Effect of housing conditions on sex differences in spatial cognition in rats

Male mammals typically outperform females in tests of spatial ability. However, in laboratory rats (Rattus norvegicus), from which the majority of data in support of this difference come, sex differences are not consistently found. Since stress affects cognition in males and females differently, I investigated possible sources of stress (e.g. housing conditions, spatial tasks) and the impact they have on cognitive performance in male and female rats. Firstly, I investigated whether isolation housing, purported to be chronically stressful, affected the presence of sex differences in a dark-eyed and an albino strain of rat. Irrespective of sex and strain, I found that young or old rats isolated for long or short periods were not behaviourally or cognitively impaired relative to pairhoused conspecifics. I found, however, that behaviour caused by the acute stress of the task impeded performance. Furthermore, sex differences in performance were found only when the females were more stressed than the males during testing. Additionally, the degree to which the rats found the task stressful depended upon the age at which they travelled from the breeding establishment. In the dark-eyed strain, males were always less stressed than the females, but also out performed the females only if they travelled while young (4-5 weeks old). Both sexes seemed to be less stressed by the task if the rats travelled as adults. Conversely, in the albino strain, males outperformed females only if the rats travelled as adults, because in the young travellers both sexes were equally and highly stressed during testing. Therefore, the acute stress response, which seems to underlie sex differences in cognitive performance, was influenced by the age at which the rats travelled in a sex and strain dependent manner. Next, I considered the impact of the physical attributes of the home cage on a rat’s welfare and performance in a cognitive task. I found that, male and female rats housed with a barrier that reduced visual contact from their cage showed higher levels of behavioural stress in their home cage than did rats housed without a barrier between the cages. Rats housed with the barrier were also more stressed during spatial testing and had poorer cognitive performance relative to rats housed without the barrier. Pair housing did not ameliorate the effect of the barrier. Based on these data, although a rather unorthodox suggestion, I propose that single housing with a view may be preferable to pair housing without a view. One implication of this finding is that the number of animals used in an experiment could be significantly reduced if the home cages allow sufficient visual interactions. Lastly, I investigated the impact of environmental enrichment on spatial cognition and behavioural stress responses. I found, contrary to current opinion, that enriched rats outperformed non-enriched animals not because they had superior cognitive ability but because their behavioural stress response was reduced significantly during testing. Furthermore, withdrawing enrichment from rats for at least one week did not increase stress responses during testing or impair cognitive performance. Therefore, exposure to enrichment, even if later withdrawn, improves welfare by reducing stress during cognitive testing. In conclusion, a differential behavioural stress response during cognitive testing may explain why males outperform females and why enriched animals do better than non-enriched animals in tests of spatial cognition. Furthermore, variation in this behavioural stress response may in part explain why sex differences in performance are not consistently found in laboratory rats

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

Background: 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. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

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 <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >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 m2), 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