Trends in the Use and Discussion of Race in Pediatrics Articles Over 75 Years.

BACKGROUND AND OBJECTIVES: Race-based medicine, which falsely assumes that race is biological, is common in the published medical literature. We analyzed trends in the use of race in Pediatrics articles over a 75-year period. METHODS: We analyzed a random sample of 50 original research articles published each decade in Pediatrics from 1948 to 2022. RESULTS: Of 375 articles, 39% (n = 147) included race. Among articles, 85% (n = 116) used race only to describe study subjects, 7% (n = 9) described race as a social construct, and 11% (n = 15) described race as a biological construct. Only 7% (n = 10) of studies provided a reason for including race. Statements reflective of racial bias or discrimination were identified in 22% (n = 30) of the articles that mentioned race. Although statements concerning for explicit racial bias were uncommon, with none identified in the most recent decade, statements suggestive of implicit racial bias still occurred (22%, 5 of 23). Race was presented as a dichotomy, such as "white/nonwhite," in 9% of studies (n = 12). Regarding currently nonrecommended terminology, the term "minorities" was used in 13% of studies (n = 18); 25% of studies used the term "others" (n = 34), and among these, 91% (n = 31 of 34) did not provide any definition, an occurrence that increased over time at a rate of 0.9%/year. CONCLUSIONS: Although there has been improvement over the past 75 years in the reporting of race in published studies in Pediatrics, significant opportunities for further improvement remain.

Epidemiology of brief resolved unexplained events and impact of clinical practice guidelines in general and pediatric emergency departments.

OBJECTIVES: The aim of this study was to describe the incidence of brief resolved unexplained events (BRUEs) and compare the impact of a national clinical practice guideline (CPG) on admission and diagnostic testing practices between general and pediatric emergency departments (EDs). METHODS: Using the Nationwide Emergency Department Sample for 2012-2019, we conducted a cross-sectional study of children <1 year of age with an International Classification of Diseases diagnostic code for BRUE. Population incidence rate was estimated using Centers for Disease Control and Prevention birth data. ED incidence rate was estimated for all ED encounters. We used interrupted time series to evaluate the associated impact of the CPG publication on the outcomes of ED disposition (discharge, admission, and transfer) and electrocardiogram (ECG) use. RESULTS: Of 133,972 encounters for BRUE, 80.0% occurred in general EDs. BRUE population incidence was 4.28 per 1000 live births and the annual incidence remained stable (p = 0.19). BRUE ED incidence was 5.06 per 1000 infant ED encounters (p = 0.14). The impact of the BRUE CPG on admission rates was limited to pediatric EDs (level shift -23.3%, p = 0.002). Transfers from general EDs did not change with the CPG (level shift 2.2%, p = 0.17). After the CPG was published, ECGs increased by 13.7% in pediatric EDs (p = 0.005) but did not change in general EDs (level shift -0.2%, p = 0.82). CONCLUSIONS: BRUEs remain a common pediatric problem at a population level and in EDs. Although a disproportionate number of infants present to general EDs, there is differential uptake of the CPG recommendations between pediatric and general EDs. These findings may support quality improvement opportunities aimed at improving care for these infants and decreasing unnecessary hospital admissions or transfers.

Short duration of parenteral antibiotics in infants with urinary tract infections.

Objectives: Current guidelines by the Canadian Paediatric Society on treating urinary tract infections (UTIs) exclude infants ≤ 60 days old. There is considerable practice variability in this age group, especially around the optimal duration of parenteral antibiotics. The study aimed to assess local practice patterns, and the safety of a short course (≤3 days) of parenteral antibiotics in young infants. Methods: In this retrospective cohort study, 95 infants (≤60 days) with confirmed UTIs were identified at British Columbia Children's Hospital. Patients receiving short (≤3 days) and long (>3 days) duration of parenteral antibiotics were compared. Outcomes of interest included urinary tract infection recurrence within 30 days, hospital length of stay (LOS), representation, and readmission. Results: Twenty infants (21%) received a short course of parenteral antibiotics. These infants were older (median 47 days versus 28 days) and non-bacteremic. Urinary tract infection recurrence was identified in 8 patients (8%), of which 7 were treated with a long duration (P = 1.0). Patients treated with a short duration had a significantly shorter LOS, with a mean difference of 4.21 days [95% CI: 3.37 to 5.05] (P < 0.001). All five (5%) bacteremic patients were treated exclusively with parenteral antibiotics. Conclusions: In a Canadian setting, a short course of parenteral antibiotics is safe in young, non-bacteremic infants with UTIs. Despite substantial evidence, local practice patterns suggest a tendency towards prescription of long courses, providing an opportunity for quality improvement.

