Development of a Strategic Initiative at MD Anderson Cancer Center to Improve Outcomes in Immune-Related Adverse Events.

Immune checkpoint inhibitors (ICIs) have transformed the treatment paradigm for many cancer types. The clinical use of ICIs is increasing rapidly, including in combinations associated with increased risk of toxicities, termed "immune-related adverse events" (irAEs). Therefore, MD Anderson Cancer Center (MDACC) in Houston, Texas has proactively responded by developing a priority endeavor known as the Immuno-Oncology Toxicity (IOTOX) initiative. This strategic initiative aims to facilitate the seamless integration of key domains: (1) standardized clinical practice and innovative decision toolsets; (2) patient and provider education; and (3) a comprehensive clinical and translational research platform. The ultimate goal of this initiative is to develop and disseminate clinical best practices and biologic insights into irAEs to improve outcomes of patients with irAEs at MDACC and in the wider oncology community.

Cutaneous toxicities of mitogen-activated protein kinase inhibitors in children and young adults with neurofibromatosis-1.

PURPOSE: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder which commonly causes neoplasms leading to disfigurement or dysfunction. Mitogen-activated protein kinase inhibitors (MEKi) are generally well-tolerated treatments which target neural tumor progression in patients with NF1. However, cutaneous adverse events (CAEs) are common and may hinder patients' abilities to remain on treatment, particularly in children. We aim to characterize CAEs secondary to MEKi treatment in pediatric and young adult patients with NF1. METHODS: We reviewed institutional medical records of patients under 30 years with a diagnosis of "NF1," "NF2," or "other neurofibromatoses" on MEKi therapy between January 1, 2019 and June 1, 2022. We recorded the time-to-onset, type, and distribution of CAEs, non-cutaneous adverse events (AEs), AE management, and tumor response. RESULTS: Our cohort consisted of 40 patients with NF1 (median age, 14 years). Tumor types included low-grade gliomas (51%) and plexiform neurofibromas (38%). MEKi used included selumetinib (69%), trametinib (25%), and mirdametinib (6%). A total of 74 CAEs occurred, with 28 cases of acneiform rash (38%). Other common CAEs were paronychia, seborrheic dermatitis, eczema, xerosis, and oral mucositis. The most common treatments included oral antibiotics and topical corticosteroids. Most patients had clinical (stable or improved) tumor response (71%) while 29% had tumor progression while on a MEKi. There was no significant association between CAE presence and tumor response (p = 0.39). CONCLUSIONS: Improvement in characterization of MEKi toxicities and their management is important to develop treatment guidelines for pediatric and young adult patients with NF1 on MEKi therapy.

Paris classification of colonic polyps using CT colonography: prospective cohort study of interobserver variation.

BACKGROUND: The Paris classification categorises colorectal polyp morphology. Interobserver agreement for Paris classification has been assessed at optical colonoscopy (OC) but not CT colonography (CTC). We aimed to determine the following: (1) interobserver agreement for the Paris classification using CTC between radiologists; (2) if radiologist experience influenced classification, gross polyp morphology, or polyp size; and (3) the extent to which radiologist classifications agreed with (a) colonoscopy and (b) a combined reference standard. METHODS: Following ethical approval for this non-randomised prospective cohort study, seven radiologists from three hospitals classified 52 colonic polyps using the Paris system. We calculated interobserver agreement using Fleiss kappa and mean pairwise agreement (MPA). Absolute agreement was calculated between radiologists; between CTC and OC; and between CTC and a combined reference standard using all available imaging, colonoscopic, and histopathological data. RESULTS: Overall interobserver agreement between the seven readers was fair (Fleiss kappa 0.33; 95% CI 0.30-0.37; MPA 49.7%). Readers with < 1500 CTC experience had higher interobserver agreement (0.42 (95% CI 0.35-0.48) vs. 0.33 (95% CI 0.25-0.42)) and MPA (69.2% vs 50.6%) than readers with ≥ 1500 experience. There was substantial overall agreement for flat vs protuberant polyps (0.62 (95% CI 0.56-0.68)) with a MPA of 87.9%. Agreement between CTC and OC classifications was only 44%, and CTC agreement with the combined reference standard was 56%. CONCLUSION: Radiologist agreement when using the Paris classification at CT colonography is low, and radiologist classification agrees poorly with colonoscopy. Using the full Paris classification in routine CTC reporting is of questionable value. CLINICAL RELEVANCE STATEMENT: Interobserver agreement for radiologists using the Paris classification to categorise colorectal polyp morphology is only fair; routine use of the full Paris classification at CT colonography is questionable. KEY POINTS: • Overall interobserver agreement for the Paris classification at CT colonography (CTC) was only fair, and lower than for colonoscopy. • Agreement was higher for radiologists with < 1500 CTC experience and for larger polyps. There was substantial agreement when classifying polyps as protuberant vs flat. • Agreement between CTC and colonoscopic polyp classification was low (44%).

