Maintenance or Discontinuation of Antidepressants in Primary Care.

BACKGROUND: Patients with depression who are treated in primary care practices may receive antidepressants for prolonged periods. Data are limited on the effects of maintaining or discontinuing antidepressant therapy in this setting. METHODS: We conducted a randomized, double-blind trial involving adults who were being treated in 150 general practices in the United Kingdom. All the patients had a history of at least two depressive episodes or had been taking antidepressants for 2 years or longer and felt well enough to consider stopping antidepressants. Patients who had received citalopram, fluoxetine, sertraline, or mirtazapine were randomly assigned in a 1:1 ratio to maintain their current antidepressant therapy (maintenance group) or to taper and discontinue such therapy with the use of matching placebo (discontinuation group). The primary outcome was the first relapse of depression during the 52-week trial period, as evaluated in a time-to-event analysis. Secondary outcomes were depressive and anxiety symptoms, physical and withdrawal symptoms, quality of life, time to stopping an antidepressant or placebo, and global mood ratings. RESULTS: A total of 1466 patients underwent screening. Of these patients, 478 were enrolled in the trial (238 in the maintenance group and 240 in the discontinuation group). The average age of the patients was 54 years; 73% were women. Adherence to the trial assignment was 70% in the maintenance group and 52% in the discontinuation group. By 52 weeks, relapse occurred in 92 of 238 patients (39%) in the maintenance group and in 135 of 240 (56%) in the discontinuation group (hazard ratio, 2.06; 95% confidence interval, 1.56 to 2.70; P<0.001). Secondary outcomes were generally in the same direction as the primary outcome. Patients in the discontinuation group had more symptoms of depression, anxiety, and withdrawal than those in the maintenance group. CONCLUSIONS: Among patients in primary care practices who felt well enough to discontinue antidepressant therapy, those who were assigned to stop their medication had a higher risk of relapse of depression by 52 weeks than those who were assigned to maintain their current therapy. (Funded by the National Institute for Health Research; ANTLER ISRCTN number, ISRCTN15969819.).

Feasibility randomised controlled trial of face-to-face counselling and mobile phone messages compared to usual care for smokeless tobacco cessation in Indian primary care: Project CERTAIN.

INTRODUCTION: Smokeless tobacco (SLT) use in low- and middle-income countries (LMICs) has adverse health consequences. We hypothesize that it is feasible to test an intervention of mobile phone messages and face-to-face counselling session for SLT cessation in India. METHODS: We conducted an exploratory, individual parallel two group, randomised controlled trial (RCT), with baseline -and end-point (three months from randomisation) assessments in urban primary health centres in Odisha, India. A total of 250 current (i.e., users in the last three months) SLT users or dual users (i.e., smokers and SLT users) were recruited to the trial (125 in each group). Participants were randomised to either routine care, face-to-face counselling, and reminder mobile messages or routine care only. The primary outcomes were to assess the feasibility of running a full RCT including recruitment, compliance, and retention. RESULTS: A total seven (77.8%) out of nine primary care centres took part in the trial. Out of the 315 SLT users invited to participate, 250 provided consent and were randomised [79.4% (95% CI: 74.5, 83.7)]. Out of the 250 randomised SLT users, 238 [95% (95% CI: 91.8, 97.5)] were followed up at three months (117 in the intervention group and 121 in the control group). Of the participants in the intervention group, 74 (63.8%) reported that they received the mobile messages. CONCLUSIONS: This exploratory trial demonstrated the feasibility of delivering and evaluating an intervention of mobile phone messages and face-to-face counselling for SLT users in Indian primary care in a full randomised trial. IMPLICATIONS: This study found that combining mobile messages with face-to-face counselling for smokeless tobacco users visiting primary health care settings in India is feasible in terms of recruitment of users, compliance with the intervention, and retention of study participants within the trial.The biochemically verified smokeless tobacco abstinence rate was higher in the intervention group compared with the control groupThere was poor agreement between self-reported tobacco cessation and the measured salivary cotinine in smokeless tobacco users.The findings support the feasibility and acceptability of the intervention signalling the need for a larger clinical trial to test effectiveness of the intervention.

Suicidal thoughts, suicide attempt and non-suicidal self-harm amongst lesbian, gay and bisexual adults compared with heterosexual adults: analysis of data from two nationally representative English household surveys.

