Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Burden of disease scenarios for 204 countries and territories, 2022–2050: a forecasting analysis for the Global Burden of Disease Study 2021

Background: Future trends in disease burden and drivers of health are of great interest to policy makers and the public at large. This information can be used for policy and long-term health investment, planning, and prioritisation. We have expanded and improved upon previous forecasts produced as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) and provide a reference forecast (the most likely future), and alternative scenarios assessing disease burden trajectories if selected sets of risk factors were eliminated from current levels by 2050. Methods: Using forecasts of major drivers of health such as the Socio-demographic Index (SDI; a composite measure of lag-distributed income per capita, mean years of education, and total fertility under 25 years of age) and the full set of risk factor exposures captured by GBD, we provide cause-specific forecasts of mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) by age and sex from 2022 to 2050 for 204 countries and territories, 21 GBD regions, seven super-regions, and the world. All analyses were done at the cause-specific level so that only risk factors deemed causal by the GBD comparative risk assessment influenced future trajectories of mortality for each disease. Cause-specific mortality was modelled using mixed-effects models with SDI and time as the main covariates, and the combined impact of causal risk factors as an offset in the model. At the all-cause mortality level, we captured unexplained variation by modelling residuals with an autoregressive integrated moving average model with drift attenuation. These all-cause forecasts constrained the cause-specific forecasts at successively deeper levels of the GBD cause hierarchy using cascading mortality models, thus ensuring a robust estimate of cause-specific mortality. For non-fatal measures (eg, low back pain), incidence and prevalence were forecasted from mixed-effects models with SDI as the main covariate, and YLDs were computed from the resulting prevalence forecasts and average disability weights from GBD. Alternative future scenarios were constructed by replacing appropriate reference trajectories for risk factors with hypothetical trajectories of gradual elimination of risk factor exposure from current levels to 2050. The scenarios were constructed from various sets of risk factors: environmental risks (Safer Environment scenario), risks associated with communicable, maternal, neonatal, and nutritional diseases (CMNNs; Improved Childhood Nutrition and Vaccination scenario), risks associated with major non-communicable diseases (NCDs; Improved Behavioural and Metabolic Risks scenario), and the combined effects of these three scenarios. Using the Shared Socioeconomic Pathways climate scenarios SSP2-4.5 as reference and SSP1-1.9 as an optimistic alternative in the Safer Environment scenario, we accounted for climate change impact on health by using the most recent Intergovernmental Panel on Climate Change temperature forecasts and published trajectories of ambient air pollution for the same two scenarios. Life expectancy and healthy life expectancy were computed using standard methods. The forecasting framework includes computing the age-sex-specific future population for each location and separately for each scenario. 95% uncertainty intervals (UIs) for each individual future estimate were derived from the 2·5th and 97·5th percentiles of distributions generated from propagating 500 draws through the multistage computational pipeline. Findings: In the reference scenario forecast, global and super-regional life expectancy increased from 2022 to 2050, but improvement was at a slower pace than in the three decades preceding the COVID-19 pandemic (beginning in 2020). Gains in future life expectancy were forecasted to be greatest in super-regions with comparatively low life expectancies (such as sub-Saharan Africa) compared with super-regions with higher life expectancies (such as the high-income super-region), leading to a trend towards convergence in life expectancy across locations between now and 2050. At the super-region level, forecasted healthy life expectancy patterns were similar to those of life expectancies. Forecasts for the reference scenario found that health will improve in the coming decades, with all-cause age-standardised DALY rates decreasing in every GBD super-region. The total DALY burden measured in counts, however, will increase in every super-region, largely a function of population ageing and growth. We also forecasted that both DALY counts and age-standardised DALY rates will continue to shift from CMNNs to NCDs, with the most pronounced shifts occurring in sub-Saharan Africa (60·1% [95% UI 56·8–63·1] of DALYs were from CMNNs in 2022 compared with 35·8% [31·0–45·0] in 2050) and south Asia (31·7% [29·2–34·1] to 15·5% [13·7–17·5]). This shift is reflected in the leading global causes of DALYs, with the top four causes in 2050 being ischaemic heart disease, stroke, diabetes, and chronic obstructive pulmonary disease, compared with 2022, with ischaemic heart disease, neonatal disorders, stroke, and lower respiratory infections at the top. The global proportion of DALYs due to YLDs likewise increased from 33·8% (27·4–40·3) to 41·1% (33·9–48·1) from 2022 to 2050, demonstrating an important shift in overall disease burden towards morbidity and away from premature death. The largest shift of this kind was forecasted for sub-Saharan Africa, from 20·1% (15·6–25·3) of DALYs due to YLDs in 2022 to 35·6% (26·5–43·0) in 2050. In the assessment of alternative future scenarios, the combined effects of the scenarios (Safer Environment, Improved Childhood Nutrition and Vaccination, and Improved Behavioural and Metabolic Risks scenarios) demonstrated an important decrease in the global burden of DALYs in 2050 of 15·4% (13·5–17·5) compared with the reference scenario, with decreases across super-regions ranging from 10·4% (9·7–11·3) in the high-income super-region to 23·9% (20·7–27·3) in north Africa and the Middle East. The Safer Environment scenario had its largest decrease in sub-Saharan Africa (5·2% [3·5–6·8]), the Improved Behavioural and Metabolic Risks scenario in north Africa and the Middle East (23·2% [20·2–26·5]), and the Improved Nutrition and Vaccination scenario in sub-Saharan Africa (2·0% [–0·6 to 3·6]). Interpretation: Globally, life expectancy and age-standardised disease burden were forecasted to improve between 2022 and 2050, with the majority of the burden continuing to shift from CMNNs to NCDs. That said, continued progress on reducing the CMNN disease burden will be dependent on maintaining investment in and policy emphasis on CMNN disease prevention and treatment. Mostly due to growth and ageing of populations, the number of deaths and DALYs due to all causes combined will generally increase. By constructing alternative future scenarios wherein certain risk exposures are eliminated by 2050, we have shown that opportunities exist to substantially improve health outcomes in the future through concerted efforts to prevent exposure to well established risk factors and to expand access to key health interventions

