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Background Understanding the safety of vaccines is critical to inform decisions about vaccination. Our objective was to conduct a systematic review of the safety of vaccines recommended for children, adults, and pregnant women in the United States. Methods We searched the literature in November 2020 to update a 2014 Agency for Healthcare Research and Quality review by integrating newly available data. Studies of vaccines that used a comparator and reported the presence or absence of key adverse events were eligible. Adhering to Evidence-based Practice Center methodology, we assessed the strength of evidence (SoE) for all evidence statements. The systematic review is registered in PROSPERO (CRD42020180089). Results Of 56,603 reviewed citations, 338 studies reported in 518 publications met inclusion criteria. For children, SoE was high for no increased risk of autism following measles, mumps, and rubella (MMR) vaccine. SoE was high for increased risk of febrile seizures with MMR. There was no evidence of increased risk of intussusception with rotavirus vaccine at the latest follow-up (moderate SoE), nor of diabetes (high SoE). There was no evidence of increased risk or insufficient evidence for key adverse events for newer vaccines such as 9-valent human papillomavirus and meningococcal B vaccines. For adults, there was no evidence of increased risk (varied SoE) or insufficient evidence for key adverse events for the new adjuvanted inactivated influenza vaccine and recombinant adjuvanted zoster vaccine. We found no evidence of increased risk (varied SoE) for key adverse events among pregnant women following tetanus, diphtheria, and acellular pertussis vaccine, including stillbirth (moderate SoE). Conclusions Across a large body of research we found few associations of vaccines and serious key adverse events; however, rare events are challenging to study. Any adverse events should be weighed against the protective benefits that vaccines provide.

Objective. This evidence report synthesizes the available evidence on radiation therapy for brain metastases. Data sources. We searched PubMed®, Embase®, Web of Science, Scopus, CINAHL®, clinicaltrials.gov, and published guidelines in July 2020; assessed independently submitted data; consulted with experts; and contacted authors. Review methods. The protocol was informed by Key Informants. The systematic review was supported by a Technical Expert Panel and is registered in PROSPERO (CRD42020168260). Two reviewers independently screened citations; data were abstracted by one reviewer and checked by an experienced reviewer. We included randomized controlled trials (RCTs) and large observational studies (for safety assessments), evaluating whole brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS) alone or in combination, as initial or postoperative treatment, with or without systemic therapy for adults with brain metastases due to non-small cell lung cancer, breast cancer, or melanoma. Results. In total, 97 studies, reported in 190 publications, were identified, but the number of analyses was limited due to different intervention and comparator combinations as well as insufficient reporting of outcome data. Risk of bias varied; 25 trials were terminated early, predominantly due to poor accrual. Most studies evaluated WBRT, alone or in combination with SRS, as initial treatment; 10 RCTs reported on post-surgical interventions. The combination treatment SRS plus WBRT compared to SRS alone or WBRT alone showed no statistically significant difference in overall survival (hazard ratio [HR], 1.09; confidence interval [CI], 0.69 to 1.73; 4 RCTs; low strength of evidence [SoE]) or death due to brain metastases (relative risk [RR], 0.93; CI, 0.48 to 1.81; 3 RCTs; low SoE). Radiation therapy after surgery did not improve overall survival compared with surgery alone (HR, 0.98; CI, 0.76 to 1.26; 5 RCTs; moderate SoE). Data for quality of life, functional status, and cognitive effects were insufficient to determine effects of WBRT, SRS, or post-surgical interventions. We did not find systematic differences across interventions in serious adverse events radiation necrosis, fatigue, or seizures (all low or moderate SoE). WBRT plus systemic therapy (RR, 1.44; CI, 1.03 to 2.00; 14 studies; moderate SoE) was associated with increased risks for vomiting compared to WBRT alone. Conclusion. Despite the substantial research literature on radiation therapy, comparative effectiveness information is limited. There is a need for more data on patient-relevant outcomes such as quality of life, functional status, and cognitive effects.

Objective. To conduct a systematic review of the literature on the safety of vaccines recommended for routine immunization in the United States, updating the 2014 Agency for Healthcare Research and Quality (AHRQ) report on the topic. Data sources. We searched MEDLINE®, Embase®, CINAHL®, Cochrane CENTRAL, Web of Science, and Scopus through November 9, 2020, building on the prior 2014 report; reviewed existing reviews, trial registries, and supplemental material submitted to AHRQ; and consulted with experts. Review methods. This report addressed three Key Questions (KQs) on the safety of vaccines currently in use in the United States and included in the Centers for Disease Control and Prevention’s (CDC) recommended immunization schedules for adults (KQ1), children and adolescents (KQ2), and pregnant women (KQ3). The systematic review was supported by a Technical Expert Panel that identified key adverse events of particular concern. Two reviewers independently screened publications; data were extracted by an experienced subject matter expert. Studies of vaccines that used a comparator and reported the presence or absence of adverse events were eligible. We documented observed rates and assessed the relative risks for key adverse events. We assessed the strength of evidence (SoE) across the existing findings from the prior 2014 report and the new evidence from this update. The systematic review is registered in PROSPERO (CRD42020180089). Results. A large body of evidence is available to evaluate adverse events following vaccination. Of 56,608 reviewed citations, 189 studies met inclusion criteria for this update, adding to data in the prior 2014 report, for a total of 338 included studies reported in 518 publications. Regarding vaccines recommended for adults (KQ1), we found either no new evidence of increased risk for key adverse events with varied SoE or insufficient evidence in this update, including for newer vaccines such as recombinant influenza vaccine, adjuvanted inactivated influenza vaccine, and recombinant adjuvanted zoster vaccine. The prior 2014 report noted a signal for anaphylaxis for hepatitis B vaccines in adults with yeast allergy and for tetanus, diphtheria, and acellular pertussis vaccines. Regarding vaccines recommended for children and adolescents (KQ2), we found either no new evidence of increased risk for key adverse events with varied SoE or insufficient evidence, including for newer vaccines such as 9-valent human papillomavirus vaccine and meningococcal B vaccine. The prior 2014 report noted signals for rare adverse events—such as anaphylaxis, idiopathic thrombocytopenic purpura, and febrile seizures—with some childhood vaccines. Regarding vaccines recommended for pregnant women (KQ3), we found no evidence of increased risk for key adverse events with varied SoE among either pregnant women or their infants following administration of tetanus, diphtheria, and acellular pertussis vaccines during pregnancy. Conclusion. Across this large body of research, we found no new evidence of increased risk since the prior 2014 report for key adverse events following administration of vaccines that are routinely recommended. Signals from the prior report remain unchanged for rare adverse events, which include anaphylaxis in adults and children, and febrile seizures and idiopathic thrombocytopenic purpura in children. There is no evidence of increased risk of adverse events for vaccines currently recommended in pregnant women. There remains insufficient evidence to draw conclusions about some rare potential adverse events.

Dietary nutrition researchers have been trying to understand how nutrition and nutrients influence immune function for a long time—over 60 years, judging by the dates of some of the earliest published research papers on nutrition and immune function. It should come as no surprise then that this interest has reached a fever pitch as governments, healthcare systems and especially public health systems worldwide face what is likely the biggest health challenge in most of our lifetimes and probably over a century—preventing, treating and averting long-term consequences of SARS-CoV-2 (COVID-19) infection. Within a month or two of acknowledgements that COVID-19 had reached pandemic proportions, it seems, the mainstream media was already reporting conflicting untested evidence about the possibility that vitamin D or C supplements might play a role in preventing or mitigating infection, and some reputable clinicians were asserting that even in the absence of evidence, perhaps it would be prudent just to take some extra vitamin D.1 It is in this context that Abioye and colleagues2 decided to systematically review the literature on the role of dietary vitamin and mineral supplements in preventing or shortening the course of upper respiratory infections (URIs). The bottom line is that much of the research, which dates back decades, was poorly designed and reported, and the evidence for benefits is weak, confirming the assertions of several other relatively recent reviews on nutrients and immune function.3 4 Nevertheless, the evidence, as weak as it is, could easily encourage false hopes, potentially improving nothing …

