Introduction:People with persistent musculoskeletal (MSK) pain often experience distress, distinct from depression. Current referral pathways and interventions are suboptimal for this group. We developed and tested the acceptability and proof of concept of De-Stress Pain, an intervention to reduce pain-related distress. Methods:Guided by principles from Acceptance and Commitment Therapy, behavioural activation, and the Person-Based Approach (PBA) De-Stress Pain provided 4-6 social prescriber sessions over 12 weeks, plus access to a mental wellbeing website promoting engagement in meaningful and pleasurable activities. Acceptability of the intervention and study procedures was assessed qualitatively using semi-structured interviews with participants and social prescribers before and after the intervention programme. Results:Sixteen participants were recruited and 11 completed the intervention alongside four social prescribers. Participants described the intervention as acceptable and valued the combination of social prescriber support, accountability, and encouragement to re-engage in meaningful and pleasurable activities. Social prescribers reported that the intervention was acceptable to deliver and aligned with their existing practice, although limited appointment time and participants' financial constraints could affect engagement. Some participants initially viewed pleasurable activities as indulgent, which acted as a barrier to engagement. Findings also suggested that future iterations may benefit from refining eligibility criteria to better identify individuals experiencing sufficient pain-related distress. Improvements in mood measures and participant reports of increased hope, activity, and wellbeing suggested the intervention showed promise for supporting people with pain-related distress. Conclusions:This study demonstrates that De-Stress Pain was acceptable to both participants and social prescribers and feasible to deliver within social prescribing services. The findings identified several factors requiring consideration in future iterations, including participant selection, time constraints, and financial barriers to engagement. De-Stress Pain is, to our knowledge, among the few pain-related interventions specifically designed for delivery by social prescribers within primary care settings.

BACKGROUND:The Immune Defence trial documented a short-term impact on respiratory tract infections (RTIs) for nasal sprays and a stress management and physical activity website. AIM:To estimate the impact of sprays and the website after 12 months. DESIGN AND SETTING:A four-arm parallel randomised controlled trial. Participants with comorbidities and/or ≥3 self-reported recurrent RTIs were recruited. METHOD:Participants were randomised by online software (stratified by recurrent illness and comorbidities) to a) usual care (n = 3451); b) Vicks First Defence (VFD) spray (n = 3448) (two sprays/nostril, ≤6 times a day; c) isotonic saline spray (n = 3450) (same dosing); or d) a website promoting physical activity and stress management (n = 3450). The primary outcome was respiratory illness days. RESULTS:Usual care participants (n = 3052) had on average 21.8 (standard deviation [SD] 35.2) illness days, reduced by VFD (n = 3076; 17.8 [SD 27.9] days, adjusted incidence rate ratio [IRR] 0.84, 99% confidence interval [CI] = 0.79 to 0.90, P<0.0001), and saline (n = 3142; 17.7 [SD 21.1 ] days, IRR 0.83, 99% CI = 0.78 to 0.89, P<0.0001), but not the website (n = 2811; 19.5 [SD 31.2] days, IRR 0.94, 99% CI = 0.88 to 1.01, P = 0.03). The website reduced incident infections (adjusted risk ratio [RR] 0.96, 95% CI = 0.93 to 0.99, P = 0.006). All interventions reduced symptom severity and work days lost, both spray groups reported lower intention to consult and fewer falls, and there were fewer antibiotic courses and practice visits with saline. Among those with recurrent illness, saline had the most impact on both recurrence and symptom days (RR 0.93, 95% CI = 0.87 to 0.99 and RR 0.70, 95% CI = 0.60 to 0.82, respectively). Headaches were higher for VFD and lower for saline (7.8% and 3.4%, respectively; 4.7% usual care). CONCLUSION:Widely available, inexpensive sprays and a website promoting self-care reduce the incidence, duration, and/or severity of RTIs and have an impact on work days lost and healthcare use.

Background Many women experience recurrent urinary tract infections (rUTIs) yet their significance for the women affected is poorly described and understood. Aim To explore women’s experiences of rUTIs and the impact on their lives. Design and setting A qualitative study embedded in a randomised controlled trial (RCT) of D-mannose with women with clinically defined rUTIs in England and Wales. Method We conducted semi-structured telephone interviews with 32 women who participated in the RCT. Interviews were audio-recorded and transcribed verbatim. Data were analysed thematically. Results Women reported how the experience of rUTIs was burdensome with distressing and debilitating physical symptoms and wider disruptive effects. Women expressed how rUTIs had an impact on different stages of their lives and we identified two types of impact. Internalised impact included the women’s emotional response to rUTIs, dread of a recurrence, and maintaining readiness to manage it. Externalised impact encompassed actions in response to rUTIs, including remaining extremely vigilant about recurrences and seeking help as soon as a recurrence was suspected, and the challenges they faced. The women explained how the responses of healthcare professionals (HCPs) when they sought care affected their help-seeking and their self-esteem, and could leave them with a sense of helplessness. Conclusion Experience of rUTIs has taught women to be vigilant and proactive about the condition but this was not always matched with understanding and validation on the part of HCPs. When women experiencing rUTIs seek care, clinicians could usefully consider the patient’s broader experience of rUTIs, including internalised and externalised impacts.

