Eligibility Criteria of Participants in Randomized Controlled Trials Assessing Conservative Management of Cervical Radiculopathy: A Systematic Review.

STUDY DESIGN: Systematic review. OBJECTIVE: The aim of this study was to evaluate the inclusion and exclusion criteria for participants in randomized control trials (RCTs) assessing conservative management for cervical radiculopathy (CR), to determine if any consensus exists within the literature. SUMMARY OF BACKGROUND DATA: A 2012 systematic review identified a lack of uniformity for the eligibility criteria of participants in RCTs evaluating conservative interventions for CR. Since then, a large number of RCTs have been published, signaling the need for an updated evaluation of this topic. MATERIALS AND METHODS: We electronically searched MEDLINE, CENTRAL, CINAHL, Embase, and PsycINFO from inception to June 15, 2022, to identify RCTs assessing conservative management of CR. Information extracted was analyzed to determine the level of homogeneity and/or heterogeneity of the inclusion and exclusion criteria across studies. RESULTS: Seventy-six RCTs met our inclusion criteria with 68 distinct trials identified. The inclusion of arm pain with or without another symptom ( i.e. numbness, paresthesia, or weakness) was required in 69.12% of trials, 50% of trials required participants to exhibit neck symptoms, and 73.53% of studies required some form of clinical examination findings, but inconsistencies existed for the number and type of tests used. Furthermore, 41.18% of trials included imaging, with 33.82% of trials requiring magnetic resonance imaging findings. The most common exclusion criteria included were the presence of red flags and cervical myelopathy in 66.18% and 58.82% of trials, respectively. CONCLUSIONS: Overall, there is still a lack of uniformity for the inclusion/exclusion criteria of trials assessing the conservative management of CR, with some improvements noted compared with the 2012 review. Based on the current literature assessing the diagnostic utility of clinical symptoms and confirmatory tests, we proposed inclusion criteria for trials assessing conservative interventions. Future research should aim to develop standardized classification criteria to improve consistency among studies.

Conservative Management of Cervical Radiculopathy: A Systematic Review.

OBJECTIVE: The purpose of this systematic review was to assess the effectiveness and safety of conservative interventions compared with other interventions, placebo/sham interventions, or no intervention on disability, pain, function, quality of life, and psychological impact in adults with cervical radiculopathy (CR). METHODS: We searched MEDLINE, CENTRAL, CINAHL, Embase, and PsycINFO from inception to June 15, 2022 to identify studies that were randomized controlled trials, had at least one conservative treatment arm, and diagnosed participants with CR through confirmatory clinical examination and/or diagnostic tests. Studies were appraised using the Cochrane Risk of Bias 2 tool and the quality of the evidence was rated using the Grades of Recommendations, Assessment, Development, and Evaluation approach. RESULTS: Of the 2561 records identified, 59 trials met our inclusion criteria (n = 4108 participants). Due to clinical and statistical heterogeneity, the findings were synthesized narratively. There is very-low certainty evidence supporting the use of acupuncture, prednisolone, cervical manipulation, and low-level laser therapy for pain and disability in the immediate to short-term, and thoracic manipulation and low-level laser therapy for improvements in cervical range of motion in the immediate term. There is low to very-low certainty evidence for multimodal interventions, providing inconclusive evidence for pain, disability, and range of motion. There is inconclusive evidence for pain reduction after conservative management compared with surgery, rated as very-low certainty. DISCUSSION: There is a lack of high-quality evidence, limiting our ability to make any meaningful conclusions. As the number of people with CR is expected to increase, there is an urgent need for future research to help address these gaps.

Reporting quality of clinical trial protocols: a repeated cross-sectional study about the Adherence to SPIrit Recommendations in Switzerland, CAnada and GErmany (ASPIRE-SCAGE).

