Cellular Microenvironment Stiffness Regulates Eicosanoid Production and Signaling Pathways.

Pathological changes in the biomechanical environment are implicated in the progression of idiopathic pulmonary fibrosis (IPF). Stiffened matrix augments fibroblast proliferation and differentiation and activates TGF-ß1 (transforming growth factor-ß1). Stiffened matrix impairs the synthesis of the antifibrogenic lipid mediator prostaglandin E2 (PGE2) and reduces the expression of the rate-limiting prostanoid biosynthetic enzyme cyclooxygenase-2 (COX-2). We now show that prostaglandin E synthase (PTGES), the final enzyme in the PGE2 biosynthetic pathway, is expressed at lower levels in the lungs of patients with IPF. We also show substantial induction of COX-2, PTGES, prostaglandin E receptor 4 (EP4), and cytosolic phospholipase A2 (cPLA2) expression in human lung fibroblasts cultured in soft collagen hydrogels or in spheroids compared with conventional culture on stiff plastic culture plates. Induction of COX-2, cPLA2, and PTGES expression in spheroid cultures was moderately inhibited by the p38 mitogen-activated protein kinase inhibitor SB203580. The induction of prostanoid biosynthetic enzyme expression was accompanied by an increase in PGE2 levels only in non-IPF-derived fibroblast spheroids. Our study reveals an extensive dysregulation of prostanoid biosynthesis and signaling pathways in IPF-derived fibroblasts, which are only partially abrogated by culture in soft microenvironments.

Annexin A2 contributes to lung injury and fibrosis by augmenting factor Xa fibrogenic activity.

In lung injury and disease, including idiopathic pulmonary fibrosis (IPF), extravascular factor X is converted into factor Xa (FXa), a coagulant protease with fibrogenic actions. Extracellular annexin A2 binds to FXa, augmenting activation of the protease-activated receptor-1 (PAR-1). In this study, the contribution of annexin A2 in lung injury and fibrosis was investigated. Annexin A2 immunoreactivity was observed in regions of fibrosis, including those associated with fibroblasts in lung tissue of IPF patients. Furthermore, annexin A2 was detected in the conditioned media and an EGTA membrane wash of human lung fibroblast (LF) cultures. Incubation with human plasma (5% vol/vol) or purified FXa (15-50 nM) evoked fibrogenic responses in LF cultures, with FXa increasing interleukin-6 (IL-6) production and cell number by 270 and 46%, respectively (P < 0.05, n = 5-8). The fibrogenic actions of plasma or FXa were attenuated by the selective FXa inhibitor apixaban (10 µM, or antibodies raised against annexin A2 or PAR-1 (2 µg/ml). FXa-stimulated LFs from IPF patients (n = 6) produced twice as much IL-6 as controls (n = 10) (P < 0.05), corresponding with increased levels of extracellular annexin A2. Annexin A2 gene deletion in mice reduced bleomycin-induced increases in bronchoalveolar lavage fluid (BALF) IL-6 levels and cell number (*P < 0.05; n = 4-12). Lung fibrogenic gene expression and dry weight were reduced by annexin A2 gene deletion, but lung levels of collagen were not. Our data suggest that annexin A2 contributes to lung injury and fibrotic disease by mediating the fibrogenic actions of FXa. Extracellular annexin A2 is a potential target for the treatment of IPF.

The Coagulant Factor Xa Induces Protease-Activated Receptor-1 and Annexin A2-Dependent Airway Smooth Muscle Cytokine Production and Cell Proliferation.

