Brain and spinal stimulation therapies for phantom limb pain: a systematic review.

BACKGROUND: Although many treatments exist for phantom limb pain (PLP), the evidence supporting them is limited and there are no guidelines for PLP management. Brain and spinal cord neurostimulation therapies are targeted at patients with chronic PLP but have yet to be systematically reviewed. OBJECTIVE: To determine which types of brain and spinal stimulation therapy appear to be the best for treating chronic PLP. DESIGN: Systematic reviews of effectiveness and epidemiology studies, and a survey of NHS practice. POPULATION: All patients with PLP. INTERVENTIONS: Invasive interventions - deep brain stimulation (DBS), motor cortex stimulation (MCS), spinal cord stimulation (SCS) and dorsal root ganglion (DRG) stimulation. Non-invasive interventions - repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). MAIN OUTCOME MEASURES: Phantom limb pain and quality of life. DATA SOURCES: Twelve databases (including MEDLINE and EMBASE) and clinical trial registries were searched in May 2017, with no date limits applied. REVIEW METHODS: Two reviewers screened titles and abstracts and full texts. Data extraction and quality assessments were undertaken by one reviewer and checked by another. A questionnaire was distributed to clinicians via established e-mail lists of two relevant clinical societies. All results were presented narratively with accompanying tables. RESULTS: Seven randomised controlled trials (RCTs), 30 non-comparative group studies, 18 case reports and 21 epidemiology studies were included. Results from a good-quality RCT suggested short-term benefits of rTMS in reducing PLP, but not in reducing anxiety or depression. Small randomised trials of tDCS suggested the possibility of modest, short-term reductions in PLP. No RCTs of invasive therapies were identified. Results from small, non-comparative group studies suggested that, although many patients benefited from short-term pain reduction, far fewer maintained their benefits. Most studies had important methodological or reporting limitations and few studies reported quality-of-life data. The evidence on prognostic factors for the development of chronic PLP from the longitudinal studies also had important limitations. The results from these studies suggested that pre-amputation pain and early PLP intensity are good predictors of chronic PLP. Results from the cross-sectional studies suggested that the proportion of patients with severe chronic PLP is between around 30% and 40% of the chronic PLP population, and that around one-quarter of chronic PLP patients find their PLP to be either moderately or severely limiting or bothersome. There were 37 responses to the questionnaire distributed to clinicians. SCS and DRG stimulation are frequently used in the NHS but the prevalence of use of DBS and MCS was low. Most responders considered SCS and DRG stimulation to be at least sometimes effective. Neurosurgeons had mixed views on DBS, but most considered MCS to rarely be effective. Most clinicians thought that a randomised trial design could be successfully used to study neurostimulation therapies. LIMITATION: There was a lack of robust research studies. CONCLUSIONS: Currently available studies of the efficacy, effectiveness and safety of neurostimulation treatments do not provide robust, reliable results. Therefore, it is uncertain which treatments are best for chronic PLP. FUTURE WORK: Randomised crossover trials, randomised N-of-1 trials and prospective registry trials are viable study designs for future research. STUDY REGISTRATION: The study is registered as PROSPERO CRD42017065387. FUNDING: The National Institute for Health Research Health Technology Assessment programme

The type and impact of Evidence Review Group (ERG) exploratory analyses in the NICE Single Technology Appraisal (STA) process

Background: As part of the UK National Institute for Health and Care Excellence (NICE) single technology appraisal process, independent evidence review groups (ERGs) critically appraise a company's submission relating to a specific technology and indication. Objectives: To explore the type of additional exploratory analyses conducted by ERGs and their impact on the recommendations made by NICE. Methods: The 100 most recently completed single technology appraisals with published guidance were selected for inclusion. A content analysis of relevant documents was undertaken to identify and extract relevant data, and narrative synthesis was used to rationalize and present these data. Results: The types of exploratory analysis conducted in relation to companies' models were fixing errors, addressing violations, addressing matters of judgment, and the provision of a new, ERG-preferred base case. Ninety-three of the 100 ERG reports contained at least one of these analyses. The most frequently reported type of analysis in these 93 ERG reports related to the category Matters of judgment, which was reported in 83 reports (89%). At least one of the exploratory analyses conducted and reported by an ERG is mentioned in 97% of NICE appraisal consultation documents and 94% of NICE final appraisal determinations, and had a clear influence on recommendations in 72% of appraisal consultation documents and 47% of final appraisal determinations. Conclusions: These results suggest that the additional analyses undertaken by ERGs in the appraisal of company submissions are highly influential in the policy-making and decision-making process

Assessing harmful effects in systematic reviews.

