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BACKGROUND: The TREX (Trial Remifentanil DEXmedetomidine) trial aimed to determine if, in children < 2 years old, low-dose sevoflurane/dexmedetomidine/remifentanil anesthesia (LD-SEVO) is superior to standard dose sevoflurane (STD-SEVO) anesthesia in terms of global cognitive function at 3 years of age. The aim of the present secondary analyses was to compare incidence of intraoperative hypotension and bradycardia, postoperative pain, time to recovery, need for treatment of intraoperative hypotension and bradycardia, incidence of light anesthesia and need for treatment, need for postoperative pain medications, and morbidity and mortality outcomes at 5 days between the two arms. METHODS: This Phase III randomized active controlled, parallel group, assessor blinded, multicenter, superiority trial was performed in 20 centers in Australia, Italy, and the United States. Four hundred and fifty-five infants <2 years of age expected to undergo general anesthesia for at least 2 hours were enrolled. They were randomized between LD-SEVO and STD-SEVO. The short-term perioperative outcomes noted above were compared between these two groups. RESULTS: There was less hypotension (risk difference -11.6%, 95% confidence interval (CI) -18.9% to -4.3%) and more bradycardia (risk difference 18.2%, 95% CI 8.8% to 27.7%) in the LD-SEVO compared to the STD-SEVO arm. There were more patients with episodes of light anesthesia (89 vs. 4), and protocol abandonments (1 vs. 0) in the LD-SEVO arm. Time from eye-opening to Post Anesthesia Care Unit (PACU) discharge was similar in both arms, as were morbidity and mortality. One patient in each arm suffered a life-threatening event but neither suffered long-term sequelae. CONCLUSIONS: These early postoperative results suggest that in children less than 2 years of age receiving greater than 2 hours of general anesthesia, the low-dose sevoflurane/dexmedetomidine/remifentanil anesthesia technique and the standard sevoflurane anesthesia technique are broadly clinically similar, with no clear evidence to support choosing one technique over the other.

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OBJECTIVE: Intranasal (IN) fentanyl and nitrous oxide (N2O) can be combined to provide procedural sedation and analgesia to children. This combination is advantageous because of rapid onset of action and non-parenteral administration, but is associated with increased vomiting. We sought to describe the associations of demographic and procedural factors with early vomiting when using this combination in children. METHODS: This was a planned secondary analysis of a randomised controlled trial comparing the effect of oral ondansetron versus placebo at a single paediatric hospital. Children aged 3 to <18 years with planned procedural sedation with IN fentanyl and N2O were randomised to receive oral ondansetron or placebo prior to N2O administration. Vomiting was defined as early if occurring during or up to 1 h after N2O delivery. We assessed the relationship between early vomiting, demographic and procedural characteristics. RESULTS: Participants were recruited between October 2016 and January 2019 and 62 out of 436 (14%) had early vomiting. The risk of early vomiting was 30% higher with higher total dose of fentanyl, risk ratio = 1.3 (95% confidence interval = 1.004-1.59). There was little evidence of a relationship between the occurrence of early vomiting and sex, age, weight, type of procedure, fasting duration, time between fentanyl administration and start of procedure, and procedure duration. CONCLUSION: We found that higher doses of IN fentanyl were associated with higher risk of early vomiting when administered with N2O in children. Other factors did not appear to be associated with vomiting.

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BACKGROUND: Missing data are common in observational studies and often occur in several of the variables required when estimating a causal effect, i.e. the exposure, outcome and/or variables used to control for confounding. Analyses involving multiple incomplete variables are not as straightforward as analyses with a single incomplete variable. For example, in the context of multivariable missingness, the standard missing data assumptions ("missing completely at random", "missing at random" [MAR], "missing not at random") are difficult to interpret and assess. It is not clear how the complexities that arise due to multivariable missingness are being addressed in practice. The aim of this study was to review how missing data are managed and reported in observational studies that use multiple imputation (MI) for causal effect estimation, with a particular focus on missing data summaries, missing data assumptions, primary and sensitivity analyses, and MI implementation. METHODS: We searched five top general epidemiology journals for observational studies that aimed to answer a causal research question and used MI, published between January 2019 and December 2021. Article screening and data extraction were performed systematically. RESULTS: Of the 130 studies included in this review, 108 (83%) derived an analysis sample by excluding individuals with missing data in specific variables (e.g., outcome) and 114 (88%) had multivariable missingness within the analysis sample. Forty-four (34%) studies provided a statement about missing data assumptions, 35 of which stated the MAR assumption, but only 11/44 (25%) studies provided a justification for these assumptions. The number of imputations, MI method and MI software were generally well-reported (71%, 75% and 88% of studies, respectively), while aspects of the imputation model specification were not clear for more than half of the studies. A secondary analysis that used a different approach to handle the missing data was conducted in 69/130 (53%) studies. Of these 69 studies, 68 (99%) lacked a clear justification for the secondary analysis. CONCLUSION: Effort is needed to clarify the rationale for and improve the reporting of MI for estimation of causal effects from observational data. We encourage greater transparency in making and reporting analytical decisions related to missing data.