Background:Peptic ulcers in patients on aspirin are associated with Helicobacter pylori infection. We investigated whether H. pylori eradication would protect against aspirin-associated ulcer bleeding. Methods:The Helicobacter Eradication Aspirin Trial was a randomised placebo-controlled trial (European Union Drug Regulating Authorities Clinical Trials 2011-003425-96), conducted in United Kingdom primary care using routinely collected clinical data. Consenting participants aged ≥ 60 years prescribed aspirin ≤ 325 mg but not ulcerogenic or gastroprotective medication underwent C13 urea breath testing for H. pylori. Those with a positive test were randomised to receive either a combination of clarithromycin 500 mg, metronidazole 400 mg and lansoprazole 30 mg, or placebos twice daily for 7 days. The primary outcome, time to death or hospitalisation due to peptic ulcer bleeding, was analysed using a Cox proportional hazards model. Findings:Between 14 September 2012 and 22 November 2017, 30,166 participants underwent H. pylori breath testing, 5367 had a positive result, 5352 were randomised to an intention-to-treat population of 2677 (eradication) and 2675 (placebo) and followed up for a median of 5.0 years (interquartile range 3.9-6.4). Statistical analysis of the primary outcome showed an overall hazard ratio of 0.69 [95% confidence interval 0.38 to 1.25; p = 0.22], but there was a significant departure from the proportional hazards assumption (p = 0.0068), requiring analysis split at the median time to event: 2.5 years. There was a significant reduction in the primary outcome in the eradication treatment group in the first 2.5 years (hazard ratio 0.35, 95% confidence interval 0.14 to 0.89; p = 0.028) but not the second period (hazard ratio 1.31, 95% confidence interval 0.55 to 3.11). The number needed to treat (first period) was 238 (95% confidence interval 184 to 1661). Results in the first 2.5 years remained significant when accounting for the competing risk of death (p = 0.028). During the study period, 657 participants died (306 in the eradication group and 351 in the controls group; hazard ratio 0.86, 95% confidence interval 0.74 to 1.01; p = 0.058). Malignancy was the most common cause of death and largely accounted for the numerical difference between the treatment groups. A health economic analysis found proactive screening not cost-effective, since the monetised benefits of the intervention in preventing a peptic ulcer bleed failed to outweigh the costs. Interpretation:Helicobacter pylori eradication protects against aspirin-associated peptic ulcer bleeding, but this may not be sustained or cost-effective when applied non-selectively to our study population. The possibility that H. pylori eradication, on a background of aspirin use, might affect death from malignancies warrants further evaluation. Limitations and future work:Studying subjects already established on aspirin probably contributed to the low event rate. A future study should investigate subjects starting on aspirin when the event rate is higher. Trial registration:This trial is registered as ISRCTN10134725; ClinicalTrials.gov number NCT01506986. Funding:This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 09/55/52) and is published in full in Health Technology Assessment; Vol. 29, No. 42. See the NIHR Funding and Awards website for further award information.

Background There is significant concern about increasing long-term antidepressant use in Western countries, much of which is not evidence-based. Median duration of treatment is more than 2 years in the United Kingdom, and more than 10% of adults are taking antidepressants, risking potentially significant adverse effects, particularly for older patients. Objectives To develop internet- and telephone-based support for practitioners and patients, through a process of co-design, and to determine its effectiveness and cost-effectiveness in helping people discontinue antidepressants without increasing depression, in a randomised controlled trial. Design Two systematic reviews (one qualitative); qualitative interviews with patients; qualitative interviews and focus groups with healthcare practitioners; co-production of online interventions with patients and practitioners; feasibility randomised controlled trial; definitive non-inferiority cluster randomised controlled trial with health economic evaluation; and quantitative and qualitative process evaluations. A booklet and video version of the patient intervention was also developed in Urdu. Setting Primary care (131 general practices in England and Wales). Participants Adults on antidepressant treatment for more than 1 year for a first episode of depression, or more than 2 years for recurrent depression, who were no longer depressed or judged to be at significant risk of relapse. Interventions Tailored internet support (ADvisor for patients, and ADvisorHP for health professionals), plus three telephone support calls from psychological well-being practitioners. Primary outcome Depressive symptoms on the Patient Health Questionnaire-9 items questionnaire at 6 months. Secondary outcomes Depressive symptoms over 12 months, antidepressant discontinuation, anxiety, quality of life, withdrawal symptoms, adverse events, mental well-being, patient enablement, patient satisfaction, health service use and costs over 12 months. Sample size The original sample size calculation gave a target of 402 patients for 90% power with one-sided significance of 2.5% to determine non-inferiority of the intervention, within 2 points on the Patient Health Questionnaire-9 items. This was reduced to 360 on finding a significant correlation between baseline and follow-up values for the Patient Health Questionnaire-9 items part-way through the trial. Randomisation Remote cluster randomisation of practices by computerised sequence generation, with minimisation by practice size, urban/rural location and deprivation index. Blinding Participants and researchers could not be blinded given the pragmatic open design, but self-complete measures avoided observer rating bias, and analyses were conducted blind. Analyses Linear mixed modelling was used to determine differences in outcomes, adjusting for previous depression, baseline outcome values, baseline anxiety, sociodemographic characteristics, and practice as a random effect. Primary analysis was performed by intention to treat, with per-protocol and complier-average sensitivity analyses. Multiple imputation was used to account for missing values. Qualitative interviews: Semistructured topic guides were used for interviews and focus groups, informed by normalisation process theory, which were audio-recorded, transcribed verbatim and analysed using reflexive thematic analysis. Results Systematic reviews, qualitative interviews and focus groups indicated that barriers to discontinuing treatment include a fear of relapse of depression and withdrawal symptoms. If practitioners do not broach possible discontinuation, patients will usually continue treatment without questioning it. Patients wanted information on antidepressant mechanisms and effects, withdrawal symptoms and coping strategies. Practitioners wanted guidance on initiating discontinuation, antidepressant tapering regimens, and distinguishing withdrawal from relapse. The definitive trial randomised 330 patients (5% of those approached; 178 in intervention practices and 152 in controls), of whom 275 (83%) were followed up at 6 months, and 240 (73%) at 12 months. Mean Patient Health Questionnaire-9 items scores were slightly higher among controls at 6 months [5.0 vs. 4.0; adjusted difference 1.07 (95% confidence interval 0.09 to 2.06; p = 0.033)]. Antidepressant discontinuation rates at 6 months were slightly higher