BACKGROUND: Balanced decisions about health care interventions require reliable evidence on harms as well as benefits. Most systematic reviews focus on efficacy and randomised trials, for which the methodology is well established. Methods to systematically review harmful effects are less well developed and there are few sources of guidance for researchers. We present our own recent experience of conducting systematic reviews of harmful effects and make suggestions for future practice and further research. METHODS: We described and compared the methods used in three systematic reviews. Our evaluation focused on the review question, study designs and quality assessment. RESULTS: One review question focused on providing information on specific harmful effects to furnish an economic model, the other two addressed much broader questions. All three reviews included randomised and observational data, although each defined the inclusion criteria differently. Standard methods were used to assess study quality. Various practical problems were encountered in applying the study design inclusion criteria and assessing quality, mainly because of poor study design, inadequate reporting and the limitations of existing tools. All three reviews generated a large volume of work that did not yield much useful information for health care decision makers. The key areas for improvement we identified were focusing the review question and developing methods for quality assessment of studies of harmful effects. CONCLUSIONS: Systematic reviews of harmful effects are more likely to yield information pertinent to clinical decision-making if they address a focused question. This will enable clear decisions to be made about the type of research to include in the review. The methodology for assessing the quality of harmful effects data in systematic reviews requires further development

Protocol for the Smoking, Nicotine and Pregnancy (SNAP) trial: double-blind, placebo-randomised, controlled trial of nicotine replacement therapy in pregnancy

Background: Smoking in pregnancy remains a public health challenge. Nicotine replacement therapy (NRT) is effective for smoking cessation in non-pregnant people, but because women metabolise nicotine and cotinine much faster in pregnancy, it is unclear whether this will be effective for smoking cessation in pregnancy. The NHS Health Technology Assessment Programme (HTA)-funded smoking, nicotine and pregnancy ( SNAP) trial will investigate whether or not nicotine replacement therapy ( NRT) is effective, cost-effective and safe when used for smoking cessation by pregnant women. Methods/Design: Over two years, in 5 trial centres, 1050 pregnant women who are between 12 and 24 weeks pregnant will be randomised as they attend hospital for ante-natal ultrasound scans. Women will receive either nicotine or placebo transdermal patches with behavioural support. The primary outcome measure is biochemically-validated, self-reported, prolonged and total abstinence from smoking between a quit date ( defined before randomisation and set within two weeks of this) and delivery. At six months after childbirth self-reported maternal smoking status will be ascertained and two years after childbirth, self-reported maternal smoking status and the behaviour, cognitive development and respiratory symptoms of children born in the trial will be compared in both groups. Discussion: This trial is designed to ascertain whether or not standard doses of NRT ( as transdermal patches) are effective and safe when used for smoking cessation during pregnancy

Nicotine patch preloading for smoking cessation (the preloading trial): study protocol for a randomized controlled trial

Background: The use of nicotine replacement therapy before quitting smoking is called nicotine preloading. Standard smoking cessation protocols suggest commencing nicotine replacement therapy only on the first day of quitting smoking (quit day) aiming to reduce withdrawal symptoms and craving. However, other, more successful smoking cessation pharmacotherapies are used prior to the quit day as well as after. Nicotine preloading could improve quit rates by reducing satisfaction from smoking prior to quitting and breaking the association between smoking and reward. A systematic literature review suggests that evidence for the effectiveness of preloading is inconclusive and further trials are needed. Methods/Design: This is a study protocol for a multicenter, non-blinded, randomized controlled trial based in the United Kingdom, enrolling 1786 smokers who want to quit, funded by the National Institute for Health Research, Health Technology Assessment program, and sponsored by the University of Oxford. Participants will primarily be recruited through general practices and smoking cessation clinics, and randomized (1:1) either to use 21 mg nicotine patches, or not, for four weeks before quitting, whilst smoking as normal. All participants will be referred to receive standard smoking cessation service support. Follow-ups will take place at one week, four weeks, six months and 12 months after quit day. The primary outcome will be prolonged, biochemically verified six-month abstinence. Additional outcomes will include point prevalence abstinence and abstinence of four-week and 12-month duration, side effects, costs of treatment, and markers of potential mediators and moderators of the preloading effect. Discussion: This large trial will add substantially to evidence on the effectiveness of nicotine preloading, but also on its cost effectiveness and potential mediators, which have not been investigated in detail previously. A range of recruitment strategies have been considered to try and compensate for any challenges encountered in recruiting the large sample, and the multicentre design means that knowledge can be shared between recruitment teams. The pragmatic study design means that results will give a realistic estimate of the success of the intervention if it were to be rolled out as part of standard smoking cessation service practice. Trial registration: Current Controlled Trials ISRCTN33031001. Registered 27 April 2012

