Non-inferiority Analysis Research Articles

Does race-ethnicity affect upper airway stimulation adherence and treatment outcome of obstructive sleep apnea?

Untreated obstructive sleep apnea (OSA) is associated with excessive daytime sleepiness, decreased quality of life, and cardiovascular disease. Positive airway pressure is the first-line therapy for OSA; however, adherence is difficult. Upper airway stimulation is a Food and Drug Administration-approved treatment of OSA. The objective of this study was to evaluate for a difference in treatment efficacy and adherence of upper airway stimulation therapy for OSA between individuals who are White and non-White using data from the ADHERE registry. ADHERE registry is a multicenter prospective study of real-world experience of upper airway stimulation for treatment of OSA in the United States and Europe. Propensity score matching was used to create a balanced dataset between the White and non-White groups. t-Tests at a significance level of 5% were used to compare numeric values between groups. There were 2,755 participants of the ADHERE registry: 27 were excluded due to not having a race identified, 125 participants identified as non-White, 2,603 identify as White, and 27 did not provide race information. Propensity score matching was used to select 110 participants, with 55 White and 55 non-White for the noninferiority analysis. We did not find a difference in adherence, treatment apnea-hypopnea index, changes in Epworth Sleepiness Scale score, or clinical global impression after intervention score between White and non-White individuals. Our study found that there was no statistically significant difference in adherence or efficacy with upper airway stimulation therapy between White and non-White individuals. However, the percent of non-White people implanted is low, which suggests a need to expand access to this therapy for non-White populations with OSA who cannot tolerate positive airway pressure therapy. Khan M, Stone A, Soose RJ, etal. Does race-ethnicity affect upper airway stimulation adherence and treatment outcome of obstructive sleep apnea? J Clin Sleep Med. 2022;18(9):2167-2172.

Rapid versus slow withdrawal of antiepileptic monotherapy in two-year seizure-free adults patients with epilepsy (RASLOW) study: A pragmatic multicentre, prospective, randomized, controlled study.

To establish whether a slow or a rapid withdrawal of antiepileptic monotherapy influences relapse rate in seizure-free adults with epilepsy and calculates compliance and differences in the severity of relapses, based on the occurrence of status epilepticus, seizure-related injuries, and death. This is a multicentre, prospective, randomized, open label, non-inferiority trial in people aged 16 + years who were seizure-free for more than 2years. Patients were randomized to slow withdrawal (160days) or rapid withdrawal (60days) and were followed for 12months. The primary outcome was the probability of a first seizure relapse within the 12-months follow-up. The secondary outcomes included the cumulative probability of relapse at 3, 6, 9, and 12months. A non-inferiority analysis was performed with non-inferiority margin of - 0.15 for the difference between the probabilities of seizure recurrence in slow versus rapid withdrawal. The sample comprised 48 patients, 25 randomized to slow withdrawal and 23 to rapid withdrawal. Median follow-up was 11.9months. In the intention-to-treat population, 3 patients in the slow-withdrawal group and 1 in the rapid withdrawal group experienced seizure relapses. The corresponding probabilities of seizure recurrence were 0.12 for slow withdrawal and 0.04 for rapid withdrawal, giving a difference of 0.08 (95% CI - 0.12; 0.27), which is entirely above the non-inferiority margin. No patients developed status epilepticus and seizure-related injuries or died. Risks were similar in the Per-Protocol population. Seizure-relapse rate after drug discontinuation is lower than in other reports, without complications and unrelated to the duration of tapering.

Efficacy, Tolerability, and Acceptance of Long-Lasting Antipsychotics in Children and Adolescents: A Systematic Review.

Objectives: While long-lasting antipsychotics (LLA) were specifically developed to address the problem of adherence in patients with chronic psychiatric disorders, their role in pediatric populations is not clear. Methods: To document the efficacy, tolerance, and acceptance of LLAs in children and adolescents, a literature search was conducted using several databases for published studies (PubMed, PsycINFO) from January 1965 to December 2020. Twenty-two studies were identified (16 case reports/series, 3 open label studies, 2 controlled studies, and 1 retrospective analysis of national database). Results: Demographic features were widely heterogeneous across studies (total N = 480, 58% male, mean age = 15.0 ± 1.8). Case reports/series presented positive therapeutic outcomes in noncompliant youths with severe mental illness. Three open-label one-arm studies supported the clinical efficacy of risperidone long-acting injection in patients previously stabilized with oral risperidone. One study showed lower clinical symptoms and higher functioning at 12 months in youths treated for an acute psychotic episode with paliperidone palmitate compared to oral risperidone. The types and rates of side effects of LLA were comparable to those observed for oral antipsychotics. Two studies suggested better metabolic and neurological tolerance of LLA compared to an oral form. Preliminary evidence supported a satisfactory level of treatment satisfaction in patients treated with LLA and their families, while concerns were raised regarding practical administration in outpatient services. However, the average quality of the evidence based on the RoB2 tool was low. Conclusions: The level of evidence was low for the efficacy of LLA in pediatric populations and very low for the tolerance and acceptance. It concerned mostly the effect of risperidone long-acting injection in adolescents with psychotic disorders. Randomized maintenance clinical trials using noninferiority analysis would be more appropriate for further research.

Curettage vs. cryosurgery for superficial basal cell carcinoma: a prospective, randomised and controlled trial.

