The Future of Antibody Drug Conjugation by Comparing Various Methods of Site-Specific Conjugation.

The field of oncology is continuously seeking to find effective treatment therapies with limited side effects. Antibody-drug conjugates (ADCs) are a promising class of cancer therapies that have been shown to be effective with limited side effects. Although promising, these therapies experience shortcomings, such as the stability and reproducibility of current conjugation methods. Historically, ADCs have been produced by stochastic conjugation methods; however, new methods of site-specific conjugation have evolved to mitigate current ADC shortcomings. In this article, we highlight the success of ADCs as well as some of their challenges. We also highlight the shortcomings of stochastic conjugation and explore the various site-specific conjugation methods and their advantages over stochastic conjugation.

The Laro Kwo Project: A train the trainer model combined with mobile health technology for community health workers in Northern Uganda.

Community Health Workers (CHWs) in low and middle income countries (LMICs) provide invaluable health resources to their community members. Best practices for developing and sustaining CHW training programs in LMICs have yet to be defined using rigorous standards and measures of effectiveness. With the expansion of digital health to LMICs, few studies have evaluated the role of participatory methodologies combined with the use of mobile health (mHealth) for CHW training program development. We completed a three-year prospective observational study aligned with the development of a community-based participatory CHW training program in Northern Uganda. Twenty-five CHWs were initially trained using a community participatory training methodology combined with mHealth and a train-the-trainer model. Medical skill competency exams were evaluated after the initial training and annually thereafter to assess retention with use of mHealth. After three years, CHWs who advanced to trainer status redeveloped all program materials using a mHealth application and trained a new cohort of 25 CHWs. Implementation of this methodology coupled with longitudinal mHealth training demonstrated an improvement in medical skills over three years among the original cohort of CHWs. Further, we found that the train-the-trainer model with mHealth was highly effective, as the new cohort of 25 CHWs trained by the original CHWs exhibited higher scores when tested on medical skill competencies. The combination of mHealth and participatory methodologies can facilitate the sustainability of CHW training programs in LMIC. Further investigations should focus on comparing specific mHealth modalities for training and clinical outcomes using similar combined methodologies.

Parent Priorities in End-of-Life Care for Children With Cancer.

Importance: Robust quality measures to benchmark end-of-life care for children with cancer do not currently exist; 28 candidate patient-centered quality measures were previously developed. Objective: To prioritize quality measures among parents who lost a child to cancer. Design, Setting, and Participants: This survey study was conducted using an electronic, cross-sectional discrete choice experiment (DCE) with maximum difference scaling from January to June 2021 in the US. In each of 21 questions in the DCE, participants were presented with a set of 4 quality measures and were asked to select the most and least important measures within each set. All 28 quality measures were presented an equal number of times in different permutations. In the volunteer sample, 69 eligible bereaved parents enrolled in the study; 61 parents completed the DCE (participation rate, 88.4%). Main Outcomes and Measures: Using choices participants made, a hierarchical bayesian multinomial logistic regression was fit to derive mean importance scores with 95% credible intervals (95% Crs) for each quality measure, representing the overall probability of a quality measure being selected as most important. Importance scores were rescaled proportionally from 0 to 100, with the sum of scores for all quality measures adding up to 100. This enabled interpretation of scores as the relative importance of quality measures. Results: Participants included 61 bereaved parents (median [range] age, 48 [24-74] years; 55 individuals self-identified as women [90.2%]; 1 American Indian or Alaska Native [1.6%], 1 Asian [1.6%], 2 Black or African American [3.3%], 1 Native Hawaiian or Pacific Islander, and 58 White [91.8%]; 58 not Hispanic or Latinx [95.1%]). Highest-priority quality measures by mean importance score included having a child's symptoms treated well (9.25 [95% Cr, 9.06-9.45]), feeling that a child's needs were heard by the health care team (8.39 [95% Cr, 8.05-8.73]), and having a goal-concordant end-of-life experience (7.45 [95% Cr, 6.84-8.05]). Lowest-priority quality measures included avoiding chemotherapy (0.33 [95% Cr, 0.21-0.45]), provision of psychosocial support for parents (1.01 [95% Cr, 0.57-1.45]), and avoiding the intensive care unit (1.09 [95% Cr, 0.74-1.43]). Rank-ordering measures by mean importance revealed that symptom management was 9 times more important to parents than psychosocial support for themselves. Conclusions and Relevance: This study found that bereaved parents prioritized end-of-life quality measures focused on symptom management and goal-concordant care while characterizing quality measures assessing their own psychosocial support and their child's hospital resource use as substantially less important. These findings suggest that future research should explore innovative strategies to measure care attributes that matter most to families of children with advanced cancer.

