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:Osteoarthritis of the hip is a leading cause of chronic disability. The cycling and education intervention (CLEAT) trial aimed to compare the clinical and cost-effectiveness of the cycling against hip pain (CHAIN) intervention, a group-based cycling and education programme, with usual physiotherapy care for patients with hip osteoarthritis referred for physiotherapy at a UK hospital. METHODS:CLEAT was a pragmatic, single-centre, randomised controlled trial done in Bournemouth, UK. Patients older than 18 years with activity-related joint pain, either no morning stiffness or morning stiffness lasting no longer than 30 min, and who met the primary-care criteria for exercise referral were eligible to participate. Patients aged 18-45 years were only eligible to participate if an x-ray confirmed the presence of hip osteoarthritis. Participants were randomly assigned (1:1) to either the CHAIN intervention or usual physiotherapy care using random permuted blocks of sizes 2, 4, and 6. Participants in the CHAIN intervention group attended an 8-week group programme at a local leisure centre comprised of education and static cycling. Participants in the physiotherapy group had usual one-to-one care with a physiotherapist at the local hospital or by telephone, depending on usual care at the time of treatment. The primary outcome was the difference in Hip Disability and Osteoarthritis Outcome Score (HOOS) activities of daily living subscale at 10 weeks post-treatment (visit 4) between groups. The trial included a parallel economic evaluation from the primary perspective of the UK NHS and personal social services. All participants who provided data at visit 4 were included in the efficacy analysis, and data on safety and adverse events were collected between baseline and visit 4. People with lived experience of hip osteoarthritis were involved in the design and management of the study. This trial is registered with ISRCTN (ISRCTN19778222). FINDINGS:Between Feb 24, 2020, and April 28, 2023, 221 participants were recruited to the study and randomly assigned to the CHAIN intervention (110 [50%]) or usual physiotherapy care (111 [50%]). 126 (57%) participants were female, 95 (43%) were male, 217 (98%) were White, and the mean age was 64·4 years (SD 9·5). Participants in the CHAIN group had greater improvements in mean HOOS activities of daily living subscale scores (from 60·8 [SD 19·2] at baseline to 73·5 [20·0] at 10 weeks) compared with participants in the usual physiotherapy care group (from 59·3 [19·6] to 65·4 [19·9]; adjusted mean difference 6·9 [95% CI 2·5-11·2]; p=0·0023). Although the primary outcome showed a statistically significant improvement for CHAIN over usual physiotherapy, the between-group difference of 6·9 HOOS points did not meet the pre-defined minimum clinically important difference of 7·4. CHAIN cost £4092 per quality-adjusted life year gained compared with usual physiotherapy care, below the £20 000 to £30 000 National Institute of Health and Care Excellence threshold for cost-effectiveness. There were no treatment-related serious adverse events. INTERPRETATION:The CHAIN intervention showed superior outcomes compared with usual physiotherapy care, and the feasibility of delivering a low-cost, community-based intervention within the NHS was shown. However, longer-term benefits and broader generalisability warrant further investigation. FUNDING:The National Institute for Health and Care Research for Patient Benefit Programme.