PURPOSE: We aimed to compare differences in suicidality and self-harm between specific lesbian, gay and bisexual (LGB) groups, and investigate whether minority stress factors might contribute to any associations, addressing methodological limitations of previous research. METHODS: We analysed data combined from two population-based representative household surveys of English adults (N = 10,443) sampled in 2007 and 2014. Using multivariable logistic regression models adjusted for age, gender, educational attainment, area-level deprivation, and common mental disorder, we tested the association between sexuality and three suicide-related outcomes: past-year suicidal thoughts, past-year suicide attempt, and lifetime non-suicidal self-harm (NSSH). We added bullying and discrimination (separately) to final models to explore whether these variables might mediate the associations. We tested for interactions with gender and survey year. RESULTS: Lesbian/gay people were more likely to report past-year suicidal thoughts [adjusted odds ratio (AOR) = 2.20; 95% CI 1.08-4.50] than heterosexuals. No minority group had an increased probability of suicide attempt. Bisexual (AOR = 3.02; 95% CI = 1.78-5.11) and lesbian/gay (AOR = 3.19; 95% CI = 1.73-5.88) individuals were more likely to report lifetime NSSH than heterosexuals. There was some evidence to support a contribution of bullying in the association between lesbian/gay identity and past-year suicidal thoughts, and of each minority stress variable in the associations with NSSH. There was no interaction with gender or survey year. CONCLUSION: Specific LGB groups are at elevated risk of suicidal thoughts and NSSH, with a possible contribution of lifetime bullying and homophobic discrimination. These disparities show no temporal shift despite apparent increasing societal tolerance towards sexual minorities.

Anomalies in the review process and interpretation of the evidence in the NICE guideline for chronic fatigue syndrome and myalgic encephalomyelitis.

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disabling long-term condition of unknown cause. The National Institute for Health and Care Excellence (NICE) published a guideline in 2021 that highlighted the seriousness of the condition, but also recommended that graded exercise therapy (GET) should not be used and cognitive-behavioural therapy should only be used to manage symptoms and reduce distress, not to aid recovery. This U-turn in recommendations from the previous 2007 guideline is controversial.We suggest that the controversy stems from anomalies in both processing and interpretation of the evidence by the NICE committee. The committee: (1) created a new definition of CFS/ME, which 'downgraded' the certainty of trial evidence; (2) omitted data from standard trial end points used to assess efficacy; (3) discounted trial data when assessing treatment harm in favour of lower quality surveys and qualitative studies; (4) minimised the importance of fatigue as an outcome; (5) did not use accepted practices to synthesise trial evidence adequately using GRADE (Grading of Recommendations, Assessment, Development and Evaluations trial evidence); (6) interpreted GET as mandating fixed increments of change when trials defined it as collaborative, negotiated and symptom dependent; (7) deviated from NICE recommendations of rehabilitation for related conditions, such as chronic primary pain and (8) recommended an energy management approach in the absence of supportive research evidence.We conclude that the dissonance between this and the previous guideline was the result of deviating from usual scientific standards of the NICE process. The consequences of this are that patients may be denied helpful treatments and therefore risk persistent ill health and disability.

Long-term systemic glucocorticoid therapy and weight gain: a population-based cohort study.

OBJECTIVES: To describe the variation in weight gain in people chronically exposed to systemic glucocorticoids in primary care and to identify the risk factors for weight gain. METHODS: Data were analysed from the British database, The Health Improvement Network. Body weight variations of individuals prescribed systemic glucocorticoids for at least 3 months at a mean dose ≥10 mg/day were described. The risk factors associated with weight gain ≥10% of the usual weight were assessed. RESULTS: A total of 31 516 adults prescribed glucocorticoids and 26 967 controls were included in the study. During glucocorticoid exposure, only 12 475 (39.6%) individuals gained >2 kg compared with their usual weight. Younger women were more likely to gain weight (mean weight gain in 18-39-year-old glucocorticoid-exposed women: 3.6 kg (s.d. 8.6) compared with 2 kg (s.d. 7.3) in the control group; the absolute mean difference was 1.6 kg (95% CI 0.9, 2.2; P < 0.001). Weight gain ≥10% of the usual weight was observed in 10.2% (n = 3208) of those chronically exposed to glucocorticoids. Women, younger people, those living in areas of higher deprivation, smokers, those on higher doses of the drug and those previously exposed to glucocorticoids were at higher risk. The risk was lower in people prescribed glucocorticoids for an inflammatory condition when compared with asthma or chronic obstructive pulmonary disease. CONCLUSION: After taking into account usual weight rather than weight just before glucocorticoid initiation and the natural history of weight variation, the amount of weight gain induced by systemic glucocorticoids as prescribed in primary care is less than usually thought. CLINICAL TRIAL REGISTRATION: 18THIN081.

Serum urate and lung cancer: a cohort study and Mendelian randomization using UK Biobank.