Impact of school-supervised ultra-long-acting basal insulin injections on ketosis in youth with T1D and elevated haemoglobin A1c: A pilot study.

BACKGROUND: In youth with type 1 diabetes (T1D), high haemoglobin A1c (HbA1c) levels are associated with an increased risk for diabetic ketoacidosis (DKA). AIMS: This study examined whether daily school-supervised basal insulin injections were feasible and if they reduced the risk of morning ketosis in children and adolescents with high HbA1c levels. We hypothesized that supervised glargine and degludec would reduce the risk of ketosis and that the prolonged action of degludec would protect from ketosis after consecutive days of unsupervised injections. MATERIALS & METHODS: After a 2-4-week run-in, youth (10-18 years, HbA1c ≥ 8.5%) managing T1D with injections were randomized to school-supervised administration of degludec or glargine for 4 months. School nurses observed daily blood ß-hydroxybutyrate (BHB) and glucose checks. During COVID closures, the research team supervised procedures remotely. RESULTS: Data from 28 youth (age 14.3 ± 2.3 years, HbA1c 11.4 ± 1.9%, 64% F) were analysed. School-supervised injections of both basal insulins for 1-4 days progressively lowered the percent of participants with elevated BHB. The percent of participants with elevated BHB (≥0.6 mmol/L) after 2 days of unsupervised basal insulin doses at home was greater in the glargine than degludec group but had a high p-value (17.2% vs. 9.0%, p = 0.3). HbA1c was unchanged in both groups. DISCUSSION: In youth with T1D at high risk for DKA, daily supervised long-acting insulin administration decreased the probability of elevated ketone levels on subsequent school days, regardless of basal insulin type. A larger sample size may have demonstrated that the longer action profile of degludec would offer additional protection from ketosis during days of not attending school. CONCLUSION: Engaging school-based caregivers in management of youth with T1D on injected insulin may decrease clinically significant ketosis and minimize acute complications of diabetes.

Validated anxiety assessments among pediatric patients with peanut allergy on oral immunotherapy.

BACKGROUND: Although efficacy, safety, and quality of life measures associated with peanut oral immunotherapy (OIT) have been studied, the relationship between peanut OIT and clinical anxiety has not yet been evaluated. The latter is important to help providers and families have an improved shared medical decision discussion around the benefits of initiating OIT. OBJECTIVE: To investigate the relationship between undergoing OIT and anxiety in patients with peanut allergy. METHODS: In this prospective cross-sectional cohort study, using validated and age-appropriate anxiety scales administered with electronic survey questionnaires, we used generalized linear regressions to compare anxiety between patients undergoing OIT and similar patients with peanut allergy but not on OIT (controls). RESULTS: In the younger cohort (<7 years, n = 80), there was generally a low prevalence of diagnosable anxiety across patients on OIT and controls. In the older cohort (>7 years, n = 125), there was a higher prevalence of anxiety but no clinically meaningful difference between anxiety scores of patients on OIT and controls. In the older cohort, patients with asthma were more likely to have higher mean anxiety scores (P = .04), as were female patients compared with male patients (P = .004). A subanalysis of separation anxiety scores in the older cohort revealed that younger age (7-12 years vs >12 years, P < .001), non-White race (P = .04), and eczema (P = .02) were found to be meaningful predictors of higher scores. A subanalysis of social anxiety on the older cohort pointed toward non-White race as a meaningful predictor of higher scores (P < .02). CONCLUSION: The clinical implications of these findings suggest that allergists should particularly consider screening children with food allergy for anxiety and anxiety subtypes among patients who are non-White, female, or have asthma.

Insurance and Health Care Outcomes in Regions Where Undocumented Children Are Medicaid-Eligible.

