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Systematic review of the adverse bone and calcium balance effects of caffeine consumption in healthy adults, pregnant women, adolescents, and children


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Statistics: 14 Studies, 1 Key Question, 1 Extraction Form,
Date Published: Mar 21, 2019 09:12AM
Description: To date, one of the most heavily cited assessments of caffeine safety in the peer-reviewed literature is that issued by Health Canada (Nawrot et al., 2003). Since then, >10,000 papers have been published related to caffeine, including hundreds of reviews on specific human health effects; however, to date, none have compared the wide range of topics evaluated by Nawrot et al. (2003). Thus, as an update to this foundational publication, we conducted a systematic review of data on potential adverse effects of caffeine published from 2001 to June 2015. Subject matter experts and research team participants developed five PECO (population, exposure, comparator, and outcome) questions to address five types of outcomes (acute toxicity, cardiovascular toxicity, bone and calcium effects, behavior, and development and reproduction) in four healthy populations (adults, pregnant women, adolescents, and children) relative to caffeine intake doses determined not to be associated with adverse effects by Health Canada (comparators: 400 mg/day for adults [10 g for lethality], 300 mg/day for pregnant women, and 2.5 mg/kg/day for children and adolescents). The a priori search strategy identified >5000 articles that were screened, with 381 meeting inclusion/exclusion criteria for the five outcomes (pharmacokinetics was addressed contextually, adding 46 more studies). Data were extracted by the research team and rated for risk of bias and indirectness (internal and external validity). Selected no- and low-effect intakes were assessed relative to the population-specific comparator. Conclusions were drawn for the body of evidence for each outcome, as well as endpoints within an outcome, using a weight of evidence approach. When the total body of evidence was evaluated and when study quality, consistency, level of adversity, and magnitude of response were considered, the evidence generally supports that consumption of up to 400 mg caffeine/day in healthy adults is not associated with overt, adverse cardiovascular effects, behavioral effects, reproductive and developmental effects, acute effects, or bone status. Evidence also supports consumption of up to 300 mg caffeine/day in healthy pregnant women as an intake that is generally not associated with adverse reproductive and developmental effects. Limited data were identified for child and adolescent populations; the available evidence suggests that 2.5 mg caffeine/kg body weight/day remains an appropriate recommendation. The results of this systematic review support a shift in caffeine research to focus on characterizing effects in sensitive populations and establishing better quantitative characterization of interindividual variability (e.g., epigenetic trends), subpopulations (e.g., unhealthy populations, individuals with preexisting conditions), conditions (e.g., coexposures), and outcomes (e.g., exacerbation of risk-taking behavior) that could render individuals to be at greater risk relative to healthy adults and healthy pregnant women. This review, being one of the first to apply systematic review methodologies to toxicological assessments, also highlights the need for refined guidance and frameworks unique to the conduct of systematic review in this field.
Contributor(s): None Provided
Funding Source: The systematic review of the adverse bone and calcium balance effects of caffeine consumption in healthy adults, pregnant women, adolescents, and children is sponsored by the North American Branch of the International Life Sciences Institute (ILSI) Caffeine Working Group. Unrestricted grants from the American Beverage Association (ABA) and the National Coffee Association (NCA) were also received.
Methodology Description: Problem formulation was based on providing an update of Nawrot et al. (2003), “Effects of caffeine on human health,” [PMID 12519715]. No comprehensive studies of similar scope have been published in the peer-reviewed literature, and thus the overall objective is to conduct an update to Nawrot et al. that applies the rigor of a systematic review. This review is one of five systematic reviews being conducted simultaneously (other endpoints include acute toxicity and adverse effects on reproduction/development, cardiovascular, and bone and calcium balance outcomes. Exposure and comparators were thus based on levels determined by Nawrot et al., (2003). Searches: The searches were conducted using: PubMed, EMBASE, and the Cochrane Database of Systematic Review. The restrictions will be articles published in English between 2001 and June 8, 2015. EMBASE searches were exclusive of MEDLINE and restricted to selected journals (430 journals were selected based on relevance). The Cochrane library was searched between Jan 2001 and June 2015 for review articles. Search strategies were informed and reviewed by a librarian. Types of studies included: All study types (excluding case studies) characterizing a quantitative exposure to caffeine and an adverse bone and calcium balance endpoint will be included. Both exposure and response must be evaluated at the individual