BACKGROUND: Serum urate is the most abundant small molecule with antioxidant properties found in blood and the epithelial lining fluid of the respiratory system. Moderately raised serum urate is associated with lower rates of lung cancer and COPD in smokers but whether these relationships reflect antioxidant properties or residual confounding is unknown. METHODS: We investigated the observational and potentially causal associations of serum urate with lung cancer incidence and FEV1 using one-sample Mendelian randomization (MR) and the UK Biobank resource. Incident lung cancer events were identified from national cancer registries as FEV1 was measured at baseline. Observational and genetically instrumented incidence rate ratios (IRRs) and risk differences per 10,000 person-years (PYs) by smoking status were estimated. RESULTS: The analysis included 359,192 participants and 1,924 lung cancer events. The associations between measured urate levels and lung cancer were broadly U-shaped but varied by sex at birth with the strongest associations in current smoking men. After adjustment for confounding variables, current smoking men with low serum urate (100 µmol/L) had the highest predicted lung cancer incidence at 125/10,000 PY (95%CI 56-170/10,000 PY) compared with 45/10,000 PY (95%CI 38-47/10,000 PY) for those with the median level (300 µmol/L). Raised measured urate was associated with a lower baseline FEV1. The MR results did not support a causal relationship between serum urate and lung cancer or FEV1. CONCLUSIONS: We found no evidence that serum urate is a modifiable risk factor for respiratory health or lung cancer.

Trends in generalised anxiety disorders and symptoms in primary care: UK population-based cohort study.

BACKGROUND: Generalised anxiety disorder and symptoms are associated with poor physical, emotional and social functioning and frequent primary and acute care visits. We investigated recent temporal trends in anxiety and related mental illness in UK general practice. AIMS: The aims of this analysis are to examine temporal changes in recording of generalised anxiety in primary care and initial pharmacologic treatments. METHOD: Annual incidence rates of generalised anxiety diagnoses and symptoms were calculated from 795 UK general practices contributing to The Health Improvement Network (THIN) database between 1998 and 2018. Poisson mixed regression was used to account for age, gender and general practitioner practice. Subsequent pharmacologic treatment was examined. RESULTS: Generalised anxiety recording rates increased in both genders aged 18-24 between 2014 and 2018. For women, the increase was from 17.06 to 23.33/1000 person years at risk (PYAR); for men, 8.59 to 11.65/1000 PYAR. Increases persisted for a composite of anxiety and depression (49.74 to 57.81/1000 PYAR for women; 25.41 to 31.45/1000 PYAR for men). Smaller increases in anxiety were seen in both genders age 25-34 and 35-44. Anxiety rates among older patients remained stable, although a composite of anxiety and depression decreased for older women. About half of drug-naïve patients were prescribed anxiety drugs within 1 year following diagnosis. The most common choice was a selective serotonin reuptake inhibitor. Benzodiazepine prescription rate has fallen steadily. CONCLUSIONS: We observed a substantial increase in general practitioner consulting for generalised anxiety and depression recently, concentrated within younger people and in particular women.

Cigarette smoking as a risk factor for schizophrenia or all non-affective psychoses.

BACKGROUND: Smoking tobacco is regarded as an epiphenomenon in patients with schizophrenia when it may be causal. We aimed to examine whether smoking status is related to the onset of schizophrenia or the broader diagnosis of non-affective psychosis, including schizophrenia. METHODS: We used data from The Health Improvement Network primary care database to identify people aged 15-24 between 1 January 2004 and 31 December 2009. We followed them until the earliest of: first diagnosis of schizophrenia (or psychosis), patient left the practice, practice left THIN, patient died or 31 December 2014. RESULTS: In men, incidence rates for schizophrenia per 100 000 person years at risk were higher in smoking initiators (non-smoker who became a smoker during the study) than in non-smokers (adjusted IRR 1.94; 95% CI 1.29-2.91) and higher still in smokers (adjusted IRR 3.32; 95% CI 2.67-4.14). Among women, the incidence rate of schizophrenia was higher in smokers than in non-smokers (adjusted IRR 1.50; 95% CI 1.06-2.12), but no higher in smoking initiators than non-smokers. For non-affective psychosis, the pattern was similar for men but more evident in women where psychosis incidence rates were higher in smoking initiators (adjusted IRR 1.90; 95% CI 1.40-2.56) and in smokers (adjusted IRR 2.13; 95% CI 1.76-2.57) than in non-smokers. CONCLUSIONS: We found an important and strong association between smoking and incidence of schizophrenia. Smoking may increase risk through as yet unknown pathways or smoking may share genetic risk with schizophrenia and non-affective psychoses.

Antibiotic prescribing for lower UTI in elderly patients in primary care and risk of bloodstream infection: A cohort study using electronic health records in England.