Conservative and Surgical Modalities in the Management of Pediatric Parapneumonic Effusion and Empyema: A Living Systematic Review and Network Meta-Analysis.

BACKGROUND: The optimal treatment for community-acquired childhood pneumonia complicated by empyema remains unclear. RESEARCH QUESTION: In children with parapneumonic effusion or empyema, do hospital length of stay and other key clinical outcomes differ according to the treatment modality used? STUDY DESIGN AND METHODS: A living systematic review of randomized controlled trials (RCTs) was conducted by searching the Cochrane Central Register of Controlled Trials, Embase, Latin American and Caribbean Health Sciences Literature, Ovid MEDLINE, and Web of Science Core Collection databases. Eligible RCTs included patients aged < 18 years and compared two of the following treatment modalities: antibiotics alone, chest tube insertion with or without fibrinolytics, video-assisted thoracoscopic surgery (VATS), and decortication via thoracotomy. A network meta-analysis was performed to evaluate treatment effects on hospital length of stay (LOS), the primary outcome. RESULTS: Eleven trials including a total of 590 patients were selected for the network meta-analysis. Compared with a chest tube alone, a chest tube with fibrinolytics, thoracotomy, and VATS were all associated with shorter LOS, with a mean difference of 5.05 days (95% CI, 2.46-7.64), 6.33 days (95% CI, 3.17-9.50), and 5.86 days (95% CI, 3.38-8.35), respectively. No substantial differences in LOS were observed between the latter three interventions. None of the 11 RCTs compared antibiotics alone vs other types of treatment. Most trials reported peri-procedural complications and the need for reintervention, but the descriptions differed significantly between trials, preventing meta-analysis. In trials reporting health care-associated costs, fibrinolytics had cost advantages compared with VATS. Short- and long-term morbidity and mortality were very low, regardless of the treatment modality. INTERPRETATION: The results of this network meta-analysis showed that a chest tube alone was associated with a longer LOS compared with other treatment modalities. The lower cost associated with a chest tube plus fibrinolytics warrants consideration when choosing between treatment options, given similar LOS and clinical outcomes compared with the other modalities.

Canadian infants presenting with Brief Resolved Unexplained Events (BRUEs) and validation of clinical prediction rules for risk stratification: a protocol for a multicentre, retrospective cohort study.

INTRODUCTION: Brief Resolved Unexplained Events (BRUEs) are a common presentation among infants. While most of these events are benign and self-limited, guidelines published by the American Academy of Pediatrics inaccurately identify many patients as higher-risk of a serious underlying aetiology (positive predictive value 5%). Recently, new clinical prediction rules have been derived to more accurately stratify patients. This data were however geographically limited to the USA, with no large studies to date assessing the BRUE population in a different healthcare setting. The study's aim is to describe the clinical management and outcomes of infants presenting to Canadian hospitals with BRUEs and to externally validate the BRUE clinical prediction rules in identified cases. METHODS AND ANALYSIS: This is a multicentre retrospective study, conducted within the Canadian Paediatric Inpatient Research Network (PIRN). Infants (<1 year) presenting with a BRUE at one of 11 Canadian paediatric centres between 1 January 2017 and 31 December 2021 will be included. Eligible patients will be identified using diagnostic codes.The primary outcome will be the presence of a serious underlying illness. Secondary outcomes will include BRUE recurrence and length of hospital stay. We will describe the rates of hospital admissions and whether hospitalisation was associated with an earlier diagnosis or treatment. Variation across Canadian hospitals will be assessed using intraclass correlation coefficient. To validate the newly developed clinical prediction rule, measures of goodness of fit will be evaluated. For this validation, a sample size of 1182 is required to provide a power of 80% to detect patients with a serious underlying illness with a significance level of 5%. ETHICS AND DISSEMINATION: Ethics approval has been granted by the UBC Children's and Women's Research Board (H21-02357). The results of this study will be disseminated as peer-reviewed manuscripts and presentations at national and international conferences.