level. Reviews will not be included in the systematic assessment (unless original data, such as a meta analysis, were conducted), but selected reviews will be consulted for context. Include: studies reporting parameters or effects associated with adverse effects within a benefit/therapy study. Exclude: Studies assessing only beneficial or therapeutic endpoints or outcomes following exposure to caffeine. Participants/ population: Populations: healthy adults, healthy pregnant women, healthy adolescents (aged 12-19), healthy children (aged 3-12). Exposure: = 400 mg/day, 300 mg/day, 2.5 mg/kg-bw day*, respectively (by population). Comparator: < 400 mg/day, 300 mg/day, 2.5 mg/kg-bw day*, respectively (by population). *Applies to both adolescents and children. Include: Studies evaluating a healthy population; this will include athletes, military, and pregnant women, unless otherwise noted as unhealthy. Healthy in this context was defined as subjects who were not specifically described as hospitalized, diagnosed with disease, and/or receiving medical treatment for a disease at the time of the study. Include: Studies that evaluate the effects of caffeine exposure in humans. This included studies in which healthy individuals were included as a control group (or similar) as part of a study on unhealthy populations (only information from the healthy individuals would be carried forward). Include: crossover balance studies could with a control period rather than a control group. Exclude: Studies evaluating unhealthy populations with no healthy control arm; this includes asthmatics and smoking populations. Exclude: Studies that describe effects of caffeine exposure in animal species or in vitro studies. Exclude: Case studies with no comparison group. Intervention(s), exposure(s) Exposure to caffeine: = 400 mg/day, 300 mg/day, 2.5 mg/kg-bw day*, respectively (by population). *Applies to both adolescents and children. Include: Studies that provide a quantitative exposure to a caffeine source associated with an adverse effect. Acceptable forms of caffeine are coffee, tea, chocolate, cola-type beverages, energy drinks (e.g. Monster, Red Bull, Rockstar), supplements, medicines, energy shots, caffeinated chewing gum, caffeinated sport gel, and caffeinated sport bars. Include: Studies evaluating the effects of caffeine alone, in one of the aforementioned forms, or in combination with one or more compounds occurring in the approved sources at levels designed to match constituents of valid sources (e.g., caffeine and green tea extract). Exclude: Studies that do not provide a quantitative exposure to an acceptable caffeine source associated with an adverse effect. This includes studies that evaluate only decaffeinated coffee/tea and caffeine placebo exposures (i.e. exposures where participants were expecting caffeine but did not receive the drug), Yerba mate, guarana, damiana and/or contaminants of caffeine or caffeine metabolites. Exclude: Studies that evaluate the effects of caffeine in combination with another pharmacologically active compound in an OTC medicine such as Excedrin (acetaminophen + caffeine) or in a prescribed drug, alcohol, or nicotine. Exclude: Studies less than six months in duration. Six months is the minimum time needed to see bone outcome endpoint effects on most any intervention (this does not include balance studies). Comparator(s)/ control: Comparator: < 400 mg/day, 300 mg/day, 2.5 mg/kg-bw day*, respectively (by population) *Applies to both adolescents and children Outcome(s): Primary outcomes Adverse bone and calcium balance effects include, effects on bone fracture, bone mineral density, calcium absorption and any other adverse bone and calcium balance effects reported (inclusive investigation). Exclude: Studies assessing hypertension and menopausal symptoms (not considered adverse). Studies addressing rare bone disorders like Paget’s disease, Osteoporosis Imperfecta, etc. Secondary outcomes Pharmacokinetic data that could be used to interpret the primary outcome (e.g., contextual information). Risk of bias (quality) assessment: Risk of bias will be evaluated using the U.S. National Toxicology Program: Office of Health Assessment and Translation Risk of Bias Rating Tool for Human and Animal studies (2015). Study reliability will also be characterized using the systematic approach for evaluating and scoring human data proposed by Money et al (2013) [PMID 23579077] Strategy for data synthesis: The body of evidence was evaluated and integrated using the U.S. National Toxicology Program: Office of Health Assessment and Translation Handbook for Conducting a Literature-Based Health Assessment Using OHAT Approach for Systematic Review an Evidence Integration (2015). The process will involve generation of evidence tables and a qualitative synthesis of the available data. Evidence analysts will use a weight of evidence approach incorporating concepts such as consistency, dose response, imprecision, indirectness, magnitude of effect, confounding, and risk of bias to determine conclusions regarding levels of caffeine associated with acute adverse effects. Analytical tools, such as forest plots and descriptive statistical parameters, were used to aid in the weight of evidence assessment. Based on the availability of data, considerations were also be made regarding the severity of the outcome as well as the event(s) relative to the progression of the outcome.

