Individual patient data meta-analysis of the effects of fluoxetine on functional outcomes after acute stroke.

BACKGROUND: Three large randomized controlled trials of fluoxetine for stroke recovery have been performed. We performed an individual patient data meta-analysis (IPDM) on the combined data. METHODS: Fixed effects meta-analyses were performed on the combined data set, for the primary outcome (modified Rankin scale (mRS) at 6 months), and secondary outcomes common to the individual trials. As a sensitivity analysis, summary statistics from each trial were created and combined. FINDINGS: The three trials recruited a combined total of 5907 people (mean age 69.5 years (SD 12.3), 2256 (38%) females, 2-15 days post-stroke) from Australia, New Zealand, United Kingdom, Sweden, and Vietnam; and randomized them to fluoxetine 20 mg daily or matching placebo for 6 months. Data on 5833 (98.75%) were available at 6 months. The adjusted ordinal comparison of mRS was similar in the two groups (common OR 0.96, 95% CI 0.87 to 1.05, p = 0.37). There were no statistically significant interactions between the minimization variables (baseline probability of being alive and independent at 6 months, time to treatment, motor deficit, or aphasia) and pre-specified subgroups (including age, pathological type, inability to assess mood, proxy or patient consent, baseline depression, country). Fluoxetine increased seizure risk (2.64% vs 1.8%, p = 0.03), falls with injury (6.26% vs 4.51%, p = 0.03), fractures (3.15% vs 1.39%, p < 0.0001) and hyponatremia (1.22% vs 0.61%, p = 0.01) but reduced new depression (10.05% vs 13.42%, p < 0.0001). At 12 months, there was no difference in adjusted mRS (n = 5760; common OR 0.98, 95% CI 0.89 to 1.07). Sensitivity analyses gave the same results. INTERPRETATION: Fluoxetine 20 mg daily for 6 months did not improve functional recovery. It increased seizures, falls with injury, and bone fractures but reduced depression frequency at 6 months.

Invasive cervical cancer incidence following bivalent human papillomavirus vaccination: a population-based observational study of age at immunization, dose, and deprivation.

BACKGROUND: High-risk human papillomavirus causes cervical cancer. Vaccines have been developed that significantly reduce the incidence of preinvasive and invasive disease. This population-based observational study used linked screening, immunization, and cancer registry data from Scotland to assess the influence of age, number of doses, and deprivation on the incidence of invasive disease following administration of the bivalent vaccine. METHODS: Data for women born between January 1, 1988, and June 5, 1996, were extracted from the Scottish cervical cancer screening system in July 2020 and linked to cancer registry, immunization, and deprivation data. Incidence of invasive cervical cancer per 100 000 person-years and vaccine effectiveness were correlated with vaccination status, age at vaccination, and deprivation; Kaplan Meier curves were calculated. RESULTS: No cases of invasive cancer were recorded in women immunized at 12 or 13 years of age irrespective of the number of doses. Women vaccinated at 14 to 22 years of age and given 3 doses of the bivalent vaccine showed a significant reduction in incidence compared with all unvaccinated women (3.2/100 000 [95% confidence interval (CI) = 2.1 to 4.6] vs 8.4 [95% CI = 7.2 to 9.6]). Unadjusted incidence was significantly higher in women from most deprived (Scottish Index of Multiple Deprivation 1) than least deprived (Scottish Index of Multiple Deprivation 5) areas (10.1/100 000 [95% CI = 7.8 to 12.8] vs 3.9 [95% CI = 2.6 to 5.7]). Women from the most deprived areas showed a significant reduction in incidence following 3 doses of vaccine (13.1/100 000 [95% CI = 9.95 to 16.9] vs 2.29 [95% CI = 0.62 to 5.86]). CONCLUSION: Our findings confirm that the bivalent vaccine prevents the development of invasive cervical cancer and that even 1 or 2 doses 1 month apart confer benefit if given at 12-13 years of age. At older ages, 3 doses are required for statistically significant vaccine effectiveness. Women from more deprived areas benefit more from vaccination than those from less deprived areas.

Operative vs Nonoperative Management of Unstable Medial Malleolus Fractures: A Randomized Clinical Trial.

