Emerging healthcare interventions: Patient-Centered Outcomes Research Institute's programmatic initiative.

The Patient-Centered Outcomes Research Institute (PCORI) is a nonprofit, nongovernmental organization established by the U.S. Congress to fund comparative clinical effectiveness research focusing on patient-centered outcomes through the engagement of stakeholders. Evaluation of emerging healthcare innovations is one of PCORI's five National Priorities for Health. One such initiative is PCORI's Emerging Technologies and Therapeutics Reports program, established to provide timely overviews of evidence on new drugs and other healthcare technologies. This article provides an overview of completed and ongoing Emerging Technologies and Therapeutics Reports including lessons learned to date. In addition to systematic searches, systematic selection of studies, and transparent reporting of the available evidence, informed by a select number of stakeholders (i.e., key informants), these reports focus on contextual factors shaping the diffusion of emerging technologies that are often not reported in the medical literature. This article also compares processes and methodologies of health technology assessments (HTAs) from a selected number of national and international publicly funded agencies with a goal toward potential future enhancement of PCORI's Emerging Technologies and Therapeutics Reports program. HTAs vary considerably in terms of funding, types of assessments, the role of manufacturers, stakeholder engagement, timeline to complete from the start to the finish of a draft report publication, and communication of uncertainty for informed decision making. Future Emerging Technologies and Therapeutics Reports may focus on rapid reports to support a more expedient development of evidence. Future research could explore the role of contextual factors identified in these reports on targeted evidence generation.

The Predictive Approaches to Treatment effect Heterogeneity (PATH) Statement: Explanation and Elaboration.

The PATH (Predictive Approaches to Treatment effect Heterogeneity) Statement was developed to promote the conduct of, and provide guidance for, predictive analyses of heterogeneity of treatment effects (HTE) in clinical trials. The goal of predictive HTE analysis is to provide patient-centered estimates of outcome risk with versus without the intervention, taking into account all relevant patient attributes simultaneously, to support more personalized clinical decision making than can be made on the basis of only an overall average treatment effect. The authors distinguished 2 categories of predictive HTE approaches (a "risk-modeling" and an "effect-modeling" approach) and developed 4 sets of guidance statements: criteria to determine when risk-modeling approaches are likely to identify clinically meaningful HTE, methodological aspects of risk-modeling methods, considerations for translation to clinical practice, and considerations and caveats in the use of effect-modeling approaches. They discuss limitations of these methods and enumerate research priorities for advancing methods designed to generate more personalized evidence. This explanation and elaboration document describes the intent and rationale of each recommendation and discusses related analytic considerations, caveats, and reservations.

The Predictive Approaches to Treatment effect Heterogeneity (PATH) Statement.

Heterogeneity of treatment effect (HTE) refers to the nonrandom variation in the magnitude or direction of a treatment effect across levels of a covariate, as measured on a selected scale, against a clinical outcome. In randomized controlled trials (RCTs), HTE is typically examined through a subgroup analysis that contrasts effects in groups of patients defined "1 variable at a time" (for example, male vs. female or old vs. young). The authors of this statement present guidance on an alternative approach to HTE analysis, "predictive HTE analysis." The goal of predictive HTE analysis is to provide patient-centered estimates of outcome risks with versus without the intervention, taking into account all relevant patient attributes simultaneously. The PATH (Predictive Approaches to Treatment effect Heterogeneity) Statement was developed using a multidisciplinary technical expert panel, targeted literature reviews, simulations to characterize potential problems with predictive approaches, and a deliberative process engaging the expert panel. The authors distinguish 2 categories of predictive HTE approaches: a "risk-modeling" approach, wherein a multivariable model predicts the risk for an outcome and is applied to disaggregate patients within RCTs to define risk-based variation in benefit, and an "effect-modeling" approach, wherein a model is developed on RCT data by incorporating a term for treatment assignment and interactions between treatment and baseline covariates. Both approaches can be used to predict differential absolute treatment effects, the most relevant scale for clinical decision making. The authors developed 4 sets of guidance: criteria to determine when risk-modeling approaches are likely to identify clinically important HTE, methodological aspects of risk-modeling methods, considerations for translation to clinical practice, and considerations and caveats in the use of effect-modeling approaches. The PATH Statement, together with its explanation and elaboration document, may guide future analyses and reporting of RCTs.

