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BackgroundPakistan is endemic to a diverse set of parasitic, mycobacterial and viral diseases. The recognition of BCG Trained Immunity (TI) led us to postulate that the continued presence of BCG-TI may play a protective role, previously reported for both infectious and noninfectious conditions. Most of the previous studies have addressed the issue of BCG-TI in the paediatric populations. This study addressed the key issue of maintenance of BCG-TI in a wider age range (adolescent and adults) to identify the strength and quality of the immune responses.ObjectiveTo assess the BCG-induced recall responses in healthy individuals by cytokines secreted from the TI network and its potential role in providing cross-protection against COVID-19 and other viral infections.Study designIn this cross-sectional study, healthy young adults and adolescents (n = 20) were recruited from 16-40 years of age, with no prior history of TB treatment, autoimmune, or chronic inflammatory condition.MethodsBCG-induced cytokine responses were assessed using prototypic markers for cells of the TI network [macrophages [M1 (TNFα, IFNγ), M2 (IL10)], NK (IL2), Gamma delta (γδ) T (IL17, IL4)] and SARS CoV2 IgG antibodies against RBD using short-term (12 hrs.) cultures assay.ResultsSignificant differences were observed in the magnitude of recall responses to BCG with macrophage cytokines showing the highest mean levels of TNFα (9148 pg/ml) followed by IL10 (488 pg/ml) and IFNγ (355 pg/ml). The ratio of unstimulated vs.BCG-stimulated cytokines was 132 fold higher for TNFα, 40 fold fo r IL10, and 27 fold for IFNγ. Furthermore, SARS-CoV-2 antibodies were also detected in unstimulated plasma which showed cross reactivity with BCG.ConclusionThe presence of cross reactive antibodies to SARS-CoV-2 and the relative ratio of pro- and anti-inflammatory cytokines secreted by activated TI cellular network may play a pivotal role in protection in the early stages of infection as observed during the COVID-19 pandemic in the younger age groups resulting in lower morbidity and mortality.

Physical exercise is known to modulate the intestinal microbiota composition and control the symptoms of metabolic syndrome. In this research, we intend to investigate and compare the effect of high-intensity interval and continuous endurance trainings (HIIT and CET) on cecal microbiota metabolites and inflammatory factors in diabetic rats. A number of Wistar rats were made diabetic by a high-fat diet and trained under two types of exercise protocols, HIIT and CET. After taking samples from the cecal tissue and serum of rats to reveal the effect of exercise, three microbial species from the Firmicute and Bacteroid phyla, which are the main types of intestinal microbes, and their metabolites include two short-chain fatty acids (SCFAs), butyrate and propionate and also, the inflammatory factors TLR4 and IL6 were analyzed through quantitative polymerase chain reaction (qPCR), high-performance liquid chromatography (HPLC), and Enzyme-linked immunosorbent assay (ELISA) methods. In general, exercise while increasing the representative of Firmicute has caused a relative reduction of Bacteroides and improved the concentration of SCFAs. In this regard, HIIT outperforms CET in up-regulating Akkermansia and Butyrivibrio expression, and butyrate and propionate metabolites concentration. Also, both exercises significantly reduced cecal expression of TLR4 and sera concentration of IL6 compared to the diabetic group, although the reduction rate was higher in the CET group than in HIIT. Our findings suggest that some symptoms of metabolic syndrome such as intestinal dysbiosis and the resulting metabolic disorders are better controlled by HIIT and inflammation by CET. Certainly, more extensive research on other contributing factors could help clarify the results.

BackgroundFibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies.Methods and findingsWe evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score used a meta-analysis of 11 European-ancestry prospective cohorts, free of CHD and MI at baseline, to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI). In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models.ConclusionsA small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.

The red palm weevil, Rhynchophorus ferrugineus (Oliver, 1970) (Coleoptera: Dryophthoridae) is the most devastating insect-pest of palm trees worldwide. Synthetic insecticides are the most preferred tool for the management of RPW. Alternatively, RNA interference (RNAi) mediated silencing of crucial genes provides reasonable control of insect pests. Recently, we have targeted four important genes; ecdysone receptor (EcR), serine carboxypeptidase (SCP), actin and chitin-binding peritrophin (CBP) in the 3rd and 5th instar larvae RPW. The results from 20 days trial showed that the survival rate of 3rd instar larvae fed on SCP and actin dsRNAs exhibited the lowest survival (12–68%). While, in the 5th instar larvae, the lowest survival rate (24%) was recorded for SCP after 20 days of incubation. Similarly, the weight of the 3rd and 5th instar larvae treated with SCP and actin was significantly reduced to 2.30–2.36 g and 4.64–4.78 g after 6 days of dsRNA exposure. The larval duration was also decreased significantly in the larvae treated with all the dsRNA treatments. The qRT-PCR results confirmed a significant suppression of the targeted genes as 90–97% and 85–93% in the 3rd and 5th instar larvae, respectively. The results suggest that the SCP and the actin genes can be promising targets to mediate RNAi-based control of RPW. [ABSTRACT FROM AUTHOR]

PCSK9-inhibitors (PCSK9i) are new drugs recently approved to lower LDL-cholesterol levels. However, due to the lack of long-term clinical data, the potential adverse effects of long-term use are still unknown. The PCSK9 genetic locus has been recently implicated in mood disorders and hence we wanted to assess if the effect of PCSK9i that block the PCSK9 protein can lead to an increase in the incidence of mood disorders. We used genetically-reduced PCSK9 protein levels (pQTLs) in plasma, serum, cerebrospinal fluid as a proxy for the effect of PCSK9i. We performed Mendelian randomization analyses using PCSK9 levels as exposure and mood disorder traits major depressive disorder, mood instability, and neuroticism score as outcomes. We find no association of PCSK9 levels with mood disorder traits in serum, plasma, and cerebrospinal fluid. We can conclude that genetically proxied on-target effect of pharmacological PCSK9 inhibition is unlikely to contribute to mood disorders. [ABSTRACT FROM AUTHOR]

Yucca aloifolia L. fruit (Yucca or Spanish bayonet, family Asparagaceae) is recognized for its purplish red color reflecting its anthocyanin content, which has a powerful antioxidant activity. This study aimed to investigate yucca (YA) fruit extract's protective effect on Parkinson's disease (PD). In vitro study, the anti-inflammatory activity of yucca fruit extracts was explored by measuring tumor necrosis factor receptor 2 (TNF-R2) and nuclear factor kappa B (NF-KB) to choose the most effective extract. Afterward, a detailed in vivo investigation of the protective effect of the most active extract on rotenone-induced PD was performed on male albino Wister rats. First, the safety of the extract in two different doses (50 and 100 mg/kg in 0.9% saline orally) was confirmed by a toxicological study. The rats were divided into four groups: 1) normal control (NC); 2) rotenone group; and third and fourth groups received 50 and 100 mg/kg yucca extract, respectively. The neurobehavioral and locomotor activities of the rats were tested by rotarod, open field, and forced swim tests. Striatal dopamine, renal and liver functions, and oxidative stress markers were assessed. Western blot analysis of brain tissue samples was performed for p-AMPK, Wnt3a, and β-catenin. Histopathological examination of striatal tissue samples was performed by light and electron microscopy (EM). The metabolites of the active extract were characterized using high-resolution LC-MS/MS, and the results showed the prevalence of anthocyanins, saponins, phenolics, and choline. Biochemical and histopathological tests revealed a dose-dependent improvement with oral Yucca extract. The current study suggests a possible neuroprotective effect of the acidified 50% ethanol extract (YA-C) of the edible Yucca fruit, making it a promising therapeutic target for PD.