BackgroundBasal cell carcinoma (BCC) is the most common cancer in the world and has a rising incidence. Current guidelines for low‐risk BCC including superficial BCC (sBCC) recommend several treatment options including destructive treatment methods, such as cryosurgery with or without prior curettage or curettage and electrodesiccation. Curettage only (i.e. without subsequent cryosurgery or electrodesiccation) is a simple and quick destructive treatment method used for many benign skin lesions but has not been sufficiently evaluated for the treatment of sBCCs.ObjectivesThe objective was to compare the effectiveness of curettage vs. cryosurgery for sBCCs in terms of overall clinical clearance rates after 1 year as well as wound healing times.MethodsA single‐centre non‐inferiority clinical trial was conducted. Non‐facial sBCCs with a diameter of 5–20 mm were randomised to either cryosurgery using one freeze–thaw cycle or curettage. At follow‐up visits, treatment areas were evaluated regarding the presence of residual tumour after 3–6 months and recurrence after 1 year. Further, wound healing times were assessed.ResultsIn total, 228 sBCCs in 97 patients were included in the analysis. At 3–6 months, no residual tumours were seen in any of the treated areas. After 1 year, the clinical clearance rates for curettage and cryosurgery were 95.7% and 100%, respectively (P = 0.060). However, the non‐inferiority analysis was inconclusive. Wound healing times were shorter for curettage (4 weeks) compared to cryosurgery (5 weeks; P < 0.0001). Overall, patient satisfaction at 1 year was high.ConclusionsBoth treatment methods showed high clinical clearance rates after 1 year, whilst curettage reduced the wound healing time.

Effect of Transcatheter Aortic Valve Implantation vs Surgical Aortic Valve Replacement on All-Cause Mortality in Patients With Aortic Stenosis

Transcatheter aortic valve implantation (TAVI) is a less invasive alternative to surgical aortic valve replacement and is the treatment of choice for patients at high operative risk. The role of TAVI in patients at lower risk is unclear. To determine whether TAVI is noninferior to surgery in patients at moderately increased operative risk. In this randomized clinical trial conducted at 34 UK centers, 913 patients aged 70 years or older with severe, symptomatic aortic stenosis and moderately increased operative risk due to age or comorbidity were enrolled between April 2014 and April 2018 and followed up through April 2019. TAVI using any valve with a CE mark (indicating conformity of the valve with all legal and safety requirements for sale throughout the European Economic Area) and any access route (n = 458) or surgical aortic valve replacement (surgery; n = 455). The primary outcome was all-cause mortality at 1 year. The primary hypothesis was that TAVI was noninferior to surgery, with a noninferiority margin of 5% for the upper limit of the 1-sided 97.5% CI for the absolute between-group difference in mortality. There were 36 secondary outcomes (30 reported herein), including duration of hospital stay, major bleeding events, vascular complications, conduction disturbance requiring pacemaker implantation, and aortic regurgitation. Among 913 patients randomized (median age, 81 years [IQR, 78 to 84 years]; 424 [46%] were female; median Society of Thoracic Surgeons mortality risk score, 2.6% [IQR, 2.0% to 3.4%]), 912 (99.9%) completed follow-up and were included in the noninferiority analysis. At 1 year, there were 21 deaths (4.6%) in the TAVI group and 30 deaths (6.6%) in the surgery group, with an adjusted absolute risk difference of -2.0% (1-sided 97.5% CI, -∞ to 1.2%; P < .001 for noninferiority). Of 30 prespecified secondary outcomes reported herein, 24 showed no significant difference at 1 year. TAVI was associated with significantly shorter postprocedural hospitalization (median of 3 days [IQR, 2 to 5 days] vs 8 days [IQR, 6 to 13 days] in the surgery group). At 1 year, there were significantly fewer major bleeding events after TAVI compared with surgery (7.2% vs 20.2%, respectively; adjusted hazard ratio [HR], 0.33 [95% CI, 0.24 to 0.45]) but significantly more vascular complications (10.3% vs 2.4%; adjusted HR, 4.42 [95% CI, 2.54 to 7.71]), conduction disturbances requiring pacemaker implantation (14.2% vs 7.3%; adjusted HR, 2.05 [95% CI, 1.43 to 2.94]), and mild (38.3% vs 11.7%) or moderate (2.3% vs 0.6%) aortic regurgitation (adjusted odds ratio for mild, moderate, or severe [no instance of severe reported] aortic regurgitation combined vs none, 4.89 [95% CI, 3.08 to 7.75]). Among patients aged 70 years or older with severe, symptomatic aortic stenosis and moderately increased operative risk, TAVI was noninferior to surgery with respect to all-cause mortality at 1 year. isrctn.com Identifier: ISRCTN57819173.

