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BACKGROUND: Patients hospitalised with COVID-19 suffer thrombotic complications. Risk factors for poor outcomes are shared with coronary artery disease. OBJECTIVES: To investigate efficacy of an acute coronary syndrome regimen in patients hospitalised with COVID-19 and coronary disease risk factors. PATIENTS/METHODS: A randomised controlled open-label trial across acute hospitals (UK and Brazil) added aspirin, clopidogrel, low-dose rivaroxaban, atorvastatin, and omeprazole to standard care for 28-days. Primary efficacy and safety outcomes were 30-day mortality and bleeding. The key secondary outcome was a daily clinical status (at home, in hospital, on intensive therapy unit admission, death). RESULTS: 320 patients from 9 centres were randomised. The trial terminated early due to low recruitment. At 30 days there was no significant difference in mortality (intervention: 11.5% vs control: 15%, unadjusted OR 0.73, 95%CI 0.38 to 1.41, p=0.355). Significant bleeds were infrequent and not significantly different between the arms (intervention: 1.9% vs control 1.9%, p>0.999). Using a Bayesian Markov longitudinal ordinal model, it was 93% probable that intervention arm participants were more likely to transition to a better clinical state each day (OR 1.46, 95% CrI 0.88 to 2.37, Pr(Beta>0)=93%; adjusted OR 1.50, 95% CrI 0.91 to 2.45, Pr(Beta>0)=95%) and median time to discharge home was two days shorter (95% CrI -4 to 0, 2% probability that it was worse). CONCLUSIONS: Acute coronary syndrome treatment regimen was associated with a reduction in the length of hospital stay without an excess in major bleeding. A larger trial is needed to evaluate mortality.

The COVID-19 pandemic brought along a new situation for the population worldwide. The most important safety measures and lockdown expected extreme adaptability and flexibility impacting mental well-being. The aim of our study was to identify associations between changes in lifestyle and circadian rhythm and depression during the pandemic.Our analysis has been carried out on the Hungarian data set of the COMET-G study including information on lifestyle and circadian rhythm-associated factors and severity of depression and its 3 symptom clusters. Associations were assessed using linear regression models adjusted for age and sex.All variables reflecting changes in quality and quantity of sleep showed significant associations with overall depression scores and the three distinct symptom cluster scores. All variables reflecting importance and changes in physical activity during the pandemic were similarly significantly associated with all depression measures. However, only changes in quality of diet, but not quantity was associated with depression scores.Our results may confirm the association of circadian rhythm and lifestyle-related environmental factors in deterioration of mental health during COVID and help devise prevention and intervention methods and targets for similar situations.

Background Missing data are common in randomised controlled trials (RCTs) and can bias results if not handled appropriately. A statistically valid analysis under the primary missing-data assumptions should be conducted, followed by sensitivity analysis under alternative justified assumptions to assess the robustness of results. Controlled Multiple Imputation (MI) procedures, including delta-based and reference-based approaches, have been developed for analysis under missing-not-at-random assumptions. However, it is unclear how often these methods are used, how they are reported, and what their impact is on trial results. This review evaluates the current use and reporting of MI and controlled MI in RCTs. Methods A targeted review of phase II-IV RCTs (non-cluster randomised) published in two leading general medical journals (The Lancet and New England Journal of Medicine) between January 2014 and December 2019 using MI. Data was extracted on imputation methods, analysis status, and reporting of results. Results of primary and sensitivity analyses for trials using controlled MI analyses were compared. Results A total of 118 RCTs (9% of published RCTs) used some form of MI. MI under missing-at-random was used in 110 trials; this was for primary analysis in 43/118 (36%), and in sensitivity analysis for 70/118 (59%) (3 used in both). Sixteen studies performed controlled MI (1.3% of published RCTs), either with a delta-based (n = 9) or reference-based approach (n = 7). Controlled MI was mostly used in sensitivity analysis (n = 14/16). Two trials used controlled MI for primary analysis, including one reporting no sensitivity analysis whilst the other reported similar results without imputation. Of the 14 trials using controlled MI in sensitivity analysis, 12 yielded comparable results to the primary analysis whereas 2 demonstrated contradicting results. Only 5/110 (5%) trials using missing-at-random MI and 5/16 (31%) trials using controlled MI reported complete details on MI methods. Conclusions Controlled MI enabled the impact of accessible contextually relevant missing data assumptions to be examined on trial results. The use of controlled MI is increasing but is still infrequent and poorly reported where used. There is a need for improved reporting on the implementation of MI analyses and choice of controlled MI parameters.

