Treatments for ADHD in Children and Adolescents: A Systematic Review.

CONTEXT: Effective treatment of attention-deficit/hyperactivity disorder (ADHD) is essential to improving youth outcomes. OBJECTIVES: This systematic review provides an overview of the available treatment options. DATA SOURCES: We identified controlled treatment evaluations in 12 databases published from 1980 to June 2023; treatments were not restricted by intervention content. STUDY SELECTION: Studies in children and adolescents with clinically diagnosed ADHD, reporting patient health and psychosocial outcomes, were eligible. Publications were screened by trained reviewers, supported by machine learning. DATA EXTRACTION: Data were abstracted and critically appraised by 1 reviewer and checked by a methodologist. Data were pooled using random-effects models. Strength of evidence and applicability assessments followed Evidence-based Practice Center standards. RESULTS: In total, 312 studies reported in 540 publications were included. We grouped evidence for medication, psychosocial interventions, parent support, nutrition and supplements, neurofeedback, neurostimulation, physical exercise, complementary medicine, school interventions, and provider approaches. Several treatments improved ADHD symptoms. Medications had the strongest evidence base for improving outcomes, including disruptive behaviors and broadband measures, but were associated with adverse events. LIMITATIONS: We found limited evidence of studies comparing alternative treatments directly and indirect analyses identified few systematic differences across stimulants and nonstimulants. Identified combination of medication with youth-directed psychosocial interventions did not systematically produce better results than monotherapy, though few combinations have been evaluated. CONCLUSIONS: A growing number of treatments are available that improve ADHD symptoms and other outcomes, in particular for school-aged youth. Medication therapies remain important treatment options but are associated with adverse events.

Care coordination across healthcare systems: development of a research agenda, implications for practice, and recommendations for policy based on a modified Delphi panel.

OBJECTIVE: For large, integrated healthcare delivery systems, coordinating patient care across delivery systems with providers external to the system presents challenges. We explored the domains and requirements for care coordination by professionals across healthcare systems and developed an agenda for research, practice and policy. DESIGN: The modified Delphi approach convened a 2-day stakeholder panel with moderated virtual discussions, preceded and followed by online surveys. SETTING: The work addresses care coordination across healthcare systems. We introduced common care scenarios and differentiated recommendations for a large (main) healthcare organisation and external healthcare professionals that contribute additional care. PARTICIPANTS: The panel composition included health service providers, decision makers, patients and care community, and researchers. Discussions were informed by a rapid review of tested approaches to fostering collaboration, facilitating care coordination and improving communication across healthcare systems. OUTCOME MEASURES: The study planned to formulate a research agenda, implications for practice and recommendations for policy. RESULTS: For research recommendations, we found consensus for developing measures of shared care, exploring healthcare professionals' needs in different care scenarios and evaluating patient experiences. Agreed practice recommendations included educating external professionals about issues specific to the patients in the main healthcare system, educating professionals within the main healthcare system about the roles and responsibilities of all involved parties, and helping patients better understand the pros and cons of within-system and out-of-system care. Policy recommendations included supporting time for professionals with high overlap in patients to engage regularly and sustaining support for care coordination for high-need patients. CONCLUSIONS: Recommendations from the stakeholder panel created an agenda to foster further research, practice and policy innovations in cross-system care coordination.

Sleep Management in Posttraumatic Stress Disorder (PTSD): A Systematic Review.

Posttraumatic stress disorder (PTSD) is a condition that can emerge after exposure to a traumatic event. It involves several symptoms, including distressing memories or dreams and/or dissociative reactions; psychological distress at exposure to trauma cues; physiologic reactions to cues; avoidance of stimuli associated with the event; negative alterations in cognitions and mood associated with the trauma; and alterations in arousal and reactivity, including sleep disturbance. The purpose of this systematic review is to synthesize the evidence from randomized controlled trials on the effects that interventions for adults with PTSD have on sleep outcomes. The authors searched research databases and bibliographies of existing systematic reviews to identify pertinent trials published in English; literature was identified by the searches using predetermined eligibility criteria. The primary outcome domain included sleep quality, insomnia, and nightmares. Secondary outcomes were PTSD symptoms and adverse events. Risk of bias and the quality of evidence were assessed for each outcome. The identified interventions addressed pharmacological, psychological, behavioral, complementary, and integrative medicine treatments aimed at improving sleep or lessening other PTSD symptoms. Interventions in general showed an effect on sleep. Interventions explicitly targeting sleep-particularly psychotherapy targeting sleep-showed larger effects on sleep than did interventions not targeting sleep. Heterogeneity was considerable, but sleep effect estimates were not systematically affected by trauma type, setting, or modality. Comparative effectiveness studies are needed to support the findings.

