End-Stage Kidney Failure in Oman: An Analysis of Registry Data with an Emphasis on Congenital and Inherited Renal Diseases

\ua9 2017 Intisar Al Alawi et al. Globally, end-stage kidney disease (ESKD) is a huge burden on health care systems. The aims of this study were to perform a comprehensive epidemiological and etiological report of ESKD patients commencing RRT in Oman with an emphasis on genetic causes and inherited kidney disease. All newly registered Omani patients with ESKD commencing RRT from 2001 until 2015 (n=2,922) were analysed using the RRT register in Oman. All potentially genetic or inherited causes of ESKD were reviewed. In Oman, ESKD is more prevalent in males (57.1%) than females (42.9%) with a median age of incident ESKD of 53 years. Diabetic nephropathy was the most prevalent cause of ESKD (46%), followed by hypertensive nephropathy (19%), glomerulonephritis (15%), and inherited kidney disease (5%). For patients less than 20 years of age inherited kidney disease accounted for 32.5% of cases. Of this cohort with inherited renal disease, 40.3% had autosomal dominant polycystic kidney disease, 11.5% had congenital anomalies of the kidney and urinary tract, 9.4% had Alport syndrome, and 7.2% had autosomal recessive polycystic kidney disease. This study represents a comprehensive population-based epidemiological and etiological report of ESKD patients in Oman commencing RRT. Inherited kidney disease was the leading cause of paediatric ESKD

Immunoprofiling of leukemic stem cells CD34+/CD38−/CD123+ delineate FLT3/ITD-positive clones

Abstract Background Acute myeloid leukemia (AML) is a heterogeneous clonal disorder presenting with accumulation of proliferating undifferentiated blasts. Xenograft transplantation studies have demonstrated a rare population of leukemia-initiating cells called leukemic stem cells (LSCs) capable of propagating leukemia that are enriched in the CD34+/CD38− fraction. LSCs are quiescent, resistant to chemotherapy and likely responsible for relapse and therefore represent an ideal target for effective therapy. LSCs are reported to overexpress the alpha subunit of the IL-3 receptor (CD123) compared to normal CD34+/CD38− hematopoietic stem cells. It has not been demonstrated whether CD123-positive (CD34+/CD38−) subpopulation is enriched for any clonal markers of AML or any LSC properties. The aims of this study were to investigate whether FMS-like tyrosine kinase (FLT3)/internal tandem duplication (ITD) mutations are present at LSC level and whether FLT3/ITD mutation is confined to LSC as defined by CD34+/CD38−/CD123+ and not CD34+/CD38−/CD123−. Methods Thirty-four AML cases were analyzed by five-color flow cytometry and sequential gating strategy to characterize of CD34+/CD38−/CD123+ cells. These cells were sorted, analyzed by PCR, and sequenced for FLT3/ITD. Results In this study, we confirm significant expression of CD123 in 32/34 cases in the total blast population (median expression = 86 %). CD123 was also expressed in the CD34+/CD38− cells (96 ± 2 % positive) from 28/32 for CD123+ AML. CD123 was not expressed/low in normal bone marrow CD34+/CD38− cells (median expression = 0 %, range (0–.004 %). AML samples were tested for FLT3/ITD (10 positive/25). FLT3/ITD+ AML cases were sorted into two putative LSC populations according to the expression of CD123 and analyzed for FLT3/ITD again in the stem cell fractions CD34+/CD38−/CD123+ and CD34+/CD38−/CD123−. Interestingly, FLT3/ITD was only detected in CD34+/CD38−/CD123+ (7/7) and not in CD34+/CD38−/CD123− subpopulation (6/7). Conclusions This finding shows that FLT3/ITD are present at LSC level and may be a primary and not secondary event in leukemogenesis, and the oncogenic events of FLT3/ITD happen at a cell stage possessing CD123. It shows that CD123 immunoprofiling provides further delineation of FLT3+ LSC clone. This novel finding provides a rationale for treatment involving CD123-targeting antibodies with intracellular FLT3 inhibitors directed against CD34+/CD38−/CD123+. This may result in more effective anti-LSC eradication

Structural, 57 Fe Mössbauer and XPS studies of mechanosynthesized nanocrystalline Nd0.33Eu0.67Fe1-xCrxO3 particles

