarce. Training non-physician anesthetists is a feasible and important way to scale up surgical services resource limited settings

Chapter 12: Systematic Review of Prognostic Tests

A number of new biological markers are being studied as predictors of disease or adverse medical events among those who already have a disease. Systematic reviews of this growing literature can help determine whether the available evidence supports use of a new biomarker as a prognostic test that can more accurately place patients into different prognostic groups to improve treatment decisions and the accuracy of outcome predictions. Exemplary reviews of prognostic tests are not widely available, and the methods used to review diagnostic tests do not necessarily address the most important questions about prognostic tests that are used to predict the time-dependent likelihood of future patient outcomes. We provide suggestions for those interested in conducting systematic reviews of a prognostic test. The proposed use of the prognostic test should serve as the framework for a systematic review and to help define the key questions. The outcome probabilities or level of risk and other characteristics of prognostic groups are the most salient statistics for review and perhaps meta-analysis. Reclassification tables can help determine how a prognostic test affects the classification of patients into different prognostic groups, hence their treatment. Review of studies of the association between a potential prognostic test and patient outcomes would have little impact other than to determine whether further development as a prognostic test might be warranted

A mechanism for the inhibition of DNA-PK-mediated DNA sensing by a virus

The innate immune system is critical in the response to infection by pathogens and it is activated by pattern recognition receptors (PRRs) binding to pathogen associated molecular patterns (PAMPs). During viral infection, the direct recognition of the viral nucleic acids, such as the genomes of DNA viruses, is very important for activation of innate immunity. Recently, DNA-dependent protein kinase (DNA-PK), a heterotrimeric complex consisting of the Ku70/Ku80 heterodimer and the catalytic subunit DNA-PKcs was identified as a cytoplasmic PRR for DNA that is important for the innate immune response to intracellular DNA and DNA virus infection. Here we show that vaccinia virus (VACV) has evolved to inhibit this function of DNA-PK by expression of a highly conserved protein called C16, which was known to contribute to virulence but by an unknown mechanism. Data presented show that C16 binds directly to the Ku heterodimer and thereby inhibits the innate immune response to DNA in fibroblasts, characterised by the decreased production of cytokines and chemokines. Mechanistically, C16 acts by blocking DNA-PK binding to DNA, which correlates with reduced DNA-PK-dependent DNA sensing. The C-terminal region of C16 is sufficient for binding Ku and this activity is conserved in the variola virus (VARV) orthologue of C16. In contrast, deletion of 5 amino acids in this domain is enough to knockout this function from the attenuated vaccine strain modified vaccinia virus Ankara (MVA). In vivo a VACV mutant lacking C16 induced higher levels of cytokines and chemokines early after infection compared to control viruses, confirming the role of this virulence factor in attenuating the innate immune response. Overall this study describes the inhibition of DNA-PK-dependent DNA sensing by a poxvirus protein, adding to the evidence that DNA-PK is a critical component of innate immunity to DNA viruses

Garden and landscape-scale correlates of moths of differing conservation status: significant effects of urbanization and habitat diversity

Moths are abundant and ubiquitous in vegetated terrestrial environments and are pollinators, important herbivores of wild plants, and food for birds, bats and rodents. In recent years, many once abundant and widespread species have shown sharp declines that have been cited by some as indicative of a widespread insect biodiversity crisis. Likely causes of these declines include agricultural intensification, light pollution, climate change, and urbanization; however, the real underlying cause(s) is still open to conjecture. We used data collected from the citizen science Garden Moth Scheme (GMS) to explore the spatial association between the abundance of 195 widespread British species of moth, and garden habitat and landscape features, to see if spatial habitat and landscape associations varied for species of differing conservation status. We found that associations with habitat and landscape composition were species-specific, but that there were consistent trends in species richness and total moth abundance. Gardens with more diverse and extensive microhabitats were associated with higher species richness and moth abundance; gardens near to the coast were associated with higher richness and moth abundance; and gardens in more urbanized locations were associated with lower species richness and moth abundance. The same trends were also found for species classified as increasing, declining and vulnerable under IUCN (World Conservation Union) criteria

Alirocumab therapy in individuals with type 2 diabetes mellitus and atherosclerotic cardiovascular disease:analysis of the ODYSSEY DM-DYSLIPIDEMIA and DM-INSULIN studies

