Although 5%–10% weight loss is routinely recommended for people with obesity, the precise effects of 5% and further weight loss on metabolic health are unclear. We conducted a randomized controlled ...trial that evaluated the effects of 5.1% ± 0.9% (n = 19), 10.8% ± 1.3% (n = 9), and 16.4% ± 2.1% (n = 9) weight loss and weight maintenance (n = 14) on metabolic outcomes. 5% weight loss improved adipose tissue, liver and muscle insulin sensitivity, and β cell function, without a concomitant change in systemic or subcutaneous adipose tissue markers of inflammation. Additional weight loss further improved β cell function and insulin sensitivity in muscle and caused stepwise changes in adipose tissue mass, intrahepatic triglyceride content, and adipose tissue expression of genes involved in cholesterol flux, lipid synthesis, extracellular matrix remodeling, and oxidative stress. These results demonstrate that moderate 5% weight loss improves metabolic function in multiple organs simultaneously, and progressive weight loss causes dose-dependent alterations in key adipose tissue biological pathways.
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•Moderate 5% weight loss improves multi-organ insulin sensitivity and β cell function•Additional weight loss of 11%–16% further increases insulin sensitivity in muscle•Progressive weight loss causes stepwise changes in adipose tissue biology
Magkos et al. demonstrate the profound therapeutic effects of weight loss on metabolic function in subjects with obesity. Even a moderate 5% weight loss has considerable health benefits, including decreased intra-abdominal and intra-hepatic fat and increased multi-organ insulin sensitivity and β cell function. Additional weight loss further improves many cardiometabolic outcomes.
Obesity is associated with adipose tissue dysfunction and multi-organ insulin resistance. However, the mechanisms of such obesity-associated systemic metabolic complications are not clear. Here, we ...characterized mice with adipocyte-specific deletion of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting NAD+ biosynthetic enzyme known to decrease in adipose tissue of obese and aged rodents and people. We found that adipocyte-specific Nampt knockout mice had severe insulin resistance in adipose tissue, liver, and skeletal muscle and adipose tissue dysfunction, manifested by increased plasma free fatty acid concentrations and decreased plasma concentrations of a major insulin-sensitizing adipokine, adiponectin. Loss of Nampt increased phosphorylation of CDK5 and PPARγ (serine-273) and decreased gene expression of obesity-linked phosphorylated PPARγ targets in adipose tissue. These deleterious alterations were normalized by administering rosiglitazone or a key NAD+ intermediate, nicotinamide mononucleotide (NMN). Collectively, our results provide important mechanistic and therapeutic insights into obesity-associated systemic metabolic derangements, particularly multi-organ insulin resistance.
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•Adipocyte-specific Nampt knockout (ANKO) mice have multi-organ insulin resistance•Loss of Nampt impairs adipose tissue function and decreases adiponectin production•ANKO mice display increased phosphorylation of CDK5 and PPARγ (serine-273)•Nicotinamide mononucleotide (NMN) normalizes metabolic derangements in ANKO mice
Obesity-associated insulin resistance is an important risk factor of type 2 diabetes and cardiovascular diseases. In this study, Stromsdorfer et al. demonstrate that adipocyte-specific inactivation of Nampt, a key NAD+ biosynthetic enzyme known to decrease in obese rodents and humans, causes insulin resistance in adipose tissue, liver, and skeletal muscle.
Systematic reviews (SRs) of clinical practice guidelines (CPGs) are unique knowledge syntheses that require tailored approaches to, and greater subjectivity in, design and execution compared with ...other SRs in clinical epidemiology. We provide review authors structured direction on how to design and conduct methodologically rigorous SRs of CPGs.
A guidance paper outlining suggested methodology for conducting all stages of an SR of CPGs. We present concrete examples of approaches used by published reviews, including a case exemplar demonstrating how this methodology was applied to our own SR of CPGs.
Review context and the unique characteristics of CPGs as research syntheses or clinical guidance statements must be considered in all aspects of review design and conduct. Researchers should develop a “PICAR” statement to help form and focus on the research question(s) and eligibility criteria, assess CPG quality using a validated appraisal tool, and extract, analyze, and summarize data in a way that is cogent and transparent.