Background: The COVID-19 pandemic brought about great uncertainty and significant changes in our people's everyday lives. In times of such crises, it is natural to seek explanations to overcome our fears and uncertainties, contributing to an increase to believe in conspiracy theories which, by yielding explanations, decrease uncertainty and ambiguity and may thus have an effect on mental well-being. In spite of this, the majority of research on conspiracy theories focused on their social effects with little attention to psychological effects. Thus, the aim of our present study was to examine the association between belief in conspiracy theories and different aspects of mental health during the COVID-19 pandemic in a general population sample. Methods: Our analyses included data from the Hungarian leg of the COMET-G (COVID-19 MEntal health international for the General population) study. The Hungarian sample included participants who completed a detailed questionnaire assessing belief in seven conspiracy theory items, as well as STAI-S and CES-D to measure state anxiety and depression, respectively, and answered questions related to their change in depression, anxiety and suicidal thoughts during the pandemic. Association between the individual beliefs as well as a composite Conspiracy Theory Belief Score (CTBS) and mental health measures was analysed using linear regression models. Results: Overall, belief in conspiracy theories was relatively moderate in our sample. Sex and age appeared to have a significant effect on the Overall Conspiracy Theory Belief Score (CTBS), with women having a higher score and scores increasing with age. Some of the individual beliefs also showed associations with age and sex. State anxiety and depression was not significantly associated with CTBS, however in case of depression some individual items were, and symptom clusters within CES-D also showed a pattern of association with some of the individual items. As far as changes in mental health during the pandemic is concerned, no association between overall beliefs and changes in anxiety or depression was found. However, higher overall belief in conspiracy theories was associated with a decrease in suicidal thoughts. Discussion: In our study, we explored the association between conspiracy theories and mental well-being as well as its changes during the COVID-19 pandemic. We found a specific pattern of association between belief in distinct theories and some aspects of depression, as well as lower increase in suicidal ideation in association with increased belief in conspiracy theories. Understanding the role of belief in theories can be key to designing mental health interventions when reacting to unforeseen events in the future. (Neuropsychopharmacol Hung 2022; 24(1): 42-55).

