Discovery and characterization of bromodomain 2-specific inhibitors of BRDT.

Bromodomain testis (BRDT), a member of the bromodomain and extraterminal (BET) subfamily that includes the cancer targets BRD2, BRD3, and BRD4, is a validated contraceptive target. All BET subfamily members have two tandem bromodomains (BD1 and BD2). Knockout mice lacking BRDT-BD1 or both bromodomains are infertile. Treatment of mice with JQ1, a BET BD1/BD2 nonselective inhibitor with the highest affinity for BRD4, disrupts spermatogenesis and reduces sperm number and motility. To assess the contribution of each BRDT bromodomain, we screened our collection of DNA-encoded chemical libraries for BRDT-BD1 and BRDT-BD2 binders. High-enrichment hits were identified and resynthesized off-DNA and examined for their ability to compete with JQ1 in BRDT and BRD4 bromodomain AlphaScreen assays. These studies identified CDD-1102 as a selective BRDT-BD2 inhibitor with low nanomolar potency and >1,000-fold selectivity over BRDT-BD1. Structure-activity relationship studies of CDD-1102 produced a series of additional BRDT-BD2/BRD4-BD2 selective inhibitors, including CDD-1302, a truncated analog of CDD-1102 with similar activity, and CDD-1349, an analog with sixfold selectivity for BRDT-BD2 versus BRD4-BD2. BROMOscan bromodomain profiling confirmed the great affinity and selectivity of CDD-1102 and CDD-1302 on all BET BD2 versus BD1 with the highest affinity for BRDT-BD2. Cocrystals of BRDT-BD2 with CDD-1102 and CDD-1302 were determined at 2.27 and 1.90 Å resolution, respectively, and revealed BRDT-BD2 specific contacts that explain the high affinity and selectivity of these compounds. These BD2-specific compounds and their binding to BRDT-BD2 are unique compared with recent reports and enable further evaluation of their nonhormonal contraceptive potential in vitro and in vivo.

Biotinidase biochemical and molecular analyses: Experience at a large reference laboratory.

BACKGROUND: Biotinidase deficiency is caused by absent activity of the biotinidase, encoded by the biotinidase gene (BTD). Affected individuals cannot recycle the biotin, leading to heterogeneous symptoms that are primarily neurological and cutaneous. Early treatment with biotin supplementation can prevent irreversible neurological damage and is recommended for patients with profound deficiency, defined as enzyme activity <10% mean normal (MN). Molecular testing has been utilized along with biochemical analysis for diagnosis and management. In this study, our objective was to correlate biochemical phenotype/enzyme activity to BTD genotype in patients for whom both enzyme and molecular testing were performed at our lab, and to review how the correlations inform on variant severity. METHODS: We analyzed results of biotinidase enzyme analysis and BTD gene sequencing in 407 patients where samples were submitted to our laboratory from 2008 to 2020. RESULTS: We identified 84 BTD variants; the most common was c.1330G>C, and 19/84 were novel BTD variants. A total of 36 patients had enzyme activity <10% of MN and the most common variant found in this group was c.528G>T. No variant was reported in one patient in the profound deficiency group. The most common variant found in patients with enzyme activity more than 10% MN was c.1330G>C. CONCLUSIONS: Although enzyme activity alone may be adequate for diagnosing profound biotinidase deficiency, molecular testing is necessary for accurate carrier screening and in cases where the enzyme activity falls in the range where partial deficiency and carrier status cannot be discriminated.

Is health insurance really benefitting Indian population? Evidence from a nationally representative sample survey.