OBJECTIVES: Comprehensive protocols are key for the planning and conduct of randomised clinical trials (RCTs). Evidence of low reporting quality of RCT protocols led to the publication of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist in 2013. We aimed to examine the quality of reporting of RCT protocols from three countries before and after the publication of the SPIRIT checklist. DESIGN: Repeated cross sectional study. SETTING: Swiss, German and Canadian research ethics committees (RECs). PARTICIPANTS: RCT protocols approved by RECs in 2012 (n=257) and 2016 (n=292). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcomes were the proportion of reported SPIRIT items per protocol and the proportion of trial protocols reporting individual SPIRIT items. We compared these outcomes in protocols approved in 2012 and 2016, and built regression models to explore factors associated with adherence to SPIRIT. For each protocol, we also extracted information on general trial characteristics and assessed whether individual SPIRIT items were reported RESULTS: The median proportion of reported SPIRIT items among RCT protocols showed a non-significant increase from 72% (IQR, 63%-79%) in 2012 to 77% (IQR, 68%-82%) in 2016. However, in a preplanned subgroup analysis, we detected a significant improvement in investigator-sponsored protocols: the median proportion increased from 64% (IQR, 55%-72%) in 2012 to 76% (IQR, 64%-83%) in 2016, while for industry-sponsored protocols median adherence was 77% (IQR 72%-80%) for both years. The following trial characteristics were independently associated with lower adherence to SPIRIT: single-centre trial, no support from a clinical trials unit or contract research organisation, and investigator-sponsorship. CONCLUSIONS: In 2012, industry-sponsored RCT protocols were reported more comprehensively than investigator-sponsored protocols. After publication of the SPIRIT checklist, investigator-sponsored protocols improved to the level of industry-sponsored protocols, which did not improve.

Nonregistration, discontinuation, and nonpublication of randomized trials: A repeated metaresearch analysis.

BACKGROUND: We previously found that 25% of 1,017 randomized clinical trials (RCTs) approved between 2000 and 2003 were discontinued prematurely, and 44% remained unpublished at a median of 12 years follow-up. We aimed to assess a decade later (1) whether rates of completion and publication have increased; (2) the extent to which nonpublished RCTs can be identified in trial registries; and (3) the association between reporting quality of protocols and premature discontinuation or nonpublication of RCTs. METHODS AND FINDINGS: We included 326 RCT protocols approved in 2012 by research ethics committees in Switzerland, the United Kingdom, Germany, and Canada in this metaresearch study. Pilot, feasibility, and phase 1 studies were excluded. We extracted trial characteristics from each study protocol and systematically searched for corresponding trial registration (if not reported in the protocol) and full text publications until February 2022. For trial registrations, we searched the (i) World Health Organization: International Clinical Trial Registry Platform (ICTRP); (ii) US National Library of Medicine (ClinicalTrials.gov); (iii) European Union Drug Regulating Authorities Clinical Trials Database (EUCTR); (iv) ISRCTN registry; and (v) Google. For full text publications, we searched PubMed, Google Scholar, and Scopus. We recorded whether RCTs were registered, discontinued (including reason for discontinuation), and published. The reporting quality of RCT protocols was assessed with the 33-item SPIRIT checklist. We used multivariable logistic regression to examine the association between the independent variables protocol reporting quality, planned sample size, type of control (placebo versus other), reporting of any recruitment projection, single-center versus multicenter trials, and industry versus investigator sponsoring, with the 2 dependent variables: (1) publication of RCT results; and (2) trial discontinuation due to poor recruitment. Of the 326 included trials, 19 (6%) were unregistered. Ninety-eight trials (30%) were discontinued prematurely, most often due to poor recruitment (37%; 36/98). One in 5 trials (21%; 70/326) remained unpublished at 10 years follow-up, and 21% of unpublished trials (15/70) were unregistered. Twenty-three of 147 investigator-sponsored trials (16%) reported their results in a trial registry in contrast to 150 of 179 industry-sponsored trials (84%). The median proportion of reported SPIRIT items in included RCT protocols was 69% (interquartile range 61% to 77%). We found no variables associated with trial discontinuation; however, lower reporting quality of trial protocols was associated with nonpublication (odds ratio, 0.71 for each 10% increment in the proportion of SPIRIT items met; 95% confidence interval, 0.55 to 0.92; p = 0.009). Study limitations include that the moderate sample size may have limited the ability of our regression models to identify significant associations. CONCLUSIONS: We have observed that rates of premature trial discontinuation have not changed in the past decade. Nonpublication of RCTs has declined but remains common; 21% of unpublished trials could not be identified in registries. Only 16% of investigator-sponsored trials reported results in a trial registry. Higher reporting quality of RCT protocols was associated with publication of results. Further efforts from all stakeholders are needed to improve efficiency and transparency of clinical research.