Risk Prediction After a Brief Resolved Unexplained Event.

OBJECTIVES: Only 4% of brief resolved unexplained events (BRUE) are caused by a serious underlying illness. The American Academy of Pediatrics (AAP) guidelines do not distinguish patients who would benefit from further investigation and hospitalization. We aimed to derive and validate a clinical decision rule for predicting the risk of a serious underlying diagnosis or event recurrence. METHODS: We retrospectively identified infants presenting with a BRUE to 15 children's hospitals (2015-2020). We used logistic regression in a split-sample to derive and validate a risk prediction model. RESULTS: Of 3283 eligible patients, 565 (17.2%) had a serious underlying diagnosis (n = 150) or a recurrent event (n = 469). The AAP's higher-risk criteria were met in 91.5% (n = 3005) and predicted a serious diagnosis with 95.3% sensitivity, 8.6% specificity, and an area under the curve of 0.52 (95% confidence interval [CI]: 0.47-0.57). A derived model based on age, previous events, and abnormal medical history demonstrated an area under the curve of 0.64 (95%CI: 0.59-0.70). In contrast to the AAP criteria, patients >60 days were more likely to have a serious underlying diagnosis (odds ratio:1.43, 95%CI: 1.03-1.98, P = .03). CONCLUSIONS: Most infants presenting with a BRUE do not have a serious underlying pathology requiring prompt diagnosis. We derived 2 models to predict the risk of a serious diagnosis and event recurrence. A decision support tool based on this model may aid clinicians and caregivers in the discussion on the benefit of diagnostic testing and hospitalization (https://www.mdcalc.com/calc/10400/brief-resolved-unexplained-events-2.0-brue-2.0-criteria-infants).

Treatment of UTIs in Infants <2 Months: A Living Systematic Review.

CONTEXT: Urinary tract infections (UTIs) are the most common bacterial infections in infants <2 months of age. However, there are no clear guidelines on the appropriate duration of antibiotics in this age group. OBJECTIVE: In this living systematic review, we compared different durations of parenteral antibiotics (≤3 vs >3 days) in neonates and young infants (<2 months) with UTIs. The secondary objective was to compare different durations of total antibiotic courses (≤10 vs >10 days). DATA SOURCES: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Web of Science, Literatura Latino-Americana e do Caribe em Ciências da Saúde, Google Scholar, and gray literature, up to March 2, 2021. STUDY SELECTION: Citations were screened in triplicate by using a crowdsourcing methodology, to identify randomized controlled trials and observational studies. DATA EXTRACTION: Data were extracted by 2 crowd members and verified by an expert investigator. Outcomes were pooled via random-effects models. RESULTS: A total of 10 334 citations were screened, and 12 eligible studies were identified. A total of 59 of 3480 (1.7% [95% confidence interval (CI): 1.3% to 2.2%]) infants had a UTI recurrence within 30 days after short parenteral treatment (≤3 days), and 47 of 1971 (2.4% [95% CI: 1.8% to 3.2%]) after longer courses. The pooled adjusted odds ratio for UTI recurrence with a short versus long duration of parenteral antibiotics was 1.02 (95% CI: 0.64 to 1.61; P = .95; n = 5451). A total of 5 studies assessed the risk of recurrence on the basis of the total duration of antibiotics (≤10 vs >10 days) with no significant differences (pooled odds ratio: 1.29 [95% CI: 0.45 to 3.66; P = .63; n = 491). CONCLUSIONS: On the basis of retrospective studies and Grading of Recommendations, Assessment, Development, and Evaluation level low evidence, short and long duration of parenteral antibiotics were associated with a similar risk of UTI recurrence in infants <2 months.

Evaluating the relationship between citation set size, team size and screening methods used in systematic reviews: a cross-sectional study.