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Stroke Prevention in Patients With Atrial Fibrillation: A Systematic Review Update


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Statistics: 185 Studies, 3 Key Questions, 1 Extraction Form,
Date Published: Mar 21, 2019 09:12AM
Description: Objectives: This review updates previous reviews regarding the optimal risk stratification tools for stroke and bleeding prediction and treatment options for stroke prevention. Data Sources: We searched PubMed®, Embase®, and the Cochrane Database of Systematic Reviews for relevant English-language comparative studies published from January 1, 2000, to February 14, 2018. Review Methods: Two investigators screened each abstract and full-text article for inclusion, abstracted data, rated quality and applicability, and graded evidence. When possible, random-effects models were used to compute summary estimates of effects.
Contributor(s): Gillian D. Sanders, Ph.D. Angela Lowenstern, M.D. Ethan Borre, B.A. Ranee Chatterjee, M.D., M.P.H. Adam Goode, D.P.T., Ph.D. Lauren Sharan, M.D. Nancy M. Allen LaPointe, Pharm.D., M.H.S. Giselle Raitz, M.D. Bimal Shah, M.D., M.B.A. Roshini Yapa, M.B.B.S. J. Kelly Davis, B.A. Kathryn Lallinger, M.S.L.S. Robyn Schmidt, B.A. Andrzej Kosinski, Ph.D. Sana Al-Khatib, M.D. M.H.S.
Funding Source: Agency for Healthcare Research and Quality (AHRQ), The Patient-Centered Outcomes Research Institute (PCORI)
Methodology Description: We searched PubMed®, Embase®, and the Cochrane Database of Systematic Reviews for relevant English-language comparative studies published from January 1, 2000, to February 14, 2018. Two investigators screened each abstract and full-text article for inclusion, abstracted the data, and performed quality ratings and evidence grading. Random-effects models were used to compute summary estimates of effects. See the review protocol (https://effectivehealthcare.ahrq.gov/topics/stroke-afib-update/research-protocol) for full details.

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Drug Therapy for Early Rheumatoid Arthritis in Adults: A Systematic Review Update