SRs of CPGs can be used to systematically identify, assess, and summarize the current state of guidance on a clinical topic. These types of reviews often require methodological tailoring to ensure that their objectives and timelines are effectively and efficiently addressed; however, they should all meet the criteria for an SR, follow a rigorous methodological approach, and adhere to transparent reporting practices.
We sought to assess the relative effects of individual anaplastic lymphoma kinase (ALK) inhibitors for the treatment of non-small cell lung cancer (NSCLC).
We searched MEDLINE, Embase, Cochrane ...CENTRAL, and grey literature (July 23, 2019) for randomized controlled trials (RCTs) that included participants with ALK- or ROS1-positive NSCLC who received any ALK inhibitor compared with placebo, another ALK inhibitor, or the same ALK inhibitor at a different dose. The primary outcome was treatment-related death. Secondary outcomes were overall survival (OS), progression-free survival (PFS), and serious adverse events. Data were pooled via meta-analysis and network meta-analysis, and risk of bias was assessed. PROSPERO: CRD42017077046.
Thirteen RCTs reporting outcomes of interest among participants with ALK-positive NSCLC were identified. Treatment-related deaths were rare, with 10 deaths attributed to crizotinib (risk difference v. chemotherapy: 0.49, 95% credible interval CrI -0.16 to 1.46; odds ratio 2.58 (0.76-11.37). All ALK inhibitors improved PSF relative to chemotherapy (hazard ratio 95% CrI: crizotinib 0.46 0.39-0.54; ceritinib 0.52 0.42-0.64; alectinib 300 BID 0.16 0.08-0.33; alectinib 600 BID 0.23 0.17-0.30; brigatinib 0.23 0.15-0.35), while alectinib and brigatinib improved PFS over crizotinib and ceritinib (alectinib v. crizotinib 0.34 0.17-0.70; alectinib v. ceritinib 0.30 0.14-0.64; brigatinib v. crizotinib 0.49 0.33-0.73; brigatinib v. ceritinib 0.43 0.27-0.70). OS was improved with alectinib compared with chemotherapy (HR 0.57 95% CrI 0.39-0.83) and crizotinib (0.68 0.48-0.96). Use of crizotinib (odds ratio 2.08 95% CrI 1.56-2.79) and alectinib (1.60 1.00-2.58) but not ceritinib (1.25 0.90-1.74), increased the risk of serious adverse events compared with chemotherapy. Results were generally consistent among treatment-experienced or naïve participants.
Treatment-related deaths were infrequent among ALK-positive NSCLC. PFS may be improved by alectinib and brigatinib relative to other ALK inhibitors; however, the assessment of OS is likely confounded by treatment crossover and should be interpreted with caution.
Attention deficit hyperactivity disorder (ADHD) affects approximately 3% of adults globally. Many pharmacologic treatments options exist, yet the comparative benefits and harms of individual ...treatments are largely unknown. We performed a systematic review and network meta-analysis to assess the relative effects of individual pharmacologic treatments for adults with ADHD.
We searched English-language published and grey literature sources for randomized clinical trials (RCTs) involving pharmacologic treatment of ADHD in adults (December 2018). The primary outcome was clinical response; secondary outcomes were quality of life, executive function, driving behaviour, withdrawals due to adverse events, treatment discontinuation, serious adverse events, hospitalization, cardiovascular adverse events, and emergency department visits. Data were pooled via pair-wise meta-analyses and Bayesian network meta-analyses. Risk of bias was assessed by use of Cochrane's Risk of Bias tool, and the certainty of the evidence was assessed by use of the GRADE framework.
Eighty-one unique trials that reported at least one outcome of interest were included, most of which were at high or unclear risk of at least one important source of bias. Notably, only 5 RCTs were deemed at overall low risk of bias. Included pharmacotherapies were methylphenidate, atomoxetine, dexamfetamine, lisdexamfetamine, guanfacine, bupropion, mixed amphetamine salts, and modafinil. As a class, ADHD pharmacotherapy improved patient- and clinician-reported clinical response compared with placebo (range: 4 to 15 RCTs per outcome); however, these findings were not conserved when the analyses were restricted to studies at low risk of bias, and the certainty of the finding is very low. There were few differences among individual medications, although atomoxetine was associated with improved patient-reported clinical response and quality of life compared with placebo. There was no significant difference in the risk of serious adverse events or treatment discontinuation between ADHD pharmacotherapies and placebo; however, the proportion of participants who withdrew due to adverse events was significantly higher among participants who received any ADHD pharmacotherapy. Few RCTs reported on the occurrence of adverse events over a long treatment duration.