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease (COVID-19), rapidly spread across the globe in 2019. With the emergence of the Omicron variant, COVID-19 shifted into an endemic phase. Given the anticipated rise in cases during the fall and winter seasons, the strategy of implementing seasonal booster vaccines for COVID-19 is becoming increasingly valuable to protect public health. This practice already exists for seasonal influenza vaccines to combat annual influenza seasons. Our goal was to investigate an easily modifiable vaccine platform for seasonal use against SARS-CoV-2. In this study, we evaluated the genetically modified influenza virus ΔNA(RBD) as an intranasal vaccine candidate for COVID-19. This modified virus was engineered to replace the coding sequence for the neuraminidase (NA) protein with a membrane-anchored form of the receptor binding domain (RBD) protein of SARS-CoV-2. We designed experiments to assess the protection of ΔNA(RBD) in K18-hACE2 mice using lethal (Delta) and non-lethal (Omicron) challenge models. Controls of COVID-19 mRNA vaccine and our lab's previously described intranasal virus like particle vaccine were used as comparisons. Immunization with ΔNA(RBD) expressing ancestral RBD elicited high anti-RBD IgG levels in the serum of mice, high anti-RBD IgA in lung tissue, and improved survival after Delta variant challenge. Modifying ΔNA(RBD) to express Omicron variant RBD shifted variant-specific antibody responses and limited viral burden in the lungs of mice after Omicron variant challenge. Overall, this data suggests that ΔNA(RBD) could be an effective intranasal vaccine platform that generates mucosal and systemic immunity towards SARS-CoV-2.

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A generalized fixed drug eruption (FDE) is an uncommon but potentially dangerous reaction to medication. In this case series, we present 1 patient with a generalized FDE and 2 patients with generalized bullous FDE that resolved with cyclosporine, though 1 patient required close monitoring in the intensive care unit. Immediate acceleration of care upon development and recognition of generalized bullous FDE is essential, as the mortality rate is similar to Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN).

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Accumulating world knowledge is a major task of development and education. The productive process of self-derivation through memory integration seemingly is a valid model of the process. To test the model, we examined relations between generation and retention of new factual knowledge via self-derivation through integration and world knowledge as measured by standardised assessments. We also tested whether the productive process of self-derivation predicted world knowledge even when a measure of learning through direct instruction also was considered. Participants were 162 children ages 8-12 years (53% female; 15% Black, 6% Asian, 1% Arab, 66% White, 5% mixed race, 7% unreported; 1% Latinx). Age accounted for a maximum of 4% of variance in self-derivation and retention. In contrast, substantial individual variability related to general knowledge and content knowledge in several domains, explaining 20-40% variance. In each domain for which self-derivation performance was a unique predictor, it explained a nominally greater share of the variance than the measure of learning through direct instruction. The findings imply that individual variability in self-derivation has functional consequences for accumulation of semantic knowledge across the elementary-school years.

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Prior studies suggest that only ∼30% of patients with type 1 diabetes use continuous glucose monitoring (CGM), but most studies to date focused on children and young adults seen by endocrinologists or in academic centers. This study examined national trends in CGM utilization among commercially insured children and adults with type 1 diabetes. Overall, CGM utilization was 20.12% in 2010-2013 and 49.78% in 2016-2019, reflecting a 2.5-fold increase in utilization within a period of <10 years. Identifying populations with low CGM use is a necessary first step in developing targeted interventions to increase CGM uptake.