MERLIN: Phase 3a, Multicenter, Randomized, Double-Masked Trial of Brolucizumab in Participants with Neovascular Age-Related Macular Degeneration and Persistent Retinal Fluid

To assess the 52-week efficacy and safety of brolucizumab 6 mg administered every 4 weeks compared with aflibercept 2 mg dosed every 4 weeks in eyes with neovascular age-related macular degeneration (nAMD) and persistent retinal fluid. Multicenter, randomized, double-masked phase 3a study. Participants with recalcitrant nAMD (persistent residual retinal fluid despite previous frequent anti-vascular endothelial growth factor treatment). Eyes were randomized (2:1) to intravitreal brolucizumab 6 mg or aflibercept 2 mg every 4 weeks up to and including week100. The primary end point was analysis of noninferiority in mean best-corrected visual acuity (BCVA) change from baseline to week 52 (margin, 4 letters). Other key end points included change in central subfield thickness (CST) from baseline to week 52, fluid-free status (no intraretinal fluid and no subretinal fluid), and safety. At week 52, brolucizumab was noninferior to aflibercept in BCVA change from baseline (least squares mean difference, -0.6 Early Treatment Diabetic Retinopathy Study letters; 95% confidence interval [CI], -2.1 to 0.9; P < 0.001). A total of 4.8% and 1.7% of participants reported a 15-letter or more BCVA loss from baseline at week 52 in the brolucizumab and aflibercept groups, respectively. In eyes treated with brolucizumab compared with those treated with aflibercept, the CST was reduced significantly (P < 0.001), and a significantly greater proportion of eyes were fluid free at week 52 (40.4% brolucizumab vs. 19.0% aflibercept; 95% CI, 13.9-29.0; P < 0.001). Incidence of intraocular inflammation (IOI), including retinal vasculitis and retinal vascular occlusion, were 9.3% (0.8% and 2.0%) for brolucizumab versus 4.5% (0% and 0%) for aflibercept, respectively. Visual acuity outcomes in previously treated participants with nAMD and persistent retinal fluid receiving brolucizumab 6 mg dosed every 4 weeks were noninferior to aflibercept 2 mg dosed every 4 weeks, with superior anatomic outcomes. However, incidences of IOI, including retinal vasculitis and retinal vascular occlusion, also were higher, leading to study termination.

PO-636-04 ABLATION OF ATRIAL FIBRILLATION BEYOND PULMONARY VEIN ISOLATION: DO ADDITIONAL ABLATION LESIONS IMPACT LEFT ATRIAL FUNCTION?

Electrical isolation of pulmonary veins (PVI) is a cornerstone for Atrial Fibrillation (AF) ablation therapy. Elimination of non-pulmonary vein (NPV) triggers in addition to PVI was shown to decrease long-term AF recurrence. The overall effect of AF ablation on left atrial (LA) function is poorly understood and it is unknown if additional ablation lesions can affect it. Our aim was to determine if LA function is different in patients after extensive LA ablation compared to PVI only. We hypothesized that addition of NPV ablation lesions in LA do not further deteriorate LA function compared to PVI alone. Out of consecutive 994 patients who underwent AF ablation at our center in years 2018-2019, we included 68 patients in our retrospective analysis who had echocardiograms (TTE) performed within 12 months prior to AF ablation and 1-12 months after. Redo ablations, history of mitral valve interventions were excluded. Patients were stratified into 2 groups: PVI only and PVI with additional LA ablation lesions (PVI+). Primary outcome was LA reservoir strain (LASr). We applied non-inferiority analysis with 90% CI for an overall alpha level of 0.05. Mean LASr in patients after AF ablation is reported 19 ±9%, we used a conservative 6% to define non-inferiority as a change in LASr. Patients in our study cohort had higher rates of history of HTN, HFrEF, DM, HLD, ESRD compared to all patients who underwent AF ablation. A higher rate of paroxysmal AF in the PVI only group was noted (70% vs 30%). The PVI+ group was observed to have a slightly higher increase in LASr compared to PVI alone (5.0%vs 4.3%), with 90% CI (-4.2 to 2.9). The upper bound for the true difference of 2.9% did not cross the pre-set margin of 6% (p<0.01 for test of non-inferiority). These findings were consistent when the LASr was adjusted for age, sex, hx of CAD, HLD, paroxysmal vs persistent AF, rhythm at pre-procedure TTE in a multivariable linear regression model, 90% CI (-5.46; 2.04), p<0.01. LA functional improvement evaluated by LASr is statistically non-inferior after PVI with additional LA ablation lesions compared to PVI alone. These findings were confirmed when adjusted for confounding clinical variables.

Comparing the Ratio of Therapist Support to Internet Sessions in a Blended Therapy Delivered to Trauma-Exposed Veterans: Quasi-experimental Comparison Study.

BackgroundBlended models of therapy, which incorporate elements of both internet and face-to-face methods, have been shown to be effective, but therapists and patients have expressed concerns that fewer face-to-face therapy sessions than self-guided internet sessions may be associated with lower therapeutic alliance, lower program completion rates, and poorer outcomes.ObjectiveA multisite quasi-experimental comparison study with a noninferiority design implemented in routine clinical care was used to assess webSTAIR, a 10-module blended therapy derived from STAIR (skills training in affective and interpersonal regulation) for trauma-exposed individuals delivered with 10 weekly therapist sessions (termed Coach10) compared to 5 biweekly sessions (Coach5). It was hypothesized that Coach5 would be as good as Coach10 in a range of outcomes.MethodsA total of 202 veterans were enrolled in the study with 101 assigned to Coach5 and 101 to Coach10. Posttraumatic stress disorder (PTSD) symptoms, depression, emotion regulation, interpersonal problems, and social functioning measures were collected pre-, mid-, and posttreatment, and at a 3-month follow-up. Noninferiority analyses were conducted on symptom outcome measures. Comparisons were made of continuous and categorical measures regarding participant and therapist activities.ResultsParticipants reported moderate to severe levels of baseline PTSD, depression, or both. Significant reductions were obtained in all symptom measures posttreatment and at the 3-month follow up. Coach5 was not inferior to Coach10 in any outcome. Therapeutic alliance was at an equivalently high level across the 2 treatment conditions; completion rates and web usage were similar. Total session time was substantially less for the Coach5 therapists than the Coach10 therapists. Both programs were associated with a low, but equal number of therapist activities related to scheduling and crisis or motivational sessions.ConclusionsA blended model delivered with 5 sessions of therapist support was noninferior to 10 sessions in individuals with moderate to severe symptoms. Future studies identifying patient characteristics as moderators of outcomes with high versus low doses of therapist support will help create flexible, technology-based intervention programming.

