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The most challenging issue facing peptide drug development is producing a molecule with optimal physical properties while maintaining target binding affinity. Masking peptides with protecting groups that can be removed inside the cell, produces a cell-permeable peptide, which theoretically can maintain its biological activity. Described are series of prodrugs masked using: (a) O-alkyl, (b) N-alkyl, and (c) acetyl groups, and their binding affinity for Hsp90. Alkyl moieties increased compound permeability, P app, from 3.3 to 5.6, however alkyls could not be removed by liver microsomes or in-vivo and their presence decreased target binding affinity (IC 50 of ≥10 µM). Thus, unlike small molecules, peptide masking groups cannot be predictably removed; their removal is related to the 3-D conformation. O-acetyl groups were cleaved but are labile, increasing challenges during synthesis. Utilising acetyl groups coupled with mono-methylated amines may decrease the polarity of a peptide, while maintaining binding affinity.

Background: The use of amphetamines is a global public health concern. We summarise global data on use of amphetamines and mental health outcomes. Methods: A systematic review and meta-analysis (CRD 42017081893). We searched Medline, EMBASE, PsycInfo for methamphetamine or amphetamine combined with psychosis, violence, suicidality, depression or anxiety. Included studies were human empirical cross-sectional surveys, case-control studies, cohort studies and randomised controlled trials that assessed the association between methamphetamine and one of the mental health outcomes. Random effects meta-analysis was used to pool results for any use of amphetamines and amphetamine use disorders. Findings: 149 studies were eligible and 59 were included in meta-analyses. There was significant heterogeneity in effects. Evidence came mostly from cross-sectional studies. Any use of amphetamines was associated with higher odds of psychosis (odds ratio [OR] = 2.0, 95%CI 1.3–3.3), violence (OR = 2.2, 95%CI 1.2–4.1; adjusted OR [AOR] = 1.4, 95%CI 0.8–2.4), suicidality OR = 4.4, 95%CI 2.4–8.2; AOR = 1.7, 95%CI 1.0–2.9) and depression (OR = 1.6, 95%CI 1.1–2.2; AOR = 1.3, 95%CI 1.2–1.4). Having an amphetamine use disorder was associated with higher odds of psychosis (OR = 3.0, 95%CI 1.9–4.8; AOR = 2.4, 95%CI 1.6–3.5), violence (OR = 6.2, 95%CI 3.1–12.3), and suicidality (OR = 2.3, 95%CI 1.8–2.9; AOR = 1.5, 95%CI 1.3–1.8). Interpretation: Methamphetamine use is an important risk factor for poor mental health. High quality population-level studies are needed to more accurately quantify this risk. Clinical responses to methamphetamine use need to address mental health harms.

Importance: Prior observational studies suggest that quality of care improvement (QCI) initiatives can improve the clinical outcomes of acute coronary syndrome (ACS). To our knowledge, this has never been demonstrated in a well-powered randomized clinical trial. Objective: To determine whether a clinical pathway-based, multifaceted QCI intervention could improve clinical outcomes among patients with ACS in resource-constrained hospitals in China. Design, Setting, Participants: This large, stepped-wedge cluster randomized clinical trial was conducted in nonpercutaneous coronary intervention hospitals across China and included all patients older than 18 years and with a final diagnosis of ACS who were recruited consecutively between October 2011 and December 2014. We excluded patients who died before or within 10 minutes of hospital arrival. We recruited 5768 and 0 eligible patients for the control and intervention groups, respectively, in step 1, 4326 and 1365 in step 2, 3278 and 3059 in step 3, 1419 and 4468 in step 4, and 0 and 5645 in step 5. Interventions: The intervention included establishing a QCI team, training clinical staff, implementing ACS clinical pathways, sequential site performance assessment and feedback, online technical support, and patient education. The usual care was the control that was compared. Main Outcomes and Measures: The primary outcome was the incidence of in-hospital major adverse cardiovascular events (MACE), comprising all-cause mortality, reinfarction/myocardial infarction, and nonfatal stroke. Secondary outcomes included 16 key performance indicators (KPIs) and the composite score developed from these KPIs. Results: Of 29346 patients (17639 men [61%]; mean [SD] age for control, 64.1 [11.6] years; mean [SD] age for intervention, 63.9 [11.7] years) who were recruited from 101 hospitals, 14809 (50.5%) were in the control period and 14537 (49.5%) were in the intervention period. There was no significant difference in the incidence of i

