12-(4-Methoxy­phen­yl)-10-phenyl-3,4,5,6,8,10-hexa­azatricyclo­[7.3.0.02,6]dodeca-1(9),2,4,7,11-penta­ene

In the title compound, C19H14N6O, the fused 12-membered tetra­zolo/pyrimidine/pyrrole ring system is almost planar (r.m.s. deviation = 0.013 Å). The 4-methoxy­phenyl and phenyl substituents on the pyrrole ring are both twisted with respect to the fused-ring system [dihedral angles = 25.39 (18) and 36.42 (18)°, respectively]. Intra­molecular C—H⋯N inter­actions occur. In the crystal, mol­ecules pack into layers in the ac plane and these are connected along the b axis via C—H⋯π and π–π [centroid–centroid separation = 3.608 (3) Å] inter­actions

7-(4-Chloro­phen­yl)-9-phenyl-7H-pyrrolo[3,2-e]tetra­zolo[1,5-c]pyrimidine

In the title compound, C18H11ClN6, the pyrrole, pyrimidine and tetra­zole rings form a nearly planar fused trihetrocyclic system with an r.m.s. deviation of 0.0387 (13) Å, to which the 4-chloro­phenyl group and the phenyl group are substituted at the 7 and 9 positions, respectively. The dihedral angles between the pyrrole ring and the 4-chloro­phenyl and phenyl rings are 32.1 (4) and 7.87 (7)°, respectively. In the crystal, weak inter­molecular C—H⋯N and C—H⋯Cl hydrogen bonds link the mol­ecules into a layer parallel to the (001) plane. The layers are further connected by π–π stacking inter­actions [centroid–centroid distances: 3.8413 (8) and 3.5352 (8) Å]. Intra­molecular C—H⋯N hydrogen bonds are also present

Characterization of greater middle eastern genetic variation for enhanced disease gene discovery

The Greater Middle East (GME) has been a central hub of human migration and population admixture. The tradition of consanguinity, variably practiced in the Persian Gulf region, North Africa, and Central Asia1-3, has resulted in an elevated burden of recessive disease4. Here we generated a whole-exome GME variome from 1,111 unrelated subjects. We detected substantial diversity and admixture in continental and subregional populations, corresponding to several ancient founder populations with little evidence of bottlenecks. Measured consanguinity rates were an order of magnitude above those in other sampled populations, and the GME population exhibited an increased burden of runs of homozygosity (ROHs) but showed no evidence for reduced burden of deleterious variation due to classically theorized ‘genetic purging’. Applying this database to unsolved recessive conditions in the GME population reduced the number of potential disease-causing variants by four- to sevenfold. These results show variegated genetic architecture in GME populations and support future human genetic discoveries in Mendelian and population genetics

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

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

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Efficacy and Safety Evaluation of Myostaal Forte, a Polyherbal Formulation, in Treatment of Knee Osteoarthritis: A Randomised Controlled Pilot Study

Introduction: Myostaal Forte, a proprietary poly-herbal formulation, is mixture of nine herbal plant extracts which possess analgesic, anti-inflammatory and chondroprotective properties. Aim: A prospective, randomised, active controlled, 2-arm, parallel group, assessor blind study was planned to evaluate clinical efficacy and safety of Myostaal Forte in patients of knee osteoarthritis. Materials and Methods: Idiopathic knee osteoarthritis cases as per American College of Rheumatology (ACR) clinical criteria were screened and recruited. A total of sixty patients were assigned to receive Myostaal Forte TDS (n=30) or Paracetamol 650 mg TDS (n=30) for six weeks. Naproxen was rescue analgesia. Modified Western Ontario and McMaster Universities Arthritis Index (WOMAC), Visual Analogue Scale (VAS), global assessment scores determined by orthopaedic physician at baseline, two, four, six weeks and telephonically at eight weeks. Safety was assessed through laboratory investigations at baseline and six weeks, adverse events and tolerability. Data were expressed as Mean±SD and analysed by Chi-square and unpaired t-test. p<0.05 was considered significant. Results: Myostaal Forte and Paracetamol showed significant reduction in osteoarthritis disease activity. Myostaal Forte produced significant improvement compared to Paracetamol, in the pain, stiffness and physical function from baseline to eight weeks (p0.05). No significant adverse events, changes in the laboratory parameters and excellent compliance to treatment were seen in both the groups. Conclusion: Earlier onset analgesic effect with sustained chondroprotection after treatment cessation makes Myostaal Forte, a safe and effective alternative for treatment of knee osteoarthritis

Clinical features, laboratory and molecular findings of children with leukocyte adhesion deficiency type-III from a single center in India

Leukocyte adhesion deficiency (LAD) Type-III is caused by homozygous mutations in FERMT3 causing Kindlin-3 deficiency. Here we describe three children with molecularly proven LAD-III presenting with neonatal onset mucocutaneous bleeding, infections and persistent neutrophilic leukocytosis. CD18 and CD11a expression on neutrophils was normal in all three, thus ruling out LAD-I. All three had normal platelet glycoprotein expression. Platelet aggregation studies in P2 showed an abnormality similar to Glanzmann thrombasthenia. This article aims to highlight clinical and laboratory clues to the diagnosis of LAD-III, aiding prompt administration of prophylaxis and curative therapy of haematopoietic stem cell transplant