Clinical implementation of failure modes and effects analysis for gynecological high-dose-rate brachytherapy.

Purpose: To use failure modes and effects analysis (FMEA) to identify failure modes for gynecological high-dose-rate (HDR) brachytherapy pathway and score with severity, occurrence, and detectability. Material and methods: A research team was organized to observe gynecological HDR brachytherapy pathway, and draw detailed process map to identify all potential failure modes (FMs). The whole team scored FMs based on three parameters, including occurrence (O), detectability (D), and severity (S), and then multiplied three scores to obtain risk priority number (RPN). All FMs were ranked according to RPNs and/or severity scores, and FMs with the highest RPN scores (> 100) and severity scores (> 8) were selected for in-depth analysis. Fault tree analysis (FTA) was applied to find progenitor causes of high-risk FMs and their propagation path, and determine which steps in the process need to be changed and optimized. Efficiency of each existing preventive methods to detect and stop FMs was analyzed, and proposals to improve quality management (QM) and ensure patient safety were suggested. Results: The whole gynecological HDR brachytherapy pathway consisted of 5 sub-processes and 30 specific steps, in which 57 FMs were identified. Twelve high-risk FMs were found, including 7 FMs with RPNs > 100 and 5 FMs with severity scores > 8. For these FMs, 2 were in the insertion stage, 1 in the imaging stage, 4 in the treatment planning stage, and 5 in the final stage of treatment delivery. The most serious of these FMs was the change in organ at risk (OAR) during treatment delivery (RPN = 245.7). The FM that occurred most frequently was the applicator shift during patient transfer. Conclusions: Failure modes and effects analysis is a prospective risk-based tool that can identity high-risk steps before failures occur, provide preventive measures to stop their occurrence, and improve quality management system.

Sex-biased gene expression and gene-regulatory networks of sex-biased adverse event drug targets and drug metabolism genes.

BACKGROUND: Previous pharmacovigilance studies and a retroactive review of cancer clinical trial studies identified that women were more likely to experience drug adverse events (i.e., any unintended effects of medication), and men were more likely to experience adverse events that resulted in hospitalization or death. These sex-biased adverse events (SBAEs) are due to many factors not entirely understood, including differences in body mass, hormones, pharmacokinetics, and liver drug metabolism enzymes and transporters. METHODS: We first identified drugs associated with SBAEs from the FDA Adverse Event Reporting System (FAERS) database. Next, we evaluated sex-specific gene expression of the known drug targets and metabolism enzymes for those SBAE-associated drugs. We also constructed sex-specific tissue gene-regulatory networks to determine if these known drug targets and metabolism enzymes from the SBAE-associated drugs had sex-specific gene-regulatory network properties and predicted regulatory relationships. RESULTS: We identified liver-specific gene-regulatory differences for drug metabolism genes between males and females, which could explain observed sex differences in pharmacokinetics and pharmacodynamics. In addition, we found that ~ 85% of SBAE-associated drug targets had sex-biased gene expression or were core genes of sex- and tissue-specific network communities, significantly higher than randomly selected drug targets. Lastly, we provide the sex-biased drug-adverse event pairs, drug targets, and drug metabolism enzymes as a resource for the research community. CONCLUSIONS: Overall, we provide evidence that many SBAEs are associated with drug targets and drug metabolism genes that are differentially expressed and regulated between males and females. These SBAE-associated drug metabolism enzymes and drug targets may be useful for future studies seeking to explain or predict SBAEs.

Treatment of Hidradenitis Suppurativa Evaluation Study (THESEUS): a prospective cohort study.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, painful disease affecting flexures and other skin regions, producing nodules, abscesses and skin tunnels. Laser treatment targeting hair follicles and deroofing of skin tunnels are standard HS interventions in some countries but are rarely offered in the UK. OBJECTIVES: To describe current UK HS management pathways and influencing factors to inform the design of future randomized controlled trials (RCTs). METHODS: THESEUS was a nonrandomized 12-month prospective cohort study set in 10 UK hospitals offering five interventions: oral doxycycline 200 mg daily; oral clindamycin and rifampicin both 300 mg twice daily for 10 weeks, extended for longer in some cases; laser treatment targeting hair follicles; deroofing; and conventional surgery. The primary outcome was the combination of clinician-assessed eligibility and participant hypothetical willingness to receive each intervention. The secondary outcomes were the proportion of participants selecting each intervention as their final treatment option; the proportion who switch treatments; treatment fidelity; and attrition rates. THESEUS was prospectively registered on the ISRCTN registry: ISRCTN69985145. RESULTS: The recruitment target of 150 participants was met after 18 months, in July 2021, with two pauses due to the COVID-19 pandemic. Baseline demographics reflected the HS secondary care population: average age 36 years, 81% female, 20% non-White, 64% current or ex-smokers, 86% body mass index ≥ 25, 68% with moderate disease, 19% with severe disease and 13% with mild disease. Laser was the intervention with the highest proportion (69%) of participants eligible and willing to receive treatment, then deroofing (58%), conventional surgery (54%), clindamycin and rifampicin (44%), and doxycycline (37%). Laser was ranked first choice by the greatest proportion of participants (41%). Attrition rates were 11% and 17% after 3 and 6 months, respectively. Concordance with doxycycline was 52% after 3 months due to lack of efficacy, participant choice and adverse effects. Delays with procedural interventions were common, with only 43% and 26% of participants starting laser and deroofing, respectively, after 3 months. Uptake of conventional surgery was too small to characterize the intervention. Switching treatment was uncommon and there were no serious adverse events. CONCLUSIONS: THESEUS has established laser treatment and deroofing for HS in the UK and demonstrated their popularity with patients and clinicians for future RCTs.

