Methylphenidate Versus Placebo for Treating Fatigue in Patients With Advanced Cancer: Randomized, Double-Blind, Multicenter, Placebo-Controlled Trial.

PURPOSE: To compare effects and side effects of 6 weeks of individually dose-titrated methylphenidate or placebo on fatigue in palliative care patients with advanced cancer. METHODS: This is a randomized, double-blind, placebo-controlled, multicenter trial. Eligible patients had advanced incurable cancer and fatigue >3/10. Principal exclusions were hypertension; psychiatric, cardiovascular, cerebrovascular, renal, liver, or blood disorders; substance dependency; and epilepsy. Patients were randomly assigned 1:1 methylphenidate or placebo starting at 5 mg twice daily. Dose of methylphenidate/placebo was titrated once per week, over 6 weeks, up to a maximum of 20 mg three times daily. Trial ended at 10 weeks. Primary outcome was the difference in Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) scores between groups at 6 ± 2 weeks. Secondary outcomes included adverse effects, quality of life, and mood. RESULTS: One hundred sixty-two patients (73 men; mean, 65.8; standard deviation [SD], 10.3 years) were randomly assigned, and three were excluded from analysis. Seventy-seven were allocated placebo (baseline FACIT-F = 22 [SD, 10]); 82 were allocated methylphenidate (FACIT-F = 20 [SD, 9]). After 6 ± 2 weeks, FACIT-F scores were 1.97 points (95% CI, -0.95 to 4.90; P = .186) higher (better) on methylphenidate than placebo. Across 10 weeks of the study, FACIT-F was nominally higher in the methylphenidate group versus placebo (Diff, 2.20 [95% CI, 0.39 to 4.01]), but this did not reach the minimally clinically important difference (5-points). At 6 weeks, there were no differences between groups in quality-of-life or symptom domains except for depression scores (nominally reduced in the methylphenidate group: Diff, -1.35 [95% CI, -2.41 to -0.30]). There were no differences in mortality or serious adverse events. CONCLUSION: After 6 ± 2 weeks of treatment, methylphenidate was not superior to placebo for treating fatigue in advanced cancer. Methylphenidate was safe and well-tolerated.

The Effects of Estrogen on the Risk of Developing Dementia: A Cohort Study Using the UK Biobank Data.

OBJECTIVES: The protective role of estrogen in the development of dementia remains uncertain. We investigated the role of lifetime cumulative exposure to estrogen in dementia in the UK Biobank. METHODS: Reproductive characteristics, including estrogen length and history of surgery (hysterectomy/oophorectomy), were used as exposure variables. Cox Proportional Hazard models were used to estimate hazard ratios (HR) for the development of dementia. RESULTS: A total of 273,260 female participants were included in this study. Compared to women with the shortest estrogen length, women with the longer estrogen length (38-42) had a 28% decreased risk of dementia (HR = 0.718, 95% confidence interval [CI] = 0.651-0.793). Women with later last age at estrogen exposure (50-52) had a 24% decreased risk for dementia (HR = 0.763, 95% CI = 0.695-0.839) compared to women with younger age at last estrogen exposure (≤45). Later age at menarche (≥15) was associated with a 12% increased risk for dementia (HR = 1.121, 95% CI = 1.018-1.234) compared to women with earlier age at menarche (≤12). Women with a history of surgery had an 8% increased risk of dementia (HR = 1.079, 95% CI = 1.002-1.164) compared to women without a history of surgery. CONCLUSION: This study found that more prolonged exposure to estrogen (longer estrogen length and later age at last estrogen exposure) had a decreased risk for dementia, and shorter exposure to estrogen (later age at menarche and history of reproductive surgery) had an increased risk for dementia. Based on the results of this study, estrogen might have a protective role in women in the development of dementia.

Classic ketogenic diet versus further antiseizure medicine in infants with drug-resistant epilepsy (KIWE): a UK, multicentre, open-label, randomised clinical trial.

BACKGROUND: Many infancy-onset epilepsies have poor prognosis for seizure control and neurodevelopmental outcome. Ketogenic diets can improve seizures in children older than 2 years and adults who are unresponsive to antiseizure medicines. We aimed to establish the efficacy of a classic ketogenic diet at reducing seizure frequency compared with further antiseizure medicine in infants with drug-resistant epilepsy. METHODS: In this phase 4, open-label, multicentre, randomised clinical trial, infants aged 1-24 months with drug-resistant epilepsy (defined as four or more seizures per week and two or more previous antiseizure medications) were recruited from 19 hospitals in the UK. Following a 1-week or 2-week observation period, participants were randomly assigned using a computer-generated schedule, without stratification, to either a classic ketogenic diet or a further antiseizure medication for 8 weeks. Treatment allocation was masked from research nurses involved in patient care, but not from participants. The primary outcome was the median number of seizures per day, recorded during weeks 6-8. All analyses were by modified intention to treat, which included all participants with available data. Participants were followed for up to 12 months. All serious adverse events were recorded. The trial is registered with the European Union Drug Regulating Authorities Clinical Trials Database (2013-002195-40). The trial was terminated early before all participants had reached 12 months of follow-up because of slow recruitment and end of funding. FINDINGS: Between Jan 1, 2015, and Sept 30, 2021, 155 infants were assessed for eligibility, of whom 136 met inclusion criteria and were randomly assigned; 75 (55%) were male and 61 (45%) were female. 78 infants were assigned to a ketogenic diet and 58 to antiseizure medication, of whom 61 and 47, respectively, had available data and were included in the modifified intention-to-treat analysis at week 8. The median number of seizures per day during weeks 6-8, accounting for baseline rate and randomised group, was similar between the ketogenic diet group (5 [IQR 1-16]) and antiseizure medication group (3 [IQR 2-11]; IRR 1·33, 95% CI 0·84-2·11). A similar number of infants with at least one serious adverse event was reported in both groups (40 [51%] of 78 participants in the ketogenic diet group and 26 [45%] of 58 participants in the antiseizure medication group). The most common serious adverse events were seizures in both groups. Three infants died during the trial, all of whom were randomly assigned a ketogenic diet: one child (who also had dystonic cerebral palsy) was found not breathing at home; one child died suddenly and unexpectedly at home; and one child went into cardiac arrest during routine surgery under anaesthetic. The deaths were judged unrelated to treatment by local principal investigators and confirmed by the data safety monitoring committee. INTERPRETATION: In this phase 4 trial, a ketogenic diet did not differ in efficacy and tolerability to a further antiseizure medication, and it appears to be safe to use in infants with drug-resistant epilepsy. A ketogenic diet could be a treatment option in infants whose seizures continue despite previously trying two antiseizure medications. FUNDING: National Institute for Health and Care Research.

