Study protocol of DIVERGE, the first genetic epidemiological study of major depressive disorder in Pakistan

INTRODUCTION: Globally, 80% of the burdenof major depressive disorder (MDD) pertains to low- and middle-income countries. Research into genetic and environmental risk factors has the potential to uncover disease mechanisms that may contribute to better diagnosis and treatment of mental illness, yet has so far been largely limited to participants with European ancestry from high-income countries. The DIVERGE study was established to help overcome this gap and investigate genetic and environmental risk factors for MDD in Pakistan. METHODS: DIVERGE aims to enrol 9000 cases and 4000 controls in hospitals across the country. Here, we provide the rationale for DIVERGE, describe the study protocol and characterise the sample using data from the first 500cases. Exploratory data analysis is performed to describe demographics, socioeconomic status, environmental risk factors, family history of mental illness and psychopathology. RESULTS AND DISCUSSION: Many participants had severe depression with 74% of patients who experienced multiple depressive episodes. It was a common practice to seek help for mental health struggles from faith healers and religious leaders. Socioeconomic variables reflected the local context with a large proportion of women not having access to any education and the majority of participants reporting no savings. CONCLUSION: DIVERGE is a carefully designed case-control study of MDD in Pakistan that captures diverse risk factors. As the largest genetic study in Pakistan, DIVERGE helps address the severe underrepresentation of people from South Asian countries in genetic as well as psychiatric research

Study protocol of DIVERGE, the first genetic epidemiological study of major depressive disorder in Pakistan.

INTRODUCTION: Globally, 80% of the burdenof major depressive disorder (MDD) pertains to low- and middle-income countries. Research into genetic and environmental risk factors has the potential to uncover disease mechanisms that may contribute to better diagnosis and treatment of mental illness, yet has so far been largely limited to participants with European ancestry from high-income countries. The DIVERGE study was established to help overcome this gap and investigate genetic and environmental risk factors for MDD in Pakistan. METHODS: DIVERGE aims to enrol 9000 cases and 4000 controls in hospitals across the country. Here, we provide the rationale for DIVERGE, describe the study protocol and characterise the sample using data from the first 500 cases. Exploratory data analysis is performed to describe demographics, socioeconomic status, environmental risk factors, family history of mental illness and psychopathology. RESULTS AND DISCUSSION: Many participants had severe depression with 74% of patients who experienced multiple depressive episodes. It was a common practice to seek help for mental health struggles from faith healers and religious leaders. Socioeconomic variables reflected the local context with a large proportion of women not having access to any education and the majority of participants reporting no savings. CONCLUSION: DIVERGE is a carefully designed case-control study of MDD in Pakistan that captures diverse risk factors. As the largest genetic study in Pakistan, DIVERGE helps address the severe underrepresentation of people from South Asian countries in genetic as well as psychiatric research

Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial

Background: Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding. Methods: We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124. Findings: Between July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98). Interpretation: We found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial

Psyllium-Husk-Assisted Synthesis of ZnO Microstructures with Improved Photocatalytic Properties for the Degradation of Methylene Blue (MB)

Wastewater from the textile industry is chronic and hazardous for the human body due to the presence of a variety of organic dyes; therefore, its complete treatment requires efficient, simple, and low cost technology. For this purpose, we grew ZnO microstructures in the presence of psyllium husk, and the role of psyllium husk was to modify the surface of the ZnO microstructures, create defects in the semiconducting crystal structures, and to alter the morphology of the nanostructured material. The growth process involved a hydrothermal method followed by calcination in air. Additionally, the psyllium husk, after thermal combustion, added a certain value of carbon into the ZnO nanomaterial, consequently enhancing the photocatalytic activity towards the degradation of methylene blue. We also investigated the effect of varying doses of photocatalyst on the photocatalytic properties towards the photodegradation of methylene blue in aqueous solution under the illumination of ultraviolet light. The structure and morphology of the prepared ZnO microstructures were explored by scanning electron microscopy (SEM) and powder X-ray diffraction (XRD) techniques. The degradation of methylene blue was monitored under the irradiation of ultraviolet light and in the dark. Also, the degradation of methylene blue was measured with and without photocatalyst. The photodegradation of methylene blue is highly increased using the ZnO sample prepared with psyllium husk. The photodegradation efficiency is found to be approximately 99.35% for this sample. The outperforming functionality of psyllium-husk-assisted ZnO sample is attributed to large surface area of carbon material from the psyllium husk and the synergetic effect between the incorporated carbon and ZnO itself. Based on the performance of the hybrid material, it is safe to say that psyllium husk has high potential for use where surface roughness, morphology alteration, and defects in the crystal structure are vital for the enhancing the functionality of a nanostructured material. The observed performance of ZnO in the presence of psyllium husk provides evidence for the fabrication of a low cost and efficient photocatalyst for the wastewater treatment problems

Mn3O4@ZnO Hybrid Material: An Excellent Photocatalyst for the Degradation of Synthetic Dyes including Methylene Blue, Methyl Orange and Malachite Green

