Clinical, radiological and molecular responses to combination chemotherapy with MAPK pathway inhibition in relapsed and refractory Langerhans cell histiocytosis.

Optimal therapeutic approaches for advanced Langerhans cell histiocytosis (LCH) are not known. We assessed the safety and efficacy of combined chemotherapy with MAPK pathway inhibition in 10 patients with refractory systemic disease and/or LCH-associated neurodegeneration. Overall response rate was 9/10 (90%) for the entire cohort: 5/5 (100%) for patients with systemic disease and 6/7 (86%) for patients with central nervous system disease. BRAFV600E+ peripheral blood fraction decreased in 5/6 (83%). Toxicities included fever, skin rash, myalgias, neuropathy, cytopenias and hypocalcaemia. Prospective trials are required to optimize combination strategies, determine potential to achieve cure and compare outcomes to chemotherapy or MAPK inhibitor monotherapy.

Overcoming T-cell exhaustion in LCH: PD-1 blockade and targeted MAPK inhibition are synergistic in a mouse model of LCH.

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia characterized by granulomatous lesions containing pathological CD207+ dendritic cells (DCs) with persistent MAPK pathway activation. Standard-of-care chemotherapies are inadequate for most patients with multisystem disease, and optimal strategies for relapsed and refractory disease are not defined. The mechanisms underlying development of inflammation in LCH lesions, the role of inflammation in pathogenesis, and the potential for immunotherapy are unknown. Analysis of the immune infiltrate in LCH lesions identified the most prominent immune cells as T lymphocytes. Both CD8+ and CD4+ T cells exhibited "exhausted" phenotypes with high expression of the immune checkpoint receptors. LCH DCs showed robust expression of ligands to checkpoint receptors. Intralesional CD8+ T cells showed blunted expression of Tc1/Tc2 cytokines and impaired effector function. In contrast, intralesional regulatory T cells demonstrated intact suppressive activity. Treatment of BRAFV600ECD11c LCH mice with anti-PD-1 or MAPK inhibitor reduced lesion size, but with distinct responses. Whereas MAPK inhibitor treatment resulted in reduction of the myeloid compartment, anti-PD-1 treatment was associated with reduction in the lymphoid compartment. Notably, combined treatment with MAPK inhibitor and anti-PD-1 significantly decreased both CD8+ T cells and myeloid LCH cells in a synergistic fashion. These results are consistent with a model that MAPK hyperactivation in myeloid LCH cells drives recruitment of functionally exhausted T cells within the LCH microenvironment, and they highlight combined MAPK and checkpoint inhibition as a potential therapeutic strategy.

Parent Dosing Tool Use, Beliefs, and Access: A Health Literacy Perspective.

OBJECTIVES: To assess parent decision-making regarding dosing tools, a known contributor to medication dosing errors, by evaluating parent dosing tool use, beliefs, and access, and the role of health literacy, with a focus on dosing cups, which are associated with an increased risk of multifold overdose. STUDY DESIGN: Cross-sectional analysis of data collected for randomized controlled study in 3 urban pediatric clinics. English/Spanish-speaking parents (n = 493) of children ≤8 years of age enrolled. OUTCOMES: reported tool use, beliefs, and access. Predictor variable: health literacy (Newest Vital Sign; limited [0-3], adequate [4-6]). Multiple logistic regression analyses conducted. RESULTS: Over two-thirds of parents had limited health literacy. Oral syringes (62%) and dosing cups (22%) were most commonly used. Overall, 24% believed dosing cups were the best tool type for dosing accuracy; 99% reported having access to ≥1 dosing tools with standard measurement markings. Parents with limited health literacy had greater odds of dosing cup use (limited vs adequate: aOR = 2.4 [1.2-4.6]). Parents who believed that dosing cups are best for accuracy had greater odds of dosing cup use (aOR = 16.3 [9.0-29.3]); this belief mediated health literacy-effects on dosing cup use. CONCLUSIONS: Factors associated with dosing tool choice, including parent health literacy and beliefs are important to consider in the design of interventions to reduce dosing errors; future larger-scale studies addressing this issue are needed.

Infant Feeding Outcomes From a Culturally-Adapted Early Obesity Prevention Program for Immigrant Chinese American Parents.