Predictive approaches to heterogeneous treatment effects: a scoping review.

BACKGROUND: Recent evidence suggests that there is often substantial variation in the benefits and harms across a trial population. We aimed to identify regression modeling approaches that assess heterogeneity of treatment effect within a randomized clinical trial. METHODS: We performed a literature review using a broad search strategy, complemented by suggestions of a technical expert panel. RESULTS: The approaches are classified into 3 categories: 1) Risk-based methods (11 papers) use only prognostic factors to define patient subgroups, relying on the mathematical dependency of the absolute risk difference on baseline risk; 2) Treatment effect modeling methods (9 papers) use both prognostic factors and treatment effect modifiers to explore characteristics that interact with the effects of therapy on a relative scale. These methods couple data-driven subgroup identification with approaches to prevent overfitting, such as penalization or use of separate data sets for subgroup identification and effect estimation. 3) Optimal treatment regime methods (12 papers) focus primarily on treatment effect modifiers to classify the trial population into those who benefit from treatment and those who do not. Finally, we also identified papers which describe model evaluation methods (4 papers). CONCLUSIONS: Three classes of approaches were identified to assess heterogeneity of treatment effect. Methodological research, including both simulations and empirical evaluations, is required to compare the available methods in different settings and to derive well-informed guidance for their application in RCT analysis.

Pseudomonas infections among hospitalized adults in Latin America: a systematic review and meta-analysis.

BACKGROUND: Treatment of resistant Pseudomonas aeruginosa infection continues to be a challenge in Latin American countries (LATAM). We synthesize the literature on the use of appropriate initial antibiotic therapy (AIAT) and inappropriate initial antibiotic therapy (IIAT) in P. aeruginosa infections, and the literature on risk factors for acquisition of resistant P. aeruginosa among hospitalized adult patients in LATAM. METHODS: MEDLINE, EMBASE, Cochrane, and LILAC were searched between 2000 and August 2019. Abstracts and full-text articles were screened in duplicate. Random effects meta-analysis was conducted when studies were sufficiently similar. RESULTS: The screening of 165 citations identified through literature search yielded 98 full-text articles that were retrieved and assessed for eligibility, and 19 articles conducted in Brazil (14 articles), Colombia (4 articles), and Cuba (1 article) met the inclusion criteria. Of 19 eligible articles, six articles (840 subjects) examined AIAT compared to IIAT in P. aeruginosa infections; 17 articles (3203 total subjects) examined risk factors for acquisition of resistant P. aeruginosa; and four articles evaluated both. Four of 19 articles were rated low risk of bias and the remaining were deemed unclear or high risk of bias. In meta-analysis, AIAT was associated with lower mortality for P. aeruginosa infections (unadjusted summary OR 0.48, 95% CI 0.28-0.81; I2 = 59%), compared to IIAT and the association with mortality persisted in subgroup meta-analysis by low risk of bias (3 articles; unadjusted summary OR 0.46, 95% CI 0.28-0.81; I2 = 0%). No meta-analysis was performed for studies evaluating risk factors for acquisition of resistant P. aeruginosa as they were not sufficiently similar. Significant risk factors for acquisition of resistant P. aeruginosa included: prior use of antibiotics (11 articles), stay in the intensive care unit (ICU) (3 articles), and comorbidity score (3 articles). Outcomes were graded to be of low strength of evidence owing to unclear or high risk of bias and imprecise estimates. CONCLUSION: Our study highlights the association of AIAT with lower mortality and prior use of antibiotics significantly predicts acquiring resistant P. aeruginosa infections. This review reinforces the need for rigorous and structured antimicrobial stewardship programs in the LATAM region.

