Efficacy and safety of medicines targeting neurotrophic factors in the management of low back pain: Protocol for a systematic review and meta-analysis

Background: Low back pain (LBP) is the leading cause of years lived with disability worldwide. Most people with LBP receive the diagnosis of nonspecific LBP or sciatica. Medications are commonly prescribed but have limited analgesic effects and are associated with adverse events. A novel treatment approach is to target neurotrophins such as nerve growth factor (NGF) to reduce pain intensity. NGF inhibitors have been tested in some randomized controlled trials (RCTs) in recent years, showing promise for the treatment of chronic LBP; however, their efficacy and safety need to be evaluated to guide regulatory actions. Objective: The aim of this study is to evaluate the efficacy and safety of medicines targeting neurotrophins in patients with LBP and sciatica. Methods: In this systematic review, we will include published and unpublished records of parallel RCTs and the first phase of crossover RCTs that compare the effects of medicines targeting neurotrophins with any control group. We will search the CENTRAL, MEDLINE, Embase, CINAHL, ClinicalTrials.gov, EU Clinical Trials Register, and WHO International Clinical Registry Platform databases from inception. Pairs of authors will independently screen the records for eligibility, and we will independently extract data in duplicate. We will conduct a quantitative synthesis (meta-analysis) with the studies that report sufficient data and compare the medicines of interest versus placebo. We will use random-effects models and calculate estimates of effects and heterogeneity for each outcome. We will assess the risk of bias for each study using the Cochrane Collaboration tool, and form judgments of confidence in the evidence according to GRADE recommendations. We will use the PRISMA statement to report the findings. We plan to conduct subgroup analyses by condition, type of medication, and time point. We will also assess the impact of a potential new trial on an existing meta-analysis. Data from studies that meet inclusion criteria but cannot be included in the meta-analysis will be reported narratively. Results: The protocol was registered on the Open Science Framework on May 19, 2020. As of December 2020, we have identified 1932 records. Conclusions: This systematic review and meta-analysis will assess the evidence for the efficacy and safety of NGF inhibitors for pain in patients with nonspecific LBP and sciatica. The inclusion of new studies and unpublished data may improve the precision of the effect estimates and guide regulatory actions of the medications for LBP and sciatica

Targeting neurotrophic factors for low back pain and sciatica: A systematic review and meta-analysis

Objectives: This meta-analysis aims to investigate the efficacy and safety of medicines that target neurotrophic factors for low back pain (LBP) or sciatica. Methods: We searched published and trial registry reports of randomized controlled trials evaluating the effect of medicines that target neurotrophic factors to LBP or sciatica in seven databases from inception to December 2020. Two reviewers independently identified studies, extracted data, and assessed the risk of bias and certainty in the evidence. Results: Nine studies (3370 participants) were included in the meta-analyses. Low certainty evidence showed that anti-nerve growth factor (NGF) may reduce pain at 4 weeks (mean difference [MD] -6.75, 95% CI: -8.61, -4.90) and 12 weeks (MD -6.16, 95% CI: -8.38, -3.94), and may increase adverse effects for chronic LBP (odds ratio [OR] 1.18, 95% CI: 1.01, 1.38). Higher doses of anti-NGF may offer a clinically important reduction in pain at the cost of increased adverse effects for chronic LBP. Very low certainty evidence showed that anti-NGF and glial cell line-derived neurotrophic factor (pro-GDNF) may not reduce pain for sciatica at 4 weeks (MD -1.40, 95% CI: -8.26, 5.46), at 12 weeks (MD -2.91, 95% CI: -13.69, 7.67) and may increase adverse effects for sciatica (OR 3.27, 95% CI: 1.78, 6.00). Conclusion: Anti-NGF may offer small reductions in pain intensity for chronic LBP. The effect may depend on the dose and types of medicines. For sciatica, anti-NGF or pro-GDNF may not reduce pain. Medicines that target neurotrophic factors for LBP or sciatica are associated with different adverse effects compared to those observed in commonly prescribed medicines for these conditions

“My Back is Fit for Movement”: A Qualitative Study Alongside a Randomized Controlled Trial for Chronic Low Back Pain

A new wave of treatments has emerged to target nervous system alterations and maladaptive conceptualizations about pain for chronic low back pain. The acceptability of these treatments is still uncertain. We conducted a qualitative study alongside a randomized controlled trial to identify perceptions of facilitators or barriers to participation in a non-pharmacological intervention that resulted in clinically meaningful reductions across 12 months for disability compared to a sham intervention. We conducted semi-structured interviews with participants from the trial's active arm after they completed the 12-week program. We included a purposeful sample (baseline and clinical characteristics) (n = 20). We used reflexive thematic analysis informed by the Theoretical Framework of Acceptability for health care interventions. We identified positive and negative emotional/cognitive responses associated with treatment acceptability and potential efficacy, including emotional support, cognitive empowerment, readiness for self-management, and acceptance of face-to-face and online components designed to target the brain. These findings suggest the importance of psychoeducation and behavior change techniques to create a positive attitude towards movement and increase the perception of pain control; systematic approaches to monitor and target misconceptions about the interventions during treatment; and psychoeducation and behavior change techniques to maintain the improvements after the cessation of formal care. Perspective: This article presents the experiences of people with chronic low back pain participating in a new non-pharmacological brain-targeted treatment that includes face-to-face and self-directed approaches. The facilitators and barriers of the interventions could potentially inform adaptations and optimization of treatments designed to target the brain to treat chronic low back pain

Development and measurement properties of the AxEL (attitude toward education and advice for low-back-pain) questionnaire