Treatment of Hidradenitis Suppurativa Evaluation Study: the THESEUS prospective cohort study.

Background: Hidradenitis suppurativa is a chronic inflammatory skin disease characterised by recurrent inflammatory lesions and skin tunnels in flexural sites such as the axilla. Deroofing of skin tunnels and laser treatment are standard hidradenitis suppurativa interventions in some countries but not yet introduced in the United Kingdom. Objective: To understand current hidradenitis suppurativa management pathways and what influences treatment choices to inform the design of future randomised controlled trials. Design: Prospective 12-month observational cohort study, including five treatment options, with nested qualitative interviews and an end-of-study consensus workshop. Setting: Ten United Kingdom hospitals with recruitment led by dermatology and plastic surgery departments. Participants: Adults with active hidradenitis suppurativa of any severity not adequately controlled by current treatment. Interventions: Oral doxycycline 200 mg once daily; oral clindamycin and rifampicin, both 300 mg twice daily for 10 weeks initially; laser treatment targeting the hair follicle (neodymium-doped yttrium aluminium garnet or alexandrite); deroofing; and conventional surgery. Main outcome measures: Primary outcome was the proportion of participants who are eligible, and hypothetically willing, to use the different treatment options. Secondary outcomes included proportion of participants choosing each of the study interventions, with reasons for their choices; proportion of participants who switched treatments; treatment fidelity; loss to follow-up rates over 12 months; and efficacy outcome estimates to inform outcome measure instrument responsiveness. Results: Between February 2020 and July 2021, 151 participants were recruited, with two pauses due to the COVID-19 pandemic. Follow-up rates were 89% and 83% after 3 and 6 months, decreasing to 70% and 44% at 9 and 12 months, respectively, because pandemic recruitment delays prevented all participants reaching their final review. Baseline demographics included an average age of 36 years, 81% female, 20% black, Asian or Caribbean, 64% current or ex-smokers and 86% with a raised body mass index. Some 69% had moderate disease, 19% severe disease and 13% mild disease. Regarding the study's primary outcome, laser treatment was the intervention with the highest proportion (69%) of participants who were eligible and hypothetically willing to receive treatment, followed by deroofing (58%), conventional surgery (54%), the combination of oral clindamycin and rifampicin (44%) and doxycycline (37%). Considering participant willingness in isolation, laser was ranked first choice by the greatest proportion (41%) of participants. The cohort study and qualitative study demonstrated that participant willingness to receive treatment was strongly influenced by their clinician. Fidelity to oral doxycycline was only 52% after 3 months due to lack of effectiveness, participant preference and adverse effects. Delays receiving procedural interventions were common, with only 43% and 26% of participants commencing laser therapy and deroofing, respectively, after 3 months. Treatment switching was uncommon and there were no serious adverse events. Daily pain score text messages were initiated in 110 participants. Daily responses reduced over time with greatest concordance during the first 14 days. Limitations: It was not possible to characterise conventional surgery due to a low number of participants. Conclusion: The Treatment of Hidradenitis Suppurativa Evaluation Study established deroofing and laser treatment for hidradenitis suppurativa in the United Kingdom and developed a network of 10 sites for subsequent hidradenitis suppurativa randomised controlled trials. Future work: The consensus workshop prioritised laser treatment and deroofing as interventions for future randomised controlled trials, in some cases combined with drug treatment. Trial registration: This trial is registered as ISRCTN69985145. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 12/35/64) and is published in full in Health Technology Assessment; Vol. 27, No. 30. See the NIHR Funding and Awards website for further award information.

The Treatment of Hidradenitis Suppurativa Evaluation Study introduced deroofing of skin tunnels and laser treatment for hidradenitis suppurativa and found that these are preferred interventions for future trials compared with oral antibiotics or conventional surgery.

