Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to 300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Discovering distributed processes in supply chains

Processes such as tendering. ordering. delivery, and paying are executed by several parties in al most all supply chains. However, none of these parties has a proper overview over the whole set of activities executed. Therefore, none of the parties can take the lead in business process redesign. Business processes are often not described in an explicit manner, and therefore they are not available for analysis. However, in the information system of each supply chain party, partia! information about the business process are recorded. We claim that lhe overall dislributed process can be induced, by using this partial information of all involved parties. In this paper we present an overview of methods available to discover processes across supply chains. based on the assumption that there is a common point of reference at all involved parties. e.g. an order number. Such an induced or discovered process enables ana!ysis across the supply chain, and can become an important tool to facililate business process redesign in networked organizations

Female homicidal strangulation in urban South Africa

<p>Abstract</p> <p>Background</p> <p>Female strangulation in South Africa occurs in a context of pervasive and often extreme violence perpetrated against women, and therefore represents a major public health, social and human rights concern. South African studies that provide accurate descriptions of the occurrence of strangulation incidents among female homicide victims are limited. The current study describes the extent, distribution and patterns of homicidal strangulation of women in the four largest South African metropolitan centres, Tshwane/Pretoria, Johannesburg, Cape Town and Ethekwini/Durban.</p> <p>Methods</p> <p>The study is a register-based cross sectional investigation of female homicidal strangulation, as reported in the National Injury Mortality Surveillance System for the four cities, for the period 2001 to 2005. Crude, unadjusted female strangulation rates for age and population group, and proportions of strangulation across specific circumstances of occurrence were compiled for each year and aggregated in some cases.</p> <p>Results</p> <p>This study reports that female homicidal strangulation in urban South Africa ranges from 1.71/100 000 to 0.70/100 000. Rates have generally declined in all the cities, except Cape Town. The highest rates were reported in the over 60 and the 20 to 39 year old populations, and amongst women of mixed descent. Most strangulations occurred from the early morning hours and across typical working hours in Johannesburg and Durban, and to a lesser extent in Cape Town. Occurrences across Johannesburg, Durban and Pretoria were distributed across the days of the week; an exception was Cape Town, which reported the highest rates over the weekend. Cape Town also reported distinctly high blood alcohol content levels of strangulation victims. The seasonal variation in strangulation deaths suggested a pattern of occurrence generally spanning the period from end-winter to summer. Across cities, the predominant crime scene was linked to the domestic context, suggesting that perpetration was by an intimate partner or acquaintance.</p> <p>Conclusion</p> <p>The study contributes to an emerging gendered homicide risk profile for a country with one of the highest homicide rates in the world. The results support the call for the development of evidence-based and gender-specific initiatives to especially address the forms of violence that instigate fatalities.</p

Reconceptualization of translocator protein as a biomarker of neuroinflammation in psychiatry

A great deal of interest in psychiatric research is currently centered upon the pathogenic role of inflammatory processes. Positron emission tomography (PET) using radiolabeled ligands selective for the 18 kDa translocator protein (TSPO) has become the most widely used technique to assess putative neuroimmune abnormalities in vivo. Originally used to detect discrete neurotoxic damages, TSPO has generally turned into a biomarker of ‘neuroinflammation’ or ‘microglial activation’. Psychiatric research has mostly accepted these denotations of TSPO, even if they may be inadequate and misleading under many pathological conditions. A reliable and neurobiologically meaningful diagnosis of ‘neuroinflammation’ or ‘microglial activation’ is unlikely to be achieved by the sole use of TSPO PET imaging. It is also very likely that the pathological meanings of altered TSPO binding or expression are disease-specific, and therefore, not easily generalizable across different neuropathologies or inflammatory conditions. This difficulty is intricately linked to the varying (and still ill-defined) physiological functions and cellular expression patterns of TSPO in health and disease. While altered TSPO binding or expression may indeed mirror ongoing neuroinflammatory processes in some cases, it may reflect other pathophysiological processes such as abnormalities in cell metabolism, energy production and oxidative stress in others. Hence, the increasing popularity of TSPO PET imaging has paradoxically introduced substantial uncertainty regarding the nature and meaning of neuroinflammatory processes and microglial activation in psychiatry, and likely in other neuropathological conditions as well. The ambiguity of conceiving TSPO simply as a biomarker of ‘neuroinflammation’ or ‘microglial activation’ calls for alternative interpretations and complimentary approaches. Without the latter, the ongoing scientific efforts and excitement surrounding the role of the neuroimmune system in psychiatry may not turn into therapeutic hope for affected individuals

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke