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In one comparison from a 2-by-2 factorial trial, over 12,000 participants with a mean baseline blood pressure of 138/82 mm Hg were assigned to candesartan plus hydrochlorothiazide or to placebo. At 5.6 years, there was no between-group difference in the rates of cardiovascular events. High blood pressure is the leading risk factor for cardiovascular disease globally 1 and affects more than 1 billion adults worldwide. 2 Observational studies involving persons without cardiovascular disease show a graded increase in risk at systolic blood-pressure levels above 115 mm Hg. 3 It has been suggested that lowering blood pressure at any level above this value will reduce the risk of cardiovascular events. 4 Antihypertensive therapy has been clearly shown to reduce the risk of cardiovascular disease among people with vascular or renal disease, diabetes, or hypertension with end-organ damage or, in the absence of these conditions, among persons with a systolic . . .

In a 2-by-2 factorial trial, 12,705 persons at intermediate risk were assigned to candesartan plus hydrochlorothiazide or placebo and to rosuvastatin or placebo. At 5.6 years, combination therapy resulted in a significantly lower risk of cardiovascular events than dual placebo. Cardiovascular diseases are major causes of death and illness worldwide. 1 Both systolic blood pressure and low-density lipoprotein (LDL) cholesterol show graded associations with cardiovascular disease and together account for two thirds of the population-attributable risk of cardiovascular disease. 2 – 4 Therefore, combined lowering of LDL cholesterol and blood pressure can potentially have a bigger effect in reducing cardiovascular events than either intervention alone. Because the majority of cardiovascular events occur in persons at average risk with no previous cardiovascular disease, a strategy of broad population-based treatment of LDL cholesterol and blood pressure could be more effective than targeting only high-risk persons. . . .

Atrial fibrillation is an important cause of morbidity and mortality worldwide, but scant data are available for long-term outcomes in individuals outside North America or Europe, especially in primary care settings. We did a cohort study using a prospective registry of patients in 47 countries who presented to a hospital emergency department with atrial fibrillation or atrial flutter as a primary or secondary diagnosis. 15 400 individuals were enrolled to determine the occurrence of death and strokes (the primary outcomes) in this cohort over eight geographical regions (North America, western Europe, and Australia; South America; eastern Europe; the Middle East and Mediterranean crescent; sub-Saharan Africa; India; China; and southeast Asia) 1 year after attending the emergency department. Patients from North America, western Europe, and Australia were used as the reference population, and compared with patients from the other seven regions Between Dec 24, 2007, and Oct 21, 2011, we enrolled 15 400 individuals to the registry. Follow-up was complete for 15 361 (99·7%), of whom 1758 (11%) died within 1 year. Fewer deaths occurred among patients presenting to the emergency department with a primary diagnosis of atrial fibrillation compared with patients who had atrial fibrillation as a secondary diagnosis (377 [6%] of 6825 patients vs 1381 [16%] of 8536, p<0·0001). Twice as many patients had died by 1 year in South America (192 [17%] of 1132) and Africa (225 [20%] of 1137) compared with North America, western Europe, and Australia (366 [10%] of 3800, p<0·0001). Heart failure was the most common cause of death (519 [30%] of 1758); stroke caused 148 (8%) deaths. 604 (4%) of 15361 patients had had a stroke by 1 year; 170 (3%) of 6825 for whom atrial fibrillation was a primary diagnosis and 434 (5%) of 8536 for whom it was a secondary diagnosis (p<0·0001). The highest number of strokes occurred in patients in Africa (89 [8%] of 1137), China (143 [7%] of 2023), and southeast Asia (88 [7%] of 1331) and the lowest occurred in India (20 [<1%] of 2536). 94 (3%) of 3800 patients in North America, western Europe, and Australia had a stroke. Marked unexplained inter-regional variations in the occurrence of stroke and mortality suggest that factors other than clinical variables might be important. Prevention of death from heart failure should be a major priority in the treatment of atrial fibrillation. Boehringer Ingelheim.

Despite the rising global burden of stroke and its socio-economic implications, the neuroimaging predictors of subsequent cognitive impairment are still poorly understood. We address this issue by studying the relationship of white matter integrity assessed within ten days after stroke and patients’ cognitive status one year after the attack. Using diffusion-weighted imaging, we apply the Tract-Based Spatial Statistics analysis and construct individual structural connectivity matrices by employing deterministic tractography. We further quantify the graph-theoretical properties of individual networks. The Tract-Based Spatial Statistic did identify lower fractional anisotropy as a predictor of cognitive status, although this effect was mostly attributable to the age-related white matter integrity decline. We further observed the effect of age propagating into other levels of analysis. Specifically, in the structural connectivity approach we identified pairs of regions significantly correlated with clinical scales, namely memory, attention, and visuospatial functions. However, none of them persisted after the age correction. Finally, the graph-theoretical measures appeared to be more robust towards the effect of age, but still were not sensitive enough to capture a relationship with clinical scales. In conclusion, the effect of age is a dominant confounder especially in older cohorts, and unless appropriately addressed, may falsely drive the results of the predictive modelling.

IntroductionAutosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease. Kidney cysts form over the course of the disease and kidney function slowly declines, usually leading to kidney failure in middle to late adulthood. However, some symptoms, such as hypertension or proteinuria, can be present at an earlier age. In this study, we aimed to quantify early complications in children over time.MethodsAll 69 children with ADPKD from our pediatric nephrology center who met inclusion criteria (follow-up ≥ 1 year and ≥ 2 recorded visits) were studied. Analysis of changes in kidney size, cyst count, estimated glomerular filtration rate (eGFR), urinary protein excretion, and blood pressure was performed.ResultsThe median time of follow-up was 6.3 years (range 8.4–14.8). Over the follow-up, kidneys grew from 109 to 115% of expected length (p < 0.0001), number of cysts increased at a rate of 0.8 cyst/kidney/year, and the prevalence of hypertension increased significantly from 20 to 38% (p < 0.015). The eGFR and absolute urinary protein excretion remained stable.ConclusionsThis study shows that children with ADPKD suffer from increasing prevalence of hypertension during the course of the disease parallel to the increasing number of kidney cysts and size despite normal and stable kidney function and proteinuria.

Both academic research and public policy debate around tax havens and offshore finance typically suffer from a lack of definitional consistency. Unsurprisingly then, there is little agreement about which jurisdictions ought to be considered as tax havens-or which policy measures would result in their not being so considered. In this article we explore and make operational an alternative concept, that of a secrecy jurisdiction and present the findings of the resulting Financial Secrecy Index (FSI). The FSI ranks countries and jurisdictions according to their contribution to opacity in global financial flows, revealing a quite different geography of financial secrecy from the image of small island tax havens that may still dominate popular perceptions and some of the literature on offshore finance. Some major (secrecy-supplying) economies now come into focus. Instead of a binary division between tax havens and others, the results show a secrecy spectrum, on which all jurisdictions can be situated, and that adjustment for the scale of business is necessary in order to compare impact propensity. This approach has the potential to support more precise and granular research findings and policy recommendations.

Governments’ revenues are lower when multinational enterprises avoid paying corporate income tax by shifting their profits to tax havens. In this paper, we ask which countries’ tax revenues are affected most by this tax avoidance and how much. To estimate the scale of profit shifting, we begin by observing that the higher the share of foreign direct investment from tax havens, the lower the reported rate of return on this investment. Similarly to the United Nations Conference on Trade and Development’s World Investment Report 2015, we argue that the reported rate of return is lower due to profit shifting. Unlike the report, however, we provide illustrative country-level estimates of profit shifting for as many countries as possible, including low-income ones, which enables us to study the distributional effects of international corporate tax avoidance. We compare estimated corporate tax revenue losses, relative to their GDP and tax revenues, of country groups classified by income per capita and we find that there are almost no statistically significant differences across these groups. Furthermore, we compare our results with four other recent studies that use different methodologies to estimate tax revenue losses due to profit shifting. In the first such comparison made, we find that most studies identify some differences across income groups, but the nature of these differences varies across the studies.

A growing body of economics literature shows that multinational corporations (MNCs) shift their profits to tax havens. We contribute to this evidence by comparing a range of available data sets focusing on US MNCs, including country-by-country reporting data, a full sample of which has been released in December 2019 for the first time. With each of the data sets, we analyse the effective tax rates that US MNCs face in each country and the amount of profits they report. Using country-by-country reporting data, we have been able to establish that lower effective corporate tax rates are associated with higher levels of reported profits when compared with different indicators of real economic activity. This corresponds to the notion that MNCs often shift profits to countries with low effective tax rates—without also shifting substantive economic activity. Consequently, we identify the most important tax havens for US MNCs as countries with both low effective tax rates and high profits misaligned with economic activity.

Warfarin treatment is commonly started with a fixed loading dose that might be associated with an increased risk of bleeding. An individual maintenance dose can then be estimated based on a pharmacogenetic algorithm. Starting treatment with the estimated dose implies a longer time to reach the therapeutic range. Our goal was to compare the safety and efficacy of initiating warfarin treatment with a loading dose guided by pharmacogenetics versus a maintenance dose. The primary endpoint was time in the therapeutic range (TTR) in the first 10 days of treatment. Secondary endpoints were time to the first international normalized ratio (INR) in therapeutic range (2.0–3.0) and occurrence of serious adverse events. Consenting cardioembolic stroke patients were genotyped for CYP2C9 (cytochrome P450 2C9 gene) and VKORC1 (vitamin K epoxide reductase complex, subunit 1 gene) polymorphisms and a maintenance warfarin dose was estimated. Patients were randomized into two groups. The loading dose group (LDG) patients received twice the estimated dose in the first 2 days of treatment. The maintenance dose group (MDG) patients received the estimated dose directly from day one. The TTR in the first 10 days was significantly higher in the LDG than in the MDG (50.5% vs. 38.3%, p = 0.003). The time to the first INR in this range was significantly shorter in the LDG (5.24 vs. 7.3 days). There were no significant differences in the INR above this range or serious adverse events. Warfarin loading dose guided by pharmacogenetics after recent cardioembolic stroke improved the efficacy of warfarin initiation without increasing the risk of adverse events.