Developing a model for decision-making around antibiotic prescribing for patients with COVID-19 pneumonia in acute NHS hospitals during the first wave of the COVID-19 pandemic: qualitative results from the Procalcitonin Evaluation of Antibiotic use in COVID-19 Hospitalised patients (PEACH Study).

OBJECTIVE: To explore and model factors affecting antibiotic prescribing decision-making early in the pandemic. DESIGN: Semistructured qualitative interview study. SETTING: National Health Service (NHS) trusts/health boards in England and Wales. PARTICIPANTS: Clinicians from NHS trusts/health boards in England and Wales. METHOD: Individual semistructured interviews were conducted with clinicians in six NHS trusts/health boards in England and Wales as part of the Procalcitonin Evaluation of Antibiotic use in COVID-19 Hospitalised patients study, a wider study that included statistical analysis of procalcitonin (PCT) use in hospitals during the first wave of the pandemic. Thematic analysis was used to identify key factors influencing antibiotic prescribing decisions for patients with COVID-19 pneumonia during the first wave of the pandemic (March to May 2020), including how much influence PCT test results had on these decisions. RESULTS: During the first wave of the pandemic, recommendations to prescribe antibiotics for patients with COVID-19 pneumonia were based on concerns about secondary bacterial infections. However, as clinicians gained more experience with COVID-19, they reported increasing confidence in their ability to distinguish between symptoms and signs caused by SARS-CoV-2 viral infection alone, and secondary bacterial infections. Antibiotic prescribing decisions were influenced by factors such as clinician experience, confidence, senior support, situational factors and organisational influences. A decision-making model was developed. CONCLUSION: This study provides insight into the decision-making process around antibiotic prescribing for patients with COVID-19 pneumonia during the first wave of the pandemic. The importance of clinician experience and of senior review of decisions as factors in optimising antibiotic stewardship is highlighted. In addition, situational and organisational factors were identified that could be optimised. The model presented in the study can be used as a tool to aid understanding of the complexity of the decision-making process around antibiotic prescribing and planning antimicrobial stewardship support in the context of a pandemic. TRIAL REGISTRATION NUMBER: ISRCTN66682918.

Assessing frailty in elderly patients with hip fractures: A retrospective review comparing geriatrician and orthopedic trainee assessments.

To assess the correlation of orthopedic surgery residents compared with expert geriatricians in the assessment of frailty stage using the Clinical Frailty Scale (CFS) in patients with hip fractures. A retrospective chart review was performed from January 1, 2015 to December 31, 2019. Patients admitted with a diagnosis of hip fracture were identified. Those patients with a CFS score completed by orthopedic residents with subsequent CFS score completed by a geriatrician during their admission were extracted. Six hundred and forty-eight patients over age 60 (mean 80.5 years, 73.5% female) were admitted during the study period. Orthopaedic residents completed 286 assessments in 44% of admissions. Geriatric medicine consultation was available for 215 patients such that 93 patients were assessed by both teams. Paired CFS data were extracted from the charts and tested for agreement between the 2 groups of raters. CFS assessments by orthopedic residents and geriatrician experts were significantly different at P < .05; orthopedic residents typically assessed patients to be one CFS grade less frail than geriatricians. Despite this, the CFS assessments showed good agreement between residents and geriatricians. Orthopaedic surgery residents are reliable assessors of frailty but tend to underestimate frailty level compared with specialist geriatricians. Given the evidence to support models such as orthogeriatrics to improve outcomes for frail patients, our findings suggest that orthopedic residents may be well positioned to identify patients who could benefit from such early interventions. Our findings also support recent evidence that frailty assessments by orthopedic surgeons may have predictive validity. Low rates of initial frailty assessment by orthopedic residents suggests that further work is required to integrate more global comprehensive care.