BACKGROUND: Research has questioned the safety of delaying or withholding antibiotics for suspected urinary tract infection (UTI) in older patients. We evaluated the association between antibiotic treatment for lower UTI and risk of bloodstream infection (BSI) in adults aged ≥65 years in primary care. METHODS AND FINDINGS: We analyzed primary care records from patients aged ≥65 years in England with community-onset UTI using the Clinical Practice Research Datalink (2007-2015) linked to Hospital Episode Statistics and census data. The primary outcome was BSI within 60 days, comparing patients treated immediately with antibiotics and those not treated immediately. Crude and adjusted associations between exposure and outcome were estimated using generalized estimating equations. A total of 147,334 patients were included representing 280,462 episodes of lower UTI. BSI occurred in 0.4% (1,025/244,963) of UTI episodes with immediate antibiotics versus 0.6% (228/35,499) of episodes without immediate antibiotics. After adjusting for patient demographics, year of consultation, comorbidities, smoking status, recent hospitalizations, recent accident and emergency (A&E) attendances, recent antibiotic prescribing, and home visits, the odds of BSI were equivalent in patients who were not treated with antibiotics immediately and those who were treated on the date of their UTI consultation (adjusted odds ratio [aOR] 1.13, 95% CI 0.97-1.32, p-value = 0.105). Delaying or withholding antibiotics was associated with increased odds of death in the subsequent 60 days (aOR 1.17, 95% CI 1.09-1.26, p-value < 0.001), but there was limited evidence that increased deaths were attributable to urinary-source BSI. Limitations include overlap between the categories of immediate and delayed antibiotic prescribing, residual confounding underlying differences between patients who were/were not treated with antibiotics, and lack of microbiological diagnosis for BSI. CONCLUSIONS: In this study, we observed that delaying or withholding antibiotics in older adults with suspected UTI did not increase patients' risk of BSI, in contrast with a previous study that analyzed the same dataset, but mortality was increased. Our findings highlight uncertainty around the risks of delaying or withholding antibiotic treatment, which is exacerbated by systematic differences between patients who were and were not treated immediately with antibiotics. Overall, our findings emphasize the need for improved diagnostic/risk prediction strategies to guide antibiotic prescribing for suspected UTI in older adults.

Pharmacological treatments for generalised anxiety disorder: a systematic review and network meta-analysis.

BACKGROUND: Generalised anxiety disorder is a disease that can be associated with substantial dysfunction. Pharmacological treatment is often the first choice for clinicians because of the cost and resource constraints of psychological alternatives, but there is a paucity of comparative information for the multiple available drug choices. METHODS: A systematic review and network meta-analysis was performed on randomised trials in adult outpatients with generalised anxiety disorder identified from MEDLINE, Web of Science, Cochrane Library, ClinicalTrials.gov, Chinese National Knowledge Infrastructure (CNKI), Wanfang data, Drugs@FDA and commercial pharmaceutical registries. Placebo and active control trials were included. Data were extracted from all manuscripts and reports. Primary outcomes were efficacy (mean difference [MD] in change in Hamilton Anxiety Scale Score) and acceptability (study discontinuations for any cause). We estimated summary mean treatment differences and odds ratios using network meta-analyses with random effects. This study is registered with PROSPERO, number CRD42018087106. FINDINGS: Studies were published between Jan 1, 1994 and Aug 1, 2017, in which 1992 potential studies were screened for inclusion. This analysis is based on 89 trials, which included 25 441 patients randomly assigned to 22 different active drugs or placebo. Duloxetine (MD -3·13, 95% credible interval [CrI] -4·13 to -2·13), pregabalin (MD -2·79, 95% CrI -3·69 to -1·91), venlafaxine (MD -2·69, 95% CrI -3·50 to -1·89), and escitalopram (MD -2·45, 95% CrI -3·27 to -1·63) were more efficacious than placebo with relatively good acceptability. Mirtazapine, sertraline, fluoxetine, buspirone, and agomelatine were also found to be efficacious and well tolerated but these findings were limited by small sample sizes. Quetiapine (MD -3·60 95% CrI -4·83 to -2·39) had the largest effect on HAM-A but it was poorly tolerated (odds ratio 1·44, 95% CrI 1·16-1·80) when compared with placebo. Likewise, paroxetine and benzodiazepines were effective but also poorly tolerated when compared with placebo. Risk of reporting bias was considered low, and when possible all completed studies were included to avoid publication bias. INTERPRETATION: To our knowledge, this is the largest contemporary review of pharmacological agents for the treatment of generalised anxiety disorder by use of network analysis. There are several effective treatment choices for generalised anxiety disorder across classes of medication. The failure of initial pharmacological therapy might not be a reason to abandon a pharmacological treatment strategy. FUNDING: No funding was received for this research.

