Meta-analysis informed machine learning: Supporting cytokine storm detection during CAR-T cell Therapy.

Cytokine release syndrome (CRS), also known as cytokine storm, is one of the most consequential adverse effects of chimeric antigen receptor therapies that have shown otherwise promising results in cancer treatment. When emerging, CRS could be identified by the analysis of specific cytokine and chemokine profiles that tend to exhibit similarities across patients. In this paper, we exploit these similarities using machine learning algorithms and set out to pioneer a meta-review informed method for the identification of CRS based on specific cytokine peak concentrations and evidence from previous clinical studies. To this end we also address a widespread challenge of the applicability of machine learning in general: reduced training data availability. We do so by augmenting available (but often insufficient) patient cytokine concentrations with statistical knowledge extracted from domain literature. We argue that such methods could support clinicians in analyzing suspect cytokine profiles by matching them against the said CRS knowledge from past clinical studies, with the ultimate aim of swift CRS diagnosis. We evaluate our proposed methods under several design choices, achieving performance of more than 90% in terms of CRS identification accuracy, and showing that many of our choices outperform a purely data-driven alternative. During evaluation with real-world CRS clinical data, we emphasize the potential of our proposed method of producing interpretable results, in addition to being effective in identifying the onset of cytokine storm.

What patient assessment skills are required by pharmacists prescribing systemic anti-cancer therapy? A consensus study.

BACKGROUND: In the UK, pharmacist independent prescribers can prescribe for any condition within their clinical competence including systemic anti-cancer therapy. Competency frameworks have been developed but contain little detail on the patient assessment skills pharmacist independent prescribers require to prescribe systemic anti-cancer therapy with concern in the literature over current training on these skills. AIM: To gain consensus on the patient assessment skills required by pharmacist independent prescribers prescribing systemic anti-cancer therapy for genitourinary cancer (prostate and renal) and lung cancer across National Health Service Scotland. METHOD: Two phases were performed to generate patient assessment skill consensus. Initially, the Nominal Group Technique was performed within a local cancer network by discussion and participant ranking within genitourinary and lung cancer multi-disciplinary teams. Where consensus was achieved, patient assessment skills were carried forward to try to achieve national (National Health Service Scotland) consensus using a two-round Delphi questionnaire. RESULTS: Of the 27 patient assessment skills, consensus was gained for 21 and 23 patient assessment skills in the genitourinary and lung Nominal Group Technique groups, respectively. Within the genitourinary and lung national groups, 13/21 and 18/23 patient assessment skills were agreed as required for a pharmacist independent prescriber to prescribe systemic anti-cancer therapy in genitourinary and lung cancer, respectively. Eight common patient assessment skills were identified as core skills. Reasons for not reaching consensus included pharmacist independent prescriber competence, knowledge, skills and the roles and responsibilities of pharmacist independent prescribers within the multi-disciplinary team. CONCLUSION: We identified the core and specific patient assessment skills required to prescribe systemic anti-cancer therapy within two tumour groups. Further work is necessary to develop patient assessment skill competency frameworks, training and assessment methods and to redefine the roles of pharmacist independent prescribers within the multi-disciplinary team.

Products and activities associated with non-fatal traumatic brain injuries in children and adolescents - United States 2010-2013.

Background: Traumatic brain injury (TBI) is prevalent in children and adolescents ages <1-19 years, yet we have limited understanding of consumer products that are associated with TBIs in children and adolescents of varying ages. To address this gap, we combined two data sources to investigate leading products and activities associated with TBIs in children and adolescents in different developmental age groups (i.e. <1, 1-4, 5-9, 10-14, and 15-19 years). Methods: We analysed data from the National Electronic Injury Surveillance System-All Injury Program (NEISS-AIP), augmented with product information from the National Electronic Injury Surveillance System (NEISS), for the years 2010 through 2013. Results: From 2010 to 2013, children and adolescents aged <1-19 years accounted for 4.1 million non-fatal TBI-related emergency department visits. TBIs from home furnishings and fixtures, primarily beds, were highest among infants aged <1 year and children aged 1-4 years. TBIs from sports/recreation, especially bicycles and football, were highest among those aged 5-9 years, 10-14 years, and 15-19 years. Conclusions: The combined NEISS and NEISS-AIP data allow us to comprehensively examine products and activities that contribute to emergency department visits for TBIs in children and adolescents. Our findings indicate priority areas for TBI prevention and intervention.

Building the Child Safety Collaborative Innovation and Improvement Network: How does it work and what is it achieving?