BACKGROUND: Standard practice for conducting systematic reviews (SRs) is time consuming and involves the study team screening hundreds or thousands of citations. As the volume of medical literature grows, the citation set sizes and corresponding screening efforts increase. While larger team size and alternate screening methods have the potential to reduce workload and decrease SR completion times, it is unknown whether investigators adapt team size or methods in response to citation set sizes. Using a cross-sectional design, we sought to understand how citation set size impacts (1) the total number of authors or individuals contributing to screening and (2) screening methods. METHODS: MEDLINE was searched in April 2019 for SRs on any health topic. A total of 1880 unique publications were identified and sorted into five citation set size categories (after deduplication): < 1,000, 1,001-2,500, 2,501-5,000, 5,001-10,000, and > 10,000. A random sample of 259 SRs were selected (~ 50 per category) for data extraction and analysis. RESULTS: With the exception of the pairwise t test comparing the under 1000 and over 10,000 categories (median 5 vs. 6, p = 0.049) no statistically significant relationship was evident between author number and citation set size. While visual inspection was suggestive, statistical testing did not consistently identify a relationship between citation set size and number of screeners (title-abstract, full text) or data extractors. However, logistic regression identified investigators were significantly more likely to deviate from gold-standard screening methods (i.e. independent duplicate screening) with larger citation sets. For every doubling of citation size, the odds of using gold-standard screening decreased by 15 and 20% at title-abstract and full text review, respectively. Finally, few SRs reported using crowdsourcing (n = 2) or computer-assisted screening (n = 1). CONCLUSIONS: Large citation set sizes present a challenge to SR teams, especially when faced with time-sensitive health policy questions. Our study suggests that with increasing citation set size, authors are less likely to adhere to gold-standard screening methods. It is possible that adjunct screening methods, such as crowdsourcing (large team) and computer-assisted technologies, may provide a viable solution for authors to complete their SRs in a timely manner.

Successful incorporation of single reviewer assessments during systematic review screening: development and validation of sensitivity and work-saved of an algorithm that considers exclusion criteria and count.

BACKGROUND: Accepted systematic review (SR) methodology requires citation screening by two reviewers to maximise retrieval of eligible studies. We hypothesized that records could be excluded by a single reviewer without loss of sensitivity in two conditions; the record was ineligible for multiple reasons, or the record was ineligible for one or more specific reasons that could be reliably assessed. METHODS: Twenty-four SRs performed at CHEO, a pediatric health care and research centre in Ottawa, Canada, were divided into derivation and validation sets. Exclusion criteria during abstract screening were sorted into 11 specific categories, with loss in sensitivity determined by individual category and by number of exclusion criteria endorsed. Five single reviewer algorithms that combined individual categories and multiple exclusion criteria were then tested on the derivation and validation sets, with success defined a priori as less than 5% loss of sensitivity. RESULTS: The 24 SRs included 930 eligible and 27390 ineligible citations. The reviews were mostly focused on pediatrics (70.8%, N=17/24), but covered various specialties. Using a single reviewer to exclude any citation led to an average loss of sensitivity of 8.6% (95%CI, 6.0-12.1%). Excluding citations with ≥2 exclusion criteria led to 1.2% average loss of sensitivity (95%CI, 0.5-3.1%). Five specific exclusion criteria performed with perfect sensitivity: conference abstract, ineligible age group, case report/series, not human research, and review article. In the derivation set, the five algorithms achieved a loss of sensitivity ranging from 0.0 to 1.9% and work-saved ranging from 14.8 to 39.1%. In the validation set, the loss of sensitivity for all 5 algorithms remained below 2.6%, with work-saved between 10.5% and 48.2%. CONCLUSIONS: Findings suggest that targeted application of single-reviewer screening, considering both type and number of exclusion criteria, could retain sensitivity and significantly decrease workload. Further research is required to investigate the potential for combining this approach with crowdsourcing or machine learning methodologies.

Conservative and surgical modalities in the management of paediatric parapneumonic effusion and empyema: a protocol for a living systematic review and network meta-analysis.