An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5×10-8 is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5×10-8), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development.

IntroductionDuring the COVID-19 pandemic, healthcare workers had a high workload and were exposed to multiple psychosocial stressors. However, a knowledge gap exists about the levels of burnout among Bangladeshi frontline doctors during this COVID-19 pandemic. The study investigated burnout syndrome (BOS) among frontline doctors in two public secondary and tertiary care hospitals in Chattogram, Bangladesh.Materials & methodsThis cross-sectional study involved frontline doctors working at two hospitals treating COVID-19 and non-COVID patients from June to August 2020. A self-administered questionnaire that included Maslach Burnout Inventory for Human Services Survey (MBI-HSS) was used to capture demographic and workplace environment information. ANOVA and t-test were used to determine the statistical differences in the mean values of the three dimensions of MBI-HSS. Scores for three domains of burnout: emotional exhaustion (EE), depersonalization (DP), and personal accomplishment (PA) were calculated. Post-hoc analysis was done to identify the significant pair-wise differences when the ANOVA test result was significant. Multiple logistic regression was performed to determine the influence of factors associated with BOS.ResultsA total of 185 frontline doctors were invited to participate by convenience sampling, and 168 responded. The response rate was 90.81%. The overall prevalence of BOS was 55.4% (93/168) (95% CI: 47.5% to 63.0%). Moderate to high levels of EE was found in 95.8% of the participants. High DP and reduced PA were observed in 98.2% and 97% of participants. Younger age (25-29 years), being female, and working as a medical officer were independently associated with high levels of burnout in all three domains. EE was significantly higher in females (P = 0.011). DP was significantly higher in medical officers, those at earlier job periods, and those working more than 8 hours per day.ConclusionDuring the COVID-19 outbreak, BOS was common among Bangladeshi frontline doctors. Females, medical officers, and younger doctors tended to be more susceptible to BOS. Less BOS was experienced when working in the non-COVID ward than in the mixed ward.

Prescription of PCSK9-inhibitors has increased in recent years but not much is known about its off-target effects. PCSK9-expression is evident in non-hepatic tissues, notably the brain, and genetic variation in the PCSK9 locus has recently been shown to be associated with mood disorder-related traits. We investigated whether PCSK9 inhibition, proxied by a genetic reduction in expression of PCSK9 mRNA, might have a causal adverse effect on mood disorder-related traits. We used genetic variants in the PCSK9 locus associated with reduced PCSK9 expression (eQTLs) in the European population from GTEx v8 and examined the effect on PCSK9 protein levels and three mood disorder-related traits (major depressive disorder, mood instability, and neuroticism), using summary statistics from the largest European ancestry genome-wide association studies. We conducted summary-based Mendelian randomization analyses to estimate the causal effects, and attempted replication using data from eQTLGen, Brain-eMETA, and the CAGE consortium. We found that genetically reduced PCSK9 gene-expression levels were significantly associated with reduced PCSK9 protein levels but not with increased risk of mood disorder-related traits. Further investigation of nearby genes demonstrated that reduced USP24 gene-expression levels was significantly associated with increased risk of mood instability (p-value range = 5.2x10-5-0.03), and neuroticism score (p-value range = 2.9x10-5-0.02), but not with PCSK9 protein levels. Our results suggest that genetic variation in this region acts on mood disorders through a PCSK9-independent pathway, and therefore PCSK9-inhibitors are unlikely to have an adverse impact on mood disorder-related traits.

AimWe assessed clinical risk factors, anthropometric measures of adiposity and weight gain to determine associations with development of GDM in a cohort of pregnant women with obesity.MethodsThis was a secondary analysis of the UPBEAT trial of a complex lifestyle intervention in pregnant women with obesity (ISRCTN89971375). Clinical risk factors, and measures of adiposity and weight were assessed in the early 2nd trimester (mean 17 +0 weeks), and adiposity and weight repeated in the early 3rd trimester (mean 27 +5 weeks').ResultsOf the 1117 women (median BMI 35.0 kg/m2) with complete data, 25.8% (n = 304) developed GDM (IADPSG criteria, OGTT 24-28weeks). Using multivariable analysis, early clinical risk factors associated with later development of GDM included age (adj OR 1.06 per year; 95% CI 1.04-1.09), previous GDM (3.27; 1.34-7.93) and systolic blood pressure (per 10mmHg, 1.34; 1.18-1.53). Anthropometric measures positively associated with GDM included second trimester (mean 17+0 weeks) subscapular skinfold thickness, (per 5mm, 1.12; 1.05-1.21), and neck circumference (per cm, 1.11; 1.05-1.18). GDM was not associated with gestational weight gain, or changes in skinfolds thicknesses or circumferences between visits.ConclusionsIn this cohort of women with obesity, we confirmed clinical risk factors for GDM, (age, systolic blood pressure) previously identified in heterogeneous weight women but add to these indices of adiposity which may provide a discriminatory approach to GDM risk assessment in this group. This study also underscores the need to focus on modifiable factors pre-pregnancy as an opportunity for GDM prevention, as targeting gestational weight gain and adiposity during pregnancy is likely to be less effective.

Till now the exact mechanism and effect of biogenic silver nanoparticles on fungus is an indefinable question. To focus on this issue, the first time we prepared hydrothermal assisted thyme coated silver nanoparticles (T/AgNPs) and their toxic effect on Candida isolates were determined. The role of thyme (Thymus Vulgaris) in the reduction of silver ions and stabilization of T/AgNPs was estimated by Fourier transforms infrared spectroscopy, structure and size of present silver nanoparticles were detected via atomic force microscopy as well as high-resolution transmission electron microscopy. The biological activity of T/AgNPs was observed against Candida isolates from COVID-19 Patients. Testing of virulence of Candida species using Multiplex PCR. T/AgNPs proved highly effective against Candida albicans, Candida kruzei, Candida glabrata and MIC values ranging from 156.25 to 1,250 μg/mL and MFC values ranging from 312.5 to 5,000 μg/mL. The structural and morphological modifications due to T/AgNPs on Candida albicans were detected by TEM. It was highly observed that when Candida albicans cells were subjected to 50 and 100 μg/mL T/AgNPs, a remarkable change in the cell wall and cell membrane was observed.