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Statistics: 124 Studies, 4 Key Questions, 4 Extraction Forms,
Date Published: Mar 21, 2019 09:12AM
Description: The purpose of this systematic review is to update the 2012 Comparative Effectiveness Review that evaluated the benefits and harms of drug therapies for adults with rheumatoid arthritis (RA). This updated review has a targeted scope focusing solely on patients with early RA, defined as no more than one year of diagnosed disease. This report is intended to help health care decision makers -- patients, and clinicians, health system leaders, and policymakers, among others -- make well-informed decisions regarding early RA and thereby improve the quality of health care services.
Contributor(s): Katrina Donahue, M.D., M.P.H. Gerald Gartlehner, M.D., M.P.H. Elizabeth R. Schulman, M.D. Beth Jonas, M.D., F.A.C.R. Emmanuel Coker-Schwimmer, M.P.H. Sheila V. Patel, B.S.P.H. Rachel Palmieri Weber, Ph.D. Kathleen N. Lohr, Ph.D., M.Phil., M.A. Carla Bann, Ph.D. Meera Viswanathan, Ph.D.
Funding Source: Agency for Healthcare Research and Quality (AHRQ)
Methodology Description: To identify relevant published literature, we searched the following databases: MEDLINE® via PubMed, the Cochrane Library, Embase, and International Pharmaceutical Abstracts. Our literature searches included articles published from July 2010 to October 5, 2017. We manually searched the reference lists of included systematic reviews to supplement the main database searches. We ensured that our update added to the body of evidence found in the 2012 review, including new drugs approved by the U.S. Food and Drug Administration (FDA) or undergoing FDA review during our review period. We also searched the gray literature for unpublished studies relevant to this review, including: ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform, the New York Academy of Medicine’s Grey Literature Index, and Supplemental Evidence and Data information from targeted requests and from a Federal Register Notice (public invitation posted in the Federal Register to submit relevant study data to AHRQ on behalf of Evidence-based Practice Centers). To answer the Contextual Questions, we identified relevant literature opportunistically from our literature searches for KQs and used targeted literature searches to address remaining gaps in information.

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Lower Limb Prosthesis


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Statistics: 20 Studies, 5 Key Questions, 2 Extraction Forms,
Date Published: Mar 21, 2019 09:12AM
Description: SR for AHRQ and CMS on psychometric properties of functional measures in lower limb amputees, heterogeneity of treatment effect of lower limb prostheses and components (LLP), and long term outcomes.
Contributor(s): Ethan M. Balk, M.D., M.P.H.; Abhilash Gazula, M.P.H.; Georgios Markozannes, M.Sc.; Hannah J. Kimmel, M.P.H.; Ian J. Saldanha, M.B.B.S., M.P.H., Ph.D.; Linda J. Resnik, Ph.D.; Thomas A. Trikalinos, M.D., Ph.D. Miranda Di, MD, PhD; Susan D'Andrea, PhD; Erin Twomey-Wilson, MS, MAS; Stacey Springs, PhD, Molly Magill, PhD
Funding Source: AHRQ EPC Program
Methodology Description: Standard systematic review, per AHRQ methodology. Literature searches conducted in PubMed, the Cochrane Central Trials Registry and Cochrane Database of Systematic Reviews, EMBASE, and CINAHL/PsycINFO databases through October 30, 2017.

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A Systematic Literature Review of Individuals’ Perspectives on Privacy and Genetic Information in the United States


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Statistics: 9 Studies, 1 Key Question, 1 Extraction Form,
Date Published: Mar 21, 2019 09:12AM
Description: As part of our Center focusing on understanding Genetic Privacy and Identity in Community Settings, we conducted a systematic literature review of what is already known about people’s concerns about genetic privacy in clinical care and research. We discovered that the research to date has focused primarily on concerns about downstream data users, issues of control, and whether data is revealed. Only recently have people been asked under what circumstances they might be willing to give up some privacy for another purpose. Remarkably little has been reported regarding the sociocultural factors that influence individuals’ opinions and decisions, even though these are where concerns can be addressed. Filling these gaps will be a major focus of our group’s research agenda.
Contributor(s): Ellen W. Clayton, Colin M. Halverson, Nila A. Sathe, Bradley A. Malin
Funding Source: National Human Genome Research Institute (NHGRI)
Methodology Description: We followed standard systematic review methodology including comprehensive searches of multiple databases, dual, independent screening of studies at the abstract and full text levels using a priori determined criteria; dual assessment of risk of bias; and data extraction by one investigator with checking by a second.

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