Synthesis and antimalarial activity of sulfonamide-attached coumarin-[1,2,3]-triazoles

Drug resistance in malaria parasites is one of the major stumbling blocks hindering the goal of malaria elimination. One of the major strategies to counter drug resistance is the development of new potent antimalarial drugs. In the present study, a series of novel sulfonamide based coumarin-[1,2,3]-triazole conjugates have been synthesized via Huisgen reaction between azidosulfonamides and 4-hydroxy- or 7-hydroxymethylcoumarinoalkynes. All the compounds have been characterized spectroscopically and screened for their in vitro antimalarial activity against P. falciparum 3D7 strain. Out of the twenty five synthesized compounds, four compounds displayed significant activity (IC50 <10 µM) with the most active compound having an IC50 of 3.64 µM.

Synthesis and antimalarial activity of sulfonamide-attached coumarin-[1,2,3]-triazoles

1545-1555Drug resistance in malaria parasites is one of the major stumbling blocks hindering the goal of malaria elimination. One of the major strategies to counter drug resistance is the development of new potent antimalarial drugs. In the present study, a series of novel sulfonamide based coumarin-[1,2,3]-triazole conjugates have been synthesized via Huisgen reaction between azidosulfonamides and 4-hydroxy- or 7-hydroxymethylcoumarinoalkynes. All the compounds have been characterized spectroscopically and screened for their in vitro antimalarial activity against P. falciparum 3D7 strain. Out of the twenty five synthesized compounds, four compounds displayed significant activity (IC50 50 of 3.64 µM

Global burden and strength of evidence for 88 risk factors in 204 countries and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background: Understanding the health consequences associated with exposure to risk factors is necessary to inform public health policy and practice. To systematically quantify the contributions of risk factor exposures to specific health outcomes, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 aims to provide comprehensive estimates of exposure levels, relative health risks, and attributable burden of disease for 88 risk factors in 204 countries and territories and 811 subnational locations, from 1990 to 2021. Methods: The GBD 2021 risk factor analysis used data from 54 561 total distinct sources to produce epidemiological estimates for 88 risk factors and their associated health outcomes for a total of 631 risk–outcome pairs. Pairs were included on the basis of data-driven determination of a risk–outcome association. Age-sex-location-year-specific estimates were generated at global, regional, and national levels. Our approach followed the comparative risk assessment framework predicated on a causal web of hierarchically organised, potentially combinative, modifiable risks. Relative risks (RRs) of a given outcome occurring as a function of risk factor exposure were estimated separately for each risk–outcome pair, and summary exposure values (SEVs), representing risk-weighted exposure prevalence, and theoretical minimum risk exposure levels (TMRELs) were estimated for each risk factor. These estimates were used to calculate the population attributable fraction (PAF; ie, the proportional change in health risk that would occur if exposure to a risk factor were reduced to the TMREL). The product of PAFs and disease burden associated with a given outcome, measured in disability-adjusted life-years (DALYs), yielded measures of attributable burden (ie, the proportion of total disease burden attributable to a particular risk factor or combination of risk factors). Adjustments for mediation were applied to account for relationships involving risk factors that act indirectly on outcomes via intermediate risks. Attributable burden estimates were stratified by Socio-demographic Index (SDI) quintile and presented as counts, age-standardised rates, and rankings. To complement estimates of RR and attributable burden, newly developed burden of proof risk function (BPRF) methods were applied to yield supplementary, conservative interpretations of risk–outcome associations based on the consistency of underlying evidence, accounting for unexplained heterogeneity between input data from different studies. Estimates reported represent the mean value across 500 draws from the estimate's distribution, with 95% uncertainty intervals (UIs) calculated as the 2·5th and 97·5th percentile values across the draws. Findings: Among the specific risk factors analysed for this study, particulate matter air pollution was the leading contributor to the global disease burden in 2021, contributing 8·0% (95% UI 6·7–9·4) of total DALYs, followed by high systolic blood pressure (SBP; 7·8% [6·4–9·2]), smoking (5·7% [4·7–6·8]), low birthweight and short gestation (5·6% [4·8–6·3]), and high fasting plasma glucose (FPG; 5·4% [4·8–6·0]). For younger demographics (ie, those aged 0–4 years and 5–14 years), risks such as low birthweight and short gestation and unsafe water, sanitation, and handwashing (WaSH) were among the leading risk factors, while for older age groups, metabolic risks such as high SBP, high body-mass index (BMI), high FPG, and high LDL cholesterol had a greater impact. From 2000 to 2021, there was an observable shift in global health challenges, marked by a decline in the number of all-age DALYs broadly attributable to behavioural risks (decrease of 20·7% [13·9–27·7]) and environmental and occupational risks (decrease of 22·0% [15·5–28·8]), coupled with a 49·4% (42·3–56·9) increase in DALYs attributable to metabolic risks, all reflecting ageing populations and changing lifestyles on a global scale. Age-standardised global DALY rates attributable to high BMI and high FPG rose considerably (15·7% [9·9–21·7] for high BMI and 7·9% [3·3–12·9] for high FPG) over this period, with exposure to these risks increasing annually at rates of 1·8% (1·6–1·9) for high BMI and 1·3% (1·1–1·5) for high FPG. By contrast, the global risk-attributable burden and exposure to many other risk factors declined, notably for risks such as child growth failure and unsafe water source, with age-standardised attributable DALYs decreasing by 71·5% (64·4–78·8) for child growth failure and 66·3% (60·2–72·0) for unsafe water source. We separated risk factors into three groups according to trajectory over time: those with a decreasing attributable burden, due largely to declining risk exposure (eg, diet high in trans-fat and household air pollution) but also to proportionally smaller child and youth populations (eg, child and maternal malnutrition); those for which the burden increased moderately in spite of declining risk exposure, due largely to population ageing (eg, smoking); and those for which the burden increased considerably due to both increasing risk exposure and population ageing (eg, ambient particulate matter air pollution, high BMI, high FPG, and high SBP). Interpretation: Substantial progress has been made in reducing the global disease burden attributable to a range of risk factors, particularly those related to maternal and child health, WaSH, and household air pollution. Maintaining efforts to minimise the impact of these risk factors, especially in low SDI locations, is necessary to sustain progress. Successes in moderating the smoking-related burden by reducing risk exposure highlight the need to advance policies that reduce exposure to other leading risk factors such as ambient particulate matter air pollution and high SBP. Troubling increases in high FPG, high BMI, and other risk factors related to obesity and metabolic syndrome indicate an urgent need to identify and implement interventions