INTRODUCTION: Parapneumonic effusion and empyema are common complications of paediatric pneumonia. Acceptable treatment modalities for large parapneumonic effusions include antibiotics alone or in conjunction with surgical interventions. Clear guidelines on the best treatment approach are lacking and mostly based on evidence prior to widespread pneumococcal conjugate 13-valent vaccination (PCV-13). METHODS AND ANALYSIS: A living systematic review and network meta-analysis will be performed comparing the five treatment modalities: (1) antibiotics alone; (2) chest tube drainage without fibrinolytics; (3) chest tube drainage with fibrinolytics; (4) video-assisted thoracoscopic surgery and (5) open thoracotomy. The review protocol is reported following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guidelines. Eligible studies are randomised controlled trials comparing any pair of interventions in paediatric patients with empyema or parapneumonic effusion. The following databases will be searched: Ovid MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, LILACS and Google Scholar. Citation screening and data extraction will be completed using a validated crowdsourcing methodology using InsightScope. To assess the risk of bias, we will use the revised Cochrane risk of bias tool for randomised trials. The primary outcome of the study is the length of stay. Secondary outcomes are (1) periprocedural complications and (2) need for re-intervention. A frequentist network meta-analysis design will be implemented with a random-effects model comparing different interventions. In a subgroup analysis, studies and patients will be stratified by the size of pleural effusion and the date of trial (pre/post-PCV-13). Eligible citations and available results will be uploaded to an online database, hosted on Open Science Framework. The database will be updated at least every 4 months with any newly published research. ETHICS AND DISSEMINATION: No ethics review is required for this study. Results will be published in a peer-reviewed journal. Data will be available as part of an online database summarising the evidence of this living systematic review. PROSPERO REGISTRATION: Pending peer review.

Creating enriched training sets of eligible studies for large systematic reviews: the utility of PubMed's Best Match algorithm.

INTRODUCTION: Solutions like crowd screening and machine learning can assist systematic reviewers with heavy screening burdens but require training sets containing a mix of eligible and ineligible studies. This study explores using PubMed's Best Match algorithm to create small training sets containing at least five relevant studies. METHODS: Six systematic reviews were examined retrospectively. MEDLINE searches were converted and run in PubMed. The ranking of included studies was studied under both Best Match and Most Recent sort conditions. RESULTS: Retrieval sizes for the systematic reviews ranged from 151 to 5,406 records and the numbers of relevant records ranged from 8 to 763. The median ranking of relevant records was higher in Best Match for all six reviews, when compared with Most Recent sort. Best Match placed a total of thirty relevant records in the first fifty, at least one for each systematic review. Most Recent sorting placed only ten relevant records in the first fifty. Best Match sorting outperformed Most Recent in all cases and placed five or more relevant records in the first fifty in three of six cases. DISCUSSION: Using a predetermined set size such as fifty may not provide enough true positives for an effective systematic review training set. However, screening PubMed records ranked by Best Match and continuing until the desired number of true positives are identified is efficient and effective. CONCLUSIONS: The Best Match sort in PubMed improves the ranking and increases the proportion of relevant records in the first fifty records relative to sorting by recency.

Identification and Evaluation of Controlled Trials in Pediatric Cardiology: Crowdsourced Scoping Review and Creation of Accessible Searchable Database.

Cardiac disease in children is associated with significant morbidity and mortality as well as increased health resource utilisation. There is a perception that there is a paucity of high-quality studies, particularly randomized controlled trials (RCTs), in the field of pediatric cardiology. We sought to identify, examine, and map the range of RCTs conducted in children with cardiac conditions, including the development of a searchable open-access database. A literature search was conducted encompassing MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from inception to 2018. All English-language RCTs enrolling children (age 0-21 years) with cardiac conditions were included. Data extraction and risk of bias assessments were performed in duplicate via crowdsourcing for each eligible study and entered into an online database. A total of 933 RCTs met eligibility criteria. Median trial recruitment was 49 patients (interquartile range 30-86) with 18.9% of studies (n = 176) including > 100 patients. A wide variety of populations and interventions were encompassed with congenital heart disease (79.8% of RCTs) and medications (63.3% of RCTs) often studied. Just over one-half of the trials (53.4%) clearly identified a primary outcome, and fewer than half (46.6%) fully documented a robust randomization process. Trials were summarised in a searchable online database (https://pediatrics.knack.com/cardiology-rct-database#cardiology-rcts/). Contrary to a commonly held perception, there are nearly 1,000 published RCTs in pediatric cardiology. The open-access database created as part of this project provides a resource that facilitates an efficient comprehensive review of the literature for clinicians and researchers caring for children with cardiac issues.