OBJECTIVE: This study investigated whether the Child Safety Collaborative Innovation and Improvement Network (CS CoIIN) framework could be applied in the field of injury and violence prevention to reduce fatalities, hospitalizations and emergency department visits among 0-19 year olds. SAMPLE: Twenty-one states/jurisdictions were accepted into cohort 1 of the CS CoIIN, and 14 were engaged from March 2016 through April 2017. A quality improvement framework was used to test, implement and spread evidence-based change ideas (strategies and programs) in child passenger safety, falls prevention, interpersonal violence prevention, suicide and self-harm prevention and teen driver safety. PROCEDURES: Outcome and process measure data were analyzed using run chart rules. Descriptive data were analyzed for participation measures and descriptive statistics were produced. Qualitative data were analyzed to identify key themes. RESULTS: Seventy-six percent of CS CoIIN states/jurisdictions were engaged in activities and used data to inform decision making. Within a year, states/jurisdictions were able to test and implement evidence-based change ideas in pilot sites. A small group showed improvement in process measures and were ready to spread change ideas. Improvement in outcome measures was not achieved; however, 25% of states/jurisdictions identified data sources and reported on real-time outcome measures. CONCLUSIONS: Evidence indicates the CS CoIIN framework can be applied to make progress on process measures, but more time is needed to determine if this will result in progress on long-term outcome measures of fatalities, hospitalizations and emergency department visits. Seventeen states/jurisdictions will participate in cohort 2.

Embedding clinical research in pre-registration nursing and midwifery programmes.

Background: Within the UK, there is a goal that research is embedded into everyday healthcare practice. Currently education provided to students at pre-registration level is theoretical, with little focus on clinical research delivery. Aims: The paper's aim is to report on the development and evaluation of a pre-registration clinical research resource for nursing and midwifery students with direct application to clinical settings and patient care outcomes. Methods: An initial survey assessed whether the learning resource was useful for nursing pre-registration students. Based on the findings, alongside expert stakeholder input, adaptations were made to the learning resources and a second survey re-evaluated the learning resources. Survey findings were analysed using descriptive statistics. Free text responses were thematically grouped. Results: Ninety-seven pre-registration nursing students responded. Most students agreed that they had enjoyed using the resources, had improved understanding of clinical research, anticipated being actively involved in research and would consider a future clinical research role. Conclusions: The learning resources can help overcome barriers to research engagement by nurses and midwives. The results demonstrate that research can be incorporated into clinical, educational and academic roles, highlighting their worth in supporting the clinical research workforce.

QI initiative to reduce the number of inpatient falls in an acute hospital Trust.

Inpatient falls are one of the most frequent concerns to patient safety within the acute hospital environment, equating to 1700 falls per year in an 800-bed general hospital. They are predicted to cost approximately £2600 per patient, however, this estimate does not capture the costs and impact that inpatient falls have on the wider health and social care system. It also does not take into the account loss of confidence and delays in functional recovery.This report shares the learning from a quality improvement (QI) initiative that took place in a District General Hospital (DGH) in the UK. The initiative started in February 2020, was paused November 2020 due to wave 2 of the pandemic and restarted in March 2021. Improvement was achieved in January 2021.Data for falls within the Trust identified that falls were within common cause variation. A system change was needed to achieve an improvement.A QI project was commenced with the aim to achieve a 5% reduction in falls per 1000 bed days in a care of the elderly ward.Two primary drivers were identified: recognising patients at high risk of falls and preventing them from falling. Change ideas to address these primary drivers were tested using Plan Do Study Act (PDSA) cycles. Changes tested included: the development of an assessment tool to identify patients at high risk of falls, use of a wristband to identify patients at high risk of a fall, and increased observation.Change ideas achieved some success with the process measures but did not achieve an improvement with the outcome measures. A Trust wide change idea relating to the falls prevention service did lead to a sustained improvement in falls reduction.The barriers to the improvement included changing Trust priorities during the pandemic, and limited opportunities to fully engage the ward-based team with systems thinking and changing mental models.

Clinical Outcomes of Tivozanib Monotherapy as First-Line Treatment for Metastatic Renal Cell Carcinoma: A Multicentric UK Real-World Analysis.

