UNASSIGNED: To demonstrate the long-term safety profile of canakinumab over a nine-year period by documenting adverse events in patients with various pediatric rheumatic diseases.
UNASSIGNED: This retrospective observational study was conducted at the Pediatric Rheumatology Department of Istanbul University Cerrahpasa between 2015 and 2023. The analysis concerned individuals who had been administered canakinumab treatment for at least six months. The exposure-adjusted event rates were calculated as adverse events per 100 patient days and were compared among three groups based on the cumulative canakinumab dose of <35 mg/kg, 35-70 mg/kg, and >70 mg/kg.
UNASSIGNED: Among 189 patients, the median exposure time to canakinumab was 2.9 (1.5-4.1) years, corresponding to 573.4 patient years. The median cumulative dose of canakinumab was 2205 (1312-3600) mg. The most common adverse event was upper respiratory tract infection (0.76), followed by urinary tract infection (0.02), pneumonia (0.009), latent tuberculosis (0.009) and lymphadenitis (0.004). A total of 55 serious adverse events (0.025) were reported, 12 (0.006) of which led to drug discontinuation. The event rate of macrophage activation syndrome and disease exacerbation was statistically higher in patients receiving <35 mg/kg cumulative canakinumab dose (p < 0.05).
UNASSIGNED: An increase in side effect was not observed with the increasing cumulative doses of canakinumab. Canakinumab demonstrated long-term safety with appropriate indication and monitoring.

According to the state regulation deficit (SRD) account, ADHD is associated with difficulties regulating tonic arousal levels, which may be due to inefficient effort allocation. We aimed to test the SRD account by using a target detection task with three different event rates (ER; 700 ms, 1800 ms, 6000 ms), in order to manipulate the tonic arousal state and its effects on performance and pupil indices in adults with high (n = 40) versus low (n = 36) ADHD symptom levels. In an additional condition, a fast ER (700 ms) was accompanied by auditory white noise (WN), to further increase tonic arousal level. The ER manipulation had a clear effect on RT and variability of RT. These effects were more pronounced for the high-ADHD group, especially for variability of RT with decreasing ER, suggestive of deficient upregulation of a tonic arousal state in that group, in line with their self-reported SRDs in daily life. Adding WN to the fast condition led to more errors, however similarly for both groups. Contrary to our predictions, the ER manipulation had no effect on tonic pupil size (as a measure of tonic arousal). Phasic pupil amplitude (as a measure of cognitive effort) linearly increased with decreasing ER, suggesting more effort allocation during slower ERs. WN decreased phasic pupil amplitude, but had no impact on tonic pupil size. Importantly, however, no ADHD-related differences were present for the pupil indices. In conclusion, adults with elevated levels of ADHD symptoms reported more SRDs in daily life and showed a performance pattern that suggests difficulties in upregulating but not downregulating the tonic arousal state. Surprisingly, these findings were not accompanied by group differences in pupillometric indices. This casts some doubts on the relationship between these measures of autonomic nervous system activity and state regulation, in particular in the context of ADHD symptomatology.

We consider five asymptotically unbiased estimators of intervention effects on event rates in non-matched and matched-pair cluster randomized trials, including ratio of mean counts r 1 , ratio of mean cluster-level event rates r 2 , ratio of event rates r 3 , double ratio of counts r 4 , and double ratio of event rates r 5 . In the absence of an indirect effect, they all estimate the direct effect of the intervention. Otherwise, r 1 , r 2 , and r 3 estimate the total effect, which comprises the direct and indirect effects, whereas r 4 and r 5 estimate the direct effect only. We derive the conditions under which each estimator is more precise or powerful than its alternatives. To control bias in studies with a small number of clusters, we propose a set of approximately unbiased estimators. We evaluate their properties by simulation and apply the methods to a trial of seasonal malaria chemoprevention. The approximately unbiased estimators are practically unbiased and their confidence intervals usually have coverage probability close to the nominal level; the asymptotically unbiased estimators perform well when the number of clusters is approximately 32 or more per trial arm. Despite its simplicity, r 1 performs comparably with r 2 and r 3 in trials with a large but realistic number of clusters. When the variability of baseline event rate is large and there is no indirect effect, r 4 and r 5 tend to offer higher power than r 1 , r 2 , and r 3 . We discuss the implications of these findings to the planning and analysis of cluster randomized trials.