Vincristine-induced peripheral neurotoxicity: A prospective cohort.

Vincristine-induced peripheral neuropathy (VIPN) is a serious and pervasive problem, affecting 12-78% of pediatric patients, based on retrospective studies. The study objective was to prospectively collect a cohort of well-phenotyped patients receiving vincristine in order to accurately classify and grade their neurotoxicity. All children in British Columbia with leukemia or lymphoma requiring vincristine between 2013 and 2016 were approached for consent. Those recruited were assessed by occupational and physiotherapists at baseline, mid and endpoint of their treatment. Assessments included the Bruininks-Oseretsky Test of Motor Proficiency - 2nd ed. (BOT-2), strength, "Timed up and go" test and vibration sensibility. Seventy-two patients consented (age: 2.0-18.7 years). The majority were below average for age on one or more BOT-2 domains at midpoint (N = 32/45, 71%), which decreased by the endpoint (N = 19/41, 46%, p = .049). Six patients showed severe VIPN throughout treatment (N = 6/53, 11%), defined as a BOT-2 score well below average. Muscle strength for wrist extension/flexion, anterior tibialis and peronei decreased significantly between baseline (Median = 5) and midpoint (Median = 4), with no significant change noted by endpoint. Most patients had normal vibration sensibility in lower (N = 30/60, 50%) and upper limbs (N = 26/38, 68%). In conclusion, with no differences between time points. VIPN is highly prevalent among patients with pediatric cancer, causing significant morbidity and functional deficits. Identification of risk factors would allow for resource appropriation to patients at higher risk, as well as potentially permitting dose escalation in patients with low toxicity to improve survival.

Crowdsourcing the Citation Screening Process for Systematic Reviews: Validation Study.

BACKGROUND: Systematic reviews (SRs) are often cited as the highest level of evidence available as they involve the identification and synthesis of published studies on a topic. Unfortunately, it is increasingly challenging for small teams to complete SR procedures in a reasonable time period, given the exponential rise in the volume of primary literature. Crowdsourcing has been postulated as a potential solution. OBJECTIVE: The feasibility objective of this study was to determine whether a crowd would be willing to perform and complete abstract and full text screening. The validation objective was to assess the quality of the crowd's work, including retention of eligible citations (sensitivity) and work performed for the investigative team, defined as the percentage of citations excluded by the crowd. METHODS: We performed a prospective study evaluating crowdsourcing essential components of an SR, including abstract screening, document retrieval, and full text assessment. Using CrowdScreenSR citation screening software, 2323 articles from 6 SRs were available to an online crowd. Citations excluded by less than or equal to 75% of the crowd were moved forward for full text assessment. For the validation component, performance of the crowd was compared with citation review through the accepted, gold standard, trained expert approach. RESULTS: Of 312 potential crowd members, 117 (37.5%) commenced abstract screening and 71 (22.8%) completed the minimum requirement of 50 citation assessments. The majority of participants were undergraduate or medical students (192/312, 61.5%). The crowd screened 16,988 abstracts (median: 8 per citation; interquartile range [IQR] 7-8), and all citations achieved the minimum of 4 assessments after a median of 42 days (IQR 26-67). Crowd members retrieved 83.5% (774/927) of the articles that progressed to the full text phase. A total of 7604 full text assessments were completed (median: 7 per citation; IQR 3-11). Citations from all but 1 review achieved the minimum of 4 assessments after a median of 36 days (IQR 24-70), with 1 review remaining incomplete after 3 months. When complete crowd member agreement at both levels was required for exclusion, sensitivity was 100% (95% CI 97.9-100) and work performed was calculated at 68.3% (95% CI 66.4-70.1). Using the predefined alternative 75% exclusion threshold, sensitivity remained 100% and work performed increased to 72.9% (95% CI 71.0-74.6; P<.001). Finally, when a simple majority threshold was considered, sensitivity decreased marginally to 98.9% (95% CI 96.0-99.7; P=.25) and work performed increased substantially to 80.4% (95% CI 78.7-82.0; P<.001). CONCLUSIONS: Crowdsourcing of citation screening for SRs is feasible and has reasonable sensitivity and specificity. By expediting the screening process, crowdsourcing could permit the investigative team to focus on more complex SR tasks. Future directions should focus on developing a user-friendly online platform that allows research teams to crowdsource their reviews.