Compatibility between a rabies vaccine and two canine combined vaccines against canine distemper, adenovirosis, parvovirosis, parainfluenza virus disease and leptospirosis, with or without canine coronavirus

In many countries, vaccination programs still require dogs to be vaccinated against rabies in addition to Canine distemper virus (CDV), adenovirus (CAV), parvovirus (CPV), parainfluenza virus (CPiV), Leptospira (L) or Canine coronavirus (CCV= Cv). Few vaccines containing all these antigens are commercially available and, unless compatibility between the vaccines was demonstrated, concurrent administration of a DAPPi-L(Cv) vaccine and a vaccine against rabies should not be recommended. This may be of concern for practitioners who wish to vaccinate dogs with all components on the same day. This study aimed at evaluating immunological compatibility between a monovalent rabies vaccine (Rabisin™) and two large combination vaccines against CDV, CAV, CPV, CPiV with 2 leptospira components +Cv (Recombitek® C6/Cv) or with 4 Leptospira components (Recombitek® C8), when injected concomitantly at two separate injection sites.Fourteen days after administration of the rabies vaccine, with or without concomitant administration of combo vaccines, all dogs had seroconverted against rabies and maintained protective titers over the duration of the study. In addition, 100% of the puppies vaccinated with one or the other combo vaccines seroconverted against CDV, CAV, CPV, CPiV (CCV) and Leptospira, whatever the vaccination group. Lack of immunological interference between Rabisin™ and all components of the Recombitek® C6/Cv or Recombitek® C8 Combo vaccines was demonstrated by non-inferiority analysis, except for CDV in the Recombitek®C8+ Rabisin™ group. Based on these results, a concomitant administration of Rabisin™ with Recombitek® C6/Cv or Recombitek® C8 can be recommended in daily practice, which can be essential for facilitating vaccination compliance.

Opioid-Limiting Pain Control After Transurethral Resection of the Prostate: A Randomized Controlled Trial

ObjectiveTo assess whether a multimodal opioid-limiting protocol and patient education intervention can reduce postoperative opioid use following transurethral resection of the prostate. MethodsThis prospective, non-blinded, single-institution, randomized controlled trial (NCT04102566) assigned 50 patients undergoing a transurethral resection of the prostate to either a standard of care control (SOC) or multimodal experimental group (MMG). The intervention included adding ibuprofen to the postoperative pain regimen, promoting appropriate opioid use while hospitalized, an educational intervention, and discharging without opioid prescription. Data regarding demographics, operative data, opioid use, pain scores, and patient satisfaction were compared. ResultsA total of 47 patients were included, n = 23 (MMG) and n = 24 (SOC). Demographic and operative findings were similar. Statistical analysis for noninferiority demonstrated non-inferior inpatient pain control (mean pain score 2.5 MMG vs 2.4 SOC, P = 0.0003). The multimodal group used significantly fewer morphine milligram equivalents after discharge (0 vs 4.1, P = 0.04). Inpatient use was reduced but did not reach statistical significance (6.0 vs 9.8, P = 0.2). Mean satisfaction scores with pain control were similar (9.6 MMG vs 9.2 SOC, P = 0.32). No opioid prescriptions were requested after discharge. Adverse events and medication side effects were infrequent and largely similar between groups. ConclusionImplementation of an opioid-limiting postoperative pain protocol and patient education resulted in no outpatient opioid use while maintaining patient satisfaction with pain control. Eliminating opioids following a common urologic procedure will decrease risk of opioid-related adverse events and have a positive downstream impact.

Simplifying and optimising the management of uncomplicated acute malnutrition in children aged 6–59 months in the Democratic Republic of the Congo (OptiMA-DRC): a non-inferiority, randomised controlled trial