OBJECTIVE: To identify potential bias in non-inferiority design of published cancer trials, and to provide suggestions for future practice.
METHODS: We systematically searched MEDLINE, Embase and CENTRAL databases (until April 17, 2020) to obtain non-inferiority phase III cancer trials and protocols. Distribution of essential characteristics and study design parameters was compared between trials with and without concluding non-inferiority using multivariable logistic regression.
RESULTS: A total of 291 eligible trials were included. We observed that increased odds of concluding non-inferiority was significantly associated with more lenient non-inferiority margins (OR = 1•94, 95% CI 1•02-3•69) and higher hypothesized event rate (OR = 1•24, 95% CI 1•06-1•47). Trials that established non-inferiority adopted margins that were more dispersedly distributed (dispersion OR = 2•90, 95% CI 1•88-4.48).
CONCLUSIONS: Although limited by the exploratory nature, our study demonstrated existence of possible distorted non-inferiority design which could incur excess non-inferiority in cancer clinical trials. Pre-registration and transparent reporting of detailed non-inferiority design is imperative for future research.

Coronavirus disease (COVID-19) is a respiratory disease affecting many people and able to be transmitted through direct and perhaps indirect contact. Direct contact transmission, mediated by aerosols or droplets, is widely demonstrated, whereas indirect transmission is only supported by collateral evidence such as virus persistence on inanimate surfaces and data from other similar viruses. The present systematic review aims to estimate SARS-CoV-2 prevalence on inanimate surfaces, identifying risk levels according to surface characteristics. Data were obtained from studies in published papers collected from two databases (PubMed and Embase) with the last search on 1 September 2020. Included studies had to be papers in English, had to deal with coronavirus and had to consider inanimate surfaces in real settings. Studies were coded according to our assessment of the risk that the investigated surfaces could be contaminated by SARS-CoV-2. A meta-analysis and a metaregression were carried out to quantify virus RNA prevalence and to identify important factors driving differences among studies. Thirty-nine out of forty retrieved paper reported studies carried out in healthcare settings on the prevalence of virus RNA, five studies carry out also analyses through cell culture and six tested the viability of isolated viruses. Overall prevalences of SARS-CoV-2 RNA on high-, medium- and low-risk surfaces were 0.22 (CI95 [0.152-0.296]), 0.04 (CI95 [0.007-0.090]), and 0.00 (CI95 [0.00-0.019]), respectively. The duration surfaces were exposed to virus sources (patients) was the main factor explaining differences in prevalence.

The study evaluated the quality of cardiovascular prevention in real-world clinical practice. The recurrence of up to five cardiovascular events was assessed, as data on recurrence beyond the first event and interindividual variations in event rates past the second event have been sparse. Low-density lipoprotein cholesterol concentrations and lipid-lowering therapy use were investigated.
This retrospective register-based study included adult patients with an incident cardiovascular event between 2004 and 2016 treated in the hospital district of southwest Finland. Patients were followed for consecutive cardiovascular events or cardiovascular death, low-density lipoprotein cholesterol and statin purchases. The timing of event recurrence was evaluated, and predictive factors were assessed.
A wide interindividual variation in cardiovascular event recurrence was observed, each additional event caused an increased risk, the median time of recurrence decreased from 7 to one year for the second and fifth event. Event rates increased correspondingly from 12 to 43/100 patient-years and were most pronounced in the first years following the previous event. The low-density lipoprotein cholesterol goal (<1.8 mmol/l) was reached by 18% in the year after the event and statin underuse was associated with an increased risk of recurrence. Six months after the index event high intensity statins were used by only 22% of the cohort.
The study provides new perspectives on individual risk assessment showing that event rates are not stable for all patients but increase 1.2-1.9-fold per consecutive event. The underuse of statins and poor adherence support the identification of these patients for intensified multifactorial preventive measures.

While the solid-state nanopore sensors have shown exceptional promise with their single-molecule sensitivity and label-free operations, one of the most significant challenges in the nanopore sensor is the limited analyte translocation event rate that leads to prolonged sensor response time. This issue is more pronounced when the analyte concentration is below the nanomolar (nM) range, owing to the diffusion-limited mass transport. In this work, we systematically studied the experimental factors beyond the intrinsic analyte concentration and electrophoretic mobility that affect the event rate in glass nanopore sensors. We developed a quantitative model to capture the impact of nanopore surface charge density, ionic strength, nanopore geometry, and translocation direction on the event rate. The synergistic effects of these factors on the event rates were investigated with the aim to find the optimized experimental conditions for operating the glass nanopore sensor from the response time standpoint. The findings in the study would provide useful and practical insight to enhance the device response time and achieve a lower detection limit for various glass nanopore-sensing experiments.