Ligand-specific conformational transitions and intracellular transport are required for atypical chemokine receptor 3-mediated chemokine scavenging.

The atypical chemokine receptor ACKR3 contributes to chemotaxis by binding, internalizing, and degrading the chemokines CXCL11 and CXCL12 to shape and terminate chemotactic gradients during development and immune responses. Although unable to trigger G protein activation, both ligands activate G protein-independent ACKR3 responses and prompt arrestin recruitment. This offers a model to specifically study ligand-specific receptor conformations leading to G protein-independent signaling and to functional parameters such as receptor transport and chemokine degradation. We here show chemokine specificity in arrestin recruitment, by different effects of single amino acid substitutions in ACKR3 on arrestin in response to CXCL12 or CXCL11. Chemokine specificity in receptor transport was also observed, as CXCL11 induced faster receptor internalization, slower recycling, and longer intracellular sojourn of ACKR3 than CXCL12. Internalization and recycling rates of the ACKR3 R1423.50A substitution in response to each chemokine were similar; however, ACKR3 R1423.50A degraded only CXCL12 and not CXCL11. This suggests that ligand-specific intracellular receptor transport is required for chemokine degradation. Remarkably, the failure of ACKR3 R1423.50A to degrade CXCL11 was not caused by the lack of arrestin recruitment; rather, arrestin was entirely dispensable for scavenging of either chemokine. This suggests the involvement of another, yet unidentified, ACKR3 effector in scavenging. In summary, our study correlates ACKR3 ligand-specific conformational transitions with chemokine-dependent receptor transport dynamics and points toward unexpected ligand specificity in the mechanisms of chemokine degradation.

Vitamin D deficiency in critically ill children: a systematic review and meta-analysis.

BACKGROUND: Vitamin D deficiency (VDD) has been hypothesized not only to be common but also to represent a potentially modifiable risk factor for greater illness severity and clinical outcome during critical illness. The objective of this systematic review was to determine the frequency of VDD in pediatric critical illness and its association with clinical outcomes. METHODS: MEDLINE, Embase, and CENTRAL were searched through December 12, 2016, with no date or language restrictions. The primary objective was to estimate the prevalence of VDD in the pediatric intensive care unit (PICU) and compare vitamin D status with healthy control populations. Secondary objectives were to evaluate whether VDD is associated with mortality, increased illness severity, PICU interventions, and patient clinical course. Random effects meta-analysis was used to calculate pooled VDD event rate, compare levels with those of control subjects, and evaluate for associations between VDD and clinical outcome. RESULTS: Among 2700 citations, 17 studies meeting study eligibility were identified. The studies reported a total of 2783 critically ill children and had a median sample size of 120 (range 12-511). The majority of studies used a 25-hydroxyvitamin D [25(OH)D] level less than 50 nmol/L to define VDD, and the pooled VDD prevalence was 54.8 (95% CI 45.4-63.9). Average 25(OH)D levels were significantly lower in PICU patients than in healthy control subjects (pooled difference -17.3 nmol/L, 95% CI -14.0 to -20.6). In a meta-analysis calculation, we found that VDD was associated with increased mortality (OR 1.62, 95% CI 1.11-2.36), illness severity, and need for PICU interventions. CONCLUSIONS: Approximately 50% of critically ill children have VDD at the time of PICU admission, defined as a blood total 25(OH)D concentration under 50 nmol/L. VDD was further determined to be associated with greater illness severity, multiple organ dysfunction, and mortality in the PICU setting. Clinical trials are required to determine if optimization of vitamin D status improves patient outcome. TRIAL REGISTRATION: PROSPERO, CRD42016026617 . Registered on 11 January 2016.

Medical students' perception of lesbian, gay, bisexual, and transgender (LGBT) discrimination in their learning environment and their self-reported comfort level for caring for LGBT patients: a survey study.