During asthma exacerbation, plasma circulating coagulant factor X (FX) enters the inflamed airways and is activated (FXa). FXa may have an important role in asthma, being involved in thrombin activation and an agonist of protease-activated receptor-1 (PAR-1). Extracellular annexin A2 and integrins are also implicated in PAR-1 signaling. In this study, the potential role of PAR-1 in mediating the effects of FXa on human airway smooth muscle (ASM) cell cytokine production and proliferation was investigated. FXa (5-50 nM), but not FX, stimulated increases in ASM IL-6 production and cell number after 24- and 48-hour incubation, respectively (P < 0.05; n = 5). FXa (15 nM) also stimulated increases in the levels of mRNA for cytokines (IL-6), cell cycle-related protein (cyclin D1), and proremodeling proteins (FGF-2, PDGF-B, CTGF, SM22, and PAI-1) after 3-hour incubation (P < 0.05; n = 4). The actions of FXa were insensitive to inhibition by hirudin (1 U/ml), a selective thrombin inhibitor, but were attenuated by SCH79797 (100 nM), a PAR-1 antagonist, or Cpd 22 (1 µM), an inhibitor of integrin-linked kinase. The selective targeting of PAR-1, annexin A2, or ß1-integrin by small interfering RNA and/or by functional blocking antibodies also attenuated FXa-evoked responses. In contrast, the targeting of annexin A2 did not inhibit thrombin-stimulated ASM function. In airway biopsies of patients with asthma, FXa and annexin A2 were detected in the ASM bundle by immunohistochemistry. These findings establish FXa as a potentially important asthma mediator, stimulating ASM function through actions requiring PAR-1 and annexin A2 and involving integrin coactivation.

Should magnesium sulfate be administered to women with mild pre-eclampsia? A systematic review of published reports on eclampsia.

AIM: Magnesium sulfate is an evidence-based anticonvulsant drug used to prevent and control eclampsia. Controversy persists on routine administration of magnesium sulfate in cases of pre-eclampsia without severe features. Our objective was to assess the pattern of blood pressure and maternal symptoms preceding eclamptic seizure based on the current published work. MATERIAL AND METHODS: A comprehensive computer-based publication search was conducted in the African Journals Online, Google scholar, HINARI, PubMed, and MEDLINE databases and the Cochrane library to identify descriptive study reports for blood pressure, severity symptoms or stage of pregnancy during convulsion in women with eclampsia. RESULTS: A total of 59 publications were eligible for this review. Overall, 21,149 eclamptic women from 26 countries were included for the interest of one or more of the selected variables. Out of 18,488 eclamptic women, the proportion of antepartum, intrapartum and post-partum eclampsia was 59%, 20% and 21%, respectively. Out of 3443 eclamptic women, 25% were normotensive; 20% had mild-to-moderate hypertension; 32% had severe hypertension; and 21% were hypertensive but unclassified. Out of 2163 eclamptic women, 66% and 27% had a headache and visual disturbance, respectively, preceding the occurrence of convulsion. Out of 2053 eclamptic women, 25% had epigastric area pain, and out of 1092 women with eclampsia, 25% were asymptomatic. CONCLUSION: Although eclampsia is known to result from severe pre-eclampsia with or without organ function derangement, this review has revealed that a significant number of eclamptic women had either normal blood pressure or mild-to-moderate hypertension immediately before seizure. The findings are apparently in support of initiating magnesium sulfate prophylaxis to all women with mild pre-eclampsia.

Vortioxetine in the treatment of adult patients with major depressive disorder: a meta-analysis of randomized double-blind controlled trials.

BACKGROUND: Vortioxetine is a novel multimodal compound that has recently been approved by the FDA for the treatment of major depressive disorder (MDD). It is a selective serotonin (5-HT) 3A and 5-HT7 receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and inhibitor of serotonin transporters. The objective of this meta-analysis was to evaluate the efficacy and safety of vortioxetine in adults with MDD. METHODS: A literature search was conducted in the databases of PubMed, EMBASE, Cochrane library and HINARI. The meta-analysis was conducted by including randomized controlled trials that assessed the efficacy and safety of vortioxetine in adult patients with MDD. Using the random effects model, which assumes individual studies are estimating different treatment effects, the efficacy and safety of vortioxetine was determined by weighted mean differences (WMDs) and odds ratios (ORs). The findings were considered as statistically significant when the 95% CI of WMDs and ORs did not include 0 and 1, respectively. Heterogeneity testing, meta-regression and sensitivity analysis were also performed. RESULTS: During the initial literature search about 151 publications were identified. Based on the predetermined inclusion criteria, 7 randomized controlled trials were included. The pooled analysis demonstrated a statistically significant reduction in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline among patients who were on vortioxetine (WMD = -3.92; 95% CI, -5.258 to -2.581). Furthermore, a statistically significant number of patients with MDD who were on vortioxetine have achieved a greater than or equal to 50% reduction in depression symptoms from baseline. However, a significant number of patients who were on vortioxetine therapy reported more adverse events than patients who were on placebo (overall OR = 1.21; 95% CI, 1.06 to 1.38). CONCLUSIONS: Therapy with vortioxetine was significantly associated with reduction in depression symptoms from baseline compared to placebo. Nevertheless, a significant number of patients who were on vortioxetine therapy have reported more adverse events.