Outcome risk model development for heterogeneity of treatment effect analyses: a comparison of non-parametric machine learning methods and semi-parametric statistical methods.

BACKGROUND: In randomized clinical trials, treatment effects may vary, and this possibility is referred to as heterogeneity of treatment effect (HTE). One way to quantify HTE is to partition participants into subgroups based on individual's risk of experiencing an outcome, then measuring treatment effect by subgroup. Given the limited availability of externally validated outcome risk prediction models, internal models (created using the same dataset in which heterogeneity of treatment analyses also will be performed) are commonly developed for subgroup identification. We aim to compare different methods for generating internally developed outcome risk prediction models for subject partitioning in HTE analysis. METHODS: Three approaches were selected for generating subgroups for the 2,441 participants from the United States enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) randomized controlled trial. An extant proportional hazards-based outcomes predictive risk model developed on the overall ASPREE cohort of 19,114 participants was identified and was used to partition United States' participants by risk of experiencing a composite outcome of death, dementia, or persistent physical disability. Next, two supervised non-parametric machine learning outcome classifiers, decision trees and random forests, were used to develop multivariable risk prediction models and partition participants into subgroups with varied risks of experiencing the composite outcome. Then, we assessed how the partitioning from the proportional hazard model compared to those generated by the machine learning models in an HTE analysis of the 5-year absolute risk reduction (ARR) and hazard ratio for aspirin vs. placebo in each subgroup. Cochran's Q test was used to detect if ARR varied significantly by subgroup. RESULTS: The proportional hazard model was used to generate 5 subgroups using the quintiles of the estimated risk scores; the decision tree model was used to generate 6 subgroups (6 automatically determined tree leaves); and the random forest model was used to generate 5 subgroups using the quintiles of the prediction probability as risk scores. Using the semi-parametric proportional hazards model, the ARR at 5 years was 15.1% (95% CI 4.0-26.3%) for participants with the highest 20% of predicted risk. Using the random forest model, the ARR at 5 years was 13.7% (95% CI 3.1-24.4%) for participants with the highest 20% of predicted risk. The highest outcome risk group in the decision tree model also exhibited a risk reduction, but the confidence interval was wider (5-year ARR = 17.0%, 95% CI= -5.4-39.4%). Cochran's Q test indicated ARR varied significantly only by subgroups created using the proportional hazards model. The hazard ratio for aspirin vs. placebo therapy did not significantly vary by subgroup in any of the models. The highest risk groups for the proportional hazards model and random forest model contained 230 participants each, while the highest risk group in the decision tree model contained 41 participants. CONCLUSIONS: The choice of technique for internally developed models for outcome risk subgroups influences HTE analyses. The rationale for the use of a particular subgroup determination model in HTE analyses needs to be explicitly defined based on desired levels of explainability (with features importance), uncertainty of prediction, chances of overfitting, and assumptions regarding the underlying data structure. Replication of these analyses using data from other mid-size clinical trials may help to establish guidance for selecting an outcomes risk prediction modelling technique for HTE analyses.

Forensic neuropsychological assessment.