BACKGROUND: Universal health coverage (UHC) is the centrepiece of the sustainable development goals and aims to ensure access to essential and quality healthcare services to all without facing financial hardships. Several health insurance programmes have been launched in India to progress towards UHC. OBJECTIVE: This study aims to assess the impact of health insurance (overall health insurance, government sponsored health insurance (GSHI), and private voluntary health insurance) on accessibility and utilization of inpatient care, out-of-pocket health expenditure (OOPE), catastrophic health expenditure (CHE), and impoverishment in India. DATA AND METHODOLOGY: The 75th round of National Sample Survey Office was used in the study, which covered 555,115 individuals, 113,823 households, and 91,445 hospitalization incidence all over India. Descriptive statistics, multivariable logistic regression, and propensity score matching (PSM) methods were employed. RESULTS: Enrolment under health insurance has impacted the accessibility and utilization pattern of hospitalization to some extent for the insured. PSM showed that enrolment under GSHI schemes reduced OOPE by INR 3314 (USD 49) and CHE incidence by 1%-4% at various thresholds. Among poor persons, there was a marginal but statistically significant reduction of OOPE among those enrolled under GSHI schemes (p < 0.05). However, GSHI schemes did not statistically significantly reduce the CHE burden for poor persons enrolled (p > 0.05). Furthermore, enrolment under private voluntary health insurance reduced OOPE by INR 13,511 (USD 198) and CHE by 13.47% at 10% threshold, 4.61% at 25% threshold, and 2.65% at 40% threshold. However, its uptake was primarily confined to richer economic quintiles and urban areas that exacerbates equity concerns. All the results were confirmed through robustness measures employed. CONCLUSIONS: There is a necessity to increase awareness and uptake of health insurance, along with introducing comprehensive insurance packages covering both inpatient and outpatient care. Also, increasing public health spending, strengthening public healthcare facilities, and improving regulatory implementation of private healthcare providers are imperative to augment financial protection.

Soil-mustard revitalization via rice husk ash, a promising soil amendment material for sustainable management of heavy metal contamination in tropical ecosystem.

Prolonged wastewater irrigation in agriculture has led to the accumulation of heavy metals in soil, endangering both the soil quality and food safety, thereby posing a potential threat to human health through the consumption of contaminated crops. The present study aimed to enhance the yield of mustard (Brassica juncea L. cv. Varuna and NRCHB 101) plants and stabilize heavy metals (Cd, Cr, Ni, Cu, and Zn) in wastewater-irrigated soil using rice husk ash (RHA), rice mill by-product, collected from Chandauli region of Eastern Uttar Pradesh, India. Results demonstrated significant improvements in growth, biomass, physiology, and yield of mustard plant with increasing RHA application in wastewater irrigated soil (p ≤ 0.05). Heavy metal accumulation in different parts of mustard plants decreased as RHA application rate increased. Applying RHA at 2% in soil proved to be most effective in reducing Cd, Cr, Ni, Cu, and Zn accumulation in seeds by 29%, 29.6%, 23.1%, 21.3% and 20.1%, respectively in Varuna and 30.1%, 21.4%, 11.1%, 12.1%, and 28.5%, respectively in NRCHB 101cultivars. The present findings showed that RHA amendment in wastewater irrigated soil had reduced bioaccumulation of Cd, Cr, Ni, Cu, and Zn and consequently their toxicity in cultivated mustard plants. A novel application of RHA is unveiled in this research, offering a promising solution to promote sustainable agriculture and to reduce heavy metal associated health risks within the soil-mustard system.

Pilot Training Program on Hands-Only CPR and Choking First Aid for Frontline Police Responders in Rural Nepal.

INTRODUCTION: Basic life support (BLS) is an emergency skill that includes performing appropriate cardiopulmonary resuscitation (CPR). Out-of-hospital cardiac arrest (OHCA) is a leading cause of mortality worldwide and is rising in Nepal. After an OHCA event, a bystander starting CPR quickly has been shown to increase the survival rate. While the Nepali police are generally the first responders to emergencies in rural parts, they are not trained in BLS. This program assesses a pilot training of hands-only CPR and choking first aid to the Nepal Police and Nepal Army participants in rural Nepal. METHODS: A community-based nonprofit organization, HAPSA-Nepal, coordinated with local government to pilot this program. The program included pre- and post-tests, lectures, videos, and small group hands-on exercises; facilitators included faculty emergency physicians, residents, and medical officers. Structured pre- andp post-test questionnaires, confidence surveys, and skills checklists were conducted. Descriptive analysis examined the respondent's characteristics, and paired t-test was used to compare pretest and post-test scores. RESULTS: A total of 126 participants received the training in this pilot phase. Prior to this training, 98.4% of the participants had not received any CPR training, and 100% of the participants had not received training on first aid for choking. The average pretest score was 4.4 with 95% CI ± 1.75, and the average post-test score was 8.06 with 95% CI ± 1.73 (out of a total of 11). All participants passed the skills assessment. CONCLUSIONS: Locally adapted BLS training programs that included hands-only CPR and choking first aid showed a significant knowledge gain and skills competence among the frontline participants.

