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.

CCBYNC Open access Research Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data

Objectives To assess the overall effect of vitamin D supplementation on risk of acute respiratory tract infection, and to identify factors modifying this effect.

Design Systematic review and meta-analysis of individual participant data (IPD) from randomised controlled trials.

Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials, Web of Science,, and the International Standard Randomised Controlled Trials Number registry from inception to December 2015.

Eligibility criteria for study selection Randomised, double blind, placebo controlled trials of supplementation with vitamin D3 or vitamin D2 of any duration were eligible for inclusion if they had been approved by a research ethics committee and if data on incidence of acute respiratory tract infection were collected prospectively and prespecified as an efficacy outcome.

Results 25 eligible randomised controlled trials (total 11 321 participants, aged 0 to 95 years) were identified. IPD were obtained for 10 933 (96.6%) participants. Vitamin D supplementation reduced the risk of acute respiratory tract infection among all participants (adjusted odds ratio 0.88, 95% confidence interval 0.81 to 0.96; P for heterogeneity <0.001). In subgroup analysis, protective effects were seen in those receiving daily or weekly vitamin D without additional bolus doses (adjusted odds ratio 0.81, 0.72 to 0.91) but not in those receiving one or more bolus doses (adjusted odds ratio 0.97, 0.86 to 1.10; P for interaction=0.05). Among those receiving daily or weekly vitamin D, protective effects were stronger in those with baseline 25-hydroxyvitamin D levels <25 nmol/L (adjusted odds ratio 0.30, 0.17 to 0.53) than in those with baseline 25-hydroxyvitamin D levels ≥25 nmol/L (adjusted odds ratio 0.75, 0.60 to 0.95; P for interaction=0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (adjusted odds ratio 0.98, 0.80 to 1.20, P=0.83). The body of evidence contributing to these analyses was assessed as being of high quality.

Conclusions Vitamin D supplementation was safe and it protected against acute respiratory tract infection overall. Patients who were very vitamin D deficient and those not receiving bolus doses experienced the most benefit.

Systematic review registration PROSPERO CRD42014013953.

BMJ 2017;356:i6583

Renin angiotensin system inhibitors for patients with stable coronary artery disease without heart failure: systematic review and meta-analysis of randomized trials

Objective To critically evaluate the efficacy of renin angiotensin system inhibitors (RASi) in patients with coronary artery disease without heart failure, compared with active controls or placebo.

Design Meta-analysis of randomized trials.

Data sources PubMed, EMBASE, and CENTRAL databases until 1 May 2016.

Eligibility criteria for selecting studies Randomized trials of RASi versus placebo or active controls in patients with stable coronary artery disease without heart failure (defined as left ventricular ejection fraction ≥40% or without clinical heart failure). Each trial had to enroll at least 100 patients with coronary artery disease without heart failure, with at least one year’s follow-up. Studies were excluded if they were redacted or compared use of angiotensin converting enzyme inhibitors with angiotensin receptor blockers. Outcomes were death, cardiovascular death, myocardial infarction, angina, stroke, heart failure, revascularization, incident diabetes, and drug withdrawal due to adverse effects.

Results 24 trials with 198 275 patient years of follow-up were included. RASi reduced the risk of all cause mortality (rate ratio 0.84, 95% confidence interval 0.72 to 0.98), cardiovascular mortality (0.74, 0.59 to 0.94), myocardial infarction (0.82, 0.76 to 0.88), stroke (0.79, 0.70 to 0.89), angina, heart failure, and revascularization when compared with placebo but not when compared with active controls (all cause mortality, 1.05, 0.94 to 1.17; Pinteraction=0.006; cardiovascular mortality, 1.08, 0.93 to 1.25, Pinteraction<0.001; myocardial infarction, 0.99, 0.87 to 1.12, Pinteraction=0.01; stroke, 1.10, 0.93 to 1.31; Pinteraction=0.002). Bayesian meta-regression analysis showed that the effect of RASi when compared with placebo on all cause mortality and cardiovascular mortality was dependent on the control event rate, such that RASi was only beneficial in trials with high control event rates (>14.10 deaths and >7.65 cardiovascular deaths per 1000 patient years) but not in those with low control event rates.

Conclusions In patients with stable coronary artery disease without heart failure, RASi reduced cardiovascular events and death only when compared with placebo but not when compared with active controls. Even among placebo controlled trials in this study, the benefit of RASi was mainly seen in trials with higher control event rates but not in those with lower control event rates. Evidence does not support a preferred status of RASi over other active controls.

BMJ 2017;356:j4

Efficacy and effectiveness of screen and treat policies in prevention of type 2 diabetes: systematic review and meta-analysis of screening tests and interventions

Objectives To assess diagnostic accuracy of screening tests for pre-diabetes and efficacy of interventions (lifestyle or metformin) in preventing onset of type 2 diabetes in people with pre-diabetes.

Design Systematic review and meta-analysis.