Genetically raised serum bilirubin levels and lung cancer: a cohort study and Mendelian randomisation using UK Biobank.

BACKGROUND: Moderately raised serum bilirubin levels are associated with lower rates of lung cancer, particularly among smokers. It is not known whether these relationships reflect antioxidant properties or residual confounding. OBJECTIVE: This study aimed to investigate potential causal relationships between serum total bilirubin and lung cancer incidence using one-sample Mendelian randomisation (MR) and UK Biobank. METHODS: We instrumented serum total bilirubin level using two variants (rs887829 and rs4149056) that together explain ~40% of population-level variability and are linked to mild hereditary hyperbilirubinaemia. Lung cancer events occurring after recruitment were identified from national cancer registries. Observational and genetically instrumented incidence rate ratios (IRRs) and rate differences per 10 000 person-years (PYs) by smoking status were estimated. RESULTS: We included 377 294 participants (median bilirubin 8.1 µmol/L (IQR 6.4-10.4)) and 2002 lung cancer events in the MR analysis. Each 5 µmol/L increase in observed bilirubin levels was associated with 1.2/10 000 PY decrease (95% CI 0.7 to 1.8) in lung cancer incidence. The corresponding MR estimate was a decrease of 0.8/10 000 PY (95% CI 0.1 to 1.4). The strongest associations were in current smokers where a 5 µmol/L increase in observed bilirubin levels was associated with a decrease in lung cancer incidence of 10.2/10 000 PY (95% CI 5.5 to 15.0) and an MR estimate of 6.4/10 000 PY (95% CI 1.4 to 11.5). For heavy smokers (≥20/day), the MR estimate was an incidence decrease of 23.1/10 000 PY (95% CI 7.3 to 38.9). There was no association in never smokers and no mediation by respiratory function. CONCLUSION: Genetically raised serum bilirubin, common across human populations, may protect people exposed to high levels of smoke oxidants against lung cancers.

Effectiveness of cognitive-behavioural therapy for depression in advanced cancer: CanTalk randomised controlled trial.

BACKGROUND: Depression is one of the most common mental disorders in people with advanced cancer. Although cognitive-behavioural therapy (CBT) has been shown to be effective for depression in people with cancer, it is unclear whether this is the case for people with advanced cancer and depression. AIMS: We sought to determine whether CBT is more clinically effective than treatment as usual (TAU) for treating depression in people with advanced cancer (trial registration number ISRCTN07622709). METHOD: A multi-centre, parallel-group single-blind randomised controlled trial comparing TAU with CBT (plus TAU). Participants (n = 230) with advanced cancer and depression were randomly allocated to (a) up to 12 sessions of individual CBT or (b) TAU. The primary outcome measure was the Beck Depression Inventory-II (BDI-II). Secondary outcome measures included the Patient Health Questionnaire-9, the Eastern Cooperative Oncology Group Performance Status, and Satisfaction with Care. RESULTS: Multilevel modelling, including complier-average intention-to-treat analysis, found no benefit of CBT. CBT delivery was proficient, but there was no treatment effect (-0.84, 95% CI -2.76 to 1.08) or effects for secondary measures. Exploratory subgroup analysis suggested an effect of CBT on the BDI-II in those widowed, divorced or separated (-7.21, 95% CI -11.15 to -3.28). CONCLUSIONS: UK National Institute for Health and Care Excellence (NICE) guidelines recommend CBT for treating depression. Delivery of CBT through the Improving Access to Psychological Therapies (IAPT) programme has been advocated for long-term conditions such as cancer. Although it is feasible to deliver CBT through IAPT proficiently to people with advanced cancer, this is not clinically effective. CBT for people widowed, divorced or separated needs further exploration. Alternate models of CBT delivery may yield different results.

Comparative effectiveness of sitagliptin vs sulphonylureas in older people.