Daily almond consumption in cardiovascular disease prevention via LDL-C change in the U.S. population: a cost-effectiveness analysis.

BACKGROUND: Heart disease is the leading cause of death in the United States. The U.S. Food and Drug Administration approved the health claim that 1.5 oz (42.5 g) of nut intake may reduce the risk of cardiovascular disease. Previous studies have focused on the cost-effectiveness of other foods or dietary factors on primary cardiovascular disease prevention, yet not in almond consumption. This study aimed to examine the cost-effectiveness of almond consumption in cardiovascular disease primary prevention. PERSPECTIVE & SETTING: This study assessed the cost-effectiveness of consuming 42.5 g of almond from the U.S. healthcare sector perspective. METHODS: A decision model was developed for 42.5 g of almond per day versus no almond consumption and cardiovascular disease in the U.S. POPULATION: Parameters in the model were derived from the literature, which included the probabilities of increasing low-density lipoprotein cholesterol, developing acute myocardial infarction and stroke, treating acute myocardial infarction, dying from the disease and surgery, as well as the costs of the disease and procedures in the U.S. population, and the quality-adjusted life years. The cost of almonds was based on the current price in the U.S. market. Sensitivity analyses were conducted for different levels of willingness-to-pay, the probabilistic sensitivity analysis, ten-year risk prevention, different costs of procedures and almond prices, and patients with or without cardiovascular disease. RESULTS: The almond strategy had $363 lower cost and 0.02 higher quality-adjusted life years gain compared to the non-almond strategy in the base-case model. The annual net monetary benefit of almond consumption was $1421 higher per person than no almond consumption, when the willingness to pay threshold was set at $50,000 for annual health care expenditure. Almond was more cost-effective than non-almond in cardiovascular disease prevention in all the sensitivity analyses. CONCLUSION: Consuming 42.5 g of almonds per day is a cost-effective approach to prevent cardiovascular disease in the short term and potentially in the long term.

THE EFFECTS OF HYPONATREMIA ON BONE DENSITY AND FRACTURES: A SYSTEMATIC REVIEW AND META-ANALYSIS.

Objective: Hyponatremia decreases bone mineral density and is a major risk factor for fragility fractures. Objectives of our systematic review and meta-analysis were to analyze the overall effects of hyponatremia on bone fractures, osteoporosis, and mortality. Methods: We extracted data from Medline, Cochrane Central, and EMBASE 1960-2017 and conference abstracts from 2007-2017. We included studies with data on serum sodium, fractures, bone density, or diagnoses of osteoporosis. Studies were independently reviewed by two authors and assessed for bias using the Newcastle-Ottawa scale. Random effect models meta-analysis was used when at least three studies reported the same outcome measures. We reported summary odds ratios (ORs) and 95% confidence intervals (CIs). Results: We included 26 studies for qualitative analysis. Fifteen studies were included in the meta-analysis to evaluate the effects of hyponatremia on fractures, four studies for bone mineral density changes, and six for mortality. Hyponatremia increased the odds of fractures at all sites (summary OR, 2.34 [95% CI, 1.86, 2.96]. There was an increase in the odds of osteoporosis (summary OR, 2.67 [95% CI, 2.07, 3.43]). Mortality risk among the included studies remained high (summary OR, 1.31 [95% CI, 1.16, 1.47]). Conclusion: Our meta-analysis confirms a statistically significant association of hyponatremia with bone fractures and osteoporosis along with higher mortality. Long-term prospective studies evaluating the impact of correcting hyponatremia on bone health, fractures, and mortality are required. Abbreviations: AVP = arginine vasopressin; CI = confidence interval; CKD = chronic kidney disease; OR = odds ratio; SIADH = syndrome of inappropriate antidiuretic hormone.

Long-Term Health Outcomes in Women With Silicone Gel Breast Implants: A Systematic Review.