in the intervention arm, but not significantly (45.5% vs. 41.9% in the control arm). Antidepressant withdrawal symptoms and mental well-being were significantly better in the intervention arm. There were no significant differences in anxiety, quality of life, adverse events, patient enablement, or satisfaction with care. The adjusted mean cost of services used was lower in the intervention arm by −£69 (95% confidence interval −£77 to £207). The incremental cost-effectiveness ratio was a mean saving of −£2839 per quality-adjusted life-year gained (95% confidence interval −£30,024 to £22,227). The probability of the intervention being cost-effective compared to review alone, at the National Institute for Health and Care Excellence thresholds of societal willingness to pay of £20,000 and £30,000 per quality-adjusted life-year, was > 89% for both. Qualitative interviews suggested advice to taper slowly, and information on the difference between relapse and withdrawal symptoms, contributed significantly to the success of the interventions. Participants were well and willing to attempt antidepressant discontinuation, and general practitioners excluded people considered at high risk of relapse of depression. This may explain why more than 40% of participants in each arm discontinued. The results may not generalise to an unselected sample of people on long-term antidepressants, including people at greater risk of relapse. Conclusions Comparatively high rates of discontinuation of long-term antidepressants are achievable through enabling patients, who are ready to consider stopping them, to get tapering advice and support from their general practitioners. Tailored internet and psychologist telephone support may help protect patients coming off long-term antidepressants against depressive and withdrawal symptoms, and conserve mental well-being. The interventions appear highly cost-effective at thresholds for societal willingness to pay used by the National Institute for Health and Care Excellence. Trial registration Workstream 4 (feasibility trial) is registered as International Standardised Randomised Controlled Trial Number ISRCTN15036829 and Workstream 5 (definitive trial of effectiveness and cost-effectiveness) is registered as ISRCTN12417565. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme (NIHR award ref: RP-PG-1214-20004) and is published in full in Programme Grants for Applied Research; Vol. 13, No. 7. See the NIHR Funding and Awards website for further award information. Plain language summary The REDUCE programme developed and tested internet and telephone support for people trying to stop long-term antidepressants when they no longer needed them for depression. Our searches for previous research, together with patient and practitioner interviews, showed that stopping antidepressants can be difficult, due to fear of depression returning, and withdrawal symptoms. Working with patients, general practitioners and other practitioners, we developed two websites to provide information and advice on stopping antidepressants, called ADvisor for patients and ADvisorHP for health professionals. We also developed guidance for psychological well-being practitioners to give support to people coming off antidepressants, through three telephone calls. We tested this approach in a trial. One hundred and seventy-eight people registered with 66 randomly selected practices were offered general practitioner treatment reviews plus internet and telephone support, and their success with stopping antidepressants was compared with success among 152 people from 65 practices offering general practitioner reviews alone. We found that people given the telephone and internet support in addition to the general practitioner treatment review had slightly better depression scores than those without the additional support (4.0 vs. 5.0), but the difference in antidepressant discontinuation rates was not significant (46% vs. 42%). People who received the support also had fewer withdrawal symptoms, and better mental well-being. This seemed to be because the support included advice to taper treatment slowly, and gave reassuring information on the difference between symptoms of depression and withdrawal symptoms, and what to do about them if they developed. The general practitioner’s support was found to be important to patients. Both groups in the trial had little change in their quality of life, and harmful events were few and usually not serious. So, attempting to taper off long-term antidepressants is a safe thing to do as long as the general practitioner is monitoring a person’s progress and can adjust treatment as necessary. Scientific summary Background There is significant concern about increasing long-term antidepressant use in Western countries, much of which is not evidence-based. The median duration of treatment is more than 2 years in the UK, and more than 10% of adults are taking antidepressants, risking potentially significant adverse effects, particularly for older patients. Patients may continue treatment due to fear of relapse of depression, or to experiencing withdrawal symptoms which can make discontinuation difficult. If practitioners do not broach attempting discontinuation, then patients will assume they must continue to take repeat prescriptions. Many patients want the option of being reviewed and attempting discontinuation with appropriate support, but general practitioners (GPs) often lack experience in reducing antidepressants flexibly, and their advice to withdraw treatment may not be successful. Trials of simply prompting GPs to review patients eligible for antidepressant discontinuation have found only 6–8% of patients succeed. Patients anxious about discontinuing treatment may have to be persuaded of the potential benefits, then actively engaged in the process and supported through withdrawal. We considered that providing self-management internet and telephone support for patients and practitioners might facilitate antidepressant withdrawal at scale, without adding to the workload of primary care or psychological therapies. Aim and objectives Aim To identify feasible, safe, effective and cost-effective ways of helping patients taking long-term antidepressants to withdraw from treatment where it is appropriate for them to do so. Objectives To conduct a systematic review of quantitative and qualitative literature, to identify interventions that have been used to help patients withdraw from antidepressant treatment. To identify factors that promote or inhibit the implementation of treatment withdrawal, through interviews with patients taking them long term, and focus groups with GPs, nurse practitioners (NPs) and primary care mental health workers who treat patients. To develop an internet-supported cognitive–behavioural therapy-based intervention for primary care practitioners and patients to support patient withdrawal from antidepressant treatment, through a process of co-design and co-production with practitioners and patients, taking their views into account throughout its development and implementation, in an iterative process. To determine the effectiveness of the intervention in helping patients stop treatment through a randomised controlled trial (RCT), and to estimate its cost-effectiveness from a health service perspective. To build a translational framework describing the intervention and addressing how it should be delivered, including overcoming practitioner and patient-related barriers, to facilitate implementation of treatment cessation. Methods We conducted six workstreams. In workstream 1 (WS1), two systematic reviews were completed: one of quantitative studies of interventions to facilitate antidepressant discontinuation, and one of qualitative