Numerical study of inlet cross-section effect on oblique finned microchannel heat sink

The current study is focused on the heat transfer and flow characteristics of an oblique finned micro-channel heat sink with different inlet cross-sections. Water and Al2O3-water nanofluid with 0.25% volume fraction were used as heat trans¬fer fluids. The oblique finned micro-channel heat sinks of size 48 × 80 mm were designed with three different inlet cross-sections, namely square, semicircle and trapezoidal. The ANSYS FLUENT simulations validated with the aid of an existing experimental work. The flow regime in micro-channel heat sink is constrained to laminar flow in the study. The three inlet cross-sections have been investigated by varying Reynolds number for Water and Al2O3-water nanofluid. The trapezoidal cross-section with average heat transfer rate 3.35% and pressure drop 8.6% is more efficient than other cross-sections due to larger wall area and effective entrance length. The oblique finned micro-channel heat sink with the trapezoidal cross-section is suitable for the micro-electronic cooling systems

Mental health morbidities and their correlates among the adolescents in kamrup (Metro), Assam: A school-based study

Background: India has the largest adolescent population worldwide, and among this group, mental health issues account for 16% of the total global burden of disease and injury. Disturbingly, approximately half of these health conditions manifest before the age of 14 years. To assess the prevalence of depression, anxiety, and stress along with its correlates among the adolescents in the schools of Kamrup (Metro) district, Assam. Methods and Material: This cross-sectional study was conducted in 10 randomly selected high schools in the study area among the adolescents selected from 8th to 10th standards in the age group of 14 to 17 years. A pre-designed, pre-tested interview schedule, the modified Kuppuswamy scale, and 'Depression Anxiety Stress Scale-21 Items' (DASS 21) questionnaire were used for data collection. Results: The mean ± 2SD age of the adolescents was 14.74 ± 1.58 years. Among the adolescents, the overall prevalence of depression, anxiety, and stress was found to be 22.2%, 24.4%, and 6.9%, respectively. Conclusions: The occurrence of mental health morbidities among adolescents is notably widespread, yet researchers have largely overlooked this aspect. This underscores the need for comprehensive investigations into the factors that contribute to these mental health issues

Improved Efficacy of Doxycycline in Liposomes Against Plasmodium falciparum in Culture and P. berghei infection in mice.

The rate at which Plasmodium falciparum is developing resistance to clinically used antimalarial drugs is alarming. Therefore, there is a compelling need to develop an efficient drug delivery system to improve the efficacy of existing antimalarial agents and circumvent drug resistance. Here, we report the antibacterial drug doxycycline (DOXY) in liposomal formulations exhibits enhanced antiplasmodial activity against blood stage forms of P. falciparum (3D7) in culture and established Plasmodium berghei NK-65 infection in murine model. Parasite killing on blood stage forms in culture was determined by a radiolabeled [3H] hypoxanthine incorporation assay and infected erythrocytes stained with Giemsa were counted using microscopy in vivo. The 50% inhibitory concentration (IC50) of DOXY-stearylamine liposome (IC50 0.36 μM) and DOXY-SPC:Chol-liposome (IC50 0.85 μM) exhibited marked growth inhibition of parasites compared with free DOXY (IC50 14 μM), with minimal toxicity to normal erythrocytes. Administration of polyethylene glycol distearoyl phosphatidylethanolamine-methoxy-polyethylene glycol2000 (DSPE-mPEG-2000) coated liposomes loaded with DOXY at 2.5 mg/kg per day resulted in efficacious killing of blood parasites with improved survival in mice relative to the free drug in both chloroquine sensitive and resistant strains of P. berghei infection. This is the first report to demonstrate that DOXY in liposomal system has immense chemotherapeutic potential against plasmodial infections at lower dosages.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Sustainable Diels–Alder syntheses in imidazolium ionic liquids