With its firm establishment as a neuropsychology subspecialty, forensic neuropsychological assessment is integral to many criminal and civil forensic evaluations. In addition to evaluating cognitive deficits, forensic neuropsychologists can provide reliable information regarding symptom magnification, malingering, and other neurocognitive and psychological issues that may impact the outcome of a particular legal case. This article is an overview and introduction to neuropsychological assessment in the forensic mental health context. Major issues impacting the current practice of forensic neuropsychology are summarized, and several examples from case law are highlighted.

Gene expression profiling and multiplex immunofluorescence analysis of bullous pemphigoid immune-related adverse event reveal upregulation of toll-like receptor 4/complement-induced innate immune response and increased density of TH 1 T-cells.

BACKGROUND: Immune checkpoint inhibitor (ICI)-based cancer therapies cause a variety of cutaneous immune-related adverse events (irAEs) including immunobullous skin eruptions like bullous pemphigoid (BP). However, little is known about the underlying immunopathogenic drivers of these reactions, and understanding the unique gene expression profile and immune composition of BP-irAE remains a critical knowledge gap in the field of oncodermatology/oncodermatopathology. METHODS: BP-irAE (n = 8) and de novo BP control (n = 8) biopsy samples were subjected to gene expression profiling using the NanoString® Technologies nCounter PanCancer Immune Profiling Panel. Multiplex immunofluorescence (mIF) studies using markers for T-cells (CD3 and CD8), T helper 1 (TH 1) cells (Tbet), TH 2 cells (Gata3), TH 17 cells (RORγT), and regulatory T-cells (Tregs; FoxP3) were further evaluated using InForm® image analysis. RESULTS: Compared with de novo BP controls, BP-irAE samples exhibited upregulation of 30 mRNA transcripts (p < 0.025), including toll-like receptor 4 (TLR4) and genes associated with complement activation, and downregulation of 89 mRNA transcripts (p < 0.025), including genes associated with TH 2, TH 17, and B-cell immune response. BP-irAE demonstrated a greater density of Tbet+ (TH 1) cells in the dermis (p = 0.004) and fewer Tregs in the blister floor (p = 0.028) when compared with that of de novo control BP samples. CONCLUSIONS: BP-irAE exhibited activation of the TLR4/complement-driven classical innate immune response pathway, with dermal TH 1 immune cell polarization and decreased Tregs in the blister floor. TLR/complement signaling may underlie the immunopathogenesis of BP-irAE.

Mitigating childhood food insecurity during COVID-19: a qualitative study of how school districts in California's San Joaquin Valley responded to growing needs.

OBJECTIVES: To explore best practices and challenges in providing school meals during COVID-19 in a low-income, predominantly Latino, urban-rural region. DESIGN: Semi-structured interviews with school district stakeholders and focus groups with parents were conducted to explore school meal provision during COVID-19 from June to August 2020. Data were coded and themes were identified to guide analysis. Community organisations were involved in all aspects of study design, recruitment, data collection and analysis. SETTING: Six school districts in California's San Joaquin Valley. PARTICIPANTS: School district stakeholders (n 11) included food service directors, school superintendents and community partners (e.g. funders, food cooperative). Focus groups (n 6) were comprised of parents (n 29) of children participating in school meal programmes. RESULTS: COVID-19-related challenges for districts included developing safe meal distribution systems, boosting low participation, covering COVID-19-related costs and staying informed of policy changes. Barriers for families included transportation difficulties, safety concerns and a lack of fresh foods. Innovative strategies to address obstacles included pandemic-electronic benefits transfer (EBT), bus-stop delivery, community pick-up locations, batched meals and leveraging partner resources. CONCLUSIONS: A focus on fresher, more appealing meals and greater communication between school officials and parents could boost participation. Districts that leveraged external partnerships were better equipped to provide meals during pandemic conditions. In addition, policies increasing access to fresh foods and capitalising on United States Department of Agriculture waivers could boost school meal participation. Finally, partnering with community organisations and acting upon parent feedback could improve school meal systems, and in combination with pandemic-EBT, address childhood food insecurity.

Drink Tap: A Multisector Program to Promote Water Access and Intake in San Francisco Parks.