Screening of mustard cultivars for phytoremediation of heavy metals contamination in wastewater irrigated soil systems.

The mustard (Brassica juncea L.) plant is a well-known and widely accepted hyper-accumulator of heavy metals. The genetic makeup of mustard's cultivars may significantly impact their phytoremediation capabilities. The present study aimed to investigate the growth performance, yield attributes, and heavy metal accumulation potential of B. juncea cv. Varuna, NRCHB 101, RH 749, Giriraj, and Kranti, cultivated in soil irrigated with wastewater (EPS) and bore-well water (MPS). EPS contributed more Cr, Cd, Cu, Zn, and Ni to tested mustard cultivars than the MPS. EPS reduced morphological, biochemical, physiological, and yield attributes of tested mustard cultivars significantly (p < 0.05) than the MPS. Among the tested cultivars of mustard plants, Varuna had the highest heavy metal load with the lowest harvest index (35.8 and 0.21, respectively). Whereas NRCHB 101 showed the lowest heavy metal load with the highest harvest index (26.9 and 0.43, respectively). The present study suggests that B. juncea cv. Varuna and NRCHB 101 could be used for the phytoextraction of heavy metals and reducing their contamination in food chain, respectively in wastewater irrigated areas of peri-urban India. The outcomes of the present study can also be utilized to develop a management strategy for sustainable agriculture in heavy metal polluted areas resulting from long-term wastewater irrigation.

Temporal patterns of breast cancer incidence, mortality, disability-adjusted life years and risk factors in 12 South American Countries, 1990-2019: an examination using estimates from the global burden of disease 2019 study.

BACKGROUND AND AIM: Breast cancer (BC) is one of the leading causes of cancer deaths in females in South America. This study aims to examine the BC burden in 12 South American countries between 1990 and 2019. DATA AND METHODS: The estimates of BC burden and risk factors were procured from the Global Burden of Disease 2019 study for the period 1990-2019. Development levels of countries were gauged using socio-demographic index (SDI). Decomposition analysis was employed to categorize the change in incidence between 1990 and 2019 into three factors: population growth, population aging and age-specific incidence rate. Estimated annual percent changes were calculated for each country and bivariate association between country-level age-standardized rates and SDI was examined using pooled regression. RESULTS: The age-standardized rates of breast cancer were the highest in Uruguay [incidence: 72.65 per 100,000 (55.79-92.57); mortality: 29.97 per 100,000 (27.54-32.27); disability-adjusted life years (DALYs: 810.49 per 100,000 (746.22-884.55)] and lowest in Peru [incidence: 27.63 per 100,000 (20.44-36.85); mortality: 10.79 per 100,000 (8.14-14.11); DALYs: 318.27 per 100,000 (234.47-421.16)]. Mortality-to-incidence ratio (MIR) across countries varied from 0.30 in Colombia to 0.55 in Bolivia in 2019. SDI had a positive and strong association with age-standardized incidence rate [Formula: see text] and weaker positive association with age-standardized mortality rate [Formula: see text] and age-standardized DALYs rate [Formula: see text]. Most countries experienced more than 70% increase in incident cases owing to population aging and age-specific incidence rates. Alcohol Use, diet high in red meat and smoking contributed the maximum DALYs in most countries in 2019 whereas DALYs due to high body-mass index and high fasting plasma glucose increased most substantially between 1990 and 2019. CONCLUSION: With increasing incidence, high MIR and rising BC burden due to modifiable risk factors, several public health interventions are required in South America focusing on prevention, BC awareness among general public, cost-effective early detection and treatments that suit the socio-economic setup of South American countries.

Rationale and design of the TUXEDO-2 India study: Ultra-Thin strUt Supraflex Cruz versus XiencE in a Diabetic pOpulation with multi-vessel disease-2.