We report on the structure and surface composition of Nd0.33Eu0.67Fe1-xCrxO3 (x = 0.0, 0.3, 0.5, 0.7, 0.9 and 1.0) nanoparticles (∼30 nm) mechanosynthesized at temperatures that are ∼ 470– 700 °C lower than those at which the pure and doped pristine materials conventionally form. XRD Rietveld and FT-IR analyses show that with increasing x the lattice parameters decrease and the bond lengths and angles vary in a way that reduces crystalline distortion. Whilst the majority of the Eu3+/Nd3+ and Fe3+/Cr3+ cations occupy the normal perovskite-related A- and B-sites, respectively, ∼ 5% of them exchange sites. 57Fe Mössbauer spectroscopy confirms the presence of these antisites and reveals a superparamagnetic behaviour at 298 K that enhances with increasing x. XPS measurement reveals a complex surface composition of the nanoparticles with traces of Eu2O3, Nd2O3, Cr2O3 and Fe2O3 as well as partial O2--deficiency

Forecasting the type 2 diabetes mellitus epidemic and the role of key risk factors in Oman up to 2050: Mathematical modeling analyses.

AIMS/INTRODUCTION: To investigate and forecast type 2 diabetes mellitus epidemic, its related risk factors and cost in Oman by 2050. MATERIALS AND METHODS: An age-structured mathematical model was used to characterize type 2 diabetes mellitus epidemiology and trends in Oman between 1990 and 2050. The model was parametrized using current and quality data, including six nationally representative population-based epidemiological surveys for type 2 diabetes mellitus and its key risk factors. RESULTS: The projected type 2 diabetes mellitus prevalence increased from 15.2% in 2020 to 23.8% in 2050. The prevalence increased from 16.8 and 13.8% in 2020 among women and men to 26.3 and 21.4% in 2050, respectively. In 2020, 190,489 Omanis were living with type 2 diabetes mellitus compared with 570,227 in 2050. The incidence rate per 1,000 person-years changed from 8.3 in 2020 to 12.1 in 2050. Type 2 diabetes mellitus' share of Oman's national health expenditure grew by 36% between 2020 and 2050 (from 21.2 to 28.8%). Obesity explained 56.7% of type 2 diabetes mellitus cases in 2020 and 71.4% in 2050, physical inactivity explained 4.3% in 2020 and 2.7% in 2050, whereas smoking accounted for <1% of type 2 diabetes mellitus cases throughout 2020-2050. Sensitivity and uncertainty analyses affirmed these predictions. CONCLUSIONS: The type 2 diabetes mellitus epidemic in Oman is expected to increase significantly over the next three decades, consuming nearly one-third of the national health expenditure. The type 2 diabetes mellitus burden is heavily influenced by obesity. Interventions targeting this single risk factor should be a national priority to reduce and control the burden of type 2 diabetes mellitus in Oman

Impact of mitigating obesity, smoking, and physical inactivity on type 2 diabetes mellitus burden in Oman: insights from mathematical modeling.

INTRODUCTION: To estimate the impact of reducing obesity, smoking, and physical inactivity (PIA) prevalence, and of introducing physical activity (PA) as an explicit intervention, on the prevalence, incidence, and mortality of type 2 diabetes mellitus (T2DM) in Oman. RESEARCH DESIGN AND METHODS: A deterministic population-level mathematical model was employed to investigate the impact of different scenarios for reducing T2DM risk factors on T2DM epidemiology. The model was stratified by sex, age group, risk factor status, T2DM status, and intervention status and parameterized with nationally representative data. Intervention scenarios were calculated and compared with a baseline (no-intervention) scenario for changes in T2DM prevalence, incidence, and mortality among adult Omanis between 2020 and 2050. RESULTS: In the no-intervention scenario, T2DM prevalence increased from 15.2% in 2020 to 23.8% in 2050. Achieving the goals of halting the rise of obesity, reducing smoking by 30%, and reducing PIA by 10% as outlined in the WHO's Global Action Plan for Non-communicable Diseases (implemented between 2020 and 2030 and then maintained between 2031 and 2050) would reduce T2DM prevalence by 32.2%, cumulative incidence by 31.3%, and related deaths by 19.3% by 2050. Halting the rise of or reducing obesity prevalence by 10%-50% would reduce T2DM prevalence by 33.0%-51.3%, cumulative incidence by 31.9%-53.0%, and related deaths by 19.5%-35.6%. Reducing smoking or PIA prevalence by 10%-50% would lead to smaller reductions of less than 5% in T2DM prevalence, cumulative incidence, and related deaths. Introducing PA with varying intensities at a 25% coverage would reduce T2DM prevalence by 4.9%-14.1%, cumulative incidence by 4.8%-13.8%, and related deaths by 3.4%-9.6% by 2050. CONCLUSIONS: Intervention-for-prevention efforts targeting obesity reduction and introducing PA could result in major reductions in the T2DM burden. Prioritizing such interventions could alleviate the burden of T2DM in Oman and other countries with similarly high T2DM and obesity burdens

Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO Solidarity randomised trial and updated meta-analyses

Background The Solidarity trial among COVID-19 inpatients has previously reported interim mortality analyses for four repurposed antiviral drugs. Lopinavir, hydroxychloroquine, and interferon (IFN)-beta 1a were discontinued for futility but randomisation to remdesivir continued. Here, we report the final results of Solidarity and meta-analyses of mortality in all relevant trials to date.Methods Solidarity enrolled consenting adults (aged &gt;= 18 years) recently hospitalised with, in the view of their doctor, definite COVID-19 and no contraindication to any of the study drugs, regardless of any other patient characteristics. Participants were randomly allocated, in equal proportions between the locally available options, to receive whichever of the four study drugs (lopinavir, hydroxychloroquine, IFN-beta 1a, or remdesivir) were locally available at that time or no study drug (controls). All patients also received the local standard of care. No placebos were given. The protocol specified primary endpoint was in-hospital mortality, subdivided by disease severity. Secondary endpoints were progression to ventilation if not already ventilated, and time-to-discharge from hospital. Final log-rank and Kaplan Meier analyses are presented for remdesivir, and are appended for all four study drugs. Meta-analyses give weighted averages of the mortality findings in this and all other randomised trials of these drugs among hospital inpatients. Solidarity is registered with ISRCTN, ISRCTN83971151, and ClinicalTrials.gov, NCT04315948.Findings Between March 22, 2020, and Jan 29, 2021, 14 304 potentially eligible patients were recruited from 454 hospitals in 35 countries in all six WHO regions. After the exclusion of 83 (0.6%) patients with a refuted COVID-19 diagnosis or encrypted consent not entered into the database, Solidarity enrolled 14 221 patients, including 8275 randomly allocated (1:1) either to remdesivir (ten daily infusions, unless discharged earlier) or to its control (allocated no study drug although remdesivir was locally available). Compliance was high in both groups. Overall, 602 (14.5%) of 4146 patients assigned to remdesivir died versus 643 (15.6%) of 4129 assigned to control (mortality rate ratio [RR] 0.91 [95% CI 0.82-1.02], p=0.12). Of those already ventilated, 151 (42.1%) of 359 assigned to remdesivir died versus 134 (38.6%) of 347 assigned to control (RR 1.13 [0.89-1.42], p=0.32). Of those not ventilated but on oxygen, 14.6% assigned to remdesivir died versus 16.3% assigned to control (RR 0.87 [0.76-0.99], p=0.03). Of 1730 not on oxygen initially, 2.9% assigned to remdesivir died versus 3.8% assigned to control (RR 0.76 [0.46-1.28], p=0.30). Combining all those not ventilated initially, 11.9% assigned to remdesivir died versus 13.5% assigned to control (RR 0.86 [0.76-0.98], p=0.02) and 14.1% versus 15.7% progressed to ventilation (RR 0.88 [0.77-1.00], p=0.04). The non-prespecified composite outcome of death or progression to ventilation occurred in 19.6% assigned to remdesivir versus 22.5% assigned to control (RR 0.84 [0.75-0.93], p=0.001). Allocation to daily remdesivir infusions (vs open-label control) delayed discharge by about 1 day during the 10-day treatment period. A meta-analysis of mortality in all randomised trials of remdesivir versus no remdesivir yielded similar findings.Interpretation Remdesivir has no significant effect on patients with COVID-19 who are already being ventilated. Among other hospitalised patients, it has a small effect against death or progression to ventilation (or both)

Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO Solidarity randomised trial and updated meta-analyses.

BACKGROUND World Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs - remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a - in patients hospitalized with coronavirus disease 2019 (Covid-19). METHODS We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry. RESULTS At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan-Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P = 0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P = 0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P = 0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P = 0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration. CONCLUSIONS These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. (Funded by the World Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov number, NCT04315948.)