Latinas in the United States are more likely to be diagnosed with late-stage breast cancer (BC) compared to non-Latinas. Literacy-appropriate and culturally sensitive cancer communication interventions can help address existing racial/ethnic BC disparities. We formatively developed a new BC prevention brochure for Spanish-speaking Latinas (≥35 years). Eligible women ( n = 240) from a large public hospital in California were randomly assigned to one of three study arms: Group 1 received the new brochure, Group 2 included a community health worker (CHW) who delivered the new brochure’s content, and a control group received a standard educational brochure. Participants completed three surveys (baseline, postintervention, 3-month follow-up) with a 100% completion rate for the first two surveys and 80.4% completion after 3 months. We assessed the difference in outcomes for BC risk knowledge, perceived BC susceptibility, and BC information self-efficacy between groups. Participant mean age was 52.3 years, and 82.1% reported low English proficiency. Mean knowledge scores increased and perceived BC susceptibility improved for all groups ( p ≤ .05), yet treatment effects were not significant between groups for these outcomes. BC information self-efficacy also increased from baseline to postintervention for all groups to >80%. After 3 months, only Group 2 and the control group retained their increases and treatment effects were significant only for Group 2 compared to other groups in unadjusted and adjusted models. A CHW-delivered intervention may be more effective in improving BC information self-efficacy among Latinas compared to print material alone. More research is needed to examine the efficacy of CHW-delivered interventions.

This systematic review synthesizes evidence on the effects of Medication-Assisted Treatment (MAT) for opioid use disorder (OUD) on functional outcomes, including cognitive (e.g., memory), physical (e.g., fatigue), occupational (e.g., return to work), social/behavioral (e.g., criminal activity), and neurological (e.g., balance) function. Five databases were searched from inception to July 2017 to identify English-language controlled trials, case control studies, and cohort comparisons of one or more groups; cross-sectional studies were excluded. Two independent reviewers screened identified literature, abstracted study-level information, and assessed the quality of included studies. Meta-analyses used the Hartung-Knapp method for random-effects models. The quality of evidence was assessed using the GRADE approach. A comprehensive search followed by 1411 full text publication screenings yielded 30 randomized controlled trials (RCTs) and 10 observational studies meeting inclusion criteria. The studies reported highly diverse functional outcome measures. Only one RCT was rated as high quality, but several methodologically sound observational studies were identified. The statistical power to detect differences in functional outcomes was unclear in most studies. When compared with matched "healthy" controls with no history of substance use disorder (SUD), in two studies MAT patients had significantly poorer working memory and cognitive speed. One study found MAT patients scored worse in aggressive responding than did "healthy" controls. A large observational study found that MAT users had twice the odds of involvement in an injurious traffic accident as non-users. When compared with persons with OUD not on MAT, one cohort study found lower fatigue rates among buprenorphine-treated OUD patients. No differences were reported for occupational outcomes and results for criminal activity and other social/behavioral areas were mixed. There were few differences among MAT drug types. A pooled analysis of three RCTs found a significantly lower prevalence of fatigue with buprenorphine compared to methadone, while a meta-analysis of the same RCTs found no statistical difference in insomnia prevalence. Three RCTs that focused on cognitive function compared the effects of buprenorphine to methadone; no statistically significant differences in memory, cognitive speed and flexibility, attention, or vision were reported. The quality of evidence for most functional outcomes was rated low or very low. In sum, weaknesses in the body of evidence prevent strong conclusions about the effects of MAT for opioid use disorder on functional outcomes. Rigorous studies of functional effects would strengthen the body of literature.

Objectives Systematic reviews should provide balanced assessments of benefits and harms, while focusing on the most important outcomes. Selection of harms to be reviewed can be a challenge due to the potential for large numbers of diverse harms. Study Design and Setting A workgroup of methodologists from Evidence-based Practice Centers (EPCs) developed consensus-based guidance on selection and prioritization of harms in systematic reviews. Recommendations were informed by a literature scan, review of Evidence-based Practice Center reports, and interviews with experts in conducting reviews or assessing harms and persons representing organizations that commission or use systematic reviews. Results Ten recommendations were developed on selection and prioritization of harms, including routinely focusing on serious as well as less serious but frequent or bothersome harms; routinely engaging stakeholders and using literature searches and other data sources to identify important harms; using a prioritization process (formal or less formal) to inform selection decisions; and describing the methods used to select and prioritize harms. Conclusion We provide preliminary guidance for a more structured approach to selection and prioritization of harms in systematic reviews.

Background Smokers increasingly seek alternative interventions to assist in cessation or reduction efforts. Mindfulness meditation, which facilitates detached observation and paying attention to the present moment with openness, curiosity, and acceptance, has recently been studied as a smoking cessation intervention. Aims This review synthesizes randomized controlled trials (RCTs) of mindfulness meditation (MM) interventions for smoking cessation. Methods Five electronic databases were searched from inception to October 2016 to identify English-language RCTs evaluating the efficacy and safety of MM interventions for smoking cessation, reduction, or a decrease in nicotine cravings. Two independent reviewers screened literature using predetermined eligibility criteria, abstracted study-level information, and assessed the quality of included studies. Meta-analyses used the Hartung-Knapp-Sidik-Jonkman method for random-effects models. The quality of evidence was assessed using the GRADE approach. Findings Ten RCTs of MM interventions for tobacco use met inclusion criteria. Intervention duration, intensity, and comparison conditions varied considerably. Studies used diverse comparators such as the American Lung Association's Freedom from Smoking (FFS) program, quitline counseling, interactive learning, or treatment as usual (TAU). Only one RCT was rated as good quality and reported power calculations indicating sufficient statistical power. Publication bias was detected. Overall, mindfulness meditation did not have significant effects on abstinence or cigarettes per day, relative to comparator groups. The small number of studies and heterogeneity in interventions, comparators, and outcomes precluded detecting systematic differences between adjunctive and monotherapy interventions. No serious adverse events were reported. Conclusions MM did not differ significantly from comparator interventions in their effects on tobacco use. Low-quality evidence, variability in study design among the small number of existing studies, and publication bias suggest that additional, high-quality adequately powered RCTs should be conducted.

Men and women might respond differently to some treatments for alcohol use disorder. If so, this would be important to consider when selecting treatment. The purpose of this systematic review was to synthesize evidence for gender differences in effects of treatments. While researchers did not identify systematic differences across studies, a paucity of reporting on treatment effects according to gender hindered analysis.

This report details the results of surveys of institutional research board (IRB) chairs, administrators, and members, as well as principal investigators, to obtain baseline information on their demographics and their attitudes about their IRB's efficacy and efficiency and the likely effects of proposed changes to the Revised Common Rule. Where possible, the authors also compare the survey results with the 1998 Bell Report.

Background Chronic pain patients increasingly seek treatment through mindfulness meditation. Purpose This study aims to synthesize evidence on efficacy and safety of mindfulness meditation interventions for the treatment of chronic pain in adults. Method We conducted a systematic review on randomized controlled trials (RCTs) with meta-analyses using the Hartung-Knapp-Sidik-Jonkman method for random-effects models. Quality of evidence was assessed using the GRADE approach. Outcomes included pain, depression, quality of life, and analgesic use. Results Thirty-eight RCTs met inclusion criteria; seven reported on safety. We found low-quality evidence that mindfulness meditation is associated with a small decrease in pain compared with all types of controls in 30 RCTs. Statistically significant effects were also found for depression symptoms and quality of life. Conclusions While mindfulness meditation improves pain and depression symptoms and quality of life, additional well-designed, rigorous, and large-scale RCTs are needed to decisively provide estimates of the efficacy of mindfulness meditation for chronic pain. Electronic supplementary material The online version of this article (doi:10.1007/s12160-016-9844-2) contains supplementary material, which is available to authorized users.

Objectives As time and cost constraints in the conduct of systematic reviews increase, the need to consider the use of existing systematic reviews also increases. We developed guidance on the integration of systematic reviews into new reviews. Methods A workgroup of methodologists from Evidence-based Practice Centers developed consensus-based recommendations. Discussions were informed by a literature scan and by interviews with organizations that conduct systematic reviews. Results Twelve recommendations were developed addressing selecting reviews, assessing risk of bias, qualitative and quantitative synthesis, and summarizing and assessing body of evidence. Conclusions We provide preliminary guidance for an efficient and unbiased approach to integrating existing systematic reviews with primary studies in a new review.