BACKGROUND: Silicone gel breast implants were removed from the U.S. market for cosmetic use in 1992 owing to safety concerns. They were reintroduced in 2006, with a call for improved surveillance of clinical outcomes. PURPOSE: To systematically review the literature regarding specific long-term health outcomes in women with silicone gel breast implants, including cancer; connective tissue, rheumatologic, and autoimmune diseases; neurologic diseases; reproductive issues, including lactation; offspring issues; and mental health issues (depression and suicide). DATA SOURCES: MEDLINE, EMBASE, and Ovid Healthstar (inception through 30 June 2015), and the Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (through the first quarter of 2015). STUDY SELECTION: 4 researchers double-screened articles for longitudinal studies that compared women with and without breast implants and reported long-term health outcomes of interest. DATA EXTRACTION: 4 researchers extracted data on participant and implant characteristics, analytic methods, and results. DATA SYNTHESIS: 32 studies (in 58 publications) met eligibility criteria. Random-effects model meta-analyses of effect sizes were conducted when feasible. For most outcomes, there was at most only a single adequately adjusted study, which usually found no significant associations. There were possible associations with decreased risk for primary breast and endometrial cancers and increased risks for lung cancer, rheumatoid arthritis, Sjögren syndrome, and Raynaud syndrome. Evidence on breast implants and other outcomes either was limited or did not exist. LIMITATION: The evidence was most frequently not specific to silicone gel implants, and studies were rarely adequately adjusted for potential confounders. CONCLUSION: The evidence remains inconclusive about any association between silicone gel implants and long-term health outcomes. Better evidence is needed from existing large studies, which can be reanalyzed to clarify the strength of associations between silicone gel implants and health outcomes. PRIMARY FUNDING SOURCE: The Plastic Surgery Foundation.

Comparative Effectiveness of Management Strategies for Renal Artery Stenosis: An Updated Systematic Review.

BACKGROUND: Atherosclerotic renal artery stenosis (ARAS) is associated with high blood pressure (BP), decreased kidney function, renal replacement therapy (RRT), and death. PURPOSE: To compare benefits and harms of percutaneous transluminal renal angioplasty with stent placement (PTRAS) versus medical therapy alone in adults with ARAS. DATA SOURCES: MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials from 1993 to 16 March 2016; gray literature; and prior systematic reviews. STUDY SELECTION: Randomized, controlled trials (RCTs); nonrandomized, comparative studies (NRCSs); single-group studies; and selected case reports that reported all-cause and cardiovascular mortality, RRT, kidney function, BP, and adverse events. DATA EXTRACTION: Six researchers extracted data on design, interventions, outcomes, and study quality into a Web-based database. DATA SYNTHESIS: Eighty-three studies met eligibility criteria. In 5 of 7 RCTs, PTRAS and medical therapy led to similar BP control in patients with ARAS, and no RCTs showed statistically significant differences in kidney function, mortality, RRT, cardiovascular events, or pulmonary edema. Eight NRCSs had more variable results, finding mostly no significant differences in mortality, RRT, or cardiovascular events but heterogeneous effects on kidney function and BP. Procedure-related adverse events were rare, and medication-related adverse events were not reported. Two RCTs found no patient characteristics that were associated with outcomes with either PTRAS or medical therapy. Single-group studies found various but inconsistent factors that predict outcomes. Case reports provided examples of clinical improvement after PTRAS in patients with acute decompensation. LIMITATION: Limited clinical applicability and power in RCTs, and possible publication bias and lack of adjusted analyses in NRCSs. CONCLUSION: The strength of evidence regarding the relative benefits and harms of PTRAS versus medical therapy alone for patients with ARAS is low. Studies have generally focused on patients with less severe ARAS. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Bioavailability, Efficacy and Safety of Generic Immunosuppressive Drugs for Kidney Transplantation: A Systematic Review and Meta-Analysis.