Importance: Unstable ankle fractures are routinely managed operatively. However, because of soft tissue and implant-related complications, recent literature has reported on the nonoperative management of well-reduced medial malleolus fractures after fibular stabilization, but with limited evidence supporting the routine application. Objective: To assess the superiority of internal fixation of well-reduced (displacement ≤2 mm) medial malleolus fractures compared with nonfixation after fibular stabilization. Design, Setting, and Participants: This superiority, pragmatic, parallel, prospective randomized clinical trial was conducted from October 1, 2017, to August 31, 2021. A total of 154 adult participants (≥16 years) with a closed, unstable bimalleolar or trimalleolar ankle fracture requiring surgery at an academic major trauma center in the UK were assessed. Exclusion criteria included injuries with no medial-sided fracture, open fractures, neurovascular injury, and the inability to comply with follow-up. Data analysis was performed in July 2022 and confirmed in September 2023. Interventions: Once the lateral (and where appropriate, posterior) malleolus had been fixed and satisfactory intraoperative reduction of the medial malleolus fracture was confirmed by the operating surgeon, participants were randomly allocated to fixation (n = 78) or nonfixation (n = 76) of the medial malleolus. Main Outcome and Measure: Olerud-Molander Ankle Score (OMAS) 1 year after randomization (range, 0-100 points, with 0 indicating worst possible outcome and 100 indicating best possible outcome). Results: Among 154 randomized participants (mean [SD] age, 56.5 [16.7] years; 119 [77%] female), 144 (94%) completed the trial. At 1 year, the median OMAS was 80.0 (IQR, 60.0-90.0) in the fixation group compared with 72.5 (IQR, 55.0-90.0) in the nonfixation group (P = .17). Complication rates were comparable. Significantly more patients in the nonfixation group developed a radiographic nonunion (20% vs 0%; P < .001), with 8 of 13 clinically asymptomatic; 1 patient required surgical reintervention for this. Fracture type and reduction quality appeared to influence fracture union and patient outcome. Conclusions and Relevance: In this randomized clinical trial comparing internal fixation of well-reduced medial malleolus fractures with nonfixation, after fibular stabilization, fixation was not superior according to the primary outcome. However, 1 in 5 patients developed a radiographic nonunion after nonfixation, and although the reintervention rate to manage this was low, the future implications are unknown. These results support selective nonfixation of anatomically reduced medial malleolar fractures after fibular stabilization. Trial Registration: ClinicalTrials.gov Identifier: NCT03362229.

Achieving Benchmarks for National Quality Indicators Reduces Recurrence and Progression in Non-muscle-invasive Bladder Cancer.

BACKGROUND: Noncompliance with evidence-based interventions and guidelines contributes to significant and variable recurrence and progression in patients with non-muscle-invasive bladder cancer (NMIBC). The implementation of a quality performance indicator (QPI) programme in Scotland's National Health Service (NHS) aimed to improve cancer outcomes and reduce nationwide variance. OBJECTIVE: To evaluate the effect of hospitals achieving benchmarks for two specific QPIs on time to recurrence and progression in NMIBC. DESIGN, SETTING, AND PARTICIPANTS: QPIs for bladder cancer (BC) were enforced nationally in April 2014. NHS health boards collected prospective data on all new BC patients. Prospectively recorded surveillance data were pooled from 12 collaborating centres. INTERVENTION: QPIs of interest were (1) hospitals achieving detrusor muscle (DM) sampling target at initial transurethral resection of bladder tumour (TURBT) and (2) use of single instillation of mitomycin C after TURBT (SI-MMC). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary and secondary endpoints were time to recurrence and progression, respectively. Kaplan-Meier and Cox multivariable regression analyses were performed. KEY FINDINGS AND LIMITATIONS: Between April 1, 2014 and March 31, 2017, we diagnosed 3899 patients with new BC, of which 2688 were NMIBC . With a median follow up of 60.3 mo, hospitals achieving the DM sampling target had a 5.4% lower recurrence rate at 5 yr than hospitals not achieving this target (442/1136 [38.9%] vs 677/1528 [44.3%], 95% confidence interval [CI] = 1.6-9.2, p = 0.005). SI-MMC was associated with a 20.4% lower recurrence rate (634/1791 [35.4%] vs 469/840 [55.8%], 95% CI = 16.4-24.5, p < 0.001). On Cox multivariable regression, meeting the DM target and SI-MMC were associated with significant improvement in recurrence (hazard ratio [HR] 0.81, 95% CI = 0.73-0.91, p = 0.0002 and HR 0.66, 95% CI = 0.59-0.74, p < 0.004, respectively) as well as progression-free survival (HR 0.62, 95% CI = 0.45-0.84, p = 0.002 and HR 0.65, 95% CI = 0.49-0.87, p = 0.004, respectively). We did not have a national multicentre pre-QPI control. CONCLUSIONS: Within a national QPI programme, meeting targets for sampling DM and SI-MMC in the real world were independently associated with delays to recurrence and progression in NMIBC patients. PATIENT SUMMARY: Following the first 3 yr of implementing a novel quality performance indicator programme in Scotland, we evaluated compliance and outcomes in non-muscle-invasive bladder cancer. In 2688 patients followed up for 5 yr, we found that achieving targets for sampling detrusor muscle and the single instillation of mitomycin C during and after transurethral resection of bladder tumour, respectively, were associated with delays in cancer recurrence and progression.