Effects of Aging on the Biomechanics of Slips and Falls

Although much has been learned in recent decades about the deterioration of muscular strength, gait adaptations, and sensory degradation among older adults, little is known about how these intrinsic changes affect biomechanical parameters associated with slip-induced fall accidents. In general, the objective of this laboratory study was to investigate the process of initiation, detection, and recovery of inadvertent slips and falls. We examined the initiation of and recovery from foot slips among three age groups utilizing biomechanical parameters, muscle strength, and sensory measurements. Forty-two young, middle-age, and older participants walked around a walking track at a comfortable pace. Slippery floor surfaces were placed on the track over force platforms at random intervals without the participants’ awareness. Results indicated that younger participants slipped as often as the older participants, suggesting that the likelihood of slip initiation is similar across all age groups; however, older individuals’ recovery process was much slower and less effective. The ability to successfully recover from a slip (thus preventing a fall) is believed to be affected by lower extremity muscle strength and sensory degradation among older individuals. Results from this research can help pinpoint possible intervention strategies for improving dynamic equilibrium among older adults

Promoting smoking cessation in Pakistani and Bangladeshi men in the UK: pilot cluster randomised controlled trial of trained community outreach workers

<p>Abstract</p> <p>Background</p> <p>Smoking prevalence is high among Pakistani and Bangladeshi men in the UK, but there are few tailored smoking cessation programmes for Pakistani and Bangladeshi communities. The aim of this study was to pilot a cluster randomised controlled trial comparing the effectiveness of Pakistani and Bangladeshi smoking cessation outreach workers with standard care to improve access to and the success of English smoking cessation services.</p> <p>Methods</p> <p>A pilot cluster randomised controlled trial was conducted in Birmingham, UK. Geographical lower layer super output areas were used to identify natural communities where more than 10% of the population were of Pakistani and Bangladeshi origin. 16 agglomerations of super output areas were randomised to normal care controls vs. outreach intervention. The number of people setting quit dates using NHS services, validated abstinence from smoking at four weeks, and stated abstinence at three and six months were assessed. The impact of the intervention on choice and adherence to treatments, attendance at clinic appointments and patient satisfaction were also assessed.</p> <p>Results</p> <p>We were able to randomise geographical areas and deliver the outreach worker-based services. More Pakistani and Bangladeshi men made quit attempts with NHS services in intervention areas compared with control areas, rate ratio (RR) 1.32 (95%CI: 1.03-1.69). There was a small increase in the number of 4-week abstinent smokers in intervention areas (RR 1.30, 95%CI: 0.82-2.06). The proportion of service users attending weekly appointments was lower in intervention areas than control areas. No difference was found between intervention and control areas in choice and adherence to treatments or patient satisfaction with the service. The total cost of the intervention was £124,000; an estimated cost per quality-adjusted life year (QALY) gained of £8,500.</p> <p>Conclusions</p> <p>The intervention proved feasible and acceptable. Outreach workers expanded reach of smoking cessation services in diverse locations of relevance to Pakistani and Bangladeshi communities. The outreach worker model has the potential to increase community cessation rates and could prove cost-effective, but needs evaluating definitively in a larger, appropriately powered, randomised controlled trial. These future trials of outreach interventions need to be of sufficient duration to allow embedding of new models of service delivery.</p> <p>Trial registration</p> <p>Current Controlled Trials <a href="http://www.controlled-trials.com/ISRCTN82127540">ISRCTN82127540</a></p

Vitamin D and oestrogen receptor polymorphisms in developmental dysplasia of the hip and primary protrusio acetabuli – A preliminary study