Tangier disease (TD) is an ultra-rare disease, characterised by progressive peripheral neuropathy with no established treatment. To determine whether miglustat improved the clinical status of a single patient with TD, and to investigate the possible mechanisms of miglustat in this patient. An n-of-1 ABAB study, alternating on and off treatment for 6-month periods, total study duration of 2 years with an additional compassionate-access period of 21 months. Miglustat, an orphan drug licenced to treat Gaucher disease and Niemann–Pick disease, was repurposed. The study was designed with two co-primary endpoints: (a) time taken to complete the nine-hole peg test (fine motor control and finger dexterity), and (b) hand strength: grip and three-point pinch strength tests. Secondary endpoints were quality-of-life measures and biomarkers. A 21-year-old (at baseline) left-handed male patient with TD, diagnosed at the age of 6 months, and disabling neuropathy was included in the study. Over 2 years, there was a small signal in our clinical measures that the drug may be beneficial. Compared with the 2 years prior to treatment, the patient had no relapse of neuropathy during his study period and further extension. During the 21-month treatment extension, he showed considerable improvement on primary endpoints. Biomarkers changed as expected based on the mechanism of action of miglustat. Nerve conduction studies showed a mild benefit. Importantly, the patient’s reported experience suggested a meaningful benefit from miglustat. Miglustat may be used to treat neurological complications of TD. This study showed that an n-of-1 study to inform a policy decision is practical and may offer hope to patients with rare diseases. ClinicalTrials.gov Identifier: ISRCTN17945917. Registration date: 07/06/2021; ‘retrospectively registered’.

Deaths from alcohol-related liver disease (ARLD) are rising in the UK, representing a significant public health crisis. Effective interventions are urgently needed to reduce alcohol consumption and improve outcomes for individuals with ARLD. While behaviour change interventions (BCIs) are effective, their scalability is limited. Digital therapeutics offer a promising avenue for delivering BCIs remotely and at scale. AlcoChange, a novel digital therapeutic combining a smartphone app and digital breathalyser, delivers personalised BCIs based on patient triggers. Preliminary data suggest its potential efficacy in reducing alcohol use. This is a multi-centre, two-arm, parallel-group, individually randomised controlled trial comparing usual care (review by a hospital Alcohol Care Team and brief intervention) with usual care plus AlcoChange in patients with ARLD. Adults aged 18 years or older with a diagnosis of ARLD (including cirrhosis, fibrosis, steatohepatitis, or recent alcoholic hepatitis) who have been advised to abstain from alcohol and intend to do so, and who have access to a smartphone. Usual care plus AlcoChange, comprising a smartphone app and digital breathalyser delivering personalised behaviour change techniques. Usual care alone. The primary outcome is the proportion of patients abstinent or reporting low-risk alcohol consumption (< 14 units/week) at 180 days post-randomisation, assessed using the Timeline Follow-Back (TLFB) method. Secondary outcomes include self-reported alcohol use at various time points, liver disease severity, health-related quality of life, healthcare resource utilisation, and cost-effectiveness. Four hundred participants will be recruited from up to 18 NHS hospitals in England and randomised 1:1. A mixed-methods approach was used to develop the trial protocol, including a theory of change framework and bespoke training materials for the TLFB assessment. This trial will evaluate the real-world efficacy and cost-effectiveness of AlcoChange in reducing alcohol consumption and alcohol-related harm in individuals with ARLD. The study addresses the urgent need for scalable interventions to combat the rising burden of ARLD in the UK. The pragmatic design and mixed methods approach to implementation aim to enhance the generalizability and impact of the findings. The trial will provide valuable evidence to inform clinical practice and policy regarding the use of digital therapeutics for alcohol use disorder and liver disease.