In 2009, the Institute of Medicine/Food and Nutrition Board constituted a Dietary Reference Intakes (DRI) committee to undertake a review of the evidence that had emerged (since the 1997 DRI report) on the relationship of vitamin D and calcium, both individually and combined, to a wide range of health outcomes, and potential revision of the DRI values for these nutrients. To support that review, several United States and Canadian Federal Government agencies commissioned a systematic review of the scientific literature for use during the deliberations by the committee. The intent was to support a transparent literature review process and provide a foundation for subsequent reviews of the nutrients. The committee used the resulting literature review in their revision of the DRIs.In 2013, in preparation for a project the National Institutes of Health Office of Dietary Supplements (NIH/ODS) was undertaking related to evidence-based decisionmaking for vitamin D in primary care, based on the updated DRI report, the ODS and AHRQ requested an update to the 2009 systematic review to incorporate the findings of studies conducted since the 2009 evidence review on the relationship between vitamin D alone or vitamin D plus calcium to selected health outcomes and to report on the methods used to assay vitamin D in the included trials.To systematically summarize the evidence on the relationship between vitamin D alone or in combination with calcium on selected health outcomes included in the earlier review: primarily those related to bone health, cardiovascular health, cancer, immune function, pregnancy, all-cause mortality, and vitamin D status; and to identify the vitamin D assay methods and procedures used for the interventional studies that aimed to assess the effect of vitamin D administration on serum 25(OH)D concentrations, and to stratify key outcomes by methods used to assay serum 25(OH)D concentrations.MEDLINE; Cochrane Central; Cochrane Database of Systematic Reviews; and the Health Technology Assessments; search limited to English-language articles on humans.Primary interventional or prospective observational studies that reported outcomes of interest in human subjects in relation to vitamin D alone or in combination with calcium, as well as systematic reviews that met the inclusion and exclusion criteria.A standardized protocol with predefined criteria was used to extract details on study design, interventions, outcomes, and study quality.We summarized 154 newly identified primary articles and two new systematic reviews that incorporated more than 93 additional primary articles. Available evidence focused mainly on bone health, cardiovascular diseases, or cancer outcomes. Findings were inconsistent across studies for bone health; breast, colorectal, and prostate cancer; cardiovascular disease and mortality; immune function; and pregnancy-related outcomes. Few studies assessed pancreatic cancer and birth outcomes. One new systematic review of observational studies found that circulating 25(OH)D was generally inversely associated with risk for cardiovascular disease. Methods used to assay serum 25(OH)D in studies reporting on key outcomes diverged widely. The current report also identified one new systematic review published since the original report that addressed whether a dose response relationship exists between dietary and supplemental vitamin D intake and serum 25(OH)D concentrations. The systematic review, based on 76 RCTs, reported widely varying increases in serum concentrations of 25(OH)D for similar doses of vitamin D, with a general increase in serum concentration with dietary intake. The RCTs identified for the current report found increases in serum 25(OH)D with supplementation; however, the findings varied by age group and health status of participants, baseline vitamin D status, dose, duration, and assay used to assess serum 25(OH)D.Studies on vitamin D and calcium were not specifically targeted at life stages (except for pregnant and postmenopausal women) specified for the determination of DRI and were often underpowered for their intended outcomes. Studies vary widely in methodological quality and in the assays used to measure vitamin D status.In solid agreement with the findings of the original report, the majority of the findings concerning vitamin D, alone or in combination with calcium, on the health outcomes of interest were inconsistent. Associations observed in prospective cohort and nested case-control studies were inconsistent, or when consistent, were rarely supported by the results of randomized controlled trials. Clear dose-response relationships between intakes of vitamin D and health outcomes were rarely observed. Although a large number of new studies (and longer followups to older studies) were identified, particularly for cardiovascular outcomes, all-cause mortality, several types of cancer, and intermediate outcomes for bone health, no firm conclusions can be drawn. Studies identified for the current report suggest a possible U-shaped association between serum 25(OH)D concentrations and both all-cause mortality and hypertension and also suggest that the level of supplemental vitamin D and calcium administered in the Women's Health Initiative Calcium-Vitamin D Trial are not associated with an increased risk for cardiovascular disease or cancer among postmenopausal women who are not taking additional supplemental vitamin D and calcium. Studies suggest the method used to assay 25(OH)D may influence the outcomes of dose-response assessments. Beyond these observations, it is difficult to make any substantive statements on the basis of the available evidence concerning the association of either serum 25(OH)D concentration, vitamin D supplementation, calcium intake, or the combination of both nutrients, with the various health outcomes because most of the findings were inconsistent.

To update a prior systematic review on the effects of omega-3 fatty acids (n-3 FA) on maternal and child health and to assess the evidence for their effects on, and associations with, additional outcomes.MEDLINE®, Embase®, the Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Centre for Agriculture and Biosciences (CAB) Abstracts from 2000 to August 2015; eligible studies from the original report; and relevant systematic reviews.We included randomized controlled trials (RCTs) of any defined dose of n-3 FA (or combination) compared to placebo, any other n-3 FA, or alternative dose with an outcome of interest conducted in pregnant or breastfeeding women or neonates (preterm or term). We also included prospective observational studies that analyzed the association between baseline n-3 FA intake or biomarker level and followup outcomes. Postnatal interventions began within a week of birth for term infants and within a week of beginning enteral or oral feeding for preterm infants. Standard methods were used for data abstraction and analysis, according to the Evidence-based Practice Center Methods Guide.We identified 4,275 potentially relevant titles from our searches, of which 95 RCTs and 48 observational studies met the inclusion criteria. Risk of bias was a concern with both RCTs and observational studies. Outcomes for which evidence was sufficient to draw a conclusion are summarized here with the Strength of Evidence (SoE). (Outcomes for which the evidence was insufficient to draw a conclusion are summarized in Appendix G of the report.).Maternal Exposures and Outcomes: Gestational length and risk for preterm birth: Prenatal algal docosahexaenoic acid (DHA) or DHA-enriched fish oil supplementation had a small positive effect on length of gestation (moderate SoE), but no effect on risk for preterm birth (low SoE). Prenatal EPA (eicosapentaenoic acid) plus DHA-containing fish oil supplementation has no effect on length of gestation (low SoE). Supplementation with DHA, or EPA plus DHA-, or DHA-enriched fish oil does not decreaserisk for preterm birth (low SoE).Birth weight and risk for low birth weight: Changes in maternal n-3 FA biomarkers were significantly associated with birth weight. Prenatal algal DHA or DHA-enriched fish oil supplementation had a positive effect on birth weight among healthy term infants (moderate SoE), but prenatal DHA supplementation had no effect on risk for low birth weight (low SoE). Prenatal EPA plus DHA or alpha-linolenic acid (ALA) supplementation had no effect on birth weight (low SoE).Risk for peripartum depression: Maternal n-3 FA biomarkers had no association with risk for peripartum depression. Maternal DHA, EPA, or DHA-enriched fish oil supplementation had no effect on risk for peripartum depression (low SoE).Risk for gestational hypertension/preeclampsia: Prenatal DHA supplementation among high-risk pregnant women had no effect on the risk for gestational hypertension or preeclampsia (moderate SoE). Prenatal supplementation of any n-3 FA in normal-risk women also had no significant effect on risk for gestational hypertension or preeclampsia (low SoE).Fetal, Infant, and Child Exposures and Outcomes: Postnatal growth patterns: Maternal fish oil or DHA plus EPA supplementation had no effect on postnatal growth patterns (attainment of weight, length, and head circumference) when administered prenatally (moderate SoE) or both pre- and postnatally (low SoE). Fortification of infant formulas with DHA plus arachidonic acid (AA, an n-6 FA) had no effect on growth patterns of preterm or term infants (low SoE).Visual acuity: Prenatal supplementation with DHA had no effect on development of visual acuity (low SoE). Supplementing or fortifying preterm infant formula with any n-3 FA had no significant effect on visual acuity assessed by visual evoked potentials (VEP) at 4 or 6 months corrected age (low SoE). Data conflicted on the effectiveness of supplementing infant formula for term infants with n-3 FA depending on when and how visual acuity was assessed (i.e. by VEP or by behavioral methods) and the type of essential FA provided (low SoE).Neurological development: Prenatal or postnatal n-3 FA supplementation had no consistent effect on neurological development (low SoE).Cognitive development: Prenatal DHA supplementation with AA or EPA had no effect on cognitive development (moderate SoE). Supplementing breastfeeding women with DHA plus EPA also had no effect on cognitive development in infants and children (low SoE). Supplementing or fortifying preterm infants' formula with DHA plus AA had a positive effect on infant cognition at some short-term followup times (moderate SoE). Supplementing or fortifying infant formula for term infants with any n-3 FA had no effect on cognitive development (low SoE). Evidence is insufficient to support any effect of n-3 FA infant supplementation on long-term cognitive outcomes.Autism spectrum disorder, attention deficit hyperactivity disorder (ADHD), and learning disorders: Maternal or infant n-3 FA supplementation had no effect on risk for autism spectrum disorders or ADHD (low SoE). No studies on other learning disorders were identified.Atopic dermatitis (AD), allergies, and respiratory disorders: Pre- and postnatal (maternal and infant) n-3 FA supplementation had no consistent effect on the risk for AD/eczema, allergies, asthma, and other respiratory illnesses (moderate SoE). Biomarkers and intakes had no consistent association with the risk for AD, allergies, and respiratory disorders (low SoE).Adverse events: Prenatal and infant supplementation with n-3 FA or fortification of foods with n-3 FA did not result in any serious or nonserious adverse events (moderate SoE); with the exception of an increased risk for mild gastrointestinal symptoms.Most studies in this report examined the effects of fish oil (or other combinations of DHA and EPA) supplements on pregnant or breastfeeding women or the effects of infant formula fortified with DHA plus AA. As with the original report, with the exception of small increases in birth weight and length of gestation,n-3 FA supplementation or fortification has no consistent evidence of effects on peripartum maternal or infant health outcomes. No effects of n-3 FA were seen on gestational hypertension, peripartum depression, or postnatal growth. Apparent effects of n-3 FA supplementation were inconsistent across assessment methods and followup times for outcomes related to infant visual acuity, cognitive development and prevention of allergy and asthma. Future RCTs need to assess standardized preparations of n-3 and n-6 FA, using a select group of clinically important outcomes, on populations with baseline n-3 FA intakes typical of those of most western populations.