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OBJECTIVE: To investigate fecal incontinence and defecatory, urinary, and sexual functional outcomes after transanal total mesorectal excision (taTME). BACKGROUND: Proctectomy for rectal cancer may result in alterations in defecatory, urinary, and sexual function that persist beyond 12 months. The recent multicenter phase II taTME trial demonstrated the safety of taTME in patients with stage I to III tumors. METHODS: Prospectively registered self-reported questionnaires were collected from 100 taTME patients. Fecal continence [Fecal Incontinence Quality of Life (FIQL), Wexner], defecatory function [Colorectal Functional Outcome (COREFO)], urinary function (International Prostate Symptom Score), and sexual function (Female Sexual Function Index-female, International Index of Erectile Function-male) were assessed preoperatively (PQ), 3 to 4 months postileostomy closure (FQ1), and 12 to 18 months post-taTME [postoperative questionnaire 2 (FQ2)]. RESULTS: Among 83 patients who responded at all 3 time points, FIQL, Wexner, and COREFO significantly worsened postileostomy closure. Between FQ1 and FQ2, FIQL lifestyle and coping, Wexner, and COREFO incontinence, social impact, frequency, and need for medication significantly improved, while FIQL depression and embarrassment did not change. International Prostate Symptom Score did not change relative to preoperative scores. For females, Female Sexual Function Index declined for desire, orgasm, and satisfaction between PQ and FQ1, and did not improve between FQ1 and FQ2. In males, International Index of Erectile Function declined with no change between FQ1 and FQ2. CONCLUSIONS: Although taTME resulted in initial decline in defecatory function and fecal continence, most functional domains improved by 12 months after ileostomy closure, without returning to preoperative status. Urinary function was preserved while sexual function declined without improvement by 18 months post-taTME. Our results address patient expectations and inform shared decision-making regarding taTME.

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Initial data analysis (IDA) is the part of the data pipeline that takes place between the end of data retrieval and the beginning of data analysis that addresses the research question. Systematic IDA and clear reporting of the IDA findings is an important step towards reproducible research. A general framework of IDA for observational studies includes data cleaning, data screening, and possible updates of pre-planned statistical analyses. Longitudinal studies, where participants are observed repeatedly over time, pose additional challenges, as they have special features that should be taken into account in the IDA steps before addressing the research question. We propose a systematic approach in longitudinal studies to examine data properties prior to conducting planned statistical analyses. In this paper we focus on the data screening element of IDA, assuming that the research aims are accompanied by an analysis plan, meta-data are well documented, and data cleaning has already been performed. IDA data screening comprises five types of explorations, covering the analysis of participation profiles over time, evaluation of missing data, presentation of univariate and multivariate descriptions, and the depiction of longitudinal aspects. Executing the IDA plan will result in an IDA report to inform data analysts about data properties and possible implications for the analysis plan-another element of the IDA framework. Our framework is illustrated focusing on hand grip strength outcome data from a data collection across several waves in a complex survey. We provide reproducible R code on a public repository, presenting a detailed data screening plan for the investigation of the average rate of age-associated decline of grip strength. With our checklist and reproducible R code we provide data analysts a framework to work with longitudinal data in an informed way, enhancing the reproducibility and validity of their work.

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Adaptive platform trials (APTs) offer a promising alternative to traditional randomised controlled trials for evaluating treatments for paediatric sepsis. Randomised controlled trials, despite being the gold standard for establishing causality between interventions and outcomes, make many assumptions about disease prevalence, severity and intervention effects, which are often incorrect. As a result, the evidence for most treatments for paediatric sepsis are based on low-quality evidence. APTs use accrued data rather than assumptions to power trial adaptations. They can assess multiple treatments simultaneously with shared research infrastructure. As such, APTs offer a more efficient, flexible and more effective way to identify optimal treatments. The proposed Paediatric Adaptive Sepsis Platform Trial, leveraging the Paediatric Research in Emergency Departments International Collaborative network's infrastructure, will evaluate resuscitation fluids, vasoactive medications, corticosteroids and antimicrobials. This trial has the potential to substantially impact clinical practice and reduce global sepsis mortality in children.

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We evaluated whether doses of bilateral medial rectus recessions greater than Parks's tables yielded superior outcomes for adult-onset divergence insufficiency. Forty-two patients underwent bilateral medial rectus recessions. Dose was analyzed as the average total per muscle (surgery + suture adjustment if performed) and compared with the standard dose tables (based on preoperative distance esodeviation), as difference between dose performed and dose indicated by Parks's tables. Each participant was classified as having received either Parks's dose (within 0.5 mm) or a dose greater than Parks's dose. Success was defined as "rarely" or "never" diplopia in distance straight-ahead gaze and reading. For patients classified as success, the mean difference between actual surgical dose performed and Parks's dose was calculated. Success was 91% (29/32) in those receiving greater than Parks's dose versus 67% (6/9) with Parks's dose (difference = 24%; 95% CI, -5% to 60%). The mean surgical dose was 1.0 mm greater than Parks's tables for the 35 successes (at 10 weeks) versus 0.7 mm greater for the 6 failures (difference = 0.4 mm; 95% CI, -0.2 to 0.9). For medial rectus recessions in adult-onset divergence insufficiency-type esotropia, a surgical dose 1 mm greater than Parks's tables, for each muscle, is a reasonable strategy.