We investigated the association of developmental dysplasia of the hip (DDH) and primary protrusion acetabuli (PPA) with Vitamin D receptor polymorphisms Taq I and Fok I and oestrogen receptor polymorphisms Pvu II and Xba I. 45 patients with DDH and 20 patients with PPA were included in the study. Healthy controls (n = 101) aged 18–60 years were recruited from the same geographical area. The control subjects had a normal acetabular morphology based on a recent pelvic radiograph performed for an unrelated cause. DNA was obtained from all the subjects from peripheral blood. Genotype frequencies were compared in the three groups. The relationship between the genotype and morphology of the hip joint, severity of the disease, age at onset of disease and gender were examined. The oestrogen receptor Xba I wild-type genotype (XX, compared with Xx and xx combined) was more common in the DDH group (55.8%) than controls (37.9%), though this just failed to achieve statistical significance (p = 0.053, odds ratio = 2.1, 95% CI = 0.9–4.6). In the DDH group, homozygosity for the mutant Taq I Vitamin D receptor t allele was associated with higher acetabular index (Mann-Whitney U-test, p = 0.03). Pvu II pp oestrogen receptor genotype was associated with low centre edge angle (p = 0.07). This study suggests a possible correlation between gene polymorphism in the oestrogen and vitamin D receptors and susceptibility to, and severity of DDH. The Taq I vitamin D receptor polymorphisms may be associated with abnormal acetabular morphology leading to DDH while the Xba I oestrogen receptor XX genotype may be associated with increased risk of developing DDH. No such correlations were found in the group with PPA

Randomized controlled trial of mailed Nicotine Replacement Therapy to Canadian smokers: study protocol

<p>Abstract</p> <p>Background</p> <p>Considerable public health efforts are ongoing Canada-wide to reduce the prevalence of smoking in the general population. From 1985 to 2005, smoking rates among adults decreased from 35% to 19%, however, since that time, the prevalence has plateaued at around 18-19%. To continue to reduce the number of smokers at the population level, one option has been to translate interventions that have demonstrated clinical efficacy into population level initiatives. Nicotine Replacement Therapy (NRT) has a considerable clinical research base demonstrating its efficacy and safety and thus public health initiatives in Canada and other countries are distributing NRT widely through the mail. However, one important question remains unanswered - do smoking cessation programs that involve mailed distribution of free NRT work? To answer this question, a randomized controlled trial is required.</p> <p>Methods/Design</p> <p>A single blinded, panel survey design with random assignment to an experimental and a control condition will be used in this study. A two-stage recruitment process will be employed, in the context of a general population survey with two follow-ups (8 weeks and 6 months). Random digit dialing of Canadian home telephone numbers will identify households with adult smokers (aged 18+ years) who are willing to take part in a smoking study that involves three interviews, with saliva collection for 3-HC/cotinine ratio measurement at baseline and saliva cotinine verification at 8-week and 6-month follow-ups (N = 3,000). Eligible subjects interested in free NRT will be determined at baseline (N = 1,000) and subsequently randomized into experimental and control conditions to receive versus not receive nicotine patches. The primary hypothesis is that subjects who receive nicotine patches will display significantly higher quit rates (as assessed by 30 day point prevalence of abstinence from tobacco) at 6-month follow-up as compared to subjects who do not receive nicotine patches at baseline.</p> <p>Discussion</p> <p>The findings from the proposed trial are timely and highly relevant as mailed distribution of NRT require considerable resources and there are limited public health dollars available to combat this substantial health concern. In addition, findings from this randomized controlled trial will inform the development of models to engage smokers to quit, incorporating proactive recruitment and the offer of evidence based treatment.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01429129">NCT01429129</a></p

Dual-task costs while walking increase in old age for some, but not for other tasks: an experimental study of healthy young and elderly persons

<p>Abstract</p> <p>Background</p> <p>It has been suggested in the past that the ability to walk while concurrently engaging in a second task deteriorates in old age, and that this deficit is related to the high incidence of falls in the elderly. However, previous studies provided inconsistent findings about the existence of such an age-related dual-task deficit (ARD). In an effort to explain this inconsistency, we explored whether ARD while walking emerges for some, but not for other types of task.</p> <p>Methods</p> <p>Healthy young and elderly subjects were tested under five different combinations of a walking and a non-walking task. The results were analysed jointly with those of a previous study from our lab, such that a total of 13 task combinations were evaluated. For each task combination and subject, we calculated the mean dual-task costs across both constituent tasks, and quantified ARD as the difference between those costs in elderly and in young subjects.</p> <p>Results</p> <p>An analysis of covariance yielded no significant effects of obstacle presence and overall task difficulty on ARD, but a highly significant effect of visual demand: non-walking tasks which required ongoing visual observation led to ARD of more than 8%, while those without such requirements led to near-zero ARD. We therefore concluded that the visual demand of the non-walking task is critical for the emergence of ARD while walking.</p> <p>Conclusion</p> <p>Combinations of walking and concurrent visual observation, which are common in everyday life, may contribute towards disturbed gait and falls during daily activities in old age. Prevention and rehabilitation programs for seniors should therefore include training of such combinations.</p