Background Individuals with diabetes often have high levels of atherogenic lipoproteins and cholesterol reflected by elevated low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), and LDL particle number (LDL-PN). The presence of atherosclerotic cardiovascular disease (ASCVD) increases the risk of future cardiovascular events. We evaluated the efficacy and safety of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, alirocumab, among individuals with type 2 diabetes (T2DM), high LDL-C or non-HDL-C, and established ASCVD receiving maximally tolerated statin in ODYSSEY DM-DYSLIPIDEMIA (NCT02642159) and DM-INSULIN (NCT02585778). Methods In DM-DYSLIPIDEMIA, individuals with T2DM and mixed dyslipidemia (non-HDL-C ≥ 100 mg/dL; n = 413) were randomized to open-label alirocumab 75 mg every 2 weeks (Q2W) or usual care (UC) for 24 weeks, with UC options selected before stratified randomization. In DM-INSULIN, insulin-treated individuals with T2DM (LDL-C ≥ 70 mg/dL; n = 441) were randomized in a double-blind fashion to alirocumab 75 mg Q2W or placebo for 24 weeks. Study participants also had a glycated hemoglobin < 9% (DM-DYSLIPIDEMIA) or < 10% (DM-INSULIN). Alirocumab dose was increased to 150 mg Q2W at week 12 if week 8 LDL-C was ≥ 70 mg/dL (DM-INSULIN) or non-HDL-C was ≥ 100 mg/dL (DM-DYSLIPIDEMIA). Lipid reductions and safety were assessed in patients with ASCVD from these studies. Results This analysis included 142 DM-DYSLIPIDEMIA and 177 DM-INSULIN participants with ASCVD, including 95.1% and 86.4% with coronary heart disease, and 32.4% and 49.7% with microvascular diabetes complications, respectively. At week 24, alirocumab significantly reduced LDL-C, non-HDL-C, ApoB, and LDL-PN from baseline versus control. This translated into a greater proportion of individuals achieving non-HDL-C < 100 mg/dL (64.6% alirocumab/23.8% UC [DM-DYSLIPIDEMIA]; 65.4% alirocumab/14.9% placebo [DM-INSULIN]) and ApoB < 80 mg/dL (75.1% alirocumab/35.4% UC and 76.8% alirocumab/24.8% placebo, respectively) versus control at week 24 (all P < 0.0001). In pooling these studies, 66.4% (alirocumab) and 67.0% (control) of individuals reported treatment-emergent adverse events. The adverse event pattern was similar with alirocumab versus controls. Conclusions Among individuals with T2DM and ASCVD who had high non-HDL-C/LDL-C levels despite maximally tolerated statin, alirocumab significantly reduced atherogenic cholesterol and LDL-PN versus control. Alirocumab was generally well tolerated

LDL-cholesterol concentrations: a genome-wide association study

BACKGROUND: LDL cholesterol has a causal role in the development of cardiovascular disease. Improved understanding of the biological mechanisms that underlie the metabolism and regulation of LDL cholesterol might help to identify novel therapeutic targets. We therefore did a genome-wide association study of LDL-cholesterol concentrations. METHODS: We used genome-wide association data from up to 11,685 participants with measures of circulating LDL-cholesterol concentrations across five studies, including data for 293 461 autosomal single nucleotide polymorphisms (SNPs) with a minor allele frequency of 5% or more that passed our quality control criteria. We also used data from a second genome-wide array in up to 4337 participants from three of these five studies, with data for 290,140 SNPs. We did replication studies in two independent populations consisting of up to 4979 participants. Statistical approaches, including meta-analysis and linkage disequilibrium plots, were used to refine association signals; we analysed pooled data from all seven populations to determine the effect of each SNP on variations in circulating LDL-cholesterol concentrations. FINDINGS: In our initial scan, we found two SNPs (rs599839 [p=1.7x10(-15)] and rs4970834 [p=3.0x10(-11)]) that showed genome-wide statistical association with LDL cholesterol at chromosomal locus 1p13.3. The second genome screen found a third statistically associated SNP at the same locus (rs646776 [p=4.3x10(-9)]). Meta-analysis of data from all studies showed an association of SNPs rs599839 (combined p=1.2x10(-33)) and rs646776 (p=4.8x10(-20)) with LDL-cholesterol concentrations. SNPs rs599839 and rs646776 both explained around 1% of the variation in circulating LDL-cholesterol concentrations and were associated with about 15% of an SD change in LDL cholesterol per allele, assuming an SD of 1 mmol/L. INTERPRETATION: We found evidence for a novel locus for LDL cholesterol on chromosome 1p13.3. These results potentially provide insight into the biological mechanisms that underlie the regulation of LDL cholesterol and might help in the discovery of novel therapeutic targets for cardiovascular disease