RAND researchers conducted a systematic review that synthesized evidence from randomized controlled trials of mindfulness meditation interventions — used adjunctively or as monotherapy — to provide estimates of their efficacy and safety for treating tobacco use.

Objectives Groups such as the Institute of Medicine emphasize the importance of attention to financial conflicts of interest. Little guidance exists, however, on managing the risk of bias for systematic reviews from nonfinancial conflicts of interest. We sought to create practical guidance on ensuring adequate clinical or content expertise while maintaining independence of judgment on systematic review teams. Study Design and Setting Workgroup members built on existing guidance from international and domestic institutions on managing conflicts of interest. We then developed practical guidance in the form of an instrument for each potential source of conflict. Results We modified the Institute of Medicine's definition of conflict of interest to arrive at a definition specific to nonfinancial conflicts. We propose questions for funders and systematic review principal investigators to evaluate the risk of nonfinancial conflicts of interest. Once risks have been identified, options for managing conflicts include disclosure followed by no change in the systematic review team or activities, inclusion on the team along with other members with differing viewpoints to ensure diverse perspectives, exclusion from certain activities, and exclusion from the project entirely. Conclusion The feasibility and utility of this approach to ensuring needed expertise on systematic reviews and minimizing bias from nonfinancial conflicts of interest must be investigated.

BACKGROUND:Concerns about vaccine safety have led some parents to decline recommended vaccination of their children, leading to the resurgence of diseases. Reassurance of vaccine safety remains critical for population health. This study systematically reviewed the literature on the safety of routine vaccines recommended for children in the United States.METHODS:Data sources included PubMed, Advisory Committee on Immunization Practices statements, package inserts, existing reviews, manufacturer information packets, and the 2011 Institute of Medicine consensus report on vaccine safety. We augmented the Institute of Medicine report with more recent studies and increased the scope to include more vaccines. Only studies that used active surveillance and had a control mechanism were included. Formulations not used in the United States were excluded. Adverse events and patient and vaccine characteristics were abstracted. Adverse event collection and reporting was evaluated by using the McHarm scale. We were unable to pool results. Strength of evidence was rated as high, moderate, low, or insufficient.RESULTS:Of 20 478 titles identified, 67 were included. Strength of evidence was high for measles/mumps/rubella (MMR) vaccine and febrile seizures; the varicella vaccine was associated with complications in immunodeficient individuals. There is strong evidence that MMR vaccine is not associated with autism. There is moderate evidence that rotavirus vaccines are associated with intussusception. Limitations of the study include that the majority of studies did not investigate or identify risk factors for AEs; and the severity of AEs was inconsistently reported.CONCLUSIONS:We found evidence that some vaccines are associated with serious AEs; however, these events are extremely rare and must be weighed against the protective benefits that vaccines provide.

Introduction:The US Agency for Healthcare Research and Quality (AHRQ) Evidence-based Practice Center (EPC) program sponsors the development of systematic reviews to inform clinical policy and practice. The EPC program sought to better understand how health systems identify and use this evidence.Methods:Representatives from eleven EPCs, the EPC Scientific Resource Center, and AHRQ developed a semi-structured interview script to query a diverse group of nine Key Informants (KIs) involved in health system quality, safety and process improvement about how they identify and use evidence. Interviews were transcribed and qualitatively summarized into key themes.Results:All KIs reported that their organizations have either centralized quality, safety, and process improvement functions within their system, or they have partnerships with other organizations to conduct this work. There was variation in how evidence was identified, with larger health systems having medical librarians and central bureaus to gather and disseminate information and smaller systems having local chief medical officers or individual clinicians do this work. KIs generally prefer guidelines, especially those with treatment algorithms, because they are actionable. They like systematic reviews because they efficiently condense study results and reconcile conflicting data. They prefer information from systematic reviews to be presented as short digestible summaries with the full report available on demand. KIs preferred systematic reviews from reputable entities and those without commercial bias. Some of the challenges KIs reported include how to resolve conflicting evidence, the generalizability of evidence to local needs, determining whether the evidence is up-to-date, and the length of time required to generate reviews. The topics of greatest interest included predictive analytics, high-value care, advance care planning, and care coordination. To increase awareness of AHRQ EPC reviews, KIs suggest alerting people at multiple levels in a health-system when new evidence reports are available and making reports easier to find in common search engines.Conclusions:Systematic reviews are valued by health system leaders. To be most useful they should be easy to locate and available in different formats targeted to the needs of different audiences.

Alternative strategies exist for diagnosing gout that do not rely solely on the documentation of monosodium urate (MSU) crystals.To summarize evidence regarding the accuracy of clinical tests and classification algorithms compared with that of a reference standard of MSU crystals in joint aspirate for diagnosing gout.Several electronic databases from inception to 29 February 2016.21 prospective cohort, cross-sectional, and case-control studies including participants with joint inflammation and no previous definitive gout diagnosis who had MSU analysis of joint aspirate.Data extraction and risk-of-bias assessment by 2 reviewers independently; overall strength of evidence (SOE) judgment by group.Recently developed algorithms including clinical, laboratory, and imaging criteria demonstrated good sensitivity (up to 88%) and fair to good specificity (up to 96%) for diagnosing gout (moderate SOE). Three studies of dual-energy computed tomography (DECT) showed sensitivities of 85% to 100% and specificities of 83% to 92% for diagnosing gout (low SOE). Six studies of ultrasonography showed sensitivities of 37% to 100% and specificities of 68% to 97%, depending on the ultrasonography signs assessed (pooled sensitivity and specificity for the double contour sign: 74% [95% CI, 52% to 88%] and 88% [CI, 68% to 96%], respectively [low SOE]).Important study heterogeneity and selection bias; scant evidence in primary and urgent care settings and in patients with conditions that may be confused with or occur with gout.Multidimensional algorithms, which must be validated in primary and urgent care settings, may help clinicians make a provisional diagnosis of gout. Although DECT and ultrasonography also show promise for gout diagnosis, accessibility to these methods may be limited.Agency for Healthcare Research and Quality. (Protocol registration: https://effectivehealthcare.ahrq.gov/ehc/products/564/1937/gout-protocol-140716.pdf).

