Whole-genome transcription and DNA methylation analysis of peripheral blood mononuclear cells identified aberrant gene regulation pathways in systemic lupus erythematosus

Hypermethylated CpG sites in PBMC of SLE patients comparing normal controls by genome-wide DNA methylation analysis. Three group comparisons, SLE LN+ vs. NC (S3-1), SLE LN− vs. NC (S3-2), and SLE (LN− and LN+) vs. NC (S3-3), were performed to identify hypermethylated DNA CpG sites by fold change (FC) > 1.2 and q value < 5% within each group. The 1813 common hypermethylated sites identified in each of the three group comparisons were then selected and listed in S3-4. (XLSX 814 kb

Synthesis and Characterizations of High Carbon Ferrochrome (HCFC) Slag Based Geopolymer

In the present Investigation, Geopolymer (GP) is made using High carbon Ferrochrome (HCFC) slag by synthesizing silicon and aluminum present in it with alkali liquid solution which binds other non-reactive materials present in the slag. The compressive strength of GP is found to be 11 MPa after 7-days of air curing. Increasing air curing time to 28-days, the strength is measured to be 15 MPa. XRD analyses indicate that there is gradual transformation of crystalline phases to non-crystalline glassy phases. SEM images show presence of more amount of glassy phase after air curing for a longer time. This is also corroborated with mechanical properties such as compressive strength. TGA results are also discussed for both uncured and cured GP samples. DSC isotherms indicate oozing out of inbuilt water present in the prepared GP materials which is an indication of condensation polymerization reaction occurring during the formation of Geopolymers

Clinical and Immunologic Profiles in Incomplete Lupus Erythematosus and Improvement with Hydroxychloroquine Treatment

Objective. The study goals were to evaluate performance of SLE classification criteria, to define patients with incomplete lupus erythematosus (ILE), and to probe for features in these patients that might be useful as indicators of disease status and hydroxychloroquine response. Methods. Patients with ILE (N=70) and SLE (N=32) defined by the 1997 American College of Rheumatology criteria were reclassified using the 2012 Systemic Lupus International Collaborating Clinics criteria. Disease activity, patient reported outcomes, and levels of Type I interferon- (IFN-) inducible genes, autoantibodies, and cytokines were measured. Subgroups treated with hydroxychloroquine (HCQ) were compared to patients not on this drug. Results. The classification sets were correlated (R2=0.87). ILE patients were older (P=0.0043) with lower disease activity scores (P<0.001) and greater dissatisfaction with health status (P=0.034) than SLE patients. ILE was associated with lower levels of macrophage-derived cytokines and levels of expressed Type I IFN-inducible genes. Treatment of ILE with HCQ was associated with better self-reported health status scores and lower expression levels of Type I IFN-inducible genes than ILE patients not on HCQ. Conclusion. The 2012 SLICC SLE classification criteria will be useful to define ILE in trials. Patients with ILE have better health status and immune profiles when treated with HCQ

Household, community, sub-national and country-level predictors of primary cooking fuel switching in nine countries from the PURE study

Introduction. Switchingfrom polluting (e.g. wood, crop waste, coal)to clean (e.g. gas, electricity) cooking fuels can reduce household air pollution exposures and climate-forcing emissions.While studies have evaluated specific interventions and assessed fuel-switching in repeated cross-sectional surveys, the role of different multilevel factors in household fuel switching, outside of interventions and across diverse community settings, is not well understood. Methods.We examined longitudinal survey data from 24 172 households in 177 rural communities across nine countries within the Prospective Urban and Rural Epidemiology study.We assessed household-level primary cooking fuel switching during a median of 10 years offollow up (∼2005–2015).We used hierarchical logistic regression models to examine the relative importance of household, community, sub-national and national-level factors contributing to primary fuel switching. Results. One-half of study households(12 369)reported changing their primary cookingfuels between baseline andfollow up surveys. Of these, 61% (7582) switchedfrom polluting (wood, dung, agricultural waste, charcoal, coal, kerosene)to clean (gas, electricity)fuels, 26% (3109)switched between different polluting fuels, 10% (1164)switched from clean to polluting fuels and 3% (522)switched between different clean fuels

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Tuberculous Synovitis of the knee with a discharging sinus

Extra pulmonary manifestations of tuberculosis are reported in less than one in five cases with the knee affected in 8% after the spine and hip. We report a case of tuberculous synovitis of the knee joint with a discharging sinus in a 40 year old female. The diagnosis was made by Ziehl - Neelson stain of the caseating discharge from the sinus, positive Mantoux test and radiological findings. The X-ray chest was normal. The patient responded well to anti-tuberculous treatment

Guanidinium–amino acid hydrogen-bonding interactions in protein crystal structures: implications for guanidinium-induced protein denaturation

In the present work, 86 available high resolution X-ray structures of proteins that contain one or more guanidinium ions (Gdm+) are analyzed for the distribution and nature of noncovalent interactions between Gdm+ and amino-acid residues. A total of 1044 hydrogen-bonding interactions were identified, of which 1039 are N–H⋯O, and five are N–H⋯N. Acidic amino acids are more likely to interact with Gdm+ (46% of interactions, 26% Asp and 20% Glu), followed by Pro (19% of interactions). DFT calculations on the identified Gdm+–amino acid hydrogen-bonded pairs reveal that although Gdm+ interacts primarily with the backbone amides of nonpolar amino acids, Gdm+ does interact with the sidechains of polar and acidic amino acids. We classified the optimized Gdm+–amino acid pairs into parallel [p], bifurcated [b], single hydrogen bonded [s] and triple hydrogen bonded [t] types. The [p] and [t] type pairs possess higher average interaction strength that is stronger than that of [b] and [s] type pairs. Negatively charged aspartate and glutamate residues interact with Gdm+ ion exceptionally tightly (−76 kcal mol−1) in [p] type complexes. This work provides statistical and energetics insights to better describe the observed destabilization or denaturation process of proteins by guanidinium salts

Mutation C677T in the methylenetetrahydrofolate reductase gene is associated with male infertility in an Indian population

A mutation (C677T) in the gene, MTHFR, is known to increase susceptibility to various multifactorial disorders. In order to assess this single nucleotide polymorphism (SNP) as risk factor for idiopathic male infertility, a case-control study was done on an Indian population. DNA from 151 cases of non-obstruction, idiopathic oligo-/azoospermia and 200 fertile males (controls) was polymerase chain reaction amplified using site-specific primers, and analysed for the mutation following HinfI-digestion. Our results show a significantly increased frequency of CT heterozygotes among infertile patients (p value &lt; 0.04). More importantly, while there were no T homozygotes in the control population, six of 151 infertile cases were T homozygous. Considering that T allele occurs in very low frequency in the control population, 677T is clearly a risk factor for infertility in the Indian population. We contend that the same could also be true for African and Southeast Asian populations where the frequency of 677T is very low. The lack of similar association in western populations could be because of the overall dietary enrichment of folates, which could nullify or minimize the effect of this polymorphism