Flu-like and other systemic drug reactions among persons receiving weekly rifapentine plus isoniazid or daily isoniazid for treatment of latent tuberculosis infection in the PREVENT tuberculosis study

BACKGROUND: Weekly rifapentine plus isoniazid for 3 months (3HP) is as effective as daily isoniazid for 9 months (9H) for latent tuberculosis infection in high-risk persons, but there have been reports of possible flu-like syndrome. METHODS: We identified clinically significant systemic drug reactions (SDR) and evaluated risk factors in patients who did not complete treatment in the PREVENT Tuberculosis study. RESULTS: Among 7552 persons who received ≥1 dose of study drug, 153 had a SDR: 138/3893 (3.5%) with 3HP vs 15/3659 (0.4%) with 9H (P < .001). In the 3HP arm, 87 (63%) had flu-like syndrome and 23 (17%) had cutaneous reactions; 13/3893 (0.3%) had severe reactions (6 were hypotensive) and 6 reported syncope. Symptoms occurred after a median of 3 doses, and 4 hours after the dose; median time to resolution was 24 hours. There were no deaths. In multivariate logistic regression analysis, factors independently associated with SDR included receipt of 3HP (adjusted odds ratio [aOR] 9.4; 95% confidence interval [CI], 5.5, 16.2), white non-Hispanic race/ethnicity (aOR 3.3; 95% CI, 2.3, 4.7), female sex (aOR 2.0; 95% CI, 1.4, 2.9), age ≥35 years (aOR 2.0; 95% CI, 1.4, 2.9), and lower body mass index (body mass index [BMI]; P = .009). In a separate multivariate analysis among persons who received 3HP, severe SDR were associated with white non-Hispanic race/ethnicity (aOR 5.4; 95% CI, 1.8, 16.3), and receipt of concomitant non-study medications (aOR 5.9; 95% CI, 1.3, 27.1). CONCLUSIONS: SDR were more common with 3HP, and mostly flu-like. Persons of white race, female sex, older age, and lower BMI were at increased risk. Severe reactions were rare and associated with 3HP, concomitant medication, and white race. The underlying mechanism is unclear

TMEM33 regulates intracellular calcium homeostasis in renal tubular epithelial cells

Mutations in the polycystins cause autosomal dominant polycystic kidney disease (ADPKD). Here we show that transmembrane protein 33 (TMEM33) interacts with the ion channel polycystin-2 (PC2) at the endoplasmic reticulum (ER) membrane, enhancing its opening over the whole physiological calcium range in ER liposomes fused to planar bilayers. Consequently, TMEM33 reduces intracellular calcium content in a PC2-dependent manner, impairs lysosomal calcium refilling, causes cathepsins translocation, inhibition of autophagic flux upon ER stress, as well as sensitization to apoptosis. Invalidation of TMEM33 in the mouse exerts a potent protection against renal ER stress. By contrast, TMEM33 does not influence pkd2-dependent renal cystogenesis in the zebrafish. Together, our results identify a key role for TMEM33 in the regulation of intracellular calcium homeostasis of renal proximal convoluted tubule cells and establish a causal link between TMEM33 and acute kidney injury

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Incorporating different proportions of exotic maize germplasm into two adapted populations

Maize breeders frequently wish to use exotic germplasm in their breeding programs without losing specific characteristics of their adapted material. The objective of this study was to determine the optimal proportions of exotic germplasm to incorporate into adapted populations (F2 = 50% exotic, BC1 = 25% exotic, BC2 = 12.5% exotic and BC3 = 6.25% exotic) to form the initial foundation population and to determine the heterosis between adapted x exotics. We used six exotic populations of different origins and two adapted populations representing a Brazilian heterotic pattern. In 1993-94 and 1994-95, the parents, F1, F2, BC1, BC2, BC3 and four checks were evaluated in six environments in central Brazil using an 8 x 9 simple rectangular lattice design. Higher mean values for yield were obtained as the proportion of exotic germplasm decreased. Some backcrosses produced more than the adapted populations BR 105 (7.59 ton/ha) and BR 106 (8.43 ton/ha). The best results were obtained when incorporating 6.25 or 12.5% of exotic genes. This trend was true for root lodging, stalk lodging and ear diseases but not for plant and ear height. The midparent heterosis for yield varied from -16.1 to 40.3%. Midparent heterosis with positive and negative values were also found for the other traits. The results indicate the potential of exotic germplasm for developing good hybrids. After choosing the best exotic source, some recurrent selection might be appropriate in order to adapt and improve the exotic populations.<br>Os melhoristas de milho que utilizam germoplasmas exóticos nos programas de melhoramento têm a preocupação de não perder as características desejáveis dos materiais adaptados. Buscando atender esta demanda, o presente trabalho teve por objetivo determinar a proporção ideal de germoplasma exótico que deve ser incorporado em populações melhoradas (F2 = 50% exótico; RC1 = 25% exótico; RC2 = 12,5% exótico; RC3 = 6,25% exótico), para formar as populações base para seleção e determinar a heterose entre os germoplasmas exóticos e adaptados. Em 1993/94 e 1994/95, os parentais, F1, F2, RC1, RC2, RC3 e quatro testemunhas foram avaliados em seis ambientes da região central do Brasil, utilizando-se o delineamento em látice simples 8 x 9. De um modo geral, à medida que a proporção de germoplasma exótico decresceu, valores médios mais altos foram obtidos para o caráter peso de espigas. Alguns retrocruzamentos produziram mais que as populações melhoradas BR 105 (7.500 kg/ha) e BR 106 (8.430 kg/ha). Os melhores resultados foram obtidos quando houve a incorporação de 6,25 ou 12,5% de genes exóticos. Esta tendência foi observada para acamamento, quebramento e espigas doentes, mas não para altura de planta e de espiga. A heterose média para peso de espiga variou de -16,1 a 40,3%. Heteroses médias com valores positivos e negativos também foram encontradas para outros caracteres. Os resultados obtidos mostraram o potencial em se utilizar germoplasmas exóticos para a obtenção de híbridos. Sugere-se, após a escolha dos germoplasma, algum esquema de seleção recorrente para adaptar e melhorar as populações exóticas

Investigation of major international and Turkish companies via hierarchical methods and bootstrap approach

We present a study, within the scope of econophysics, of the hierarchical structure of 98 among the largest international companies including 18 among the largest Turkish companies, namely Banks, Automobile, Software-hardware, Telecommunication Services, Energy and the Oil-Gas sectors, viewed as a network of interacting companies. We analyze the daily time series data of the Boerse-Frankfurt and Istanbul Stock Exchange. We examine the topological properties among the companies over the period 2006-2010 by using the concept of hierarchical structure methods (the minimal spanning tree (MST) and the hierarchical tree (HT)). The period is divided into three subperiods, namely 2006-2007, 2008 which was the year of global economic crisis, and 2009-2010, in order to test various time-windows and observe temporal evolution. We carry out bootstrap analyses to associate the value of statistical reliability to the links of the MSTs and HTs. We also use average linkage clustering analysis (ALCA) in order to better observe the cluster structure. From these studies, we find that the interactions among the Banks/Energy sectors and the other sectors were reduced after the global economic crisis; hence the effects of the Banks and Energy sectors on the correlations of all companies were decreased. Telecommunication Services were also greatly affected by the crisis. We also observed that the Automobile and Banks sectors, including Turkish companies as well as some companies from the USA, Japan and Germany were strongly correlated with each other in all periods