Long-term Impact of Changing Childhood Malnutrition on Rotavirus Diarrhoea: Two Decades of Adjusted Association with Climate and Socio-Demographic Factors from Urban Bangladesh

Background There is strong association between childhood rotavirus, diarrhoea, climate factors and malnutrition. Conversely, a significant nutritional transition (reduced under-nutrition) with a concurrent increasing trend of rotavirus infection in last decade was also observed among under 5 children, especially in developing countries including Bangladesh. Considering the pathophysiology of rotavirus, there might be an interaction of this nutrition transition which plays a pivotal role in increasing rotavirus infection in addition to climate and other man-made factors in urban areas such as Dhaka, Bangladesh. Methods Relevant monthly data from 1993–2012 were extracted from the archive of the Diarrhoeal Disease Surveillance System of icddr, b and linked with data collected from the Dhaka station of the Bangladesh Meteorological Department (mean temperature, rainfall, sea level pressure and humidity). Seasonal autoregressive integrated moving average time series models were deployed to determine the association between the monthly proportion of rotavirus infection and underweight, stunting and wasting adjusting for climate, socio-demographic and sanitation factors. Finding The proportion of rotavirus cases among all causes diarrhoea increased from 20% in 1993 to 43% in 2012 (Chi squared for trend p = 0.010). In contrast, underweight, stunting and wasting decreased from 59%-29% (p \u3c 0.001); 53%-21% (p \u3c 0.001) and 32%-22% (p \u3c 0.001) respectively over the same period. Mean ambient temperature increased from 25.76°C-26.62°C (p = 0.07); mean rainfall, sea level pressure and mean humidity decreased from 234.92–111.75 mm (p = 0.5), 1008.30–1006.61 mm of hg (p = 0.02) and 76.63%-70.26% (p \u3c 0.001), respectively. In the adjusted model, a decrease in monthly proportion of underweight [coef.: -0.189 (95% CI:-0.376, -0.003)] and wasting [-0.265 (-0.455, -0.075)] were significantly and inversely associated with rotavirus infection. However, an inverse but insignificant association was observed for stunting [-0.070 (-0.249, 0.109)]. Interpretation The reduction of acute childhood malnutrition is significantly associated with increasing rotavirus diarrhoea among under-5 children. Thus mass vaccination in addition to interventions directed at man-made modifiable predictors for prevention and control is warranted

Antileukemic activity of the HSP70 inhibitor pifithrin-μ in acute leukemia

Heat shock protein (HSP) 70 is aberrantly expressed in different malignancies and has emerged as a promising new target for anticancer therapy. Here, we analyzed the in vitro antileukemic effects of pifithrin-μ (PFT-μ), an inhibitor of inducible HSP70, in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) cell lines, as well as in primary AML blasts. PFT-μ significantly inhibited cell viability at low micromolar concentrations in all cell lines tested, with IC50 values ranging from 2.5 to 12.7 μ, and was highly active in primary AML blasts with a median IC50 of 8.9 μ (range 5.7–37.2). Importantly, higher IC50 values were seen in normal hematopoietic cells. In AML and ALL, PFT-μ induced apoptosis and cell cycle arrest in a dose-dependent fashion. PFT-μ also led to an increase of the active form of caspase-3 and reduced the intracellular concentrations of AKT and ERK1/2 in NALM-6 cells. Moreover, PFT-μ enhanced cytotoxicity of cytarabine, 17-(allylamino)-17-desmethoxygeldanamycin, suberoylanilide hydroxamic acid, and sorafenib in NALM-6, TOM-1 and KG-1a cells. This is the first study demonstrating significant antileukemic effects of the HSP70 inhibitor PFT-μ, alone and in combination with different antineoplastic drugs in both AML and ALL. Our results suggest a potential therapeutic role for PFT-μ in acute leukemias

Observation of Higgs boson production in association with a top quark pair at the LHC with the ATLAS detector

The observation of Higgs boson production in association with a top quark pair (tt H¯ ), based on the analysis of proton–proton collision data at a centre-of-mass energy of 13 TeV recorded with the ATLAS detector at the Large Hadron Collider, is presented. Using data corresponding to integrated luminosities of up to 79.8 fb−1, and considering Higgs boson decays into b¯ b, W W ∗, τ +τ −, γγ , and Z Z∗, the observed significance is 5.8 standard deviations, compared to an expectation of 4.9 standard deviations. Combined with the tt H¯ searches using a dataset corresponding to integrated luminosities of 4.5 fb−1 at 7 TeV and 20.3 fb−1 at 8 TeV, the observed (expected) significance is 6.3 (5.1) standard deviations. Assuming Standard Model branching fractions, the total tt H¯ production cross section at 13 TeV is measured to be 670 ± 90 (stat.) +110 −100 (syst.) fb, in agreement with the Standard Model prediction

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Vitamin D Supplementation among Bangladeshi Children under-Five Years of Age Hospitalised for Severe Pneumonia: A Randomised Placebo Controlled Trial

INTRODUCTION: Vitamin D is important for its immunomodulatory role and there is an independent association between vitamin D deficiency and pneumonia. We assessed the effect of vitamin D supplementation on the outcome in children hospitalized for severe pneumonia. METHODS: This was a randomised, double blinded, placebo-controlled clinical trial in children aged \u3e2–59 months with severe pneumonia attending Dhaka Hospital, icddr,b. Children received age-specific megadose of vitamin D3 (20,000IU: \u3c 6 months, 50,000 IU: 6–12 months, 100,000 IU:13–59 months) or placebo on first day and 10,000 IU as maintenance dose for next 4 days or until discharge (if discharged earlier) along with standard therapy. This trial is registered at ClinicalTrials.gov, number NCT02185196. FINDINGS: We enrolled 100 children in placebo group and 97 in vitamin D group. On admission, 50 (52%) and 49 (49%) of children in vitamin D and placebo groups, respectively were vitamin D deficient. Among children with a sufficient serum vitamin D level on admission, a lower trend for duration of resolution of severe pneumonia in hours [72(IQR:44-96)vs. 88(IQR:48-132);p = 0.07] and duration of hospital stay in days [4(IQR:3-5)vs.5(IQR:4-7);P = 0.09] was observed in vitamin D group compared to placebo. No beneficial effect was observed in vitamin D deficient group or irrespective of vitamin D status. CONCLUSION: Age-specific mega dose of vitamin D followed by a maintenance dose shown to have no statistical difference between the two intervention groups, however there was a trend of reduction of time to recovery from pneumonia and overall duration of hospital stay in under-five children with a sufficient serum vitamin D level on hospital admission

Moving average of yearly estimated to total patients and under-5 years children, proportion of rotavirus, underweight, stunting, wasting, mean temperature, rainfall, sea level pressure and humidity (1993–2012).

<p>Moving average of yearly estimated to total patients and under-5 years children, proportion of rotavirus, underweight, stunting, wasting, mean temperature, rainfall, sea level pressure and humidity (1993–2012).</p