Global access to acute malnutrition treatment is low. Different programmes using different nutritional products manage cases of severe acute malnutrition and moderate acute malnutrition separately. We aimed to assess whether integrating severe acute malnutrition and moderate acute malnutrition treatment into one programme, using a single nutritional product and reducing the dose as the child improves, could achieve similar or higher individual efficacy, increase coverage, and minimise costs compared with the current programmes. We conducted an open-label, non-inferiority, randomised controlled trial in the Democratic Republic of the Congo. Acutely malnourished children aged 6-59 months with a mid-upper-arm circumference (MUAC) of less than 125 mm or oedema were randomly assigned (1:1), using specially developed software and random blocks (size was kept confidential), to either the current standard strategy (one programme for severe acute malnutrition using ready-to-use therapeutic food [RUTF] at an increasing dose as weight increased, another for moderate acute malnutrition using a fixed dose of ready-to-use supplementary food [RUSF]) or the OptiMA strategy (a single programme for both severe acute malnutrition and moderate acute malnutrition using RUTF at a decreasing dose as MUAC and weight increased). The primary endpoint was a favourable outcome at 6 months, defined as being alive, not acutely malnourished as per the definition applied at inclusion, and with no further episodes of acute malnutrition throughout the 6-month observation period; the endpoint was analysed in the intention-to-treat (all children) and per-protocol populations (participants who had a minimum prescription of 4 weeks' RUTF, received at least 90% of the total amount of RUTF they were supposed to receive as per the protocol, or were prescribed RUSF rations for a minimum of 4 weeks [ie, minimum of 28 RUSF sachets], and had a maximum interval of 6 weeks between any two visits in the 6-month follow-up). The non-inferiority analysis (margin 10%) was to be followed by a superiority analysis (margin 0%) if non-inferiority was concluded. This trial is registered at ClinicalTrials.gov, NCT03751475, and is now closed. Between July 22 and Dec 6, 2019, 912 children were randomly assigned; after 16 were excluded, 896 were analysed (446 in the standard group and 450 in the OptiMA group). In the intention-to-treat analysis, 282 (63%) of 446 children in the standard group and 325 (72%) of 450 children in the OptiMA group had a favourable outcome (difference -9·0%, 95% CI -15·9 to -2·0). In the per protocol analysis, 161 (61%) of 264 children in the standard group and 291 (74%) of 392 children in the OptiMA group had a favourable outcome (-13·2%, -21·6 to -4·9). In this non-inferiority trial treating children with MUAC of less than 125 mm or oedema, decreasing RUTF dose according to MUAC and weight increase proved to be a superior strategy to the standard protocol in the Democratic Republic of the Congo. These results demonstrate the safety and benefits of an approach that could substantially increase access to treatment for millions of children with acute malnutrition in sub-Saharan Africa. Innocent Foundation and European Civil Protection and Humanitarian Aid Operations. For the French translation of the abstract see Supplementary Materials section.

A non-inferiority analysis of hemoglobin levels in postpartum IUD users in Bangladesh.

ObjectiveThe objective of this study was to compare postpartum hemoglobin (Hb) between postpartum intrauterine device (PPIUD) and non‐PPIUD users.MethodsA sample of 3697 postpartum women (475 PPIUD users, 3222 non‐PPIUD users) from 5 tertiary referral hospitals in Bangladesh were assessed at multiple time points between 6 weeks and 12 months postpartum. Non‐inferiority linear regression analysis compared changes in Hb levels at 29–52 weeks postpartum between the two groups. Non‐inferiority was declared if the lower 95% confidence interval of the estimated difference in Hb change since delivery between PPIUD and non‐PPIUD users was greater than −0.05 g/dl.ResultsAt approximately 9 months postpartum, 276 women in the PPIUD group (58.1%) and 1086 women in the comparison group (33.7%) attended follow‐up. In total, 57.9% of PPIUD users and 61.0% of non‐PPIUD users had taken iron supplementation. Change in Hb was 0.02 g/dl (95% CI: −0.16, 0.19) higher in the PPIUD users than the comparison group. The lower limit of the 95% CI was greater than −0.05 g/dl, providing good evidence that PPIUD users were non‐inferior to the comparison group in their Hb levels.ConclusionIn the presence of offering iron supplementation, and an uptake of just over 60%, no difference in anemia was observed between the PPIUD and control group.

A Prospective Randomized Study Comparing Ceftolozane/Tazobactam to Standard of Care in the Management of Neutropenia and Fever in Patients With Hematological Malignancies.

BackgroundWith increased use of antibiotics in high-risk patients, the investigation of new antibiotics to cover potentially resistant pathogens is warranted. In this prospective randomized trial, we compared ceftolozane/tazobactam (C/T), a new cephalosporin/β-lactamase inhibitor, to the standard of care (SOC) for the empiric treatment of neutropenia and fever in patients with hematological malignancies.MethodsWe enrolled 100 patients to receive intravenous (IV) C/T or SOC antibiotics (cefepime, piperacillin/tazobactam, or meropenem) in combination with gram-positive antibacterial agents. We evaluated responses at the end of IV therapy (EOIV), test of cure (TOC; days 21–28), and late follow-up (LFU; days 35–42).ResultsWe analyzed 47 C/T patients and 50 SOC patients. C/T patients had a higher rate of favorable clinical response at EOIV (87% vs 72%). A 1-sided noninferiority analysis indicated that C/T was at least not inferior to the SOC for favorable clinical response at EOIV (P = .002), TOC (P = .004), and LFU (P = .002). Superiority tests showed that C/T led to significantly lower rates of clinical failure at TOC (6% vs 30%; P = .003) and LFU (9% vs 30%; P = .008). C/T and SOC patients with documented infections had similar rates of favorable microbiological response. Serious adverse events leading to drug discontinuation (2% vs 0%; P = .48) and overall mortality (6% vs 4%; P = .67) were similar in both groups.ConclusionsThe empiric use of C/T in high-risk patients with hematological malignancies and febrile neutropenia is safe and associated with better clinical outcomes than SOC antimicrobial agents.Clinical Trials RegistrationNCT03485950.