BACKGROUND: Concerns exist over the extrapolation of bioavailability studies of generic immunosuppressive drugs in healthy volunteers, regarding their efficacy and safety in kidney transplant recipients. We conducted a meta-analysis of trials examining the bioavailability of generic (test) immunosuppressive drugs relative to their brand (reference) counterparts in healthy volunteers, based on the US Food and Drug Administration requirements for approval of generics, and their efficacy and safety in kidney transplant recipients. METHODS: Eligible studies were identified in PubMed, Cochrane Central Register of Controlled Trials, Scopus, ClinicalTrials.gov, and conference abstracts. RESULTS: Twenty crossover trials of healthy volunteers (n = 641) and 6 parallel-arm randomized controlled trials of kidney transplant recipients (n = 594) were identified. The 90% CI of the pooled test-to-reference drug ratio for maximum or peak plasma concentration (Cmax) and area under the plasma concentration time-curve from time 0 to time of last determinable concentration (AUC(0-t)) fell within the required range (0.80-1.25) for cyclosporine (Cmax 0.91; 90% CI 0.86-0.95; and AUC(0-t) 0.97; 90% CI 0.94-1.00), tacrolimus (Cmax 1.17; 90% CI 1.09-1.24; and AUC(0-t) 1.00; 90% CI 0.97-1.03) and mycophenolate mofetil (Cmax 0.98; 90% CI 0.96-1.01; and AUC(0-t) 1.00; 90% CI 0.99-1.01). In subgroup analyses, some generic cyclosporine formulations did not meet criteria for bioequivalence. No significant differences were observed in the time to maximum plasma concentration and terminal plasma half-life between generic and brand drugs. In parallel-arm trials, generic cyclosporine was non-inferior to brand counterpart in terms of acute allograft rejection, infections, and death. CONCLUSIONS: Not all generic immunosuppressive drugs have similar relative bioavailability to their brand name counterparts. Evidence on their efficacy and safety is inconclusive. Tighter regulatory requirement for approval of generic drugs with narrow therapeutic index is needed.

Combined Diet and Physical Activity Promotion Programs to Prevent Type 2 Diabetes Among Persons at Increased Risk: A Systematic Review for the Community Preventive Services Task Force.

BACKGROUND: Trials have shown efficacy of rigorous diet and physical activity promotion programs to reduce diabetes incidence and improve glycemic measures in adults at increased risk for type 2 diabetes. PURPOSE: To evaluate diet and physical activity promotion programs for persons at increased risk for type 2 diabetes, primarily to reduce diabetes risk and decrease body weight and glycemia. DATA SOURCES: MEDLINE, the Cochrane Central Register of Controlled Trials, CAB Abstracts, Global Health, and Ovid HealthSTAR from 1991 through 27 February 2015, with no language restriction. STUDY SELECTION: 8 researchers screened articles for single-group or comparative studies of combined diet and physical activity promotion programs with at least 2 sessions over at least 3 months in participants at increased risk for type 2 diabetes. DATA EXTRACTION: 7 researchers extracted data on study design; participant, intervention, and outcome descriptions; and results and assessed study quality. DATA SYNTHESIS: 53 studies (30 of diet and physical activity promotion programs vs. usual care, 13 of more intensive vs. less intensive programs, and 13 of single programs) evaluated 66 programs. Compared with usual care, diet and physical activity promotion programs reduced type 2 diabetes incidence (risk ratio [RR], 0.59 [95% CI, 0.52 to 0.66]) (16 studies), decreased body weight (net change, -2.2% [CI, -2.9% to -1.4%]) (24 studies) and fasting blood glucose level (net change, -0.12 mmol/L [-2.2 mg/dL] [CI, -0.20 to -0.05 mmol/L {-3.6 to -0.9 mg/dL}]) (17 studies), and improved other cardiometabolic risk factors. Evidence for clinical events was limited. More intensive programs were more effective. LIMITATIONS: Wide variation in diet and physical activity promotion programs limited identification of features most relevant to effectiveness. Evidence on clinical outcomes and in children was sparse. CONCLUSION: Combined diet and physical activity promotion programs are effective at decreasing diabetes incidence and improving cardiometabolic risk factors in persons at increased risk. More intensive programs are more effective. PRIMARY FUNDING SOURCE: Centers for Disease Control and Prevention Community Preventive Services Task Force.