Cheating on examinations and its predictors among undergraduate students at Hawassa University College of Medicine and Health Science, Hawassa, Ethiopia.

BACKGROUND: Cheating on examinations in academic institutions is a worldwide issue. When cheating occurs in medical schools, it has serious consequences for human life, social values, and the economy. This study was conducted to determine the prevalence of cheating and identify factors that influence cheating among students of Hawassa University College of medicine and health science. METHODS: A cross sectional study was conducted from May through June 2013. A pre-tested self-administered, structured questionnaire was used to collect self-reported data regarding cheating. Data were entered and analyzed using SPSS version 20. Descriptive statistics were used for data summarization and presentation. Degree of association was measured by Chi Square test, with significance level set at p = 0.05. Bivariate and multivariate logistic regression analyses were used to assess associations. RESULTS: The prevalence of self-reported cheating was found to be 19.8% (95% CI = 17.4-21.9). About 12.1% (95% CI = 10.2-13.9) of students disclosed cheating on the entrance examination. The majority of students (80.1% (95% CI = 77.9-82.3) disclosed that they would not report cheating to invigilators even if they had witnessed cheating. Analysis by multiple regression models showed that students who cheated in high school were more likely to cheat (adjusted OR = 1. 80, 95% CI = 1. 01-3.19) and that cheating was less likely among students who didn't cheat on entrance examinations (adjusted OR = 0. 25, 95% CI = 0. 14-0.45). Dining outside the university cafeteria and receiving pocket money of Birr 300 or more were strongly associated with cheating (adjusted OR = 3.08, 95% CI = 1.54-6.16 and adjusted OR = 1.69 (95% CI = 1.05-2.72), respectively. The odds of cheating among students were significantly higher for those who went to private high school, were substance users, and didn't attend lectures than for those who attended government schools, were not substance abusers, and attended lectures. CONCLUSION: Our findings have important implications for development of an institution's policies on academic integrity. By extension, they affect the policies of high schools. Increased levels of supervision during entrance examination, mandated attendance at lectures, and reduction of substance use are likely to reduce cheating. No significant association was found with background, level of parental education, grade point average, and interest in field of study.

Absenteeism among medical and health science undergraduate students at Hawassa University, Ethiopia.

BACKGROUND: Student absenteeism is a major concern for university education worldwide. This study was conducted to determine the prevalence and causes of absenteeism among undergraduate medical and health sciences students at Hawassa University. METHODS: We conducted a cross-sectional study using a pretested self-administered structured questionnaire from May-June 2013. The primary outcome indicator was self-reported absenteeism from lectures in the semester preceding the study period. The study included all regular undergraduate students who were enrolled in the University for at least one semester. The data was entered and analyzed using SPSS version 20. The association between class absenteeism and socio-demographic and behavioral correlates of absenteeism was determined by bivariate and multivariate analyses. Results were reported as crude odds ratios (COR), adjusted odds ratios (AOR) and 95% confidence intervals (CI). RESULTS: 1200 students consented and filled the questionnaire. Of these students, 43.7% had missed three or more lectures and 14.1% (95% CI = 12.2-16.2) missed more than 8 lectures in the preceding semester. There was a significant association between missing more than 8 lectures and age of students, chosen discipline (medicine), and social drug use. The main reasons reported for missing lectures were preparing for another examination, lack of interest, lecturer's teaching style, and availability of lecture material. CONCLUSION: At Hawassa University College of Medicine and Health Science student habits and teacher performance play a role in absenteeism from lectures. A university culture that promotes discipline and integrity especially among medical and older students discourages social drug use will likely improve motivation and attendance. Training in teaching methodologies to improve the quality and delivery of lectures should also help increase attendance.