The influence of timing of coronary angiography on acute kidney injury in out-of-hospital cardiac arrest patients: a retrospective cohort study

BackgroundAcute kidney injury (AKI) is a frequent complication in cardiac arrest survivors and associated with adverse outcome. It remains unclear whether the incidence of AKI increases after the post-cardiac arrest contrast administration for coronary angiography and whether this depends on timing of angiography. Aim of this study was to investigate whether early angiography is associated with increased development of AKI compared to deferred angiography in out-of-hospital cardiac arrest (OHCA) survivors.MethodsIn this retrospective multicenter cohort study, we investigated whether early angiography (within 2 h) after OHCA was non-inferior to deferred angiography regarding the development of AKI. We used an absolute difference of 5% as the non-inferiority margin. Primary non-inferiority analysis was done by calculating the risk difference with its 90% confidence interval (CI) using a generalized linear model for a binary outcome. As a sensitivity analysis, we repeated the primary analysis using propensity score matching. A multivariable model was built to identify predictors of acute kidney injury.ResultsA total of 2375 patients were included from 2009 until 2018, of which 1148 patients were treated with early coronary angiography and 1227 patients with delayed or no angiography. In the early angiography group 18.5% of patients developed AKI after OHCA and 24.1% in the deferred angiography group. Risk difference was − 3.7% with 90% CI ranging from − 6.7 to − 0.7%, indicating non-inferiority of early angiography. The sensitivity analysis using propensity score matching showed accordant results, but no longer non-inferiority of early angiography. The factors time to return of spontaneous circulation (odds ratio [OR] 1.12, 95% CI 1.06–1.19, p < 0.001), the (not) use of angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker (OR 0.20, 95% CI 0.04–0.91, p = 0.04) and baseline creatinine (OR 1.05, 95% CI 1.03–1.07, p < 0.001) were found to be independently associated with the development of AKI.ConclusionsAlthough AKI occurred in approximately 20% of OHCA patients, we found that early angiography was not associated with a higher AKI incidence than a deferred angiography strategy. The present results implicate that it is safe to perform early coronary angiography with respect to the risk of developing AKI after OHCA.

Effect of intrabronchial administration of autologous adipose-derived mesenchymal stem cells on severe equine asthma

BackgroundSevere equine asthma (SEA) is a common chronic respiratory disease and a significant health and well-being problem in horses. Current therapeutic strategies improve pulmonary function and clinical signs in some horses, but in the long-term, return to full athletic function appears to be rare. The aim of this study was to assess the safety and the effect of intrabronchial administration of adipose-derived mesenchymal stem cells (AD-MSC) on pulmonary inflammatory and clinical parameters in horses with SEA.MethodsThis was a randomized controlled trial. Twenty adult horses diagnosed with SEA were randomly divided into two groups (n = 10), and treated either with a single intrabronchial application of autologous AD-MSC or oral dexamethasone for three weeks. A targeted clinical examination with determination of clinical score, maximal change in pleural pressure during the breathing cycle, and an endoscopic examination of the airways were performed at baseline and three weeks after treatment. Bronchoalveolar lavage fluid was analyzed cytologically, and IL-1β, IL-4, IL-8, IL-17, TNFα and IFNγ mRNA and protein concentrations were measured at baseline and three weeks. The horses were then monitored over one year for recurrence of SEA. A non-inferiority analysis and a linear mixed-effects model were performed to assess differences between treatments.ResultsThe non-inferiority of AD-MSC treatment was not established. However, AD-MSC administration significantly ameliorated the clinical score (P = 0.01), decreased the expression of IL-17 mRNA (P = 0.05) and IL-1β (P ≤ 0.001), IL-4 (P ≤ 0.001), TNFα (P = 0.02) protein levels, and had a positive long-term effect on SEA-associated clinical signs (P = 0.02).ConclusionsIntrabronchial administration of AD-MSC had limited short-term anti-inflammatory effects but improved the clinical signs of SEA at one year.

Neonatal rotavirus vaccine (RV3-BB) immunogenicity and safety in a neonatal and infant administration schedule in Malawi: a randomised, double-blind, four-arm parallel group dose-ranging study