BACKGROUND: Historically, medical students who are lesbian, gay, bisexual or transgendered (LGBT) report higher rates of social stress, depression, and anxiety, while LGBT patients have reported discrimination and poorer access to healthcare. OBJECTIVE: The objectives of this study were: (1) to assess if medical students have perceived discrimination in their learning environment and; (2) to determine self-reported comfort level for caring for LGBT patients. DESIGN: Medical students at the University of Ottawa (N = 671) were contacted via email and invited to complete a confidential web-based survey. RESULTS: Response rate was 15.4% (103/671). This included 66 cis-gender heterosexuals (64.1%) and 37 LGBT students (35.9%). Anti-LGBT discrimination had been witnessed by 14.6% and heterosexism by 31.1% of respondents. Anti-LGBT discrimination most often originated from fellow medical students. Respondents who self-identified as LGBT were more likely to have perceived heterosexism (favoring opposite-sex relationships) (OR = 8.2, p < 0.001) or anti-LGBT discrimination (OR = 6.6, p = 0.002). While half of LGBT students shared their status with all classmates (51.4%), they were more likely to conceal this from staff physicians (OR = 27.2, p = 0.002). Almost half of medical students (41.7%) reported anti-LGBT jokes, rumors, and/or bullying by fellow medical students and/or other members of the healthcare team. Still, most respondents indicated that they felt comfortable with and capable of providing medical care to LGBT patients (≥83.5%), and were interested in further education around LGBT health issues (84.5%). CONCLUSION: Anti-LGBT discrimination and heterosexism are noted by medical students, indicating a suboptimal learning environment for LGBT students. Nonetheless, students report a high level of comfort and confidence providing health care to LGBT patients.

A pilot validation study of crowdsourcing systematic reviews: update of a searchable database of pediatric clinical trials of high-dose vitamin D.

BACKGROUND: Completing large systematic reviews and maintaining them up to date poses significant challenges. This is mainly due to the toll required of a small group of experts to screen and extract potentially eligible citations. Automated approaches have failed so far in providing an accessible and adaptable tool to the research community. Over the past decade, crowdsourcing has become attractive in the scientific field, and implementing it in citation screening could save the investigative team significant work and decrease the time to publication. METHODS: Citations from the 2015 update of a pediatrics vitamin D systematic review were uploaded to an online platform designed for crowdsourcing the screening process (http://www.CHEORI.org/en/CrowdScreenOverview). Three sets of exclusion criteria were used for screening, with a review of abstracts at level one, and full-text eligibility determined through two screening stages. Two trained reviewers, who participated in the initial systematic review, established citation eligibility. In parallel, each citation received four independent assessments from an untrained crowd with a medical background. Citations were retained or excluded if they received three congruent assessments. Otherwise, they were reviewed by the principal investigator. Measured outcomes included sensitivity of the crowd to retain eligible studies, and potential work saved defined as citations sorted by the crowd (excluded or retained) without involvement of the principal investigator. RESULTS: A total of 148 citations for screening were identified, of which 20 met eligibility criteria (true positives). The four reviewers from the crowd agreed completely on 63% (95% CI: 57-69%) of assessments, and achieved a sensitivity of 100% (95% CI: 88-100%) and a specificity of 99% (95% CI: 96-100%). Potential work saved to the research team was 84% (95% CI: 77-89%) at the abstract screening stage, and 73% (95% CI: 67-79%) through all three levels. In addition, different thresholds for citation retention and exclusion were assessed. With an algorithm favoring sensitivity (citation excluded only if all four reviewers agree), sensitivity was maintained at 100%, with a decrease of potential work saved to 66% (95% CI: 59-71%). In contrast, increasing the threshold required for retention (exclude all citations not obtaining 3/4 retain assessments) decreased sensitivity to 85% (95% CI: 65-96%), while improving potential workload saved to 92% (95% CI: 88-95%). CONCLUSIONS: This study demonstrates the accuracy of crowdsourcing for systematic review citations screening, with retention of all eligible articles and a significant reduction in the work required from the investigative team. Together, these two findings suggest that crowdsourcing could represent a significant advancement in the area of systematic review. Future directions include further study to assess validity across medical fields and determination of the capacity of a non-medical crowd.