BACKGROUND: The role of percutaneous coronary interventions (PCI) in patients with diabetes mellitus and multi-vessel disease has been questioned by the results of the FREEDOM trial, which showed superiority of coronary artery bypass graft(CABG) over first generation drug-eluting stents (DES) including a reduction in mortality. In the light of safer and more efficacious stents and significantly better medical management, those results that date back to 2012 need to be revisited. TUXEDO-2 is a study designed to compare two contemporary stents in Indian diabetic patients with multi-vessel disease. AIMS: The primary objective of the TUXEDO-2 study is to compare the clinical outcomes of PCI with ultra-thin Supraflex Cruz vs Xience when combined with contemporary optimal medical therapy (OMT) in diabetic patients with multi-vessel disease. The secondary objective is to compare clinical outcomes between a pooled cohort from both arms of the study (Supraflex Cruz + Xience; PCI arm) vs CABG based on a performance goal derived from the CABG arm of the FREEDOM trial (historical cohort). The tertiary objective is a randomized comparison of ticagrelor vs prasugrel in addition to aspirin for the composite of ischemic and bleeding events. METHODS: In this prospective, open-label, multi-centre, 2 × 2 factorial, randomized, controlled study, 1,800 patients with diabetes mellitus and multi-vessel disease (inclusion criteria similar to FREEDOM trial) with indication for coronary revascularization will be randomly assigned to Supraflex Cruz or Xience stents and also to ticagrelor- or prasugrel- based antiplatelet strategies. All patients will receive guideline directed OMT and optimal PCI including image- and physiology-guided complete revascularization where feasible. The patients will be followed through five years to assess their clinical status and major clinical events. The primary endpoint is a non-inferiority comparison of target lesion failure at one-year for Supraflex Cruz vs Xience (primary objective) with an expected event rate of 11% and a non-inferiority margin of 4.5%. For PCI vs CABG (secondary objective), the primary endpoint is major adverse cardiac events (MACE), defined as a composite of all cause death, nonfatal myocardial infarction, or stroke at one-year and yearly up to five years, with a performance goal of 21.6%. For ticagrelor vs prasugrel (tertiary objective), the primary endpoint is composite of death, myocardial infarction, stroke, and major bleeding as per the Bleeding Academic Research Consortium (BARC) at one-year with expected event rate of 15% and a non-inferiority margin of 5%. CONCLUSIONS: The TUXEDO-2 study is a contemporary study involving state-of-the-art PCI combined with guideline directed OMT in a complex subset of patients with diabetes mellitus and multi-vessel disease. The trial will answer the question as to whether a biodegradable polymer coated ultra-thin Supraflex Cruz stent is an attractive option for PCI in diabetic patients with multi-vessel disease. It will also help address the question whether the results of FREEDOM trial would have been different in the current era of safer and more efficacious stents and modern medical therapy. In addition, the comparative efficacy and safety of ticagrelor vs prasugrel in addition to aspirin will be evaluated. (CTRI/2019/11/022088).

Spatial and temporal patterns of colorectal cancer in Asia, 1990-2019.

BACKGROUND: Asia accounts for the largest burden of colorectal cancer (CRC) worldwide. This study examines the temporal patterns of CRC in Asia in the last three decades. METHODS: The data pertaining to CRC burden measured by incidence, mortality, and disability-adjusted-life-years (DALYs) and its risk factors for 49 countries in the Asian continent were drawn from the Global Burden of Disease 2019 study between 1990 and 2019. Mortality-to-incidence ratio (MIR) was employed as a proxy indicator of 5-year survival rates. RESULTS: In Asia, incident cases more than tripled from 270,851 to 1.1 million, deaths tripled from 183,252 to 560,426, and DALYs more than doubled from 5 million to 13.4 million between 1990 and 2019. The age-standardized incidence rate (ASIR) increased from 14.0/100,000 to 23.9/100,000, age-standardized mortality rate (ASMR) increased from 10.1/100,000 to 12.5/100,000, and MIR decreased from 0.68 to 0.50 between 1990 and 2019. ASIR varied 10-folds across countries from 5.6/100,000 in Bangladesh to 62.0/100,000 in Taiwan in 2019 and ASMR from 4.9/1000 in Bangladesh to 30.3/100,000 in Brunei. In 2019, diet low in milk (18.7%) and whole grains (15.2%) and calcium (16.6%) were the major contributory risk factors in CRC DALYs in 2019. CONCLUSION: CRC is a fast-rising neoplasm in Asia and its burden can be curtailed by focusing on primary prevention (e.g., diet and physical activity) and secondary prevention through screening. The policy focus and resources must be directed towards capacity building, including cancer infrastructure and quality data availability from cancer registries.

Ecological niche modelling and population genetic analysis of Indian temperate bamboo Drepanostachyum falcatum in the western Himalayas.