Combat and Operational Stress Control Interventions and PTSD: A Systematic Review and Meta-Analysis.

INTRODUCTION: Military personnel must prepare for and respond to life-threatening crises on a daily basis. This lifestyle places stress on personnel, and particularly so on deployed service members who are isolated from support systems and other resources. As part of a larger systematic review on the acceptability, efficacy, and comparative effectiveness of interventions designed to prevent, identify, and manage stress reactions, we assessed posttraumatic stress disorder (PTSD) outcomes. MATERIALS AND METHODS: We searched the electronic databases PsycINFO, PubMed, PTSDPubs, the Defense Technical Information Center, and Cochrane Central, as well as bibliographies of existing systematic reviews, to identify English-language studies evaluating the efficacy or comparative effectiveness of stress control interventions published since 1990. Controlled trials and cohort comparisons of interventions with military, law enforcement, and first responders were included. Two independent reviewers screened literature using predetermined eligibility criteria. Researchers individually abstracted study-level information and outcome data and assessed the risk of bias of included studies; data were reviewed for accuracy by the project leader. Changes in PTSD symptom scores from baseline to post-intervention were converted to standardized mean differences for comparison across studies. Risk ratios were calculated for PTSD case rates post-deployment. When several studies that compared an intervention group with a similar control/comparator reported the same outcome category and measure type, we conducted meta-analysis. We conducted meta-regression by adding a categorical variable, representing setting (i.e., in theater) or population (military vs. law enforcement or first responders) to the meta-analysis model to assess whether this variable was associated with the outcome across studies. The quality of the body of evidence (QoE) was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, which considers study limitations (risk of bias), directness, consistency, precision, and publication bias. RESULTS: Sixteen controlled trials and 13 cohort comparisons reporting PTSD outcomes met inclusion criteria. Eight controlled trials and two cohort studies had high risk of bias, primarily due to poor, differential, or unknown response rate at follow-up. Twenty-four of the 29 studies included military personnel. Interventions included Acceptance-based Skills training, Attention Bias Modification training, stress inoculation with biofeedback, Critical Incident Stress Debriefing, group psychological debriefing, Eye Movement Desensitization and Reprocessing for sub-clinical stress, embedding mental health providers in theater, Third Location Decompression, reintegration programs, and a 3-week post-deployment residential program for psychological resource strengthening.Meta-analyses of studies comparing a group that received a stress control intervention to a group that did not receive an intervention found no significant difference in reduction in PTSD symptom scores (moderate QoE) or PTSD case rate post-deployment (low QoE). A meta-analysis of studies comparing a specific stress control intervention to an active comparator (usually standard stress management education) found no significant effect on PTSD symptom scores (moderate QoE). CONCLUSION: Although combat and operational stress control (COSC) interventions may play a valuable role in decreasing stress, decreasing absenteeism, and enabling return to duty, a systematic review of 29 studies that included a control/comparison group found little evidence that COSC is effective in preventing PTSD or decreasing PTSD symptom scores in military personnel.

Mindfulness meditation for workplace wellness: An evidence map.