Intra- and inter-rater reliability of an electronic health record audit used in a chiropractic teaching clinic system: an observational study.

BACKGROUND: There is a dearth of information about health education clinical file audits in the context of completeness of records and demonstrating program-wide competency achievement. We report on the reliability of an audit instrument used for electronic health record (EHR) audits in the clinics of a chiropractic college in Canada. METHODS: The instrument is a checklist built within an electronic software application designed to pull data automatically from the EHR. It consists of a combination of 61 objective (n = 20) and subjective (n = 41) elements, representing domains of standards of practice, accreditation and in-house educational standards. Trained auditors provide responses to the elements and the software yields scores indicating the quality of clinical record per file. A convenience sample of 24 files, drawn randomly from the roster of 22 clinicians, were divided into three groups of eight to be completed by one of three auditors in the span of 1 week, at the end of which they were transferred to another auditor. There were four audit cycles; audits from cycles 1 and 4 were used to assess intra-rater (test-retest) reliability and audits from cycles 1, 2 and 3 were used to assess inter-rater reliability. Percent agreement (PA) and Kappa statistics (K) were used as outcomes. Scatter plots and intraclass correlation (ICC) coefficients were used to assess standards of practice, accreditation, and overall audit scores. RESULTS: Across all 3 auditors test-retest reliability for objective items was PA 89% and K 0.75, and for subjective items PA 82% and K 0.63. In contrast, inter-rater reliability was moderate at PA 82% and K 0.59, and PA 70% and K 0.44 for objective and subjective items, respectively. Element analysis indicated a wide range of PA and K values inter-rater reliability of many elements being rated as poor. ICC coefficient calculations indicated moderate reliability for the domains of standards of practice, accreditation, and overall file scores. CONCLUSION: The file audit process has substantial test-retest reliability and moderate inter-rater reliability. Recommendations are made to improve reliability outcomes. These include modifying the audit checklist with a view of improving clarity of elements, and enhancing uniformity of auditor responses by increased training aided by preparation of an audit guidebook.

Reporting quality of trial protocols improved for non-regulated interventions but not regulated interventions: A repeated cross-sectional study.

OBJECTIVES: To investigate the adherence of randomised controlled trial (RCT) protocols evaluating non-regulated interventions (including dietary interventions, surgical procedures, behavioural and lifestyle interventions, and exercise programmes) in comparison with regulated interventions to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Statement. METHODS: We conducted a repeated cross-sectional investigation in a random sample of RCT protocols approved in 2012 (n = 257) or 2016 (n = 292) by research ethics committees in Switzerland, Germany, or Canada. We investigated the proportion of accurately reported SPIRIT checklist items in protocols of trials with non-regulated as compared to regulated interventions. RESULTS: Overall, 131 (24%) of trial protocols tested non-regulated interventions. In 2012, the median proportion of SPIRIT items reported in these protocols (59%, interquartile range [IQR], 53%-69%) was lower than in protocols with regulated interventions (median, 74%, IQR, 66%-80%). In 2016, the reporting quality of protocols with non-regulated interventions (median, 75%, IQR, 62%-83%) improved to the level of regulated intervention protocols, which had not changed on average. CONCLUSIONS: Reporting of RCT protocols evaluating non-regulated interventions improved between 2012 and 2016, although remained suboptimal. SPIRIT recommendations need to be further endorsed by researchers, ethics committees, funding agencies, and journals to optimize reporting of RCT protocols.