The present study was conducted to understand the key ecological and biological questions of conservation importance in Drepanostachyum falcatum which aimed to map potential distribution in the western Himalayas and decipher spatial genetic structure. Eco-distribution maps were generated through ecological niche modelling using the Maximum Entropy (MaxEnt) algorithm implemented with 228 geocoordinates of species presence and 12 bioclimatic variables. Concomitantly, 26 natural populations in the western Himalayas were genetically analysed using ten genomic sequence-tagged microsatellite (STMS) markers. Model-derived distribution was adequately supported with appropriate statistical measures, such as area under the 'receiver operating characteristics (ROC)' curve (AUC; 0.917 ± 0.034)", Kappa (K; 0.418), normalized mutual information (NMI; 0.673) and true skill statistic (TSS; 0.715). Further, Jackknife test and response curves showed that the precipitation (pre- and post-monsoon) and temperature (average throughout the year and pre-monsoon) maximize the probabilistic distribution of D. falcatum. We recorded a wide and abundant (4096.86 km2) distribution of D. falcatum in the western Himalayas with maximum occurrence at 1500 to 2500 m asl. Furthermore, marker analysis exemplified high gene diversity with low genetic differentiation in D. falcatum. Relatively, the populations of Uttarakhand are more genetically diverse than Himachal Pradesh, whereas within the Uttarakhand, the Garhwal region captured a higher allelic diversity than Kumaon. Clustering and structure analysis indicated two major gene pools, where genetic admixing appeared to be controlled by long-distance gene flow, horizontal geographical distance, aspect, and precipitation. Both the species distribution map and population genetic structure derived herein may serve as valuable resources for conservation and management of Himalayan hill bamboos.

Users' Concerns About Endometriosis on Social Media: Sentiment Analysis and Topic Modeling Study.

BACKGROUND: Endometriosis is a debilitating and difficult-to-diagnose gynecological disease. Owing to limited information and awareness, women often rely on social media platforms as a support system to engage in discussions regarding their disease-related concerns. OBJECTIVE: This study aimed to apply computational techniques to social media posts to identify discussion topics about endometriosis and to identify themes that require more attention from health care professionals and researchers. We also aimed to explore whether, amid the challenging nature of the disease, there are themes within the endometriosis community that gather posts with positive sentiments. METHODS: We retrospectively extracted posts from the subreddits r/Endo and r/endometriosis from January 2011 to April 2022. We analyzed 45,693 Reddit posts using sentiment analysis and topic modeling-based methods in machine learning. RESULTS: Since 2011, the number of posts and comments has increased steadily. The posts were categorized into 11 categories, and the highest number of posts were related to either asking for information (Question); sharing the experiences (Rant/Vent); or diagnosing and treating endometriosis, especially surgery (Surgery related). Sentiment analysis revealed that 92.09% (42,077/45,693) of posts were associated with negative sentiments, only 2.3% (1053/45,693) expressed positive feelings, and there were no categories with more positive than negative posts. Topic modeling revealed 27 major topics, and the most popular topics were Surgery, Questions/Advice, Diagnosis, and Pain. The Survey/Research topic, which brought together most research-related posts, was the last in terms of posts. CONCLUSIONS: Our study shows that posts on social media platforms can provide insights into the concerns of women with endometriosis symptoms. The analysis of the posts confirmed that women with endometriosis have to face negative emotions and pain daily. The large number of posts related to asking questions shows that women do not receive sufficient information from physicians and need community support to cope with the disease. Health care professionals should pay more attention to the symptoms and diagnosis of endometriosis, discuss these topics with patients to reduce their dissatisfaction with doctors, and contribute more to the overall well-being of women with endometriosis. Researchers should also become more involved in social media and share new science-based knowledge regarding endometriosis.

Optimal vitamin D level ameliorates neurological outcome and quality of life after traumatic brain injury: a clinical perspective.

BACKGROUND: Deficiency of vitamin D along with traumatic brain injury (TBI) augments the risk of injury severity. This possibly affects the therapeutic regimen prescribed for TBI which may pessimistically affects its outcome. METHODS: Studies literature search was conducted in Google Scholar and PubMed. The inclusions were studies performed clinically on both male and female. All included studies' references were also reviewed to find any additional relevance related to this review. Studies published in English were considered for this review. This review focuses upon the incidence of vitamin D deficiency in TBI and how it affects the Quality of life of the sufferer. RESULTS: A total of 176 studies were reviewed and 58 were thoroughly focussed for review as they met inclusion criteria. These studies demonstrate that levels of vitamin D influence the recovery outcome after TBI. Vitamin D deficiency has been found to cause more deterioration in severe TBI than in patients with mild TBI. CONCLUSION: Paucity of vitamin D significantly affects the outcome after brain injury. This clearly validates the necessity for screening of vitamin D levels in neurological deficit in order to reduce the risk of morbidity in terms of neurocognitive disorder.