Taxes on sugar-sweetened beverages (SSBs), or drinks with added sugars, show promise in decreasing purchases and consumption of SSBs. Some have called for coupling such taxes with improvements in access to safe drinking water as a strategy for reducing inequities in SSB intake, yet no studies have examined such an approach. Drink Tap is a San Francisco-based program in which public tap water stations were installed in parks and public spaces (winter 2017) and promotional efforts (fall and winter 2018) encouraged water intake. At the same time, San Francisco and surrounding communities were also implementing SSB taxes. We conducted a quasi-experimental study to examine whether water access and promotion combined with SSB taxes affected beverage intake habits more than SSB taxes alone. We conducted 1-hour observations (N = 960) at 10 intervention parks (Drink Tap plus SSB taxes) and 20 comparison parks (SSB taxes only) in San Francisco Bay Area cities before (July-September 2016) and after (June-August 2019) implementation of Drink Tap. We found significant adjusted percentage increases in drinking water among visitors to intervention parks, compared with comparison parks: water from park water sources (+80%, P < .001) and water from reusable bottles (+40%, P = .02). We found no significant reductions in visitors observed drinking bottled water, juices, or SSBs. The Drink Tap intervention led to increases in water intake from park sources and reusable bottles across parks that surpassed increases achieved through SSB taxes alone. Jurisdictions should consider coupling tap water access and promotion with policies for reducing intake of SSBs.

Cutaneous adverse events in 155 patients with metastatic melanoma consecutively treated with anti-CTLA4 and anti-PD1 combination immunotherapy: Incidence, management, and clinical benefit.

BACKGROUND: In response to the increased use of combination checkpoint inhibitors (CPIs) and the resulting increased cutaneous adverse events (CAEs), this study reviewed patients with melanoma treated with combination CPIs to characterize CAE features and their clinical impact, correlation to adverse events in other organs, and correlation to tumor response. METHODS: Patients from the authors' institutional database who received at least 1 dose of ipilimumab in combination with either nivolumab or pembrolizumab between January 1, 2012, and December 31, 2017, for stage IV or unresectable stage III melanoma were identified. The time to next treatment (TTNT) was calculated from the start of CPI therapy to the start of the next treatment or death, and the development of CAEs was tested in a time-dependent Cox regression to identify associations with TTNT. RESULTS: Eighty-one patients (52.3%) experienced a total of 92 CAEs, including eczematous dermatitis (25.0%), morbilliform eruption (22.8%), vitiligo (12.0%), and pruritus without rash (8.7%). The median times to the onset and resolution of CAEs were 21 days (range, 0-341 days) and 50 days (range, 1-352 days), respectively. Most CAEs resolved after patients entered the CPI maintenance phase and treatment with oral antihistamines with or without topical steroids. CPI discontinuation occurred in 4 patients (2.6%) because of CAEs, in 49 (31.6%) because of other immune-related adverse events, and in 20 (12.9%) because of melanoma progression or death. For patients definitively treated with CPIs (n = 134; 86.5%), TTNT was significantly longer with CAEs than without CAEs (hazard ratio, 0.567; 95% CI, 0.331-0.972; P = .039). CONCLUSIONS: CAEs were mostly reversible and rarely required therapy discontinuation. The development of CAEs was associated with a longer TTNT, and this suggested a possible clinical benefit.

Clinical activity of checkpoint inhibitors in angiosarcoma: A retrospective cohort study.