Assessment of Studies Evaluating Spinal Manipulative Therapy and Infectious Disease and Immune System Outcomes: A Systematic Review.

Importance: Claims that spinal manipulative therapy (SMT) can improve immune function have increased substantially during the COVID-19 pandemic and may have contributed to the rapid spread of both accurate and inaccurate information (referred to as an infodemic by the World Health Organization). Objective: To identify, appraise, and synthesize the scientific literature on the efficacy and effectiveness of SMT in preventing the development of infectious disease or improving disease-specific outcomes in patients with infectious disease and to examine the association between SMT and selected immunological, endocrine, and other physiological biomarkers. Evidence Review: A literature search of MEDLINE, the Cumulative Index to Nursing and Allied Health Literature, the Index to Chiropractic Literature, the Cochrane Central Register of Controlled Trials, and Embase was conducted from inception to April 15, 2020. Randomized clinical trials and cohort studies were included. Eligible studies were critically appraised, and evidence with high and acceptable quality was synthesized using the Synthesis Without Meta-Analysis guideline. Findings: A total of 2593 records were retrieved; after exclusions, 50 full-text articles were screened, and 16 articles reporting the findings of 13 studies comprising 795 participants were critically appraised. The literature search found no clinical studies that investigated the efficacy or effectiveness of SMT in preventing the development of infectious disease or improving disease-specific outcomes among patients with infectious disease. Eight articles reporting the results of 6 high- and acceptable-quality RCTs comprising 529 participants investigated the effect of SMT on biomarkers. Spinal manipulative therapy was not associated with changes in lymphocyte levels or physiological markers among patients with low back pain or participants who were asymptomatic compared with sham manipulation, a lecture series, and venipuncture control groups. Spinal manipulative therapy was associated with short-term changes in selected immunological biomarkers among asymptomatic participants compared with sham manipulation, a lecture series, and venipuncture control groups. Conclusions and Relevance: In this systematic review of 13 studies, no clinical evidence was found to support or refute claims that SMT was efficacious or effective in changing immune system outcomes. Although there were limited preliminary data from basic scientific studies suggesting that SMT may be associated with short-term changes in immunological and endocrine biomarkers, the clinical relevance of these findings is unknown. Given the lack of evidence that SMT is associated with the prevention of infectious diseases or improvements in immune function, further studies should be completed before claims of efficacy or effectiveness are made.

Rationale and design of repeated cross-sectional studies to evaluate the reporting quality of trial protocols: the Adherence to SPIrit REcommendations (ASPIRE) study and associated projects.

BACKGROUND: Clearly structured and comprehensive protocols are an essential component to ensure safety of participants, data validity, successful conduct, and credibility of results of randomized clinical trials (RCTs). Funding agencies, research ethics committees (RECs), regulatory agencies, medical journals, systematic reviewers, and other stakeholders rely on protocols to appraise the conduct and reporting of RCTs. In response to evidence of poor protocol quality, the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guideline was published in 2013 to improve the accuracy and completeness of clinical trial protocols. The impact of these recommendations on protocol completeness and associations between protocol completeness and successful RCT conduct and publication remain uncertain. OBJECTIVES AND METHODS: Aims of the Adherence to SPIrit REcommendations (ASPIRE) study are to investigate adherence to SPIRIT checklist items of RCT protocols approved by RECs in the UK, Switzerland, Germany, and Canada before (2012) and after (2016) the publication of the SPIRIT guidelines; determine protocol features associated with non-adherence to SPIRIT checklist items; and assess potential differences in adherence across countries. We assembled an international cohort of RCTs based on 450 protocols approved in 2012 and 402 protocols approved in 2016 by RECs in Switzerland, the UK, Germany, and Canada. We will extract data on RCT characteristics and adherence to SPIRIT for all included protocols. We will use multivariable regression models to investigate temporal changes in SPIRIT adherence, differences across countries, and associations between SPIRIT adherence of protocols with RCT registration, completion, and publication of results. We plan substudies to examine the registration, premature discontinuation, and non-publication of RCTs; the use of patient-reported outcomes in RCT protocols; SPIRIT adherence of RCT protocols with non-regulated interventions; the planning of RCT subgroup analyses; and the use of routinely collected data for RCTs. DISCUSSION: The ASPIRE study and associated substudies will provide important information on the impact of measures to improve the reporting of RCT protocols and on multiple aspects of RCT design, trial registration, premature discontinuation, and non-publication of RCTs observing potential changes over time.