Mapping incidence and mortality of leukemia and its subtypes in 21 world regions in last three decades and projections to 2030.

This study examines the burden of leukemia and its subtypes at the global, regional, and national levels in 21 world regions and 204 countries in the last three decades. The estimates of incidence, deaths, and age-standardized rates of leukemia for 21 regions and 204 countries for 1990-2019 were extracted from the Global Burden of Disease 2019 study. Average annual percentage change in 1990-2019 for 21 regions was utilized for projecting leukemia burden in 2030. Globally, there were 643,579 [586,980-699,729] incident cases and 334,592 [306,818-360,214] deaths in 2019 due to leukemia, up from 474,924 [388,559-560,550] cases and 263,263 [233,664-298,696] deaths in 1990. Between 1990 and 2019, the age-standardized incidence rate (ASIR) decreased from 9.6 [8.1-11.0] in 1990 to 8.2 [7.5-8.9] per 100,000 person-years in 2019, and the age-standardized mortality rate (ASMR) decreased from 5.8/100,000 [5.2-6.4] in 1990 to 4.3/100,000 [3.9-4.6] in 2019. Between 1990 and 2019, the ASIR decreased in majority of regions except Western Europe and high-income Asia Pacific, whereas the ASMR decreased in all 21 regions. In 2019, country-wise, the ASIR varied from 3.0/100,000 [2.3-3.7] in Palau to 35.1/100,000 [26.4-47.2] in San Marino and the ASMR spanned from 2.3/100,000 [1.7-2.8] in San Marino to 15.8/100,000 [12.0-20.4] in Syria. As per our projections, globally, there will be 720,168 incident cases and 367,804 deaths due to leukemia in 2030. Substantial improvements have been witnessed in leukemia mortality rates in all regions, especially high-income regions and countries. Health care policies focusing on diagnostic improvements, cancer registration, and newer therapeutics at reduced cost or with insurance coverage are needed in low and middle-income countries.

Perioperative albuminuria and clinical model to predict acute kidney injury in paediatric cardiac surgery.

BACKGROUND: AKI is an important complication post cardiac surgery in children. An early diagnosis can help in mitigating complications and allow for prognostication. Urinary albumin:creatinine ratio (ACR) as a biomarker can provide a cheaper and more accessible AKI risk assessment and prediction. There is a paucity of paediatric literature regarding its utility. METHODS: This was a prospective observational study, enrolling all children aged 1 month to 18 years, who underwent cardiac surgery, with use of cardiopulmonary bypass. Cohort was divided into groups < 2 years and ≥ 2 years for analyses to account for differences in physiological albumin excretion with age. RESULTS: Of 143 children enrolled in the study, 36 developed AKI. In both age groups, the post-operative ACR was higher than pre-operative ACR among patients with and without AKI. In the group aged ≥ 2 years, the highest first post-operative ACR tertile (> 75.8 mg/g) predicted post-operative AKI after adjusting for clinical variables (adjusted RR, 11.71; 1.85-16.59). In the group aged < 2 years, the highest first post-operative ACR tertile (> 141.3 mg/g) predicted post-operative AKI in unadjusted analysis but not after adjusting for clinical variables (RR, 2.78; 0.70-6.65). For AKI risk prediction, AUC (95% CI) was highest after combining clinical model and pre-operative ACR for groups aged < 2 years [0.805 (0.713-0.896)] and ≥ 2 years [0.872 (0.772-0.973)]. CONCLUSIONS: This study provides evidence for use of albuminuria as a feasible biomarker in AKI prediction in children post cardiac surgery, especially when added to a clinical model. A higher resolution version of the Graphical abstract is available as Supplementary information.

A comparative examination of colorectal cancer burden in European Union, 1990-2019: Estimates from Global Burden of Disease 2019 Study.