TM7SF3 controls TEAD1 splicing to prevent MASH-induced liver fibrosis.

The mechanisms of hepatic stellate cell (HSC) activation and the development of liver fibrosis are not fully understood. Here, we show that deletion of a nuclear seven transmembrane protein, TM7SF3, accelerates HSC activation in liver organoids, primary human HSCs, and in vivo in metabolic-dysfunction-associated steatohepatitis (MASH) mice, leading to activation of the fibrogenic program and HSC proliferation. Thus, TM7SF3 knockdown promotes alternative splicing of the Hippo pathway transcription factor, TEAD1, by inhibiting the splicing factor heterogeneous nuclear ribonucleoprotein U (hnRNPU). This results in the exclusion of the inhibitory exon 5, generating a more active form of TEAD1 and triggering HSC activation. Furthermore, inhibiting TEAD1 alternative splicing with a specific antisense oligomer (ASO) deactivates HSCs in vitro and reduces MASH diet-induced liver fibrosis. In conclusion, by inhibiting TEAD1 alternative splicing, TM7SF3 plays a pivotal role in mitigating HSC activation and the progression of MASH-related fibrosis.

Meta-analysis on risky sexual behaviour of men: consistent findings from different parts of the world.

The aim of this analysis was to determine the consistency of higher-risk sex practice among educated and/or wealthy men in different parts of the world. Meta-analysis was done on risky sexual behaviour of men using the recent Demographic and Health Surveys (DHS 2003-2009) data from 26 countries in and outside Africa. DHS data were accessed through electronic databases. In this analysis, since there was significant heterogeneity (I(2)>50%) among surveys findings, random effects analytic model was applied. Mantel-Haenszel statistical method was used to calculate the pooled odds ratios across countries. Out of 79,736 men aged 15-49 years who had sexual intercourse in 12 months preceding the respective survey, 35.7% reported to have higher-risk sex. The proportion of higher-risk sex was found positively correlated with increased wealth index. In 24 countries, higher-risk sex was found to have highly statistically significant association with men living in urban areas, educated to secondary and above, and owned middle to highest wealth index. The overall condom use during the last higher-risk sexual encounter was 47% but condom use was better practiced by educated men. Nearly in two-thirds of countries reported HIV-prevalence, the proportion of HIV infection was highest among better educated. In conclusion, this meta-analysis has shown that risk taking sexual behaviour is invariably associated with high educational attainment, urban residence and better wealth index regardless of geographic location of men participated in the surveys.

Efficacy of alogliptin in type 2 diabetes treatment: a meta-analysis of randomized double-blind controlled studies.

BACKGROUND: Alogliptin is a new dipeptidyl peptidase (DPP-4) inhibitor, which is under investigation for treatment of type 2 diabetes either alone or in combination with other antidiabetic drugs. The aim of this meta-analysis was to assess the efficacy and tolerability of alogliptin in patients with type 2 diabetes. METHODS: Computer based search was performed in MEDLINE, Cochrane library, and HINARI (Health InterNetwork Access to Research Initiative) databases. Meta-analysis was carried out by incorporating double-blind randomized controlled studies done on the efficacy of alogliptin in patients with type 2 diabetes. The efficacy and tolerability of alogliptin was determined by standardized mean differences (SMDs) and Mantel-Haenszel odds ratio. Heterogeneity was assessed by the chi-squared test (Cochran Q test) and I2 statistics. RESULTS: The pooled SMDs demonstrated a significant reduction in HbA1c in patients treated with alogliptin 12.5 mg (SMD = -0.81; 95% CI, -1.11 to -0.51) or alogliptin 25 mg (SMD= -0.98; 95%CI= -1.30 to -0.66) as compared with controls. The SMD for reduction in fasting plasma glucose level (FPG) from baseline was also statistically significant among alogliptin treated patients. However, the effect of alogliptin on body weight change was inconclusive. The proportion of patients who discontinued alogliptin due to adverse events was not different from controls. Similarly, the meta-analyses of specific adverse events did not demonstrate statistically significant differences. CONCLUSIONS: Alogliptin alone or in combination with other antidiabetic drug has shown a significant reduction in HbA1c and FPG level in patients with type 2 diabetes. However, its consistent efficacy for longer duration of therapy needs further investigation.