Ghana 3D Telemedicine International MDT: A proof-of-concept study.

A real-time 3D Telemedicine system - leveraging Microsoft's Holoportation™ communication technology - enabled an international multidisciplinary team meeting (MDT) to consult with complex reconstructive patients before, during, and after an overseas surgical collaboration. METHODS: A proof-of-concept international 3D MDT clinic took place in November 2022, between the Canniesburn Plastic Surgery Unit, UK, and the National Reconstructive Plastic Surgery and Burns Centre, Korle Bu Teaching Hospital, Ghana. The 3D system was utilised 1) previsit to assess patients and enable logistical planning, 2) on-site in Ghana to further allow patients to see themselves and proposed operations in 3D, and 3) post visit to debrief the team and patients. RESULTS: Four Ghana patients were followed through their patient journey (mandibular ameloblastoma, sarcoma thigh, maxillary tumour, sarcoma back). Thirteen participants (four patients, four Ghana clinicians, and five UK clinicians) completed feedback on the 3D MDT. Outcome measures were rated highly with satisfaction 84.31/100, perceived benefit 4.54/5, overall quality 127.3/147 (Telehealth Usability Questionnaire), and usability 83.2/100 (System Usability Scale). These data show close alignment with that previously published on high-income countries. CONCLUSIONS: This novel technology has the potential to enhance the delivery of overseas surgical visits to low-to-middle-income countries, by improving planning, informed discussion with patients, expert consensus on complex cases, and fostering engagement with professionals who may be thousands of miles away. This is the first demonstration that real-time 3D Telemedicine can both work, and enhance care within an international MDT clinic, and may thus enable change in the approach to overseas surgical collaborations.

Videolaryngoscopy use before and after the initial phases of the COVID-19 pandemic: The report of the VL-iCUE survey with responses from 96 countries.

BACKGROUND: The potential benefit of videolaryngoscopy use in facilitating tracheal intubation has already been established, however its use was actively encouraged during the COVID-19 pandemic as it was likely to improve intubation success and increase the patient-operator distance. OBJECTIVES: We sought to establish videolaryngoscopy use before and after the early phases of the pandemic, whether institutions had acquired new devices during the COVID-19 pandemic, and whether there had been teaching on the devices acquired. DESIGN: We designed a survey with 27 questions made available via the Joint Information Scientific Committee JISC online survey platform in English, French, Spanish, Chinese, Japanese and Portuguese. This was distributed through 18 anaesthetic and airway management societies. SETTING: The survey was open for 54 to 90 days in various countries. The first responses were logged on the databases on 28 October 2021, with all databases closed on 26 January 2022. Reminders to participate were sent at the discretion of the administering organisations. PARTICIPANTS: All anaesthetists and airway managers who received the study were eligible to participate. MAIN OUTCOME MEASURES: Videolaryngoscopy use before the COVID-19 pandemic and at the time of the survey. RESULTS: We received 4392 responses from 96 countries: 944/4336 (21.7%) were from trainees. Of the 3394 consultants, 70.8% (2402/3394) indicated no change in videolaryngoscopy use, 19.9% (675/3394) increased use and 9.3% (315/3393) reduced use. Among trainees 65.5% (618/943) reported no change in videolaryngoscopy use, 27.7% (261/943) increased use and 6.8% (64/943) reduced use. Overall, videolaryngoscope use increased by 10 absolute percentage points following the pandemic. CONCLUSIONS: Videolaryngoscopy use increased following the early phase of the COVID-19 pandemic but this was less than might have been expected.

The changing nature of HPV associated with high grade cervical lesions in vaccinated populations, a retrospective study of over 1700 cases in Scotland.

BACKGROUND: Understanding the pattern and dominance of HPV types in high grade cervical disease within increasingly vaccinated populations will help inform the development of appropriate screening and management protocols. METHODS: Over 1700 cases of cervical intraepithelial neoplasia (CIN) diagnosed between 2011 and 2017 in women younger than 25 were genotyped for HPV. Logistic regression was used to assess the association between HPV 16/18 positivity with biopsy-collection year, birth year, deprivation and vaccination status. Regression analysis was repeated for cross-protective types (31, 33 and 45). Type specific detail of non-vaccine types by vaccination status was presented descriptively. RESULTS: Detection of HPV 16/18 or 16/18/31/33 and 45 was lower in CIN2 associated with full vaccination vs no vaccination (OR 0.3; 95% CI 0.2-0.5 & 0.4; 95% CI 0.3-0.6 respectively) Similar observations were made for CIN3. The relative contribution of non-established high-risk types including those considered low risk was greater among vaccinated women with CIN2+ vs unvaccinated women with CIN2+. CONCLUSIONS: The change in HPV distribution in CIN2+ in vaccinated populations is a further marker of vaccine impact. Additionally, the progression rate of CIN2+ in vaccinated populations may be lower given the shift in type distribution. The definition of high grade disease in vaccinated populations may warrant reassessment.