Interventions for treating pain and disability in adults with complex regional pain syndrome- an overview of systematic reviews.

BACKGROUND: Complex regional pain syndrome (CRPS) is a chronic pain condition that usually occurs in a limb following trauma or surgery. It is characterised by persisting pain that is disproportionate in magnitude or duration to the typical course of pain after similar injury. There is currently no consensus regarding the optimal management of CRPS, although a broad range of interventions have been described and are commonly used. This is the first update of the original Cochrane review published in Issue 4, 2013. OBJECTIVES: To summarise the evidence from Cochrane and non-Cochrane systematic reviews of the efficacy, effectiveness, and safety of any intervention used to reduce pain, disability, or both, in adults with CRPS. METHODS: We identified Cochrane reviews and non-Cochrane reviews through a systematic search of Ovid MEDLINE, Ovid Embase, Cochrane Database of Systematic Reviews, CINAHL, PEDro, LILACS and Epistemonikos from inception to October 2022, with no language restrictions. We included systematic reviews of randomised controlled trials that included adults (≥18 years) diagnosed with CRPS, using any diagnostic criteria.  Two overview authors independently assessed eligibility, extracted data, and assessed the quality of the reviews and certainty of the evidence using the AMSTAR 2 and GRADE tools respectively. We extracted data for the primary outcomes pain, disability and adverse events, and the secondary outcomes quality of life, emotional well-being, and participants' ratings of satisfaction or improvement with treatment.  MAIN RESULTS: We included six Cochrane and 13 non-Cochrane systematic reviews in the previous version of this overview and five Cochrane and 12 non-Cochrane reviews in the current version. Using the AMSTAR 2 tool, we judged Cochrane reviews to have higher methodological quality than non-Cochrane reviews. The studies in the included reviews were typically small and mostly at high risk of bias or of low methodological quality. We found no high-certainty evidence for any comparison.  There was low-certainty evidence that bisphosphonates may reduce pain intensity post-intervention (standardised mean difference (SMD) -2.6, 95% confidence interval (CI) -1.8 to -3.4, P = 0.001; I2 = 81%; 4 trials, n = 181) and moderate-certainty evidence that they are probably associated with increased adverse events of any nature (risk ratio (RR) 2.10, 95% CI 1.27 to 3.47; number needed to treat for an additional harmful outcome (NNTH) 4.6, 95% CI 2.4 to 168.0; 4 trials, n = 181).  There was moderate-certainty evidence that lidocaine local anaesthetic sympathetic blockade probably does not reduce pain intensity compared with placebo, and low-certainty evidence that it may not reduce pain intensity compared with ultrasound of the stellate ganglion. No effect size was reported for either comparison. There was low-certainty evidence that topical dimethyl sulfoxide may not reduce pain intensity compared with oral N-acetylcysteine, but no effect size was reported. There was low-certainty evidence that continuous bupivacaine brachial plexus block may reduce pain intensity compared with continuous bupivacaine stellate ganglion block, but no effect size was reported. For a wide range of other commonly used interventions, the certainty in the evidence was very low and provides insufficient evidence to either support or refute their use. Comparisons with low- and very low-certainty evidence should be treated with substantial caution. We did not identify any RCT evidence for routinely used pharmacological interventions for CRPS such as tricyclic antidepressants or opioids. AUTHORS' CONCLUSIONS: Despite a considerable increase in included evidence compared with the previous version of this overview, we identified no high-certainty evidence for the effectiveness of any therapy for CRPS. Until larger, high-quality trials are undertaken, formulating an evidence-based approach to managing CRPS will remain difficult. Current non-Cochrane systematic reviews of interventions for CRPS are of low methodological quality and should not be relied upon to provide an accurate and comprehensive summary of the evidence.

Risk factors, ethnicity and dementia: A UK Biobank prospective cohort study of White, South Asian and Black participants.

BACKGROUND: Our knowledge of the effect of potentially modifiable risks factors on people developing dementia is mostly from European origin populations. We aimed to explore if these risk factors had similar effects in United Kingdom (UK) White, South Asian and Black UK Biobank participants recruited from 2006-2010 and followed up until 2020. METHODS: We reviewed the literature to 25.09.2020 for meta-analyses identifying potentially modifiable risk factors preceding dementia diagnosis by ≥10 years. We calculated prevalence of each identified risk factor and association with dementia for participants aged ≥55 at registration in UK Biobank. We calculated hazard ratios using Cox regression for each risk factor, stratified by ethnic group, and tested for differences using interaction effects between each risk factor and ethnicity. FINDINGS: We included education, hearing loss, hypertension, obesity, excess alcohol consumption, physical inactivity, smoking, high total cholesterol, depression, diabetes, social isolation, and air pollution as risks. Out of 294,162 participants, there were 287,806 White, 3590 South Asian and 2766 Black people, followed up for up to 14.8 years, with a total follow-up time of 3,392,095 years. During follow-up, 5,972 people (2.03%) developed dementia. Risk of dementia was higher in Black participants than White participants (HR for dementia compared to White participants as reference 1.43, 95% CI 1.16-1.77, p = 0.001) but South Asians had a similar risk. Association between each risk factor and dementia was similar in each ethnic group with no evidence to support any differences. INTERPRETATION: We find that Black participants were more likely to develop dementia than White participants, but South Asians were not. Identified risk factors in White European origin participants had a similar effect in Black and South Asian origin participants. Volunteers in UK Biobank are not representative of the population and interaction effects were underpowered so further work is needed.