studies of barriers and facilitators to antidepressant discontinuation identified by patients and health professionals. In workstream 2 (WS2), qualitative interviews were carried out with people taking long-term antidepressants, and focus groups and interviews were carried out with GPs, NPs and mental health practitioners. In workstream 3 (WS3), we developed internet-based interventions for patients (‘ADvisor’) and primary care practitioners (‘ADvisorHP’) to support antidepressant discontinuation, through co-design and co-production with patients and practitioners, taking their views into account in an iterative process. Prototype interventions were tested using ‘think-aloud’ interviews where participants described their opinions while using the prototypes. We also developed guidance for psychological well-being practitioners (PWPs) to provide support to people coming off antidepressants through three telephone calls, one of 30 minutes and two follow-up calls of 15 minutes. Workstream 4 (WS4) was a feasibility RCT to assess procedures for a definitive RCT to follow, including practice and patient recruitment (from both medical record searches and opportunistically in consultations); follow-up rates; the acceptability and feasibility of our internet and PWP telephone interventions; the acceptability and feasibility of the trial procedures and outcome measures; and participants’ views of involvement in the trial, through qualitative interviews with patients and practitioners. Workstream 5 (WS5) was a definitive non-inferiority cluster RCT with health economic evaluation; and quantitative and qualitative process evaluations. Randomisation was by remote computerised sequence generation, with minimisation by practice size, urban/rural location and deprivation index. Participants and researchers could not be blinded given the pragmatic open design, but self-complete measures avoided observer rating bias, and analyses were conducted blind. The participants were adults on antidepressant treatment for more than 1 year for a first episode of depression, or for more than 2 years for a recurrent episode, who were no longer depressed or judged to be at significant risk of relapse. The primary outcome was depressive symptoms on the Patient Health Questionnaire-9 items (PHQ-9) questionnaire at 6 months. Secondary outcomes were depressive symptoms over 12 months; antidepressant discontinuation at 6 and 12 months; withdrawal symptoms at 3 and 6 months; and anxiety, quality of life, adverse events, mental well-being, patient enablement, patient satisfaction, health service use and costs over 12 months. The original sample size calculation gave a target of 402 patients for 90% power with one-sided significance of 2.5% to determine non-inferiority of the intervention, within 2 points on the PHQ-9. This was reduced to 360 on finding a significant correlation between baseline and follow-up values for the PHQ-9 part-way through the trial. Linear mixed modelling was used to determine differences in outcomes, adjusting for previous depression, baseline outcome values, baseline anxiety, sociodemographic characteristics and practice as a random effect. Primary analysis was by intention to treat, with per-protocol and complier-average sensitivity analyses. Multiple imputation was used to account for missing values. A quantitative process evaluation looked at participants’ use of the online interventions (automatically recorded), and the fidelity of the PWP calls against the guidance provided. A qualitative process evaluation involved interviewing practitioners and patients. Semistructured topic guides were used for interviews which were audio-recorded, transcribed verbatim and analysed using reflexive thematic analysis. Normalisation process theory was used as a framework to identify issues related to implementing the interventions in practice beyond the trial. An additional workstream was requested by the Programme Grants Board, aimed at developing a prototype intervention for a major ethnic minority group. We worked with Urdu-speaking people of South Asian origin in the north-west of England to develop a culturally acceptable version of the ADvisor patient intervention using the methods of co-production used in WS3. Results Our systematic reviews, qualitative interviews and focus groups indicated that barriers to discontinuing treatment include a fear of relapse of depression and withdrawal symptoms. If practitioners do not raise possible discontinuation, patients will usually continue treatment without questioning it. Patients wanted information on the underlying mechanisms, effects and side effects of antidepressants, withdrawal symptoms and coping strategies. Practitioners wanted guidance on initiating discontinuation, antidepressant-tapering regimens, and distinguishing withdrawal from relapse. Practices and patients In the feasibility trial, we successfully recruited 14 practices, 7 randomised to each arm. In the definitive trial, we recruited 131 practices, 66 randomised to the intervention arm, and 65 to the control. We recruited a total of 330 patients (178 in intervention practices and 152 in controls), of whom 275 (83%) were followed up at 6 months, and 240 (73%) at 12 months. The 330 included 52 recruited for the feasibility trial, which was approved as an internal pilot as the protocol was not changed significantly. Clinical outcomes The intervention proved non-inferior to the control for the development of depression. In fact, mean PHQ-9 depression symptom scores were slightly higher among controls at 6 months {5.0 vs. 4.0; adjusted difference 1.07 [95% confidence interval (CI) 0.09 to 2.06; p = 0.033]}. Antidepressant discontinuation rates at 6 months were slightly higher in the intervention arm, but not significantly (45.5% vs. 41.9% in the control arm). Over 6 months antidepressant withdrawal symptoms on the Discontinuation Emergent Signs and Symptoms Scale were fewer in the intervention arm, although the difference, while statistically significant, was small [adjusted mean difference −1.56 points (95% CI −2.85 to −0.26); p = 0.018]. Similarly, over 12 months, mental well-being scores on the Warwick-Edinburgh Mental Wellbeing Scale were slightly better in the intervention arm [mean difference 2.17 points (95% CI 0.21 to 4.14); p = 0.030]. There were no significant differences in anxiety, quality of life, patient enablement, or patient satisfaction. Adverse events occurred for 15% of patients in each arm, which were mostly not serious. One serious adverse reaction to discontinuation occurred in each arm. Health economic outcomes The adjusted mean cost of services used was lower in the intervention arm by −£69 (95% CI −£77 to £207). The incremental cost-effectiveness ratio was a mean saving of −£2839 per quality-adjusted life-year gained (95% CI −£30,024 to £22,227). The probability of the intervention being cost-effective compared to usual care at the National Institute for Health and Care Excellence thresholds of societal willingness to pay, of £20,000 and £30,000, was > 89% for both. Qualitative interviews Qualitative interviews suggested successful antidepressant discontinuation was more likely if the invitation for a review came at a time when the person was feeling well and stable, and ready to try to discontinue. Advice to taper slowly, and information on the difference between relapse and withdrawal symptoms, seemed to contribute significantly to the success of the interventions. Urdu version of ADvisor Interviews and focus groups with Urdu-speaking patients, practitioners and community leaders informed the development of a prototype Urdu version of the ADvisor intervention for patients, but as a booklet and online videos, as participants did not consider an interactive