BACKGROUND: Tivozanib is a licensed as first-line treatment for metastatic renal cell carcinoma (mRCC). OBJECTIVE: To evaluate the outcomes from tivozanib in a real-world mRCC population. PATIENTS AND METHODS: Patients with mRCC commencing first-line tivozanib between March 2017 and May 2019 were identified across four specialist cancer centres in the UK. Data relating to response, overall survival (OS), progression-free survival (PFS) and adverse events (AEs) were collected retrospectively with censoring on 31 December 2020. RESULTS: A total of 113 patients were identified: median age was 69 years; 78% had ECOG PS 0-1; 82% had clear cell histology; 66% had previous nephrectomy; International Metastatic RCC Database Consortium (IMDC) score was 22% favourable (F), 52% intermediate (I) and 26% poor (P). Twenty-six per cent were switched from another tyrosine kinase inhibitor (TKI) to tivozanib due to toxicity. Median follow-up was 26.6 months with 18% remaining on treatment at data censoring. Median PFS was 8.75 months. Median PFS by IMDC risk group was: F = 23.0 months; I = 10.0 months; P = 3.0 months, p value < 0.0001. Median OS was 25.0 months (F = not reached (NR) with 72% alive at data cut-off; I = 26.0 months; P = 7.0 months, p value < 0.0001). Seventy-seven per cent had an AE of any grade, and 13% had a grade ≥ 3 AE. Eighteen per cent of patients discontinued treatment due to toxicity. No patients who discontinued a prior TKI due to AEs stopped tivozanib due to AEs. CONCLUSIONS: These data suggest comparable activity of tivozanib with the pivotal trial data and other TKIs in a real-world population. Its tolerability positions tivozanib as an attractive first-line option for those unsuitable for combination therapies or unable to tolerate other TKIs.

Emerging and Fastidious Uropathogens Were Detected by M-PCR with Similar Prevalence and Cell Density in Catheter and Midstream Voided Urine Indicating the Importance of These Microbes in Causing UTIs.

Introduction: This study compared microbial compositions of midstream and catheter urine specimens from patients with suspected complicated urinary tract infections to determine if emerging and fastidious uropathogens are infecting the bladder or are contaminants. Methods: Urine was collected by in-and-out catheter (n = 1000) or midstream voiding (n = 1000) from 2000 adult patients (≥60 years of age) at 17 DispatchHealth sites across 11 states. The two groups were matched by age (mean 81 years), sex (62.1% female, 37.9% male), and ICD-10-CM codes. Microbial detection was performed with multiplex polymerase chain reaction (M-PCR) with a threshold for "positive detection" ≥ 10,000 cells/mL for bacteria or any detection for yeast. Results were divided by sex. Results: In females, 28 of 30 microorganisms/groups were found by both collection methods, while in males 26 of 30 were found by both. There were significant overlaps in the detection and densities of classical uropathogens including Escherichia coli, Enterococcus faecalis, and Klebsiella pneumoniae, as well as emerging uropathogens including Actinotignum schaalii and Aerococcus urinae. In females, detection rates were slightly higher in midstream voided compared to catheter-collected (p = 0.0005) urine samples, while males showed the opposite trend (p < 0.0001). More polymicrobial infections were detected in midstream voided compared to catheter-collected samples (64.4% vs 45.7%, p < 0.0001) in females but the opposite in males (35.6% vs 47.0%, p = 0.002). Discussion: In-and-out catheter-collected and midstream voided urine specimens shared significant similarities in microbial detections by M-PCR, with some differences found for a small subset of organisms and between sexes. Conclusion: Non-invasive midstream voided collection of urine specimens for microbial detection and identification in cases of presumed UTI does not result in significantly more contamination compared to in-and-out catheter-collected specimens. Additionally, organisms long regarded as contaminants should be reconsidered as potential uropathogens.

The Management and Outcomes of Patients with Extra-Pulmonary Neuroendocrine Neoplasms and Brain Metastases.

BACKGROUND: Brain metastases (BMs) in patients with extra-pulmonary neuroendocrine neoplasms (EP-NENs) are rare, and limited clinical information is available. The aim of this study was to detail the clinicopathological features, management and outcomes in patients with EP-NENs who developed BMs. METHODS: A retrospective single-centre analysis of consecutive patients with EP-NENs (August 2004-February 2020) was conducted. Median overall survival (OS)/survival from BMs diagnosis was estimated (Kaplan-Meier). RESULTS: Of 730 patients, 17 (1.9%) had BMs, median age 61 years (range 15-77); 8 (53%) male, unknown primary NEN site: 40%. Patients with BMs had grade 3 (G3) EP-NENs 11 (73%), G2: 3 (20%), G1: 1 (7%). Eight (53%) had poorly differentiated NENs, 6 were well-differentiated and 1 was not recorded. Additionally, 2 (13%) patients had synchronous BMs at diagnosis, whilst 13 (87%) developed BMs metachronously. The relative risk of developing BMs was 7.48 in patients with G3 disease vs. G1 + G2 disease (p = 0.0001). Median time to the development of BMs after NEN diagnosis: 15.9 months (range 2.5-139.5). Five patients had a solitary BM, 12 had multiple BMs. Treatment of BMs were surgery (n = 3); radiotherapy (n = 5); 4: whole brain radiotherapy, 1: conformal radiotherapy (orbit). Nine (53%) had best supportive care. Median OS from NEN diagnosis was 23.6 months [95% CI 15.2-31.3]; median time to death from BMs diagnosis was 3.0 months [95% CI 0.0-8.3]. CONCLUSION: BMs in patients with EP-NENs are rare and of increased risk in G3 vs. G1 + G2 EP-NENs. Survival outcomes are poor, and a greater understanding is needed to improve therapeutic outcomes.