BACKGROUND: two common anti-diabetic treatments used are sitagliptin and sulphonylureas however evidence examining their comparative effectiveness in older people is limited. OBJECTIVE: to evaluate effectiveness of sitagliptin vs sulphonylureas when added to metformin in older (aged ≥75) vs younger people (18-75). DESIGN: retrospective cohort study. SETTING: UK Primary Care. SUBJECTS: 2,904 individuals prescribed sitagliptin (223 aged≥75) and 13,683 prescribed sulphonylureas (1,725 aged ≥75). METHODS: multivariable regression to analyse difference in HbA1c and weight, 12 months after add-on initiation and proportion achieving different glycaemic targets. RESULTS: after multivariate adjustment to remove baseline differences, the HbA1c after 12 months of treatment was on average 1 mmol/mol (95%CI -0.7 to 2.8) higher with sitagliptin vs sulphonylureas in older people though this was not statistically significant. The weight however, was significantly lower -1.4 kg (95%CI -2.1 to -0.7) with sitagliptin vs sulphonylureas. A lower proportion prescribed sitagliptin vs sulphonylureas recorded HbA1c < 48 mmol/mol by study end: Odds Ratio 0.63 (95%CI 0.42-0.95). In younger people, similar HbA1c reductions were also observed with both treatments, however weight after 12 months was even lower with sitagliptin vs sulphonylureas: -2.3 kg (95%CI -2.5 to -2.0). CONCLUSIONS: similar HbA1c reduction was observed when sitagliptin or sulphonylureas were added to metformin in older and younger age-groups. Sitagliptin use led to modest comparative weight loss. There may be greater risk of over-treatment with sulphonylureas evidenced by greater proportion recording HbA1c < 48 mmol/mol by study end. This evidence supporting use of sitagliptin when add-on therapy is selected in older adults should be considered alongside the wider evidence-base and patient-preference.

Context, mechanisms and outcomes in end-of-life care for people with advanced dementia: family carers perspective.

BACKGROUND: Keeping people living with advanced dementia in their usual place of residence is becoming a key governmental goal but to achieve this, family carers and health care professionals must negotiate how to provide optimal care. Previously, we reported a realist analysis of the health care professional perspective. Here, we report on family carer perspectives. We aimed to understand the similarities and differences between the two perspectives, gain insights into how the interdependent roles of family carers and HCPs can be optimised, and make recommendations for policy and practice. METHOD: Qualitative study using a realist approach in which we used the criteria from guidance on optimal palliative care in advanced dementia to examine key contexts, mechanisms and outcomes highlighted by family carers. RESULTS: The themes and views of family caregivers resonate with those of health care professionals. Their overlapping anxieties related to business-driven care homes, uncertainty of families when making EOL decisions and the importance of symptom management referring to contexts, mechanisms and outcomes, respectively. Contexts specific to family carers were ad hoc information about services, dementia progression and access to funding. Not all family carers identified dementia as terminal, but many recognised the importance of continuity of care and knowing the wishes of the person with dementia. New mechanisms included specific resources for improving EOL care and barriers to discussing and planning for future care. Family carers identified the importance of comfort, being present, the meeting of basic care needs and feeling the right decisions have been made as good outcomes of care. CONCLUSIONS: Family carers and health care professionals share similar concerns about the challenges to good EOL dementia care. Better understanding of the effects of dementia at the advanced stages would improve confidence in EOL care and reduce uncertainty in decision making for family carers and health care professionals.

Landmark Models for Optimizing the Use of Repeated Measurements of Risk Factors in Electronic Health Records to Predict Future Disease Risk.

The benefits of using electronic health records (EHRs) for disease risk screening and personalized health-care decisions are being increasingly recognized. Here we present a computationally feasible statistical approach with which to address the methodological challenges involved in utilizing historical repeat measures of multiple risk factors recorded in EHRs to systematically identify patients at high risk of future disease. The approach is principally based on a 2-stage dynamic landmark model. The first stage estimates current risk factor values from all available historical repeat risk factor measurements via landmark-age-specific multivariate linear mixed-effects models with correlated random intercepts, which account for sporadically recorded repeat measures, unobserved data, and measurement errors. The second stage predicts future disease risk from a sex-stratified Cox proportional hazards model, with estimated current risk factor values from the first stage. We exemplify these methods by developing and validating a dynamic 10-year cardiovascular disease risk prediction model using primary-care EHRs for age, diabetes status, hypertension treatment, smoking status, systolic blood pressure, total cholesterol, and high-density lipoprotein cholesterol in 41,373 persons from 10 primary-care practices in England and Wales contributing to The Health Improvement Network (1997-2016). Using cross-validation, the model was well-calibrated (Brier score = 0.041, 95% confidence interval: 0.039, 0.042) and had good discrimination (C-index = 0.768, 95% confidence interval: 0.759, 0.777).

Effectiveness of personalised risk information and taster sessions to increase the uptake of smoking cessation services (Start2quit): a randomised controlled trial.