RAND researchers conducted a systematic review that synthesized evidence from randomized controlled trials of mindfulness meditation interventions — used adjunctively or as monotherapy — to provide estimates of their efficacy and safety in alleviating chronic pain in adults.

Apply and compare two methods that identify signals for the need to update systematic reviews, using three Evidence-based Practice Center reports on omega-3 fatty acids as test cases.We applied the RAND method, which uses domain (subject matter) expert guidance, and a modified Ottawa method, which uses quantitative and qualitative signals. For both methods, we conducted focused electronic literature searches of recent studies using the key terms from the original reports. We assessed the agreement between the methods and qualitatively assessed the merits of each system.Agreement between the two methods was "substantial" or better (kappa0.62) in three of the four systematic reviews. Overall agreement between the methods was "substantial" (kappa=0.64, 95% confidence interval [CI] 0.45-0.83).The RAND and modified Ottawa methods appear to provide similar signals for the possible need to update systematic reviews in this pilot study. Future evaluation with a broader range of clinical topics and eventual comparisons between signals to update reports and the results of full evidence review updates will be needed. We propose a hybrid approach combining the best features of both methods, which should allow efficient review and assessment of the need to update.

We systematically reviewed the published literature on the effects of omega–3 fatty acids on measures of cognitive function in normal aging, incidence and treatment of dementia. Computerized databases were searched for published literature to identify potentially relevant studies with the intent to conduct a meta-analysis. We screened 5,865 titles, reviewed 497 studies of which 49 underwent a detailed review, and found 5 studies that pertained to our objectives. We included controlled clinical trials and observational studies, including prospective cohort, case-control, and case series designs; we excluded case reports. We had no language restrictions. We abstracted data on the effects of omega–3 fatty acids and on study design, relevant outcomes, study population, source, type, amount, and duration of omega–3 fatty acid consumption, and parameters of methodological quality. A single cohort study has assessed the effects of omega–3 fatty acids on cognitive function with normal aging and found no association for fish or total omega–3 consumption. In four studies that assessed the effects of omega–3 fatty acids on incidence and treatment of dementia, a trend in favor of omega–3 fatty acids (fish and total omega–3 consumption) toward reducing risk of dementia and improving cognitive function was reported. The available data are insufficient to draw strong conclusions about the effects of omega–3 fatty acids on cognitive function in normal aging or on the incidence or treatment of dementia. However, limited evidence suggests a possible association between omega–3 fatty acids and reduced risk of dementia.

We used a method that combined literature review and expertjudgment to assess potential medical innovations for older adults. We evaluated innovations in four domains: cardiovascular disease, cancer, the biology of aging, and neurologic disease. The innovations can be categorized by common themes: improved disease prevention, better detection of subclinical or early clinical disease, and treatments for established disease. We report the likelihood, potential impact, and potential cost implications for thirty-four innovations, and we revisit this forecast five years later. Many of the innovations have the potential to greatly affect the costs and outcomes of health care.

Objectives: To perform a systematic review of published research trials of preconception care services to determine what evidence for effectiveness of care at improving the course of pregnancy or its outcomes has accumulated since the last major review in 1990. Methods: The review was conducted adapting the systematic methods developed by the Cochrane Collaboration to collect evidence from published clinical research literature with as little bias as possible. The review included literature published after January 1990, and posted on MEDLINE by July 1999. Results: Although more than 40 preconception risk conditions were searched and 470 articles were abstracted, only four problem areas and 19 research trials met the review criteria. New evidence of effectiveness was found for screening women who are seeking family planning for risk conditions; having sexually active women of reproductive age take dietary folate supplements; and providing women affected by certain metabolic conditions (diabetes and hyperphenylalanemia) with nutrition services. Conclusions: To help improve pregnancy outcomes MCH professionals need to promote the concept of readiness for pregnancy and help see that women are as healthy and appropriately nourished as possible before they become pregnant.

Machine-learning methods can help decrease the effort involved in updating searches for systematic reviews.

This systematic review of trials and observational studies examines conflicting evidence about potential cardiovascular risks associated with high levels of calcium intake.

Background Osteoporosis is a major contributor to the propensity to fracture among older adults, and various pharmaceuticals are available to treat it. Purpose To update a review about the benefits and harms of pharmacologic treatments used to prevent fractures in adults at risk. Data sources Multiple computerized databases were searched between 2 January 2005 and 4 March 2014 for English-language studies. Study selection Trials, observational studies, and systematic reviews. Data extraction Duplicate extraction and assessment of data about study characteristics, outcomes, and quality. Data synthesis From more than 52 000 titles screened, 315 articles were included in this update. There is high-strength evidence that bisphosphonates, denosumab, and teriparatide reduce fractures compared with placebo, with relative risk reductions from 0.40 to 0.60 for vertebral fractures and 0.60 to 0.80 for nonvertebral fractures. Raloxifene has been shown in placebo-controlled trials to reduce only vertebral fractures. Since 2007, there is a newly recognized adverse event of bisphosphonate use: atypical subtrochanteric femur fracture. Gastrointestinal side effects, hot flashes, thromboembolic events, and infections vary among drugs. Limitations Few studies have directly compared drugs used to treat osteoporosis. Data in men are very sparse. Costs were not assessed. Conclusion Good-quality evidence supports that several medications for bone density in osteoporotic range and/or preexisting hip or vertebral fracture reduce fracture risk. Side effects vary among drugs, and the comparative effectiveness of the drugs is unclear. Primary funding source Agency for Healthcare Research and Quality and RAND Corporation.