Must antidepressants be avoided in patients with neuroendocrine tumors? Results of a systematic review.

OBJECTIVE: Symptoms of depression and anxiety are common in neuroendocrine tumor (NET), yet controversy exists over whether serotonin-mediated antidepressants (SAs) are safe in this population. We sought to address this knowledge gap. METHOD: Following PRISMA guidelines, we conducted a systematic review to identify NET patients who were prescribed SA. RESULTS: We identified 15 articles, reporting on 161 unique patients, 72 with carcinoid syndrome (CS) and 89 without. There was substantial agreement between reviewers at the full-text stage (κ = 0.69). Three of the articles, all with low risk of bias, accounted for most of the cases (149/161; 93%). Among the 72 NET patients with CS prior to antidepressant usage, CS was exacerbated in 6 cases (8%), only 3 (4%) of whom chose to discontinue the antidepressant. The remaining 89 patients had no prior CS symptoms, and none developed CS following antidepressant usage. Overall, no instances of carcinoid crisis or death were reported. CONCLUSIONS: We found no evidence for serious adverse outcomes related to SA usage in NET patients. Previous authors have recommended avoiding antidepressants in NET, but our findings do not support those recommendations. Oncologists should nonetheless monitor for symptom exacerbation when prescribing SA to patients with NET.

Clinical Outcomes in Neurogenic Claudication Using a Multimodal Program for Lumbar Spinal Stenosis: A Study of 49 Patients With Prospective Long-term Follow-up.

OBJECTIVE: The purpose of this study was to assess long-term outcomes of a 6-week multimodal program (manual therapy, exercises, and self-management strategies) in patients with neurogenic claudication due to degenerative lumbar spinal stenosis. METHODS: This study evaluated 49 patients with neurogenic claudication who completed a 6-week multimodal program between 2010 and 2013. Outcomes included Oswestry Disability Index (ODI), Zurich Claudication Questionnaire (ZCQ), and Numeric Rating Scale. Mean differences, paired t tests, and the Wilcoxon rank-sum test were used to compare outcomes at baseline, 6 weeks, and long-term follow-up. RESULTS: Twenty-three patients completed the follow-up questionnaire (47% response rate). Median follow-up was 3.6 years (interquartile range: 3.3-4.6). The mean age was 73.5 years (standard deviation: 8.5). Between baseline and long-term follow-up, there were statistically significant and clinically important improvements in disability (ODI: -23.7 [95% confidence interval (CI): -15.7 to -31.6]; ODI walking item: -1.96 [95% CI: -1.34 to -2.57]; ZCQ function scale: -0.42 [95% CI: -0.10 to -0.70]) and pain (leg pain: -3.53 [95% CI: -1.80 to -5.20]; ZCQ symptom scale: -0.71 [95% CI: -0.30 to -1.10]), but not low back pain (Numeric Rating Scale: -1.03 [95% CI: -1.00 to 3.10]). There was no statistically significant change in any outcomes between 6 weeks and long-term follow-up. CONCLUSION: In a sample of patients with neurogenic claudication participating in a 6-week multimodal program, clinically important improvements in leg pain and disability, but not low back pain while walking, were maintained in the long term (median duration of 3.6 years) when compared to baseline.

Evidence-based medicine and precision medicine: Complementary approaches to clinical decision-making.