Sodium glucose co-transport 2 inhibitors in the treatment of type 2 diabetes mellitus: a meta-analysis of randomized double-blind controlled trials.

BACKGROUND: The discovery of sodium-glucose co-transporter 2 (SGLT2) inhibitors, with a novel mechanism independent of insulin secretion or sensitization, bring about a new therapeutic approach to the management of type 2 diabetes mellitus. The aim of this meta-analysis was to evaluate the safety and efficacy of SGLT2 inhibitors at different doses in randomized double blind clinical trials. METHODS: This meta-analysis was conducted by including randomized double-blind controlled trials of SGLT2 inhibitors in patients with type 2 diabetes irrespective of their antidiabetic drug exposure history but with an inadequate glycemic control. All the effect sizes were computed using the random effects model. Standardized mean differences (SMDs) and odds ratios (OR) were computed for continuous and dichotomous variables, respectively. Additional analyses like sensitivity analysis, subgroup analysis and meta-regression were also performed. RESULTS: The pooled analyses demonstrated a significant reduction in mean changes in Hemoglobin A1c (HbA1c) (SMD = -0.78%, 95% CI, -0.87 to -0.69), fasting plasma glucose (FPG) (SMD = -0.70 mg/dl, 95% CI, -0.79 to -0.61), body weight (overall SMD = -0.59 kg, 95% CI, -0.65 to -0.52) and blood pressure from baseline with SGLT2 inhibitors based therapy. Consistently a significant number of patients treated with SGLT2 inhibitors achieved HbA1c < 7% (OR = 2.09, 95% CI, 1.77 to 2.46). SGLT2 inhibitors based therapy was associated with adverse events like genital and urinary tract infections. CONCLUSION: All studied doses of SGLT2 inhibitors, either as monotherapy or in combination with other antidiabetic agents, consistently improved glycemic control in patients with type 2 diabetes. However, a small percentage of patients suffer from genital and urinary tract infections.

Meta-analyses of fertility desires of people living with HIV.

BACKGROUND: Literature review has shown that some years back the fertility desires of people living with HIV was low but in the recent years, it was reported as increasing. However, little is known about the strength of association of fertility desire of HIV positive people with antiretroviral therapy (ART) experience, age, sex, education level, and number of children. METHODS: In these meta-analyses, twenty studies from different parts of the world were included. The odds ratios of fertility desires were determined using the random-effects model. Heterogeneity among the studies was assessed by computing values for Tau(2), Chi-square (Q), I(2) and P-value. Sensitivity analysis and funnel plot were done to assess the stability of pooled values to outliers and publication bias, respectively. RESULTS: The pooled analysis demonstrated that fertility desires of study participants had no association with ART. Similarly, the overall odds ratio did not show statistically significant association of fertility desires with sex and educational attainment of study participants although forest plots of some studies fall on increased and some others on decreased sides of fertility desires. The two variables that demonstrated a strong association with fertility desires were age less than 30 years and being childless. The lowest heterogeneity was found in a meta-analysis comparing ART experienced and ART naïve HIV positive people. In all meta-analyses, the sensitivity analyses showed the stability of the pooled odds ratios; and the funnel plots did not show publication or disclosure bias. CONCLUSION: Although the fertility desires among childless and younger age group was very strong, we realized that quite a significant segment of HIV-infected people have desire for fertility. Therefore, including fertility issue as integral part of HIV patient care may help several of them in their reproductive decision making (letting them know the risks and methods of prevention while anticipating pregnancy).

Efficacy, safety and tolerability of tofacitinib in patients with an inadequate response to disease modifying anti-rheumatic drugs: a meta-analysis of randomized double-blind controlled studies.