Consumer Products Contributing to Fall Injuries in Children Aged <1 to 19 Years Treated in US Emergency Departments, 2010 to 2013: An Observational Study.

Consumer products are often associated with fall injuries, but there is limited research on nonfatal unintentional falls in children that examines both the child's age group and the involvement of consumer products and activities. We combined 2 data sources to investigate products and activities that contribute to fall injuries in children at different developmental ages (ie, <1, 1-2, 3-4, 5-9, 10-14, and 15-19 years). We analyzed data from the National Electronic Injury Surveillance System-All Injury Program for the years 2010 through 2013 and augmented it with product information from the National Electronic Injury Surveillance System. Between 2010 and 2013, children aged <1 to 19 years accounted for 11.1 million nonfatal unintentional fall-related emergency department visits. Fall injuries associated with home furnishings/fixtures were highest among children in age groups <1 year, 1 to 2 years, and 3 to 4 years. In the home furnishings/fixtures product group, beds were the leading contributor to falls. Fall injuries associated with sports/recreation were highest among children in age groups 5 to 9 years, 10 to 14 years, and 15 to 19 years. In this product group, monkey bars and basketball were the leading contributors to falls. Our findings indicate priority areas for falls injury prevention and intervention.

Trends in Drug Poisoning Deaths Among Adolescents and Young Adults in the United States, 2006-2015.

OBJECTIVE: Despite the rising toll of drug poisoning deaths in the United States, the extent of the problem among adolescents and young adults ages 15-24 years has received relatively little attention. We examined sociodemographic characteristics and state trends in drug poisoning deaths among adolescents and young adults from 2006 to 2015 and estimated the costs of drug poisoning mortality in this population. METHOD: We used the National Vital Statistics System's Multiple Cause of Death files from 2006 to 2015. We analyzed trends using Joinpoint regression analysis and calculated total costs of drug poisoning deaths, including medical costs, work loss costs, and quality of life loss, based on widely used cost estimates. RESULTS: Drug poisoning death rates (per 100,000 population) in adolescents and young adults increased from 8.1 in 2006 to 9.7 in 2015. The rates increased significantly for Whites (1.7% per year) and Asian/Pacific Islanders (4.3% per year) from 2006 to 2015 and for Blacks (11.8% per year) from 2009 to 2015. By U.S. region, the rates increased significantly in the Midwest (4.4% per year) from 2006 to 2015 and in the Northeast (11.0% per year) from 2009 to 2015. Trends varied by age group, intent for drug poisoning, drug category (i.e., opioids, pharmaceutical drugs excluding opioids, illicit drugs excluding opioids, and unspecified drugs), urbanization level, and state. The estimated costs of drug poisoning deaths among adolescents and young adults totaled approximately $35 billion in 2015. CONCLUSIONS: Trends in drug poisoning deaths and estimated costs inform state-specific prevention and intervention efforts.

Credentialing of Pediatric Pharmacists in Collaborative Drug Therapy Management.

Pediatric clinical pharmacists have evolved over the last 2 decades and have proven to be a key player in the multidisciplinary team. The American College of Clinical Pharmacy recently published (in 2015) a position statement on collaborative drug therapy management and comprehensive medication management. The Council on Credentialing in Pharmacy published a 2014 article on credentialing and privileging of pharmacists. Neither offered requirements for pediatric pharmacists in training and credentialing. This position statement provides a detailed outline defining adequate training for a pediatric clinical pharmacist in order to participate in collaborative drug therapy management for pediatric patients.

Opioid Use in Children.