Evidence-based medicine is widely promoted for decision-making in health care and is associated with improved patient outcomes. Critics have suggested that evidence-based medicine focuses primarily on groups of patients rather than individuals, but often fail to consider subgroup analyses, N-of-1 trials, and the incorporation of patient values and preferences. Precision medicine has been promoted as an approach to individualize diagnosis and treatment of diseases through genetic, biomarker, phenotypic, and psychosocial characteristics. However, there are often high costs associated with personalized medicine, and high-quality evidence is lacking for effectiveness in many applications. For the potential of personalized medicine to be realized, it must adhere to the principles of evidence-based medicine: (1) evidence in isolation is not sufficient to make clinical decisions-patient's values and preferences as well as resource implications must be considered, and (2) there is a hierarchy of evidence to guide clinical decision-making and studies at lower risk of bias are likely to provide more trustworthy findings.

Clinical outcomes for neurogenic claudication using a multimodal program for lumbar spinal stenosis: a retrospective study.

OBJECTIVE: The purpose of this preliminary study was to assess the effectiveness of a 6-week, nonsurgical, multimodal program that addresses the multifaceted aspects of neurogenic claudication. METHODS: In this retrospective study, 2 researchers independently extracted data from the medical records from January 2010 to April 2013 of consecutive eligible patients who had completed the 6-week Boot Camp Program. The program consisted of manual therapy twice per week (eg, soft tissue and neural mobilization, chiropractic spinal manipulation, lumbar flexion-distraction, and muscle stretching), structured home-based exercises, and instruction of self-management strategies. A paired t test was used to compare differences in outcomes from baseline to 6-week follow-up. Outcomes included self-reported pain, disability, walking ability, and treatment satisfaction. RESULTS: A total of 49 patients were enrolled, with a mean age of 70 years. The mean difference in the Oswestry Disability Index was 15.2 (95% confidence interval [CI], 11.39-18.92), and that for the functional and symptoms scales of the Swiss Spinal Stenosis Questionnaire was 0.41 (95% CI, 0.26-0.56) and 0.74 (95% CI, 0.55-0.93), respectively. Numeric pain scores for both leg and back showed statistically significant improvements. Improvements in all outcomes were clinically important. CONCLUSIONS: This study showed preliminary evidence for improved outcomes in patients with neurogenic claudication participating in a 6-week nonsurgical multimodal Boot Camp Program.

Houttuynia cordata inhibits lipopolysaccharide-induced rapid pulmonary fibrosis by up-regulating IFN-γ and inhibiting the TGF-ß1/Smad pathway.

This study aimed to explore the effect and mechanism of H. cordata vapor extract on acute lung injury (ALI) and rapid pulmonary fibrosis (RPF). We applied the volatile extract of HC to an RPF rat model and analyzed the effect on ALI and RPF using hematoxylin-eosin (H&E) staining, routine blood tests, a cell count of bronchoalveolar lavage fluid (BALF), lactate dehydrogenase (LDH) content, van Gieson (VG) staining, hydroxyproline (Hyp) content and the dry/wet weight ratio. The expression of IFN-γ/STAT(1), IL-4/STAT(6) and TGF-ß(1)/Smads was analyzed using ELISA, immunohistochemistry and western blotting methods. The active ingredients of the HC vapor extract were analyzed using a gas chromatograph-mass spectrometer (GC-MS), and the effects of the active ingredients of HC on the viability of NIH/3T3 and RAW264.7 cells were detected using an MTT assay. The active ingredients of the HC vapor extract included 4-terpineol, α-terpineol, l-bornyl acetate and methyl-n-nonyl ketone. The results of the lung H&E staining, Hyp content, dry/wet weight ratio and VG staining suggested that the HC vapor extract repaired lung injury and reduced RPF in a dose-dependent manner and up-regulated IFN-γ and inhibited the TGF-ß1/Smad pathway in vivo. In vitro, it could inhibit the viability of RAW264.7 and NIH/3T3 cells. It also dose-dependently inhibited the expression of TGF-ß1 and enhanced the expression of IFN-γ in NIH/3T3. The HC vapor extract inhibited LPS-induced RPF by up-regulating IFN-γ and inhibiting the TGF-ß1/Smad pathway.