Participatory development of a 3D telemedicine system during COVID: The future of remote consultations.

BACKGROUND: The COVID pandemic brought the need for more realistic remote consultations into focus. 2D Telemedicine solutions fail to replicate the fluency or authenticity of in-person consultations. This research reports on an international collaboration on the participatory development and first validated clinical use of a novel, real-time 360-degree 3D Telemedicine system worldwide. The development of the system - leveraging Microsoft's Holoportation™ communication technology - commenced at the Canniesburn Plastic Surgery Unit, Glasgow, in March 2020. METHODS: The research followed the VR CORE guidelines on the development of digital health trials, placing patients at the heart of the development process. This consisted of three separate studies - a clinician feedback study (23 clinicians, Nov-Dec 2020), a patient feedback study (26 patients, Jul-Oct 2021), and a cohort study focusing on safety and reliability (40 patients, Oct 2021-Mar 2022). "Lose, Keep, and Change" feedback prompts were used to engage patients in the development process and guide incremental improvements. RESULTS: Participatory testing demonstrated improved patient metrics with 3D in comparison to 2D Telemedicine, including validated measures of satisfaction (p<0.0001), realism or 'presence' (Single Item Presence scale, p<0.0001), and quality (Telehealth Usability Questionnaire, p = 0.0002). The safety and clinical concordance (95%) of 3D Telemedicine with a face-to-face consultation were equivalent or exceeded estimates for 2D Telemedicine. CONCLUSIONS: One of the ultimate goals of telemedicine is for the quality of remote consultations to get closer to the experience of face-to-face consultations. These data provide the first evidence that Holoportation™ communication technology brings 3D Telemedicine closer to this goal than a 2D equivalent.

Influence of resuspension volume on dry sampling devices taken for human papillomavirus testing: implications for self-sampling.

Optimization of technical parameters that influence the performance of human papillomavirus (HPV) testing on self-taken samples is important. Here, the authors assessed the impact of resuspension volume on the detection of HPV using four validated HPV assays. Two self-sampling devices, FLOQSwabs® and Evalyn® Brushes, were inoculated with dilutions of HPV-16-positive cell line, then resuspended in various volumes of ThinPrep. The influence of vortexing during resuspension was also assessed. At target concentrations around the assay cutoff, larger volumes led to decreased HPV detection. Interestingly, the effect(s) of vortexing differed by the self-sampling device. Resuspension in 5 ml or less may maximize the detection of HPV sequences. Using a proxy of clinical material, the current observations underline the importance of optimizing preanalytical laboratory processes to support high-quality HPV testing of self-samples.

Agreement between L1 and E6/E7-based assays for detection of high-risk HPV in cervical, oropharyngeal and penile cancers.

AIMS: Human papillomavirus (HPV) molecular testing targets either the late gene L1 or early genes E6 and/or E7. Loss of L1 during integration is suggested to compromise sensitivity in samples associated with cancer, however, clear evidence for this is lacking. Our aim is to address this by performing a head-to-head comparison between assays targeting L1 vs E6/E7, using a series of high-grade and invasive disease samples within different biological matrices and anatomical sites. METHODS: We obtained 298 samples comprising of liquid-based cytology and biopsies of cervical cancer and cervical intraepithelial neoplasia grade 3, in addition to biopsies of penile and oropharyngeal cancers. Two commercially available HPV primary screening assays and two assays with extended genotyping were applied to the sample set targeting L1 (Abbott RealTime HR HPV Assay and Optiplex HPV Genotyping Test) and E6/E7 genes (Xpert HPV Test and EuroArray HPV Test). RESULTS: Agreement for high-risk HPV (hrHPV) for all samples types between the screening assays is over 88% and over 96% for the two genotyping assays. For HPV 16 agreement is over 90% for both screening and genotyping assays. Kappa statistics show good to very good agreement between the screening and genotyping assays for hrHPV and HPV 16. CONCLUSIONS: Analysis of the valid results from our data indicates that L1 and E6/E7 targeting assays show similar performance for detection of hrHPV in high grade cervical lesions and cancers of cervix, penis and oropharynx.

Increased risk of type 3c diabetes mellitus after acute pancreatitis warrants a personalized approach including diabetes screening.