<p>An effective and simple protocol for the Diels–Alder reactions catalyzed and mediated by ionic liquid in conjunction with Lewis acid was studied. Diels–Alder adduct of the reaction of 1,4-benzoquinone with isoprene and 2,3-dimethyl-1,3-butadiene was obtained in good to excellent yields within the time span of 5.00–4.00 min under microwave irradiation. Due to the excellent activity of 2,3-dimethyl-1,3-butadiene as a diene, its efficiency was further analyzed by performing against four different dienophiles under various reaction conditions. The ionic liquid, 3-methyl-1-octyl-imidazolium tetrachloroaluminate mixed with Lewis acids, could be recycled and reused for consecutive cycles. The recovered ionic liquid in conjunction with Lewis acid displayed almost similar activity without any significant loss. This system is an essential upgrade and related to the reactions consuming common organic solvents at high temperatures and longer duration. Diels–Alder reactions under solventless conditions have also been investigated for the aforesaid reactions.</p

Misuse of Antibiotic during COVID 19 Outbreaks

The COVID-19 outbreak, caused by the severe acute respiratory syndrome coronavirus 2, has been detected in December 2019 in Wuhan, China, and is accompanied by significant degrees of morbidity and mortality. Antibiotic resistance (AMR) threatens to wreak havoc on healthcare system and the impact of globalization, and COVID-19 is intended to keep it at bay for the time being. During the COVID-19 crisis, a wide range of antimicrobial medicines were promoted as viable treatments. While both industrialized and industrializing nations have seen a rise in antimicrobial medication usage, use and abuse have been significantly more prevalent in developing countries. Antibiotic resistance&nbsp;is still a concern since microorganisms that cause resistant infections develop in hospitals and medical institutions, placing all patients at risk, complicating the care of COVID-19. Improper prescriptions, a lack of care management policies and needless self-administration by the general population are examples of these. Antibiotics seem to be more motivated to abuse and misusing antibiotics than to keep them safe and take them only when prescribed. Almost all of the substantial antibiotic usage in COVID-19 patients is inevitable. Patients having lung viral infections are more likely to develop subsequent bacterial infections, which lead to higher disease severity and death. Immediately crucial components of any AMR mitigation approach are increased spending in education and increased public knowledge of AMR. More studies are needed to better understand the health risks and rate of co-infection in COVID-19 patients in order to promote a decrease in any unnecessary antimicrobial prescribing. Keywords: COVID-19; Antibiotic use and misuse; Antimicrobial Resistance

Preclinical Evidence of Nanomedicine Formulation to Target Mycobacterium tuberculosis at Its Bone Marrow Niche

One-third of the world&rsquo;s population is estimated to be latently infected with Mycobacterium tuberculosis (Mtb). Recently, we found that dormant Mtb hides in bone marrow mesenchymal stem cells (BM-MSCs) post-chemotherapy in mice model and in clinical subjects. It is known that residual Mtb post-chemotherapy may be responsible for increased relapse rates. However, strategies for Mtb clearance post-chemotherapy are lacking. In this study, we engineered and formulated novel bone-homing PEGylated liposome nanoparticles (BTL-NPs) which actively targeted the bone microenvironment leading to Mtb clearance. Targeting of BM-resident Mtb was carried out through bone-homing liposomes tagged with alendronate (Ald). BTL characterization using TEM and DLS showed that the size of bone-homing isoniazid (INH) and rifampicin (RIF) BTLs were 100 &plusmn; 16.3 nm and 84 &plusmn; 18.4 nm, respectively, with the encapsulation efficiency of 69.5% &plusmn; 4.2% and 70.6% &plusmn; 4.7%. Further characterization of BTLs, displayed by sustained in vitro release patterns, increased in vivo tissue uptake and enhanced internalization of BTLs in RAW cells and CD271+BM-MSCs. The efficacy of isoniazid (INH)- and rifampicin (RIF)-loaded BTLs were shown using a mice model where the relapse rate of the tuberculosis was decreased significantly in targeted versus non-targeted groups. Our findings suggest that BTLs may play an important role in developing a clinical strategy for the clearance of dormant Mtb post-chemotherapy in BM cells