BACKGROUND: Systemic treatments for angiosarcoma remains an area of unmet clinical need. The authors conducted this retrospective study to assess the clinical activity of checkpoint inhibitors in patients with angiosarcoma. The primary objective was to assess the objective response rate, and the secondary objective was to assess the progression-free and overall survival durations and disease control rate. METHODS: Patient data were obtained using The University of Texas MD Anderson Cancer Center Tumor Registry database. The final study population was refined to only include patients who had undergone pembrolizumab monotherapy. The objective response rate was evaluated using RECIST/irRECIST version 1.1. Progression-free survival and overall survival were defined as the time from the initiation of immunotherapy to disease progression or recurrence, death, or last follow-up and to death or last follow-up, respectively. RESULTS: The final cohort comprised 25 patients. Most patients had metastatic disease (72%) and had undergone at least two lines of systemic therapy (80%) before starting pembrolizumab. The objective response rate was 18%, whereas the disease control rate was 59%. The median progression-free survival duration was 6.2 months and was not significantly different between the cutaneous (4.7 months) and visceral angiosarcoma (6.2 months) groups (p = .42). The median overall survival duration was 72.6 months. Toxicities were recorded for eight patients, with fatigue, anemia, constipation, and rash being the most common. CONCLUSIONS: Pembrolizumab shows durable clinical activity in angiosarcoma. These findings suggest that checkpoint inhibition as monotherapy or combination therapy is likely to have a high probability of success.© 2022 American Cancer Society. LAY SUMMARY: This is the largest retrospective study to assess the clinical activity of checkpoint inhibitor monotherapy in angiosarcomas. The study includes an adequate number of patients with visceral angiosarcoma that enabled to obtain meaningful clinical insights that were previously unavailable. Our findings indicate an improvement in progression-free survival with pembrolizumab that is comparable to other active agents in angiosarcoma. Pembrolizumab monotherapy in angiosarcomas also has a favorable tolerability profile. Our findings emphasize the need for prospective studies to evaluate the activity of pembrolizumab monotherapy and combination therapy.

Management of Dermatologic Events Associated With the Nectin-4-directed Antibody-Drug Conjugate Enfortumab Vedotin.

Enfortumab vedotin is a first-in-class Nectin-4-directed antibody-drug conjugate approved by the US Food and Drug Administration for the treatment of patients with locally advanced or metastatic urothelial cancer (la/mUC) previously treated with a platinum-based chemotherapy and a programmed death receptor-1/programmed death-ligand 1 (PD-1/L1) inhibitor, or patients with la/mUC who are ineligible for cisplatin-based chemotherapy and have previously received one or more prior lines of therapy. Enfortumab vedotin is the only drug to have demonstrated survival benefit versus chemotherapy in a randomized controlled trial in patients with la/mUC previously treated with platinum-based chemotherapy and a PD-1/L1 inhibitor. The development of dermatologic events following the administration of enfortumab vedotin is anticipated given the expression of Nectin-4 in epidermal keratinocytes and skin appendages (eg, sweat glands and hair follicles). There is the potential for rare but severe and possibly fatal cutaneous adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrosis, as described in the boxed warning of the US prescribing information for enfortumab vedotin. This manuscript describes the presumed pathophysiology and manifestations of dermatologic reactions related to enfortumab vedotin, and presents recommendations for prevention and treatment, to provide oncologists and other healthcare providers with an awareness of these potential adverse events to best anticipate and manage them.

Epidemiology of Huntington's Disease in the United States Medicare and Medicaid Populations.

INTRODUCTION: Huntington's disease (HD) is a rare, genetic, and ultimately fatal neurodegenerative disease, with a devastating impact on individuals and families across generations. Few estimates of HD epidemiology in the United States (US) exist. METHODS: This study employed a retrospective cross-sectional design to examine the epidemiology of HD in the US Medicare and Medicaid beneficiary populations using 2016-2017 claims data from the Medicare 100% Research Identifiable Files (RIFs) and 2014 claims data from the Medicaid Analytic eXtract (MAX) files for 17 states. Medicare beneficiaries ≥65 years with a diagnosis of HD (≥1 claim with ICD-10-CM code G10) in 2017 and Medicaid beneficiaries <65 years with a diagnosis of HD (≥1 claim with ICD-9-CM code 333.4) in 2014 were identified. The study outcomes included the 2017 prevalence proportion and incidence rate of HD in the Medicare population and the 2014 prevalence proportion of HD in the Medicaid population. RESULTS: In the Medicare population, 1,941 prevalent and 819 incident cases of HD were identified in 2017, corresponding to a prevalence proportion of 13.1 per 100,000 persons and incidence rate of 6.1 per 100,000 person-years. In the Medicaid population, 353 prevalent cases of HD were identified in 2014, corresponding to a prevalence proportion of 15.2 per 100,000 persons. CONCLUSION: This study suggests that prevalence and incidence of HD in the US may be higher than previously estimated. This has important implications in raising awareness of HD among providers and payers and ensuring availability of and access to services for HD patients and care partners in the Medicare and Medicaid populations.