USING 2MM TITANIUM MINIPLATES AND 3D LOCKING PLATE IN THE TREATMENT OF SYMPHYSIS AND PARA-SYMPHYSIS FRACTURE OF MANDIBLE

Introduction: In India, the most frequent surgical emergency is perforation peritonitis. Despite improvements in surgical methods, antimicrobial therapy, and critical care support, peritonitis treatment remains a very demanding, challenging, and complicated task. The highest dependability on the Risks' assessment is achieved by MPI, enabling the individual prognosis of peritonitis patients to be predicted. Objectives: The goal of the current research was to use Mannheim's Peritonitis Index to assess the prognosis for patients with perforation peritonitis. Results: In the current research, we found that the majority of the participants were men (65.38%) and that the bulk of the cases belonged to the 46-55 year age group (25%), which was followed by the 36-45 year age group (23.07%). The most common perforation found in the patients was duodenal (42.30%), which was followed by appendicular (13.46%), gastric (28.84%), fileal (9.61%), jejunal (3.8%), and colonic perforations (1.9%). Conclusion: The majority of research participants (46.15%) reported MPI scores between 21 and 29, followed by situations where the MPI score was more than 29, and cases where the MPI score was less than 21, in that order (38.46%)

Tree responses to foliar dust deposition and gradient of air pollution around opencast coal mines of Jharia coalfield, India: gas exchange, antioxidative potential and tolerance level

Atmospheric pollution by opencast mining activities affects tree species around the mining area. The present study evaluated the responses of five native tree species to air pollution in Jharia coalfield. Sites were selected as closest to farthest from the mining area. Foliar dust deposition and foliar sulphate content affected stomatal conductance, superoxide dismutase activity and ascorbic acid and, thus, increased the susceptibility of sensitive species. Ficus benghalensis and Butea monosperma showed maximum dust deposition, while Adina cordifolia showed minimum deposition. Maximum dust deposition in Ficus benghalensis lowered stomatal conductance and, thus, checked the flux of other acidic gaseous pollutants which led to minimum variation in leaf extract pH. Higher stomatal conductance in Adina cordifolia and Aegle marmelos, on the other hand, facilitated the entry of acidic pollutants and disrupted many biological functions by altering photosynthesis and inducing membrane damage. Low variations in Ficus religiosa, Ficus benghalensis and Butea monosperma with sites and seasons suggest better physiological and morphological adaptations towards pollution load near coal mining areas. Tree species with better adaptation resisted variation in leaf extract pH by effectively metabolising sulphate and, thus, had higher chlorophyll content and relative water content

Combining Ultrasound and Capillary-Embedded T-Junction Microfluidic Devices to Scale Up the Production of Narrow-Sized Microbubbles through Acoustic Fragmentation