Appropriate initial antibiotic therapy in hospitalized patients with gram-negative infections: systematic review and meta-analysis.

BACKGROUND: The rapid global spread of multi-resistant bacteria and loss of antibiotic effectiveness increases the risk of initial inappropriate antibiotic therapy (IAT) and poses a serious threat to patient safety. We conducted a systematic review and meta-analysis of published studies to summarize the effect of appropriate antibiotic therapy (AAT) or IAT against gram-negative bacterial infections in the hospital setting. METHODS: MEDLINE, EMBASE, and Cochrane CENTRAL databases were searched until May 2014 to identify English-language studies examining use of AAT or IAT in hospitalized patients with Gram-negative pathogens. Outcomes of interest included mortality, clinical cure, cost, and length of stay. Citations and eligible full-text articles were screened in duplicate. Random effect models meta-analysis was used. RESULTS: Fifty-seven studies in 60 publications were eligible. AAT was associated with lower risk of mortality (unadjusted summary odds ratio [OR] 0.38, 95 % confidence interval [CI] 0.30-0.47, 39 studies, 5809 patients) and treatment failure (OR 0.22, 95 % CI 0.14-0.35; 3 studies, 283 patients). Conversely, IAT increased risk of mortality (unadjusted summary OR 2.66, 95 % CI 2.12-3.35; 39 studies, 5809 patients). In meta-analyses of adjusted data, AAT was associated with lower risk of mortality (adjusted summary OR 0.43, 95 % CI 0.23-0.83; 6 studies, 1409 patients). Conversely, IAT increased risk of mortality (adjusted summary OR 3.30, 95 % CI 2.42-4.49; 16 studies, 2493 patients). A limited number of studies suggested higher cost and longer hospital stay with IAT. There was considerable heterogeneity in the definition of AAT or IAT, pathogens studied, and outcomes assessed. DISCUSSION: Using a large set of studies we found that IAT is associated with a number of serious consequences,including an increased risk of hospital mortality. Infections caused by drug-resistant, Gram-negative organisms represent a considerable financial burden to healthcare systems due to the increased costs associated with the resources required to manage the infection, particularly longer hospital stays. However, there were insufficient data that evaluated AAT for the outcome of costs among patients with nosocomialGram-negative infections. CONCLUSIONS: IAT in hospitalized patients with Gram-negative infections is associated with adverse outcomes. Technological advances for rapid diagnostics to facilitate AAT along with antimicrobial stewardship, surveillance, infection control, and prevention is needed.

Non-tuberculous mycobacterium skin infections after tattooing in healthy individuals: A systematic review of case reports.

In recent years, several case reports and outbreaks reported occurrence of non-tuberculous mycobacteria (NTM) infections within 6 months after receiving a tattoo in healthy individuals. NTM species (e.g., Chelonae, Fortuitum, Hemophillum, and Abscessus) are widespread in the environment and it is often suspected that contamination may occur through unsterile instrumentation or unsterile water used for diluting tattoo ink to dilute color. In reported cases, lesions were mainly restricted to a single color 'gray' part of the tattoo. Mycobacterium Chelonae was the most common cause of tattoo associated NTM infections. Less than 50% of the case reports tested tattoo ink for acid fast bacilli stains and cultures. Subjects required treatment with either clarithromycin alone or in combination with quinolones for 6 to 9 months. An increase in NTM skin infections in healthy individuals after tattooing indicates the need for sterile standards during tattooing and improved local and regional regulatory oversight.

Asymptomatic carotid artery stenosis treated with medical therapy alone: temporal trends and implications for risk assessment and the design of future studies.