BACKGROUND: Mindfulness interventions aim to foster greater attention and awareness of present moment experiences. Uptake of mindfulness programs in the workplace has grown as organizations look to support employee health, wellbeing, and performance. OBJECTIVE: In support of evidence-based decision making in workplace contexts, we created an evidence map summarizing physical and mental health, cognitive, affective, and interpersonal outcomes from systematic reviews of randomized controlled trials (RCTs) of mindfulness interventions. METHODS: We searched nine electronic databases to July 2017, dually-screened all reviews, and consulted topic experts to identify systematic reviews on mindfulness interventions. The distribution of evidence is presented as an evidence map in a bubble plot. RESULTS: In total, 175 systematic reviews met inclusion criteria. Reviews included a variety of mindfulness-based interventions. The largest review included 109 randomized controlled trials. The majority of these addressed general health, psychological conditions, chronic illness, pain, and substance use. Twenty-six systematic reviews assessed studies conducted in workplace settings and with healthcare professionals, educators, and caregivers. The evidence map shows the prevalence of research by the primary area of focus. An outline of promising applications of mindfulness interventions is included. CONCLUSIONS: The evidence map provides an overview of existing mindfulness research. It shows the body of available evidence to inform policy and organizational decision-making supporting employee wellbeing in work contexts.

Acupuncture for the Treatment of Adults with Posttraumatic Stress Disorder: A Systematic Review and Meta-Analysis.

Acupuncture has been suggested as a treatment for posttraumatic stress disorder (PTSD), yet its clinical effects are unclear. This review aims to estimate effects of acupuncture on PTSD symptoms, depressive symptoms, anxiety symptoms, and sleep quality for adults with PTSD. We searched 10 databases in January 2016 to identify eligible randomized controlled trials (RCTs). We performed random effects meta-analyses and examined quality of the body of evidence (QoE) using the GRADE approach to rate confidence in meta-analytic effect estimates. Seven RCTs with 709 participants met inclusion criteria. We identified very low QoE indicating significant differences favoring acupuncture (versus any comparator) at post-intervention on PTSD symptoms (standardized mean difference [SMD] = -0.80, 95% confidence interval [CI] [-1.59, -0.01], 6 RCTs), and low QoE at longer follow-up on PTSD (SMD = -0.46, 95% CI [-0.85, -0.06], 4 RCTs) and depressive symptoms (SMD = -0.56; 95% CI [-0.88, -0.23], 4 RCTs). No significant differences were observed between acupuncture and comparators at post-intervention for depressive symptoms (SMD = -0.58, 95% CI [-1.18, 0.01], 6 RCTs, very low QoE), anxiety symptoms (SMD = -0.82, 95% CI [-2.16, 0.53], 4 RCTs, very low QoE), and sleep quality (SMD = -0.46, 95% CI [-3.95, 3.03], 2 RCTs, low QoE). Safety data (7 RCTs) suggest little risk of serious adverse events, though some participants experienced minor/moderate pain, superficial bleeding, and hematoma at needle insertion sites. To increase confidence in findings, sufficiently powered replication trials are needed that measure all relevant clinical outcomes and dedicate study resources to minimizing participant attrition.

Mindfulness-based Relapse Prevention for Substance Use Disorders: A Systematic Review and Meta-analysis.

OBJECTIVES: Substance use disorder (SUD) is a prevalent health issue with serious personal and societal consequences. This review aims to estimate the effects and safety of Mindfulness-based Relapse Prevention (MBRP) for SUDs. METHODS: We searched electronic databases for randomized controlled trials evaluating MBRP for adult patients diagnosed with SUDs. Two reviewers independently assessed citations, extracted trial data, and assessed risks of bias. We conducted random-effects meta-analyses and assessed quality of the body of evidence (QoE) using the Grading of Recommendations Assessment, Development, and Evaluation approach. RESULTS: We identified 9 randomized controlled trials comprising 901 participants. We did not detect statistically significant differences between MBRP and comparators on relapse (odds ratio [OR] 0.72, 95% confidence interval [CI] 0.46-1.13, low QoE), frequency of use (standardized mean difference [SMD] 0.02, 95% CI -0.40 to 0.44, low QoE), treatment dropout (OR 0.81, 95% CI 0.40 to 1.62, very low QoE), depressive symptoms (SMD -0.09, 95% CI -0.39 to 0.21, low QoE), anxiety symptoms (SMD -0.32, 95% CI -1.16 to 0.52, very low QoE), and mindfulness (SMD -0.28, 95% CI -0.72 to 0.16, very low QoE). We identified significant differences in favor of MBRP on withdrawal/craving symptoms (SMD -0.13, 95% CI -0.19 to -0.08, I = 0%, low QoE) and negative consequences of substance use (SMD -0.23, 95% CI -0.39 to -0.07, I = 0%, low QoE). We found negligible evidence of adverse events. CONCLUSIONS: We have limited confidence in estimates suggesting MBRP yields small effects on withdrawal/craving and negative consequences versus comparator interventions. We did not detect differences for any other outcome. Future trials should aim to minimize participant attrition to improve confidence in effect estimates.