BACKGROUND: Acute pancreatitis (AP) is a frequent cause of hospitalization with long-term health consequences, including type 3c diabetes mellitus (DM). The incidence and risk factors for new-onset morbidities after AP need to be clarified to inform a personalized medicine approach. METHODS: Using a longitudinal electronic healthcare record-linkage analysis, all patients admitted to hospital in Scotland with a first episode of AP between 1 April 2009 and 31 March 2012 and followed for a minimum of 5 years after their index AP admission were identified. All new-onset morbidity with specific focus on type 3c DM were analysed and, using time-split multiple regression. RESULTS: A total of 2047 patients were included. AP requiring critical care was followed by 2 years of heightened risk (HR 5.24) of developing type 3c DM, increased risk of new-onset cardiac disease (HR 1.61), and renal disease (HR 2.96). The additional risk conferred by critical care AP had a negative interaction with time, whereas additional risk associated with male sex and a non-gallstone aetiology was long lasting. CONCLUSION: Based on these findings, a personalized approach to include type 3c DM screening for a minimum of 2 years for individuals who required critical care when hospitalized with AP is recommended.

Clinical Diagnosis and Magnetic Resonance Imaging in Patients With Transient and Minor Neurological Symptoms: A Prospective Cohort Study.

BACKGROUND: The utility of magnetic resonance imaging (MRI) brain in patients with transient or minor neurological symptoms is uncertain. We sought to determine the proportion of participants with transient or minor neurological symptoms who had MRI evidence of acute ischemia at different clinical probabilities of transient ischemic attack (TIA) or minor stroke. METHODS: Cohort of participants with transient or minor neurological symptoms from emergency and outpatient settings. Clinicians at different levels of training gave each participant a diagnostic probability (probable when TIA/stroke was the most likely differential diagnosis; possible when TIA/stroke was not the most likely differential diagnosis; or uncertain when diagnostic probability could not be given) before 1.5 or 3T brain MRI ≤5 days from onset. Post hoc, each clinical syndrome was defined blind to MRI findings as National Institute of Neurological Disorders and Stroke criteria TIA/stroke; International Headache Society criteria migraine aura; non-TIA focal symptoms; or nonfocal symptoms. MRI evidence of acute ischemia was defined by 2 reads of MRI. Stroke was ascertained for at least 90 days and up to 18 months after recruitment. RESULTS: Two hundred seventy-two participated (47% female, mean age 60, SD 14), 58% with MRI ≤2 days of onset. Most (92%) reported focal symptoms. MR evidence of acute ischemia was found, for stroke/TIA clinical probabilities of probable 23 out of 75 (31% [95% CI, 21%-42%]); possible 26 out of 151 (17% [12%-24%]); and uncertain 9 out of 43, (20% [10%-36%]). MRI evidence of acute ischemia was found in National Institute of Neurological Disorders and Stroke criteria TIA/stroke 40 out of 95 (42% [32%-53%]); migraine aura 4 out of 38 (11% [3%-25%]); non-TIA focal symptoms 16 out of 99 (16% [10%-25%]); and no focal features 1 out of 29 (3% [0%-18%]). After MRI, a further 14 (5% [95% CI, 3-8]) would be treated with an antiplatelet drug compared with treatment plan before MRI. By 18 months, a new ischemic stroke occurred in 9 out of 61 (18%) patients with MRI evidence of acute ischemia and 2 out of 211 (1%) without (age-adjusted hazard ratio, 13 [95% CI, 3-62]; P<0.0001). CONCLUSIONS: MRI evidence of acute brain ischemia was found in about 1 in 6 transient or minor neurological symptoms patients with a nonstroke/TIA initial diagnosis or uncertain diagnosis. Methods to determine the clinical and cost-effectiveness of MRI are needed in this population.

Clinical performance of DNA and RNA based HPV tests for test of cure (TOC) post treatment for cervical intraepithelial neoplasia (CIN) - a retrospective study.

HPV testing as a "test of cure" (TOC) of women treated for cervical high-grade lesions can support and inform appropriate clinical management pathways. However, there is a lack of studies that report the discrete performance of different HPV assays in this context, including HPV mRNA based assays. To address this, we performed an analysis of the clinical performance of two hrHPV assays in the (TOC) setting; the recently launched DNA based Alinity m HR HPV (Abbott Molecular) and RNA based Aptima HPV assay (Hologic). Using a retrospective case-control design, two panels of archived cervical liquid based cytology samples, originally taken as per routine TOC protocols in Scotland were assessed. Each panel contained 63 cases, where cervical intraepithelial neoplasia 2 or worse (CIN2+) was detected and 160 controls (women with no CIN2+ and two subsequent cytology negative results (minimum) 3 years apart or women who had histologically confirmed ≤CIN1). All samples were previously tested using the RealTime High Risk HPV assay (Abbott Molecular) as per national TOC protocol. Panel A and Panel B were tested using Alinity and Aptima assay respectively. Both assays showed similar performance to the original RealTime assay. Aptima had sensitivity for CIN2+ of 96.8% (95% CI: 89.0- 99.6) compared to RealTime (93.7% (95% CI: 84.5 - 98.2)). Alinity had sensitivity for CIN2+ of 92.1% (95% CI: 82.4- 97.4) compared to RealTime (98.4% (95% CI: 91.5- 99.95)). Both mRNA based and DNA based HPV tests show robust performance for the monitoring of residual disease post-treatment.