A Review of Time Courses and Predictors of Lipid Changes with Fenofibric Acid-Statin Combination

Fibrates activate peroxisome proliferator activated receptor α and exert beneficial effects on triglycerides, high-density lipoprotein cholesterol, and low density lipoprotein subspecies. Fenofibric acid (FA) has been studied in a large number of patients with mixed dyslipidemia, combined with a low- or moderate-dose statin. The combination of FA with simvastatin, atorvastatin and rosuvastatin resulted in greater improvement of the overall lipid profile compared with the corresponding statin dose. The long-term efficacy of FA combined with low- or moderate- dose statin has been demonstrated in a wide range of patients, including patients with type 2 diabetes mellitus, metabolic syndrome, or elderly subjects. The FA and statin combination seems to be a reasonable option to further reduce cardiovascular risk in high-risk populations, although trials examining cardiovascular disease events are missing

Increased proportion of nitric oxide synthase immunoreactive neurons in rat ileal myenteric ganglia after severe acute pancreatitis

<p>Abstract</p> <p>Background</p> <p>Severe acute pancreatitis (SAP) remains a potentially life-threatening disease. Gastrointestinal motility disturbance such as intestinal ileus is seen in every case. By now, the mechanisms of pancreatitis-induced ileus are largely unknown. The main purpose of the present study was to observe changes of nitric oxide synthase-immunoreactive (NOS-IR) neurons in ileal myenteric ganglia in SAP rats with gastrointestinal dysmotility, trying to explore underlying nervous mechanisms of pancreatitis-induced ileus.</p> <p>Methods</p> <p>Twenty Sprague Dawley rats were randomly divided into sham operated group and SAP group. SAP was induced by retrograde cholangiopancreatic duct injection of 5% sodium taurocholate. Abdominal X-ray and intestinal transit were performed to detect the existence of paralytic ileus and intestinal dysmotility. Pathological damage of pancreas was evaluated. Double-immunolabeling was employed for the whole-mount preparations of ileal myenteric ganglia. The morphology of NOS-IR neurons were observed and the percentage of NOS-IR neurons was calculated based on the total Hu-immunoreactive neurons. Total RNA of ileum was extracted according to Trizol reagent protocol. Neuronal NOS (nNOS) mRNA expression was evaluated by RT-PCR.</p> <p>Results</p> <p>The small intestinal transit index in the SAP group was significantly lower compared with the sham operated group (29.21 ± 3.68% vs 52.48 ± 6.76%, <it>P <</it>0.01). The percentage of NOS-IR neurons in ileal myenteric ganglia in the SAP group was significantly higher than that in the sham operated group (37.5 ± 12.28% vs 26.32 ± 16.15%, <it>P <</it>0.01). nNOS mRNA expression in ileum of SAP group was significantly higher than that in the sham operated group (1.02 ± 0.10 vs 0.70 ± 0.06, <it>P </it>< 0.01).</p> <p>Conclusions</p> <p>The increased quantity of NOS-IR neurons in ileal myenteric ganglia and increased nNOS mRNA expression may suggest nNOS over expression as one of the nervous mechanisms of gastrointestinal dysmotility in SAP rat.</p

Accounting For Alignment Uncertainty in Phylogenomics

Uncertainty in multiple sequence alignments has a large impact on phylogenetic analyses. Little has been done to evaluate the quality of individual positions in protein sequence alignments, which directly impact the accuracy of phylogenetic trees. Here we describe ZORRO, a probabilistic masking program that accounts for alignment uncertainty by assigning confidence scores to each alignment position. Using the BALIBASE database and in simulation studies, we demonstrate that masking by ZORRO significantly reduces the alignment uncertainty and improves the tree accuracy