Immune Cell Abundance and T-cell Receptor Landscapes Suggest New Patient Stratification Strategies in Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is a molecularly and spatially heterogeneous disease frequently characterized by impairment of immunosurveillance mechanisms. Despite recent success with immunotherapy treatment, disease progression still occurs quickly after treatment in the majority of cases, suggesting the need to improve patient selection strategies. In the quest for biomarkers that may help inform response to checkpoint blockade, we characterized the tumor microenvironment (TME) of 162 HNSCC primary tumors of diverse etiologic and spatial origin, through gene expression and IHC profiling of relevant immune proteins, T-cell receptor (TCR) repertoire analysis, and whole-exome sequencing. We identified five HNSCC TME categories based on immune/stromal composition: (i) cytotoxic, (ii) plasma cell rich, (iii) dendritic cell rich, (iv) macrophage rich, and (v) immune-excluded. Remarkably, the cytotoxic and plasma cell rich subgroups exhibited a phenotype similar to tertiary lymphoid structures (TLS), which have been previously linked to immunotherapy response. We also found an increased richness of the TCR repertoire in these two subgroups and in never smokers. Mutational patterns evidencing APOBEC activity were enriched in the plasma cell high subgroup. Furthermore, specific signal propagation patterns within the Ras/ERK and PI3K/AKT pathways associated with distinct immune phenotypes. While traditionally CD8/CD3 T-cell infiltration and immune checkpoint expression (e.g., PD-L1) have been used in the patient selection process for checkpoint blockade treatment, we suggest that additional biomarkers, such as TCR productive clonality, smoking history, and TLS index, may have the ability to pull out potential responders to benefit from immunotherapeutic agents. SIGNIFICANCE: Here we present our findings on the genomic and immune landscape of primary disease in a cohort of 162 patients with HNSCC, benefitting from detailed molecular and clinical characterization. By employing whole-exome sequencing and gene expression analysis of relevant immune markers, TCR profiling, and staining of relevant proteins involved in immune response, we highlight how distinct etiologies, cell intrinsic, and environmental factors combine to shape the landscape of HNSCC primary disease.

ISGylation-independent protection of cell growth by USP18 following interferon stimulation.

Type 1 interferon stimulation highly up-regulates all elements of a ubiquitin-like conjugation system that leads to ISGylation of target proteins. An ISG15-specific member of the deubiquitylase family, USP18, is up-regulated in a co-ordinated manner. USP18 can also provide a negative feedback by inhibiting JAK-STAT signalling through protein interactions independently of DUB activity. Here, we provide an acute example of this phenomenon, whereby the early expression of USP18, post-interferon treatment of HCT116 colon cancer cells is sufficient to fully suppress the expression of the ISG15 E1 enzyme, UBA7. Stimulation of lung adenocarcinoma A549 cells with interferon reduces their growth rate but they remain viable. In contrast, A549 USP18 knock-out cells show similar growth characteristics under basal conditions, but upon interferon stimulation, a profound inhibition of cell growth is observed. We show that this contingency on USP18 is independent of ISGylation, suggesting non-catalytic functions are required for viability. We also demonstrate that global deISGylation kinetics are very slow compared with deubiquitylation. This is not influenced by USP18 expression, suggesting that enhanced ISGylation in USP18 KO cells reflects increased conjugating activity.

Sex-biased gene expression and gene-regulatory networks of sex-biased adverse event drug targets and drug metabolism genes.

Background: Previous pharmacovigilance studies and a retroactive review of cancer clinical trial studies identified that women were more likely to experience drug adverse events (i.e., any unintended effects of medication), and men were more likely to experience adverse events that resulted in hospitalization or death. These sex-biased adverse events (SBAEs) are due to many factors not entirely understood, including differences in body mass, hormones, pharmacokinetics, and liver drug metabolism enzymes and transporters. Methods: We first identified drugs associated with SBAEs from the FDA Adverse Event Reporting System (FAERS) database. Next, we evaluated sex-specific gene expression of the known drug targets and metabolism enzymes for those SBAE-associated drugs. We also constructed sex-specific tissue gene-regulatory networks to determine if these known drug targets and metabolism enzymes from the SBAE-associated drugs had sex-specific gene-regulatory network properties and predicted regulatory relationships. Results: We identified liver-specific gene-regulatory differences for drug metabolism genes between males and females, which could explain observed sex differences in pharmacokinetics and pharmacodynamics. In addition, we found that ~85% of SBAE-associated drug targets had sex-biased gene expression or were core genes of sex- and tissue-specific network communities, significantly higher than randomly selected drug targets. Lastly, we provide the sex-biased drug-adverse event pairs, drug targets, and drug metabolism enzymes as a resource for the research community. Conclusions: Overall, we provide evidence that many SBAEs are associated with drug targets and drug metabolism genes that are differentially expressed and regulated between males and females. These SBAE-associated drug metabolism enzymes and drug targets may be useful for future studies seeking to explain or predict SBAEs.

Biomarker-guided duration of antibiotic treatment in children hospitalised with confirmed or suspected bacterial infection: statistical analysis plan for the BATCH trial and PRECISE sub-study.