BackgroundThe increasing number of aerobiological stations empower comparative studies to determine the relationship between pollen concentrations in different localities and the appropriate distance, which should be established between sampling stations. In Qatar, this is basically the first aerobiological study for a continuous monitoring interval.ObjectivesThe study aimed to assess the abundance and seasonality of the most prevalent pollen types, plus identify potential differences between two sites within the country.MethodsAirborne pollen data were collected during 2017-2020 by using Hirst-type volumetric samplers in Doha capital city and Al Khor city in Qatar, placed 50 km apart.ResultsHigher total pollen indexes were recorded in the Al Khor station (2931 pollen * day/m3) compared to the Doha station (1618 pollen * day/m3). Comparing the pollen spectrum between the sampling stations revealed that ten pollen types were found in common. Amaranthaceae and Poaceae airborne pollen constituted 73.5% and 70.9% of the total amount of pollen detected at the samplers of Al Khor station and Doha station. In both sampling sites, a very pronounced seasonality was shown; August-October appeared as the period with the most intense incidence of atmospheric herbaceous pollen, with 71% and 51% of the annual total counts in Al Khor and Doha stations, respectively. August (Al Khor, 21%; Doha, 9%), September (Al Khor, 33%; Doha, 26%), October (Al Khor, 17%; Doha, 16%) were the months in which the herbs pollen concentrations were highest. Significant statistical differences between the two stations were observed in specific pollen types with local distribution in each trap's vicinity.ConclusionsComparison of data obtained by the two samplers running at a distance of 50 Km indicated that potential inter-site differences could be attributed to the vegetation surrounding the city having a decisive influence on data collected.

Research into the metabolism of the non-essential amino acid (NEAA) proline in cancer has gained traction in recent years. The last step in the proline biosynthesis pathway is catalyzed by pyrroline-5-carboxylate reductase (PYCR) enzymes. There are three PYCR enzymes: mitochondrial PYCR1 and 2 and cytosolic PYCR3 encoded by separate genes. The expression of the PYCR1 gene is increased in numerous malignancies and correlates with poor prognosis. PYCR1 expression sustains cancer cells' proliferation and survival and several mechanisms have been implicated to explain its oncogenic role. It has been suggested that the biosynthesis of proline is key to sustain protein synthesis, support mitochondrial function and nucleotide biosynthesis. However, the links between proline metabolism and cancer remain ill-defined and are likely to be tissue specific. Here we use a combination of human dataset, human tissue and mouse models to show that the expression levels of the proline biosynthesis enzymes are significantly increased during colorectal tumorigenesis. Functionally, the expression of mitochondrial PYCRs is necessary for cancer cells' survival and proliferation. However, the phenotypic consequences of PYCRs depletion could not be rescued by external supplementation with either proline or nucleotides. Overall, our data suggest that, despite the mechanisms underlying the role of proline metabolism in colorectal tumorigenesis remain elusive, targeting the proline biosynthesis pathway is a suitable approach for the development of novel anti-cancer therapies.

BackgroundWe report the first study to estimate the socioeconomic gap in period life expectancy (LE) and life years spent with and without complications in a national cohort of individuals with type 1 diabetes.MethodsThis retrospective cohort study used linked healthcare records from SCI-Diabetes, the population-based diabetes register of Scotland. We studied all individuals aged 50 and older with a diagnosis of type 1 diabetes who were alive and residing in Scotland on 1 January 2013 (N = 8591). We used the Scottish Index of Multiple Deprivation (SIMD) 2016 as an area-based measure of socioeconomic deprivation. For each individual, we constructed a history of transitions by capturing whether individuals developed retinopathy/maculopathy, cardiovascular disease, chronic kidney disease, and diabetic foot, or died throughout the study period, which lasted until 31 December 2018. Using parametric multistate survival models, we estimated total and state-specific LE at an attained age of 50.ResultsAt age 50, remaining LE was 22.2 years (95% confidence interval (95% CI): 21.6 - 22.8) for males and 25.1 years (95% CI: 24.4 - 25.9) for females. Remaining LE at age 50 was around 8 years lower among the most deprived SIMD quintile when compared with the least deprived SIMD quintile: 18.7 years (95% CI: 17.5 - 19.9) vs. 26.3 years (95% CI: 24.5 - 28.1) among males, and 21.2 years (95% CI: 19.7 - 22.7) vs. 29.3 years (95% CI: 27.5 - 31.1) among females. The gap in life years spent without complications was around 5 years between the most and the least deprived SIMD quintile: 4.9 years (95% CI: 3.6 - 6.1) vs. 9.3 years (95% CI: 7.5 - 11.1) among males, and 5.3 years (95% CI: 3.7 - 6.9) vs. 10.3 years (95% CI: 8.3 - 12.3) among females. SIMD differences in transition rates decreased marginally when controlling for time-updated information on risk factors such as HbA1c, blood pressure, BMI, or smoking.ConclusionsIn addition to societal interventions, tailored support to reduce the impact of diabetes is needed for individuals from low socioeconomic backgrounds, including access to innovations in management of diabetes and the prevention of complications.

Staphylococcus aureus (S. aureus) is one of the earliest pathogens involved in human infections, responsible for a large variety of pathologies. Methicillin was the first antibiotic used to treat infections due to S. aureus but infections due to Methicillin resistant Staphylococcus aureus (MRSA) originated from hospital settings. Later, severe infections due to MRSA without any contact with the hospital environment or health care workers arose. Prevalence of MRSA has shown an alarming increase worldover including Cameroon. This Cross-sectional study was designed to evaluate the occurrence of MRSA infections in five different, most frequented Hospitals in northern Cameroon. Socio demographic data was recorded through questionnaire and different clinical specimens were collected for bacterial isolation. Identification of S. aureus was confirmed via 16s rRNA amplification using S. aureus specific primers. Molecular characterisation was performed through mecA gene, Luk PV gene screening and SCCmec typing. A total of 380 S. aureus clinical isolates were obtained of which 202 (53.2%) were nonduplicate multidrug resistant isolates containing, 45.5% MRSA. Higher number of MRSA was isolated from pus (30.4%) followed by blood culture (18.5%), and urine (17.4%). Patients aged 15 to 30 years presented high prevalence of MRSA (30.4%). Majority isolates (97.8%) carried the mecA gene, PVL toxin screening indicated 53.3% isolates carried the lukPV gene. Based on PVL detection and clinical history, CA-MRSA represented 53.3% of isolates. SCCmec typing showed that the Type IV was most prevalent (29.3%), followed by type I (23.9%). Amongst MRSA isolates high resistance to penicillin (91.1%), cotrimoxazole (86.7%), tetracycline (72.2%), and ofloxacin (70.0%) was detected. Meanwhile, rifampicin, fusidic acid, lincomycin and minocycline presented high efficacy in bacterial control. This study revealed a high prevalence of MRSA among infections due to S. aureus in Northern Cameroon. All MRSA recorded were multidrug resistant and the prevalence of CA MRSA are subsequently increasing, among population.