BACKGROUND: This meta-analysis was conducted to determine the efficacy, safety and tolerability of tofacitinib in the treatment of rheumatoid arthritis in patients with an inadequate response or intolerance to at least one of the nonbiologic or biologic disease-modifying antirheumatic drugs (DMARDs). METHODS: Electronic based literature search was conducted in the databases of HINARI (Health InterNetwork Access to Research Initiative), MEDLINE and Cochrane library. The studies included in the meta-analysis were double-blind randomized clinical trials that were conducted in treatment-refractory or intolerant patients with rheumatoid arthritis. The odds ratios (OR), standardized mean differences (SMD) and the 95% confidence intervals (95% CI) were determined by using the random effects model. Heterogeneity among the included studies was evaluated by I² statistics. RESULTS: The odds of tofacitinib treated patients who met the criteria for an at least a 20% improvement in the American College of Rheumatology scale (ACR 20) was more than 4 times higher than placebo treated patients (overall OR = 4.15; 95% CI, 3.23 to 5.32). Even though the discontinuation rate due to adverse events was not different from placebo groups, tofacitinib was associated with infections (overall SMD = 1.96, 95% CI = 1.428 to 2.676), reduction in neutrophil counts (overall SMD = -0.34, 95% CI = -0.450 to -0.223) and elevated levels of LDL cholesterol and liver enzymes. CONCLUSIONS: Tofacitinib was effective in the treatment of active rheumatoid arthritis in patients with an inadequate response or intolerance to at least one DMARDs. However, treatment with tofacitinib was associated with infections and laboratory abnormalities.

Is the Sexual Behaviour of HIV Patients on Antiretroviral therapy safe or risky in Sub-Saharan Africa? Meta-Analysis and Meta-Regression.

BACKGROUND: Reports on the sexual behavior of people on antiretroviral therapy (ART) are inconsistent. We selected 14 articles that compared the sexual behavior of people with and without ART for this analysis. METHODS: We included both cross-sectional studies that compared different ART-naïve and ART-experienced participants and longitudinal studies examining the behavior of the same individuals pre- and post-ART start. Meta-analyses were performed both stratified by type of study and combined. Outcome variables assessed for association with ART experience were any sexual activity, unprotected sex and having multiple sexual partners. Random-effect models were applied to determine the overall odds ratios. Sub-group analyses and meta-regression analyses were performed to examine sources of heterogeneity among the studies. Sensitivity analysis was also conducted to evaluate the stability of the overall odds ratio in the presence of outliers. RESULTS: The meta-analysis failed to show a statistically significant association of any sexual activity with ART experience. It did, however, show an overall statistically significant reduction of any unprotected sex, having multiple sexual partners and unprotected sex with HIV negative or unknown HIV status with ART experience. Meta-regression showed no interaction between duration of ART use or recall period of sexual behavior with the sexual activity variables. However, there was an association between the percentage of married or cohabiting participants included in a study and reductions in the practice of unprotected sex with ART. CONCLUSION: In general, this meta-analysis demonstrated a significant reduction in risky sexual behavior among people on ART in sub-Saharan Africa. Future studies should investigate the reproducibility and continuity of the observed positive behavioural changes as the duration of ART lasts a decade or more.

Casein Kinase 1δ/ε Inhibitor, PF670462 Attenuates the Fibrogenic Effects of Transforming Growth Factor-ß in Pulmonary Fibrosis.

Transforming growth factor-beta (TGF-ß) is a major mediator of fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). However, therapeutic global inhibition of TGF-ß is limited by unwanted immunosuppression and mitral valve defects. We performed an extensive literature search to uncover a little-known connection between TGF-ß signaling and casein kinase (CK) activity. We have examined the abundance of CK1 delta and epsilon (CK1δ/ε) in lung tissue from IPF patients and non-diseased controls, and investigated whether inhibition of CK1δ/ε with PF670462 inhibits pulmonary fibrosis. CK1δ/ε levels in lung tissue from IPF patients and non-diseased controls were assessed by immunohistochemistry. Anti-fibrotic effects of the CK1δ/ε inhibitor PF670462 were assessed in pre-clinical models, including acute and chronic bleomycin mouse models and in vitro experiments on spheroids made from primary human lung fibroblast cells from IPF and control donors, and human A549 alveolar-like adenocarcinoma-derived epithelial cells. Increased expression of CK1δ and ε in IPF lungs compared to non-diseased controls was accompanied by increased levels of the product, phospho-period 2. In vitro, PF670462 prevented TGF-ß-induced epithelial-mesenchymal transition. The stiffness of IPF-derived spheroids was reduced by PF670462 and TGF-ß-induced fibrogenic gene expression was inhibited. The CK1δ/ε inhibitor PF670462 administered systemically or locally by inhalation prevented both acute and chronic bleomycin-induced pulmonary fibrosis in mice. PF670462 administered in a 'therapeutic' regimen (day 7 onward) prevented bleomycin-induced lung collagen accumulation. Elevated expression and activity of CK1 δ and ε in IPF and anti-fibrogenic effects of the dual CK1δ/ε inhibitor, PF670462, support CK1δ/ε as novel therapeutic targets for IPF.