Overall, despite a class effect of improving clinical response relative to placebo, there were few differences among the individual ADHD pharmacotherapies, and most studies were at risk of at least one important source of bias. Furthermore, the certainty of the evidence was very low to low for all outcomes, and there was limited reporting of long-term adverse events. As such, the choice between ADHD pharmacotherapies may depend on individual patient considerations, and future studies should assess the long-term effects of individual pharmacotherapies on patient-important outcomes, including quality of life, in robust blinded RCTs.
PROSPERO no. CRD 42015026049.
High-protein (HP) intake during weight loss (WL) therapy is often recommended because it reduces the loss of lean tissue mass. However, HP intake could have adverse effects on metabolic function, ...because protein ingestion reduces postprandial insulin sensitivity. In this study, we compared the effects of ∼10% WL with a hypocaloric diet containing 0.8 g protein/kg/day and a hypocaloric diet containing 1.2 g protein/kg/day on muscle insulin action in postmenopausal women with obesity. We found that HP intake reduced the WL-induced decline in lean tissue mass by ∼45%. However, HP intake also prevented the WL-induced improvements in muscle insulin signaling and insulin-stimulated glucose uptake, as well as the WL-induced adaptations in oxidative stress and cell structural biology pathways. Our data demonstrate that the protein content of a WL diet can have profound effects on metabolic function and underscore the importance of considering dietary macronutrient composition during WL therapy for people with obesity.
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•A high-protein weight loss (HP-WL) diet preserves lean body mass•A HP-WL diet prevents the WL-induced improvement in insulin sensitivity•A HP-WL diet alters WL-induced transcriptional changes in muscle
Smith et al. found that high-protein intake during weight loss (WL) preserves lean tissue mass but eliminates the WL-induced improvement in muscle insulin action. The authors suggest that this occurs through increasing oxidative stress and modulating WL-induced changes in cell structure and organization.
Venous thromboembolism (VTE) is a major global cause of morbidity and mortality. Low molecular weight heparin (LMWH) and fondaparinux (FDP) are frequently used to treat and prevent VTE and have a ...variety of safety and practical advantages over other anticoagulants, including use in outpatient settings. These medications are commonly listed on drug formularies, which act as a gateway for health plan prescription coverage by outlining the circumstances under which patients will be covered for specific drugs and drug products. Because patient access to medications is impacted by the nature of their listing on formularies, they must be rigorously reviewed and modernized as new evidence emerges.
As part of a broader drug class review team, we completed a systematic review of clinical practice guidelines to determine whether the recommendations they reported aligned with the indications listed for the coverage of LMWH and FDP in an outpatient drug formulary. Guideline quality was assessed using the Appraisal of Guidelines for Research & Evaluation (AGREE) II tool. Recommendation matrices were used to systematically compare, categorize, and summarize included recommendations.
Twenty-seven guidelines were included from which 168 eligible recommendations were identified. Generally, AGREE II domains were adequately addressed; however, domain five (applicability) was poorly addressed. Most recommendations were based on moderate- to low-quality/limited evidence and reported on the use of LMWHs generally; few reported on specific agents.
Our findings contributed to the recommendation that the formulary listing for LMWH and FDP be streamlined to include coverage for specific outpatient indications. The paucity of available evidence on the comparative efficacy of specific LMWH agents against each other and FDP limited agent-specific listing recommendations, highlighting the need for high-quality comparative studies on this topic.
The mesolimbic dopamine system-which originates in the ventral tegmental area and projects to the striatum-has been shown to be involved in the expression of sex-specific behavior and is thought to ...be a critical mediator of many psychiatric diseases. While substantial work has focused on sex differences in the anatomy of dopamine neurons and relative dopamine levels between males and females, an important characteristic of dopamine release from axon terminals in the striatum is that it is rapidly modulated by local regulatory mechanisms independent of somatic activity. These processes can occur via homosynaptic mechanisms-such as presynaptic dopamine autoreceptors and dopamine transporters-as well as heterosynaptic mechanisms, such as retrograde signaling from postsynaptic cholinergic and GABAergic systems, among others. These regulators serve as potential targets for the expression of sex differences in dopamine regulation in both ovarian hormone-dependent and independent fashions. This review describes how sex differences in microcircuit regulatory mechanisms can alter dopamine dynamics between males and females. We then describe what is known about the hormonal mechanisms controlling/regulating these processes. Finally, we highlight the missing gaps in our knowledge of these systems in females. Together, a more comprehensive and mechanistic understanding of how sex differences in dopamine function manifest will be particularly important in developing evidence-based therapeutics that target this system and show efficacy in both sexes.