Data sources and method Medline, PreMedline, and Embase. Study protocols and seminal papers were citation-tracked in Google Scholar to identify definitive trials and additional publications. Data on study design, methods, and findings were extracted onto Excel spreadsheets; a 20% sample was checked by a second researcher. Data extracted for screening tests included diagnostic accuracy and population prevalence. Two meta-analyses were performed, one summarising accuracy of screening tests (with the oral glucose tolerance test as the standard) for identification of pre-diabetes, and the other assessing relative risk of progression to type 2 diabetes after either lifestyle intervention or treatment with metformin.

Eligibility criteria Empirical studies evaluating accuracy of tests for identification of pre-diabetes. Interventions (randomised trials and interventional studies) with a control group in people identified through screening. No language restrictions.

Results 2874 titles were scanned and 148 papers (covering 138 studies) reviewed in full. The final analysis included 49 studies of screening tests (five of which were prevalence studies) and 50 intervention trials. HbA1chad a mean sensitivity of 0.49 (95% confidence interval 0.40 to 0.58) and specificity of 0.79 (0.73 to 0.84), for identification of pre-diabetes, though different studies used different cut-off values. Fasting plasma glucose had a mean sensitivity of 0.25 (0.19 to 0.32) and specificity of 0.94 (0.92 to 0.96). Different measures of glycaemic abnormality identified different subpopulations (for example, 47%of people with abnormal HbA1chad no other glycaemic abnormality). Lifestyle interventions were associated with a 36% (28% to 43%) reduction in relative risk of type 2 diabetes over six months to six years, attenuating to 20% (8% to 31%) at follow-up in the period after the trails.

Conclusions HbA1c is neither sensitive nor specific for detecting pre-diabetes; fasting glucose is specific but not sensitive. Interventions in people classified through screening as having pre-diabetes have some efficacy in preventing or delaying onset of type 2 diabetes in trial populations. As screening is inaccurate, many people will receives an incorrect diagnosis and be referred on for interventions while others will be falsely reassured and not offered the intervention. These findings suggest that “screen and treat” policies alone are unlikely to have substantial impact on the worsening epidemic of type 2 diabetes.

Registration PROSPERO (No CRD42016042920).

Differential effect of mass deworming and targeted deworming for soil-transmitted helminth control in children: a systematic review and meta-analysis


Soil-transmitted helminth infections are a major global health issue, causing substantial morbidity in the world’s poorest populations. Regular delivery of anthelmintic drugs is the mainstay for global soil-transmitted helminth control. Deworming campaigns are often targeted to school-aged children, who are at high risk of soil-transmitted-helminth-associated morbidity. However, findings from modelling studies suggest that deworming campaigns should be expanded community-wide for effective control of soil-transmitted helminth transmission. We aimed to do a systematic review and meta-analysis to compare the effect of mass (community-wide) and targeted (children only) anthelmintic delivery strategies on soil-transmitted helminth prevalence in school-aged children.


In this systematic review and meta-analysis, we searched MEDLINE, Embase, and Web of Science for articles published on or before Nov 5, 2015, reporting soil-transmitted helminth prevalence before and after distribution of albendazole or mebendazole, either targeted to children or delivered to the whole community. We excluded studies in which drug delivery was restricted to infected individuals or to a subset of the community or school, or if follow-up time was less than 3 months or greater than 18 months after drug delivery. We extracted data on study year, country, drug administration strategy, drug dose, number of deworming rounds, treatment coverage, diagnostic method, follow-up interval, and soil-transmitted helminth prevalence before and after treatment. We used inverse variance weighted generalised linear models, with prevalence reduction as the outcome variable, to examine the effect of mass versus targeted drug administration, as well as baseline prevalence, number of drug doses, and follow-up time. This study is registered with PROSPERO, number CRD42016026929.


Of 10 538 studies identified, 56 studies were eligible for the systematic review and 38 of these were included in meta-analysis. Results of the regression models showed that mass deworming led to a significantly greater reduction in prevalence in children than targeted deworming, for both hookworm (odds ratio 4·6, 95% CI 1·8–11·6; p=0·0020) and Ascaris lumbricoides (16·4, 2·1–125·8; p=0·0092), with no effect seen for Trichuris trichiura. There was significant heterogeneity across studies; for targeted studies I2 was 97% for A lumbricoides and hookworm, and 96% for T trichiura, and for mass studies, I2 was 89% for A lumbricoides, 49% for hookworm, and 66% for T trichiura.


The results of this meta-analysis suggest that expanding deworming programmes community-wide is likely to reduce the prevalence of soil-transmitted helminths in the high-risk group of school-aged children, which could lead to improved morbidity outcomes. These findings are in support of recent calls for re-evaluation of global soil-transmitted helminth control guidelines.



Reference: The Lancet online, 12th December 2016

Association Between Palliative Care and Patient and Caregiver Outcomes: A Systematic Review and Meta-analysis

Importance  The use of palliative care programs and the number of trials assessing their effectiveness have increased.

Objective  To determine the association of palliative care with quality of life (QOL), symptom burden, survival, and other outcomes for people with life-limiting illness and for their caregivers.