Background: rituximab is often used as rescue therapy in interstitial lung disease (ILD) associated with connective tissue disease (CTD), but has not been studied in clinical trials. This study aimed to assess whether rituximab is superior to cyclophosphamide as a treatment for severe or progressive CTD associated ILD.Methods: we conducted a randomised, double-blind, double-dummy, phase 2b trial to assess the superiority of rituximab compared with cyclophosphamide. Patients aged 18-80 years with severe or progressive ILD related to scleroderma, idiopathic inflammatory myositis, or mixed CTD, recruited across 11 specialist ILD or rheumatology centres in the UK, were randomly assigned (1:1) to receive rituximab (1000 mg at weeks 0 and 2 intravenously) or cyclophosphamide (600 mg/m2 body surface area every 4 weeks intravenously for six doses). The primary endpoint was rate of change in forced vital capacity (FVC) at 24 weeks compared with baseline, analysed using a mixed-effects model with random intercepts, adjusted for baseline FVC and CTD type. Prespecified secondary endpoints reported in this Article were change in FVC at 48 weeks versus baseline; changes from baseline in 6 min walk distance, diffusing capacity of the lung for carbon monoxide (DLCO), physician-assessed global disease activity (GDA) score, and quality-of-life scores on the St George's Respiratory Questionnaire (SGRQ), King's Brief Interstitial Lung Disease (KBILD) questionnaire, and European Quality of Life Five-Dimension (EQ-5D) questionnaire at 24 and 48 weeks; overall survival, progression-free survival, and time to treatment failure; and corticosteroid use. All endpoints were analysed in the modified intention-to-treat population, which comprised all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT01862926).Findings: between Dec 1, 2014, and March 31, 2020, we screened 145 participants, of whom 101 participants were randomly allocated: 50 (50%) to receive cyclophosphamide and 51 (50%) to receive rituximab. 48 (96%) participants in the cyclophosphamide group and 49 (96%) in the rituximab group received at least one dose of treatment and were included in analyses; 43 (86%) participants in the cyclophosphamide group and 42 (82%) participants in the rituximab group completed 24 weeks of treatment and follow-up. At 24 weeks, FVC was improved from baseline in both the cyclophosphamide group (unadjusted mean increase 99 mL [SD 329]) and the rituximab group (97 mL [234]); in the adjusted mixed-effects model, the difference in the primary endpoint at 24 weeks was -40 mL (95% CI -153 to 74; p=0·49) between the rituximab group and the cyclophosphamide group. KBILD quality-of-life scores were improved at 24 weeks by a mean 9·4 points (SD 20·8) in the cyclophosphamide group and 8·8 points (17·0) in the rituximab group. No significant differences in secondary endpoints were identified between the treatment groups, with the exception of change in GDA score at week 48, which favoured cyclophosphamide (difference 0·90 [95% CI 0·11 to 1·68]). Improvements in lung function and respiratory-related quality-of-life measures were observed in both treatment groups. Lower corticosteroid exposure over 48 weeks of follow-up was recorded in the rituximab group. Two (4%) of 48 participants who received cyclophosphamide and three (6%) of 49 who received rituximab died during the study, all due to complications of CTD or ILD. Overall survival, progression-free survival, and time to treatment failure did not significantly differ between the two groups. All participants reported at least one adverse event during the study. Numerically fewer adverse events were reported by participants receiving rituximab (445 events) than those receiving cyclophosphamide (646 events). Gastrointestinal and respiratory disorders were the most commonly reported adverse events in both groups. There were 62 serious adverse events of which 33 occurred in the cyclophosphamide group and 29 in the rituximab group.Interpretation: rituximab was not superior to cyclophosphamide to treat patients with CTD-ILD, although participants in both treatment groups had increased FVC at 24 weeks, in addition to clinically important improvements in patient-reported quality of life. Rituximab was associated with fewer adverse events. Rituximab should be considered as a therapeutic alternative to cyclophosphamide in individuals with CTD-ILD requiring intravenous therapy.Funding: efficacy and Mechanism Evaluation Programme (Medical Research Council and National Institute for Health Research, UK).

Objective: Characterizing blood glucose curves and providing precise patient level risk assessment of hyperglycemia using extreme value statistics and comparing these assessments with traditional indicators of glycemic variability which are not designed to specifically capture the risk of hyperglycemia. Research Design and Methods: One year return level (blood glucose level exceeded exactly once every year on average) and probability of exceeding and expected time spent above certain thresholds (600 and 400 mg/dL) per year were calculated. As a comparison, traditional metrics for glycemic variability were determined too. The effect of body mass index on extremes was also investigated using non-stationary models. Metrics were calculated on a dataset containing 170.8 patient-years of measurements of 226 patients. Results: Nine high-risk patients were identified with the novel metrics: their estimated time spent above 600 mg/dL per year were above 2 hours. These patients were at moderate risk according to the traditional metrics. Higher body mass index was associated with more extreme glucose levels. Conclusions: Through these estimates it is possible to assess each patient’s individual clinical risk of hyperglycemia even beyond the observed blood glucose levels and detection limits. Additionally, it allows the assessment of the impact of clinical characteristics and treatments on blood glucose control in a novel, mathematically well-founded and potentially clinically more useful way than the already existing indicators.

Additional file 2: Table S1. Underlying assumptions for missing data. Table S2. Model details for trials implementing MICE (n=12). Table S3.Model details for trials implementing regression based MI (n=4). Table S4. Key characteristic of the 16 RCTs that performed controlled MI. Table S5. Assessing the robustness of the results from the 16 RCTs that performed controlled MI.

Additional file 1 Table S1. PRISMA checklist for reporting systematic reviews.