Regular Acetaminophen Use and Blood Pressure in People With Hypertension: The PATH-BP Trial.

BACKGROUND: Acetaminophen is widely used as first-line therapy for chronic pain because of its perceived safety and the assumption that, unlike nonsteroidal anti-inflammatory drugs, it has little or no effect on blood pressure (BP). Although observational studies suggest that acetaminophen may increase BP, clinical trials are lacking. We, therefore, studied the effects of regular acetaminophen dosing on BP in individuals with hypertension. METHODS: In this double-blind, placebo-controlled, crossover study, 110 individuals were randomized to receive 1 g acetaminophen 4× daily or matched placebo for 2 weeks followed by a 2-week washout period before crossing over to the alternate treatment. At the beginning and end of each treatment period, 24-hour ambulatory BPs were measured. The primary outcome was a comparison of the change in mean daytime systolic BP from baseline to end of treatment between the placebo and acetaminophen arms. RESULTS: One-hundred three patients completed both arms of the study. Regular acetaminophen, compared with placebo, resulted in a significant increase in mean daytime systolic BP (132.8±10.5 to 136.5±10.1 mm Hg [acetaminophen] vs 133.9±10.3 to 132.5±9.9 mm Hg [placebo]; P<0.0001) with a placebo-corrected increase of 4.7 mm Hg (95% CI, 2.9-6.6) and mean daytime diastolic BP (81.2±8.0 to 82.1±7.8 mm Hg [acetaminophen] vs 81.7±7.9 to 80.9±7.8 mm Hg [placebo]; P=0.005) with a placebo-corrected increase of 1.6 mm Hg (95% CI, 0.5-2.7). Similar findings were seen for 24-hour ambulatory and clinic BPs. CONCLUSIONS: Regular daily intake of 4 g acetaminophen increases systolic BP in individuals with hypertension by ≈5 mm Hg when compared with placebo; this increases cardiovascular risk and calls into question the safety of regular acetaminophen use in this situation. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01997112. URL: https://www.clinicaltrialsregister.eu; Unique identifier: 2013-003204-40.

Study protocol: a multicentre, open-label, parallel-group, phase 2, randomised controlled trial of autologous macrophage therapy for liver cirrhosis (MATCH).

INTRODUCTION: Liver cirrhosis is a growing global healthcare challenge. Cirrhosis is characterised by severe liver fibrosis, organ dysfunction and complications related to portal hypertension. There are no licensed antifibrotic or proregenerative medicines and liver transplantation is a scarce resource. Hepatic macrophages can promote both liver fibrogenesis and fibrosis regression. The safety and feasibility of peripheral infusion of ex vivo matured autologous monocyte-derived macrophages in patients with compensated cirrhosis has been demonstrated. METHODS AND ANALYSIS: The efficacy of autologous macrophage therapy, compared with standard medical care, will be investigated in a cohort of adult patients with compensated cirrhosis in a multicentre, open-label, parallel-group, phase 2, randomised controlled trial. The primary outcome is the change in Model for End-Stage Liver Disease score at 90 days. The trial will provide the first high-quality examination of the efficacy of autologous macrophage therapy in improving liver function, non-invasive fibrosis markers and other clinical outcomes in patients with compensated cirrhosis. ETHICS AND DISSEMINATION: The trial will be conducted according to the ethical principles of the Declaration of Helsinki 2013 and has been approved by Scotland A Research Ethics Committee (reference 15/SS/0121), National Health Service Lothian Research and Development department and the Medicine and Health Care Regulatory Agency-UK. Final results will be presented in peer-reviewed journals and at relevant conferences. TRIAL REGISTRATION NUMBERS: ISRCTN10368050 and EudraCT; reference 2015-000963-15.

A randomized, feasibility trial of an exercise and nutrition-based rehabilitation programme (ENeRgy) in people with cancer.