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BACKGROUND: Randomised controlled trials (RCTs) aim to estimate the causal effect of one or more interventions relative to a control. One type of outcome that can be of interest in an RCT is an ordinal outcome, which is useful to answer clinical questions regarding complex and evolving patient states. The target parameter of interest for an ordinal outcome depends on the research question and the assumptions the analyst is willing to make. This review aimed to provide an overview of how ordinal outcomes have been used and analysed in RCTs. METHODS: The review included RCTs with an ordinal primary or secondary outcome published between 2017 and 2022 in four highly ranked medical journals (the British Medical Journal, New England Journal of Medicine, The Lancet, and the Journal of the American Medical Association) identified through PubMed. Details regarding the study setting, design, the target parameter, and statistical methods used to analyse the ordinal outcome were extracted. RESULTS: The search identified 309 studies, of which 144 were eligible for inclusion. The most used target parameter was an odds ratio, reported in 78 (54%) studies. The ordinal outcome was dichotomised for analysis in 47 ( 33 % ) studies, and the most common statistical model used to analyse the ordinal outcome on the full ordinal scale was the proportional odds model (64 [ 44 % ] studies). Notably, 86 (60%) studies did not explicitly check or describe the robustness of the assumptions for the statistical method(s) used. CONCLUSIONS: The results of this review indicate that in RCTs that use an ordinal outcome, there is variation in the target parameter and the analytical approaches used, with many dichotomising the ordinal outcome. Few studies provided assurance regarding the appropriateness of the assumptions and methods used to analyse the ordinal outcome. More guidance is needed to improve the transparent reporting of the analysis of ordinal outcomes in future trials.

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In the context of missing data, the identifiability or "recoverability" of the average causal effect (ACE) depends not only on the usual causal assumptions but also on missingness assumptions that can be depicted by adding variable-specific missingness indicators to causal diagrams, creating missingness directed acyclic graphs (m-DAGs). Previous research described canonical m-DAGs, representing typical multivariable missingness mechanisms in epidemiological studies, and examined mathematically the recoverability of the ACE in each case. However, this work assumed no effect modification and did not investigate methods for estimation across such scenarios. Here, we extend this research by determining the recoverability of the ACE in settings with effect modification and conducting a simulation study to evaluate the performance of widely used missing data methods when estimating the ACE using correctly specified g-computation. Methods assessed were complete case analysis (CCA) and various implementations of multiple imputation (MI) with varying degrees of compatibility with the outcome model used in g-computation. Simulations were based on an example from the Victorian Adolescent Health Cohort Study (VAHCS), where interest was in estimating the ACE of adolescent cannabis use on mental health in young adulthood. We found that the ACE is recoverable when no incomplete variable (exposure, outcome, or confounder) causes its own missingness, and nonrecoverable otherwise, in simplified versions of 10 canonical m-DAGs that excluded unmeasured common causes of missingness indicators. Despite this nonrecoverability, simulations showed that MI approaches that are compatible with the outcome model in g-computation may enable approximately unbiased estimation across all canonical m-DAGs considered, except when the outcome causes its own missingness or causes the missingness of a variable that causes its own missingness. In the latter settings, researchers may need to consider sensitivity analysis methods incorporating external information (e.g., delta-adjustment methods). The VAHCS case study illustrates the practical implications of these findings.

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In this paper, we disclose insights on the root causes of three structure-activity relationship (SAR) observations encountered in the discovery of the IRAK4 inhibitor Zimlovisertib (PF-06650833). The first is a nonlinear potency SAR encountered with the isoquinoline ether substituent, the second is a potency enhancement introduced by fluorine substitution on the lactam, and the third is a slight potency preference for all-syn (2S,3S,4S) stereochemistry in the fluorine-substituted lactam. We present new data that help to inform us of the origins of these unexpected SAR trends.