INTRODUCTION: The BATCH trial is a multi-centre randomised controlled trial to compare procalcitonin-guided management of severe bacterial infection in children with current management. PRECISE is a mechanistic sub-study embedded into the BATCH trial. This paper describes the statistical analysis plan for the BATCH trial and PRECISE sub-study. METHODS: The BATCH trial will assess the effectiveness of an additional procalcitonin test in children (aged 72 h to 18 years) hospitalised with suspected or confirmed bacterial infection to guide antimicrobial prescribing decisions. Participants will be enrolled in the trial from randomisation until day 28 follow-up. The co-primary outcomes are duration of intravenous antibiotic use and a composite safety outcome. Target sample size is 1942 patients, based on detecting a 1-day reduction in intravenous antibiotic use (90% power, two-sided) and on a non-inferiority margin of 5% risk difference in the composite safety outcome (90% power, one-sided), while allowing for up to 10% loss to follow-up. RESULTS: Baseline characteristics will be summarised overall, by trial arm, and by whether patients were recruited before or after the pause in recruitment due to the COVID-19 pandemic. In the primary analysis, duration of intravenous antibiotic use will be tested for superiority using Cox regression, and the composite safety outcome will be tested for non-inferiority using logistic regression. The intervention will be judged successful if it reduces the duration of intravenous antibiotic use without compromising safety. Secondary analyses will include sensitivity analyses, pre-specified subgroup analyses, and analysis of secondary outcomes. Two sub-studies, including PRECISE, involve additional pre-specified subgroup analyses. All analyses will be adjusted for the balancing factors used in the randomisation, namely centre and patient age. CONCLUSION: We describe the statistical analysis plan for the BATCH trial and PRECISE sub-study, including definitions of clinical outcomes, reporting guidelines, statistical principles, and analysis methods. The trial uses a design with co-primary superiority and non-inferiority endpoints. The analysis plan has been written prior to the completion of follow-up. TRIAL REGISTRATION: BATCH: ISRCTN11369832, registered 20 September 2017, doi.org/10.1186/ISRCTN11369832. PRECISE: ISRCTN14945050, registered 17 December 2020, doi.org/10.1186/ISRCTN14945050.

A novel, evidence-based, comprehensive clinical decision support system improves outcomes for patients with traumatic rib fractures.

BACKGROUND: Traumatic rib fractures are associated with high morbidity and mortality. Clinical decision support systems (CDSS) have been shown to improve adherence to evidence-based (EB) practice and improve clinical outcomes. The objective of this study was to investigate if a rib fracture CDSS reduced hospital length of stay (LOS), 90-day and 1-year mortality, unplanned ICU transfer, and the need for mechanical ventilation. The independent association of two process measures, an admission EB order set and a pain-inspiratory-cough score early warning system, with LOS were investigated. METHODS: The CDSS was scaled across nine US trauma centers. Following multiple imputation, multivariable regression models were fit to evaluate the association of the CDSS on primary and secondary outcomes. As a sensitivity analysis, propensity score matching was also performed to confirm regression findings. RESULTS: Overall, 3,279 patients met inclusion criteria. Rates of EB practices increased following implementation. On risk-adjusted analysis, in-hospital LOS preintervention versus postintervention was unchanged (incidence rate ratio [IRR], 1.06; 95% confidence interval [CI], 0.97-1.15, p = 0.2) but unplanned transfer to the ICU was reduced (odds ratio, 0.28; 95% CI, 0.09-0.84, p = 0.024), as was 1-year mortality (hazard ratio, 0.6; 95% CI, 0.4-0.89, p = 0.01). Provider utilization of the admission order bundle was 45.3%. Utilization was associated with significantly reduced LOS (IRR, 0.87; 95% CI, 0.77-0.98; p = 0.019). The early warning system triggered on 34.4% of patients; however, was not associated with a significant reduction in hospital LOS (IRR, 0.76; 95% CI, 0.55-1.06; p = 0.1). CONCLUSION: A novel, user-centered, comprehensive CDSS improves adherence to EB practice and is associated with a significant reduction in unplanned ICU admissions and possibly mortality, but not hospital LOS. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Re-Aiming Equity Evaluation in Clinical Decision Support: A Scoping Review of Equity Assessments in Surgical Decision Support Systems.

OBJECTIVE: We critically evaluated the surgical literature to explore the prevalence and describe how equity assessments occur when using clinical decision support systems. BACKGROUND: Clinical decision support (CDS) systems are increasingly used to facilitate surgical care delivery. Despite formal recommendations to do so, equity evaluations are not routinely performed on CDS systems and underrepresented populations are at risk of harm and further health disparities. We explored surgical literature to determine frequency and rigor of CDS equity assessments and offer recommendations to improve CDS equity by appending existing frameworks. METHODS: We performed a scoping review up to Augus 25, 2021 using PubMed and Google Scholar for the following search terms: clinical decision support, implementation, RE-AIM, Proctor, Proctor's framework, equity, trauma, surgery, surgical. We identified 1415 citations and 229 abstracts met criteria for review. A total of 84 underwent full review after 145 were excluded if they did not assess outcomes of an electronic CDS tool or have a surgical use case. RESULTS: Only 6% (5/84) of surgical CDS systems reported equity analyses, suggesting that current methods for optimizing equity in surgical CDS are inadequate. We propose revising the RE-AIM framework to include an Equity element (RE 2 -AIM) specifying that CDS foundational analyses and algorithms are performed or trained on balanced datasets with sociodemographic characteristics that accurately represent the CDS target population and are assessed by sensitivity analyses focused on vulnerable subpopulations. CONCLUSION: Current surgical CDS literature reports little with respect to equity. Revising the RE-AIM framework to include an Equity element (RE 2 -AIM) promotes the development and implementation of CDS systems that, at minimum, do not worsen healthcare disparities and possibly improve their generalizability.