OBJECTIVES: Expansion of insurance eligibility is associated with positive health outcomes. We compared uninsurance and health care utilization for (1) all children, and (2) children in immigrant families (CIF) and non-CIF who resided inside and outside of the seven US states/territories offering public health insurance to children regardless of documentation status ("extended-eligibility states/territories"). METHODS: Using the cross-sectional, nationally representative National Survey of Children's Health-2019, we used survey-weighted, multivariable Poisson regression to assess the association of residence in nonextended- versus extended-eligibility states/territories with uninsurance and with health care utilization measures for (1) all children, and (2) CIF versus non-CIF, adjusting for demographic covariates. RESULTS: Of the 29 433 respondents, the 4035 (weighted 27.2%) children in extended- versus nonextended-eligibility states/territories were more likely to be CIF (27.4% vs 20.5%, P < .001), 12 to 17 years old (37.2% vs 33.2%, P = .048), non-White (60.1% vs 45.9%, P < .001), and have a non-English primary language (20.6% vs 11.1%, P < .001).The relative risk of uninsurance for children in nonextended- versus extended-eligibility states/territories was 2.0 (95% confidence interval 1.4-3.0), after adjusting for covariates. Fewer children in extended- versus nonextended-eligibility states/territories were uninsured (adjusted prevalence 3.7% vs 7.5%, P < .001), had forgone medical (2.2% vs 3.1%, P = .07) or dental care (17.1% vs 20.5%, P = .02), and had no preventive visit (14.3% vs 17.0%, P = .04). More CIF than non-CIF were uninsured, regardless of residence in nonextended- versus extended-eligibility states/territories: CIF 11.2% vs 5.7%, P < .001; non-CIF 6.1% vs 3.1% P < .001. CONCLUSIONS: Residence in nonextended-eligibility states/territories, compared with in extended-eligibility states/territories, was associated with higher uninsurance and less preventive health care utilization.

The Evolving Needs of Children Hospitalized for Eating Disorders During the COVID-19 Pandemic.

BACKGROUND AND OBJECTIVES: Throughout the COVID-19 pandemic, there has been an increase in hospital admissions for adolescents with eating disorders (EDs). However, there is a paucity of information on how this increase has affected hospitalization courses and disposition planning. We sought to describe the changes in hospitalizations for EDs at our institution during the pandemic. METHODS: We reviewed charts of patients admitted to our academic medical center for nutritional restoration from January 1, 2017, to June 30, 2021. We report differences in patient characteristics and hospitalization courses using descriptive statistics and Poisson regression. RESULTS: We reviewed charts for 85 patients for 108 hospital admissions. Admissions increased from 1.4 per month prepandemic to 3.6 per month during the pandemic (P < .001). Most patients were female (91%), White (79%), had private insurance, (80%) and had restrictive eating behaviors (97%). During the pandemic, we found (1) an increase in the average length of stay (12.6 days vs. 18.0 days) with younger age associated with longer length of stay (P < .001); (2) more patients requiring psychotropic medication management (11% vs 31%, P = .01); and (3) fewer patients discharged from the hospital with outpatient therapy (43% vs 24%, P = .03). CONCLUSIONS: In addition to an increase in hospital admissions for ED management during the pandemic, our study highlights the evolving needs of ED patients during their hospitalizations. The implications of longer admissions with higher acuity at discharge represent areas where appropriate adaptations in inpatient management and disposition planning may improve the quality of care for ED patients.

Oncostatin M Receptor as a Therapeutic Target for Radioimmune Therapy in Synovial Sarcoma.

Synovial sarcoma (SS) is a pediatric muscle cancer that primarily affects adolescents and young adults and has few treatment options. Complicating the treatment of synovial sarcoma is the low mutational burden of SS. Inflammatory pathways have been identified as being upregulated in some SS, leading to the discovery of upregulated oncostatin M receptor (OSMR). It was found that OSMR is upregulated in SS by RNAseq analysis and quantitative PCR, highlighting its potential in the treatment of SS. Also, OSMR is upregulated in mouse models for synovial sarcoma as demonstrated by western blot and immunohistochemistry, and the protein is present in both primary and metastatic sites of disease. Using a radioimmune therapy drug model, targeted therapy was synthesized for use in OSMR expressing SS and it was demonstrated that this drug is stable, while capable of efficient OSMR binding and isotope capture. Finally, this antibody conjugate exhibited ideal pharmacokinetics and targeted sites of disease in our mouse model and was taken up in both primary and metastatic diseased tissue. This suggests OSMR as an ideal target for therapy and this radioimmune therapy provides a novel treatment option for a disease with few therapy choices.

Mechanistic Insights Into the Heterogeneity of Glucose Response Classes in Youths With Obesity: A Latent Class Trajectory Approach.