The impact of comorbid severe mental illness and common chronic physical health conditions on hospitalisation: A systematic review and meta-analysis.

BACKGROUND: People with severe mental illness (SMI) are at higher risk of physical health conditions compared to the general population, however, the impact of specific underlying health conditions on the use of secondary care by people with SMI is unknown. We investigated hospital use in people managed in the community with SMI and five common physical long-term conditions: cardiovascular diseases, COPD, cancers, diabetes and liver disease. METHODS: We performed a systematic review and meta-analysis (Prospero: CRD42020176251) using terms for SMI, physical health conditions and hospitalisation. We included observational studies in adults under the age of 75 with a diagnosis of SMI who were managed in the community and had one of the physical conditions of interest. The primary outcomes were hospital use for all causes, physical health causes and related to the physical condition under study. We performed random-effects meta-analyses, stratified by physical condition. RESULTS: We identified 5,129 studies, of which 50 were included: focusing on diabetes (n = 21), cardiovascular disease (n = 19), COPD (n = 4), cancer (n = 3), liver disease (n = 1), and multiple physical health conditions (n = 2). The pooled odds ratio (pOR) of any hospital use in patients with diabetes and SMI was 1.28 (95%CI:1.15-1.44) compared to patients with diabetes alone and pooled hazard ratio was 1.19 (95%CI:1.08-1.31). The risk of 30-day readmissions was raised in patients with SMI and diabetes (pOR: 1.18, 95%CI:1.08-1.29), SMI and cardiovascular disease (pOR: 1.27, 95%CI:1.06-1.53) and SMI and COPD (pOR:1.18, 95%CI: 1.14-1.22) compared to patients with those conditions but no SMI. CONCLUSION: People with SMI and five physical conditions are at higher risk of hospitalisation compared to people with that physical condition alone. Further research is warranted into the combined effects of SMI and physical conditions on longer-term hospital use to better target interventions aimed at reducing inappropriate hospital use and improving disease management and outcomes.

A cross-sectional study of potentially modifiable risk factors for dementia and cognitive function in India: A secondary analysis of 10/66, LASI, and SAGE data.

OBJECTIVES: Dementia is rising globally, particularly in low-and-middle-income countries. India has almost four million people living with dementia, set to double by 2050. Targeting nine potentially modifiable risk factors (less education, hearing impairment, depression, physical inactivity, hypertension, obesity, smoking, diabetes, and social isolation) could possibly prevent or delay many dementias. We aimed for the first time to examine risk factors for dementia in India and their link with cognitive status and dementia, to inform prioritisation of public health interventions that could prevent or delay dementia. METHODS: We conducted a cross-sectional analysis using three studies: 10/66 Dementia Study (n = 2004), Longitudinal Aging Study of India (n = 386), and Study of Global Ageing (n = 2441). Our exposures were the nine risk factors above. We calculated a cognitive z-score within each study and used dementia diagnosis in 10/66. We adjusted for socioeconomic factors, age, and sex using multivariable linear for cognition and logistic regression for dementia. RESULTS: Less education, hearing impairment, depression, and physical inactivity were associated with lower z-scores and increased odds of dementia. Obesity was associated with higher z-score and lower odds of dementia. Social isolation was associated with lower z-scores and decreased odds of dementia. Results for smoking, diabetes, and hypertension were inconsistent. CONCLUSION: Our risk estimates were larger for less education, hearing impairment and physical inactivity compared to global estimates and should be intervention priorities. This study highlights the need for longitudinal studies to clarify the relationship between these potentially modifiable risk factors and dementia in India.

Is there an association between perceived social support and cardiovascular health behaviours in people with severe mental illnesses?

PURPOSE: People with severe mental illnesses (SMI) have an increased risk of cardiovascular disease (CVD). Research in the general population suggests that social support may protect against increased CVD morbidity and mortality; however, this may not apply to those with SMI. We aimed to explore the association between perceived social support and attendance at primary care nurse CVD risk reduction clinic appointments and CVD risk-reducing behaviours in an SMI population with elevated CVD risk factors. METHODS: We used longitudinal and cross-sectional data from a randomised controlled trial on 326 adults with SMI recruited via 76 general practices in England. Multilevel regression analysis estimated the effect of perceived social support on attendance at CVD risk reduction clinic appointments over 6 months, and adherence to CVD medication, physical activity, diet, smoking and alcohol use at baseline, adjusted by age, sex, ethnicity, deprivation, psychiatric diagnosis and employment. RESULTS: Perceived social support predicted greater appointment attendance in unadjusted (IRR = 1.005; 1.000-1.010; p = 0.05) but not adjusted analysis (IRR = 1.003; 0.998-1.009; p = 0.25). Perceived social support was associated with greater adherence to medication; for each 1% increase in social support, there was a 4.2% increase in medication adherence (OR = 1.042; 1.015-1.070; p = 0.002). No association was found between greater perceived social support and greater physical activity, lower sedentary behaviour, healthier diet, lower alcohol use or being a non-smoker. CONCLUSIONS: Social support may be an important facilitator for CVD medication adherence and is potentially important for primary care appointment attendance; however, alternative strategies might be needed to help people with SMI engage in physical activity, healthier diets and to reduce their smoking and alcohol use.

Health indicator recording in UK primary care electronic health records: key implications for handling missing data.