BACKGROUND: Despite rehabilitation being increasingly advocated for people living with incurable cancer, there is limited evidence supporting efficacy or component parts. The progressive decline in function and nutritional in this population would support an approach that targets these factors. This trial aimed to assess the feasibility of an exercise and nutrition based rehabilitation programme in people with incurable cancer. METHODS: We randomized community dwelling adults with incurable cancer to either a personalized exercise and nutrition based programme (experimental arm) or standard care (control arm) for 8 weeks. Endpoints included feasibility, quality of life, physical activity (step count), and body weight. Qualitative and health economic analyses were also included. RESULTS: Forty-five patients were recruited (23 experimental arm, 22 control arm). There were 26 men (58%), and the median age was 78 years (IQR 69-84). At baseline, the median BMI was 26 kg/m2 (IQR: 22-29), and median weight loss in the previous 6 months was 5% (IQR: -12% to 0%). Adherence to the experimental arm was >80% in 16/21 (76%) patients. There was no statistically significant difference in the following between trial arms: step count - median % change from baseline to endpoint, per trial arm (experimental -18.5% [IQR: -61 to 65], control 5% [IQR: -32 to 50], P = 0.548); weight - median % change from baseline to endpoint, per trial arm (experimental 1%[IQR: -3 to 3], control -0.5% [IQR: -3 to 1], P = 0.184); overall quality of life - median % change from baseline to endpoint, per trial arm (experimental 0% [IQR: -20 to 19], control 0% [IQR: -23 to 33], P = 0.846). Qualitative findings observed themes of capability, opportunity, and motivation amongst patients in the experimental arm. The mean incremental cost of the experimental arm versus control was £-319.51 [CI -7593.53 to 6581.91], suggesting the experimental arm was less costly. CONCLUSIONS: An exercise and nutritional rehabilitation intervention is feasible and has potential benefits for people with incurable cancer. A larger trial is now warranted to test the efficacy of this approach.

Feasibility of shortening intravenous antibiotic therapy for bronchiectasis based on bacterial load: a proof-of-concept randomised controlled trial.

BACKGROUND: There is a lack of evidence to guide the duration of intravenous antibiotics for bronchiectasis exacerbations. AIMS: The aim of this study was to assess whether it is feasible, based on bacterial load, to shorten intravenous antibiotics during exacerbations and whether 14 days of treatment is superior. METHODS: We recruited participants requiring intravenous antibiotics for exacerbations. Participants were randomised into two groups: to receive antibiotics for 14 days (14-day group) or to have a shorter duration of treatment based on bacterial load (bacterial load-guided group (BLGG)). Bacterial load was checked on days 0, 7, 10, 14 and 21. If the bacterial load was <106 CFU·mL-1 on day 7 or day 10 in the BLGG, antibiotics were stopped the following day. RESULTS: A total of 47 participants were in the 14-day group and 43 were in the BLGG. 88% of participants in the BLGG were able to stop antibiotics by day 8 and potentially 81% of participants in the 14-day group could have stopped antibiotics at day 8. There was a nonsignificant trend for increased clinical improvement by day 21 in the 14-day group compared to the BLGG. However, overall group data showed the median (interquartile range) time to next exacerbation was 27.5 days (12.5-60 days) in the 14-day group and 60 days (18-110 days) in the in BLGG (p=0.0034). In a Cox proportional hazard model, participants in the 14-day group were more likely to experience exacerbations (HR 1.80, 95% CI 1.16-2.80, p=0.009) than those in the BLGG, and those with mild bronchiectasis were less likely to experience exacerbations than patients with more severe bronchiectasis (HR 0.359, 95% CI 0.13-0.99, p=0.048). CONCLUSIONS: Bacterial load-guided therapy is feasible in most exacerbations requiring intravenous antibiotics. There was a nonsignificant trend for increased clinical improvement by day 21 with 14 days of antibiotics compared with bacterial load-guided therapy but paradoxically there was a prolonged time to next exacerbation in the BLGG.

Study protocol of the Edinburgh and Lothian Virus Intervention Study in Kids: a randomised controlled trial of hypertonic saline nose drops in children with upper respiratory tract infections (ELVIS Kids).

INTRODUCTION: Edinburgh and Lothians' Viral Intervention Study Kids is a parallel, open-label, randomised controlled trial of hypertonic saline (HS) nose drops (~2.6% sodium chloride) vs standard care in children <7 years of age with symptoms of an upper respiratory tract infection (URTI). METHODS AND ANALYSIS: Children are recruited prior to URTI or within 48 hours of developing URTI symptoms by advertising in areas such as local schools/nurseries, health centres/hospitals, recreational facilities, public events, workplaces, local/social media. Willing parents/guardians, of children <7 years of age will be asked to contact the research team at their local site. Children will be randomised to either a control arm (standard symptomatic care), or intervention arm (three drops/nostril of HS, at least four times a day, until 24 hours after asymptomatic or a maximum of 28 days). All participants are requested to provide a nasal swab at the start of the study (intervention arm: before HS drops) and then daily for four more days. Parent/guardian complete a validated daily diary, an end of illness diary, a satisfaction questionnaire and a wheeze questionnaire (day 28). The parent/guardian of a child in the intervention arm is taught to prepare HS nose drops. Parent/guardian of children asymptomatic at recruitment are requested to inform the research team within 48 hours of their child developing an URTI and follow the instructions already provided. The day 28 questionnaire determines if the child experienced a wheeze following illness. Participation in the study ends on day 28. ETHICS AND DISSEMINATION: The study has been approved by the West of Scotland Research Ethics Service (18/WS/0080). It is cosponsored by Academic and Clinical Central Office for Research and Development-a partnership between the University of Edinburgh and National Health Service Lothian Health Board. The findings will be disseminated through peer-reviewed publications, conference presentations and via the study website. TRIAL REGISTRATION NUMBER: NCT03463694.