SummaryBackgroundRotavirus vaccines reduce rotavirus-related deaths and hospitalisations but are less effective in high child mortality countries. The human RV3-BB neonatal G3P[6] rotavirus vaccine administered in a neonatal schedule was efficacious in reducing severe rotavirus gastroenteritis in Indonesia but had not yet been evaluated in African infants.MethodsWe did a phase 2, randomised, double-blind, parallel group dose-ranging study of three doses of oral RV3-BB rotavirus vaccine in infants in three primary health centres in Blantyre, Malawi. Healthy infants less than 6 days of age with a birthweight 2·5 to 4·0 kg were randomly assigned (1:1:1:1) into one of four treatment groups: neonatal vaccine group, which included high-titre (1·0 × 107 focus-forming unit [FFU] per mL), mid-titre (3·0 × 106 FFU per mL), or low-titre (1·0 × 106 FFU per mL); and infant vaccine group, which included high-titre (1·0 × 107 FFU per mL) using a computer generated code (block size of four), stratified by birth (singleton vs multiple). Neonates received their three doses at 0–5 days to 10 weeks and infants at 6–14 weeks. Investigators, participant families, and laboratory staff were masked to group allocation. Anti-rotavirus IgA seroconversion and vaccine take (IgA seroconversion and stool shedding) were evaluated. Safety was assessed in all participants who received at least one dose of vaccine or placebo. The primary outcome was the cumulative IgA seroconversion 4 weeks after three doses of RV3-BB in the neonatal schedule in the high-titre, mid-titre, and low-titre groups in the per protocol population, with its 95% CI. With the high-titre group as the active control group, we did a non-inferiority analysis of the proportion of participants with IgA seroconversion in the mid-titre and low-titre groups, using a non-inferiority margin of less than 20%. This trial is registered at ClinicalTrials.gov (NCT03483116).FindingsBetween Sept 17, 2018, and Jan 27, 2020, 711 participants recruited were randomly assigned into four treatment groups (neonatal schedule high titre n=178, mid titre n=179, low titre n=175, or infant schedule high titre n=179). In the neonatal schedule, cumulative IgA seroconversion 4 weeks after three doses of RV3-BB was observed in 79 (57%) of 139 participants in the high-titre group, 80 (57%) of 141 participants in the mid-titre group, and 57 (41%) of 138 participants in the low-titre group and at 18 weeks in 100 (72%) of 139 participants in the high-titre group, 96 (67%) of 143 participants in the mid-titre group, and 86 (62%) of 138 of participants in the low-titre. No difference in cumulative IgA seroconversion 4 weeks after three doses of RV3-BB was observed between high-titre and mid-titre groups in the neonatal schedule (difference in response rate 0·001 [95%CI −0·115 to 0·117]), fulfilling the criteria for non-inferiority. In the infant schedule group 82 (59%) of 139 participants had a cumulative IgA seroconversion 4 weeks after three doses of RV3-BB at 18 weeks. Cumulative vaccine take was detected in 483 (85%) of 565 participants at 18 weeks. Three doses of RV3-BB were well tolerated with no difference in adverse events among treatment groups: 67 (39%) of 170 participants had at least one adverse event in the high titre group, 68 (40%) of 172 participants had at least one adverse event in the mid titre group, and 69 (41%) of 169 participants had at least one adverse event in the low titre group.InterpretationRV3-BB was well tolerated and immunogenic when co-administered with Expanded Programme on Immunisation vaccines in a neonatal or infant schedule. A lower titre (mid-titre) vaccine generated similar IgA seroconversion to the high-titre vaccine presenting an opportunity to enhance manufacturing capacity and reduce costs. Neonatal administration of the RV3-BB vaccine has the potential to improve protection against rotavirus disease in children in a high-child mortality country in Africa.FundingBill & Melinda Gates Foundation, Australian Tropical Medicine Commercialisation Grant.

Comparative efficacy of two pyrethroid-piperonyl butoxide nets (Olyset Plus and PermaNet 3.0) against pyrethroid resistant malaria vectors: a non-inferiority assessment

BackgroundPyrethroid-PBO nets were conditionally recommended for control of malaria transmitted by mosquitoes with oxidase-based pyrethroid-resistance based on epidemiological evidence of additional protective effect with Olyset Plus compared to a pyrethroid-only net (Olyset Net). Entomological studies can be used to assess the comparative performance of other brands of pyrethroid-PBO ITNs to Olyset Plus.MethodsAn experimental hut trial was performed in Cové, Benin to compare PermaNet 3.0 (deltamethrin plus PBO on roof panel only) to Olyset Plus (permethrin plus PBO on all panels) against wild pyrethroid-resistant Anopheles gambiae sensu lato (s.l.) following World Health Organization (WHO) guidelines. Both nets were tested unwashed and after 20 standardized washes compared to Olyset Net. Laboratory bioassays were also performed to help explain findings in the experimental huts.ResultsWith unwashed nets, mosquito mortality was higher in huts with PermaNet 3.0 compared to Olyset Plus (41% vs. 28%, P < 0.001). After 20 washes, mortality declined significantly with PermaNet 3.0 (41% unwashed vs. 17% after washing P < 0.001), but not with Olyset Plus (28% unwashed vs. 24% after washing P = 0.433); Olyset Plus induced significantly higher mortality than PermaNet 3.0 and Olyset Net after 20 washes. PermaNet 3.0 showed a higher wash retention of PBO compared to Olyset Plus. A non-inferiority analysis performed with data from unwashed and washed nets together using a margin recommended by the WHO, showed that PermaNet 3.0 was non-inferior to Olyset Plus in terms of mosquito mortality (25% with Olyset Plus vs. 27% with PermaNet 3.0, OR = 1.528, 95%CI = 1.02–2.29) but not in reducing mosquito feeding (25% with Olyset Plus vs. 30% with PermaNet 3.0, OR = 1.192, 95%CI = 0.77–1.84). Both pyrethroid-PBO nets were superior to Olyset Net.ConclusionOlyset Plus outperformed PermaNet 3.0 in terms of its ability to cause greater margins of improved mosquito mortality compared to a standard pyrethroid net, after multiple standardized washes. However, using a margin of non-inferiority defined by the WHO, PermaNet 3.0 was non-inferior to Olyset Plus in inducing mosquito mortality. Considering the low levels of mortality observed and increasing pyrethroid-resistance in West Africa, it is unclear whether either of these nets would demonstrate the same epidemiological impact observed in community trials in East Africa.

