Estimating the causal effects of modifiable, non-genetic factors on Huntington disease progression using propensity score weighting.

INTRODUCTION: Despite being genetically inherited, it is unclear how non-genetic factors (e.g., substance use, employment) might contribute to the progression and severity of Huntington's disease (HD). METHODS: We used propensity score (PS) weighting in a large (n = 2914) longitudinal dataset (Enroll-HD) to examine the impact of education, employment status, and use of tobacco, alcohol, and recreational and therapeutic drugs on HD progression. Each factor was investigated in isolation while controlling for 19 other factors to ensure that groups were balanced at baseline on potential confounders using PS weights. Outcomes were compared several years later using doubly robust models. RESULTS: Our results highlighted cases where modifiable (non-genetic) factors - namely light and moderate alcohol use and employment - would have been associated with HD progression in models that did not use PS weights to control for baseline imbalances. These associations did not hold once we applied PS weights to balance baseline groups. We also found potential evidence of a protective effect of substance use (primarily marijuana use), and that those who needed antidepressant treatment were likely to progress faster than non-users. CONCLUSIONS: Our study is the first to examine the effect of non-genetic factors on HD using a novel application of PS weighting. We show that previously-reported associated factors - including light and moderate alcohol use - are reduced and no longer significantly linked to HD progression after PS weighting. This indicates the potential value of PS weighting in examining non-genetic factors contributing to HD as well as in addressing the known biases that occur with observational data.

Manipulation and Mobilization for Treating Chronic Nonspecific Neck Pain: A Systematic Review and Meta-Analysis for an Appropriateness Panel.

BACKGROUND: Mobilization and manipulation therapies are widely used by patients with chronic nonspecific neck pain; however, questions remain around efficacy, dosing, and safety, as well as how these approaches compare to other therapies. OBJECTIVES: Based on published trials, to determine the efficacy, effectiveness, and safety of various mobilization and manipulation therapies for treatment of chronic nonspecific neck pain. STUDY DESIGN: A systematic literature review and meta-analysis. METHODS: We identified studies published between January 2000 and September 2017, by searching multiple electronic databases, examining reference lists, and communicating with experts. We selected randomized controlled trials comparing manipulation and/or mobilization therapies to sham, no treatment, each other, and other active therapies, or when combined as multimodal therapeutic approaches. We assessed risk of bias by using the Scottish Intercollegiate Guidelines Network criteria. When possible, we pooled data using random-effects meta-analysis. Grading of Recommendations, Assessment, Development, and Evaluation was applied to determine the confidence in effect estimates. This project was funded by the National Center for Complementary and Integrative Health under award number U19AT007912 and ultimately used to inform an appropriateness panel. RESULTS: A total of 47 randomized trials (47 unique trials in 53 publications) were included in the systematic review. These studies were rated as having low risk of bias and included a total of 4,460 patients with nonspecific chronic neck pain who were being treated by a practitioner using various types of manipulation and/or mobilization interventions. A total of 37 trials were categorized as unimodal approaches and involved thrust or nonthrust compared with sham, no treatment, or other active comparators. Of these, only 6 trials with similar intervention styles, comparators, and outcome measures/timepoints were pooled for meta-analysis at 1, 3, and 6 months, showing a small effect in favor of thrust plus exercise compared to an exercise regimen alone for a reduction in pain and disability. Multimodal approaches appeared to be effective at reducing pain and improving function from the 10 studies evaluated. Health-related quality of life was seldom reported. Some 22/47 studies did not report or mention adverse events. Of the 25 that did, either no or minor events occurred. LIMITATIONS: The current evidence is heterogeneous, and sample sizes are generally small. CONCLUSIONS: Studies published since January 2000 provide low-moderate quality evidence that various types of manipulation and/or mobilization will reduce pain and improve function for chronic nonspecific neck pain compared to other interventions. It appears that multimodal approaches, in which multiple treatment approaches are integrated, might have the greatest potential impact. The studies comparing to no treatment or sham were mostly testing the effect of a single dose, which may or may not be helpful to inform practice. According to the published trials reviewed, manipulation and mobilization appear safe. However, given the low rate of serious adverse events, other types of studies with much larger sample sizes would be required to fully describe the safety of manipulation and/or mobilization for nonspecific chronic neck pain. KEY WORDS: Chronic neck pain, nonspecific, chiropractic, manipulation, mobilization, systematic review, meta-analysis, appropriateness.