OBJECTIVE: To examine whether a cultural adaptation of an early childhood obesity prevention program promotes healthy infant feeding practices. METHODS: Prospective quasi-experimental study of a community-engaged multiphasic cultural adaptation of an obesity prevention program set at a federally qualified health center serving immigrant Chinese American parent-child dyads (N = 298). In a group of historical controls, we assessed early infant feeding practices (breastfeeding, sugar-sweetened beverage intake) in 6-month-olds and then the same practices alongside early solid food feeding practices (bottle weaning, fruit, vegetable, sugary or salty snack consumption) in 12-month-olds. After implementation, we assessed these practices in an intervention cohort group at 6 and 12 months. We used cross-sectional groupwise comparisons and adjusted regression analyses to evaluate group differences. RESULTS: At 6 months, the intervention group had increased odds of no sugar-sweetened beverage intake (aOR: 5.69 [95% confidence interval (CI): 1.65, 19.63], P = .006). At 12 months, the intervention group also had increased odds of no sugar-sweetened beverage intake (aOR: 15.22 [95% CI: 6.33, 36.62], P < .001), increased odds of bottle weaning (aOR: 2.34 [95% CI: 1.05, 5.23], P = .03), and decreased odds of sugary snack consumption (aOR: 0.36 [0.18, 0.70], P = .003). We did not detect improvements in breastfeeding, fruit, vegetable, or salty snack consumption. CONCLUSIONS: A cultural adaptation of a primary care-based educational obesity prevention program for immigrant Chinese American families with low income is associated with certain healthy infant feeding practices. Future studies should evaluate cultural adaptations of more intensive interventions that better address complex feeding practices, such as breastfeeding, and evaluate long-term weight outcomes.

Lineage switching of the cellular distribution of BRAFV600E in multisystem Langerhans cell histiocytosis.

Most children with high-risk Langerhans cell histiocytosis (LCH) have BRAFV600E mutation. BRAFV600E alleles are detectable in myeloid mononuclear cells at diagnosis but it is not known if the cellular distribution of mutation evolves over time. Here, the profiles of 16 patients with high-risk disease were analyzed. Two received conventional salvage chemotherapy, 4 patients on inhibitors were tracked at intervals of 3 to 6 years, and 10 patients, also given inhibitors, were analyzed more than 2 years after diagnosis. In contrast to the patients responding to salvage chemotherapy who completely cleared BRAFV600E within 6 months, children who received inhibitors maintained high BRAFV600E alleles in their blood. At diagnosis, mutation was detected predominantly in monocytes and myeloid dendritic cells. With time, mutation switched to the T-cell compartment, which accounted for most of the mutational burden in peripheral blood mononuclear cells, more than 2 years from diagnosis (median, 85.4%; range, 44.5%-100%). The highest level of mutation occurred in naïve CD4+ T cells (median, 51.2%; range, 3.8%-93.5%). This study reveals an unexpected lineage switch of BRAFV600E mutation in high-risk LCH, which may influence monitoring strategies for the potential withdrawal of inhibitor treatment and has new implications for the pathogenesis of neurodegeneration, which occurred in 4 patients.

Management of Pediatric Atopic Dermatitis by Primary Care Providers: A Systematic Review.

BACKGROUND: Primary care providers (PCPs), including pediatricians and general practitioners, are often the first to see children with eczema/atopic dermatitis (AD). Little is known about management of pediatric AD by PCPs and adherence to national guidelines. OBJECTIVE: To review existing literature examining management components of pediatric AD (topical corticosteroids [TCS], topical calcineurin inhibitors [TCIs], antihistamines, bathing, emollients, and diet) by PCPs. DATA SOURCES: PubMed/Medline and Embase. STUDY ELIGIBILITY CRITERIA: English-language articles dated 2015 to 2020 reporting outcomes addressing management of pediatric AD by PCPs. STUDY APPRAISAL AND SYNTHESIS METHODS: Two authors independently screened titles/abstracts, reviewed full-text articles, extracted relevant data, and evaluated study quality. Disagreements were resolved by a third author. RESULTS: Twenty articles were included. Surveys and national database analyses were the most common methodologies (n = 7 each). PCPs commonly prescribed TCS but had a preference for low-potency agents, overprescribed nonsedating antihistamines, and avoided TCIs. PCPs commonly recommended emollients, although this was not universal. Data characterizing nonmedication management were limited. LIMITATIONS: Most studies did not examine individual patient encounters, but rather relied on providers reporting their general behaviors. Provider behavior may vary based on country of practice. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Knowledge and management gaps exist among PCPs in treating pediatric AD in key areas including knowledge of TCS safety profiles and prescribing of TCIs. The current literature is largely limited to small studies that evaluate prescribing behaviors with limited data characterizing nonmedication management, highlighting the need for future research in this area.

Parents' Use of Technologies for Health Management: A Health Literacy Perspective.