Cotton (Gossypium hirsutum L.) is one of the most important cash crops primarily grown for fiber. It is a perennial crop with indeterminate growth pattern. Nitrogen (N) is extremely important for vegetative growth as balanced N-nutrition improves photosynthesis, resulting in better vegetative growth. Excessive N-supply results in more vegetative growth, which increases the incidence of insect pest and diseases' infestation, pollute surface and ground water, delays maturity and produces low crop yield with poor quality. The use of plant growth regulators (PGRs) is an emerging option to control excessive vegetative growth. The PGRs help in improving plant architecture, boll retention, boll opening, yield and quality by altering growth and physiological processes such as photosynthesis, assimilate partitioning and nutrients dynamic inside the plant body. Mepiquat chloride (1,1-dimethylpiperidinum chloride) is globally used PGR for canopy development and control of excessive vegetative growth in cotton. This study investigated the effect of mepiquat chloride (MC) and N application on yield and yield components of transgenic cotton variety 'BT-FSH-326'. Two N rates (0, 198 kg ha-1) and five MC rates (0, 30,60, 90 and 120 g ha-1) were included in the study. Results revealed that MC and N application improved boll weight, number of bolls per plant, and seed cotton and lint yields. The highest seed cotton and lint yields (3595 kg ha-1 and 1701 kg ha-1, respectively) were observed under foliar application of 198 kg ha-1 N and 120 g ha-1 MC. Fiber length, fiber strength, micronaire and uniformity were significantly improved with foliar application of MC and N. In conclusion, foliar application of MC and N could be helpful in improving yield and fiber quality of cotton.

BackgroundHypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals.MethodsUsing a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases).ResultsAlthough drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0×10-8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction ≥ 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD.

IntroductionCoronavirus disease 2019 (COVID-19) is the ongoing pandemic with multitude of manifestations and association of ABO blood group in South-East Asian population needs to be explored.MethodsIt was a retrospective study of patients with COVID-19. Blood group A, B, O, and AB were identified in every participant, irrespective of their RH type and allotted groups 1, 2,3, and 4, respectively. Correlation between blood group and lab parameters was presented as histogram distributed among the four groups. Multivariate regression and logistic regression were used for inferential statistics.ResultsThe cohort included 1067 patients: 521 (48.8%) participants had blood group O as the prevalent blood type. Overall, 10.6% COVID-19-related mortality was observed at our center. Mortality was 13.9% in blood group A, 9.5% in group B, 10% in group C, and 10.2% in AB blood group (p = 0.412). IL-6 was elevated in blood group A (median [IQR]: 23.6 [17.5,43.8]), Procalcitonin in blood group B (median [IQR]: 0.54 [0.3,0.7]), D-dimers and CRP in group AB (median [IQR]: 21.5 [9,34]; 24 [9,49], respectively). Regarding severity of COVID-19 disease, no statistical difference was seen between the blood groups. Alteration of the acute phase reactants was not positively associated with any specific blood type.ConclusionIn conclusion, this investigation did not show significant association of blood groups with severity and of COVID-19 disease and COVID-19-associated mortality.

Peanut (Arachis hypogea L.) is an important nut crop extensively grown in rainfed regions of Pakistan. The crop requires low inputs; thus, could grow successfully under diverse environmental conditions. Due to pegging ability, peanut grows aggressively in sandy and sandy-loam soils. However, it has not introduced to Thal region of southern Punjab, Pakistan. A two-year field experiment was conducted to optimize sowing dates for two peanut genotypes (‘BARI-2016’ and ‘NO-334’) in Thal region (Layyah). Similarly, a yield trial was conducted at Chakwal where both genotypes are extensively grown. Five sowing dates (10th April, 1st May, 20th May, 10th June and 30th June) were included in the study. The highest seed yield was obtained with early sown crop (10th April) during both years. Pod formation reduced with increasing atmospheric temperature and no pods were formed on the plants sown on 30th June. Decreased pod formation seemed a major reason for low yield in late-sown crop. The highest yield was observed for the crop sown on 10th April, which was decreased by 40% for the crop sown on 1st May. Genotype ‘BARI-2016’ performed better for seed yield at both locations compared with ‘NO-334’. The results suggested that genotype ‘BARI-2016’ is more adaptive to arid and semi-arid condition under rainfed or irrigated conditions. Sowing peanut at optimum time would increase seed yield in arid and semi-arid regions. Nonetheless, ‘BARI-2016’ can be grown under rainfed and irrigated conditions successfully.

Fruit quality attributes are important factors for designing a market for agricultural goods and commodities. Support vector regression (SVR), MLR, and ANN models were established to predict the mass of ber fruits (Ziziphus mauritiana Lamk.) based on the axial dimensions of the fruit from manual measurements of fruit length, minor fruit diameter, and maximum fruit diameter of four ber cultivars. The precision and accuracy of the established models were assessed given their predicted values. The results revealed that using the validation dataset, the developed ANN (R2 = 0.9771; root mean square error [RMSE] = 1.8479 g) and SVR (R2 = 0.9947; RMSE = 1.8814 g) models produced better results when predicting ber fruit mass than those obtained by the MLR model (R2 = 0.4614; RMSE = 11.3742 g). In estimating ber fruit mass, the established SVR and ANN models produced more precise prediction values than those produced by the MLR model; however, the performance differences between the SVR and ANN models were not clear.

Over the last three decades, Information and Communication Technologies (ICTs) have changed the world in all walks of life. It has not only influenced the ways of human communication but also changed the way of learning. However, to utilize the facility of the Internet in effective manners, people need a certain set of skills called "Internet Literacy Skills". The purpose of the study was to explore the level of Internet literacy skills of Undergraduate first-year students (Digital Natives) of the University of the Punjab, Lahore, Pakistan. The study is quantitative, and data were gathered through questionnaires. A total of 180 students from three disciplines i.e. Pure Sciences, Social Sciences, and Arts and Humanities were approached for the final data collection. Descriptive (mean and standard deviation) and inferential statistics (regression analysis) were applied to analyze the collected data. Results further revealed that respondents possess very good knowledge to identify legal and illegal activities and information on the Internet. Findings of the study, not only reported the Internet literacy skills of digital natives but also helped to come up with a theoretical model that may be useful to design an efficient and effective Internet literacy module/subject to help students increase their Internet use-related skills.

Faculty development programs (FD) prepare the faculty for their educational role and career tasks. We aimed to evaluate the effectiveness of FDP in advancing the quality of short-answer questions (SAQs). This was a quasi-experimental study, comprising 37 new faculty. The SAQs were examined on psychometric analysis and Bloom's cognitive levels for the two educational blocks of 1st medical year (i.e. Musculoskeletal (MSK) and Renal blocks). We found substantial improvement in the discrimination index values of SAQs prepared after the workshop (p = 0.04). A higher number of SAQs with moderate difficulty and higher discrimination were also observed. Flaws within the post-workshop questions were reduced (3.0%) when compared with pre-workshop (12.5%). The major incline was also reported within Bloom's cognitive levels when pre-workshop K2 questions (30%) were compared with post-workshop (45.5%) with a p-value = 0.05. The SAQs constructed by the faculty member without participating in FDP are generally of unsatisfactory quality. After the FDP the assessment items of two blocks improved for various parameters of student assessment. The current study advocates that newly joined faculty shall be provided with the FDP to be guided, trained and supported for improving the quality of assessment through SAQs items writing.