Dietary Therapy to Improve Nutrition and Gut Health in Paediatric Crohn's Disease; A Feasibility Study.

Bovine colostrum (BC) has anti-inflammatory, anti-infective, growth and intestinal repair factors that may be beneficial in Crohn's disease (CD). We assessed whether daily BC for up to 3 months was acceptable to children and young people (CYP) with CD in remission or of mild/moderate severity. CYP were randomised to receive either BC or matching placebo milk daily for 6 weeks (blinded phase); all received BC for the following 6 weeks (open phase). In 23 CYP, median (inter-quartile range) age was 15.2 (13.9-16.1) years and 9 (39.1%) were girls. A similar proportion of CYP in the BC and placebo arms completed the blinded phase (8/12, 75.0% and 9/11, 81.8% respectively). Twelve (70.6%) CYP completed the open phase with 7 (58.3%) tolerating BC for 3 months. Diaries in weeks 2, 6 and 12 revealed that most CYP took BC every day (5/7, 71.4%; 5/8, 62.5% and 6/11, 54.5% respectively). In interviews, opinions were divided as to preference of BC over the placebo milk and some preferred BC over other nutritional supplements. Symptoms, clinical and laboratory variables and quality of life were similar in the two arms. BC may be an acceptable nutritional supplement for daily, longer-term use in CYP with CD.

Mid-Regional Pro-Adrenomedullin in Combination With Pediatric Early Warning Scores for Risk Stratification of Febrile Children Presenting to the Emergency Department: Secondary Analysis of a Nonprespecified United Kingdom Cohort Study.

OBJECTIVES: Current sepsis guidelines do not provide good risk stratification of subgroups in whom prompt IV antibiotics and fluid resuscitation might of benefit. We evaluated the utility of mid-regional pro-adrenomedullin (MR-proADM) in identification of patient subgroups at risk of requiring PICU or high-dependency unit (HDU) admission or fluid resuscitation. DESIGN: Secondary, nonprespecified analysis of prospectively collected dataset. SETTING: Pediatric Emergency Department in a United Kingdom tertiary center. PATIENTS: Children less than 16 years old presenting with fever and clinical indication for venous blood sampling ( n = 1,183). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Primary outcome measures were PICU/HDU admission or administration of fluid resuscitation, with a secondary outcome of definite or probable bacterial infection. Biomarkers were measured on stored plasma samples and children phenotyped into bacterial and viral groups using a previously published algorithm. Of the 1,183 cases, 146 children (12.3%) required fluids, 48 (4.1%) were admitted to the PICU/HDU, and 244 (20.6%) had definite or probable bacterial infection. Area under the receiver operating characteristic (AUC) was used to assess performance. MR-proADM better predicted fluid resuscitation (AUC, 0.73; 95% CI, 0.67-0.78), than both procalcitonin (AUC, 0.65; 95% CI, 0.59-0.71) and Pediatric Early Warning Score (PEWS: AUC, 0.62; 95% CI, 0.56-0.67). PEWS alone showed good accuracy for PICU/HDU admission 0.83 (0.78-0.89). Patient subgroups with high MR-proADM (≥ 0.7 nmol/L) and high procalcitonin (≥ 0.5 ng/mL) had increased association with PICU/HDU admission, fluid resuscitation, and bacterial infection compared with subgroups with low MR-proADM (< 0.7 nmol/L). For children with procalcitonin less than 0.5 ng/mL, high MR-proADM improved stratification for fluid resuscitation only. CONCLUSIONS: High MR-proADM and high procalcitonin were associated with increased likelihood of subsequent disease progression. Incorporating MR-proADM into clinical risk stratification may be useful in clinician decision-making regarding initiation of IV antibiotics, fluid resuscitation, and escalation to PICU/HDU admission.

A systematic literature review and narrative synthesis on the risk factors for developing affective disorders in open lower-limb fracture patients.