The PRESERVE trial used a 2 × 2 factorial design to compare intravenous saline solution with intravenous sodium bicarbonate solution and oral N-acetylcysteine with placebo for the prevention of 90-day major adverse kidney events and death (MAKE-D) and contrast-associated acute kidney injury (CA-AKI) among patients with chronic kidney disease undergoing angiography. In this ancillary study, we evaluated the predictive capacities of preangiography injury and repair proteins in urine and plasma for MAKE-D, CA-AKI, and their impact on trial design.
Longitudinal analysis.
A subset of participants from the PRESERVE trial.
Injury (KIM-1, NGAL, and IL-18) and repair (MCP-1, UMOD, and YKL-40) proteins in urine and plasma 1 to 2 hours preangiography.
MAKE-D and CA-AKI.
We analyzed the associations of preangiography biomarkers with MAKE-D and with CA-AKI. We evaluated whether the biomarker levels could enrich the MAKE-D event rate and improve future clinical trial efficiency through an online biomarker prognostic enrichment tool available at prognosticenrichment.com.
We measured plasma biomarkers in 916 participants and urine biomarkers in 797 participants. After adjusting for urinary albumin-creatinine ratio and baseline estimated glomerular filtration rate, preangiography levels of 4 plasma (KIM-1, NGAL, UMOD, and YKL-40) and 3 urine (NGAL, IL-18, and YKL-40) biomarkers were associated with MAKE-D. Only plasma KIM-1 level was significantly associated with CA-AKI after adjustment. Biomarker levels provided modest discriminatory capacity for MAKE-D. Screening patients using the 50th percentile of preangiography plasma KIM-1 or YKL-40 levels would have reduced the required sample size by 30% (∼2,000 participants).
Evaluation of prognostic enrichment does not account for changing trial costs, time needed to screen patients, or loss to follow-up. Most participants were male, limiting the generalizability of our findings.
Preangiography levels of injury and repair biomarkers modestly predict the development of MAKE-D and can be used to improve the efficiency of future CA-AKI trials.

Many clinical studies have shown that performance of subjects with attention-deficit/hyperactivity disorder (ADHD) is impaired when stimuli are presented at a slow rate compared to a medium or fast rate. According to the cognitive-energetic model, this finding may reflect difficulty in allocating sufficient effort to regulate the motor activation state. Other studies have shown that the left hemisphere is relatively responsible for keeping humans motivated, allocating sufficient effort to complete their tasks. This leads to a prediction that poor effort allocation might be associated with an affected left-hemisphere functioning in ADHD. So far, this prediction has not been directly tested, which is the aim of the present study.
Seventy-seven adults with various scores on the Conners\' Adult ADHD Rating Scale performed a lateralized lexical decision task in three conditions with stimuli presented in a fast, a medium, and a slow rate. The left-hemisphere functioning was measured in terms of visual field advantage (better performance for the right than for the left visual field).
All subjects showed an increased right visual field advantage for word processing in the slow presentation rate of stimuli compared to the fast and the medium rate. Higher ADHD scores were related to a reduced right visual field advantage in the slow rate only.
The present findings suggest that ADHD symptomatology is associated with less involvement of the left hemisphere when extra effort allocation is needed to optimize the low motor activation state.

Slow, variable, and error-prone performance on speeded reaction time (RT) tasks has been well documented in childhood ADHD, but equally well documented is the context-dependent nature of those deficits, particularly with respect to event rate. As event rates increase (or, as the interstimulus intervals become shorter), RTs decrease, a pattern of performance that has long been interpreted as evidence that cognitive deficits in ADHD are a downstream consequence of a fundamental difficulty in the regulation of arousal to meet task demands. We test the extent to which this is a misinterpretation of the data that occurs when RT and accuracy are considered separately, as is common in neurocognitive research. In two samples of children aged 8-10 with (N = 97; 33 girls) and without (N = 39; 26 girls) ADHD, we used the diffusion model, an influential computational model of RT, to examine the effect of event rate on inhibitory control in a go-no-go task. Contrary to longstanding belief, we found that fast event rates slowed the rate at which children with ADHD accumulated evidence to make a decision to \"no-go\", as indexed by drift rate. This in turn resulted in a higher proportion of failed inhibits, and occurred despite increased task engagement, as reflected by changes in the starting point of the decision process. Thus, although faster event rates increased task engagement among children with ADHD, the increased engagement was unable to counteract the concurrent slowing of processing speed to \"no-go\" decisions. Implications for theoretical models of ADHD and treatments are discussed.