BACKGROUND: Clinical databases are increasingly used for health research; many of them capture information on common health indicators including height, weight, blood pressure, cholesterol level, smoking status, and alcohol consumption. However, these are often not recorded on a regular basis; missing data are ubiquitous. We described the recording of health indicators in UK primary care and evaluated key implications for handling missing data. METHODS: We examined the recording of health indicators in The Health Improvement Network (THIN) UK primary care database over time, by demographic variables (age and sex) and chronic diseases (diabetes, myocardial infarction, and stroke). Using weight as an example, we fitted linear and logistic regression models to examine the associations of weight measurements and the probability of having weight recorded with individuals' demographic characteristics and chronic diseases. RESULTS: In total, 6,345,851 individuals aged 18-99 years contributed data to THIN between 2000 and 2015. Women aged 18-65 years were more likely than men of the same age to have health indicators recorded; this gap narrowed after age 65. About 60-80% of individuals had their height, weight, blood pressure, smoking status, and alcohol consumption recorded during the first year of registration. In the years following registration, these proportions fell to 10%-40%. Individuals with chronic diseases were more likely to have health indicators recorded, particularly after the introduction of a General Practitioner incentive scheme. Individuals' demographic characteristics and chronic diseases were associated with both observed weight measurements and missingness in weight. CONCLUSION: Missing data in common health indicators will affect statistical analysis in health research studies. A single analysis of primary care data using the available information alone may be misleading. Multiple imputation of missing values accounting for demographic characteristics and disease status is recommended but should be considered and implemented carefully. Sensitivity analysis exploring alternative assumptions for missing data should also be evaluated.

Factors prospectively associated with physical activity and dietary related outcomes in people with severe mental illness: A systematic review of longitudinal studies.

Understanding factors that contribute towards physical activity and diet outcomes are important for health improvement in people with severe mental illness. Cross-sectional findings on factors associated with diet and physical activity outcomes provide limited information on what predicts changes or long-term outcomes in lifestyle behaviours in people with severe mental illness. A systematic review was therefore conducted to identify prospective studies with quantitative data on baseline factors associated with follow-up diet or physical activity related outcomes. MEDLINE, EMBASE, PsycINFO, CINAHL Plus and grey literature databases were searched from inception to March 2018. From 6921 studies, 5 were eligible for physical activity related outcomes and 2 for diet related outcomes. The follow-up duration was 4 weeks to 24 months and participants were mostly diagnosed with schizophrenia. Older age was commonly related to better physical activity related outcomes, whilst higher negative symptoms were related to poorer-related outcomes. Physical activity intentions and gender were unrelated to physical activity outcomes. There was a lack of data on factors influencing dietary outcomes. Although there were some common factors predictive of physical activity including older age and negative symptoms, more high-quality research is needed to determine the effect of sociodemographic, mental health, social, clinical, lifestyle and other factors on both physical activity and dietary outcomes.

Non-invasive brain stimulation techniques for chronic pain.

BACKGROUND: This is an updated version of the original Cochrane Review published in 2010, Issue 9, and last updated in 2014, Issue 4. Non-invasive brain stimulation techniques aim to induce an electrical stimulation of the brain in an attempt to reduce chronic pain by directly altering brain activity. They include repetitive transcranial magnetic stimulation (rTMS), cranial electrotherapy stimulation (CES), transcranial direct current stimulation (tDCS), transcranial random noise stimulation (tRNS) and reduced impedance non-invasive cortical electrostimulation (RINCE). OBJECTIVES: To evaluate the efficacy of non-invasive cortical stimulation techniques in the treatment of chronic pain. SEARCH METHODS: For this update we searched CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, LILACS and clinical trials registers from July 2013 to October 2017. SELECTION CRITERIA: Randomised and quasi-randomised studies of rTMS, CES, tDCS, RINCE and tRNS if they employed a sham stimulation control group, recruited patients over the age of 18 years with pain of three months' duration or more, and measured pain as an outcome. Outcomes of interest were pain intensity measured using visual analogue scales or numerical rating scales, disability, quality of life and adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted and verified data. Where possible we entered data into meta-analyses, excluding studies judged as high risk of bias. We used the GRADE system to assess the quality of evidence for core comparisons, and created three 'Summary of findings' tables. MAIN RESULTS: We included an additional 38 trials (involving 1225 randomised participants) in this update, making a total of 94 trials in the review (involving 2983 randomised participants). This update included a total of 42 rTMS studies, 11 CES, 36 tDCS, two RINCE and two tRNS. One study evaluated both rTMS and tDCS. We judged only four studies as low risk of bias across all key criteria. Using the GRADE criteria we judged the quality of evidence for each outcome, and for all comparisons as low or very low; in large part this was due to issues of blinding and of precision.rTMSMeta-analysis of rTMS studies versus sham for pain intensity at short-term follow-up (0 to < 1 week postintervention), (27 studies, involving 655 participants), demonstrated a small effect with heterogeneity (standardised mean difference (SMD) -0.22, 95% confidence interval (CI) -0.29 to -0.16, low-quality evidence). This equates to a 7% (95% CI 5% to 9%) reduction in pain, or a 0.40 (95% CI 0.53 to 0.32) point reduction on a 0 to 10 pain intensity scale, which does not meet the minimum clinically important difference threshold of 15% or greater. Pre-specified subgroup analyses did not find a difference between low-frequency stimulation (low-quality evidence) and rTMS applied to the prefrontal cortex compared to sham for reducing pain intensity at short-term follow-up (very low-quality evidence). High-frequency stimulation of the motor cortex in single-dose studies was associated with a small short-term reduction in pain intensity at short-term follow-up (low-quality evidence, pooled n = 249, SMD -0.38 95% CI -0.49 to -0.27). This equates to a 12% (95% CI 9% to 16%) reduction in pain, or a 0.77 (95% CI 0.55 to 0.99) point change on a 0 to 10 pain intensity scale, which does not achieve the minimum clinically important difference threshold of 15% or greater. The results from multiple-dose studies were heterogeneous and there was no evidence of an effect in this subgroup (very low-quality evidence). We did not find evidence that rTMS improved disability. Meta-analysis of studies of rTMS versus sham for quality of life (measured using the Fibromyalgia Impact Questionnaire (FIQ) at short-term follow-up demonstrated a positive effect (MD -10.80 95% CI -15.04 to -6.55, low-quality evidence).CESFor CES (five studies, 270 participants) we found no evidence of a difference between active stimulation and sham (SMD -0.24, 95% CI -0.48 to 0.01, low-quality evidence) for pain intensity. We found no evidence relating to the effectiveness of CES on disability. One study (36 participants) of CES versus sham for quality of life (measured using the FIQ) at short-term follow-up demonstrated a positive effect (MD -25.05 95% CI -37.82 to -12.28, very low-quality evidence).tDCSAnalysis of tDCS studies (27 studies, 747 participants) showed heterogeneity and a difference between active and sham stimulation (SMD -0.43 95% CI -0.63 to -0.22, very low-quality evidence) for pain intensity. This equates to a reduction of 0.82 (95% CI 0.42 to 1.2) points, or a percentage change of 17% (95% CI 9% to 25%) of the control group outcome. This point estimate meets our threshold for a minimum clinically important difference, though the lower confidence interval is substantially below that threshold. We found evidence of small study bias in the tDCS analyses. We did not find evidence that tDCS improved disability. Meta-analysis of studies of tDCS versus sham for quality of life (measured using different scales across studies) at short-term follow-up demonstrated a positive effect (SMD 0.66 95% CI 0.21 to 1.11, low-quality evidence).Adverse eventsAll forms of non-invasive brain stimulation and sham stimulation appear to be frequently associated with minor or transient side effects and there were two reported incidences of seizure, both related to the active rTMS intervention in the included studies. However many studies did not adequately report adverse events. AUTHORS' CONCLUSIONS: There is very low-quality evidence that single doses of high-frequency rTMS of the motor cortex and tDCS may have short-term effects on chronic pain and quality of life but multiple sources of bias exist that may have influenced the observed effects. We did not find evidence that low-frequency rTMS, rTMS applied to the dorsolateral prefrontal cortex and CES are effective for reducing pain intensity in chronic pain. The broad conclusions of this review have not changed substantially for this update. There remains a need for substantially larger, rigorously designed studies, particularly of longer courses of stimulation. Future evidence may substantially impact upon the presented results.