In contrast to regular statistics where the focus is on the most typical part of the data and the used metrics are describing that part (usually with the mean or median and variance and interquartile range) where most of the observations came from, there is a branch of statistics which focuses on the extreme events, i.e, the tails of the distributions. These are not simple outliers, like data entry errors, but real part of the data which are far from the central tendency and occur rarely, yet, have relevance and impact. Thus, in many application, they can’t be simply neglected. The use of extreme value statistics allows us to fit models on this part of the data and like “regular” statistics, enables us to calculate estimates and predictions, but in this case for extreme values. These methods are frequently used in fields like meteorology and finance where the extreme events have large impact despite their rarity. Because of this rarity, however, only a small fraction of the data can be used so much higher sample size is required for such analysis. This factor limited the use of extreme value statistics in biomedical field where available technology and costs are strong limitations at frequently measuring most of the biomarkers until recently. Blood glucose level is one of the exceptions nowadays, as with recent advancements it can be monitored for relatively long time and with high frequency for a patient. Additionally, extreme values of blood glucose levels (both high and low) are associated with- chronic or acute- complications of diabetes. This paper aims to demonstrate that the use of extreme value statistics, in particular the block maxima approach could be a possible way to characterize blood glucose curves. In addition to providing a metric for the state of the patient and therefore hopefully the associated risks, it allows the comparison of the performance of artificial pancreas systems. Block maxima method was used to model extreme values of a dataset containing measurements of a single patient with 476 complete days of data acquired with sampling frequency of 15 minutes. Probabilities for exceeding the clinically relevant levels of 270 mg/dl (cognitive symptoms expected) and 600 mg/dl (diabetic hyperosmolar syndrome) were calculated and were 3.47% and 4.96.10-7% respectively. Through these estimates it is possible to characterise each patient’s status and compare different controllers.

In contrast to regular statistics which focuses on the typical part of the data and use metrics to describe that part (usually the mean or variance), there is a branch of statistics which focuses on the extreme and thus rare events. The use of extreme value statistics allows us to fit models on this part of the data and like ,,regular" statistics, enables us to calculate estimates and predictions, but in this case for extreme values. These methods are frequently used in fields like meteorology and finance where the extreme events has large impact despite their rarity. Because of this rarity, however, only a small fraction of the data can be used so much higher sample size is required for such analysis – thus fields with a large amount of historical data have an advantage.This factor limited the use of extreme value statistics in biomedical field where available technology and costs are strong limitations at measuring most of the biomarkers until recently.Blood glucose level is one of the exceptions nowadays, as with recent advancements it can be monitored for relatively long time and with high frequency for a patient. Additionally, extreme values of blood glucose levels (both high and low) are associated with – chronic or acute – complications of diabetes.This paper aims to demonstrate that the use of extreme value statistics could be a possible way to characterize blood glucose curves. In addition to providing a metric for the state of the patient, it allows the comparison of the performance of artificial pancreas models.Peak over threshold method was used to model extreme values of a simulated dataset containing 1440 measurements of 99 patients with 250 mg/dl as threshold. Probabilities for exceeding the clinically relevant levels of 270 mg/dl (cognitive symptoms expected) and 600 mg/dl (diabetic hyperosmolar syndrome) were calculated and were 23.9% and 8.0 • 10−6% respectively in the region above the threshold (250 mg/dl). Through these estimates it is possible to compare different controllers.

Some data suggest that nocturnal dosing of antihypertensive agents may reduce cardiovascular outcomes more than daytime dosing. This trial was designed to evaluate whether ambulatory blood pressure monitoring levels differ by timing of drug dosing. Patients aged 18 to 80 years with reasonably controlled hypertension (≤150/≤90 mm Hg) on stable therapy of ≥1 antihypertensive agent were recruited from 2 centers in London and Thessaloniki. Patients were randomized to receive usual therapy either in the morning (6 am –11 am ) or evening (6 pm –11 pm ) for 12 weeks when participants crossed over to the alternative timing for a further 12 weeks. Clinic blood pressures and a 24-hour recording were taken at baseline, 12, and 24 weeks and routine blood tests were taken at baseline. The study had 80% power to detect 3 mm Hg difference in mean 24-hour systolic blood pressure (α=0.05) by time of dosing. A 2-level hierarchical regression model adjusted for center, period, and sequence was used. Of 103 recruited patients (mean age, 62; 44% female), 95 patients (92%) completed all three 24-hour recordings. Mean 24-hour systolic and diastolic blood pressures did not differ between daytime and evening dosing. Similarly, morning and evening dosing had no differential impact on mean daytime (7 am –10 pm ) and nighttime (10 pm –7 am ) blood pressure levels nor on clinic levels. Stratification by age (≤65/≥65 years) or sex did not affect results. In summary, among hypertensive patients with reasonably well-controlled blood pressure, the timing of antihypertensive drug administration (morning or evening) did not affect mean 24-hour or clinic blood pressure levels. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01669928.