Microbubbles are tiny gas-filled bubbles that have a variety of applications in ultrasound imaging and therapeutic drug delivery. Microbubbles can be synthesized using a number of techniques including sonication, amalgamation, and saline shaking. These approaches can produce highly concentrated microbubble suspensions but offer minimal control over the size and polydispersity of the microbubbles. One of the simplest and effective methods for producing monodisperse microbubbles is capillary-embedded T-junction microfluidic devices, which offer great control over the microbubble size. However, lower production rates (∼200 bubbles/s) and large microbubble sizes (∼300 μm) limit the applicability of such devices for biomedical applications. To overcome the limitations of these technologies, we demonstrate in this work an alternative approach to combine a capillary-embedded T-junction device with ultrasound to enhance the generation of narrow-sized microbubbles in aqueous suspensions. Two T-junction microfluidic devices were connected in parallel and combined with an ultrasonic horn to produce lipid-coated SF6 core microbubbles in the size range of 1-8 μm. The rate of microbubble production was found to increase from 180 microbubbles/s in the absence of ultrasound to (6.5 ± 1.2) × 106 bubble/s in the presence of ultrasound (100% ultrasound amplitude). When stored in a closed environment, the microbubbles were observed to be stable for up to 30 days, with the concentration of the microbubble suspension decreasing from ∼2.81 × 109/mL to ∼2.3 × 106/mL and the size changing from 1.73 ± 0.2 to 1.45 ± 0.3 μm at the end of 30 days. The acoustic response of these microbubbles was examined using broadband attenuation spectroscopy, and flow phantom imaging was performed to determine the ability of these microbubble suspensions to enhance the contrast relative to the surrounding tissue. Overall, this approach of coupling ultrasound with microfluidic parallelization enabled the continuous production of stable microbubbles at high production rates and low polydispersity using simple T-junction devices

Phytostabilization of coal mine overburden waste, exploiting the phytoremedial efficacy of lemongrass under varying level of cow dung manure

A pot study was performed to assess the phytoremedial potential of Cymbopogon citratus (D.C.) Staf. for reclamation of coal mine overburden dump wastes, emphasizing the outcome of amendment practices using cow dung manure (CM) and garden soil mixtures on the revegetation of over-burden wastes (OB). Wastes amendment with cow dung manure and garden soil resulted in a significant increase in soil health and nutrient status along with an increment in the phytoavailability of Zn and Cu which are usually considered as micronutrients, essential for plant growth. A significant increment in the total biomass of lemongrass by 38.6% under CM20 (OB: CM 80:20) was observed along with improved growth parameters under amended treatments as compared to OB (100% waste). Furthermore, the proportionate increases in the assimilative rate, water use efficiency, and chlorophyll fluorescence have been observed with the manure application rates. Lemongrass emerged out to be an efficient metal-tolerant herb species owing to its high metal-tolerance index (>100%). Additionally, lemongrass efficiently phytostablized Pb and Ni in the roots. Based on the strong plant performances, the present study highly encourages the cultivation of lemongrass in coal mining dumpsites for phytostabilization coupled with cow-dung manure application (20% w/w)

Air quality modeling for impact evaluation of a mica, feldspar, and quartz mine in Nellore district, Andhra Pradesh, India

The dust emission from the mining area is the primary source of air pollution for the surrounding environment. This paper deals with the study of baseline air quality assessment and air pollution modeling exercise for a mica, feldspar, and quartz mine to predict the maximum dust concentration from the mine with and without control measures. Baseline PM10, PM2.5, SO2, and NO2 levels in the bufer zone of the planned mine site were found to be 53.1–79.5, 20.2–43.2, 16.6–31.2, and 21.2–50.1 mg m−3, respectively, and these values were lesser than the corresponding permissible limit of 100, 60, 80, and 80 µg m−3. The respective predicted PM10 and PM2.5 levels will be 73.9–97.1 and 31.9–44.2 mg m−3 without control measures, and 73.5–82.5 and 31.8–43.8 µg m−3 with control measures during operation of the mine. It is estimated that PM10and PM2.5 will remain below the permissible limit in the buffer zone of the mine. The paper suggests effective air pollution control measures, including a description of the developed smart dry fog dust suppression system and wirelessly controlled sprinkling system for applications at various dust emitting sources in the mining area

Prevalence and prognostic implications of reduced left ventricular ejection fraction among patients with STEMI in India