Limited guidance on opioid use exists in the pediatric population, causing medication safety concerns for pain management in children and adolescents. Opioid misuse and use disorder continue to greatly affect adolescents and young adults in the United States, furthering the apprehension of their use. Pediatric Pharmacy Advocacy Group (PPAG) recommends pharmacists contribute their knowledge to pain management in children, including the discussion of appropriate use of non-opioid alternatives for pain and when to recommend coprescribing of naloxone. PPAG also supports the review of electronic prescription drug-monitoring programs prior to opioid prescribing and dispensing by both prescribers and pharmacists. Education by pharmacists of children and their families regarding proper administration, storage, and disposal, as well as the awareness of opioid misuse and use disorder among adolescents and young adults, is key to prevention. If opioid use disorder is diagnosed, PPAG encourages improved access among adolescents to evidence-based medications including methadone, buprenorphine, and naltrexone. Furthermore, pharmacists should assist in screening and referral to evidence-based treatment.

Accuracy and Precision of an Effect Size and Its Variance From a Multilevel Model for Cluster Randomized Trials: A Simulation Study.

This article investigates an effect size (MLM ES) and its variance for cluster randomized trials based on parameter estimates from multilevel modeling analysis. Accuracy and precision of MLM ES were evaluated using Monte Carlo simulation methods and compared with the performance of an effect size, computed from summary statistics, proposed by Hedges (2007; Hedges' dB ). Simulation results indicated that MLM ES had acceptable accuracy in all conditions, also demonstrating efficiency and consistency. With small sample sizes, MLM ES did not suffer from the same negative bias as Hedges' dB due to overestimation of between-cluster variance. With large sample sizes, MLM ES and Hedges' dB were comparable for accuracy and efficiency. Both MLM ES and Hedges' dB showed considerable bias in some conditions when cluster sizes were unequal. An illustrative example using real data was provided.

Mutation analyses of Uroplakin II in children with renal tract malformations.

BACKGROUND: Uroplakin (UP) proteins cover urothelial apical surfaces. Mice lacking UPIIIa have elevated urothelial permeability and congenital renal tract anomalies, and UPIIIa mutations have been reported in children with kidney and ureter malformations. Mice with null mutation of another UP family member, UPII, are often born with congenital hydronephrosis. We hypothesized that UPII mutations may be present in humans with renal tract malformations. METHODS: Mutations were sought, using direct sequencing of the five UPII exons, in 42 children with diverse renal tract anomalies. RESULTS: No UPII abnormalities were detected in 41 patients, whereas one index case had a heterozygous frameshift change which, if expressed, would generate a truncated protein. This Caucasian child presented with vesicoureteric reflux (VUR), bilateral nephropathy and renal failure. The genetic change was also found in the index case's mother who had normal renal ultrasonography, but it was absent in 150 healthy Caucasian control individuals (96 assessed by direct sequencing and another 54 assessed by restriction digests). UPII was immunolocalized in urothelium of the normal human embryonic renal pelvis in a pattern similar to UPIIIa. CONCLUSION: This study offers no definitive support for UPII mutations causing human renal tract malformations. In rare patients, UPII variants might be implicated in pathogenesis when acting in conjunction with other yet-to-be-defined, genetic or environmental modifying factors.

De novo Uroplakin IIIa heterozygous mutations cause human renal adysplasia leading to severe kidney failure.

Human renal adysplasia usually occurs sporadically, and bilateral disease is the most common cause of childhood end-stage renal failure, a condition that is lethal without intervention using dialysis or transplantation. De novo heterozygous mutations in Uroplakin IIIa (UPIIIa) are reported in four of 17 children with kidney failure caused by renal adysplasia in the absence of an overt urinary tract obstruction. One girl and one boy in unrelated kindreds had a missense mutation at a CpG dinucleotide in the cytoplasmic domain of UPIIIa (Pro273Leu), both of whom had severe vesicoureteric reflux, and the girl had persistent cloaca; two other patients had de novo mutations in the 3' UTR (963 T-->G; 1003 T-->C), and they had renal adysplasia in the absence of any other anomaly. The mutations were absent in all sets of parents and in siblings, none of whom had radiologic evidence of renal adysplasia, and mutations were absent in two panels of 192 ethnically matched control chromosomes. UPIIIa was expressed in nascent urothelia in ureter and renal pelvis of human embryos, and it is suggested that perturbed urothelial differentiation may generate human kidney malformations, perhaps by altering differentiation of adjacent smooth muscle cells such that the metanephros is exposed to a functional obstruction of urine flow. With advances in renal replacement therapy, children with renal failure, who would otherwise have died, are surviving to adulthood. Therefore, although the mechanisms of action of the UPIIIa mutations have yet to be determined, these findings have important implications regarding genetic counseling of affected individuals who reach reproductive age.