It has been widely argued that absolute treatment effect measurements (such as risk difference) reveal the “clinical benefit” of an intervention. Yet, many previous experience with binary endpoints have shown that they are unlikely to be transportable between populations. As absolute metrics are usually derived from baseline risk and relative metric (such as odds ratio), it seems logical to rather measure relative metrics, assuming they are stable. In the present study, a continuous endpoint was used to assess the stability of both relative and absolute metrics using a empirical data from pulmonology. Results are preliminary due to the low baseline variability, yet, the difference was significantly correlated with the baseline, unlike the ratio, which is in line with previous experience with binary endpoints. Further research is needed to explore the stability with continuous endpoints.

This randomized clinical trial uses data from the Early Venous Reflux Ablation trial to evaluate the long-term clinical and cost benefits of combined early endovenous ablation and compression compared with compression therapy alone and deferred ablation for treating superficial venous reflux of the leg., Key Points Question In patients with venous leg ulceration and superficial reflux, what is the clinical and cost-effectiveness of early endovenous ablation of reflux? Findings In this 450-patient, multicenter, randomized clinical trial, early endovenous ablation with compression accelerated venous ulcer healing, reduced the overall incidence of ulcer recurrence, and was highly cost-effective compared with compression with deferred intervention. Meaning To deliver clinical and cost benefits, leg ulcer care pathways should be revised to include early assessment and treatment of superficial venous reflux., Importance One-year outcomes from the Early Venous Reflux Ablation (EVRA) randomized trial showed accelerated venous leg ulcer healing and greater ulcer-free time for participants who are treated with early endovenous ablation of lower extremity superficial reflux. Objective To evaluate the clinical and cost-effectiveness of early endovenous ablation of superficial venous reflux in patients with venous leg ulceration. Design, Setting, and Participants Between October 24, 2013, and September 27, 2016, the EVRA randomized clinical trial enrolled 450 participants (450 legs) with venous leg ulceration of less than 6 months’ duration and superficial venous reflux. Initially, 6555 patients were assessed for eligibility, and 6105 were excluded for reasons including ulcer duration greater than 6 months, healed ulcer by the time of randomization, deep venous occlusive disease, and insufficient superficial venous reflux to warrant ablation therapy, among others. A total of 426 of 450 participants (94.7%) from the vascular surgery departments of 20 hospitals in the United Kingdom were included in the analysis for ulcer recurrence. Surgeons, participants, and follow-up assessors were not blinded to the treatment group. Data were analyzed from August 11 to November 4, 2019. Interventions Patients were randomly assigned to receive compression therapy with early endovenous ablation within 2 weeks of randomization (early intervention, n = 224) or compression with deferred endovenous treatment of superficial venous reflux (deferred intervention, n = 226). Endovenous modality and strategy were left to the preference of the treating clinical team. Main Outcomes and Measures The primary outcome for the extended phase was time to first ulcer recurrence. Secondary outcomes included ulcer recurrence rate and cost-effectiveness. Results The early-intervention group consisted of 224 participants (mean [SD] age, 67.0 [15.5] years; 127 men [56.7%]; 206 White participants [92%]). The deferred-intervention group consisted of 226 participants (mean [SD] age, 68.9 [14.0] years; 120 men [53.1%]; 208 White participants [92%]). Of the 426 participants whose leg ulcer had healed, 121 (28.4%) experienced at least 1 recurrence during follow-up. There was no clear difference in time to first ulcer recurrence between the 2 groups (hazard ratio, 0.82; 95% CI, 0.57-1.17; P = .28). Ulcers recurred at a lower rate of 0.11 per person-year in the early-intervention group compared with 0.16 per person-year in the deferred-intervention group (incidence rate ratio, 0.658; 95% CI, 0.480-0.898; P = .003). Time to ulcer healing was shorter in the early-intervention group for primary ulcers (hazard ratio, 1.36; 95% CI, 1.12-1.64; P = .002). At 3 years, early intervention was 91.6% likely to be cost-effective at a willingness to pay of £20 000 ($26 283) per quality-adjusted life year and 90.8% likely at a threshold of £35 000 ($45 995) per quality-adjusted life year. Conclusions and Relevance Early endovenous ablation of superficial venous reflux was highly likely to be cost-effective over a 3-year horizon compared with deferred intervention. Early intervention accelerated the healing of venous leg ulcers and reduced the overall incidence of ulcer recurrence. Trial Registration ClinicalTrials.gov identifier: ISRCTN02335796