OBJECTIVE: Parent use of technology to manage child health issues has the potential to improve access and health outcomes. Few studies have examined how parent health literacy affects usage of Internet and cell phone technologies for health management. METHODS: Cross-sectional analysis of data collected as part of a randomized controlled experiment in 3 urban pediatric clinics. English- and Spanish-speaking parents (n = 858) of children ≤8 years answered questions regarding use of and preferences related to Internet and cell phone technologies. Parent health literacy was measured using the Newest Vital Sign. RESULTS: The majority of parents were high Internet (70.2%) and cell phone (85.1%) users (multiple times a day). A total of 75.1% had limited health literacy (32.1% low, 43.0% marginal). Parents with higher health literacy levels had greater Internet and cell phone use (adequate vs low: adjusted odds ratio [AOR], 1.7 [confidence interval, 1.2-2.5]) and were more likely to use them for health management (AOR, 1.5 [confidence interval, 1.2-1.8]); those with higher health literacy levels were more likely to use the Internet for provider communication (adequate vs marginal vs low: 25.0% vs 18.0% vs 12.0%, P = .001) and health-related cell phone apps (40.6% vs 29.7% vs 16.4%, P < .001). Overall preference for using technology for provider communication was high (∼70%) and did not differ by health literacy, although Internet and cell phone apps were preferred by higher literacy parents; no differences were seen for texting. CONCLUSIONS: Health literacy-associated disparities in parent use of Internet and cell phone technologies exist, but parents' desire for use of these technologies for provider communication was overall high and did not differ by health literacy.

Evaluation of Pediatric Human Papillomavirus Vaccination Provider Counseling Written Materials: A Health Literacy Perspective.

BACKGROUND AND OBJECTIVES: Despite recommendations supporting human papillomavirus (HPV) vaccination, pediatric vaccination rates remain suboptimal in the United States; lack of tools to support provider counseling is one barrier. We sought to evaluate HPV-related counseling materials for readability, suitability, and content, and assess parent perceptions of materials, using a health literacy perspective. METHODS: A systematic search was conducted for written materials developed for HPV vaccination counseling by examining state Department of Health Web sites and associated links to local and national organizations. Materials were assessed for the following: 1) readability (Flesch Reading Ease, Flesch-Kincaid, Gunning Fog, Simple Measure of Gobbledygook, Fry), 2) suitability (understandability and actionability) (Suitability Assessment of Materials; Patient Education Materials Assessment Tool for Printable Materials), and 3) coverage of 8 key content areas (recommended by Centers for Disease Control and Prevention). Semistructured interviews were conducted with English-speaking parents or caregivers of children 9 to 17 years of age from 3 pediatric clinics (New York, Ohio, Illinois) serving predominantly low-income families to assess perceptions and usefulness of 4 handouts selected for review. RESULTS: Thirty-eight documents were assessed. Mean ± standard deviation (SD) reading grade level was 9.4 ± 2; 10.5% (n = 4) had a reading level of 6th grade or below; 68.4% (n = 26) were considered not suitable. Mean understandability was 41.7% and mean actionability was 20.7%. Only 5.3% (n = 2) addressed all 8 content areas mean ± SD (number of areas = 6.7 ± 1.2). Brochure comprehensiveness and inclusion of a personal story were cited as factors that would be helpful in influencing parents to vaccinate against HPV. CONCLUSIONS: Few written materials for HPV vaccination counseling were optimal from a health literacy best practices perspective. Content comprehensiveness was important for informed decision making.

Synthesis of 2-Tetrazolylmethyl-isoindolin-1-ones via a One-Pot Ugi-Azide/(N-Acylation/exo-Diels-Alder)/Dehydration Process.

A series of fifteen 2-tetrazolylmethyl-isoindolin-1-one linked-type bis-heterocycles were synthesized in 10-76% yields under mild conditions via a one-pot Ugi-azide/(N-acylation/exo-Diels-Alder)/dehydration process from furan-2-ylmethanamine, aldehydes, isocyanides, azidotrimethylsilane, and maleic anhydride. Density functional theory calculations were performed using the polarizable continuum model (toluene)-M06-2X-D3/6-311+G(d)//M06-2X-D3/6-31G(d) level of theory to obtain the full energy profile when investigating over eight possible pathways. An anthracene-containing analogue displayed a distribution of its highest occupied molecular orbital-lowest unoccupied molecular orbital throughout both cyclic moieties.

Probabilidad de evento coronario en los próximos 10 años en pacientes diabéticos según la escala de Framingham - REGICOR