Climate change is causing soil salinization, resulting in huge crop losses throughout the world. Multiple physiological and biochemical pathways determine the ability of plants to tolerate salt stress. Chili (Capsicum annum L.) is a salt-susceptible crop; therefore, its growth and yield is negatively impacted by salinity. Irreversible damage at cell level and photo inhibition due to high production of reactive oxygen species (ROS) and less CO2 availability caused by water stress is directly linked with salinity. A pot experiment was conducted to determine the impact of five NaCl salinity levels, i.e., 0,1.5, 3.0, 5.0 and 7.0 dS m-1 on growth, biochemical attributes and yield of two chili genotypes (‘Plahi’ and ‘A-120’). Salinity stress significantly reduced fresh and dry weight, relative water contents, water use efficiency, leaf osmotic potential, glycine betaine (GB) contents, photosynthetic rate (A), transpiration rate (E), stomatal conductance (Ci), and chlorophyll contents of tested genotypes. Salinity stress significantly enhanced malondialdehyde (MDA) contents and activities of the enzymatic antioxidants such as superoxide dismutase (SOD), catalase (CAT) and peroxidase (POD). In addition, increasing salinity levels significantly reduced the tissue phosphorus and potassium concentrations, while enhanced the tissue sodium and chloride concentrations. Genotype ‘Plahi’ had better growth and biochemical attributes compared to ‘A-120’. Therefore, ‘Plahi’ is recommended for saline areas to improve chili production.

Background Antibiotic resistance is a growing public health threat. In Afghanistan, high levels of indiscriminate antibiotic use exist, and healthcare programmes are not informed by understanding of local attitudes towards rational antibiotic use. Médecins Sans Frontières is an international non-governmental organization providing healthcare services to the Ahmad Shah Baba (ASB) District Hospital in Kabul, Afghanistan, since 2009. This mixed-methods study aimed to explore the perceptions and attitudes toward antibiotics among patients, prescribers, and pharmacists in the ASB District hospital outpatient department. Methods and findings Knowledge of antibiotics including their purpose and function, how and why they are used, and drivers for choice of antibiotic was examined at patient, prescriber, and provider-level. The first phase of the study, an exploratory qualitative component using an interpretative approach, was used to inform the second phase, a structured survey. Thirty-six interviews were conducted with 39 participants (21 patients or caretakers and 18 hospital health workers). Three hundred and fifty-one (351) patients and caretakers completed the second phase, the structured survey. This study found that poor knowledge of antibiotics and antibiotic resistance is a driving factor for inappropriate use of antibiotics. Participant perceptions of living in a polluted environment drove the high demand and perceived ‘need’ for antibiotics: patients, doctors and pharmacists alike consider dirty and dusty living conditions as causes of ‘disease’ in the body, requiring antibiotics to ‘clean’ and ‘strengthen’ it. Conclusions Findings highlight the need for strategies to improve awareness and knowledge of the general public, improve practice of doctors and pharmacists, regulate antibiotic dispensing in private pharmacies, and implement antibiotic stewardship in hospitals.

This investigation aimed to develop a method to predict the total soluble solids (TSS), titratable acidity, TSS/titratable acidity, vitamin C, anthocyanin, and total carotenoids contents using surface color values (L*, Hue and chroma), single fruit weight, juice volume, and sphericity percent of fresh peach fruit. Multiple regression analysis (MLR) and an artificial neural network (ANN) were employed. An ANN model was developed with six inputs and 15 neurons in the first hidden layer for the prediction of six chemical composition parameters. The results confirmed that the ANN model R2 = 974-0.998 outperformed the MLR models R2 = 0.473-0.840 using testing dataset. Moreover, sensitivity analysis revealed that the juice volume was the most dominating parameter for the prediction of titratable acidity, TSS/titratable acidity and vitamin C with corresponding contribution values of 39.97%, 50.40%, and 33.08%, respectively. In addition, sphericity percent contributed by 23.70% to anthocyanin and by 24.08% to total carotenoids. Furthermore, hue on TSS prediction was the highest compared with the other parameters, with a contribution percentage of 20.86%. Chroma contributed by different values to all variables in the range of 5.29% to 19.39%. Furthermore, fruit weight contributed by different values to all variables in the range of 16.67% to 23.48%. The ANN prediction method denotes a promising methodology to estimate targeted chemical composition levels of fresh peach fruits. The information of peach quality reported in this investigation can be used as a baseline for understanding and further examining peach fruit quality.

ObjectivesTo determine clinical, laboratory features and outcomes of Multisystem Inflammatory Syndrome in children (MIS-C) and its comparison with historic Kawasaki Disease (KD) and Viral Myocarditis (VM) cohorts.MethodsAll children (1 month- 18 years) who fulfilled the World Health Organization criteria of MIS-C presenting to two tertiary care centers in Karachi from May 2020 till August 31st were included. KD and VM admitted to one of the study centers in the last five years prior to this pandemic, was compared to MIS-C.ResultsThirty children with median age of 24 (interquartile range (IQR)1-192) months met the criteria for MIS-C. Three phenotypes were identified, 12 patients (40%) with KD, ten (33%) VM and eight (26%) had features of TSS. Echocardiography showed coronary involvement in 10 (33%), and moderate to severe Left Ventricular dysfunction in 10 (33%) patients. Steroids and intravenous immunoglobulins (IVIG) were administered to 24 (80%) and 12 (41%) patients respectively while 7 (23%) received both. Overall, 20% children expired. During the last five years, 30 and 47 children were diagnosed with KD and VM, respectively. Their comparison with MIS-C group showed lymphopenia, thrombocytosis, and higher CRP as well as more frequent atypical presentation in MIS-C KD group with less coronary involvement. The MIS-C VM was more likely to present with fulminant myocarditis.ConclusionsOur MIS-C cohort is younger with higher mortality compared to previous reports. MIS-C is distinct from historic cohorts of KD and VM in both in clinical features and outcomes.