OBJECTIVE: In a large, multiethnic cohort of youths with obesity, we analyzed pathophysiological and genetic mechanisms underlying variations in plasma glucose responses to a 180 min oral glucose tolerance test (OGTT). RESEARCH DESIGN AND METHODS: Latent class trajectory analysis was used to identify various glucose response profiles to a nine-point OGTT in 2,378 participants in the Yale Pathogenesis of Youth-Onset T2D study, of whom 1,190 had available TCF7L2 genotyping and 358 had multiple OGTTs over a 5 year follow-up. Insulin sensitivity, clearance, and ß-cell function were estimated by glucose, insulin, and C-peptide modeling. RESULTS: Four latent classes (1 to 4) were identified based on increasing areas under the curve for glucose. Participants in class 3 and 4 had the worst metabolic and genetic risk profiles, featuring impaired insulin sensitivity, clearance, and ß-cell function. Model-predicted probability to be classified as class 1 and 4 increased across ages, while insulin sensitivity and clearance showed transient reductions and ß-cell function progressively declined. Insulin sensitivity was the strongest determinant of class assignment at enrollment and of the longitudinal change from class 1 and 2 to higher classes. Transitions between classes 3 and 4 were explained only by changes in ß-cell glucose sensitivity. CONCLUSIONS: We identified four glucose response classes in youths with obesity with different genetic risk profiles and progressive impairment in insulin kinetics and action. Insulin sensitivity was the main determinant in the transition between lower and higher glucose classes across ages. In contrast, transitions between the two worst glucose classes were driven only by ß-cell glucose sensitivity.

Addressing Mistreatment of Providers by Patients and Family Members as a Patient Safety Event.

OBJECTIVE: Mistreatment of health care providers (HCPs) is associated with burnout and lower-quality patient care, but mistreatment by patients and family members is underreported. We hypothesized that an organizational strategy that includes training, safety incident reporting, and a response protocol would increase HCP knowledge, self-efficacy, and reporting of mistreatment. METHODS: In this single-center, serial, cross-sectional study, we sent an anonymous survey to HCPs before and after the intervention at a 213-bed tertiary care university children's hospital between 2018 and 2019. We used multivariable logistic regression to examine the effect of training on the outcomes of interest and whether this association was moderated by staff role. RESULTS: We received 309 baseline surveys from 72 faculty, 191 nurses, and 46 residents, representing 39.1%, 27.1%, and 59.7%, respectively, of eligible HCPs. Verbal threats from patients or family members were reported by 214 (69.5%) HCPs. Offensive behavior was most commonly based on provider age (85, 28.5%), gender (85, 28.5%), ethnicity or race (55, 18.5%), and appearance (43, 14.6%) but varied by role. HCPs who received training had a higher odds of reporting knowledge, self-efficacy, and experiencing offensive behavior. Incident reporting of mistreatment increased threefold after the intervention. CONCLUSIONS: We report an effective organizational approach to address mistreatment of HCPs by patients and family members. Our approach capitalizes on existing patient safety culture and systems that can be adopted by other institutions to address all forms of mistreatment, including those committed by other HCPs.

Dexmedetomidine for Sedation During Pediatric Noninvasive Ventilation.

BACKGROUND: Noninvasive ventilation (NIV) facilitates management of acute respiratory failure without intubation. Many pediatric patients cannot tolerate the discomfort associated with noninvasive support and require sedation with agents that may decrease respiratory drive. Dexmedetomidine does not decrease respiratory drive, and we hypothesized that its use would increase tolerance of noninvasive respiratory support without increasing risk for intubation. METHODS: A retrospective chart review was performed of all subjects at least 3 months of age with acute respiratory failure requiring NIV who were admitted to the pediatric ICU at a children's hospital for a 3-y period from 2015-2018. Subjects were stratified to those receiving continuous dexmedetomidine versus those not receiving sedation. Medical history was reviewed for developmental delay (DD) or intellectual disability (ID) as well as basic demographic information. To control the association between these variables with both dexmedetomidine use and intubation, augmented inverse probability weighting was utilized to establish equivalent baselines between the dexmedetomidine and no-sedation groups. Primary outcome was intubation rate within 6 h of initiation of dexmedetomidine infusion or NIV. RESULTS: Based on the strong association between age and dexmedetomidine use, a statistical model including subjects > age 5 was not able to be generated, and these subjects were excluded from final analysis. One-hundred eight subjects were included in the final statistical analysis, with 60 receiving dexmedetomidine and 48 receiving no sedation. Dexmedetomidine was effective at reducing agitation, with no difference noted in intubation rate at 6 h between subjects receiving dexmedetomidine versus no sedation (13.1 vs 12.4%). CONCLUSIONS: Dexmedetomidine may allow tolerance of NIV in acute respiratory failure without increasing risk for intubation, especially in preschool age patients and those with DD or ID. A larger study involving multiple centers would help support our conclusions.

An examination of fatal child poisonings in the United States using the National Violent Death Reporting System (NVDRS), 2012-2017.

