Hypertension Canada provides annually updated, evidence-based guidelines for the diagnosis, assessment, prevention, and treatment of hypertension in adults and children. This year, the adult and pediatric guidelines are combined in one document. The new 2018 pregnancy-specific hypertension guidelines are published separately. For 2018, 5 new guidelines are introduced, and 1 existing guideline on the blood pressure thresholds and targets in the setting of thrombolysis for acute ischemic stroke is revised. The use of validated wrist devices for the estimation of blood pressure in individuals with large arm circumference is now included. Guidance is provided for the follow-up measurements of blood pressure, with the use of standardized methods and electronic (oscillometric) upper arm devices in individuals with hypertension, and either ambulatory blood pressure monitoring or home blood pressure monitoring in individuals with white coat effect. We specify that all individuals with hypertension should have an assessment of global cardiovascular risk to promote health behaviours that lower blood pressure. Finally, an angiotensin receptor-neprilysin inhibitor combination should be used in place of either an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in individuals with heart failure (with ejection fraction < 40%) who are symptomatic despite appropriate doses of guideline-directed heart failure therapies. The specific evidence and rationale underlying each of these guidelines are discussed.

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The magnitude of heart rate reduction is statistically significantly associated with the survival benefit of beta-blockers in heart failure, whereas the dose of beta-blocker is not.

IntroductionOur aim was to investigate the impact of early versus late initiation of renal replacement therapy (RRT) on clinical outcomes in critically ill patients with acute kidney injury (AKI).MethodsSystematic review and meta-analysis were used in this study. PUBMED, EMBASE, SCOPUS, Web of Science and Cochrane Central Registry of Controlled Clinical Trials, and other sources were searched in July 2010. Eligible studies selected were cohort and randomised trials that assessed timing of initiation of RRT in critically ill adults with AKI.ResultsWe identified 15 unique studies (2 randomised, 4 prospective cohort, 9 retrospective cohort) out of 1,494 citations. The overall methodological quality was low. Early, compared with late therapy, was associated with a significant improvement in 28-day mortality (odds ratio (OR) 0.45; 95% confidence interval (CI), 0.28 to 0.72). There was significant heterogeneity among the 15 pooled studies (I2 = 78%). In subgroup analyses, stratifying by patient population (surgical, n = 8 vs. mixed, n = 7) or study design (prospective, n = 10 vs. retrospective, n = 5), there was no impact on the overall summary estimate for mortality. Meta-regression controlling for illness severity (Acute Physiology And Chronic Health Evaluation II (APACHE II)), baseline creatinine and urea did not impact the overall summary estimate for mortality. Of studies reporting secondary outcomes, five studies (out of seven) reported greater renal recovery, seven (out of eight) studies showed decreased duration of RRT and five (out of six) studies showed decreased ICU length of stay in the early, compared with late, RRT group. Early RRT did not; however, significantly affect the odds of dialysis dependence beyond hospitalization (OR 0.62 0.34 to 1.13, I2 = 69.6%).ConclusionsEarlier institution of RRT in critically ill patients with AKI may have a beneficial impact on survival. However, this conclusion is based on heterogeneous studies of variable quality and only two randomised trials. In the absence of new evidence from suitably-designed randomised trials, a definitive treatment recommendation cannot be made.

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Hypertension Canada provides annually updated, evidence-based guidelines for the diagnosis, assessment, prevention, and treatment of hypertension. This year, we introduce 10 new guidelines. Three previous guidelines have been revised and 5 have been removed. Previous age and frailty distinctions have been removed as considerations for when to initiate antihypertensive therapy. In the presence of macrovascular target organ damage, or in those with independent cardiovascular risk factors, antihypertensive therapy should be considered for all individuals with elevated average systolic nonautomated office blood pressure (non-AOBP) readings ≥ 140 mm Hg. For individuals with diastolic hypertension (with or without systolic hypertension), fixed-dose single-pill combinations are now recommended as an initial treatment option. Preference is given to pills containing an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in combination with either a calcium channel blocker or diuretic. Whenever a diuretic is selected as monotherapy, longer-acting agents are preferred. In patients with established ischemic heart disease, caution should be exercised in lowering diastolic non-AOBP to ≤ 60 mm Hg, especially in the presence of left ventricular hypertrophy. After a hemorrhagic stroke, in the first 24 hours, systolic non-AOBP lowering to < 140 mm Hg is not recommended. Finally, guidance is now provided for screening, initial diagnosis, assessment, and treatment of renovascular hypertension arising from fibromuscular dysplasia. The specific evidence and rationale underlying each of these guidelines are discussed.

Rising drug resistance is limiting treatment options for infections by methicillin-resistant Staphylococcus aureus (MRSA). Herein we provide new evidence that wall teichoic acid (WTA) biogenesis is a remarkable antibacterial target with the capacity to destabilize the cooperative action of penicillin-binding proteins (PBPs) that underlie β-lactam resistance in MRSA. Deletion of gene tarO, encoding the first step of WTA synthesis, resulted in the restoration of sensitivity of MRSA to a unique profile of β-lactam antibiotics with a known selectivity for penicillin binding protein 2 (PBP2). Of these, cefuroxime was used as a probe to screen for previously approved drugs with a cryptic capacity to potentiate its activity against MRSA. Ticlopidine, the antiplatelet drug Ticlid, strongly potentiated cefuroxime, and this synergy was abolished in strains lacking tarO. The combination was also effective in a Galleria mellonella model of infection. Using both genetic and biochemical strategies, we determined the molecular target of ticlopidine as the N-acetylglucosamine-1-phosphate transferase encoded in gene tarO and provide evidence that WTA biogenesis represents an Achilles heel supporting the cooperative function of PBP2 and PBP4 in creating highly cross-linked muropeptides in the peptidoglycan of S. aureus. This approach represents a new paradigm to tackle MRSA infection.