Evidence-based models of care for the treatment of alcohol use disorder in primary health care settings : Protocol for systematic review

Background Alcohol use disorder (AUD) is highly prevalent and accounts globally for 1.6% of disability-adjusted life years (DALYs) among females and 6.0% of DALYs among males. Effective treatments for AUDs are available but are not commonly practiced in primary health care. Furthermore, referral to specialized care is often not successful and patients that do seek treatment are likely to have developed more severe dependence. A more cost-efficient health care model is to treat less severe AUD in a primary care setting before the onset of greater dependence severity. Few models of care for the management of AUD in primary health care have been developed and with limited implementation. This proposed systematic review will synthesize and evaluate differential models of care for the management of AUD in primary health care settings. Methods We will conduct a systematic review to synthesize studies that evaluate the effectiveness of models of care in the treatment of AUD in primary health care. A comprehensive search approach will be conducted using the following databases; MEDLINE (1946 to present), PsycINFO (1806 to present), Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL) (1991 to present), and Embase (1947 to present). Reference searches of relevant reviews and articles will be conducted. Similarly, a gray literature search will be done with the help of Google and the gray matter tool which is a checklist of health-related sites organized by topic. Two researchers will independently review all titles and abstracts followed by full-text review for inclusion. The planned method of extracting data from articles and the critical appraisal will also be done in duplicate. For the critical appraisal, the Cochrane risk of bias tool 2.0 will be used. Discussion This systematic review and meta-analysis aims to guide improvement of design and implementation of evidence-based models of care for the treatment of alcohol use disorder in primary health care settings. The evidence will define which models are most promising and will guide further research. Protocol registration number PROSPERO CRD42019120293

Evidence based models of care for the treatment of alcohol use disorder in primary health care settings : A systematic review

Background Pharmacological and behavioural treatments for alcohol use disorders (AUDs) are effective but the uptake is limited. Primary care could be a key setting for identification and continuous care for AUD due to accessibility, low cost and acceptability to patients. We aimed to synthesise the literature regarding differential models of care for the management of AUD in primary health care settings. Methods We conducted a systematic review of articles published worldwide (1998-present) using the following databases; Medline, PsycINFO, Cochrane database of systematic reviews, Cochrane Central Register of Controlled Trials and Embase. The Grey Matters Tool guided the grey literature search. We selected randomised controlled trials evaluating the effectiveness of a primary care model in the management of AUD. Two researchers independently assessed and then reached agreement on the included studies. We used the Cochrane risk of bias tool 2.0 for the critical appraisal. Results Eleven studies (4186 participants) were included. We categorised the studies into ‘lower’ versus ‘higher’ intensity given the varying intensity of clinical care evaluated across the studies. Significant differences in treatment uptake were reported by most studies. The uptake of AUD medication was reported in 5 out of 6 studies that offered AUD medication. Three studies reported a significantly higher uptake of AUD medication in the intervention group. A significant reduction in alcohol use was reported in two out of the five studies with lower intensity of care, and three out of six studies with higher intensity of care. Conclusion Our results suggest that models of care in primary care settings can increase treatment uptake (e.g. psychosocial and/or pharmacotherapy) although results for alcohol-related outcomes were mixed. More research is required to determine which specific patient groups are suitable for AUD treatment in primary health care settings and to identify which models and components are most effective. Trial Registration PROSPERO: CRD42019120293

Baclofen Response in Alcohol Dependent Patients Concurrently Receiving Antidepressants: Secondary Analysis From the BacALD Study

Background and Aims: There is little information with regards to the efficacy of baclofen among alcohol patients concurrently receiving antidepressants (AD). The present study aimed to conduct a secondary analysis of the moderating role of antidepressants in the BacALD trial which evaluated the efficacy of baclofen to reduce alcohol consumption in alcohol dependent patients.Methods: Alcohol dependent patients (N = 104) were treated for 12 weeks with 30 mg/day of baclofen (21 = AD and 15 = no AD), 75 mg baclofen (19 = AD and 16 = no AD) or placebo (17 = AD and 16 = no AD). Patients were included in the trial if they were concurrently receiving anti-depressants upon enrolment but were excluded if they commenced antidepressants 2 months prior to enrolment. Patients were also excluded in the case of concurrent psychotropic medications, active major mental disorder such as bipolar disorder, psychosis, or history of suicide attempt. Predefined primary outcomes included time to lapse (any drinking), relapse (>5 drinks per day in men and >4 in women). Other outcomes included drinks per drinking day, number of heavy drinking days, and percentage days abstinent and frequency of adverse events.Results: For the number of days to first lapse, there was a trend of significance for the interaction baclofen × AD (Log Rank: χ2 = 2.98, P = 0.08, OR: 0.41, 95%CI: 0.15–1.12). For the number of days to relapse, there was a trend of significance for the interaction of baclofen × AD (Log Rank: χ2 = 3.72, P = 0.05, OR: 3.40, 95%CI: 1.01–11.46). Placing significant baseline variables into the models as covariates (tobacco, ALD) weakened these interactions (P's > 0.15). There were no significant effects of ADs on the frequency of adverse events reported (P's > 0.19).Conclusion: Concurrent receipt of ADs commenced more than 2 months prior to baclofen treatment did not negatively impact on drinking outcomes. Future research examining the interaction between commencing ADs during baclofen treatment on alcohol dependent patients is required.Trial Registration: ClinicalTrials.gov, NCT01711125, https://clinicaltrials.gov/ct2/show/NCT0171112

Pharmacokinetic/pharmacodynamic modelling approaches in paediatric infectious diseases and immunology.