In this study, we synthesized hybrid systems based on manganese oxide@zinc oxide (Mn3O4@ZnO), using sol gel and hydrothermal methods. The hybrid materials exhibited hierarchical morphologies and structures characterized by the hexagonal phase of ZnO and the tetragonal phase of Mn3O4. The hybrid materials were tested for degradation of methylene blue (MB), methyl orange (MO), and malachite green (MG) under ultraviolet (UV) light illumination. The aim of this work was to observe the effect of various amounts of Mn3O4 in enhancing the photocatalytic properties of ZnO-based hybrid structures towards the degradation of MB, MO and MG. The ZnO photocatalyst showed better performance with an increasing amount of Mn3O4, and the degradation efficiency for the hybrid material containing the maximum amount of Mn3O4 was found to be 94.59%, 89.99%, and 97.40% for MB, MO and MG, respectively. The improvement in the performance of hybrid materials can be attributed to the high charge separation rate of electron-hole pairs, the co-catalytic role, the large number of catalytic sites, and the synergy for the production of high quantities of oxidizing radicals. The performance obtained from the various Mn3O4@ZnO hybrid materials suggest that Mn3O4 can be considered an effective co-catalyst for a wide range of photocatalytic materials such as titanium dioxide, tin oxide, and carbon-based materials, in developing practical hybrid photocatalysts for the degradation of dyes and for wastewater treatment

Annotation of Potential Vaccine Targets and Design of a Multi-Epitope Subunit Vaccine against <i>Yersinia pestis</i> through Reverse Vaccinology and Validation through an Agent-Based Modeling Approach

Yersinia pestis is responsible for plague and major pandemics in Asia and Europe. This bacterium has shown resistance to an array of drugs commonly used for the treatment of plague. Therefore, effective therapeutics measurements, such as designing a vaccine that can effectively and safely prevent Y. pestis infection, are of high interest. To fast-track vaccine development against Yersinia pestis, herein, proteome-wide vaccine target annotation was performed, and structural vaccinology-assisted epitopes were predicted. Among the total 3909 proteins, only 5 (rstB, YPO2385, hmuR, flaA1a, and psaB) were shortlisted as essential vaccine targets. These targets were then subjected to multi-epitope vaccine design using different linkers. EAAK, AAY, and GPGPG as linkers were used to link CTL, HTL, and B-cell epitopes, and an adjuvant (beta defensin) was also added at the N-terminal of the MEVC. Physiochemical characterization, such as determination of the instability index, theoretical pI, half-life, aliphatic index, stability profiling, antigenicity, allergenicity, and hydropathy of the ensemble, showed that the vaccine is highly stable, antigenic, and non-allergenic and produces multiple interactions with immune receptors upon docking. In addition, molecular dynamics simulation confirmed the stable binding and good dynamic properties of the vaccine–TLR complex. Furthermore, in silico and immune simulation of the developed MEVC for Y. pestis showed that the vaccine triggered strong immune response after several doses at different intervals. Neutralization of the antigen was observed at the third day of injection. Conclusively, the vaccine designed here for Y. pestis produces an immune response; however, further immunological testing is needed to unveil its real efficacy

Design of γ-Alumina-Supported Phosphotungstic Acid-Palladium Bifunctional Catalyst for Catalytic Liquid-Phase Citral Hydrogenation

This study primarily addresses the development of dynamic, selective and economical metal–acid (bifunctional) catalysts for one-pot menthol production by citral hydrogenation. Specifically, various metals such as Pd, Pt, Ni, Cs and Sn were doped over alumina support. Additionally, bifunctional composite catalysts were also prepared with the impregnation of heteropoly acids and Pd precursors over alumina support. Analytical techniques (e.g., BET, PXRD, FT-IR, pyridine adsorption and amine titration methods) were applied for characterization of the most efficient and selective catalysts (e.g., Al2O3 and PTA-Cat-I). Similarly, most of the essential operational variables (e.g., loading rate of metal precursor, type of heteropoly acid, temperature, gas pressure and reaction time) were examined during this study. The experimental data shows that the bifunctional catalyst (PTA-Cat-I) produced 45% menthol at full citral substrate conversion (r = 0.038 mmoles.min−1) in liquid-phase citral hydrogenation (at optimized operating conditions: 70 °C, 0.5 MPa and 8 h). However, the heteropoly acid-supported bifunctional catalysts (e.g., PTA-Cat-I, PMA-Cat-I, SMA-Cat-I and STA-Cat-I) resulted in cracking and the dehydration of isopulegol/menthol by the generation of side products (e.g., 4-isopropyl-1-methyl, cyclohex-1-ane/ene); therefore, menthol yield was extensively diminished. On the other hand, non-acidic catalysts (e.g., Cat-I, Cat-II, Cat-III, Cat-IV and Cat-V) readily promoted hydrogenation reactions. The optimum menthol yield occurred due to the presence of strong Lewis and weak Bronsted acid sites. Mass transfer and reaction rate were substantially diminished due to acidity strength, heteropoly acid type and blockage of pores by the applied bifunctional catalysts