Magnitude of Antiretroviral Drug Toxicity in Adult HIV Patients in Ethiopia: A cohort study at seven teaching hospitals.

BACKGROUND: The introduction of antiretroviral therapy (ART) has resulted in significant mortality reduction and improvement in the quality of life. However, this has come at a cost of increased drug toxicity. The objective of this study was to assess the patterns and predictors of ART toxicity in adult HIV patients in Ethiopia. METHODS: This is a prospective cohort study conducted at seven teaching hospitals between September 2009 and December 2013 involving 3921 HIV patients on ART. Adverse drug reactions (ADR) due to ART were identified based on clinical assessment and/or laboratory parameters. Multivariable random effects Poisson regression analysis was used to identify factors independently associated with toxicity. RESULT: ADR due to ART drugs was reported in 867 (22.1 %) of the participants; 374 (9.5%) had severe forms. About 87% of reported toxicities were limited to three organ systems - the skin, nervous system and blood. The overall incidence of ADR was 9 per 100 person years. About a third of toxicities occurred during the first six months after ART initiation with the incidence rate of 22.4 per 100 person years. Concomitant anti-tuberculosis treatment was the strongest independent predictor of toxicity. CONCLUSION: ADR was found to be highly prevalent in HIV patients on ART at tertiary hospitals in Ethiopia. Most of these conditions occurred early after ART initiation and in those with concomitant anti-tuberculosis treatment. Thus, routine monitoring of patients on ART should be strengthened with particular emphasis in the first 6 months. Strategies should also be devised to replace older and more toxic agents with newer and safer drugs available.

Is higher risk sex common among male or female youths?

There are several studies that showed the high prevalence of high-risk sexual behaviors among youths, but little is known how significant the proportion of higher risk sex is when the male and female youths are compared. A meta-analysis was done using 26 countries' Demographic and Health Survey data from and outside Africa to make comparisons of higher risk sex among the most vulnerable group of male and female youths. Random effects analytic model was applied and the pooled odds ratios were determined using Mantel-Haenszel statistical method. In this meta-analysis, 19,148 male and 65,094 female youths who reported to have sexual intercourse in a 12-month period were included. The overall OR demonstrated that higher risk sex was ten times more prevalent in male youths than in female youths. The practice of higher risk sex by male youths aged 15-19 years was more than 27-fold higher than that of their female counterparts. Similarly, male youths in urban areas, belonged to a family with middle to highest wealth index, and educated to secondary and above were more than ninefold, eightfold and sixfold at risk of practicing higher risk sex than their female counterparts, respectively. In conclusion, this meta-analysis demonstrated that the practice of risky sexual intercourse by male youths was incomparably higher than female youths. Future risky sex protective interventions should be tailored to secondary and above educated male youths in urban areas.

A Meta-Analysis of Risky Sexual Behaviour among Male Youth in Developing Countries.