Effect of Denosumab or Alendronic Acid on the Progression of Aortic Stenosis: A Double-Blind Randomized Controlled Trial.

BACKGROUND: Valvular calcification is central to the pathogenesis and progression of aortic stenosis, with preclinical and observational studies suggesting that bone turnover and osteoblastic differentiation of valvular interstitial cells are important contributory mechanisms. We aimed to establish whether inhibition of these pathways with denosumab or alendronic acid could reduce disease progression in aortic stenosis. METHODS: In a single-center, parallel group, double-blind randomized controlled trial, patients >50 years of age with calcific aortic stenosis (peak aortic jet velocity >2.5 m/s) were randomized 2:1:2:1 to denosumab (60 mg every 6 months), placebo injection, alendronic acid (70 mg once weekly), or placebo capsule. Participants underwent serial assessments with Doppler echocardiography, computed tomography aortic valve calcium scoring, and 18F-sodium fluoride positron emission tomography and computed tomography. The primary end point was the calculated 24-month change in aortic valve calcium score. RESULTS: A total of 150 patients (mean age, 72±8 years; 21% women) with calcific aortic stenosis (peak aortic jet velocity, 3.36 m/s [2.93-3.82 m/s]; aortic valve calcium score, 1152 AU [655-2065 AU]) were randomized and received the allocated trial intervention: denosumab (n=49), alendronic acid (n=51), and placebo (injection n=25, capsule n=25; pooled for analysis). Serum C-terminal telopeptide, a measure of bone turnover, halved from baseline to 6 months with denosumab (0.23 [0.18-0.33 µg/L] to 0.11 µg/L [0.08-0.17 µg/L]) and alendronic acid (0.20 [0.14-0.28 µg/L] to 0.09 µg/L [0.08-0.13 µg/L]) but was unchanged with placebo (0.23 [0.17-0.30 µg/L] to 0.26 µg/L [0.16-0.31 µg/L]). There were no differences in 24-month change in aortic valve calcium score between denosumab and placebo (343 [198-804 AU] versus 354 AU [76-675 AU]; P=0.41) or alendronic acid and placebo (326 [138-813 AU] versus 354 AU [76-675 AU]; P=0.49). Similarly, there were no differences in change in peak aortic jet velocity or 18F-sodium fluoride aortic valve uptake. CONCLUSIONS: Neither denosumab nor alendronic acid affected progression of aortic valve calcification in patients with calcific aortic stenosis. Alternative pathways and mechanisms need to be explored to identify disease-modifying therapies for the growing population of patients with this potentially fatal condition. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02132026.

Predicting specific abilities after disabling stroke: Development and validation of prognostic models.

BACKGROUND: Predicting specific abilities (e.g. walk and talk) to provide a functional profile six months after disabling stroke could help patients/families prepare for the consequences of stroke and facilitate involvement in treatment decision-making. AIM: To develop new statistical models to predict specific abilities six months after stroke and test their performance in an independent cohort of patients with disabling stroke. METHODS: We developed models to predict six specific abilities (to be independent, walk, talk, eat normally, live without major anxiety/depression, and to live at home) using data from seven large multicenter stroke trials with multivariable logistic regression. We included 13,117 participants recruited within three days of hospital admission. We assessed model discrimination and derived optimal cut-off values using four statistical methods. We validated the models in an independent single-center cohort of patients (n = 403) with disabling stroke. We assessed model discrimination and calibration and reported the performance of our models at the statistically derived cut-off values. RESULTS: All six models had good discrimination in external validation (AUC 0.78-0.84). Four models (predicting to walk, eat normally, live without major anxiety/depression, live at home) calibrated well. Models had sensitivities between 45.0 and 97.9% and specificities between 21.6 and 96.5%. CONCLUSIONS: We have developed statistical models to predict specific abilities and demonstrated that these models perform reasonably well in an independent cohort of disabling stroke patients. To aid decision-making regarding treatments, further evaluation of our models is required.