Data Sources  MEDLINE, EMBASE, CINAHL, and Cochrane CENTRAL to July 2016.

Study Selection  Randomized clinical trials of palliative care interventions in adults with life-limiting illness.

Data Extraction and Synthesis  Two reviewers independently extracted data. Narrative synthesis was conducted for all trials. Quality of life, symptom burden, and survival were analyzed using random-effects meta-analysis, with estimates of QOL translated to units of the Functional Assessment of Chronic Illness Therapy–palliative care scale (FACIT-Pal) instrument (range, 0-184 [worst-best]; minimal clinically important difference [MCID], 9 points); and symptom burden translated to the Edmonton Symptom Assessment Scale (ESAS) (range, 0-90 [best-worst]; MCID, 5.7 points).

Main Outcomes and Measures  Quality of life, symptom burden, survival, mood, advance care planning, site of death, health care satisfaction, resource utilization, and health care expenditures.

Results  Forty-three RCTs provided data on 12 731 patients (mean age, 67 years) and 2479 caregivers. Thirty-five trials used usual care as the control, and 14 took place in the ambulatory setting. In the meta-analysis, palliative care was associated with statistically and clinically significant improvements in patient QOL at the 1- to 3-month follow-up (standardized mean difference, 0.46; 95% CI, 0.08 to 0.83; FACIT-Pal mean difference, 11.36] and symptom burden at the 1- to 3-month follow-up (standardized mean difference, −0.66; 95% CI, −1.25 to −0.07; ESAS mean difference, −10.30). When analyses were limited to trials at low risk of bias (n = 5), the association between palliative care and QOL was attenuated but remained statistically significant (standardized mean difference, 0.20; 95% CI, 0.06 to 0.34; FACIT-Pal mean difference, 4.94), whereas the association with symptom burden was not statistically significant (standardized mean difference, −0.21; 95% CI, −0.42 to 0.00; ESAS mean difference, −3.28). There was no association between palliative care and survival (hazard ratio, 0.90; 95% CI, 0.69 to 1.17). Palliative care was associated consistently with improvements in advance care planning, patient and caregiver satisfaction, and lower health care utilization. Evidence of associations with other outcomes was mixed.

Conclusions and Relevance  In this meta-analysis, palliative care interventions were associated with improvements in patient QOL and symptom burden. Findings for caregiver outcomes were inconsistent. However, many associations were no longer significant when limited to trials at low risk of bias, and there was no significant association between palliative care and survival.

Association between prediabetes and risk of cardiovascular disease and all cause mortality: systematic review and meta-analysis

Objectives To evaluate associations between different definitions of prediabetes and the risk of cardiovascular disease and all cause mortality.

Design Meta-analysis of prospective cohort studies.

Data sources Electronic databases (PubMed, Embase, and Google Scholar).

Selection criteria Prospective cohort studies from general populations were included for meta-analysis if they reported adjusted relative risks with 95% confidence intervals for associations between the risk of composite cardiovascular disease, coronary heart disease, stroke, all cause mortality, and prediabetes.

Review methods Two authors independently reviewed and selected eligible studies, based on predetermined selection criteria. Prediabetes was defined as impaired fasting glucose according to the criteria of the American Diabetes Association (IFG-ADA; fasting glucose 5.6-6.9 mmol/L), the WHO expert group (IFG-WHO; fasting glucose 6.1-6.9 mmol/L), impaired glucose tolerance (2 hour plasma glucose concentration 7.8-11.0 mmol/L during an oral glucose tolerance test), or raised haemoglobin A1c (HbA1c) of 39-47 mmol/mol(5.7-6.4%) according to ADA criteria or 42-47 mmol/mol (6.0-6.4%) according to the National Institute for Health and Care Excellence (NICE) guideline. The relative risks of all cause mortality and cardiovascular events were calculated and reported with 95% confidence intervals.

Results 53 prospective cohort studies with 1 611 339 individuals were included for analysis. The median follow-up duration was 9.5 years. Compared with normoglycaemia, prediabetes (impaired glucose tolerance or impaired fasting glucose according to IFG-ADA or IFG-WHO criteria) was associated with an increased risk of composite cardiovascular disease (relative risk 1.13, 1.26, and 1.30 for IFG-ADA, IFG-WHO, and impaired glucose tolerance, respectively), coronary heart disease (1.10, 1.18, and 1.20, respectively), stroke (1.06, 1.17, and 1.20, respectively), and all cause mortality (1.13, 1.13 and 1.32, respectively). Increases in HBA1c to 39-47 mmol/mol or 42-47 mmol/mol were both associated with an increased risk of composite cardiovascular disease (1.21 and 1.25, respectively) and coronary heart disease (1.15 and 1.28, respectively), but not with an increased risk of stroke and all cause mortality.

Conclusions Prediabetes, defined as impaired glucose tolerance, impaired fasting glucose, or raised HbA1c, was associated with an increased risk of cardiovascular disease. The health risk might be increased in people with a fasting glucose concentration as low as 5.6 mmol/L or HbA1c of 39 mmol/mol.

Reference: BMJ 2016;355:i5953