BACKGROUND: National Health Service Stop Smoking Services (SSSs) offer help to smokers motivated to quit; however, attendance rates are low and recent figures show a downward trend. We aimed to assess the effectiveness of a two-component personalised intervention on attendance at SSSs. METHODS: We did this randomised controlled trial in 18 SSSs in England. Current smokers (aged ≥16 years) were identified from medical records in 99 general practices and invited to participate by their general practitioner. Individuals who gave consent, were motivated to quit, and had not attended the SSS within the past 12 months, were randomly assigned (3:2), via computer-generated randomisation with permuted blocks (block size of five), to receive either an individually tailored risk letter and invitation to attend a no-commitment introductory session run by the local SSS (intervention group) or a standard generic letter advertising the local SSS (control group). Randomisation was stratified by sex. Masking of participants to receipt of a personal letter and invitation to a taster session was not possible. The personal letter was generated by a research assistant, but the remainder of the research team were masked to group allocation. General practitioners, practice staff, and SSS advisers were unaware of their patients' allocation. The primary outcome was attendance at the first session of an SSS course within 6 months from randomisation. We did analysis by intention to treat. This trial is registered with Current Controlled Trials, number ISRCTN 76561916. FINDINGS: Recruitment, collection of baseline data, delivery of the intervention, and follow up of participants took place between Jan 31, 2011, and July 12, 2014. We randomly assigned 4384 smokers to the intervention group (n=2636) or the control group (n=1748); 4383 participants comprised the intention-to-treat population. Attendance at the first session of an SSS course was significantly higher in the intervention group than in the control group (458 [17·4%] vs 158 [9·0%] participants; unadjusted odds ratio 2·12 [95% CI 1·75-2·57]; p<0·0001). INTERPRETATION: Delivery of personalised risk information alongside an invitation to an introductory session more than doubled the odds of attending the SSS compared with a standard generic invitation to contact the service. This result suggests that a more proactive approach, combined with an opportunity to experience local services, can reduce patient barriers to receiving treatment and has high potential to increase uptake. FUNDING: National Institutes of Health Research Health Technology Assessment.

A personalized intervention to prevent depression in primary care: cost-effectiveness study nested into a clustered randomized trial.

BACKGROUND: Depression is viewed as a major and increasing public health issue, as it causes high distress in the people experiencing it and considerable financial costs to society. Efforts are being made to reduce this burden by preventing depression. A critical component of this strategy is the ability to assess the individual level and profile of risk for the development of major depression. This paper presents the cost-effectiveness of a personalized intervention based on the risk of developing depression carried out in primary care, compared with usual care. METHODS: Cost-effectiveness analyses are nested within a multicentre, clustered, randomized controlled trial of a personalized intervention to prevent depression. The study was carried out in 70 primary care centres from seven cities in Spain. Two general practitioners (GPs) were randomly sampled from those prepared to participate in each centre (i.e. 140 GPs), and 3326 participants consented and were eligible to participate. The intervention included the GP communicating to the patient his/her individual risk for depression and personal risk factors and the construction by both GPs and patients of a psychosocial programme tailored to prevent depression. In addition, GPs carried out measures to activate and empower the patients, who also received a leaflet about preventing depression. GPs were trained in a 10- to 15-h workshop. Costs were measured from a societal and National Health care perspective. Qualityadjustedlife years were assessed using the EuroQOL five dimensions questionnaire. The time horizon was 18 months. RESULTS: With a willingness-to-pay threshold of €10,000 (£8568) the probability of cost-effectiveness oscillated from 83% (societal perspective) to 89% (health perspective). If the threshold was increased to €30,000 (£25,704), the probability of being considered cost-effective was 94% (societal perspective) and 96%, respectively (health perspective). The sensitivity analysis confirmed these results. CONCLUSIONS: Compared with usual care, an intervention based on personal predictors of risk of depression implemented by GPs is a cost-effective strategy to prevent depression. This type of personalized intervention in primary care should be further developed and evaluated. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01151982. Registered on June 29, 2010.

Living and dying with advanced dementia: A prospective cohort study of symptoms, service use and care at the end of life.

BACKGROUND: Increasing number of people are dying with advanced dementia. Comfort and quality of life are key goals of care. AIMS: To describe (1) physical and psychological symptoms, (2) health and social care service utilisation and (3) care at end of life in people with advanced dementia. DESIGN: 9-month prospective cohort study. SETTING AND PARTICIPANTS: Greater London, England, people with advanced dementia (Functional Assessment Staging Scale 6e and above) from 14 nursing homes or their own homes. MAIN OUTCOME MEASURES: At study entry and monthly: prescriptions, Charlson Comorbidity Index, pressure sore risk/severity (Waterlow Scale/Stirling Scale, respectively), acute medical events, pain (Pain Assessment in Advanced Dementia), neuropsychiatric symptoms (Neuropsychiatric Inventory), quality of life (Quality of Life in Late-Stage Dementia Scale), resource use (Resource Utilization in Dementia Questionnaire and Client Services Receipt Inventory), presence/type of advance care plans, interventions, mortality, place of death and comfort (Symptom Management at End of Life in Dementia Scale). RESULTS: Of 159 potential participants, 85 were recruited (62% alive at end of follow-up). Pain (11% at rest, 61% on movement) and significant agitation (54%) were common and persistent. Aspiration, dyspnoea, septicaemia and pneumonia were more frequent in those who died. In total, 76% had 'do not resuscitate' statements, less than 40% advance care plans. Most received primary care visits, there was little input from geriatrics or mental health but contact with emergency paramedics was common. CONCLUSION: People with advanced dementia lived with distressing symptoms. Service provision was not tailored to their needs. Longitudinal multidisciplinary input could optimise symptom control and quality of life.