Introducción: los pacientes diabéticos tienen un riesgo coronario 2 a 4 veces superior al observado en la población general. Objetivo: estimar la probabilidad de evento coronario en los próximos 10 años en pacientes diabéticos del Hospital Regional de Coronel Oviedo, Paraguay. Sujetos y métodos: estudio observacional, descriptivo de corte transversal. Muestreo no probabilístico de casos consecutivos con revisión de expedientes clínicos de pacientes diabéticos que acudieron al Departamento de diabetes durante el 2013. El instrumento utilizado para la estimación de evento coronario fue la Escala de Framingham calibrada para España, conocida como REGICOR. Resultados: se incluyeron 82 expedientes clínicos de pacientes diabéticos con edades de 30 a 76 años (media 56,29 ± 11,62 años). El 61% pertenece al sexo femenino y 97,6% padece diabetes mellitus tipo 2. El 56,1% tiene entre 3 a 4 factores de riesgo coronario, siendo el más frecuente la hiperglucemia (97,6%). El 46,3% tiene una probabilidad moderada de 5 a 9% de acontecimiento coronario a los 10 años. Conclusión: los factores de riesgo coronario más frecuentes fueron hiperglucemia, hipertrigliceridemia y obesidad abdominal. Casi la mitad de los pacientes tiene una probabilidad moderada de acontecimiento coronario a los 10 años.

Introduction: Diabetic patients have a coronary risk 2 to 4 times higher than the one observed in the general population. Objective: To estimate the probability of a coronary event in next 10 years in diabetic patients of the Regional Hospital Regional of Coronel Oviedo, Paraguay. Subjects and methods: Cross-sectional descriptive observational study. Non-probabilistic sampling of consecutive cases by revision of the clinical records of diabetic patients that attended the Department of diabetes during 2013. The instrument used for the estimation of the coronary event was the Framingham Scale calibrated for Spain, known as REGICOR. Results: Eighty two clinical records of diabetic patients aged 30 to 76 years (mean 56.29 ± 11.62 years) were included. Sixty one percent was female and 97.6% had type 2 diabetes mellitus. About fifty six percent (56.1%) has 3 to 4 coronary risk factors, being the most frequent the hyperglycemia (97.6%). Forty six point three has moderate probability of 5 to 9% of a coronary event at 10 years. Conclusion: The most frequent coronary risk factors were hyperglycemia, hypertriglyceridemia and abdominal obesity. Almost half the patients have moderate probability of coronary events at 10 years.

Frecuencia de tratamiento quirurgico curativo de las neoplasias periampulares. Experiencia en base a 122 casos / Frequency in curative surgical treatment of periampullary tumors. Experience based on 122 cases

Introducción Los tumores periampulares son aquellos que se desarrollan en un área de 2 cm próxima de la papila de Vater; en este grupo se encuentran los tumores de cabeza de páncreas, los de la ampolla de Vater, los del colédoco intrapancreático y duodenales. Objetivo: Determinar la frecuencia de tratamiento quirúrgico curativo de los tumores de la región periampular en el servicio de Cirugía General del Hospital Central del Instituto de Previsión Social. Metodología: Investigación retrospectiva, observacional descriptiva y de corte transverso en el periodo 2009-2015. Resultados Se estudiaron 122 casos, la frecuencia de tumores periampulares resecables intraoperatoriamente, y por tanto sometidos a duodeno pancreatectomía cefálica fue de 38.52%, que corresponde a 47 casos del total. La relación de varón/mujer fue de 1,3/1. El promedio de edad fue 64,67 años. La ictericia fue el signo y síntoma prevalente y el primero en aparecer. Se realizó ecografía y tomografía en todos los pacientes. Ningún paciente fue sometido a ecoendoscopia. El tipo histológico más frecuente fue adenocarcinoma ductal de páncreas con 89 casos (72,95%). Conclusión: La estatificación quirúrgica determinando la resecabilidad o no de dichos tumores es fundamental para evitar procedimientos cruentos innecesarios, la ecografía y tomografía son estudios necesarios para la determinación de resecabilidad, pero que muchas veces necesitan ser reforzados con otros estudios como la eco endoscopia que evitaría los falsos resecables que ingresan a quirófano innecesariamente. Situación encontrada muy frecuentemente en este estudio.

Introduction: Periampullary tumors are most often localizated in a 2 cm area next to the ampulla of Vater, and this group included the head of pancreas carcinoma, Vater´s ampulla carcinoma, intrapancreatic cholangiocarcinoma and duodenal carcinoma. Objective: to define the frequency of curative surgical treatment in tumors of periampullar region at the Service of General Surgery of Instituto de Previsión Social. Patients and Method: a retrospective, observational and descriptive study between 2009 and 2015. Results: In 122 cases, 47 of them (38,5%) had a resectability criteria and was performed a CDP surgery in these cases. There wasn´t difference of presentation according to gender. The average age was 64,67 years old. Jaundice was the first symptom showed and the most common. It was performed ultrasonography and CT scan in all patients. The most common histological type was the pancreatic ductal adenocarcinoma in 89 patients. Conclusion: The staging of the periampullar tumors and the resectabilty criteria are very important parameters to avoid an unnecessary surgical procedure. Ultrasonography and CT scan are important tools to clarify the resectability criteria, even better if they are accompanied by endoscopic ultrasound.