online intervention would be acceptable. The prototype was optimised through think-aloud interviews and is available for future testing and implementation. Limitations In our WS1 qualitative evidence synthesis, coding to generate themes was performed by one researcher and discussed with two others, due to time constraints. Similarly, in the systematic review, one researcher performed study selection, data extraction and risk of bias assessment, checked by another reviewer. Ideally, coding, study selection, data extraction and bias assessment would be done independently by two reviewers. The use of focus groups to elicit barriers and facilitators to discontinuation from health professionals in WS1 facilitated discussion and candid responses from participants. However, discussions can become polarised or influenced by dominant members in a group, and some participants’ views may be less well represented. The GPs we enrolled were interested in mental health research and may be more knowledgeable than practitioners generally, which may explain why some felt that some of the information in ADvisorHP was not new. Other GPs may have learnt more from the intervention, particularly trainees and GPs new to UK practice. The development work included only two NPs, which made it difficult to identify differences between GP and NP perspectives. In the main WS5 trial, we recruited 330 patients, falling short of the (revised) target sample size of 360. We had sufficient power to address the primary outcome, as 6-month follow-up (83%) was greater than the 80% predicted. However, only 73% were followed up at 12 months which reduced the power of the sample to exclude differences in depression and discontinuation of antidepressants developing beyond 6 months. In the missing cases multiple imputation analysis, while the non-inferiority conclusion remained, the intervention no longer appeared superior to the control. Vetting by GPs of patient lists generated by the medical records searches would have introduced selection bias, towards including people who were well and considered ready to try tapering by the GP, and excluding people who were considered to be at greater risk of relapse. This may explain why we found a high rate of discontinuation compared to the 6–8% found in previous trials of GP reviews. In the previous trials, patients identified from medical records searches were approached directly by the researchers and many were found to be unwilling to try discontinuing their antidepressants. Finally, we had no information on the numbers of patients in each arm who did not taper their antidepressant, or embarked on tapering, but subsequently resumed the original dose. The qualitative interviews indicated some patients went quickly back on to their original dose of antidepressants when new symptoms developed, and were not supported by their GPs to try and get through them by going back up in dose temporarily, but we do not know how many did this. Conclusions Rates of discontinuation of long-term antidepressants of more than 40% are achievable through enabling patients who are ready to consider reducing them to get active support from primary care practitioners. Online and telephone support appears to help protect patients against depressive and withdrawal symptoms, and conserve mental well-being, although the benefits are modest. Advice to taper slowly and information on differences between relapse and withdrawal symptoms appear to be major factors contributing to successful discontinuation. Adverse events from attempting discontinuation are likely to be few, and usually not serious, so this is a relatively safe thing to do in primary care, where relapse of depression is likely to occur in a minority of patients, and treatment can be quickly restarted if patients are monitored. Patients may be greatly reassured by being able to ask questions through telephone support calls. Implications for practice and future research In the definitive RCT, only 8% of patients approached were willing to take part and only 5% could be consented and enrolled in the trial. However, uptake in routine clinical practice is likely to be higher now the interventions have been shown to be effective. Our qualitative process evaluation suggested that implementation methods need to include: Creating opportunities for discussing antidepressant discontinuation (more active reviews of people on long-term treatment and fewer routinely repeated prescriptions). Flagging the electronic records of patients who qualify for considering discontinuation. Delegation of medication reviews and tapering support to other professionals besides GPs. Making patients more aware of how withdrawal symptoms differ from relapse, and how to cope with them. Adopting tapering regimens over months rather than weeks, to reduce the occurrence and severity of withdrawal symptoms, with flexibility to go back up in dose if necessary. Proactive follow-up during tapering where possible, including brief telephone calls or text messages. Embedding links to alternative treatment resources in the electronic patient record. Future research should: Try to engage a greater proportion of people taking antidepressants, including younger people, unemployed people, people from deprived areas and of ethnic minority groups. Follow people more closely through their attempts to taper antidepressants, record the development of depressive and withdrawal symptoms, distinguish where possible between withdrawal and relapse, and determine relationships between symptoms and progress in tapering. Assess barriers and facilitators to wider implementation of support to practitioners and patients in clinical practice for antidepressant discontinuation. Assess the potential for involvement in deprescribing of other healthcare professionals (HCPs) besides GPs and NPs, in particular pharmacists, and mental health professionals. Compare new interventions against best practice, that is active review of medication by HCPs, rather than usual care, which currently often means no active review for many people taking long-term antidepressants. Permissions Some of the text on the context for the REDUCE programme is reproduced from: Kendrick, T. Strategies to reduce use of antidepressants. Br J Clin Pharmacol 2020;1–11. https://doi.org/10.1111/bcp.14475 This is an open access article under the terms of the Creative Commons Attribution 4.0 International License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Some of the text on WS5, the definitive RCT, is reproduced from Kendrick T, Geraghty AWA, Bowers H, Stuart B, Leydon G, May C, et al. REDUCE (Reviewing long-term antidepressant use by careful monitoring in everyday practice) internet and telephone support to people coming off long-term antidepressants: protocol for a randomised controlled trial. Trials 2020;21:419. https://doi.org/10.1186/s13063-020-04338-7. This is an open access article under the terms of the Creative Commons Attribution 4.0 International License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Some of the text, figures and tables on WS5, the definitive RCT, are reproduced from Kendrick T, Stuart B, Bowers H, Haji Sadeghi M, Page H, Dowrick C, et al. Internet and telephone support for discontinuing long-term antidepressants: the REDUCE cluster randomized trial. JAMA Network Open 2024;7(6):e2418383. https://doi.org/10.1001/jamanetworkopen.2024.18383 This is an open access article under the terms of the Creative Commons Attribution 4.0 International License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme (NIHR award ref: RP-PG-1214-20004) and is published in full in Programme Grants for Applied Research; Vol. 13, No. 7. See the NIHR Funding and Awards website for further award information.

