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

Relevance of Molecular Mimicry in the Mediation of Infectious Myocarditis

Heart disease, the leading cause of death in humans, is estimated to affect one in four American adults in some form. One predominant cause of heart failure in young adults is myocarditis, which can lead to the development of dilated cardiomyopathy, a major indication for heart transplantation. Environmental microbes, including viruses, bacteria, and fungi that are otherwise innocuous, have the potential to induce inflammatory heart disease. As the list is growing, it is critical to determine the mechanisms by which microbes can trigger heart autoimmunity and, importantly, to identify their target antigens. This is especially true as microbes showing structural similarities with the cardiac antigens can predispose to heart autoimmunity by generating cross-reactive immune responses. In this review, we discuss the relevance of molecular mimicry in the mediation of infectious myocarditis

Why people die in novels: testing the ordeal simulation hypothesis

A Correction to this article was published on 29 August 2019 (https://www.nature.com/articles/s41599-019-0294-x).© The Author(s) 2019. What is fiction about, and what is it good for? An influential family of theories sees fiction as rooted in adaptive simulation mechanisms. In this view, our propensity to create and enjoy narrative fictions was selected and maintained due to the training that we get from mentally simulating situations relevant to our survival and reproduction. We put forward and test a precise version of this claim, the “ordeal simulation hypothesis”. It states that fictional narrative primarily simulates “ordeals”: situations where a person’s reaction might dramatically improve or decrease her fitness, such as deadly aggressions, or decisions on long-term matrimonial commitments. Experience does not prepare us well for these rare, high-stakes occasions, in contrast with situations that are just as fitness-relevant but more frequent (e.g., exposure to pathogens). We study mortality in fictional and non-fictional texts as a partial test for this view. Based on an analysis of 744 extensive summaries of twentieth century American novels of various genres, we show that the odds of dying (in a given year) are vastly exaggerated in fiction compared to reality, but specifically more exaggerated for homicides as compared to suicides, accidents, war-related, or natural deaths. This evidence supports the ordeal simulation hypothesis but is also compatible with other accounts. For a more specific test, we look for indications that this focus on death, and in particular on death caused by an agent, is specific to narrative fiction as distinct from other verbal productions. In a comparison of 10,810 private letters and personal diary entries written by American women, with a set of 811 novels (also written by American women), we measure the occurrence of words related to natural death or agentive death. Private letters and diaries are as likely, or more likely, to use words relating to natural or agentive death. Novels written for an adult audience contain more words relating to natural deaths than do letters (though not diary entries), but this is not true for agentive death. Violent death, in spite of its clear appeal for fiction, does not necessarily provide a clear demarcation point between fictional and non-fictional content