Non-invasive brain stimulation techniques for chronic pain.

BACKGROUND: This is an updated version of the original Cochrane Review published in 2010, Issue 9, and last updated in 2014, Issue 4. Non-invasive brain stimulation techniques aim to induce an electrical stimulation of the brain in an attempt to reduce chronic pain by directly altering brain activity. They include repetitive transcranial magnetic stimulation (rTMS), cranial electrotherapy stimulation (CES), transcranial direct current stimulation (tDCS), transcranial random noise stimulation (tRNS) and reduced impedance non-invasive cortical electrostimulation (RINCE). OBJECTIVES: To evaluate the efficacy of non-invasive cortical stimulation techniques in the treatment of chronic pain. SEARCH METHODS: For this update we searched CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, LILACS and clinical trials registers from July 2013 to October 2017. SELECTION CRITERIA: Randomised and quasi-randomised studies of rTMS, CES, tDCS, RINCE and tRNS if they employed a sham stimulation control group, recruited patients over the age of 18 years with pain of three months' duration or more, and measured pain as an outcome. Outcomes of interest were pain intensity measured using visual analogue scales or numerical rating scales, disability, quality of life and adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted and verified data. Where possible we entered data into meta-analyses, excluding studies judged as high risk of bias. We used the GRADE system to assess the quality of evidence for core comparisons, and created three 'Summary of findings' tables. MAIN RESULTS: We included an additional 38 trials (involving 1225 randomised participants) in this update, making a total of 94 trials in the review (involving 2983 randomised participants). This update included a total of 42 rTMS studies, 11 CES, 36 tDCS, two RINCE and two tRNS. One study evaluated both rTMS and tDCS. We judged only four studies as low risk of bias across all key criteria. Using the GRADE criteria we judged the quality of evidence for each outcome, and for all comparisons as low or very low; in large part this was due to issues of blinding and of precision.rTMSMeta-analysis of rTMS studies versus sham for pain intensity at short-term follow-up (0 to < 1 week postintervention), (27 studies, involving 655 participants), demonstrated a small effect with heterogeneity (standardised mean difference (SMD) -0.22, 95% confidence interval (CI) -0.29 to -0.16, low-quality evidence). This equates to a 7% (95% CI 5% to 9%) reduction in pain, or a 0.40 (95% CI 0.53 to 0.32) point reduction on a 0 to 10 pain intensity scale, which does not meet the minimum clinically important difference threshold of 15% or greater. Pre-specified subgroup analyses did not find a difference between low-frequency stimulation (low-quality evidence) and rTMS applied to the prefrontal cortex compared to sham for reducing pain intensity at short-term follow-up (very low-quality evidence). High-frequency stimulation of the motor cortex in single-dose studies was associated with a small short-term reduction in pain intensity at short-term follow-up (low-quality evidence, pooled n = 249, SMD -0.38 95% CI -0.49 to -0.27). This equates to a 12% (95% CI 9% to 16%) reduction in pain, or a 0.77 (95% CI 0.55 to 0.99) point change on a 0 to 10 pain intensity scale, which does not achieve the minimum clinically important difference threshold of 15% or greater. The results from multiple-dose studies were heterogeneous and there was no evidence of an effect in this subgroup (very low-quality evidence). We did not find evidence that rTMS improved disability. Meta-analysis of studies of rTMS versus sham for quality of life (measured using the Fibromyalgia Impact Questionnaire (FIQ) at short-term follow-up demonstrated a positive effect (MD -10.80 95% CI -15.04 to -6.55, low-quality evidence).CESFor CES (five studies, 270 participants) we found no evidence of a difference between active stimulation and sham (SMD -0.24, 95% CI -0.48 to 0.01, low-quality evidence) for pain intensity. We found no evidence relating to the effectiveness of CES on disability. One study (36 participants) of CES versus sham for quality of life (measured using the FIQ) at short-term follow-up demonstrated a positive effect (MD -25.05 95% CI -37.82 to -12.28, very low-quality evidence).tDCSAnalysis of tDCS studies (27 studies, 747 participants) showed heterogeneity and a difference between active and sham stimulation (SMD -0.43 95% CI -0.63 to -0.22, very low-quality evidence) for pain intensity. This equates to a reduction of 0.82 (95% CI 0.42 to 1.2) points, or a percentage change of 17% (95% CI 9% to 25%) of the control group outcome. This point estimate meets our threshold for a minimum clinically important difference, though the lower confidence interval is substantially below that threshold. We found evidence of small study bias in the tDCS analyses. We did not find evidence that tDCS improved disability. Meta-analysis of studies of tDCS versus sham for quality of life (measured using different scales across studies) at short-term follow-up demonstrated a positive effect (SMD 0.66 95% CI 0.21 to 1.11, low-quality evidence).Adverse eventsAll forms of non-invasive brain stimulation and sham stimulation appear to be frequently associated with minor or transient side effects and there were two reported incidences of seizure, both related to the active rTMS intervention in the included studies. However many studies did not adequately report adverse events. AUTHORS' CONCLUSIONS: There is very low-quality evidence that single doses of high-frequency rTMS of the motor cortex and tDCS may have short-term effects on chronic pain and quality of life but multiple sources of bias exist that may have influenced the observed effects. We did not find evidence that low-frequency rTMS, rTMS applied to the dorsolateral prefrontal cortex and CES are effective for reducing pain intensity in chronic pain. The broad conclusions of this review have not changed substantially for this update. There remains a need for substantially larger, rigorously designed studies, particularly of longer courses of stimulation. Future evidence may substantially impact upon the presented results.