BACKGROUND: Fatal drug overdoses are predominantly attributed to opioids. Women of childbearing age are among those at greatest risk, underscoring the need to understand the overlapping risk of fatal poisoning in children. METHODS: A retrospective analysis of fatal poisonings among decedents aged 0-9 years captured in the National Violent Death Reporting System (NVDRS) from 2012 to 2017 was employed. Poisonings were identified using International Classification of Diseases, Tenth Revision (ICD-10) codes for poisonings (T36-T50, Y10-Y19), toxic effects of substances (T51-T65), and assault (X85-X90). The frequency and types of drugs involved in poisonings were derived from toxicological analysis. Logistic regression was used to model the odds of fatal poisoning by decedent and perpetrator characteristics. Qualitative content analysis was used to contextualize the patterns of fatal poisonings. FINDINGS: 1850 violent deaths were identified; 7% (n = 122) were poisoning-related, and 50% of these were attributed to opioids. Next, benzodiazepines (8%), amphetamines (7%), and antidepressants (5%) were most prevalent. Among poisoning-related deaths, 25% involved homicide-suicide. No differences in deaths were observed according to child race/ethnicity, and the risk of fatal poisoning decreased 6% with each year of child age. Following qualitative analysis, three unique categories of fatal poisoning emerged: "intentional administration without documented benign intent", "intentional administration with benign intent", and "unclear administration". CONCLUSION: The high proportion of fatal poisonings in children attributed to opioids in this study suggests a need for universal dissemination and training of naloxone in households comprised of children living with parents experiencing, or in recovery for substance misuse. Findings also indicate a needed emphasis on safe storage practices and education to parents about the risk of prescription drug toxicity in children.

CIDEA expression in SAT from adolescent girls with obesity and unfavorable patterns of abdominal fat distribution.

OBJECTIVE: This study investigated whether variations in cell death-inducing DNA fragmentation factor alpha subunit-like effector A (CIDEA) mRNA expression and protein levels are modulated by the pattern of abdominal fat distribution in adolescent girls with obesity. METHODS: This study recruited 35 adolescent girls with obesity and characterized their abdominal fat distribution by magnetic resonance imaging. Participants had only a periumbilical/abdominal (n = 14) or a paired abdominal and gluteal subcutaneous adipose tissue (SAT) biopsy (n = 21). CIDEA expression was determined by reverse transcription-polymerase chain reaction, CIDEA protein level by Western blot, and the turnover of adipose lipids and adipocytes by 2 H2 O labeling. In six girls, a second abdominal SAT biopsy was performed (after ~34.2 months) to explore the weight gain effect on CIDEA expression in abdominal SAT. RESULTS: CIDEA expression decreased in abdominal SAT from participants with high visceral adipose tissue (VAT)/(VAT+SAT); CIDEA inversely correlated with number of small adipocytes, with the increase in preadipocyte proliferation, and with adipogenesis. A strong inverse correlation was found between CIDEA protein level with the newly synthetized glycerol (r = -0.839, p = 0.0047). Following weight gain, an increase in adipocytes' cell diameter with a decrease in CIDEA expression and RNA-sequencing transcriptomic profile typical of adipocyte dysfunction was observed. CONCLUSIONS: Reduced expression of CIDEA in girls with high VAT/(VAT+SAT) is associated with adipocyte hypertrophy and insulin resistance.

A state-wide analysis of pediatric scald burns by tap water, 2016-2018.

INTRODUCTION: Unsafe tap water temperatures (>120 °F) are a risk factor for pediatric burns, which may disproportionally impact low-income, urban communities. We sought to estimate the incidence and demographic characteristics of tap water burns and their association with housing characteristics. METHODS: We performed a secondary data analysis to summarize emergency department discharge records from 2016 to 2018 involving children <18 years with an ICD-10-CM code for tap water burn (X11), and town-level housing data from the American Community Survey. Unpaired student's t-test and spearman's correlation analysis were performed for comparative analyses. RESULTS: A total of 146 tap water burn visits were identified, representing an incidence of 2 per 10,000 ED visits. The majority of cases were male, non-Hispanic White, of public insurance type, and from an urban CT town. The median age was 3 years, with 58% of cases <5 years. Towns with at least one tap water burn had a significantly higher average percentage of multi-family unit and renter housing as compared to towns with no tap water burns (p < 0.0001). CONCLUSIONS: Our results identified a significant number of tap water burns in children. Primary prevention efforts targeting education or regulation of water temperatures may work to reduce burns in underserved areas.