Severe de novo pustular psoriasiform immune-related adverse event associated with nivolumab treatment for metastatic esophageal adenocarcinoma.

Breakthrough targeted therapies have produced significant improvements in survival for cancer patients, but have a propensity to cause cutaneous immune-related adverse events (irAEs). Psoriasiform irAEs, representing about 4% of dermatologic toxicities associated with immune checkpoint inhibitor (ICI) therapy, are usually mild, occur in older patients and present as an exacerbation of existing psoriasis after several doses of ICI therapy. We report a case of a 58-year-old woman with metastatic esophageal adenocarcinoma and no prior history of psoriasis who developed a pustular psoriasiform irAE, beginning 3 days after initiation of nivolumab and progressing to confluent erythroderma with pustules over 2 weeks despite topical steroid use. She had concurrent acrodermatitis enteropathica, clinically diagnosed and confirmed with a low serum zinc level, that improved with supplementation. Her psoriasiform irAE was refractory to systemic steroids and acitretin, prompting discontinuation of nivolumab and treatment with ustekinumab and concomitant slow taper of acitretin and prednisone. Pustular psoriasiform irAE is a rare but severe dermatologic toxicity resulting from ICI therapy. Given the diverse morphologic types of cutaneous irAEs that can occur during ICI therapy, a clinical and histopathologic examination of dermatologic toxicities is critical to identify patients who may benefit from biologic therapy.

Acneiform eruptions with combination targeted cancer therapy in colorectal cancer patients.

PURPOSE: Epidermal growth factor receptor inhibitors (EGFRI) can be used with pathway inhibitors, including mitogen-activated protein kinase kinase inhibitors (MEKIs), BRAF inhibitors (BRAFIs), and checkpoint inhibitors such as programmed death-ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) to treat colorectal cancer. These can precipitate treatment-resistant acneiform eruptions, prompting dose modification or discontinuation. Predicting the likelihood of severe rash development and crafting effective treatments may promote adherence to life-saving chemotherapy. METHODS: An Institutional Review Board-approved retrospective chart review of patients with colorectal cancer treated with EGFRI or MEKI in combination with HER2, BRAF, PI3K, or checkpoint inhibitors between January 1, 2016, and January 1, 2020, was performed. Surrogates for rash severity were investigated, including lower extremity involvement, utilization of oral steroids or retinoids, dose modification, and incidence of superinfection. RESULTS: Of 122 patients treated with combination therapy, 105 developed a rash, and 87 developed an acneiform eruption. Common combinations included MEKI/PD-LI, EGFRI/MEKI, and MEKI/PD-1I. Patients treated with EGFRI/MEKI developed the most severe rashes (p = 0.02). Lower extremity involvement was more frequent with EGFRI/MEKI compared to alternative combinations (p = 0.05). Drug holiday correlated with all rash severity surrogates, including rash grade, lower extremity involvement, oral steroid or retinoid use, and incidence of superinfection. Use of oral steroids or retinoids was associated with development of superinfection (p = 0.002). Prophylactic tetracycline use did not impact rash severity or rash incidence. CONCLUSION: This is the first descriptive analysis to characterize acneiform eruptions for patients with colorectal cancer on combination cancer therapy. Approximately 85% of patients developed a cutaneous toxicity with what appears to be synergistic effects of EGFRI and MEKI combination therapy causing the most severe eruptions. Superinfection rate correlated to systemic therapy use beyond oral tetracyclines. Further investigation into the utility of prophylactic oral tetracyclines in this population is needed.

Biologic therapies for checkpoint inhibitor-induced cutaneous toxicities: a single-institution study of 17 consecutively treated patients.