Effectiveness of multifocal and monofocal intraocular lenses for cataract surgery and lens replacement: a systematic review and meta-analysis.

PURPOSE: Multifocal intraocular lenses (IOLs) offer the possibility of spectacle-free vision following cataract surgery compared to standard IOLs. Existing systematic reviews have generally concluded that multifocal IOLs result in better uncorrected near vision and greater spectacle independence, but more unwanted visual phenomena such as glare and halos, compared to monofocal IOLs. However, the certainty of evidence has been low for most outcomes, and pooled analyses have grouped together technologically obsolete lenses with newer lenses, potentially obscuring differences in performance across different lens types. METHODS: We performed a systematic review searching for RCTs of a multifocal IOL to a standard IOL or monovision that reported spectacle independence, visual acuity, or quality of life. Databases were searched from 1/1/2006-4/30/2017. Existing reviews were used to identify older studies. Title/abstract screening and data extraction were done in duplicate. Where possible, random effects meta-analysis was performed to synthesize results. In addition to comparing multifocal IOLs as a group to monofocal IOLs, we also compared newer diffractive lenses to obsolete or refractive lenses. RESULTS: Twenty-five eligible studies were identified. There was no difference in pooled estimates of corrected or uncorrected distance vision between multifocal and standard IOLs. Compared to monofocal IOLs, multifocal IOLs had statistically significantly better pooled results for the outcome of near vision (10 studies, 1025 patients, mean difference in logMAR of -0.26 (95% CI -0.37, -0.15)); spectacle dependence (12 studies, 1237 patients, relative risk of 0.27 (95% CI 0.20, 0.38)) and borderline significantly better quality of vision (6 studies, 596 patients, standardized mean difference of -0.54, (95% CI -1.12, 0.04)). Compared to monofocal IOLs, multifocal IOLs had statistically significantly worse pooled results for the outcomes of glare (9 studies, 847 patients, risk ratio of 1.36 (95% CI 1.15, 1.61) and halos (7 studies, 754 patients, risk ratio of 3.14 (95% CI 1.63, 6.08). Newer multifocal lenses had statistically significantly better outcomes than older diffractive lenses or refractive lenses, when compared to monofocal IOLs, in near vision, quality of vision, and risk of halos. CONCLUSIONS: Multifocal IOLs compared to standard IOLs or monovision result in better uncorrected near vision and a higher proportion of patients who achieve spectacle independence, but greater risk of unwanted visual phenomena. Newer diffractive lenses may be better than refractive lenses in near vision and quality of vision outcomes, with less risk of halos than older diffractive lenses and refractive lenses. (PROSPERO registration CRD42017069949).

Benefits and Harms of Cranial Electrical Stimulation for Chronic Painful Conditions, Depression, Anxiety, and Insomnia: A Systematic Review.

Background: Cranial electrical stimulation (CES) is increasingly popular as a treatment, yet its clinical benefit is unclear. Purpose: To review evidence about the benefits and harms of CES for adult patients with chronic painful conditions, depression, anxiety, and insomnia. Data Sources: Several databases from inception to 10 October 2017 without language restrictions and references from experts, prior reviews, and manufacturers. Study Selection: Randomized controlled trials of CES versus usual care or sham CES that reported pain, depression, anxiety, or sleep outcomes in any language. Data Extraction: Single-reviewer extraction checked by another; dual independent quality assessment; strength-of-evidence grading by the first author with subsequent group discussion. Data Synthesis: Twenty-eight articles from 26 randomized trials met eligibility criteria. The 2 trials that compared CES with usual care were small, and neither reported a statistically significant benefit in pain or anxiety outcomes for patients with fibromyalgia or anxiety, respectively. Fourteen trials with sham or placebo controls involving patients with painful conditions, such as headache, neuromuscular pain, or musculoskeletal pain, had conflicting results. Four trials done more than 40 years ago and 1 from 2014 provided low-strength evidence of a possible modest benefit compared with sham treatments in patients with anxiety and depression. Trials in patients with insomnia (n = 2), insomnia and anxiety (n = 1), or depression (n = 3) had inconclusive or conflicting results. Low-strength evidence suggested that CES does not cause serious side effects. Limitation: Most trials had small sample sizes and short durations; all had high risk of bias due to inadequate blinding. Conclusion: Evidence is insufficient that CES has clinically important effects on fibromyalgia, headache, neuromusculoskeletal pain, degenerative joint pain, depression, or insomnia; low-strength evidence suggests modest benefit in patients with anxiety and depression. Primary Funding Source: Veterans Affairs Quality Enhancement Research Initiative. (PROSPERO: CRD42016023951).

