Comparison of nuisance parameters in pediatric versus adult randomized trials: a meta-epidemiologic empirical evaluation

BACKGROUND We wished to compare the nuisance parameters of pediatric vs. adult randomized-trials (RCTs) and determine if the latter can be used in sample size computations of the former. METHODS In this meta-epidemiologic empirical evaluation we examined meta-analyses from the Cochrane Database of Systematic-Reviews, with at least one pediatric-RCT and at least one adult-RCT. Within each meta-analysis of binary efficacy-outcomes, we calculated the pooled-control-group event-rate (CER) across separately all pediatric and adult-trials, using random-effect models and subsequently calculated the control-group event-rate risk-ratio (CER-RR) of the pooled-pediatric-CERs vs. adult-CERs. Within each meta-analysis with continuous outcomes we calculated the pooled-control-group effect standard deviation (CE-SD) across separately all pediatric and adult-trials and subsequently calculated the CE-SD-ratio of the pooled-pediatric-CE-SDs vs. adult-CE-SDs. We then calculated across all meta-analyses the pooled-CER-RRs and pooled-CE-SD-ratios (primary endpoints) and the pooled-magnitude of effect-sizes of CER-RRs and CE-SD-ratios using REMs. A ratio < 1 indicates that pediatric trials have smaller nuisance parameters than adult trials. RESULTS We analyzed 208 meta-analyses (135 for binary-outcomes, 73 for continuous-outcomes). For binary outcomes, pediatric-RCTs had on average 10% smaller CERs than adult-RCTs (summary-CE-RR: 0.90; 95% CI: 0.83, 0.98). For mortality outcomes the summary-CE-RR was 0.48 (95% CIs: 0.31, 0.74). For continuous outcomes, pediatric-RCTs had on average 26% smaller CE-SDs than adult-RCTs (summary-CE-SD-ratio: 0.74). CONCLUSIONS Clinically relevant differences in nuisance parameters between pediatric and adult trials were detected. These differences have implications for design of future studies. Extrapolation of nuisance parameters for sample-sizes calculations from adult-trials to pediatric-trials should be cautiously done

Positive predictive value of ELISpot in BAL and pleural fluid from patients with suspected pulmonary tuberculosis

Background: The aim of this study was to evaluate the positive predictive value (PPV) of ELISpot in bronchoalveolar lavage (BAL) and pleural fluid for the diagnosis of active tuberculosis (TB) in real-life clinical practice, together with the added value of a cut-off >1.0 for the ratio between the extra-sanguineous and systemic interferon-gamma responses in positive samples. Methods: A retrospective, single-centre study was performed. Patients with positive ELISpot in BAL and pleural fluid were included. Results: The PPV for TB in patients with positive ELISpot in BAL (n = 40) was 64.9%, which increased to 82.6% for the ESAT-6 panel and 71.4% for the CFP-10 panel after the introduction of a cut-off >1.0 for the ratio between the BAL and blood interferon-gamma responses. In patients with positive ELISpot in pleural fluid (n = 16), the PPV for TB was 85.7%, which increased to 91.7% for the ESAT-6 panel and 92.3% for the CFP-10 panel after the introduction of a cut-off >1.0 for the ratio between the pleural fluid and blood interferon-gamma responses. Conclusions: This report describes the PPV of ELISpot in BAL and pleural fluid for the diagnosis of active TB in real-life clinical practice. The results indicate the possibility of an increase of the PPV using a cut-off >1.0 for the ratio between the extra-sanguineous and systemic interferon-gamma responses. Further studies are needed to underline this ratio-approach and to evaluate the full diagnostic accuracy of ELISpot in extra-sanguineous fluids like BAL and pleural fluid

Design and implementation of Pharyngeal electrical Stimulation for early de-cannulation in TRACheotomized (PHAST-TRAC) stroke patients with neurogenic dysphagia: a prospective randomized single-blinded interventional study

Rationale: Ongoing dysphagia in stroke patients weaned from mechanical ventilation often requires long-term tracheotomy to protect the airway from aspiration. In a recently reported single-centre pilot study, a significantly larger proportion (75%) of tracheotomized dysphagic stroke patients regained sufficient control of airway management allowing tracheotomy tube removal (decannulation) 24–72 h after pharyngeal electrical stimulation (PES) compared to controls who received standard therapy over the same time period (20%). Aim: To assess the safety and efficacy of PES in accelerating dysphagia rehabilitation and enabling decannulation of tracheotomized stroke patients. Design: International multi-centre prospective randomized controlled single-blind trial in approximately 126 ICU patients (the 90th percentile of the calculated maximum sample size). Study outcomes: Primary outcome: proportion of stroke patients considered safe for decannulation 24–72 h after PES compared to control patients who do not receive PES. Key secondary outcomes focus on: dysphagia severity, decannulation rates, decannulation rate after a repeat PES treatment in patients persistently dysphagic after an initial PES treatment, stroke severity, duration of ICU-stay, occurrence of adverse events including pneumonia and need for recannulation over 30 days or until hospital discharge (if earlier). Discussion: Dysphagia and related airway complications are reported as one of the main reasons for stroke patients remaining tracheotomized once successfully weaned from ventilation. This study will evaluate if PES can improve airway safety sufficiently enough to allow earlier tracheotomy tube removal