PURPOSE: Treatment options for corticosteroid-refractory and/or high-grade checkpoint inhibitor (CPI)-induced cutaneous adverse events (CAEs) are limited; however, anecdotal reports of biologic therapies have been successful. We aim to characterize the appropriate treatment scenarios and safety and efficacy profiles of biologics used to treat patients with CPI-induced CAEs at a single institution. METHODS: This is a retrospective case series of patients from January 1st, 2015 to October 20th, 2020, with CPI-induced CAEs who were treated with biologics at a single cancer center. Patients were identified using institutional electronic medical record who underwent CPI therapy with subsequent CAEs that necessitated biologic therapy. Diagnostic criteria utilized for CAEs were based on documentation by four board-certified dermatologists, in combination with detailed chart reviews and pathology findings. Primary study outcome measurements include CAE response, tumor response, and adverse events during biologics treatment. RESULTS: We identified 17 patients who fit study criteria. Sixteen patients experienced some degree of CAE improvement on biologics, with 10 of 10 patients reaching CAE resolution at 6 months post biologics. Eight patients needed new systemic treatment post biologics treatment, while 9 patients received no further treatment or stayed on the CPI. Thirteen patients tolerated biologics well with no significant adverse events or blood abnormalities, with only 2 patients experiencing biologic dose delays. CONCLUSION: In our cohort, biologics appear to be extremely efficacious in the treatment of severe-grade and/or steroid refractory CAEs. They also appeared to be well-tolerated without overtly negative effects on tumor response. In patients with limited cancer treatment options and good tumor response to CPIs, biologics should be considered for severe-grade and/or refractory CAEs.

Examining recent trends in the racial disparity gap in tap water consumption: NHANES 2011-2018.

OBJECTIVE: As tap water distrust has grown in the USA with greater levels among Black and Hispanic households, we aimed to examine recent trends in not drinking tap water including the period covering the US Flint Water Crisis and racial/ethnic disparities in these trends. DESIGN: Cross-sectional analysis. We used log-binomial regressions and marginal predicted probabilities to examine US nationally representative trends in tap and bottled water consumption overall and by race/ethnicity. SETTING: The National Health and Nutrition Examination Survey data, 2011-2018. PARTICIPANTS: Nationally representative sample of 9439 children aged 2-19 years and 17 268 adults. RESULTS: Among US children and adults, respectively, in 2017-2018 there was a 63 % (adjusted prevalence ratio (PR): 1·63, 95 % CI (1·25, 2·12), P < 0·001)) and 40 % (PR: 1·40, 95 % CI (1·16, 1·69), P = 0·001)) higher prevalence of not drinking tap water compared to 2013-2014 (pre-Flint Water Crisis). For Black children and adults, the probability of not drinking tap water increased significantly from 18·1 % (95 % CI (13·4, 22·8)) and 24·6 % (95 % CI (20·7, 28·4)) in 2013-2014 to 29·3 % (95 % CI (23·5, 35·1)) and 34·5 % (95 % CI (29·4, 39·6)) in 2017-2018. Among Hispanic children and adults, not drinking tap water increased significantly from 24·5 % (95 % CI (19·4, 29·6)) and 27·1 % (95 % CI (23·0, 31·2)) in 2013-2014 to 39·7 % (95 % CI (32·7, 46·8)) and 38·1 % (95 % CI (33·0, 43·1)) in 2017-2018. No significant increases were observed among Asian or White persons between 2013-2014 and 2017-2018. Similar trends were found in bottled water consumption. CONCLUSIONS: This study found persistent disparities in the tap water consumption gap from 2011 to 2018. Black and Hispanics' probability of not drinking tap water increased following the Flint Water Crisis.

Drinking Water in the United States: Implications of Water Safety, Access, and Consumption.

Recent water quality crises in the United States, and recognition of the health importance of drinking water in lieu of sugar-sweetened beverages, have raised interest in water safety, access, and consumption. This review uses a socioecological lens to examine these topics across the life course. We review water intakes in the United States relative to requirements, including variation by age and race/ethnicity. We describe US regulations that seek to ensure that drinking water is safe to consume for most Americans and discuss strategies to reduce drinking water exposure to lead, a high-profile regulated drinking water contaminant. We discuss programs, policies, and environmental interventions that foster effective drinking water access, a concept that encompasses key elements needed to improve water intake. We conclude with recommendations for research, policies, regulations, and practices needed to ensure optimal water intake by all in the United States and elsewhere.