Influence of 3D analysis software on measured deviations of CAD-CAM resin crowns from virtual design file: An in-vitro study

Objectives: To evaluate a nonmetrology-grade and a metrology-grade 3D analysis software when measuring the deviations of computer-aided-design/ computer-aided-manufacturing (CAD-CAM) fabricated crowns from the virtual design file.Materials and Methods: A right first molar on a mandibular dentate model was prepared and scanned with an intraoral scanner, i500 (Medit). A complete coverage crown was designed in standard tessellation language (STL) format and 20 resin crowns were fabricated with CAD-CAM. The crowns were then digitized using the same intraoral scanner (test-scans). Root mean square (RMS) method was used to evaluate the deviations between the test-scans and the design file of the crowns on 3 surfaces (overall, external, and internal) using a metrology-grade, Geomagic Control X (3D Systems) and a nonmetrology-grade, Medit Link (Medit) software. The data were analyzed with Welch two-sample t-tests to compare two software for the non-inferiority of the nonmetrology-grade software with a 50 µm threshold and the potential superiority of the metrology-grade software (α = 0.05).Results: The Welch two-sample t-tests for the non-inferiority analysis showed that the differences between the nonmetrology-grade and the metrology-grade software were below the threshold of 50 µm for each surface tested (p <0.001). The differences between the two-tested software were nonsignificant for each surface analyzed when superiority was considered (p ≥.194).Conclusion: The nonmetrology-grade software performed similar to the metrology-grade software when analyzing the deviations of CAD-CAM crowns. Therefore, the nonmetrology-grade 3D analysis software may be considered for the deviation measurements of similar restorations.Clinical Significance: The trueness of crowns after fabrication may affect their fit, and 3D analysis of trueness prior to the delivery appointment with the tested nonmetrology-grade software after fabrication may facilitate potential clinical adjustments and delivery of the crowns.

The impact on obstetric and perinatal outcomes in term infants following the introduction of a colour-coded, hierarchical cardiotocography classification system: A retrospective non-inferiority study.

Queensland introduced a colour-coded cardiotocograph (CTG) classification system (green, blue, yellow and red) to complement the Royal Australian and New Zealand College of Obstetricians and Gynaecologists prose-based classification system of 'low, unlikely, maybe or likely' fetal compromise. The aim of the study was to determine the clinical impact of the introduction of the colour-coded CTG classification system compared to the prose-based system. We hypothesised there would be no change in the rate of operative delivery for intrapartum fetal compromise (OD-IFC). This retrospective non-inferiority study from November 2014 to May 2018 used routinely collected data from the Mater Mother's Hospital. Non-insured women with a singleton, non-anomalous, cephalic fetus at term, attempting a vaginal birth with continuous intrapartum CTG were included. The primary outcome was OD-IFC. Secondary outcomes included various obstetric and perinatal outcomes. Non-inferiority analysis was performed with a pre-specified non-inferiority margin of 2% risk difference. Eleven thousand seven hundred and twenty-seven participants were included. The OD-IFC rate was similar across the study groups (prose-based 15.1% vs colour-coded 15.3%, adjusted odds ratio (aOR) 1.02, 95% CI 0.93-1.13) with the adjusted risk difference of 0.29% (95% CI -0.98 to 1.56), which did not exceed the inferiority margin. There were more spontaneous (aOR 1.11, 95% CI 1.04-1.19) and fewer instrumental (aOR 0.87, 95% CI 0.80-0.95) vaginal births in the colour-coded cohort. There were no differences in neonatal outcomes. Reassuringly, the colour-coded CTG classification system was non-inferior to the prose-based system, did not influence OD-IFC but was associated with more spontaneous vaginal deliveries.

Validation of a proxy-reported SARC-F questionnaire for current and retrospective screening of sarcopenia-related functional impairments.

BackgroundThe strength, assistance walking, rise from a chair, climb stairs, and falls (SARC‐F) questionnaire is a well‐established instrument for screening of sarcopenia and sarcopenia‐related functional impairments. As it is based on self‐reporting, its use precludes patients who are unable to answer the questionnaire as a consequence of severe acute diseases or cognitive impairment. Therefore, we aimed to validate a proxy‐reported version of the SARC‐F for both ad‐hoc as well as retrospective screening for severe sarcopenia‐related functional impairments.MethodsPatients aged ≥60 years completed the SARC‐F and performed the short physical performance battery (SPPB) at baseline (T1). Proxies in Cohort A gave a simultaneous assessment of the patients' functional status with the proxy‐reported SARC‐F at T1 and again, retrospectively, after 3 months (T2). Proxies in Cohort B only completed the SARC‐F retrospectively at T2.The questionnaires' performances were assessed through sensitivity/specificity analyses and receiver operating characteristic (ROC) curves. For non‐inferiority analyses, results of both the patient‐reported and proxy‐reported SARC‐F were correlated with the SPPB total score as well as the results of the chair‐rise test subcategory; the respective correlation coefficients were tested against each other.ResultsOne hundred and four patients and 135 proxies participated. Using a SPPB score < 9 points as the reference standard, the proxy‐reported SARC‐F identified patients at high risk for sarcopenia‐related functional impairment with a sensitivity of 0.81 (ad‐hoc), 0.88 (retrospective Cohort A), and 0.87 (retrospective Cohort B) as well as a specificity of 0.89 (ad‐hoc), 0.78 (retrospective Cohort A), and 0.64 (retrospective Cohort B). Areas under the ROC curves were ≥ 0.9 for the ad‐hoc proxy‐reported SARC‐F and the retrospective proxy‐reported SARC‐F in both cohorts. The proxy‐reported SARC‐F showed a non‐inferior correlation with the SPPB compared with the patient‐reported SARC‐F for ad‐hoc (P = <0.001) as well as retrospective screening for severe sarcopenia‐related functional impairment in both Cohorts A (P = 0.007) and B (P = 0.026).ConclusionsProxy‐reported SARC‐F is a valid instrument for both ad‐hoc as well as retrospective screening for sarcopenia‐related functional impairment and could become the standard tool for evaluating this risk in older adults with severe acute disease, for example, in patients with quickly evolving haematological conditions.