Background In 2009, the Institute of Medicine/Food and Nutrition Board constituted a Dietary Reference Intakes (DRI) committee to undertake a review of the evidence that had emerged (since the 1997 DRI report) on the relationship of vitamin D and calcium, both individually and combined, to a wide range of health outcomes, and potential revision of the DRI values for these nutrients. To support that review, several United States and Canadian Federal Government agencies commissioned a systematic review of the scientific literature for use during the deliberations by the committee. The intent was to support a transparent literature review process and provide a foundation for subsequent reviews of the nutrients. The committee used the resulting literature review in their revision of the DRIs. In 2013, in preparation for a project the National Institutes of Health Office of Dietary Supplements (NIH/ODS) was undertaking related to evidence-based decisionmaking for vitamin D in primary care, based on the updated DRI report, the ODS and AHRQ requested an update to the 2009 systematic review to incorporate the findings of studies conducted since the 2009 evidence review on the relationship between vitamin D alone or vitamin D plus calcium to selected health outcomes and to report on the methods used to assay vitamin D in the included trials. Purpose To systematically summarize the evidence on the relationship between vitamin D alone or in combination with calcium on selected health outcomes included in the earlier review: primarily those related to bone health, cardiovascular health, cancer, immune function, pregnancy, all-cause mortality, and vitamin D status; and to identify the vitamin D assay methods and procedures used for the interventional studies that aimed to assess the effect of vitamin D administration on serum 25(OH)D concentrations, and to stratify key outcomes by methods used to assay serum 25(OH)D concentrations. Data sources MEDLINE; Cochrane Central; Cochrane Database of Systematic Reviews; and the Health Technology Assessments; search limited to English-language articles on humans. Study selection Primary interventional or prospective observational studies that reported outcomes of interest in human subjects in relation to vitamin D alone or in combination with calcium, as well as systematic reviews that met the inclusion and exclusion criteria. Data extraction A standardized protocol with predefined criteria was used to extract details on study design, interventions, outcomes, and study quality. Data synthesis We summarized 154 newly identified primary articles and two new systematic reviews that incorporated more than 93 additional primary articles. Available evidence focused mainly on bone health, cardiovascular diseases, or cancer outcomes. Findings were inconsistent across studies for bone health; breast, colorectal, and prostate cancer; cardiovascular disease and mortality; immune function; and pregnancy-related outcomes. Few studies assessed pancreatic cancer and birth outcomes. One new systematic review of observational studies found that circulating 25(OH)D was generally inversely associated with risk for cardiovascular disease. Methods used to assay serum 25(OH)D in studies reporting on key outcomes diverged widely. The current report also identified one new systematic review published since the original report that addressed whether a dose response relationship exists between dietary and supplemental vitamin D intake and serum 25(OH)D concentrations. The systematic review, based on 76 RCTs, reported widely varying increases in serum concentrations of 25(OH)D for similar doses of vitamin D, with a general increase in serum concentration with dietary intake. The RCTs identified for the current report found increases in serum 25(OH)D with supplementation; however, the findings varied by age group and health status of participants, baseline vitamin D status, dose, duration, and assay used to assess serum 25(OH)D. Limitations Studies on vitamin D and calcium were not specifically targeted at life stages (except for pregnant and postmenopausal women) specified for the determination of DRI and were often underpowered for their intended outcomes. Studies vary widely in methodological quality and in the assays used to measure vitamin D status. Conclusions In solid agreement with the findings of the original report, the majority of the findings concerning vitamin D, alone or in combination with calcium, on the health outcomes of interest were inconsistent. Associations observed in prospective cohort and nested case-control studies were inconsistent, or when consistent, were rarely supported by the results of randomized controlled trials. Clear dose-response relationships between intakes of vitamin D and health outcomes were rarely observed. Although a large number of new studies (and longer followups to older studies) were identified, particularly for cardiovascular outcomes, all-cause mortality, several types of cancer, and intermediate outcomes for bone health, no firm conclusions can be drawn. Studies identified for the current report suggest a possible U-shaped association between serum 25(OH)D concentrations and both all-cause mortality and hypertension and also suggest that the level of supplemental vitamin D and calcium administered in the Women's Health Initiative Calcium-Vitamin D Trial are not associated with an increased risk for cardiovascular disease or cancer among postmenopausal women who are not taking additional supplemental vitamin D and calcium. Studies suggest the method used to assay 25(OH)D may influence the outcomes of dose-response assessments. Beyond these observations, it is difficult to make any substantive statements on the basis of the available evidence concerning the association of either serum 25(OH)D concentration, vitamin D supplementation, calcium intake, or the combination of both nutrients, with the various health outcomes because most of the findings were inconsistent.

Objectives To conduct a systematic review of the literature on the safety of vaccines recommended for routine immunization of children, adolescents, and adults in the United States as of 2011. Data sources We included placebo-controlled clinical trials and cohort studies comparing vaccinated and unvaccinated patients. We also included the following types of post-licensure analyses: case-control studies, self-controlled case series, and multivariate risk factor analyses. We conducted an electronic search of PubMed from inception through August 2013, and reviewed Advisory Committee for Immunization Practices statements, vaccine package inserts, and previously published reviews to identify studies. Scientific Information Packets were requested from vaccine manufacturers. Review methods We reviewed the methodology of the 2011 Institute of Medicine (IOM) consensus report "Adverse Effects of Vaccines: Evidence and Causality" and accepted their findings. We augmented their work with new studies and additional vaccines. For studies not included in the IOM report, we abstracted data on the presence or absence of adverse health outcomes, characteristics of patients, study design, and vaccine description, including brand, potency, dosage, timing, and formulation, where available. We excluded formulations not used in the United States. The McHarm instrument was used to evaluate the quality of adverse events collection and reporting in each study. We were unable to pool results; we rated the overall strength of evidence (SOE) as high, moderate, low, or insufficient by using guidance suggested by the Agency for Healthcare Research and Quality for its Effective Health Care Program. Results A total of 20,478 titles were identified; after title, abstract, and full-text review, 166 studies were accepted for abstraction. The vast majority of studies either did not investigate or could not identify risk factors for adverse events (AEs) associated with vaccination. Similarly, the severity of AEs was inconsistently reported, as was information that would make independent severity determination possible. SOE was high for the following associations in nonpregnant adults: seasonal influenza vaccine and arthralgia, myalgia, malaise, fever, pain at injection site; 2009 monovalent H1N1 vaccine and Guillain-Barre syndrome (GBS); and a lack of association between influenza and pneumococcal vaccines and cardiovascular events in the elderly. Risk of GBS was estimated at 1.6 excess cases per million persons vaccinated. SOE was high for the following associations in children and adolescents: measles, mumps, rubella (MMR) vaccine and febrile seizures in children under age 5; lack of association between MMR vaccine and autism spectrum disorders; and varicella vaccine and disseminated Oka strain varicella zoster virus with associated complications (i.e., meningitis, encephalitis) in individuals with demonstrated immunodeficiencies. There is moderate SOE that vaccines against rotavirus are associated with intussusception in children; risk was estimated as 1 to 5 cases per 100,000 vaccine doses, depending on brand. Moderate-strength evidence exists regarding human papillomavirus vaccine and a lack of association with onset of juvenile rheumatoid arthritis, type 1 diabetes, and GBS. Moderate-strength evidence shows no association between inactivated influenza vaccine and serious AEs in pregnant women.Evidence was insufficient to make conclusions regarding whether several routinely recommended vaccines are associated with serious conditions such as multiple sclerosis, transverse myelitis, and acute disseminated encephalomyelitis. Conclusions There is evidence that some vaccines are associated with serious adverse events; however, these events are extremely rare and must be weighed against the protective benefits that vaccines provide. Careful consideration should be given to the investigation of research gaps, including patient risk factors that may be associated with AEs; however, important factors must be taken into account when determining whether studies are warranted, including the severity and frequency of the AE being studied and the challenges of conducting sufficiently powered studies when investigating rare events.

Background An exponential increase in the number of systematic reviews published, and constrained resources for new reviews, means that there is an urgent need for guidance on explicitly and transparently integrating existing reviews into new systematic reviews. The objectives of this paper are: 1) to identify areas where existing guidance may be adopted or adapted, and 2) to suggest areas for future guidance development. Methods We searched documents and websites from healthcare focused systematic review organizations to identify and, where available, to summarize relevant guidance on the use of existing systematic reviews. We conducted informational interviews with members of Evidence-based Practice Centers (EPCs) to gather experiences in integrating existing systematic reviews, including common issues and challenges, as well as potential solutions. Results There was consensus among systematic review organizations and the EPCs about some aspects of incorporating existing systematic reviews into new reviews. Current guidance may be used in assessing the relevance of prior reviews and in scanning references of prior reviews to identify studies for a new review. However, areas of challenge remain. Areas in need of guidance include how to synthesize, grade the strength of, and present bodies of evidence composed of primary studies and existing systematic reviews. For instance, empiric evidence is needed regarding how to quality check data abstraction and when and how to use study-level risk of bias assessments from prior reviews. Conclusions There remain areas of uncertainty for how to integrate existing systematic reviews into new reviews. Methods research and consensus processes among systematic review organizations are needed to develop guidance to address these challenges.

Gout is a common type of inflammatory arthritis in patients seen by primary care physicians.To review evidence about treatment of acute gout attacks, management of hyperuricemia to prevent attacks, and discontinuation of medications for chronic gout in adults.Multiple electronic databases from January 2010 to March 2016, reference mining, and pharmaceutical manufacturers.Studies of drugs approved by the U.S. Food and Drug Administration and commonly prescribed by primary care physicians, randomized trials for effectiveness, and trials and observational studies for adverse events.Data extraction was performed by one reviewer and checked by a second reviewer. Study quality was assessed by 2 independent reviewers. Strength-of-evidence assessment was done by group discussion.High-strength evidence from 28 trials (only 3 of which were placebo-controlled) shows that colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), and corticosteroids reduce pain in patients with acute gout. Moderate-strength evidence suggests that low-dose colchicine is as effective as high-dose colchicine and causes fewer gastrointestinal adverse events. Moderate-strength evidence suggests that urate-lowering therapy (allopurinol or febuxostat) reduces long-term risk for acute gout attacks after 1 year or more. High-strength evidence shows that prophylaxis with daily colchicine or NSAIDs reduces the risk for acute gout attacks by at least half in patients starting urate-lowering therapy, and moderate-strength evidence indicates that duration of prophylaxis should be longer than 8 weeks. Although lower urate levels reduce risk for recurrent acute attacks, treatment to a specific target level has not been tested.Few studies of acute gout treatments, no placebo-controlled trials of management of hyperuricemia lasting longer than 6 months, and few studies in primary care populations.Colchicine, NSAIDs, and corticosteroids relieve pain in adults with acute gout. Urate-lowering therapy decreases serum urate levels and reduces risk for acute gout attacks.Agency for Healthcare Research and Quality. (Protocol registration: http://effectivehealth-care.ahrq.gov/ehc/products/564/1992/Gout-managment-protocol-141103.pdf).