BackgroundBacterial infections are implicated in the pathogenesis of asthma exacerbation but guidelines recommend that antibiotics should not be administered. Telithromycin shows clinical benefit compared with placebo but toxicity limits its use.ObjectiveTo evaluate the efficacy of azithromycin compared with placebo in reducing the severity of asthma exacerbations.DesignMulticentre, randomised, double-blind, placebo-controlled study.SettingAccident and emergency and acute medical units, and one primary care centre.ParticipantsAdults with a history of asthma presenting within 48 hours (of initial presentation requesting medical care) with an acute deterioration in asthma control [increased wheeze, dyspnoea and/or cough with reduced peak expiratory flow (PEF)] requiring treatment with corticosteroids.InterventionsAzithromycin (500 mg once daily) or two placebo capsules once a day for 3 days.Main outcome measureDiary card summary symptom score assessed at 10 days after randomisation.ResultsIn total, 4582 patients were screened at 31 centres, of whom 199 were randomised to the study (azithromycin,n = 97; placebo,n = 102) (of the intended 380). The major reasons for non-recruitment were already receiving antibiotics (n = 2044; 44.6% of screened subjects), unable to contact (n = 315; 6.9%), declined participation (n = 191; 4.2%) and other (e.g. underlying health condition, on steroids;n = 1833; 40.0%). The mean age of participants was 39.9 years and 69.8% were female; 61.1% had never smoked, 22.7% were former smokers and 16.2% were current smokers (mean pack-years 3.45). The median time from presentation to drug administration was 22 hours. Lung function at baseline (exacerbation) was PEF 69.4% predicted, forced expiratory volume in 1 second (FEV1) 64.8% predicted and FEV1/forced vital capacity ratio 69.2%. Baseline characteristics were well balanced across treatment arms and centres. The mean (standard deviation) scores on the primary outcome asthma symptom score were 4.14 (1.38) at baseline and 2.09 (1.71) at the end of treatment for the azithromycin group, and 4.18 (1.48) at baseline and 2.20 (1.51) at the end of treatment for the placebo group. Using multilevel modelling there was no statistically significant difference in symptom scores between groups at day 10 (unbiased estimated mean difference –0.166, 95% confidence interval –0.670 to 0.337); similarly, no significant between-group differences were seen in symptom scores on any other day between baseline and day 10. No significant between-group differences were seen in the Acute Asthma Quality of Life Questionnaire (AQLQ) score, Mini AQLQ score or any measure of lung function on any day, and there were no differences in time to a 50% reduction in symptom score. Sputum bacterial culture was positive in 6% of subjects, atypical pathogen polymerase chain reaction (PCR) and/or serology was positive in 4.5% of subjects and virus PCR analysis was positive in 18.1% of subjects. There was no difference in the primary outcome between the active group and the placebo group among those with a positive sputum bacterial test, although numbers for these analyses were small.ConclusionsIn the population of patients randomised to treatment, the addition of azithromycin to standard medical care demonstrated no statistically significant or clinically important benefit, although this could not be ruled out based on the confidence intervals. A limitation of this study was that, for each subject randomised, > 10 failed screening because they had already been prescribed antibiotic therapy. Further clinical trials are needed in settings of less antibiotic usage.Trial registrationClinicalTrials.gov NCT01444469; EudraCT 2011–001093–26.FundingThis project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership.

