Five-year mortality in a cohort of people with schizophrenia in Ethiopia

<p>Abstract</p> <p>Background</p> <p>Schizophrenia is associated with a two to three fold excess mortality. Both natural and unnatural causes were reported. However, there is dearth of evidence from low and middle income (LAMIC) countries, particularly in Africa. To our knowledge this is the first community based report from Africa.</p> <p>Methods</p> <p>We followed a cohort of 307 (82.1% males) patients with schizophrenia for five years in Butajira, rural Ethiopia. Mortality was recorded using broad rating schedule as well as verbal autopsy. Standardized Mortality Ratio (SMR) was calculated using the mortality in the demographic and surveillance site as a reference.</p> <p>Result</p> <p>Thirty eight (12.4%) patients, 34 men (11.1%) and 4 women (1.3%), died during the five-year follow up period. The mean age (SD) of the deceased for both sexes was 35 (7.35). The difference was not statistically significant (p = 0.69). It was 35.3 (7.4) for men and 32.3 (6.8) for women. The most common cause of death was infection, 18/38 (47.4%) followed by severe malnutrition, 5/38 (13.2%) and suicide 4/38 (10.5%). The overall SMR was 5.98 (95% CI = 4.09 to7.87). Rural residents had lower mortality with adjusted hazard ratio (HR) of 0.30 (95% CI = 0.12-0.69) but insidious onset and antipsychotic treatment for less than 50% of the follow up period were associated with higher mortality, adjusted HR 2.37 (95% CI = 1.04-5. 41) and 2.66(1.054-6.72) respectively.</p> <p>Conclusion</p> <p>The alarmingly high mortality observed in this patient population is of major concern. Most patients died from potentially treatable conditions. Improving medical and psychiatric care as well as provision of basic needs is recommended.</p

Automatic Filtering and Substantiation of Drug Safety Signals

Drug safety issues pose serious health threats to the population and constitute a major cause of mortality worldwide. Due to the prominent implications to both public health and the pharmaceutical industry, it is of great importance to unravel the molecular mechanisms by which an adverse drug reaction can be potentially elicited. These mechanisms can be investigated by placing the pharmaco-epidemiologically detected adverse drug reaction in an information-rich context and by exploiting all currently available biomedical knowledge to substantiate it. We present a computational framework for the biological annotation of potential adverse drug reactions. First, the proposed framework investigates previous evidences on the drug-event association in the context of biomedical literature (signal filtering). Then, it seeks to provide a biological explanation (signal substantiation) by exploring mechanistic connections that might explain why a drug produces a specific adverse reaction. The mechanistic connections include the activity of the drug, related compounds and drug metabolites on protein targets, the association of protein targets to clinical events, and the annotation of proteins (both protein targets and proteins associated with clinical events) to biological pathways. Hence, the workflows for signal filtering and substantiation integrate modules for literature and database mining, in silico drug-target profiling, and analyses based on gene-disease networks and biological pathways. Application examples of these workflows carried out on selected cases of drug safety signals are discussed. The methodology and workflows presented offer a novel approach to explore the molecular mechanisms underlying adverse drug reactions

Respiratory and haemodynamic effects of volume-controlled vs pressure-controlled ventilation during laparoscopy: a cross-over study with echocardiographic assessment.

International audienceBACKGROUND: The effects of pressure-controlled (PC) ventilation on the ventilatory and haemodynamic parameters during laparoscopy procedures had not been carefully assessed. This prospective cross-over study was undertaken to compare how volume-controlled (VC) and PC modes could affect pulmonary mechanics, gas exchange, and cardiac function in patients undergoing laparoscopy. METHODS: Twenty-one patients undergoing laparoscopic urological procedures had their lungs ventilated at the beginning with VC ventilation. PC ventilation was instituted at the end of the VC sequence. Ventilator settings were adjusted to keep tidal volume, respiratory rate, and Fi(o(2)) constant in every mode. A complete set of ventilatory, haemodynamic, and gas exchange parameters was obtained under VC after 40 min of pneumoperitoneum and 20 min after switching for PC. Transoesophageal echocardiography was performed in order to evaluate systolic and diastolic function of the heart. RESULTS: When VC was switched to PC, peak airway pressure decreased [mean (sd) 32 (6) vs 27 (6) cm H(2)O; P < 0.0001], peak inspiratory flow increased [17 (3) vs 48 (8) litre min(-1); P < 0.0001), and dynamic compliance improved [+15 (8)%]. No difference was noted for static airway pressure, static compliance, and arterial oxygenation. No significant change could be demonstrated in the systolic [left ventricular end-systolic wall stress 66 (16) vs 63 (14) x 10(3) dyn cm(-2) m(-2)] or diastolic function [early diastolic velocity 10.3 (2.5) vs 10.5 (2.7) cm s(-1)]. CONCLUSIONS: In this study, no short-term beneficial effect of PC ventilation could be demonstrated over conventional VC ventilation in patients with pneumoperitoneum

Combined approaches for drug design points the way to novel proline racemase inhibitor candidates to fight Chagas' disease.

International audienceChagas' disease is caused by Trypanosoma cruzi, a protozoan transmitted to humans by blood-feeding insects, blood transfusion or congenitally. Previous research led us to discover a parasite proline racemase (TcPRAC) and to establish its validity as a target for the design of new chemotherapies against the disease, including its chronic form. A known inhibitor of proline racemases, 2-pyrrolecarboxylic acid (PYC), is water-insoluble. We synthesized soluble pyrazole derivatives, but they proved weak or inactive TcPRAC inhibitors. TcPRAC catalytic site is too small and constrained when bound to PYC to allow efficient search for new inhibitors by virtual screening. Forty-nine intermediate conformations between the opened enzyme structure and the closed liganded one were built by calculating a transition path with a method we developed. A wider range of chemical compounds could dock in the partially opened intermediate active site models in silico. Four models were selected for known substrates and weak inhibitors could dock in them and were used to screen chemical libraries. Two identified soluble compounds, (E)-4-oxopent-2-enoic acid (OxoPA) and its derivative (E)-5-bromo-4-oxopent-2-enoic acid (Br-OxoPA), are irreversible competitive inhibitors that presented stronger activity than PYC on TcPRAC. We show here that increasing doses of OxoPA and Br-OxoPA hamper T. cruzi intracellular differentiation and fate in mammalian host cells. Our data confirm that through to their binding mode, these molecules are interesting and promising as lead compounds for the development of chemotherapies against diseases where active proline racemases play essential roles