Background Conflicting evidence exists regarding potential cardiovascular risks associated with high levels of calcium intake. Purpose To update and reanalyze 2 systematic reviews to examine the effects of calcium intake on cardiovascular disease (CVD) among generally healthy adults. Data sources MEDLINE; Cochrane Central Register of Controlled Trials; Scopus, including EMBASE; and previous evidence reports from English-language publications from 1966 to July 2016. Study selection Randomized trials and prospective cohort and nested case-control studies with data on dietary or supplemental intake of calcium, with or without vitamin D, and cardiovascular outcomes. Data extraction Study characteristics and results extracted by 1 reviewer were confirmed by a second reviewer. Two raters independently assessed risk of bias. Data synthesis Overall risk of bias was low for the 4 randomized trials (in 10 publications) and moderate for the 27 observational studies included. The trials did not find statistically significant differences in risk for CVD events or mortality between groups receiving supplements of calcium or calcium plus vitamin D and those receiving placebo. Cohort studies showed no consistent dose-response relationships between total, dietary, or supplemental calcium intake levels and cardiovascular mortality and highly inconsistent dose-response relationships between calcium intake and risks for total stroke or stroke mortality. Limitations CVD disease outcomes were secondary end points in all trials. Dose-response metaregression analysis of cohort studies was limited by potential confounding, ecological bias, and imprecise measures of calcium exposures. Data were scarce regarding very high calcium intake-that is, beyond recommended tolerable upper intake levels. Conclusion Calcium intake within tolerable upper intake levels (2000 to 2500 mg/d) is not associated with CVD risk in generally healthy adults. Primary funding source National Osteoporosis Foundation.

Acute Otitis Media (AOM), a viral or bacterial infection of the ear, is the most common childhood infection for which antibiotics are prescribed in the United States. In 2001, the Southern California Evidence-based Practice Center conducted a systematic review of the evidence comparing treatments of AOM.This review updates the 2001 review findings on diagnosis and treatment of uncomplicated AOM, assesses the evidence for treatment of recurrent AOM, and assesses the impact of the heptavalent pneumococcal conjugate (PCV7) vaccine on the microbiology of AOM.Searches of PubMed® and the Cochrane databases were conducted from January 1998 to July 2010 using the same search strategies used for the 2001 report, with the addition of terms not considered in the 2001 review. The Web of Science was also searched for citations of the 2001 report and its peer-reviewed publications.After review by two investigators against pre-determined inclusion/exclusion criteria, we included existing systematic reviews and randomized controlled clinical trials for assessment of treatment efficacy and safety. Pooled analysis was performed for comparisons with three or more trials.Few studies were found that examined the accuracy and precision of the diagnosis of AOM. Since PCV7's introduction, AOM microbiology has shifted significantly, with Streptococcus pneumoniae becoming less prevalent and Haemophilus influenzae (HF) increasing in importance. For uncomplicated AOM, pooled analysis indicates that nine children (95% CI: 6, 20) would need to be treated with ampicillin or amoxicillin rather than placebo to note a difference in the rate of clinical success. However, in four studies of delayed treatment approaches for uncomplicated AOM, two had higher rates of clinical success with immediate antibiotic therapy while two did not, and in three studies, a marked decrease in antibiotic utilization was noted. We are unable to draw definitive conclusions regarding the comparative effectiveness of different antibiotics for AOM in children with recurrent otitis media (ROM). For ROM, long-term antibiotic administration will decrease AOM episodes from 3 to 1.5 for every 12 months of treatment per otitis prone child during active treatment (95% CI: 1.2, 2.1); however, potential consequences of long-term treatment need to be considered. Data were insufficient to draw conclusions about comparative effectiveness of different treatment strategies in subgroups of children with uncomplicated AOM. Adverse events were generally more frequent for amoxicillin-clavulanate than for cefdinir, ceftriaxone, or azithromycin. Higher quality studies and improved reporting of study characteristics related to quality are needed to provide definitive conclusions for AOM and ROM treatment options.

Summarizes key RAND studies on the causes of obesity, its economic and health consequences, and potential strategies for prevention, including work on health care costs, junk food, food deserts, school meals, and proximity of parks.

This research brief summarizes studies showing that medical innovations will improve health and extend life but will likely increase Medicare spending; eliminating obesity and better prevention could save Medicare money and improve health.

Although several agents are available to treat osteoporosis, the relative efficacy and toxicity of these agents when used to prevent fractures has not been well described.To compare the benefits in fracture reduction and the harms from adverse events of various therapies for osteoporosis.MEDLINE (1966 to November 2007) and other selected databases were searched for English-language studies.For the efficacy analysis, investigators selected studies that reported the rate of or risk for fractures. For the adverse event analysis, they selected studies that reported the relationship between an agent and cardiovascular, thromboembolic, or upper gastrointestinal events; malignant conditions; and osteonecrosis.Using a standardized protocol, investigators abstracted data on fractures and adverse events, agents and comparators, study design, and variables of methodological quality.Good evidence suggests that alendronate, etidronate, ibandronate, risedronate, zoledronic acid, estrogen, parathyroid hormone (1-34), and raloxifene prevent vertebral fractures more than placebo; the evidence for calcitonin was fair. Good evidence suggests that alendronate, risedronate, and estrogen prevent hip fractures more than placebo; the evidence for zoledronic acid was fair. The effects of vitamin D varied with dose, analogue, and study population for both vertebral and hip fractures. Raloxifene, estrogen, and estrogen-progestin increased the risk for thromboembolic events, and etidronate increased the risk for esophageal ulcerations and gastrointestinal perforations, ulcerations, and bleeding.Few studies have directly compared different agents or classes of agents used to treat osteoporosis.Although good evidence suggests that many agents are effective in preventing osteoporotic fractures, the data are insufficient to determine the relative efficacy or safety of these agents.

Evidence-based systematic reviews evaluating dietary intake and nutritional interventions are becoming common but are relatively few compared with other applications. Concerns remain that systematic reviews of nutrition topics pose several unique challenges. We present a successful collaboration to systematically review the health effects of a common nutrient, n-3 (or omega-3) fatty acids, across a wide range of clinical conditions. More generally, we discuss the challenges faced and the lessons learned during the review, the benefits of systematic review of nutritional topics, and recommendations for conducting and reviewing nutrition-related studies. Through a structured but flexible process, 3 Evidence-based Practice Centers in the Agency for Healthcare Research and Quality program produced 11 reports on a wide range of n-3 fatty acid-related topics. An important resource has been created, through which nutrition and dietetics researchers, clinical dietitians and nutritionists, clinicians, and the general public can understand the state of the science. The process identified challenges and problems in evaluating the health effects of n-3 fatty acid consumption, highlighted challenges to reviewing the human nutrition literature, and yielded recommendations for future research. The goals of these systematic reviews, the processes that were used, the benefits and limitations of the collaboration, and the conclusions of the reviews, including recommendations for future research, are summarized here.