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Randomized controlled trials can be used to generate evidence on the efficacy and safety of new treatments in eating disorders research. Many of the trials previously conducted in this area have been deemed to be of low quality, in part due to a number of practical constraints. This article provides an overview of established and more innovative clinical trial designs, accompanied by pertinent examples, to highlight how design choices can enhance flexibility and improve efficiency of both resource allocation and participant involvement. Trial designs include individually randomized, cluster randomized, and designs with randomizations at multiple time points and/or addressing several research questions (master protocol studies). Design features include the use of adaptations and considerations for pragmatic or registry-based trials. The appropriate choice of trial design, together with rigorous trial conduct, reporting and analysis, can establish high-quality evidence to advance knowledge in the field. It is anticipated that this article will provide a broad and contemporary introduction to trial designs and will help researchers make informed trial design choices for improved testing of new interventions in eating disorders. PUBLIC SIGNIFICANCE: There is a paucity of high quality randomized controlled trials that have been conducted in eating disorders, highlighting the need to identify where efficiency gains in trial design may be possible to advance the eating disorder research field. We provide an overview of some key trial designs and features which may offer solutions to practical constraints and increase trial efficiency.

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Variable temperature electrospray mass spectrometry is useful for multiplexed measurements of the thermal stabilities of biomolecules, but the ionization process can be disrupted by aggregation-prone proteins/complexes that have irreversible unfolding transitions. Resistively heating solutions containing a mixture of bovine carbonic anhydrase II (BCAII), a CO2 fixing enzyme involved in many biochemical pathways, and cytochrome c leads to complete loss of carbonic anhydrase signal and a significant reduction in cytochrome c signal above ∼72 °C due to aggregation. In contrast, when the tips of borosilicate glass nanoelectrospray emitters are heated with a laser, complete thermal denaturation curves for both proteins are obtained in <1 minute. The simultaneous measurements of the melting temperature of BCAII and BCAII bound to bicarbonate reveal that the bicarbonate stabilizes the folded form of this protein by ∼6.4 °C. Moreover, the temperature dependences of different bicarbonate loss pathways are obtained. Although protein analytes are directly heated by the laser for only 140 ms, heat conduction further up the emitter leads to a total analyte heating time of ∼41 s. Pulsed laser heating experiments could reduce this time to ∼0.5 s for protein aggregation that occurs on a faster time scale. Laser heating provides a powerful method for studying the detailed mechanisms of cofactor/ligand loss with increasing temperature and promises a new tool for studying the effect of ligands, drugs, growth conditions, buffer additives, or other treatments on the stabilities of aggregation-prone biomolecules.

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OBJECTIVE: Acrobatics and Tumbling (A&T), an emerging National Collegiate Athletics Association (NCAA) sport, involves athletes with rigorous training backgrounds, usually extending from youth through early adulthood. This study examines the sleep health, diet quality, and lipid profile of A&T athletes clustered by their performance position. METHODS: Forty-two A&T athletes, clustered as tops (n = 19; age = 19.6 ± 1.0 years; body mass index [BMI] = 22.3 ± 1.7 kg/m2) and bases (n = 23; age = 19.6 ± 1.3 years; BMI = 25.7 ± 2.5 kg/m2), completed preseason sleep and diet quality (Rapid Eating Assessment for Participants-Shortened [REAP-S]) surveys. Fasting blood samples were collected for lipid analysis. Body composition was assessed via dual-energy X-ray absorptiometry. RESULTS: Most athletes (71.4%; base n = 14, top n = 16) reported insufficient sleep (≤7 hours) and "good" sleep quality (90.4%, n = 38; base n = 18, top n = 20). Average REAP-S score was 29.24 ± 3.74. Approximately 31% (n = 13) displayed at least one undesirable lipid concentration according to medical guidelines for normal levels (total cholesterol [TC] < 200 mg/dL, triglycerides [TG] < 150 mg/dL, high-density lipoprotein cholesterol [HDL-C] > 40 mg/dL, low-density lipoprotein cholesterol [LDL-C] < 130 mg/dL). Approximately 20% exhibited elevated TC (top n = 4, base n = 4), 12.5% had elevated TG (base n = 5), 2.5% showed low HDL-C (base n = 1), and 10% presented elevated LDL-C (top n = 2, base n = 2). CONCLUSIONS: Most athletes experienced suboptimal sleep (≤7 hours/night) and 31% displayed at least one undesirable lipid concentration (elevated TC, TG, or LDL-C or reduced HDL-C). Tailoring interventions with sports dietitians is recommended, focused on increasing monounsaturated and polyunsaturated fat intake while reducing saturated fat consumption. These interventions could mitigate cardiovascular risks, improve recovery, and possibly enhance athletic performance.

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