Clinical and cost-effectiveness of an intervention for reducing cholesterol and cardiovascular risk for people with severe mental illness in English primary care: a cluster randomised controlled trial.

BACKGROUND: People with severe mental illnesses, including psychosis, have an increased risk of cardiovascular disease. We aimed to evaluate the effects of a primary care intervention on decreasing total cholesterol concentrations and cardiovascular disease risk in people with severe mental illnesses. METHODS: We did this cluster randomised trial in general practices across England, with general practices as the cluster unit. We randomly assigned general practices (1:1) with 40 or more patients with severe mental illnesses using a computer-generated random sequence with a block size of four. Researchers were masked to allocation, but patients and general practice staff were not. We included participants aged 30-75 years with severe mental illnesses (schizophrenia, bipolar disorder, or psychosis), who had raised cholesterol concentrations (5·0 mmol/L) or a total:HDL cholesterol ratio of 4·0 mmol/L or more and one or more modifiable cardiovascular disease risk factors. Eligible participants were recruited within each practice before randomisation. The Primrose intervention consisted of appointments (≤12) with a trained primary care professional involving manualised interventions for cardiovascular disease prevention (ie, adhering to statins, improving diet or physical activity levels, reducing alcohol, or quitting smoking). Treatment as usual involved feedback of screening results only. The primary outcome was total cholesterol at 12 months and the primary economic analysis outcome was health-care costs. We used intention-to-treat analysis. The trial is registered with Current Controlled Trials, number ISRCTN13762819. FINDINGS: Between Dec 10, 2013, and Sept 30, 2015, we recruited general practices and between May 9, 2014, and Feb 10, 2016, we recruited participants and randomly assigned 76 general practices with 327 participants to the Primrose intervention (n=38 with 155 patients) or treatment as usual (n=38 with 172 patients). Total cholesterol concentration data were available at 12 months for 137 (88%) participants in the Primrose intervention group and 152 (88%) participants in the treatment-as-usual group. The mean total cholesterol concentration did not differ at 12 months between the two groups (5·4 mmol/L [SD 1·1] for Primrose vs 5·5 mmol/L [1·1] for treatment as usual; mean difference estimate 0·03, 95% CI -0·22 to 0·29; p=0·788). This result was unchanged by pre-agreed supportive analyses. Mean cholesterol decreased over 12 months (-0·22 mmol/L [1·1] for Primrose vs -0·36 mmol/L [1·1] for treatment as usual). Total health-care costs (£1286 [SE 178] in the Primrose intervention group vs £2182 [328] in the treatment-as-usual group; mean difference -£895, 95% CI -1631 to -160; p=0·012) and psychiatric inpatient costs (£157 [135] vs £956 [313]; -£799, -1480 to -117; p=0·018) were lower in the Primrose intervention group than the treatment-as-usual group. Six serious adverse events of hospital admission and one death occurred in the Primrose group (n=7) and 23, including three deaths, occurred in the treatment-as-usual group (n=18). INTERPRETATION: Total cholesterol concentration at 12 months did not differ between the Primrose and treatment-as-usual groups, possibly because of the cluster design, good care in the treatment-as-usual group, short duration of the intervention, or suboptimal focus on statin prescribing. The association between the Primrose intervention and fewer psychiatric admissions, with potential cost-effectiveness, might be important. FUNDING: National Institute of Health Research Programme Grants for Applied Research.

Evaluating the clinical and cost effectiveness of a behaviour change intervention for lowering cardiovascular disease risk for people with severe mental illnesses in primary care (PRIMROSE study): study protocol for a cluster randomised controlled trial.