Background:Antimicrobial resistance is a global health threat. Antibiotics are commonly prescribed for children with uncomplicated lower respiratory tract infections, but there is little randomised evidence to support the effectiveness of antibiotics in treating these infections, either overall or relating to key clinical subgroups in which antibiotic prescribing is common (chest signs; fever; physician rating of unwell; sputum/rattly chest; shortness of breath). Objectives:To estimate the clinical effectiveness and cost-effectiveness of amoxicillin for uncomplicated lower respiratory tract infections in children both overall and in clinical subgroups. Design:Placebo-controlled trial with qualitative, observational and cost-effectiveness studies. Setting:UK general practices. Participants:Children aged 1-12 years with acute uncomplicated lower respiratory tract infections. Outcomes:The primary outcome was the duration in days of symptoms rated moderately bad or worse (measured using a validated diary). Secondary outcomes were symptom severity on days 2-4 (0 = no problem to 6 = as bad as it could be); symptom duration until very little/no problem; reconsultations for new or worsening symptoms; complications; side effects; and resource use. Methods:Children were randomised to receive 50 mg/kg/day of oral amoxicillin in divided doses for 7 days, or placebo using pre-prepared packs, using computer-generated random numbers by an independent statistician. Children who were not randomised could participate in a parallel observational study. Semistructured telephone interviews explored the views of 16 parents and 14 clinicians, and the data were analysed using thematic analysis. Throat swabs were analysed using multiplex polymerase chain reaction. Results:A total of 432 children were randomised (antibiotics, n = 221; placebo, n = 211). The primary analysis imputed missing data for 115 children. The duration of moderately bad symptoms was similar in the antibiotic and placebo groups overall (median of 5 and 6 days, respectively; hazard ratio 1.13, 95% confidence interval 0.90 to 1.42), with similar results for subgroups, and when including antibiotic prescription data from the 326 children in the observational study. Reconsultations for new or worsening symptoms (29.7% and 38.2%, respectively; risk ratio 0.80, 95% confidence interval 0.58 to 1.05), illness progression requiring hospital assessment or admission (2.4% vs. 2.0%) and side effects (38% vs. 34%) were similar in the two groups. Complete-case (n = 317) and per-protocol (n = 185) analyses were similar, and the presence of bacteria did not mediate antibiotic effectiveness. NHS costs per child were slightly higher (antibiotics, £29; placebo, £26), with no difference in non-NHS costs (antibiotics, £33; placebo, £33). A model predicting complications (with seven variables: baseline severity, difference in respiratory rate from normal for age, duration of prior illness, oxygen saturation, sputum/rattly chest, passing urine less often, and diarrhoea) had good discrimination (bootstrapped area under the receiver operator curve 0.83) and calibration. Parents found it difficult to interpret symptoms and signs, used the sounds of the child's cough to judge the severity of illness, and commonly consulted to receive a clinical examination and reassurance. Parents acknowledged that antibiotics should be used only when 'necessary', and clinicians noted a reduction in parents' expectations for antibiotics. Limitations:The study was underpowered to detect small benefits in key subgroups. Conclusion:Amoxicillin for uncomplicated lower respiratory tract infections in children is unlikely to be clinically effective or to reduce health or societal costs. Parents need better access to information, as well as clear communication about the self-management of their child's illness and safety-netting. Future work:The data can be incorporated in the Cochrane review and individual patient data meta-analysis. Trial registration:This trial is registered as ISRCTN79914298. Funding:This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 9. See the NIHR Journals Library website for further project information.

Introduction: Respiratory tract infections (RTIs) are a major cause of morbidity and mortality in some high-risk groups including children and older adults. There is evidence that Chinese herbal medicine has an effect on RTIs. Reynoutria japonica Houtt (better known under its synonym Fallopia japonica (Houtt.) Ronse Decr.) (F. japonica), a commonly used Chinese herbal medicine, has a high content of resveratrol and glycosides. In traditional Chinese medicine theory, F. japonica has the effect of clearing heat in the body, improving blood and qi circulation, eliminating phlegm, and relieving cough, so it may have an effect on RTIs.Methods: This systematic review was registered under PROSPERO CRD42020188604. Databases were searched for randomized controlled trials of F. japonica as a single herb, or as a component of a complex herbal formula for RTIs. Quality of methodology was assessed by two reviewers independently using the Cochrane Risk of Bias Tool. The primary outcome was symptom improvement rate. The secondary outcome measures were fever clearance time, Murray lung injury score and incidence of adverse effects. The extracted data were pooled and meta-analysed by RevMan 5.3 software.Results: Eight RCTs with 1,123 participants with acute RTIs were included in this systematic review, and all the RCTs used F. japonica as part of a herbal mixture. Only one included trial used F. japonica in a herbal mixture without antibiotics in the treatment group. The findings showed that herbal remedies that included F. japonica could increase the symptom improvement rate (risk ratio 1.14, 95% confidence intervals [1.09, 1.20], I-2 = 0%, p < 0.00001, n = 7 trials, 1,013 participants), shorten fever duration, reduce Murray lung injury score and did not increase adverse events (RR 0.33, 95% CI [0.11, 1.00], I-2 = 0%, p = 0.05, n = 5 trials, 676 participants).Conclusion: There is limited but some evidence that F. japonica as part of a herbal mixture may be an effective and safe intervention for acute RTIs in clinical practice. In future studies it would be preferable to evaluate the effectiveness and safety of using F. japonica without antibiotics for acute RTIs.