BACKGROUND: The use of amphetamines is a global public health concern. We summarise global data on use of amphetamines and mental health outcomes. METHODS: A systematic review and meta-analysis (CRD 42017081893). We searched Medline, EMBASE, PsycInfo for methamphetamine or amphetamine combined with psychosis, violence, suicidality, depression or anxiety. Included studies were human empirical cross-sectional surveys, case-control studies, cohort studies and randomised controlled trials that assessed the association between methamphetamine and one of the mental health outcomes. Random effects meta-analysis was used to pool results for any use of amphetamines and amphetamine use disorders. FINDINGS: 149 studies were eligible and 59 were included in meta-analyses. There was significant heterogeneity in effects. Evidence came mostly from cross-sectional studies. Any use of amphetamines was associated with higher odds of psychosis (odds ratio [OR] = 2.0, 95%CI 1.3-3.3), violence (OR = 2.2, 95%CI 1.2-4.1; adjusted OR [AOR] = 1.4, 95%CI 0.8-2.4), suicidality OR = 4.4, 95%CI 2.4-8.2; AOR = 1.7, 95%CI 1.0-2.9) and depression (OR = 1.6, 95%CI 1.1-2.2; AOR = 1.3, 95%CI 1.2-1.4). Having an amphetamine use disorder was associated with higher odds of psychosis (OR = 3.0, 95%CI 1.9-4.8; AOR = 2.4, 95%CI 1.6-3.5), violence (OR = 6.2, 95%CI 3.1-12.3), and suicidality (OR = 2.3, 95%CI 1.8-2.9; AOR = 1.5, 95%CI 1.3-1.8). INTERPRETATION: Methamphetamine use is an important risk factor for poor mental health. High quality population-level studies are needed to more accurately quantify this risk. Clinical responses to methamphetamine use need to address mental health harms.

Objective: The aim of this study was to investigate statin description on discharge and the benefit on the long-term outcomes in acute coronary syndromes (ACS) patients with very low baseline LDL-cholesterol (LDL-c). Methods: This is a post-hoc analysis of 3374 ACS patients who were discharged alive and had baseline LDL-c levels below 70 mg/dL (1.8 mmol/L). The propensity score of using statin was estimated with a multivariable Logistic model including patient's demography, social economic status, cardiovascular risk factors, subtype of the diagnosis, and treatments received during hospitalization and current LDL-c level. The risk of major adverse cardiovascular events (MACEs) was compared between patients received and not-received statin with Cox-regression models adjusting for the propensity score plus other factors. A sensitivity analysis was done in propensity score matched patients. Results: Compared with nonstatin group, the incidence of MACE at 12 months after discharge was lower in the statin group (11.1% vs 5.8%; P < 0.001). The propensity score plus other factors-adjusted hazard ratios for MACEs was significant (0.58; 95% CI: 0.39, 0.87). The effect showed a significant dose-response relationship (P for trend = 0.02). The results in analyses with propensity-score matched participants were in consistent with above findings. Analyses on total mortality in 12 months showed similar results. Conclusions: Among ACS survivors with a very low baseline LDL-c, low to moderate intensity statin therapy was associated significantly with lower risk of MACEs and total mortality at 12 months. The results suggested that ACS survivors should take statin regardless of the baseline of LDL-c.

Introduction Masked uncontrolled hypertension (MUCH) carries an increased risk of cardiovascular (CV) complications and can be identified through combined use of office (O) and ambulatory (A) blood pressure (BP) monitoring (M) in treated patients. However, it is still debated whether the information carried by ABPM should be considered for MUCH management. Aim of the MASked-unconTrolled hypERtension management based on OBP or on ambulatory blood pressure measurement (MASTER) Study is to assess the impact on outcome of MUCH management based on OBPM or ABPM. Methods and analysis MASTER is a 4-year prospective, randomised, open-label, blinded-endpoint investigation. A total of 1240 treated hypertensive patients from about 40 secondary care clinical centres worldwide will be included -upon confirming presence of MUCH (repeated on treatment OBP <140/90 mm Hg, and at least one of the following: Daytime ABP ≥135/85 mm Hg; night-time ABP ≥120/70 mm Hg; 24 hour ABP ≥130/80 mm Hg), and will be randomised to a management strategy based on OBPM (group 1) or on ABPM (group 2). Patients in group 1 will have OBP measured at 0, 3, 6, 12, 18, 24, 30, 36, 42 and 48 months and taken as a guide for treatment; ABPM will be performed at randomisation and at 12, 24, 36 and 48 months but will not be used to take treatment decisions. Patients randomised to group 2 will have ABPM performed at randomisation and all scheduled visits as a guide to antihypertensive treatment. The effects of MUCH management strategy based on ABPM or on OBPM on CV and renal intermediate outcomes (changing left ventricular mass and microalbuminuria, coprimary outcomes) at 1 year and on CV events at 4 years and on changes in BP-related variables will be assessed. Ethics and dissemination MASTER study protocol has received approval by the ethical review board of Istituto Auxologico Italiano. The procedures set out in this protocol are in accordance with principles of Declaration of Helsinki and Good Clinical Practice

The timing of mechanical cardiac events is usually evaluated by conventional echocardiography as an index of cardiac systolic function and predictor of cardiovascular outcomes. We aimed to measure the systolic time intervals, namely the isovolumetric contraction time (ICT) and pre-ejection period (PEP), by arterial tonometry.