Due to the voluntary withdrawals and/or bans on the use of two polybrominated diphenyl ether (PBDE) commercial mixtures, an increasing number of alternate flame retardant chemicals are being ...introduced in commercial applications. To determine if these alternate BFRs are present in indoor environments, we analyzed dust samples collected from 19 homes in the greater Boston, MA area during 2006. Using pure and commercial standards we quantified the following brominated flame retardant chemicals using GC/ECNI-MS methods: hexabromocyclododecane (ΣHBCD), bis(2,4,6,-tribromphenoxy)ethane (BTBPE), decabromodiphenyl ethane (DBDPE), and the brominated components found in Firemaster 550 (FM 550): 2-ethylhexyl 2,3,4,5-tetrabromobenzoate (TBB) and (2-ethylhexyl) tetrabromophthalate (TBPH), the latter compound being a brominated analogue of di(2-ethylhexyl)phthalate (DEHP). The concentrations of all compounds were log-normally distributed and the largest range in concentrations was observed for HBCD (sum of all isomers), with concentrations ranging from <4.5 ng/g to a maximum of 130,200 ng/g with a median value of 230 ng/g. BTBPE ranged from 1.6 to 789 ng/g with a median value of 30 ng/g and DBDPE ranged from <10.0 to 11,070 ng/g with a median value of 201 ng/g. Of the FM 550 components, TBB ranged from <6.6 to 15,030 ng/g with a median value of 133 ng/g; whereas TBPH ranged from 1.5 to 10,630 ng/g with a median value of 142 ng/g. Furthermore, the ratio of TBB/TBPH present in the dust samples ranged from 0.05 to 50 (average 4.4), varying considerably from the ratio observed in the FM 550 commercial mixture (4:1 by mass), suggesting different sources with different chemical compositions, and/or differential fate and transport within the home. Analysis of paired dust samples collected from different rooms in the same home suggests HBCD, TBB, and TBPH are higher in dust from the main living area compared to dust collected in bedrooms; however, BTBPE and DBDPE levels were comparable between rooms. This study highlights the fact that numerous types of brominated flame retardants are present in indoor environments, raising questions about exposure to mixtures of these contaminants.
Systematic reviews are the cornerstone of evidence-based medicine. However, systematic reviews are time consuming and there is growing demand to produce evidence more quickly, while maintaining ...robust methods. In recent years, artificial intelligence and active-machine learning (AML) have been implemented into several SR software applications. As some of the barriers to adoption of new technologies are the challenges in set-up and how best to use these technologies, we have provided different situations and considerations for knowledge synthesis teams to consider when using artificial intelligence and AML for title and abstract screening.
We retrospectively evaluated the implementation and performance of AML across a set of ten historically completed systematic reviews. Based upon the findings from this work and in consideration of the barriers we have encountered and navigated during the past 24 months in using these tools prospectively in our research, we discussed and developed a series of practical recommendations for research teams to consider in seeking to implement AML tools for citation screening into their workflow.
We developed a seven-step framework and provide guidance for when and how to integrate artificial intelligence and AML into the title and abstract screening process. Steps include: (1) Consulting with Knowledge user/Expert Panel; (2) Developing the search strategy; (3) Preparing your review team; (4) Preparing your database; (5) Building the initial training set; (6) Ongoing screening; and (7) Truncating screening. During Step 6 and/or 7, you may also choose to optimize your team, by shifting some members to other review stages (e.g., full-text screening, data extraction).
Artificial intelligence and, more specifically, AML are well-developed tools for title and abstract screening and can be integrated into the screening process in several ways. Regardless of the method chosen, transparent reporting of these methods is critical for future studies evaluating artificial intelligence and AML.
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