AimsTo describe clinical characteristics and outcomes for those with STEMI and reduced left ventricular ejection fraction (LVEF) in low-income and middle-income countries (LMICs).Methods and resultsAdults presenting with STEMI to two government-owned tertiary care centres in Delhi, India were prospectively enrolled in the North India ST-elevation myocardial infarction (NORIN-STEMI) registry. LVEF was evaluated at presentation and clinical characteristics were compared across LVEF categories. Overall, 3597 patients were included, of whom 468 (13%) had LVEF >50%, 1482 (41%) had mildly reduced LVEF (40-49%), 1357 (38%) had moderately reduced LVEF (30-39%), and 290 (8%) had severely reduced LVEF (<30%). Presentation delay >24 h, prior MI, and hyperlipidaemia were associated with decreasing LVEF category. Although most patients with reduced LVEF were discharged on appropriate guideline-directed therapies, adherence at 1 year was low (ACE inhibitor/ARB 91% to 41%, beta blocker 98% to 78%, aldosterone receptor antagonist 69% to 6%). After multivariable adjustment, a Cox regression model showed moderately reduced LVEF (HR 1.77, 95% CI 1.20, 2.60) and severely reduced LVEF (HR 3.63, 95% CI 2.41, 5.48) were associated with increased risk of all-cause mortality compared with LVEF ≥50%.ConclusionsOn presentation for STEMI, almost 90% of NORIN-STEMI participants had at least mildly reduced LVEF and almost half had LVEF <40%. Patients with LVEF <40% had significantly higher risk of mortality at 1 year, and adherence to guideline-directed therapies at 1 year was poor. Systematic initiatives to improve access to timely revascularization and guideline-directed therapies are essential in advancing STEMI care in LMICs

Protocol for ICiCLe-ALL-14 (InPOG-ALL-15-01):a prospective, risk stratified, randomised, multicentre, open label, controlled therapeutic trial for newly diagnosed childhood acute lymphoblastic leukaemia in India

BACKGROUND: In the west, survival following treatment of childhood acute lymphoblastic leukaemia (ALL) approaches 90%. Outcomes in India do not exceed 70%. To address this disparity, the Indian Collaborative Childhood Leukaemia group (ICiCLe) developed in 2013 a contemporary treatment protocol for uniform risk-stratified management of first presentation ALL based on cytogenetics and minimal residual disease levels (MRD). A multicentre randomised clinical trial opened in 2016 (ICiCLe-ALL-14) and examines the benefit of randomised interventions to decrease toxicity and improve outcomes.METHODS: Patients 1-18 years with newly diagnosed ALL are categorised into four risk groups based on presentation features, tumour genetics and treatment response. Standard risk includes young (&lt; 10 years) B cell precursor ALL (BCP-ALL) patients with low presentation leucocyte count (&lt; 50 × 109/L) and no high-risk features. Intermediate risk includes BCP-ALL patients with no high-risk features but are older and have high presentation leucocyte counts and/or bulky disease. High risk includes BCP-ALL patients with any high-risk feature, including high-risk genetics, central nervous system leukaemia, poor prednisolone response at treatment day 8 and high MRD (≥ 0·01%) at the end of induction. Patients with T-lineage ALL constitute the fourth risk group. All patients receive four intensive treatment blocks (induction, consolidation, interim maintenance, delayed intensification) followed by 96 weeks of maintenance. Treatment intensity varies by risk group. Clinical data management is based on a web-based remote data capture system. The first randomisation examines the toxicity impact of a shorter induction schedule of prednisolone (3 vs 5 weeks) in young non-high-risk BCP-ALL. The second randomisation examines the survival benefit of substituting doxorubicin with mitoxantrone in delayed intensification for all patients. Primary outcome measures include event-free survival (overall, by risk groups), sepsis rates in induction (first randomisation) and event-free survival rates following second randomisation.DISCUSSION: ICiCLe-ALL-14 is the first multicentre randomised childhood cancer clinical trial in India. The pre-trial phase allowed standardisation of risk-stratification diagnostics and established the feasibility of collaborative practice, uniform treatment, patient enrolment and data capture. Pre-trial observations confirm the impact of risk-stratified therapy in reducing treatment-related deaths and costs. Uniform practice across centres allows patients to access care locally, potentially decreasing financial hardship and dislocation.TRIAL REGISTRATION: Clinical Trials Registry-India (CTRI) CTRI/2015/12/006434 . Registered on 11 December 2015.</p