BACKGROUND: The rate of adverse clinical outcomes among patients with asymptomatic carotid stenosis receiving medical therapy alone can be used to guide clinical decision-making and to inform future research. We aimed to investigate temporal changes in the incidence rate of clinical outcomes among patients with asymptomatic carotid stenosis receiving medical therapy alone and to explore the implications of these changes for the design of future comparative studies. SUMMARY: We searched MEDLINE, the Cochrane Central Register of Controlled Trials, US Food and Drug Administration documents, and reference lists of included studies (last search: December 31, 2012). We selected prospective cohort studies of medical therapy for asymptomatic carotid artery stenosis and we extracted information on study characteristics, risk of bias, and outcomes. We performed meta-analyses to estimate summary incidence rates, meta-regressions to assess trends over time, and simulations to explore sample size requirements for the design of future studies comparing new treatments against medical therapy. The main outcomes of interest were ipsilateral stroke, any stroke, cardiovascular death, death, and myocardial infarction. We identified 41 studies of medical therapy for patients with asymptomatic carotid stenosis (last recruitment year: 1978-2009). The summary incidence rate of ipsilateral carotid territory stroke (25 studies) was 1.7 per 100 person-years. This incidence rate was significantly lower in recent studies (last recruitment year from 2000 onwards) as compared to studies that ended recruitment earlier (1.0 vs. 2.3 events per 100 person-years; p < 0.001). The incidence rates of any territory stroke (17 studies), cardiovascular death (6 studies), death (13 studies), and myocardial infarction (5 studies) were 2.7, 4.1, 4.6, and 1.8 per 100 person-years, respectively. Simulations showed that future studies would need to enroll large numbers of patients with a relatively high incidence rate under medical therapy, and evaluate interventions with large effect sizes, to have adequate power to reliably detect treatment effects. KEY MESSAGES: Improved prognosis under medical therapy alone has narrowed the potential range of risk reduction attainable with new treatments for asymptomatic carotid stenosis. Future comparative studies will need to enroll large numbers of patients to assess treatment effectiveness.

Management strategies for asymptomatic carotid stenosis: a systematic review and meta-analysis.

BACKGROUND: Adults with asymptomatic carotid artery stenosis are at increased risk for ipsilateral carotid territory ischemic stroke. PURPOSE: To examine comparative evidence on management strategies for asymptomatic carotid stenosis and the incidence of ipsilateral stroke with medical therapy alone. DATA SOURCES: MEDLINE, Cochrane Central Register of Controlled Trials, U.S. Food and Drug Administration documents, and review of references through 31 December 2012. STUDY SELECTION: Randomized, controlled trials (RCTs) and prospective or retrospective nonrandomized, comparative studies of medical therapy alone, carotid endarterectomy (CEA) plus medical therapy, or carotid artery stenting (CAS) plus medical therapy for adults with asymptomatic carotid stenosis, as well as single-group prospective cohort studies of medical therapy, were reviewed. DATA EXTRACTION: Two investigators extracted information on study and population characteristics, results, and risk of bias. DATA SYNTHESIS: Forty-seven studies in 56 publications were eligible. The RCTs comparing CAS and CEA were clinically heterogeneous; 1 RCT reported more but not statistically significant ipsilateral stroke events (including any periprocedural stroke) in CAS compared with CEA, whereas another RCT, in a population at high surgical risk for CEA, did not. Three RCTs showed that CEA reduced the risk for ipsilateral stroke (including any periprocedural stroke) compared with medical therapy alone, but these results may no longer be applicable to contemporary clinical practice. No RCT compared CAS versus medical therapy alone. The summary incidence of ipsilateral stroke across 26 cohorts receiving medical therapy alone was 1.68% per year. LIMITATIONS: Studies defined asymptomatic status heterogeneously. Participants in RCTs did not receive best-available medical therapy. CONCLUSION: Future RCTs of asymptomatic carotid artery stenosis should explore whether revascularization interventions provide benefit to patients treated by best-available medical therapy. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Two-stage arthroplasty for prosthetic joint infection: a systematic review of acute kidney injury, systemic toxicity and infection control.