BACKGROUND:A small amount of evidence suggests that nasal sprays, or physical activity and stress management, could shorten the duration of respiratory infections. This study aimed to assess the effect of nasal sprays or a behavioural intervention promoting physical activity and stress management on respiratory illnesses, compared with usual care. METHODS:This randomised, controlled, open-label, parallel-group trial was done at 332 general practitioner practices in the UK. Eligible adults (aged ≥18 years) had at least one comorbidity or risk factor increasing their risk of adverse outcomes due to respiratory illness (eg, immune compromise due to serious illness or medication; heart disease; asthma or lung disease; diabetes; mild hepatic impairment; stroke or severe neurological problem; obesity [BMI ≥30 kg/m2]; or age ≥65 years) or at least three self-reported respiratory tract infections in a normal year (ie, any year before the COVID-19 pandemic). Participants were randomly assigned (1:1:1:1) using a computerised system to: usual care (brief advice about managing illness); gel-based spray (two sprays per nostril at the first sign of an infection or after potential exposure to infection, up to 6 times per day); saline spray (two sprays per nostril at the first sign of an infection or after potential exposure to infection, up to 6 times per day); or a brief behavioural intervention in which participants were given access to a website promoting physical activity and stress management. The study was partially masked: neither investigators nor medical staff were aware of treatment allocation, and investigators who did the statistical analysis were unaware of treatment allocation. The sprays were relabelled to maintain participant masking. Outcomes were assessed using data from participants' completed monthly surveys and a survey at 6 months. The primary outcome was total number of days of illness due to self-reported respiratory tract illnesses (coughs, colds, sore throat, sinus or ear infections, influenza, or COVID-19) in the previous 6 months, assessed in the modified intention-to-treat population, which included all randomly assigned participants who had primary outcome data available. Key secondary outcomes were possible harms, including headache or facial pain, and antibiotic use, assessed in all randomly assigned participants. This trial was registered with ISRCTN, 17936080, and is closed to recruitment. FINDINGS:Between Dec 12, 2020, and April 7, 2023, of 19 475 individuals screened for eligibility, 13 799 participants were randomly assigned to usual care (n=3451), gel-based nasal spray (n=3448), saline nasal spray (n=3450), or the digital intervention promoting physical activity and stress management (n=3450). 11 612 participants had complete data for the primary outcome and were included in the primary outcome analysis (usual care group, n=2983; gel-based spray group, n=2935; saline spray group, n=2967; behavioural website group, n=2727). Compared with participants in the usual care group, who had a mean of 8·2 (SD 16·1) days of illness, the number of days of illness was significantly lower in the gel-based spray group (mean 6·5 days [SD 12·8]; adjusted incidence rate ratio [IRR] 0·82 [99% CI 0·76-0·90]; p<0·0001) and the saline spray group (6·4 days [12·4]; 0·81 [0·74-0·88]; p<0·0001), but not in the group allocated to the behavioural website (7·4 days [14·7]; 0·97 [0·89-1·06]; p=0·46). The most common adverse event was headache or sinus pain in the gel-based group: 123 (4·8%) of 2556 participants in the usual care group; 199 (7·8%) of 2498 participants in the gel-based group (risk ratio 1·61 [95% CI 1·30-1·99]; p<0·0001); 101 (4·5%) of 2377 participants in the saline group (0·81 [0·63-1·05]; p=0·11); and 101 (4·5%) of 2091 participants in the behavioural intervention group (0·95 [0·74-1·22]; p=0·69). Compared with usual care, antibiotic use was lower for all interventions: IRR 0·65 (95% CI 0·50-0·84; p=0·001) for the gel-based spray group; 0·69 (0·45-0·88; p=0·003) for the saline spray group; and 0·74 (0·57-0·94; p=0·02) for the behavioural website group. INTERPRETATION:Advice to use either nasal spray reduced illness duration and both sprays and the behavioural website reduced antibiotic use. Future research should aim to address the impact of the widespread implementation of these simple interventions. FUNDING:National Institute for Health and Care Research.