Temperature Measurement at Well-Child Visits in the United States.

OBJECTIVE: To determine the frequency and predictors of temperature measurement at well-child visits in the US and report rates of interventions associated with visits at which temperature is measured and fever is detected. STUDY DESIGN: In this cross-sectional study, we analyzed 22 518 sampled well-child visits from the National Ambulatory Medical Care Survey between 2003 and 2015. We estimated the frequency of temperature measurement and performed multivariable regression to identify patient, provider/clinic, and seasonal factors associated with the practice. We described rates of interventions (complete blood count, radiograph, urinalysis, antibiotic prescription, and emergency department/hospital referral) by measurement and fever (temperature ≥100.4 °F, ≥38.0 °C) status. RESULTS: Temperature was measured in 48.5% (95% CI 45.6-51.4) of well-child visits. Measurement was more common during visits by nonpediatric providers (aOR 2.0, 95% CI 1.6-2.5; reference: pediatricians), in Hispanic (aOR 1.9, 95% CI 1.6-2.3) and Black (aOR 1.5, 95% CI 1.2-1.9; reference: non-Hispanic White) patients, and in patients with government (aOR 2.0, 95% CI 1.7-2.4; reference: private) insurance. Interventions were more commonly pursued when temperature was measured (aOR 1.3, 95% CI 1.1-1.6) and fever was detected (aOR 3.8, 95% CI 1.5-9.4). CONCLUSIONS: Temperature was measured in nearly one-half of all well-child visits. Interventions were more common when temperature was measured and fever was detected. The value of routine temperature measurement during well-child visits warrants further evaluation.

Lithium ion battery degradation: what you need to know.

The expansion of lithium-ion batteries from consumer electronics to larger-scale transport and energy storage applications has made understanding the many mechanisms responsible for battery degradation increasingly important. The literature in this complex topic has grown considerably; this perspective aims to distil current knowledge into a succinct form, as a reference and a guide to understanding battery degradation. Unlike other reviews, this work emphasises the coupling between the different mechanisms and the different physical and chemical approaches used to trigger, identify and monitor various mechanisms, as well as the various computational models that attempt to simulate these interactions. Degradation is separated into three levels: the actual mechanisms themselves, the observable consequences at cell level called modes and the operational effects such as capacity or power fade. Five principal and thirteen secondary mechanisms were found that are generally considered to be the cause of degradation during normal operation, which all give rise to five observable modes. A flowchart illustrates the different feedback loops that couple the various forms of degradation, whilst a table is presented to highlight the experimental conditions that are most likely to trigger specific degradation mechanisms. Together, they provide a powerful guide to designing experiments or models for investigating battery degradation.

Application of least absolute shrinkage and selection operator logistic regression for the histopathological comparison of chondrodermatitis nodularis helicis and hyperplastic actinic keratosis.

BACKGROUND: The distinction between chondrodermatitis nodularis helicis (CNH) and hyperplastic actinic keratosis (HAK) on the ear can pose a diagnostic challenge. We aimed to identify histopathological characteristics that could distinguish between CNH and HAK on routine sections using penalized least absolute shrinkage and selection operator (LASSO) logistic regression analysis. METHODS: Cases of CNH (n = 80) and HAK (n = 28) were analyzed for selected histopathological characteristics. Fisher's exact test and LASSO regression were performed. RESULTS: In univariate analyses, the following were significantly associated with CNH: ulceration, acanthosis, granular layer in the majority of the lesion, hypergranulosis at the periphery of the lesion, hyperkeratosis at the periphery of the lesion, hyperparakeratosis at the periphery of the lesion, fibrosis, increased blood vessels, vertically oriented blood vessels, and fibrin. A LASSO model excluding atypia found that fibrin, fibrosis, presence of granular layer, ulceration, and vertically oriented blood vessels were most predictive of CNH. Keratinized strap cells were not a significant predictor. CONCLUSION: We have identified features that may aid in differentiating these entities and demonstrated that a LASSO regression model can identify predictors that may improve diagnostic accuracy. Our results indicate that the highest diagnostic accuracy in this dilemma is dependent on obtaining biopsy specimens with visible dermis.