Association of Spinal Manipulative Therapy With Clinical Benefit and Harm for Acute Low Back Pain: Systematic Review and Meta-analysis.

IMPORTANCE: Acute low back pain is common and spinal manipulative therapy (SMT) is a treatment option. Randomized clinical trials (RCTs) and meta-analyses have reported different conclusions about the effectiveness of SMT. OBJECTIVE: To systematically review studies of the effectiveness and harms of SMT for acute (≤6 weeks) low back pain. DATA SOURCES: Search of MEDLINE, Cochrane Database of Systematic Reviews, EMBASE, and Current Nursing and Allied Health Literature from January 1, 2011, through February 6, 2017, as well as identified systematic reviews and RCTs, for RCTs of adults with low back pain treated in ambulatory settings with SMT compared with sham or alternative treatments, and that measured pain or function outcomes for up to 6 weeks. Observational studies were included to assess harms. DATA EXTRACTION AND SYNTHESIS: Data extraction was done in duplicate. Study quality was assessed using the Cochrane Back and Neck (CBN) Risk of Bias tool. This tool has 11 items in the following domains: randomization, concealment, baseline differences, blinding (patient), blinding (care provider [care provider is a specific quality metric used by the CBN Risk of Bias tool]), blinding (outcome), co-interventions, compliance, dropouts, timing, and intention to treat. Prior research has shown the CBN Risk of Bias tool identifies studies at an increased risk of bias using a threshold of 5 or 6 as a summary score. The evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. MAIN OUTCOMES AND MEASURES: Pain (measured by either the 100-mm visual analog scale, 11-point numeric rating scale, or other numeric pain scale), function (measured by the 24-point Roland Morris Disability Questionnaire or Oswestry Disability Index [range, 0-100]), or any harms measured within 6 weeks. FINDINGS: Of 26 eligible RCTs identified, 15 RCTs (1711 patients) provided moderate-quality evidence that SMT has a statistically significant association with improvements in pain (pooled mean improvement in the 100-mm visual analog pain scale, -9.95 [95% CI, -15.6 to -4.3]). Twelve RCTs (1381 patients) produced moderate-quality evidence that SMT has a statistically significant association with improvements in function (pooled mean effect size, -0.39 [95% CI, -0.71 to -0.07]). Heterogeneity was not explained by type of clinician performing SMT, type of manipulation, study quality, or whether SMT was given alone or as part of a package of therapies. No RCT reported any serious adverse event. Minor transient adverse events such as increased pain, muscle stiffness, and headache were reported 50% to 67% of the time in large case series of patients treated with SMT. CONCLUSIONS AND RELEVANCE: Among patients with acute low back pain, spinal manipulative therapy was associated with modest improvements in pain and function at up to 6 weeks, with transient minor musculoskeletal harms. However, heterogeneity in study results was large.

Provision of mental health services as a quality indicator for adolescent substance abuse treatment facilities.

OBJECTIVE: The study tested whether adolescents receiving substance abuse treatment at facilities offering full (can treat all psychiatric conditions) or partial (cannot treat severe or persistent mental illness) mental health services have better 12-month substance use and mental health outcomes than youths at facilities with no mental health services. METHODS: Data were collected from 3,235 adolescents who were assessed at baseline and at 12 months at one of 50 adolescent treatment facilities. Propensity scores were applied to compare client outcomes from three types of facilities (full, partial, or no mental health services); weighted linear models were estimated to examine outcomes. RESULTS: Youths attending facilities offering full or partial mental health services had better substance abuse treatment outcomes than youths attending facilities offering no such services. There was no evidence of a difference in substance use outcomes between facilities offering full versus partial services, nor was there evidence of differences in mental health outcomes. CONCLUSIONS: These preliminary findings suggest that the availability of mental health services may be a useful quality indicator for adolescent substance abuse treatment facilities. More research is needed to examine specific types of mental health services offered at different facilities.

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.