Pharmacokinetic/pharmacodynamic (PKPD) modelling is used to describe and quantify dose-concentration-effect relationships. Within paediatric studies in infectious diseases and immunology these methods are often applied to developing guidance on appropriate dosing. In this paper, an introduction to the field of PKPD modelling is given, followed by a review of the PKPD studies that have been undertaken in paediatric infectious diseases and immunology. The main focus is on identifying the methodological approaches used to define the PKPD relationship in these studies. The major findings were that most studies of infectious diseases have developed a PK model and then used simulations to define a dose recommendation based on a pre-defined PD target, which may have been defined in adults or in vitro. For immunological studies much of the modelling has focused on either PK or PD, and since multiple drugs are usually used, delineating the relative contributions of each is challenging. The use of dynamical modelling of in vitro antibacterial studies, and paediatric HIV mechanistic PD models linked with the PK of all drugs, are emerging methods that should enhance PKPD-based recommendations in the future

A Cost-Effectiveness Analysis of “Test” versus “Treat” Patients Hospitalized with Suspected Influenza in Hong Kong

BACKGROUND: Seasonal and 2009 H1N1 influenza viruses may cause severe diseases and result in excess hospitalization and mortality in the older and younger adults, respectively. Early antiviral treatment may improve clinical outcomes. We examined potential outcomes and costs of test-guided versus empirical treatment in patients hospitalized for suspected influenza in Hong Kong. METHODS: We designed a decision tree to simulate potential outcomes of four management strategies in adults hospitalized for severe respiratory infection suspected of influenza: "immunofluorescence-assay" (IFA) or "polymerase-chain-reaction" (PCR)-guided oseltamivir treatment, "empirical treatment plus PCR" and "empirical treatment alone". Model inputs were derived from literature. The average prevalence (11%) of influenza in 2010-2011 (58% being 2009 H1N1) among cases of respiratory infections was used in the base-case analysis. Primary outcome simulated was cost per quality-adjusted life-year (QALY) expected (ICER) from the Hong Kong healthcare providers' perspective. RESULTS: In base-case analysis, "empirical treatment alone" was shown to be the most cost-effective strategy and dominated the other three options. Sensitivity analyses showed that "PCR-guided treatment" would dominate "empirical treatment alone" when the daily cost of oseltamivir exceeded USD18, or when influenza prevalence was <2.5% and the predominant circulating viruses were not 2009 H1N1. Using USD50,000 as the threshold of willingness-to-pay, "empirical treatment alone" and "PCR-guided treatment" were cost-effective 97% and 3% of time, respectively, in 10,000 Monte-Carlo simulations. CONCLUSIONS: During influenza epidemics, empirical antiviral treatment appears to be a cost-effective strategy in managing patients hospitalized with severe respiratory infection suspected of influenza, from the perspective of healthcare providers in Hong Kong

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&lt;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 (&lt;1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (&lt;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

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis

Search for heavy resonances decaying to two Higgs bosons in final states containing four b quarks

A search is presented for narrow heavy resonances X decaying into pairs of Higgs bosons (H) in proton-proton collisions collected by the CMS experiment at the LHC at root s = 8 TeV. The data correspond to an integrated luminosity of 19.7 fb(-1). The search considers HH resonances with masses between 1 and 3 TeV, having final states of two b quark pairs. Each Higgs boson is produced with large momentum, and the hadronization products of the pair of b quarks can usually be reconstructed as single large jets. The background from multijet and t (t) over bar events is significantly reduced by applying requirements related to the flavor of the jet, its mass, and its substructure. The signal would be identified as a peak on top of the dijet invariant mass spectrum of the remaining background events. No evidence is observed for such a signal. Upper limits obtained at 95 confidence level for the product of the production cross section and branching fraction sigma(gg -> X) B(X -> HH -> b (b) over barb (b) over bar) range from 10 to 1.5 fb for the mass of X from 1.15 to 2.0 TeV, significantly extending previous searches. For a warped extra dimension theory with amass scale Lambda(R) = 1 TeV, the data exclude radion scalar masses between 1.15 and 1.55 TeV

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Search for supersymmetry in events with one lepton and multiple jets in proton-proton collisions at root s=13 TeV

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