AIM: This study examines the burden of colorectal cancer (CRC) in European Union (EU) countries in the last 3 decades. METHODS: The data pertaining to CRC burden were procured from the Global Burden of Disease 2019 Study for 28 EU countries (including United Kingdom) for the period 1990-2019. The age-standardized rates of CRC were utilized to compare the country-wise burden and joinpoint regression models were applied to examine the trends. RESULTS: In EU, CRC incident cases increased by 70.2% from 261,306 to 444,872 and deaths increased by 36.8% from 155,823 to 213,174 between 1990 and 2019. The age-standardized incidence rate (ASIR) increased by 11.9% from 37.8/100,000 to 42.3/100,000 between 1990 and 2019; in contrast, the age-standardized mortality rate (ASMR) decreased by 16.9% (1990: 22.4/100,000; 2019: 18.6/100,000) and age-standardized DALYs rate (ASDALR) decreased by 18.6% (1990: 472.9/100,000; 2019: 385.1/100,000) in the study period. In 2019, Hungary was the leading country in terms of ASMR (28.6/100,000) and ASDALR (630.3/100,000), and Lithuania (29.2/100,000) had the lowest ASIR, whereas Finland had the lowest ASMR (12.3/100,000) and ASDALR (253.6/100,000) in 2019. CONCLUSION: CRC incidence is increasing in EU and mortality rates, although decreasing, are still unacceptably high. CRC control efforts must be focused around early detection using screening and prevention through reduction of modifiable risk factors. Increasing CRC incidence rates in young adults in recent years requires more research to pinpoint risk factors, and there must be more awareness of this recent development among general public and clinicians.

Mapping of global, regional and national incidence, mortality and mortality-to-incidence ratio of lung cancer in 2020 and 2050.

AIM: Lung cancer is the leading cause of cancer deaths worldwide. This study examines the current and future burden of lung cancer at global, regional, and national levels. METHODS: The estimates of lung cancer incident cases, deaths, and their age-standardized rates are drawn from GLOBOCAN 2020 for 21 regions and 185 countries. Mortality-to-incidence ratio (MIR) is considered as a proxy indicator of 5-year survival rates. Lung cancer burden in 2050 is projected using age-specific incidence and death rates in 2020. RESULTS: In 2020, there were 2.21 million new cases and 1.8 million deaths due to lung cancer worldwide with age-standardized incidence rate (ASIR) of 22.4/100,000 (male: 31.5; female: 14.6) and age-standardized mortality rates (ASMR) of 18.0/100,000, (male: 25.9; female: 11.2/100,000). Global MIR of lung cancer was 0.82 (males 0.83; females: 0.79), varying from 0.59 (Japan) to 1.0 (Belize). Hungary had the highest age-standardized rates (ASIR: 50.1/100,000; ASMR: 42.4/100,000) and Nigeria (ASIR: 0.88; ASMR: 0.86) had the lowest age-standardized rates in 2020. Both ASIR and ASMR were positively correlated with country-level tobacco smoking prevalence and human development index (HDI), whereas MIR exhibited a negative correlation with HDI. As per our projections, there will be 3.8 million incident cases and 3.2 million deaths globally due to lung cancer in 2050. CONCLUSION: With close to 2 million cases and deaths already in 2020, lung cancer has already become a global public health threat. Even with current risk levels and age-specific rates, lung cancer annual cases are expected to reach 3.8 million in 2050. Until smoking prevalence is reduced and ambient air pollution levels are checked, particularly in low/medium HDI countries, the lung cancer epidemic will continue unfolding.

The burden of chronic kidney disease in Asia, 1990-2019: Examination of estimates from global burden of disease 2019 study.