Annual US health-related productivity losses are estimated to reach some $260 billion, attributable not only to absenteeism but also to presenteeism (being present at work but working at a reduced capacity). The search for remedies has been hampered by the lack of accurate estimates of the loss of productivity and its true costs. To date, little effort has been made to assess the availability of measurement instruments or the validity and reliability of those that exist.To systematically review the instruments used to measure productivity loss and its costs and to assess limitations in current research.A systematic search was conducted of the published and gray-market research literature from 1995 through 2005 on methods for estimating productivity loss and monetizing that loss.Twenty survey instruments were identified that assess the effect of health problems on absenteeism or presenteeism by attempting to quantify self-perceived or comparative impairment or by measuring unproductive work time. Some of the methods have been validated. The challenges of measuring presenteeism far exceed those of measuring absenteeism primarily because many jobs do not have easily measurable output. Methods to estimate the cost of lost productivity were also identified; however, none have been validated, to our knowledge.The greatest impediment to estimating the cost of productivity lost to illness is the lack of established and validated methods for monetization. The issues raised in this review are intended to stimulate future research to validate and improve such methods.

ContextOmega-3 fatty acids are purported to reduce the risk of cancer. Studies have reported mixed results.ObjectiveTo synthesize published and unpublished evidence to determine estimates of the effect of omega-3 fatty acids on cancer risk in prospective cohort studies.Data SourcesArticles published from 1966 to October 2005 identified through MEDLINE, PREMEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and CAB Health; unpublished literature sought through letters to experts in the neutraceutical industry.Study SelectionA total of 38 articles with a description of effects of consumption of omega-3 fatty acids on tumor incidence, prospective cohort study design, human study population; and description of effect of omega-3 among groups with different levels of exposure in the cohort were included. Two reviewers independently reviewed articles using structured abstraction forms; disagreements were resolved by consensus.Data ExtractionTwo reviewers independently abstracted detailed data about the incidence of cancer, the type of cancer, the number and characteristics of the patients, details on the exposure to omega-3 fatty acids, and the elapsed time between the intervention and outcome measurements. Data about the methodological quality of the study were also abstracted.Data SynthesisAcross 20 cohorts from 7 countries for 11 different types of cancer and using up to 6 different ways to categorize omega-3 fatty acid consumption, 65 estimates of the association between omega-3 fatty acid consumption were reported. Among these, only 8 were statistically significant. The high degree of heterogeneity across these studies precluded pooling of data. For breast cancer 1 significant estimate was for increased risk (incidence risk ratio [IRR], 1.47; 95% confidence interval [CI], 1.10-1.98) and 3 were for decreased risk (RR, 0.68-0.72); 7 other estimates did not show a significant association. For colorectal cancer, there was 1 estimate of decreased risk (RR, 0.49; 95% CI, 0.27-0.89) and 17 estimates without association. For lung cancer one of the significant associations was for increased cancer risk (IRR, 3.0; 95% CI, 1.2-7.3), the other was for decreased risk (RR, 0.32; 95% CI, 0.13-0.76), and 4 other estimates were not significant. For prostate cancer, there was 1 estimate of decreased risk (RR, 0.43; 95% CI, 0.22-0.83) and 1 of increased risk (RR, 1.98; 95% CI, 1.34-2.93) for advanced prostate cancer; 15 other estimates did not show a significant association. The study that assessed skin cancer found an increased risk (RR, 1.13; 95% CI, 1.01-1.27). No significant associations between omega-3 fatty acid consumption and cancer incidence were found for aerodigestive cancer, bladder cancer, lymphoma, ovarian cancer, pancreatic cancer, or stomach cancer.ConclusionsA large body of literature spanning numerous cohorts from many countries and with different demographic characteristics does not provide evidence to suggest a significant association between omega-3 fatty acids and cancer incidence. Dietary supplementation with omega-3 fatty acids is unlikely to prevent cancer.

We used a method that combined literature review and expert judgment to assess potential medical innovations for older adults. We evaluated innovations in four domains: cardiovascular disease, cancer, the biology of aging, and neurologic disease. The innovations can be categorized by common themes: improved disease prevention, better detection of subclinical or early clinical disease, and treatments for established disease. We report the likelihood, potential impact, and potential cost implications for thirty-four innovations, and we revisit this forecast five years later. Many of the innovations have the potential to greatly affect the costs and outcomes of health care. The unprecedented progress in biomedical as well as clinical and health services research during the final quarter of the twentieth century will continue to drive a revolution in medicine that is expected to last for at least the next quarter-century. Every aspect of the prevention, diagnosis, treatment, and monitoring of disease processes has been affected by this revolution. Behind this wave of advancement is a convergence of progress in many of the traditional life science fields, including anatomy, biochemistry, immunology, microbiology, physiology, genetics, pharmacology, health services, and clinical medicine, together with contributions from chemistry, physics, mathematics, computer science, and engineering. Scientists from widely divergent disciplines are now crossing over to other fields or collaborating to form multidisciplinary teams that are tackling problems of such magnitude that they could not have been approached within any one field. Keeping up with the rapidity of change is difficult enough. Predicting its possible course may be foolhardy. Nonetheless, because new technologies of all types are a driving force behind changes in health-related outcomes and costs of care, we accepted the dual challenge of developing a method to predict the impact of new technologies on health care for the elderly in the next ten and twenty years and then applying this method to estimate the impact of these innovations. Used appropriately, the results of our analyses might help us make more rational health policies as we cope with questions ranging from, “Will these new innovations improve important outcomes?” to, “Will we be able to afford them?” to, “What personnel will be needed to provide them?” In this paper we outline the systematic method we developed for identifying expert opinion to synthesize the range of possible scenarios. The result is a list of innovations with the probability of their entrance into clinical practice over the next ten to twenty years. The results should focus attention on the key innovations that have the most potential to change the way we prevent, diagnose, and treat disease.

Background n-3 Fatty acids are purported to have health effects in patients with inflammatory bowel disease (IBD), but studies have reported mixed results. Objective We aimed to synthesize published and unpublished evidence to determine estimates of the effect of n-3 fatty acids on clinical outcomes in IBD and whether n-3 fatty acids modify the effects of or need for treatment with other agents. Design Computerized databases were searched for studies of n-3 fatty acids in immune-mediated diseases from 1966 to 2003. We also contacted experts in the nutraceutical industry to identify unpublished studies; however, none were identified. Results Reviewers identified 13 controlled trials that assessed the effects of n-3 fatty acids on clinical, sigmoidoscopic, or histologic scores; rates of induced remission or relapse; or requirements for steroids and other immunosuppressive agents in Crohn disease or ulcerative colitis. Most clinical trials were of good quality. Fewer than 6 were identified that assessed the effects of n-3 fatty acids on any single outcome of clinical, endoscopic, or histologic scores or remission or relapse rates. Consistent across 3 studies was the finding that n-3 fatty acids reduce corticosteroid requirements, although statistical significance was shown in only 1 of these studies. Conclusion The available data are insufficient to draw conclusions about the effects of n-3 fatty acids on clinical, endoscopic, or histologic scores or remission or relapse rates.

s of all RAND publications and full text of many research documents can be found on the RAND web site at www.rand.org/publications. The RAND Corporation is a nonprofit research organization providing objective analysis and effective solutions that address the challenges facing the public and private sectors around the world. RAND’s publications do not necessarily reflect the opinions of its research clients and sponsors. R® is a registered trademark. RAND Offices Santa Monica • Washington • Pittsburgh • New York • Doha • Berlin • Cambridge • Leiden RB-9065-DVA (2005 ) Yet another important factor found to affect patient costs is reliance on Medicare: The higher the proportion of patients receiving Medicare benefits in a particular region, the lower that region’s VA patient care costs. Based on this finding, RAND recommended that the VA consider Medicare reliance in its allocation decisions. What Did the VA Do with RAND’s Advice? Responding to RAND’s findings, the VA decided to adopt a more precise adjustment for patients’ health status, one that employs ten illness categories (see the table). Should they have adopted an even more complex adjustment system? RAND’s findings suggested that the complexity of switching to such a system would more than offset any advantage that might be gained from doing so. While we don’t yet know whether the regional managers agreed with the changes in allocation, the VA administrators accepted the change in case-mix adjustment as an improvement in the equity of allocation processes and decisions. RAND’s detailed modeling efforts demonstrated convincingly that the more detailed allocation, based on ten illness categories, captured the bulk of the variation in patient costs and that other factors were simply not important enough to enter into the calculations. How Three Categories Expanded to Ten VERA-3 VERA-10 Yearly Patient Allocation (in dollars)