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PHAryngeal electrical STimulation for early decannulation in TRACheotomised stroke patients with neurogenic dysphagia (PHAST-TRAC): a prospective randomised single-blinded trial

Background Dysphagia after stroke is common, especially in severely affected, tracheotomised patients. In a pilot trial, pharyngeal electrical stimulation (PES) improved swallowing function in this group of patients. The PHAryngeal electrical STimulation for early decannulation in TRACheotomised stroke patients with neurogenic dysphagia trial (PHAST-TRAC) was designed to replicate and extend this single-centre experience. Methods Patients with recent stroke who required tracheotomy were randomised to receive three days of PES or sham. All patients had the stimulation catheter inserted; sham treatment was applied by connecting the base station to a simulator box instead of the catheter. Randomisation was done via a computerised interactive system with randomisation (stratified by site) in blocks of 4 patients per site. Patients and investigators applying PES were not masked. The primary-endpoint was assessed blinded to treatment assignment by a separate investigator at each site. The primary outcome was readiness for decannulation 24-72 hours post-treatment, assessed using fiberoptic endoscopic evaluation of swallowing and based on a standardised protocol including absence of massive saliva, presence of spontaneous swallows and laryngeal sensation. We planned a sequential statistical analysis of superiority for the primary endpoint. Interim analyses were to be performed after primary outcome data were available for 50 patients (futility), 70 patients, and every additional 10 patients thereafter up to 140. Analysis was by intention-to-treat. The trial was registered as ISRCTN18137204. Findings From 29th May 2015 to 5th July 2017, 69 patients (PES 35, sham 34) from 9 sites (7 acute care hospitals, 2 rehabilitation facilities) in Germany, Austria and Italy were included: PES group mean age 61.7 (SD 13.0) years, 8 (23%) patients with haemorrhagic stroke, median time onset to randomisation 28.0 [IQR 20, 49] days; sham group age 66.8 (10.3) years, 12 (35%) patients with haemorrhagic stroke, onset to randomisation 28.0 [18, 40] days). The Independent Data & Safety Monitoring Board recommended to stop the trial early for efficacy after 70 patients had been recruited and primary endpoint data of 69 patients were available. This decision was approved by the steering committee. PES was associated with more patients being ready for decannulation as compared to sham: 17 (49%) vs. 3 (9%), odds ratio (OR) 7.00 (2.41-19.88), p=0.00082). No patient required recannulation within 48 hours or during their documented follow-up period up to 30 days or hospital discharge. Adverse events (AEs) were reported in 24 patients (69%) of the PES group and 24 patients (71%) of the sham group. The number of patients with at least one serious adverse event (SAE) did not differ between the groups: 10 (29%) vs. 8 (23%), OR 1.3 (0.44-3.83), p=0.7851). 7 patients (20%) from the PES group and 3 patients (9%) from the sham group died during the study period. None of the patient deaths or SAEs reported were judged to be PES-treatment- or investigational device-related. Interpretation PES increased the proportion of patients with stroke and subsequent tracheotomy who were ready for decannulation in this study population, many of whom received PES within a month of their stroke. Future trials should confirm whether PES is beneficial in tracheostomised patients who receive stimulation similarly early after stroke and explore its effects in other cohorts

A randomised clinical trial on cardiotocography plus fetal blood sampling versus cardiotocography plus ST-analysis of the fetal electrocardiogram (STAN®) for intrapartum monitoring