BACKGROUND: Chronic kidney disease (CKD) is a global public health issue, with Asia accounting for one of the highest CKD prevalence worldwide. This study examines the burden of CKD in Asian continent in the last three decades. DATA AND METHODS: The estimates of age, sex and year wise burden of CKD for 49 countries in Asia for 1990 to 2019 were procured from the Global Burden of Disease 2019 study. FINDINGS: In 2019, there were 9.8 million [9.0-10.6 million] new cases and 763 024 [696 050-823 829] deaths due to CKD in Asia. Between 1990 and 2019, CKD prevalence doubled from 202.4 million [186.5-219.1 million] to 431.2 [400.3-462.0 million]. Although age-standardized incidence rate (ASIR) of CKD increased from 170.6 [156.7-186.2] in 1990 to 206.3 [190.4-223.4] per 100 000 person-years in 2019, the age-standardized mortality rate (ASMR) witnessed a modest reduction from 18.4/100 000 [17.0-20.1] to 17.3/100 000 [15.7-18.7]. In 2019, the ASIR spanned from 141.9/100 000 [126.2-159.2] in Tajikistan to 561.4/100 000 [524.6-598.6] in Saudi Arabia, and ASMR varied from 8.9/100 000 [7.2-9.8] in Japan to Saudi Arabia (52.9 [42.8-63.1]). Between 1990 and 2019, absolute count of CKD incident cases, deaths, prevalent cases and disability-adjusted life years (DALYs) increased 100% or more in 48/49, 32/49, 43/49 and 23/49 countries, respectively. INTERPRETATION: CKD is widespread in the Asian region, with an alarming burden in resource-constrained countries. Strategies such as promoting awareness, screening among high-risk individuals, provision of cost-effective therapies, and increased healthcare coverage could help deal with the CKD epidemic in Asia.

Renal Outcomes in Neonates and Infants with Transposition Physiology Undergoing Arterial Switch Procedure.

Acute kidney injury (AKI) in children with Transposition of Great arteries (TGA) undergoing Arterial Switch operation (ASO) is an important complication in the post-operative period associated with worse outcomes. AKI in children post open cardiac surgery has been well studied, with lesser data in literature pertaining to TGA and its sub-types specifically. This was a prospective, observational study enrolling infants with TGA undergoing ASO at a single center over a span of a decade from January 2010 to December 2020. The infants were followed during the duration of ICU and hospital stay, with documentation of baseline and intraoperative parameters as well as post-operative course. Out of 145 infants enrolled in the study, 83.1% developed AKI with majority (83.9%) having stage 1 AKI. Higher odds of AKI were seen in infants requiring Norepinephrine [odds ratio - 16.76 (95% CI 2.19-128.2), p < 0.001] and those who developed gram-negative infections [2.81 (1.04-7.56), p - 0.036]. Infants with AKI had significantly higher vasoactive-inotropic support at day 1 than those without AKI [16 (12.5-21.50 vs 13 (10.25-15.75), p - 0.014]. Seventeen infants in the AKI group (14%) died as opposed to none in the non-AKI group (p = 0.076). Median hours of ventilator support required were significantly higher in those with AKI than those who did not develop AKI (48 vs 45.5 p = 0.015). The infants with ASO + ASD + PDA (53% of neonates who died) were younger, had less weight at admission, more gram-negative sepsis and need for dopamine, as compared to ASO + VSD + ASD (23.5% of mortality) and ASO + ASD + VSD + aortic arch repair (23.5% of mortality). AKI in infants with TGA undergoing ASO is common and associated with poorer outcomes. In this subpopulation, AKI development is associated most commonly with hemodynamic instability and infections. This is the first study, looking at outcomes of TGA depending on the sub-types of ASO surgeries done in the infants [ASO with ASD + PDA or ASD + VSD or ASD + VSD + Arch Repair].

DNA Knot Malleability in Single-Digit Nanopores.

Knots in long DNA molecules are prevalent in biological systems and serve as a model system for investigating static and dynamic properties of biopolymers. We explore the dynamics of knots in double-stranded DNA in a new regime of nanometer-scale confinement, large forces, and short time scales, using solid-state nanopores. We show that DNA knots undergo isomorphic translocation through a nanopore, retaining their equilibrium morphology by swiftly compressing in a lateral direction to fit the constriction. We observe no evidence of knot tightening or jamming, even for single-digit nanopores. We explain the observations as the malleability of DNA, characterized by sharp buckling of the DNA in nanopores, driven by the transient disruption of base pairing. Our molecular dynamics simulations support the model. These results are relevant not only for the understanding of DNA packing and manipulation in living cells but also for the polymer physics of DNA and the development of nanopore-based sequencing technologies.

Gastric Outlet Obstruction: Don't Miss Duodenal Tuberculosis.

We report a case of isolated duodenal tuberculosis (TB) in a patient who presented with features of gastric outlet obstruction. The diagnosis was made on repeat endoscopic duodenal biopsy after initial histopathology failed to reveal the diagnosis. The patient recovered with antitubercular therapy. The index of suspicion has to be high in TB endemic countries as clinical, radiological, and endoscopic features are nonspecific.