Background: Despite the advancements made in the management of the physical complications of open lower-limb fractures, few studies have been performed which investigate the association of such injuries with affective disorders. The complications resulting from this injury may result in significant psychological distress. Aim: To evaluate the risk factors associated with the development of affective disorders, in patients with open lower-limb fractures. Methods: A systematic review protocol was registered with PROSPERO and reported in accordance with the Preferred Reporting for Items for Systematic Reviews and Meta-Analyses. A comprehensive literature search was performed to gather relevant papers. Two independent reviewers screened titles and abstracts according to the inclusion and exclusion criteria. Results: 2488 were screened according to the inclusion and exclusion criteria resulting in seven articles eligible for inclusion. Of the seven articles, two assessed for PTSD, one assessed for depression and PTSD concurrently, two assessed for anxiety and depression concurrently, and two assessed for psychological distress. With the exception of two studies, open lower limb fracture patients were included with other lower-limb injuries in their analysis. Furthermore, not all variables were available in all included studies. Risk factors identified included post-operative pain, mechanism and severity of injury, age of patient, social support and social deprivation. Conclusions: Further studies are required within this area. However, addressing risk factors such as pain management, poor social support and inappropriate coping mechanisms, may reduce the incidence of affective disorders by equipping patients with necessary psychosocial resources.

Short-term risk prediction after major lower limb amputation: PERCEIVE study.

BACKGROUND: The accuracy with which healthcare professionals (HCPs) and risk prediction tools predict outcomes after major lower limb amputation (MLLA) is uncertain. The aim of this study was to evaluate the accuracy of predicting short-term (30 days after MLLA) mortality, morbidity, and revisional surgery. METHODS: The PERCEIVE (PrEdiction of Risk and Communication of outcomE following major lower limb amputation: a collaboratIVE) study was launched on 1 October 2020. It was an international multicentre study, including adults undergoing MLLA for complications of peripheral arterial disease and/or diabetes. Preoperative predictions of 30-day mortality, morbidity, and MLLA revision by surgeons and anaesthetists were recorded. Probabilities from relevant risk prediction tools were calculated. Evaluation of accuracy included measures of discrimination, calibration, and overall performance. RESULTS: Some 537 patients were included. HCPs had acceptable discrimination in predicting mortality (931 predictions; C-statistic 0.758) and MLLA revision (565 predictions; C-statistic 0.756), but were poor at predicting morbidity (980 predictions; C-statistic 0.616). They overpredicted the risk of all outcomes. All except three risk prediction tools had worse discrimination than HCPs for predicting mortality (C-statistics 0.789, 0.774, and 0.773); two of these significantly overestimated the risk compared with HCPs. SORT version 2 (the only tool incorporating HCP predictions) demonstrated better calibration and overall performance (Brier score 0.082) than HCPs. Tools predicting morbidity and MLLA revision had poor discrimination (C-statistics 0.520 and 0.679). CONCLUSION: Clinicians predicted mortality and MLLA revision well, but predicted morbidity poorly. They overestimated the risk of mortality, morbidity, and MLLA revision. Most short-term risk prediction tools had poorer discrimination or calibration than HCPs. The best method of predicting mortality was a statistical tool that incorporated HCP estimation.

Combined Expert and User-Driven Usability Assessment of Trauma Decision Support Systems Improves User-Centered Design.

BACKGROUND: Trauma clinical decision support systems improve adherence with evidence-based practice but suffer from poor usability and the lack of a user-centered design. The objective of this study was to compare the effectiveness of user and expert-driven usability testing methods to detect usability issues in a rib fracture clinical decision support system and identify guiding principles for trauma clinical decision support systems. METHODS: A user-driven and expert-driven usability investigation was conducted using a clinical decision support system developed for patients with rib fractures. The user-driven usability evaluation was as follows: 10 clinicians were selected for simulation-based usability testing using snowball sampling, and each clinician completed 3 simulations using a video-conferencing platform. End-users participated in a novel team-based approach that simulated realistic clinical workflows. The expert-driven heuristic evaluation was as follows: 2 usability experts conducted a heuristic evaluation of the clinical decision support system using 10 common usability heuristics. Usability issues were identified, cataloged, and ranked for severity using a 4-level ordinal scale. Thematic analysis was utilized to categorize the identified usability issues. RESULTS: Seventy-nine usability issues were identified; 63% were identified by experts and 48% by end-users. Notably, 58% of severe usability issues were identified by experts alone. Only 11% of issues were identified by both methods. Five themes were identified that could guide the design of clinical decision support systems-transparency, functionality and integration into workflow, automated and noninterruptive, flexibility, and layout and appearance. Themes were preferentially identified by different methods. CONCLUSION: We found that a dual-method usability evaluation involving usability experts and end-users drastically improved detection of usability issues over single-method alone. We identified 5 themes to guide trauma clinical decision support system design. Performing usability testing via a remote video-conferencing platform facilitated multi-site involvement despite a global pandemic.