Introduction: Clinician time and resources may be underutilised if the treatment they offer does not match patient expectations and attitudes. We developed a questionnaire (AxEL-Q) to guide clinicians toward elements of first-line care that are pertinent to their patients with low back pain. Methods: We used guidance from the COSMIN consortium to develop the questionnaire and evaluated it in a sample of people with low back pain of any duration. Participants were recruited from the community, were over 18 years and fluent in English. Statements that represented first-line care were identified. Semantic scales were used to measure attitude towards these statements. These items were combined to develop the questionnaire draft. Construct validity was evaluated with exploratory factor analysis and hypotheses testing, comparing to the Back Beliefs Questionnaire and modified Pain Self-Efficacy Questionnaire. Reliability was evaluated and floor and ceiling effects calculated. Results: We recruited 345 participants, and had complete data for analysis for 313 participants. The questionnaire draft was reduced to a 3-Factor questionnaire through exploratory factor analysis. Factor 1 comprised 9 items and evaluated Attitude toward staying active, Factor 2 comprised 4 items and evaluated Attitude toward low back pain being rarely caused by a serious health problem, Factor 3 comprised 4 items and evaluated Attitude toward not needing to know the cause of back pain to manage it effectively. There was a strong inverse association between each factor and the Back Beliefs Questionnaire and a moderate positive association with the modified Pain Self-Efficacy Questionnaire. Each independent factor demonstrated acceptable internal consistency; Cronbach α Factor 1 = 0.92, Factor 2 = 0.91, Factor 3 = 0.90 and adequate interclass correlation coefficients; Factor 1 = 0.71, Factor 2 = 0.73, Factor 3 = 0.79. Conclusion: This study demonstrates acceptable construct validity and reliability of the AxEL-Q, providing clinicians with an insight into the likelihood of patients following first-line care at the outset

Probabilistic machine learning and artificial intelligence.

How can a machine learn from experience? Probabilistic modelling provides a framework for understanding what learning is, and has therefore emerged as one of the principal theoretical and practical approaches for designing machines that learn from data acquired through experience. The probabilistic framework, which describes how to represent and manipulate uncertainty about models and predictions, has a central role in scientific data analysis, machine learning, robotics, cognitive science and artificial intelligence. This Review provides an introduction to this framework, and discusses some of the state-of-the-art advances in the field, namely, probabilistic programming, Bayesian optimization, data compression and automatic model discovery.The author acknowledges an EPSRC grant EP/I036575/1, the DARPA PPAML programme, a Google Focused Research Award for the Automatic Statistician and support from Microsoft Research.This is the author accepted manuscript. The final version is available from NPG at http://www.nature.com/nature/journal/v521/n7553/full/nature14541.html#abstract

Significance testing as perverse probabilistic reasoning

Truth claims in the medical literature rely heavily on statistical significance testing. Unfortunately, most physicians misunderstand the underlying probabilistic logic of significance tests and consequently often misinterpret their results. This near-universal misunderstanding is highlighted by means of a simple quiz which we administered to 246 physicians at two major academic hospitals, on which the proportion of incorrect responses exceeded 90%. A solid understanding of the fundamental concepts of probability theory is becoming essential to the rational interpretation of medical information. This essay provides a technically sound review of these concepts that is accessible to a medical audience. We also briefly review the debate in the cognitive sciences regarding physicians' aptitude for probabilistic inference

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

Inflammatory biomarkers in Alzheimer's disease plasma

Introduction: Plasma biomarkers for Alzheimer's disease (AD)diagnosis/stratification are a “Holy Grail” of AD research and intensively sought; however, there are no well-established plasma markers. Methods: A hypothesis-led plasma biomarker search was conducted in the context of international multicenter studies. The discovery phase measured 53 inflammatory proteins in elderly control (CTL; 259), mild cognitive impairment (MCI; 199), and AD (262)subjects from AddNeuroMed. Results: Ten analytes showed significant intergroup differences. Logistic regression identified five (FB, FH, sCR1, MCP-1, eotaxin-1)that, age/APOε4 adjusted, optimally differentiated AD and CTL (AUC: 0.79), and three (sCR1, MCP-1, eotaxin-1)that optimally differentiated AD and MCI (AUC: 0.74). These models replicated in an independent cohort (EMIF; AUC 0.81 and 0.67). Two analytes (FB, FH)plus age predicted MCI progression to AD (AUC: 0.71). Discussion: Plasma markers of inflammation and complement dysregulation support diagnosis and outcome prediction in AD and MCI. Further replication is needed before clinical translation

Evaluation of appendicitis risk prediction models in adults with suspected appendicitis

Background Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis. Methods A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis). Results Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent). Conclusion Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified

Reassurance for patients with non-specific conditions – a user's guide

© 2017 Associação Brasileira de Pesquisa e Pós-Graduação em Fisioterapia Introduction Reassurance is the removal of fears and concerns about illness. In practice reassurance for non-specific conditions, where a diagnosis is unclear or unavailable, is difficult and can have unexpected effects. Many clinical guidelines for non-specific conditions such as low back pain recommend reassurance. Until recently, there was little evidence on how to reassure patients effectively. Results High distress causes patients to consult more often for low back pain. To reduce distress, clinicians should provide structured education, which is effective in the short- and long-term. A newly developed online prognostic tool has the potential to improve the quality of reassurance and reduce the number of inappropriate interventions provided for low back pain. Conclusion Targeted reassurance, including enhanced, prognosis-specific education, could optimize reassurance and possibly prevent disabling symptoms