BACKGROUND: People with severe mental illnesses die up to 20 years earlier than the general population, with cardiovascular disease being the leading cause of death. National guidelines recommend that the physical care of people with severe mental illnesses should be the responsibility of primary care; however, little is known about effective interventions to lower cardiovascular disease risk in this population and setting. Following extensive peer review, funding was secured from the United Kingdom National Institute for Health Research (NIHR) to deliver the proposed study. The aim of the trial is to test the effectiveness of a behavioural intervention to lower cardiovascular disease risk in people with severe mental illnesses in United Kingdom General Practices. METHODS/DESIGN: The study is a cluster randomised controlled trial in 70 GP practices for people with severe mental illnesses, aged 30 to 75 years old, with elevated cardiovascular disease risk factors. The trial will compare the effectiveness of a behavioural intervention designed to lower cardiovascular disease risk and delivered by a practice nurse or healthcare assistant, with standard care offered in General Practice. A total of 350 people will be recruited and followed up at 6 and 12 months. The primary outcome is total cholesterol level at the 12-month follow-up and secondary outcomes include blood pressure, body mass index, waist circumference, smoking status, quality of life, adherence to treatments and services and behavioural measures for diet, physical activity and alcohol use. An economic evaluation will be carried out to determine the cost effectiveness of the intervention compared with standard care. DISCUSSION: The results of this pragmatic trial will provide evidence on the clinical and cost effectiveness of the intervention on lowering total cholesterol and addressing multiple cardiovascular disease risk factors in people with severe mental illnesses in GP Practices. TRIAL REGISTRATION: Current Controlled Trials ISRCTN13762819. Date of Registration: 25 February 2013. Date and Version Number: 27 August 2014 Version 5.

Online health check for reducing alcohol intake among employees: a feasibility study in six workplaces across England.

BACKGROUND: Most hazardous and harmful drinkers are of working age and do not seek help with their drinking. Occupational health services are uniquely placed to universally screen employees across the range of socioeconomic and ethnic groups. The aim was to explore the feasibility and acceptability of offering electronic screening and brief intervention for alcohol misuse in the context of a health check in six different workplace settings. METHODS AND FINDINGS: Employees were recruited from six workplaces across England, including three local authorities, one university, one hospital and one petro-chemical company. A total of 1,254 (8%) employees completed the health check and received personalised feedback on their alcohol intake, alongside feedback on smoking, fruit and vegetable consumption and physical activity. Most participants were female (65%) and of 'White British' ethnicity (94%), with a mean age of 43 years (SD 11). Participants were mostly in Intermediate occupations (58%), followed by Higher managerial / professional (39%) and Routine and manual occupations (2%). A quarter of participants (25%) were drinking at hazardous levels (33% male, 21% female), which decreased with age. Sixty-four percent (n=797) of participants completed online follow-up at three months. Most participants were supportive of workplaces offering employees an online health check (95%), their preferred format was online (91%) and many were confident of the confidentiality of their responses (60%). Whilst the feedback reminded most participants of things they already knew (75%), some were reportedly motivated to change their behaviour (13%). CONCLUSIONS: Online health screening and personalised feedback appears feasible and acceptable, but challenges include low participation rates, potentially attracting 'worried well' employees rather than those at greatest health risk, and less acceptance of the approach among older employees and those from ethnic minority backgrounds and routine or manual occupations.

Cardiovascular risk prediction models for people with severe mental illness: results from the prediction and management of cardiovascular risk in people with severe mental illnesses (PRIMROSE) research program.

IMPORTANCE: People with severe mental illness (SMI), including schizophrenia and bipolar disorder, have excess rates of cardiovascular disease (CVD). Risk prediction models validated for the general population may not accurately estimate cardiovascular risk in this group. OBJECTIVE: To develop and validate a risk model exclusive to predicting CVD events in people with SMI incorporating established cardiovascular risk factors and additional variables. DESIGN, SETTING, AND PARTICIPANTS: We used anonymous/deidentified data collected between January 1, 1995, and December 31, 2010, from the Health Improvement Network (THIN) to conduct a primary care, prospective cohort and risk score development study in the United Kingdom. Participants included 38,824 people with a diagnosis of SMI (schizophrenia, bipolar disorder, or other nonorganic psychosis) aged 30 to 90 years. During a median follow-up of 5.6 years, 2324 CVD events (6.0%) occurred. MAIN OUTCOMES AND MEASURES: Ten-year risk of the first cardiovascular event (myocardial infarction, angina pectoris, cerebrovascular accidents, or major coronary surgery). Predictors included age, sex, height, weight, systolic blood pressure, diabetes mellitus, smoking, body mass index (BMI), lipid profile, social deprivation, SMI diagnosis, prescriptions for antidepressants and antipsychotics, and reports of heavy alcohol use. RESULTS: We developed 2 CVD risk prediction models for people with SMI: the PRIMROSE BMI model and the PRIMROSE lipid model. These models mutually excluded lipids and BMI. In terms of discrimination, from cross-validations for men, the PRIMROSE lipid model D statistic was 1.92 (95% CI, 1.80-2.03) and C statistic was 0.80 (95% CI, 0.76-0.83) compared with 1.74 (95% CI, 1.63-1.86) and 0.78 (95% CI, 0.75-0.82) for published Cox Framingham risk scores. The corresponding results in women were 1.87 (95% CI, 1.76-1.98) and 0.79 (95% CI, 0.76-0.82) for the PRIMROSE lipid model and 1.58 (95% CI, 1.48-1.68) and 0.77 (95% CI, 0.73-0.81) for the Cox Framingham model. Discrimination statistics for the PRIMROSE BMI model were comparable to those for the PRIMROSE lipid model. Calibration plots suggested that both PRIMROSE models were superior to the Cox Framingham models. CONCLUSIONS AND RELEVANCE: The PRIMROSE BMI and lipid CVD risk prediction models performed better in SMI compared with models that include only established CVD risk factors. Further work on the clinical effectiveness and cost-effectiveness of the PRIMROSE models is needed to ascertain the best thresholds for offering CVD interventions.