Importance: Guidelines recommend against antibiotic use to treat asthma attacks. A study with telithromycin reported benefit, but adverse reactions limit its use.Objective: To determine whether azithromycin added to standard care for asthma attacks in adults results in clinical benefit.Design, Setting, and Participants: The Azithromycin Against Placebo in Exacerbations of Asthma (AZALEA) randomized, double-blind, placebo-controlled clinical trial, a United Kingdom-based multicenter study in adults requesting emergency care for acute asthma exacerbations, ran from September 2011 to April 2014. Adults with a history of asthma for more than 6 months were recruited within 48 hours of presentation to medical care with an acute deterioration in asthma control requiring a course of oral and/or systemic corticosteroids.Interventions: Azithromycin 500 mg daily or matched placebo for 3 days.Main Outcomes and Measures: The primary outcome was diary card symptom score 10 days after randomization, with a hypothesized treatment effect size of -0.3. Secondary outcomes were diary card symptom score, quality-of-life questionnaires, and lung function changes, all between exacerbation and day 10, and time to a 50% reduction in symptom score.Results: Of 4582 patients screened at 31 centers, 199 of a planned 380 were randomized within 48 hours of presentation. The major reason for nonrecruitment was receipt of antibiotics (2044 [44.6%] screened patients). Median time from presentation to drug administration was 22 hours (interquartile range, 14-28 hours). Exacerbation characteristics were well balanced across treatment arms and centers. The primary outcome asthma symptom scores were mean (SD), 4.14 (1.38) at exacerbation and 2.09 (1.71) at 10 days for the azithromycin group and 4.18 (1.48) and 2.20 (1.51) for the placebo group, respectively. Using multilevel modeling, there was no significant difference in symptom scores between azithromycin and placebo at day 10 (difference, -0.166; 95% CI, -0.670 to 0.337), nor on any day between exacerbation and day 10. No significant between-group differences were observed in quality-of-life questionnaires or lung function between exacerbation and day 10, or in time to 50% reduction in symptom score.Conclusions and Relevance: In this randomized population, azithromycin treatment resulted in no statistically or clinically significant benefit. For each patient randomized, more than 10 were excluded because they had already received antibiotics.Trial Registration: clinicaltrials.gov Identifier: NCT01444469.

Context: In vitro fertilization (IVF) treatment is an effective therapy for infertility, but can result in the potentially life-threatening complication, ovarian hyperstimulation syndrome (OHSS). Objective: This study aimed to investigate whether kisspeptin-54 can be used to effectively and safely trigger oocyte maturation in women undergoing IVF treatment at high risk of developing OHSS. Setting and Design: This was a phase 2, multi-dose, open-label, randomized clinical trial of 60 women at high risk of developing OHSS carried out during 2013–2014 at Hammersmith Hospital IVF unit, London, United Kingdom. Intervention: Following a standard recombinant FSH/GnRH antagonist protocol, patients were randomly assigned to receive a single injection of kisspeptin-54 to trigger oocyte maturation using an adaptive design for dose allocation (3.2 nmol/kg, n = 5; 6.4 nmol/kg, n = 20; 9.6 nmol/kg, n = 15; 12.8 nmol/kg, n = 20). Oocytes were retrieved 36 h after kisspeptin-54 administration, assessed for maturation, and fertilized by intracytoplasmic sperm injection with subsequent transfer of one or two embryos. Women were routinely screened for the development of OHSS. Main Outcome Measure: Oocyte maturation was measured by oocyte yield (percentage of mature oocytes retrieved from follicles ≥ 14 mm on ultrasound). Secondary outcomes include rates of OHSS and pregnancy. Results: Oocyte maturation occurred in 95% of women. Highest oocyte yield (121%) was observed following 12.8 nmol/kg kisspeptin-54, which was +69% (confidence interval, −16–153%) greater than following 3.2 nmol/kg. At all doses of kisspeptin-54, biochemical pregnancy, clinical pregnancy, and live birth rates per transfer (n = 51) were 63, 53, and 45%, respectively. Highest pregnancy rates were observed following 9.6 nmol/kg kisspeptin-54 (85, 77, and 62%, respectively). No woman developed moderate, severe, or critical OHSS. Conclusion: Kisspeptin-54 is a promising approach to effectively and safely trigger oocyte maturation in women undergoing IVF treatment at high risk of developing OHSS.

Objective:Some data suggest that nocturnal rather than daytime dosing of antihypertensive agents may have beneficial effects on consequent cardiovascular outcomes. This trial was designed to evaluate whether ABPM levels differ by timing of drug dosing, as a possible explanation for these observation