OBJECTIVES:This study aimed to assess whether the presence of bacteria or viruses in the upper airway of children presenting with uncomplicated lower respiratory tract infection (LRTI) predicts the benefit of antibiotics.METHODS:Children between 6 months and 12 years presenting to UK general practices with an acute LRTI were randomized to receive amoxicillin 50 mg/kg/d for 7 days or placebo. Children not randomized (ineligible or clinician/parental choice) could participate in a parallel observational study. The primary outcome was the duration of symptoms rated moderately bad or worse. Throat swabs were taken and analyzed for the presence of bacteria and viruses by multiplex PCR.RESULTS:Swab results were available for most participants in the trial (306 of 432; 71%) and in the observational (182 of 326; 59%) studies. Bacterial pathogens potentially sensitive to amoxicillin (Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae) were detected among 51% of the trial placebo group and 49% of the trial antibiotic group. The median difference in the duration of symptoms rated moderately bad or worse between antibiotic and placebo was similar when potentially antibiotic-susceptible bacteria were present (median: -1 day; 99% CI, -12.3 to 10.3) or not present (median: -1 day; 99% CI, -4.5 to 2.5). Furthermore, bacterial genome copy number did not predict benefit. There were similar findings for all secondary outcomes and when including the data from the observational study.DISCUSSION:There was no clear evidence that antibiotics improved clinical outcomes conditional on the presence or concentration of bacteria or viruses in the upper airway. Before deploying microbiologic point-of-care tests for children with uncomplicated LRTI in primary care, rigorous validating trials are needed.

Review question / Objective: A systematic review and meta-analysis will be conducted to evaluate whether Chinese patent medicine Shufeng Jiedu capsule (SFJD) is effective in relieving symptoms, shortening the course, and influencing the use of antibiotics or antivirals in acute upper respiratory tract infections (AURTIs).Parallel group, randomized controlled trials in regardless of blinding will be included.

Background Benefits to patients from reduced depression have been shown from monitoring progress with patient-reported outcome measures (PROMs) in psychological therapy and mental health settings. This approach has not yet been researched in the United Kingdom for primary care, which is where most people with depression are treated in the United Kingdom. Methods This is a parallel-group cluster randomised trial with 1:1 allocation to intervention and control. Patients who are age 18+ years, with a new episode of depressive disorder/symptoms, meet the inclusion criteria. Patients with current depression treatment, comorbid dementia/psychosis/substance misuse/suicidal ideas are excluded. The intervention includes the Administration of Patient Health Questionnaire (PHQ-9) as a PROM within 2 weeks of diagnosis and at follow-up 4 weeks later. General practitioners are trained in interpreting scores and asked to take them into account in their treatment decisions. Patients are given written feedback on scores and suggested treatments. The primary outcome measure is Depression on the Beck Depression Inventory BDI-II at 12 weeks. Secondary outcomes include BDI-II at 26 weeks, changes in drug treatments and referrals, social functioning (Work & Social Adjustment Scale) and quality of life (EQ-5D) at 12 and 26 weeks, service use over 26 weeks (modified Client Services Receipt Inventory) to calculate NHS costs, and patient satisfaction at 26 weeks (Medical Informant Satisfaction Scale). The sample includes 676 total participants from 113 practices across three centres. Randomisation is achieved by computerised sequence generation. Blinding is impossible given the nature of the intervention (self-report outcome measures prevent rating bias). Differences at 12 and 26 weeks between intervention and controls in depression, social functioning and quality of life are analysed using linear mixed models, adjusted for socio-demographics, baseline depression, anxiety, and clustering, while including practice as a random effect. Patient satisfaction, quality of life (QALYs) and costs over 26 weeks will be compared between arms. Qualitative process analysis includes interviews with 15–20 GP/NPs and 15–20 patients per arm to reflect trial results and implementation issues, using Normalization Process Theory as a theoretical framework. Discussion If PROMs are helpful in improving patient outcomes for depression even to a small extent, then they are likely to be good value for money, given their low cost. The benefits could be considerable, given that depression is common, disabling, and costly. Trial registration ISRCTN no: 17299295 . Registered 1st October 2018.

Background: There is accumulating evidence suggesting that long-term antibiotic use may alter the gut microbiome which has, in turn, been linked to type 2 diabetes. We undertake this study to investigate whether antibiotic use was associated with increased risk of type 2 diabetes.Methods: This prospective cohort study included U.S. women free of diabetes, cardiovascular disease and cancer in the Nurses' Health Study (NHS 2004-2012) and NHS II (2005-2013). We evaluated the overall duration of antibiotics use in the past four years and at different ages (NHS: age 20-39, 40-59, and 60+; NHS II: age 20-39, 40-49, and 50+) and subsequent diabetes risk with a time-dependent COX proportional hazards model.Findings: Pooled analyses of NHS and NHS II (1 476 cases, 379 143 person-years) revealed that a longer duration of antibiotic use in the past 4 years was significantly associated with higher risk of diabetes (Ptrend = 0·002). As compared with non-users, participants who received antibiotics treatment for a medium duration of 15 days to 2 months (HR 1.29, 95% CI 1·11 to 1·51) or long duration of over 2 months (HR 1·27, 95% CI 1·12 to 1·58) had significantly higher risk. We also noted significant positive associations between antibiotic use duration at age 40-49 and the diabetes risk in NHS II (Ptrend < 0·0001) and between antibiotic use at age 60+ and diabetes risk in NHS (Ptrend = 0·01).Interpretation: A longer duration of antibiotic use in recent years and in middle or older age was associated with increased risk of type 2 diabetes in women.Funding Statement: This study was supported by the startup grant for the 100 Top Talents Program, The Seventh Affiliated Hospital, Sun Yat-sen University (392012). The NHS and NHS II were supported by the National Cancer Institute (UM1 CA176726, and UM1 CA186107), and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK58845, DK112940).Declaration of Interests: The authors declared that there was no potential conflicts of interest relevant to this article.Ethics Approval Statement: The NHS and NHS II were approved by the Human Research Committee at the Brigham and Women’s Hospital, Boston, MA. All participants provided written informed consent.

Antidepressants are one of the most commonly prescribed medications in young and middle-aged adults, but there is relatively little information on their safety across a range of adverse outcomes in this age group. This study aimed to assess associations between antidepressant treatment and several adverse outcomes in people aged 20–64 years diagnosed with depression.