<p>Abstract</p> <p>Background</p> <p>Cardiotocography (CTG) is worldwide the method for fetal surveillance during labour. However, CTG alone shows many false positive test results and without fetal blood sampling (FBS), it results in an increase in operative deliveries without improvement of fetal outcome. FBS requires additional expertise, is invasive and has often to be repeated during labour. Two clinical trials have shown that a combination of CTG and ST-analysis of the fetal electrocardiogram (ECG) reduces the rates of metabolic acidosis and instrumental delivery. However, in both trials FBS was still performed in the ST-analysis arm, and it is therefore still unknown if the observed results were indeed due to the ST-analysis or to the use of FBS in combination with ST-analysis.</p> <p>Methods/Design</p> <p>We aim to evaluate the effectiveness of non-invasive monitoring (CTG + ST-analysis) as compared to normal care (CTG + FBS), in a multicentre randomised clinical trial setting. Secondary aims are: 1) to judge whether ST-analysis of fetal electrocardiogram can significantly decrease frequency of performance of FBS or even replace it; 2) perform a cost analysis to establish the economic impact of the two treatment options.</p> <p>Women in labour with a gestational age ≥ 36 weeks and an indication for CTG-monitoring can be included in the trial.</p> <p>Eligible women will be randomised for fetal surveillance with CTG and, if necessary, FBS or CTG combined with ST-analysis of the fetal ECG.</p> <p>The primary outcome of the study is the incidence of serious metabolic acidosis (defined as pH < 7.05 and Bd_ecf> 12 mmol/L in the umbilical cord artery). Secondary outcome measures are: instrumental delivery, neonatal outcome (Apgar score, admission to a neonatal ward), incidence of performance of FBS in both arms and cost-effectiveness of both monitoring strategies across hospitals.</p> <p>The analysis will follow the intention to treat principle. The incidence of metabolic acidosis will be compared across both groups. Assuming a reduction of metabolic acidosis from 3.5% to 2.1 %, using a two-sided test with an alpha of 0.05 and a power of 0.80, in favour of CTG plus ST-analysis, about 5100 women have to be randomised. Furthermore, the cost-effectiveness of CTG and ST-analysis as compared to CTG and FBS will be studied.</p> <p>Discussion</p> <p>This study will provide data about the use of intrapartum ST-analysis with a strict protocol for performance of FBS to limit its incidence. We aim to clarify to what extent intrapartum ST-analysis can be used without the performance of FBS and in which cases FBS is still needed.</p> <p>Trial Registration Number</p> <p>ISRCTN95732366</p

Effect of increased convective clearance by on-line hemodiafiltration on all cause and cardiovascular mortality in chronic hemodialysis patients – the Dutch CONvective TRAnsport STudy (CONTRAST): rationale and design of a randomised controlled trial [ISRCTN38365125]

BACKGROUND: The high incidence of cardiovascular disease in patients with end stage renal disease (ESRD) is related to the accumulation of uremic toxins in the middle and large-middle molecular weight range. As online hemodiafiltration (HDF) removes these molecules more effectively than standard hemodialysis (HD), it has been suggested that online HDF improves survival and cardiovascular outcome. Thus far, no conclusive data of HDF on target organ damage and cardiovascular morbidity and mortality are available. Therefore, the CONvective TRAnsport STudy (CONTRAST) has been initiated. METHODS: CONTRAST is a Dutch multi-center randomised controlled trial. In this trial, approximately 800 chronic hemodialysis patients will be randomised between online HDF and low-flux HD, and followed for three years. The primary endpoint is all cause mortality. The main secondary outcome variables are fatal and non-fatal cardiovascular events. CONCLUSION: The study is designed to provide conclusive evidence whether online HDF leads to a lower mortality and less cardiovascular events as compared to standard HD

Severe Pediatric COVID-19 and Multisystem Inflammatory Syndrome in Children from Wild-type to Population Immunity: A Prospective Multicenter Cohort Study with Real-time Reporting

Background: SARS-CoV-2 variant evolution and increasing immunity altered the impact of pediatric SARS-CoV-2 infection. Public health decision-making relies on accurate and timely reporting of clinical data. Methods: This international hospital-based multicenter, prospective cohort study with real-time reporting was active from March 2020 to December 2022. We evaluated longitudinal incident rates and risk factors for disease severity. Results: We included 564 hospitalized children with acute COVID-19 (n = 375) or multisystem inflammatory syndrome in children (n = 189) from the Netherlands, Curaçao and Surinam. In COVID-19, 134/375 patients (36%) needed supplemental oxygen therapy and 35 (9.3%) required intensive care treatment. Age above 12 years and preexisting pulmonary conditions were predictors for severe COVID-19. During omicron, hospitalized children had milder disease. During population immunity, the incidence rate of pediatric COVID-19 infection declined for older children but was stable for children below 1 year. The incidence rate of multisystem inflammatory syndrome in children was highest during the delta wave and has decreased rapidly since omicron emerged. Real-time reporting of our data impacted national pediatric SARS-CoV-2 vaccination- and booster-policies. Conclusions: Our data supports the notion that similar to adults, prior immunity protects against severe sequelae of SARS-CoV-2 infections in children. Real-time reporting of accurate and high-quality data is feasible and impacts clinical and public health decision-making. The reporting framework of our consortium is readily accessible for future SARS-CoV-2 waves and other emerging infections