The purpose of this meta-analysis was to assess the association between risky sexual behaviour and level of education and economic status in male youth. Previous tests of the association of risky sexual behaviour with levels of education and economic status have yielded inconsistent results. Using data from 26 countries, from both within and outside Africa, we performed a meta-analysis with a specific focus on male youths' risky sexual behaviour. We applied a random effects analytic model and calculated a pooled odds ratio. Out of 19,148 males aged 15-24 years who reported having sexual intercourse in the 12 months preceding the survey, 75% engaged in higher-risk sex. The proportion of higher-risk sex among male youth aged 15-19 years was nearly 90% in 21 of the 26 countries. The pooled odds ratio showed a statistically significant association of higher-risk sex with male youth younger than 20 years, living in urban centers, well educated, and of a high economic status. The overall proportion of condom use during youths' most recent higher-risk sexual encounter was 40% and 51% among 15-19-year-olds and 20-24-year-olds, respectively. Our findings suggest that male youth's socioeconomic status is directly related to the likelihood that they practice higher-risk sex. The relationship between income and sexual behaviour should be explored further.

Is desvenlafaxine effective and safe in the treatment of menopausal vasomotor symptoms? A meta-analysis and meta-regression of randomized double-blind controlled studies.

BACKGROUND: During perimenopause, vasomotor symptoms are known to have a detrimental effect on women's functional ability and quality of life. For symptomatic women not eligible for hormonal therapy, desvenlafaxine is an option, but its safety margin and tolerability are not yet determined. METHODS: A computer-based literature search was done in the databases of MEDLINE, Cochrane library, and HINARI (Health InterNetwork Access to Research Initiative). Meta-analysis was conducted by including double-blind randomized controlled studies on the effectiveness and safety of desvenlafaxine in the treatment of hot flashes. The effectiveness, safety and tolerability of desvenlafaxine were determined by standardized mean differences (SMDs) and Mantel-Haenszel odds ratio. Subgroup analysis based on doses of desvenlafaxine and linear meta-regression analyses were performed for several covariates. Heterogeneity testing, the risk of bias assessment and sensitivity analyses were done. RESULTS: Desvenlafaxine was associated with a statistically significant reduction in the number and severity of daily moderate to severe hot flashes. The number of nighttime awakenings because of hot flashes was also significantly decreased. However, the rate of desvenlafaxine treatment discontinuation because of adverse events was a significantly higher than placebo treated women and the risk ratios of adverse events like asthenia, hypertension, anorexia, constipation, diarrhea, dry mouth, nausea, dizziness, insomnia, somnolence and mydriasis were very high. CONCLUSION: Desvenlafaxine is effective in the treatment of hot flashes but it is strongly associated with several adverse events and treatment discontinuation. Further clinical trials focusing only on desvenlafaxine related adverse events are highly warranted before it is approved for public use.

Review of maternal mortality in Ethiopia: a story of the past 30 years.

BACKGROUND: Ethiopia is one of the six countries which have contributed to more than 50% of all maternal deaths across the world. This country has adopted the millennium development goals (MDGs) including reducing the maternal mortality by three-quarter, and put improvement in maternal health as one of the health sector development program (HSDP) performance indicators. The purpose of this study was to review the maternal mortality ratio (MMR) in Ethiopia in the past 30 years using available literature. METHODS: A computer based literature search in the databases of MEDLINE, PubMed, HINARI, EBASE, MEASURE DHS, The Cochrane Library, Google Search and Google Scholar was carried out. Manual search for local articles that are not available electronically in full document were also conducted. Eighteen data sources (3 nationally representative surveys, 2 secondary data analyses, 5 small scale community based studies, and 8 hospital based studies) were included in the review. The results of this review are presented in the form of line and stock graphs. RESULTS: The national maternal mortality trend estimated by the central statistics agency of Ethiopia, The Institute for Health Metrics and Evaluation, WHO and other UN agencies showed inconsistent results. Similarly, although there were marked variations in the 95% confidence intervals among individual studies, the small scale community based and hospital based studies have shown that there has been no significant change in maternal mortality over the last three decades. A 22-year cohort analysis from Atat Hospital is the only evidence that demonstrated a very significant drop in maternal mortality among mothers who were kept in the maternity waiting area before the onset of labor. CONCLUSION: Although the MDG and HSDP envisaged significant improvement in maternal health by this time, this review has shown that the performances are still far from the target. The multisectoral huge investment by the Ethiopian Government is a big hope to reduce the maternal mortality by three-quarters in the near future beyond 2015.