Background Pelargonium sidoides DC (Geraniaceae) root extract, EPs®7630 or “Kaloba®”, is a widely used herbal remedy for respiratory infections, with some evidence of effectiveness for acute bronchitis. However, it is not yet widely recommended by medical professionals in the UK. There is a need to undertake appropriately designed randomised trials to test its use as an alternative to antibiotics. The aim was to assess the feasibility of conducting a double-blind randomised controlled trial of Pelargonium sidoides root extract for treatment of acute bronchitis in UK primary care, investigating intervention compliance, patient preference for dosage form and acceptability of patient diaries. Study design Feasibility double-blind randomised placebo-controlled clinical trial. Methods We aimed to recruit 160 patients with cough (≤ 21 days) caused by acute bronchitis from UK general practices. Practices were cluster-randomised to liquid or tablet preparations and patients were individually randomised to Kaloba® or placebo. We followed participants up for 28 days through self-reported patient diaries with telephone support and reviewed medical records at one month. Outcomes included recruitment, withdrawal, safety, reconsultation and symptom diary completion rates. We also assessed treatment adherence, antibiotic prescribing and consumption, mean symptom severity (at days 2–4 after randomisation) and time to symptom resolution. We interviewed 29 patients and 11 health professionals to identify barriers and facilitators to running such a randomised trial. Results Of 543 patients screened, 261 were eligible, of whom 134 (51%) were recruited and 103 (77%) returned a completed diary. Overall, 41% (41/100) of patients took antibiotics (Kaloba® liquid group: 48% [15/31]; placebo liquid group: 23% [6/26]; Kaloba® tablet group: 48% [9/21]; placebo tablet group: 50% [11/22]). Most patients adhered to the study medication (median 19 out of 21 doses taken in week 1, IQR 18–21 - all arms combined). There were no serious adverse events relating to treatment. Most patients interviewed found study recruitment to be straightforward, but some found the diary too complex. Conclusions It was feasible and acceptable to recruit patients from UK primary care to a double-blind placebo-controlled trial of herbal medicine (Kaloba®) for the treatment of acute bronchitis, with good retention and low data attrition. Trial registration HATRIC was registered on the ISRCTN registry ( ISRCTN17672884 ) on 16 August 2018, retrospectively registered. The record can be found at http://www.isrctn.com/ISRCTN17672884 .

New format for BMJ research articles It's nearly 10 years since we began abridging original research articles for readers of the print BMJ. Now we're going a step further, using the advantages of both web and print. The full, open access version of this original article is published online (doi:10.1 1 36/bmj. a2656), alongwith our first BM] research video and a podcast. Here are two abridged versions: an abstract prepared by the authors and a Short Cuts article written by the BMJ. Which version would you read and use? Which would you prefer if you were the author? Please tell us yourviews, as readers and researchers, by posting rapid responses to this article online (doi:10.1136/ bmj.a2946). Randomised controlled trial of Alexander technique for chronic and recurrent back pain: economic evaluation

OBJECTIVE:To determine the effectiveness of lessons in the Alexander technique, massage therapy, and advice from a doctor to take exercise (exercise prescription) along with nurse delivered behavioural counselling for patients with chronic or recurrent back pain.DESIGN:Factorial randomised trial. Setting 64 general practices in England.PARTICIPANTS:579 patients with chronic or recurrent low back pain; 144 were randomised to normal care, 147 to massage, 144 to six Alexander technique lessons, and 144 to 24 Alexander technique lessons; half of each of these groups were randomised to exercise prescription.INTERVENTIONS:Normal care (control), six sessions of massage, six or 24 lessons on the Alexander technique, and prescription for exercise from a doctor with nurse delivered behavioural counselling.MAIN OUTCOME MEASURES:Roland Morris disability score (number of activities impaired by pain) and number of days in pain.RESULTS:Exercise and lessons in the Alexander technique, but not massage, remained effective at one year (compared with control Roland disability score 8.1: massage -0.58, 95% confidence interval -1.94 to 0.77, six lessons -1.40, -2.77 to -0.03, 24 lessons -3.4, -4.76 to -2.03, and exercise -1.29, -2.25 to -0.34). Exercise after six lessons achieved 72% of the effect of 24 lessons alone (Roland disability score -2.98 and -4.14, respectively). Number of days with back pain in the past four weeks were lower after lessons (compared with control median 21 days: 24 lessons -18, six lessons -10, massage -7) and quality of life improved significantly. No significant harms were reported.CONCLUSIONS:One to one lessons in the Alexander technique from registered teachers have long term benefits for patients with chronic back pain. Six lessons followed by exercise prescription were nearly as effective as 24 lessons.