Wheat is an important global staple food crop; however, its productivity is severely hampered by changing climate. Erratic rain patterns cause terminal drought stress, which affect reproductive development and crop yield. This study investigates the potential and zinc (Zn) and silicon (Si) to ameliorate terminal drought stress in wheat and associated mechanisms. Two different drought stress levels, i.e., control [80% water holding capacity (WHC) was maintained] and terminal drought stress (40% WHC maintained from BBCH growth stage 49 to 83) combined with five foliar-applied Zn-Si combinations (i.e., control, water spray, 4 mM Zn, 40 mM Si, 4 mM Zn + 40 mM Si applied 7 days after the initiation of drought stress). Results revealed that application of Zn and Si improved chlorophyll and relative water contents under well-watered conditions and terminal drought stress. Foliar application of Si and Zn had significant effect on antioxidant defense mechanism, proline and soluble protein, which showed that application of Si and Zn ameliorated the effects of terminal drought stress mainly by regulating antioxidant defense mechanism, and production of proline and soluble proteins. Combined application of Zn and Si resulted in the highest improvement in growth and antioxidant defense. The application of Zn and Si improved yield and related traits, both under well-watered conditions and terminal drought stress. The highest yield and related traits were recorded for combined application of Zn and Si. For grain and biological yield differences among sole and combined Zn-Si application were statistically non-significant (p>0.05). In conclusion, combined application of Zn-Si ameliorated the adverse effects of terminal drought stress by improving yield through regulating antioxidant mechanism and production of proline and soluble proteins. Results provide valuable insights for further cross talk between Zn-Si regulatory pathways to enhance grain biofortification.

Root and bark of Limonium axillare (Forssk) Kuntze are used as antidiabetic remedies in parts of East Africa, but this activity has never been fully investigated. To validate its ethnobotanical use, we compared the chemical and pharmacological profiles of the ethanolic extracts of L. axillare root (REE) and aerial parts (AEE). Administration of REE (500 mg kg-1) reduced streptozotocin-induced hyperglycemia by 44%, restored serum insulin levels, reestablished Glut2 and Glut4 expression and ameliorated pancreatic tissue damage in diabetic rats. In vitro studies revealed a strong radical scavenging effect, α-glucosidase, and α-amylase inhibition activity of REE at IC50 at 25.2, 44.8 and 89.1μg/mL, respectively. HPLC analysis identified ten phenolic compounds in REE with umbelliferone as the major constituents at 10 ± 0.081 mg/g of extract. Additionally, six compounds were isolated from REE including, β-sitosterol-3-palmitate, β-sitosterol, myricetin and gallic acids with two new tetrahydrofuran monoterpenes; 2-isopropyl- 3,4,4, trimethyl-tetrahydrofuran (3), and 2-isopropyl-4-methyl-tetrahydrofuran-3,4 dicarboxylic acid (4), the latter was revealed by molecular docking to be a good ligand to glycerol-3-phosphate dehydrogenase a key enzyme in glycolysis.

Sunflower production is significantly lower in arid and semi-arid regions due to various crop management problem. Conservation of tillage provides the most excellent opportunity to reduce degradation of soil reserves and increase soil productivity. The main objective of this study was to investigate the combined effects of conservation tillage and drought stress on growth and productivity of different sunflower hybrids. Experimental treatments included two sunflower hybrids ('NK-Senji' and 'S-278'), two drought stress treatments (i.e., well-watered and drought stress at flowering and grain filling stages) and three tillage practices (i.e., conservation, minimum and deep tillage). The results indicated that morphological and physiological parameters, and yield-related traits were significantly (P≤0.05) affected by all individual factors; however, their interactive effects were non-significant. Among sunflower hybrids, 'NK-Senji' performed better for morphological, physiological, and yield-related traits than 'S-278'. Similarly, conservation tillage observed better traits compared to the rest of the tillage practices included in the study. Nonetheless, conservation tillage improved growth and yield-related traits of hybrid 'NK-Senji' under drought stress. Hence, it is concluded that conservation tillage can improve the productivity of sunflower under low moisture availability. Therefore, conservation tillage could be suggested in the areas of lower water ability to improve sunflower production. Nonetheless, sunflower hybrids or varieties need thorough testing for their adaptability to conservation tillage and low moisture availability before making recommendations.

[This corrects the article DOI: 10.1371/journal.pone.0238091.].

Background and objectiveThe effectiveness of deferred surgical repair of ventricular septal rupture (VSR) post-myocardial infarction (MI) with cardiogenic shock remains limited to case reports. Our study aimed to investigate the outcomes and survival analysis following mechanical circulatory support (MCS) in patients after VSR who develop cardiogenic shock.MethodsWe analyzed 27 patients with post-MI VSR and cardiogenic shock who received deferred surgical repair while stabilized on MCS between January 2018 and March 2020. After normality test adjustments, continuous variables were expressed as mean ± standard deviation (SD). These were compared using the Mann-Whitney U test and Student's t-test. Categorical variables were compared using chi-square or Fisher's exact test. To identify predictors of operative mortality, univariate analysis of clinical characteristics and interventions followed by logistic regression was carried out. P-value of < 0.05 was considered significant.ResultsAll patients had preoperative MCS. Emergency repair was avoided in all the patients. The mean age of the participants was 64.96 with the majority being males (74.1%). On average, the mean time from MI to VSR repair was 18.85 days. Delayed revascularization was associated with increased mortality (OR 17.500, 95% CI 2.365-129.506, P = 0.005). Other factors associated with increased mortality were ejection fraction (EF), three-vessel disease, Killip class, early surgery, and prolonged use of inotropes. The operative mortality was 11% with an overall mortality of 33.3%. The one-year survival rate was 66.7%.ConclusionThe use of MCS in adjunct to a deferred surgical approach shows an improved survival outcome of patients with VSR complicated by cardiogenic shock. Further investigations are required regarding the optimal time for MCS and surgical repair.

Precise choice of potassium (K) source and application method does matter for its cost-effectiveness. This study was aimed to evaluate the best source and method of K fertilizer application to improve cotton productivity and profitability under an arid climate. Three different K sources (KNO3, K2SO4 and KCl) were applied at 100 kg ha-1 by four methods, i.e. a) basal application, b) side dressing, c) fertigation and d) foliar application of 2% K2SO4. The highest productivity and profitability were recorded with K2SO4 applied as foliar application. Total boll weight per plant was similar in foliar applied K2SO4 and basal application of KNO3. Better boll opening in foliar applied K2SO4, perhaps, played decisive role for increased seed-cotton yield. For basal application and side dressing, KNO3 produced the highest seed-cotton yield, but the benefit cost ratio was better for foliar applied K2SO4. In crux, foliar application of K2SO4 might be opted to improve the seed cotton yield, fiber quality and net returns under the arid climate. However, soil K application through K2SO4 and/or KNO3 is essential to balance the K removal from soil.