The role of self-regulatory skills and automaticity on the effectiveness of a brief weight loss habit-based intervention: secondary analysis of the 10 top tips randomised trial.

BACKGROUND: Habit-interventions are designed to promote the automaticity of healthy behaviours and may also enhance self-regulatory skills during the habit-formation process. A recent trial of habit-based advice for weight loss (10 Top Tips; 10TT), found that patients allocated to 10TT lost significantly more weight over 3 months than those allocated to usual care, and reported greater increases in automaticity for the target behaviours. The current study aimed to test the hypothesis that i) 10TT increased self-regulatory skills more than usual care, and ii) that self-regulatory skills and automaticity changes mediated the effect of 10TT on weight loss. METHODS: 537 obese patients from 14 primary care practices in the UK were randomized to receive 10TT or usual care. Patients in the 10TT group received a leaflet containing tips for weight loss and healthy habits formation, a self-monitoring log book and a wallet-sized shopping guide on how to read food labels. Patients were weighed and completed validated questionnaires for self-regulation and automaticity at baseline and 3-month follow-up. Within-group and Between-group effects were explored using Paired T-test and ANCOVA, respectively. Mediation was assessed using bootstrapping to estimate indirect effects and the sobel test. RESULTS: Over 3 months patients who were given 10TT reported greater increases in self-regulatory skills (Mean difference: .08; 95% CI .01; .15) than those who received usual care. Changes in self-regulatory skills and automaticity over 3 months mediated the effect of the intervention on weight loss (ß = .52, 95% Bias Corrected CI .17; .91). CONCLUSIONS: As hypothesised, 10TT enhanced self-regulatory skills and changes in self-regulatory skills and automaticity mediated the effect of the intervention on weight loss. This supports the proposition that self-regulatory training and habit formation are important features of weight loss interventions. TRIAL REGISTRATION: This study was prospectively registered with the International Standard Randomised Controlled Trials ( ISRCTN16347068 ) on 26 September 2011.

Experiences of end of life amongst family carers of people with advanced dementia: longitudinal cohort study with mixed methods.

BACKGROUND: Many studies have examined the mental health of carers of people with dementia. Few have examined their experiences in the advanced stages of disease and into bereavement. We aimed to understand the experiences of carers during advanced dementia exploring the links between mental health and experiences of end of life care. METHODS: Mixed methods longitudinal cohort study. Thirty-five family carers of people with advanced dementia (6 at home, 29 in care homes) were recruited and assessed monthly for up to nine months or until the person with dementia died, then at two and seven months into bereavement. Assessments included: Hospital Anxiety and Depression Scale, Short Form 12 health-related quality of life, 22-item Zarit Burden Interview, Brief Coping Orientation to Problems Experienced, Inventory of Complicated Grief and Satisfaction with Care at End of Life in Dementia. Subsequently, 12 carers (34%) were bereaved and 12 undertook a qualitative interview two months after death; these data were analysed thematically. We analysed quantitative and qualitative data independently and then merged findings at the point of interpretation. RESULTS: At study entry psychological distress was high; 26% reached caseness for depression and 41% for anxiety and median complicated grief scores were 27 [IQR 22-37] indicating that on average 11 of the 16 grief symptoms occurred at least monthly. Physical health reflected population norms (mean = 50) and median burden scores were 17 [IQR 9-30]. Three qualitative themes were identified: the importance of relationships with care services, understanding of the progression of dementia, and emotional responses to advanced dementia. An overarching theme tying these together was the carer's ability to control and influence end of life care. CONCLUSIONS: While carers report high levels of psychological distress during advanced dementia, the experience of end of life care in dementia may be amenable to change with the provision of sensitive and timely information about the natural progression of dementia. Regular health status updates and end of life discussions can help families understand dementia progression and prepare for end of life. The extent to which our findings reflect practice across the UK or internationally warrants further investigation.