OBJECTIVE: To compare clinical practice guideline recommendations on the use of oral patent Traditional Chinese Medicines (PTCMs) for uncomplicated acute lower respiratory tract infections (ALRTIs) in adults with the existing evidence using results of a systematic review of randomized controlled trials (RCTs). METHODS: A systematic review on RCTs and a systematic review of current guidelines on orally taken PTCMs for uncomplicated ALRTIs were performed. PubMed, Cochrane Library, EMBASE and four Chinese databases were searched from inception to September 2016 for RCTs testing orally taken PTCMs for uncomplicated ALRTIs (excluding pneumonia). Two reviewers independently screened each study, extracted study data, and assessed risk of bias. Disagreements were resolved through discussion or by consultation with a third reviewer. Clinical practice guidelines for uncomplicated ALRTIs containing PTCM recommendations were identified and quality appraised. The quality of pooled evidence of the RCTs and the guidelines was assessed with GRADE and AGREE II respectively. The consistency of the evidence base in RCTs and the guideline recommendations were then compared. RESULTS: For the systematic review of RCTs, 4810 papers were identified, among which 29 RCTs (5093 patients) were included in the review. PTCMs compared to placebo increased the effective treatment rate of cough (3 trials, 949 patients, risk ratio (RR) 2.50, 1.16 to 5.43; low certainty); improved assessment of global health (3 trials, 948 patients, RR 1.70, 1.44 to 2.01; low certainty); and increased the effective rate of specific symptom relief (1 trial, 478 patients, RR 4.01, 2.76 to 5.81; moderate certainty). 21 trials (3432 patients) compared effects of different PTCMs. For the guideline evaluation, 29 PTCMs were recommended for the use of uncomplicated ALRTIs, of which27 had no supportive evidence from RCTs. CONCLUSION: The evidence base of PTCMs for uncomplicated ALRTIs is weak and the guideline recommendations were based on almost no clinical trial evidence. Rigorous clinical research is urgently needed to inform the clinical use of these herbal medicines. Further training in evidence-based medicine methods for Traditional Chinese Medicine guideline developers is essential. (C) 2018 JTCM. All rights reserved.

Objectives To explore feasibility of a randomised study using standardised or individualised multiherb Chinese herbal medicine (CHM) for oligomenorrhoea and amenorrhoea in women with polycystic ovary syndrome (PCOS), to pilot study methods and to obtain clinical data to support sample size calculations. Design Prospective, pragmatic, randomised feasibility and pilot study with participant and practitioner blinding. Setting 2 private herbal practices in the UK. Participants 40 women diagnosed with PCOS and oligomenorrhoea or amenorrhoea following Rotterdam criteria. Intervention 6 months of either standardised CHM or individualised CHM, 16 g daily taken orally as a tea. Main outcome measures Our primary objective was to determine whether oligomenorrhoea and amenorrhoea were appropriate as the primary outcome measures for the main study. Estimates of treatment effects were obtained for menstrual rate, body mass index (BMI), weight and hirsutism. Data were collected regarding safety, feasibility and acceptability. Results Of the 40 participants recruited, 29 (72.5%) completed the study. The most frequently cited symptoms of concern were hirsutism, weight and menstrual irregularity. Statistically significant improvements in menstrual rates were found at 6 months within group for both standardised CHM (mean difference (MD) 0.18±0.06, 95% CI 0.06 to 0.29; p=0.0027) and individualised CHM (MD 0.27±0.06, 95% CI 0.15 to 0.39; p<0.001), though not between group (p=0.26). No improvements were observed for BMI nor for weight in either group. Improvements in hirsutism scores found within group for both groups were not statistically significant between group (p=0.09). Liver and kidney function and adverse events data were largely normal. Participant feedback suggests changing to tablet administration could facilitate adherence. Conclusions A CHM randomised controlled trial for PCOS is feasible and preliminary data suggest that both individualised and standardised multiherb CHMs have similar safety profiles and clinical effects on promoting menstrual regularity. These data will inform the design of a study in primary care that will incorporate an appropriate control. Trial registration number ISRCTN 31072075; Results.

OBJECTIVES:To determine the feasibility of a trial of patient-reported outcome measures (PROMs) for monitoring primary care patients with depression. DESIGN:Partly individually randomised, partly cluster-randomised controlled trial. SETTING:Nine general practices in Southern England. PARTICIPANTS:47 adults with new episodes of depression: 22 intervention, 25 control. RANDOMISATION:Remote computerised sequence generation and allocation. INTERVENTIONS:Patient Health Questionnaire, Distress Thermometer Analogue Scale and PSYCHLOPS problem profile for monitoring depression, following diagnosis and at 10-35 days later. Feedback of scores to patients was determined by practitioners. BLINDING:Non-blinded, using self-completed measures. PRIMARY OUTCOME:Beck Depression Inventory (BDI-II). SECONDARY OUTCOME MEASURES:Work and Social Adjustment Scale (WSAS), EuroQol Five-item, Five-level (EQ-5D-5L) Scale for quality of life, modified Client Service Receipt Inventory for costs, Medical Informant Satisfaction Scale (MISS), qualitative interviews with 14 patients and 13 practice staff about feasibility and acceptability of trial design. RESULTS:Three practices failed to recruit the target of six patients in 12 months. Follow-up rates were intervention patients: 18 (82%) at 12 weeks and 15 (68%) at 26 weeks; controls: 18 (72%) and 15 (60%), respectively. At 12 weeks, mean BDI-II score was lower among intervention group patients than controls by 5.8 points (95% CI -11.1 to -0.5), adjusted for baseline differences and clustering. WSAS scores were not significantly different. At 26 weeks, there were no significant differences in symptoms, social functioning, quality of life or costs, but mean satisfaction score was higher among controls by 22.0 points (95% CI -40.7 to -3.29). Intervention patients liked completing PROMs, but were disappointed when practitioners did not use the results to inform management. CONCLUSIONS:PROMs may improve depression outcome in the short term, even if PROM scores do not inform practitioners' management. Challenges in recruiting and following up patients need addressing for a definitive trial of relatively brief measures which can potentially inform management. https://www.isrctn.com/search?q=97492541 TRIAL REGISTRATION NUMBER: ISRCTN 97492541; Pre-results.