Oxidative stress is involved in the pathogenesis of a number of diseases including hypertension and renal failure. There is enhanced expression of nicotinamide adenine dinucleotide (NADPH oxidase) and therefore production of hydrogen peroxide (H2O2) during renal disease progression. This study investigated the effect of apocynin, an NADPH oxidase inhibitor and catalase, an H2O2 scavenger on Cyclosporine A (CsA) nephrotoxicity in Wistar-Kyoto rats. Rats received CsA (25mg/kg/day via gavage) and were assigned to vehicle, apocynin (2.5mmol/L p.o.), catalase (10,000U/kg/day i.p.) or apocynin plus catalase for 14 days. Renal functional and hemodynamic parameters were measured every week, and kidneys were harvested at the end of the study for histological and NADPH oxidase 4 (NOX4) assessment. Oxidative stress markers and blood urea nitrogen (BUN) were measured. CsA rats had higher plasma malondialdehyde (by 340%) and BUN (by 125%), but lower superoxide dismutase and total antioxidant capacity (by 40%, all P

Heat stress along with low water availability at reproductive stage (terminal growth phase of wheat crop) is major contributing factor towards less wheat production in tropics and sub-tropics. Flag leaf plays a pivotal role in assimilate partitioning and stress tolerance of wheat during terminal growth phase. However, limited is known about biochemical response of flag leaf to combined and individual heat and drought stress during terminal growth phase. Therefore, current study investigated combined and individual effect of terminal drought and heat stress on water relations, photosynthetic pigments, osmolytes accumulation and antioxidants defense mechanism in flag leaf of bread wheat. Experimental treatments comprised of control, terminal drought stress alone (50% field capacity during reproductive phase), terminal heat stress alone (wheat grown inside plastic tunnel during reproductive phase) and terminal drought stress + terminal heat stress. Individual and combined imposition of drought and heat stresses significantly (p≤0.05) altered water relations, osmolyte contents, soluble proteins and sugars along with activated antioxidant defensive system in terms of superoxide dismutase (SOD), peroxidase (POD) and ascorbate peroxidase (APX). Turgor potential, POD and APX activities were lowest under individual heat stress; however, these were improved when drought stress was combined with heat stress. It is concluded that combined effect of drought and heat stress was more detrimental than individual stresses. The interactive effect of both stresses was hypo-additive in nature, but for some traits (like turgor potential and APX) effect of one stress neutralized the other. To best of our knowledge, this is the first report on physiological and biochemical response of flag leaf of wheat to combine heat and drought stress. These results will help future studies dealing with improved stress tolerance in wheat. However, detailed studies are needed to fully understand the genetic mechanisms behind these physiological and biochemical changes in flag leaf in response to combined heat and drought stress.

A two-year field trial was conducted in a vineyard (northern Egypt)cultivated with Thompson seedless grapevines to evaluate the effectiveness of four "alternative" (biological/chemical) treatments, Bacillus megaterium, boric acid, calcium nitrate and chitosan, against the root-knot nematode Meloidogyne incognita (Mi), compared to that of the nematicide oxamyl. The influence of these treatments on plant nutritional status and fruit yield and quality was also assessed. All treatments significantly inhibited Mi reproduction parameters in both seasons, decreasing the numbers of nematode galls and egg masses (roots) and of second-stage juveniles (soil). Oxamyl application resulted in the highest reductions in Mi-reproduction parameters, followed by boric acid, which also showed the highest relative nematicidal efficacy (respect to oxamyl). In the 1st season, the highest fruit yield (10.34 kg/grapevine) was recorded from boric acid-treated plants, followed by that from oxamyl-treated plants (7.50 kg/grapevine); in the subsequent season (2019), oxamyl use led to the highest yield, followed by boric acid + chitosan use (10.04 and 8.62 kg/grapevine, respectively). In both seasons, application of boric acid alone and combined with chitosan enhanced the total soluble solids (TSS)/total acidity ratio in grape juice. All treatments led to higher nutrient contents (leaf petioles) and chlorophyll levels (leaves) as well as enhanced fruit size and weight. We conclude that the tested treatments can be safely applied for nematode management in Thompson seedless grapevines, with positive effects on fruit yield and quality.

Pioglitazone, a therapeutic drug for diabetes, possesses full PPAR-γ agonist activity and increase circulating adiponectin plasma concentration. Plasma adiponectin concentration decreases in hypertensive patients with renal dysfunctions. Present study investigated the reno-protective, altered excretory functions and renal haemodynamic responses to adrenergic agonists and ANG II following separate and combined therapy with pioglitazone in diabetic model of hypertensive rats. Pioglitazone was given orally [10mg/kg/day] for 28 days and adiponectin intraperitoneally [2.5μg/kg/day] for last 7 days. Groups of SHR received either pioglitazone or adiponectin in combination. A group of Wistar Kyoto rats [WKY] served as normotensive controls, whereas streptozotocin administered SHRs served as diabetic hypertensive rats. Metabolic data and plasma samples were taken on day 0, 8, 21 and 28. In acute studies, the renal vasoconstrictor actions of Angiotensin II [ANGII], noradrenaline [NA], phenylephrine [PE] and methoxamine [ME] were determined. Diabetic SHRs control had a higher basal mean arterial blood pressure than the WKY, lower RCBP and plasma adiponectin, higher creatinine clearance and urinary sodium excretion compared to WKY [all P

IntroductionOlder people have been reported to be at higher risk of COVID-19 mortality. This study explored the factors mediating this association and whether older age was associated with increased mortality risk in the absence of other risk factors.MethodsIn UK Biobank, a population cohort study, baseline data were linked to COVID-19 deaths. Poisson regression was used to study the association between current age and COVID-19 mortality.ResultsAmong eligible participants, 438 (0.09%) died of COVID-19. Current age was associated exponentially with COVID-19 mortality. Overall, participants aged ≥75 years were at 13-fold (95% CI 9.13-17.85) mortality risk compared with those ConclusionsHigher COVID-19 mortality among older adults was partially explained by other risk factors. 'Healthy' older adults were at much lower risk. Nonetheless, older age was an independent risk factor for COVID-19 mortality.

Background and purposeExcess insulin resistance is considered the predominant pathophysiological mechanism in obese women who develop gestational diabetes (GDM). We hypothesised that obese women requiring differing treatment modalities for GDM may have diverse underlying metabolic pathways.MethodsIn this secondary analysis of the UK pregnancies Better Eating and Activity Trial (UPBEAT) we studied women from the control arm with complete biochemical data at three gestational time points; at 15-18+6 and 27-28+6 weeks (before treatment), and 34-36+0 weeks (after treatment). A total of 89 analytes were measured (plasma/serum) using a targeted nuclear magnetic resonance (NMR) platform and conventional assays. We used linear regression with appropriate adjustment to model metabolite concentration, stratified by treatment group.Main findings300 women (median BMI 35kg/m2; inter quartile range 32.8-38.2) were studied. 71 developed GDM; 28 received dietary treatment only, 20 metformin, and 23 received insulin. Prior to the initiation of treatment, multiple metabolites differed (pConclusions/interpretationThis exploratory study suggests that GDM pathophysiological processes may differ amongst obese women who require different treatment modalities to achieve glucose control and can be revealed using metabolic profiling.