Acupuncture for substance use disorders: A systematic review and meta-analysis.

BACKGROUND: This systematic review aims to estimate the effects of acupuncture for adults with substance use disorders (SUDs). METHODS: We searched 7 electronic databases and bibliographies of previous studies to identify eligible randomized trials. Two independent reviewers screened citations, extracted data, and assessed risks of bias. We performed random effects meta-analyses. We assessed quality of evidence using the GRADE approach. RESULTS: We included 41 studies with 5,227 participants. No significant differences were observed between acupuncture and comparators (passive controls, sham acupuncture, treatment as usual, and active interventions) at post-intervention for relapse (SMD -0.12; 95%CI -0.46 to 0.22; 10 RCTs), frequency of substance use (SMD -0.27; -2.67 to 2.13; 2 RCTs), quantity of substance use (SMD 0.01; -0.40 to 0.43; 3 RCTs), and treatment dropout (OR 0.82; 0.63 to 1.09; 22 RCTs). We identified a significant difference in favor of acupuncture versus comparators for withdrawal/craving at post-intervention (SMD -0.57, -0.93 to -0.20; 20 RCTs), but we identified evidence of publication bias. We also identified a significant difference in favor of acupuncture versus comparators for anxiety at post-intervention (SMD -0.74, -1.15 to -0.33; 6 RCTs). Results for withdrawal/craving and anxiety symptoms were not significant at longer follow-up. Safety data (12 RCTs) suggests little risk of serious adverse events, though participants may experience slight bleeding or pain at needle insertion sites. CONCLUSIONS: Available evidence suggests no consistent differences between acupuncture and comparators for substance use. Results in favor of acupuncture for withdrawal/craving and anxiety symptoms are limited by low quality bodies of evidence.

Omega-3 Fatty Acids and Maternal and Child Health: An Updated Systematic Review.

OBJECTIVES: 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. DATA SOURCES: 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. REVIEW METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Development of the Quality Improvement Minimum Quality Criteria Set (QI-MQCS): a tool for critical appraisal of quality improvement intervention publications.

OBJECTIVE: Valid, reliable critical appraisal tools advance quality improvement (QI) intervention impacts by helping stakeholders identify higher quality studies. QI approaches are diverse and differ from clinical interventions. Widely used critical appraisal instruments do not take unique QI features into account and existing QI tools (eg, Standards for QI Reporting Excellence) are intended for publication guidance rather than critical appraisal. This study developed and psychometrically tested a critical appraisal instrument, the QI Minimum Quality Criteria Set (QI-MQCS) for assessing QI-specific features of QI publications. METHODS: Approaches to developing the tool and ensuring validity included a literature review, in-person and online survey expert panel input, and application to empirical examples. We investigated psychometric properties in a set of diverse QI publications (N=54) by analysing reliability measures and item endorsement rates and explored sources of disagreement between reviewers. RESULTS: The QI-MQCS includes 16 content domains to evaluate QI intervention publications: Organisational Motivation, Intervention Rationale, Intervention Description, Organisational Characteristics, Implementation, Study Design, Comparator Description, Data Sources, Timing, Adherence/Fidelity, Health Outcomes, Organisational Readiness, Penetration/Reach, Sustainability, Spread and Limitations. Median inter-rater agreement for QI-MQCS items was κ 0.57 (83% agreement). Item statistics indicated sufficient ability to differentiate between publications (median quality criteria met 67%). Internal consistency measures indicated coherence without excessive conceptual overlap (absolute mean interitem correlation=0.19). The critical appraisal instrument is accompanied by a user manual detailing What to consider, Where to look and How to rate. CONCLUSIONS: We developed a ready-to-use, valid and reliable critical appraisal instrument applicable to healthcare QI intervention publications, but recognise scope for continuing refinement.

Vitamin D and Calcium: A Systematic Review of Health Outcomes (Update).

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.