Surgical management of delayed-presentation diaphragm hernia: A single-institution experience.

Objectives: Delayed-presentation diaphragm hernias are uncommon, and surgical management varies widely across practices. We describe our surgical experience with delayed-presentation diaphragm hernias as a case series of 14 patients, 9 of whom underwent minimally invasive repair. Methods: We performed a retrospective chart review of our prospective database of all patients treated surgically for delayed-presentation diaphragm hernia at our institution from January 1, 2005, to April 30, 2021. We excluded patients with poststernotomy, post-left ventricular assist device, and previously diagnosed congenital hernias. We recorded patient demographics, etiology, laterality, chronicity, operative details, postoperative complications, and long-term results. Results: We performed surgical repair of delayed-presentation diaphragm hernia in 14 patients. Eleven patients (79%) were male, the median age was 61 (18-83) years, the median body mass index was 29.2 (14.5-33.7), and 8 (57%) hernias were left-sided. Etiology was trauma (n = 7, 50%), iatrogenic (n = 5, 36%), and unknown (n = 2, 14%). Median time to presentation in patients with traumatic and iatrogenic hernias was 7.5 years (6 weeks to 38 years). Nine patients (64%) underwent minimally invasive repair, and 5 patients (36%) underwent open repair. We used a synthetic patch in all but 2 patients (86%). Median length of stay was 5 (3-27) days. Two patients (14%) had major complications. There were no deaths. Twelve patients (86%) had follow-up imaging at a median follow-up of 17 months (1-192) with zero recurrences. Conclusions: Our experience suggests that a minimally invasive or an open approach to patients with a delayed-presentation diaphragm hernia is safe and effective. We recommend tailoring the surgical approach based on patient characteristics, anatomic considerations, and surgeons' experience.

PROcalcitonin and NEWS2 evaluation for Timely identification of sepsis and Optimal use of antibiotics in the emergency department (PRONTO): protocol for a multicentre, open-label, randomised controlled trial.

INTRODUCTION: Sepsis is a common, potentially life-threatening complication of infection. The optimal treatment for sepsis includes prompt antibiotics and intravenous fluids, facilitated by its early and accurate recognition. Currently, clinicians identify and assess severity of suspected sepsis using validated clinical scoring systems. In England, the National Early Warning Score 2 (NEWS2) has been mandated across all National Health Service (NHS) trusts and ambulance organisations. Like many clinical scoring systems, NEWS2 should not be used without clinical judgement to determine either the level of acuity or a diagnosis. Despite this, there is a tendency to overemphasise the score in isolation in patients with suspected infection, leading to the overprescription of antibiotics and potentially treatment-related complications and rising antimicrobial resistance. The biomarker procalcitonin (PCT) has been shown to be useful in specific circumstances to support appropriate antibiotics prescribing by identifying bacterial infection. PCT is not routinely used in the care of undifferentiated patients presenting to emergency departments (EDs), and the evidence base of its optimal usage is poor. The PROcalcitonin and NEWS2 evaluation for Timely identification of sepsis and Optimal (PRONTO) study is a randomised controlled trial (RCT) in adults with suspected sepsis presenting to the ED to compare standard clinical management based on NEWS2 scoring plus PCT-guided risk assessment with standard clinical management based on NEWS2 scoring alone and compare if this approach reduces prescriptions of antibiotics without increasing mortality. METHODS AND ANALYSIS: PRONTO is a parallel two-arm open-label individually RCT set in up to 20 NHS EDs in the UK with a target sample size of 7676 participants. Participants will be randomised in a ratio of 1:1 to standard clinical management based on NEWS2 scoring or standard clinical management based on NEWS2 scoring plus PCT-guided risk assessment. We will compare whether the addition of PCT measurement to NEWS2 scoring can lead to a reduction in intravenous antibiotic initiation in ED patients managed as suspected sepsis, with at least no increase in 28-day mortality compared with NEWS2 scoring alone (in conjunction with local standard care pathways). PRONTO has two coprimary endpoints: initiation of intravenous antibiotics at 3 hours (superiority comparison) and 28-day mortality (non-inferiority comparison). The study has an internal pilot phase and group-sequential stopping rules for effectiveness and futility/safety, as well as a qualitative substudy and a health economic evaluation. ETHICS AND DISSEMINATION: The trial protocol was approved by the Health Research Authority (HRA) and NHS Research Ethics Committee (Wales REC 2, reference 20/WA/0058). In England and Wales, the law allows the use of deferred consent in approved research situations (including ED studies) where the time dependent nature of intervention would not allow true informed consent to be obtained. PRONTO has approval for a deferred consent process to be used. Findings will be disseminated through peer-reviewed journals and presented at scientific conferences. TRIAL REGISTRATION NUMBER: ISRCTN54006056.