BackgroundIt is now well recognised that the risk of severe COVID-19 increases with some long-term conditions (LTCs). However, prior research primarily focuses on individual LTCs and there is a lack of data on the influence of multimorbidity (≥2 LTCs) on the risk of COVID-19. Given the high prevalence of multimorbidity, more detailed understanding of the associations with multimorbidity and COVID-19 would improve risk stratification and help protect those most vulnerable to severe COVID-19. Here we examine the relationships between multimorbidity, polypharmacy (a proxy of multimorbidity), and COVID-19; and how these differ by sociodemographic, lifestyle, and physiological prognostic factors.Methods and findingsWe studied data from UK Biobank (428,199 participants; aged 37-73; recruited 2006-2010) on self-reported LTCs, medications, sociodemographic, lifestyle, and physiological measures which were linked to COVID-19 test data. Poisson regression models examined risk of COVID-19 by multimorbidity/polypharmacy and effect modification by COVID-19 prognostic factors (age/sex/ethnicity/socioeconomic status/smoking/physical activity/BMI/systolic blood pressure/renal function). 4,498 (1.05%) participants were tested; 1,324 (0.31%) tested positive for COVID-19. Compared with no LTCs, relative risk (RR) of COVID-19 in those with 1 LTC was no higher (RR 1.12 (CI 0.96-1.30)), whereas those with ≥2 LTCs had 48% higher risk; RR 1.48 (1.28-1.71). Compared with no cardiometabolic LTCs, having 1 and ≥2 cardiometabolic LTCs had a higher risk of COVID-19; RR 1.28 (1.12-1.46) and 1.77 (1.46-2.15), respectively. Polypharmacy was associated with a dose response higher risk of COVID-19. All prognostic factors were associated with a higher risk of COVID-19 infection in multimorbidity; being non-white, most socioeconomically deprived, BMI ≥40 kg/m2, and reduced renal function were associated with the highest risk of COVID-19 infection: RR 2.81 (2.09-3.78); 2.79 (2.00-3.90); 2.66 (1.88-3.76); 2.13 (1.46-3.12), respectively. No multiplicative interaction between multimorbidity and prognostic factors was identified. Important limitations include the low proportion of UK Biobank participants with COVID-19 test data (1.05%) and UK Biobank participants being more affluent, healthier and less ethnically diverse than the general population.ConclusionsIncreasing multimorbidity, especially cardiometabolic multimorbidity, and polypharmacy are associated with a higher risk of developing COVID-19. Those with multimorbidity and additional factors, such as non-white ethnicity, are at heightened risk of COVID-19.

Aurora kinases (AURKs) have been identified as promising biological targets for the treatment of cancer. In this study, molecular dynamics simulations were employed to investigate the binding selectivity of three inhibitors (HPM, MPY, and VX6) towards AURKA and AURKB by predicting their binding free energies. The results show that the inhibitors HPM, MPY, and VX6 have more favorable interactions with AURKB as compared to AURKA. The binding energy decomposition analysis revealed that four common residue pairs (L139, L83), (V147, V91), (L210, L154), and (L263, L207) showed significant binding energies with HPM, MPY, and VX6, hence responsible for the binding selectivity of AURKA and AURKB to the inhibitors. The MD trajectory analysis also revealed that the inhibitors affect the dynamic flexibility of protein structure, which is also responsible for the partial selectivity of HPM, MPY, and VX6 towards AURKA and AURKB. As expected, this study provides useful insights for the design of potential inhibitors with high selectivity for AURKA and AURKB. [ABSTRACT FROM AUTHOR]

The increased prevalence of obesity and associated insulin resistance calls for effective therapeutic treatment of metabolic diseases. The current PPARγ-targeting antidiabetic drugs have undesirable side effects. The present study investigated the anti-diabetic and anti-obesity effects of withaferin A (WFA) in diet-induced obese (DIO) C57BL/6J mice and also the anti-adipogenic effect of WFA in differentiating 3T3- F442A cells. DIO mice were treated with WFA (6 mg/kg) or rosiglitazone (10 mg/kg) for 8 weeks. At the end of the treatment period, metabolic profile, liver function and inflammatory parameters were obtained. Expression of selective genes controlling insulin signaling, inflammation, adipogenesis, energy expenditure and PPARγ phosphorylation-regulated genes in epididymal fats were analyzed. Furthermore, the anti-adipogenic effect of WFA was evaluated in 3T3- F442A cell line. WFA treatment prevented weight gain without affecting food or caloric intake in DIO mice. WFA-treated group also exhibited lower epididymal and mesenteric fat pad mass, an improvement in lipid profile and hepatic steatosis and a reduction in serum inflammatory cytokines. Insulin resistance was reduced as shown by an improvement in glucose and insulin tolerance and serum adiponectin. WFA treatment upregulated selective insulin signaling (insr, irs1, slc2a4 and pi3k) and PPARγ phosphorylation-regulated (car3, selenbp1, aplp2, txnip, and adipoq) genes, downregulated inflammatory (tnf-α and il-6) genes and altered energy expenditure controlling (tph2 and adrb3) genes. In 3T3- F442A cell line, withaferin A inhibited adipogenesis as indicated by a decrease in lipid accumulation in differentiating adipocytes and protein expression of PPARγ and C/EBPα. The effect of rosiglitazone on physiological and lipid profiles, insulin resistance, some genes expression and differentiating adipocytes were markedly different. Our data suggest that WFA is a promising therapeutic agent for both diabetes and obesity.

The objective of the study was to evaluate role of zeolite and Enterobacter sp. MN17 on Cd uptake, growth, physiological and biochemical responses of Brassica napus on Cd-contaminated soil. A sandy clay loam soil in plastic pots was spiked with Cd (0 and 80 mg kg-1) and amended with zeolite (0 and 10 g kg-1). Seeds of B. napus were inoculated with Enterobacter sp. MN17. Both inoculated and non-inoculated seeds of B. napus were sown and plants were harvested after 60 days of growth and data were collected. Although sole application of zeolite and seed inoculation reverted adverse effects of Cd in B. napus plants, the combined use resulted in even higher growth and physiological responses compared to control plants. The combined use under Cd stress increased plant height, root length, dry biomass of shoot and root up to 32%, 57%, 42% and 64%, respectively compared to control. The different physiological attributes (photosynthetic rate, chlorophyll content, transpiration rate, stomatal conductance) of B. napus were improved from 6% to 137%. Moreover, combined use of zeolite and seed inoculation on Cd-contaminated soil reduced the stress to plants as antioxidant activities decreased up to 25-64%, however enzyme activities were still higher than plants grown on normal soil. Root and shoot analysis of B. napus for Cd content depicted that zeolite and bacterium decreased Cd uptake from soil. It is concluded that combined use of zeolite and strain MN17 reduces Cd uptake from soil and improves physiological and biochemical responses of B. napus which is helpful to alleviate Cd toxicity to plants.

BackgroundFibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies.Methods and findingsWe evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score used a meta-analysis of 11 European-ancestry prospective cohorts, free of CHD and MI at baseline, to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI). In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models.ConclusionsA small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.

[This corrects the article DOI: 10.1371/journal.pone.0196827.].