Smoker, ex-smoker or non-smoker? The validity of routinely recorded smoking status in UK primary care: a cross-sectional study.

OBJECTIVE: To investigate how smoking status is recorded in UK primary care; to evaluate whether appropriate multiple imputation (MI) of smoking status yields results consistent with health surveys. SETTING: UK primary care and a population survey conducted in the community. PARTICIPANTS: We identified 354 204 patients aged 16 or over in The Health Improvement Network (THIN) primary care database registered with their general practice 2008-2009 and 15 102 individuals aged 16 or over in the Health Survey for England (HSE). OUTCOME MEASURES: Age-standardised and age-specific proportions of smokers, ex-smokers and non-smokers in THIN and the HSE before and after MI. Using information on time since quitting in the HSE, we estimated when ex-smokers are typically recorded as non-smokers in primary care records. RESULTS: In THIN, smoking status was recorded for 84% of patients within 1 year of registration. Of these, 28% were smokers (21% in the HSE). After MI of missing smoking data, the proportion of smokers was 25% (missing at random) and 20% (missing not at random). With increasing age, more were identified as ex-smokers in the HSE than THIN. It appears that those who quit before age 30 were less likely to be recorded as an ex-smoker in primary care than people who quit later. CONCLUSIONS: Smoking status was relatively well recorded in primary care. Misclassification of ex-smokers as non-smokers is likely to occur in those quitting smoking at an early age and/or a long time ago. Those with no smoking status information are more likely to be ex-smokers or non-smokers than smokers.

Desarrollo y validación de un algoritmo para predecir riesgo de depresión en consultantes de atención primaria en Chile / Development of an algorithm to predict the incidence of major depression among primary care consultants

Background: The reduction of major depression incidence is a public health challenge. Aim: To develop an algorithm to estimate the risk of occurrence of major depression in patients attending primary health centers (PHC). Material and Methods: Prospective cohort study of a random sample of 2832 patients attending PHC centers in Concepción, Chile, with evaluations at baseline, six and twelve months. Thirty nine known risk factors for depression were measured to build a model, using a logistic regression. The algorithm was developed in 2,133 patients not depressed at baseline and compared with risk algorithms developed in a sample of 5,216 European primary care attenders. The main outcome was the incidence of major depression in the follow-up period. Results: The cumulative incidence of depression during the 12 months follow up in Chile was 12%. Eight variables were identified. Four corresponded to the patient (gender, age, depression background and educational level) and four to patients' current situation (physical and mental health, satisfaction with their situation at home and satisfaction with the relationship with their partner). The C-Index, used to assess the discriminating power of the final model, was 0.746 (95% confidence intervals (CI = 0,707-0,785), slightly lower than the equation obtained in European (0.790 95% CI = 0.767-0.813) and Spanish attenders (0.82; 95% CI = 0.79-0.84). Conclusions: Four of the factors identified in the risk algorithm are not modifiable. The other two factors are directly associated with the primary support network (family and partner). This risk algorithm for the incidence of major depression provides a tool that can guide efforts towards design, implementation and evaluation of effectiveness of interventions to prevent major depression.

Mortality and medical care after bereavement: a general practice cohort study.

Bereaved spouses or partners are thought to be at increased risk of morbidity and mortality. However, there are few large prospective studies and results are inconsistent. We estimated the relative mortality, prescription of psychotropic medication and use of primary medical care services in adults whose cohabitee died of cancer. To do this, we undertook a cohort study using The Health Improvement Network (THIN) UK primary care database. Participants were 1) people aged over 40, who were registered with general practices and had been exposed to the death of a cohabitee from cancer; and 2) a comparison cohort frequency matched on five year age bands and sex who were cohabiting with a living partner. The baseline was chosen as six months before the date of the cancer death for the exposed group and a random date for the unexposed group. Incidence rate ratios (IRR) with 95% confidence intervals (CI) were estimated using random effects Poisson regression to account for clustering within general practices and adjusting for other key variables. 92,129 patients were studied for a median follow up of 4 years. Cohabitees of patients who died of cancer were less likely to die of any cause (IRR 0.71, CI 0.68-0.74) after adjustment for age, gender, number of non-psychotropic prescriptions 6 months before the cancer death/index date, use of psychotropic medication 6 months before the cancer death/index date, smoking, alcohol and area deprivation score. Exposed patients were more likely to receive a prescription for antidepressant or hypnotic medication and to attend their GP both before and after the death of the cohabitee. In conclusion, we did not confirm increased mortality in cohabitees of people dying from cancer.

Issues in multiple imputation of missing data for large general practice clinical databases.

PURPOSE: Missing data are a substantial problem in clinical databases. This paper aims to examine patterns of missing data in a primary care database, compare this to nationally representative datasets and explore the use of multiple imputation (MI) for these data. METHODS: The patterns and extent of missing health indicators in a UK primary care database (THIN) were quantified using 488 384 patients aged 16 or over in their first year after registration with a GP from 354 General Practices. MI models were developed and the resulting data compared to that from nationally representative datasets (14 142 participants aged 16 or over from the Health Survey for England 2006 (HSE) and 4 252 men from the British Regional Heart Study (BRHS)). RESULTS: Between 22% (smoking) and 38% (height) of health indicator data were missing in newly registered patients, 2004-2006. Distributions of height, weight and blood pressure were comparable to HSE and BRHS, but alcohol and smoking were not. After MI the percentage of smokers and non-drinkers was higher in THIN than the comparison datasets, while the percentage of ex-smokers and heavy drinkers was lower. Height, weight and blood pressure remained similar to the comparison datasets. CONCLUSIONS: Given available data, the results are consistent with smoking and alcohol data missing not at random whereas height, weight and blood pressure missing at random. Further research is required on suitable imputation methods for smoking and alcohol in such databases.