Periprosthetic infections of hip and knee joints are now treated by two-stage revision arthroplasty with an infection control rate of 91%. The present systematic review studied the reported incidence of acute kidney injury (AKI) and infection recurrence from January 1989 to June 2012 to assess the risk-benefit ratio of antibiotic spacer use. Ten observational studies (n=544 patients) with clinical outcomes showed an average incidence of AKI of 4.8%. The average reported persistence or recurrence rate of infection was 11% during a follow-up period that ranged from 13 to 108 months. The risk-benefit ratio presently favors treatment although there appears to be higher complication rates and incidence of AKI than previously reported. Marked heterogeneity in practice and lack of detail in reporting precluded more robust quantitative synthesis. Clinicians need to be aware of the potential risk of AKI, particularly in high-risk patients; practice patterns for the use of antibiotic spacers need to be standardized.

Blueberry Consumption and Exercise: Gap Analysis Using Evidence Mapping.

Objective: Strenuous muscular workouts can increase markers of inflammation that can potentially damage components of skeletal muscles. Blueberries contain a variety of nutrients and phytochemicals that have individually been related to reduction in oxidative stress and inflammation. The objective was to conduct a systematic overview using evidence mapping to identify research-dense and evidence gap areas that examine the impact of blueberry consumption on exercise performance and inflammatory markers in adults. Design: The authors searched Medline, Cochrane Central, and Commonwealth Agricultural Bureau for literature published between 1946 and September 2019. Abstracts and full-text publications were screened in duplicate for studies that evaluated outcomes related to metabolism, lipoprotein, muscle damage, markers of oxidative stress, inflammatory markers, or gait after participants consumed blueberries and were subjected to some form of exercise. Results: The authors found nine randomized controlled trials, one single-arm study, and one observational study that met the eligibility criteria. Inflammatory markers, F2-isoprostanes, and gait speed were the most frequently reported outcomes, with each one reported by at least three studies. Outcomes related to metabolism, lipoproteins, muscle damage, and most markers of oxidative stress and most gait-related outcomes were each reported by one study. Intervention trials were generally conducted with a small number of participants and the majority included mostly younger individuals. Using multivariate analysis, the sole observational study examined physical ability among participants who consumed higher doses of blueberries compared with participants who consumed a half cup of blueberries less than once a month. Conclusions: Evidence mapping found that further research in both randomized controlled trials and cohort studies examining the impact of blueberry consumption on exercise performance and inflammatory markers is needed to establish an association.

The association between macular pigment optical density and visual function outcomes: a systematic review and meta-analysis.

OBJECTIVES: To conduct a systematic review and meta-analysis on data related to macular pigment optical density (MPOD) and visual function in adults with healthy eyes. METHODS: MEDLINE®, Cochrane, and Commonwealth of Agriculture Bureau abstracts databases were searched for English-language publications between 1946 and August 2018. Included studies examined correlation of MPOD and visual function in adults with healthy eyes at all timepoints and all designs, except for case-control, case reports, and reviews. Visual function outcomes of interest included photostress recovery, contrast sensitivity, visual acuity, glare sensitivity/disability, and dark adaptation. Random effects model meta-analyses combined study-level correlation (r). RESULTS: Twenty-two publications were included. In meta-analysis MPOD was found to be significantly correlated with contrast sensitivity at 30' (two studies, summary r: 0.37; 95% CI 0.15, 0.56), and at 1° eccentricity with a spatial frequency of 7, 11, and 21 cpd (three studies, summary r: 0.31; 95% CI 0.06, 0.52), with photostress recovery at a 1° eccentricity with a moderate background, 10 cpd, and 16% contrast (two studies, summary r: -0.17; 95% CI -0.31, -0.02), and at 30' (four studies, summary r: -0.57; 95% CI -0.78, -0.24), and with glare disability at 30' eccentricity with a log scale at 460 nm (three studies, summary r = 0.47; 95% CI 0.32; 0.59). There were insufficient data for meta-analysis for other visual functions. CONCLUSIONS: Our review identifies a link between MPOD and visual function with significant correlations with photostress recovery, glare disability, and contrast sensitivity.