Phase II study of vemurafenib in children and young adults with tumors harboring BRAF V600 mutations: NCI-COG pediatric MATCH trial (APEC1621) Arm G.

BACKGROUND: This is a phase II subprotocol of the NCI-COG Pediatric MATCH study evaluating vemurafenib, a selective oral inhibitor of BRAF V600 mutated kinase, in patients with relapsed or refractory solid tumors harboring BRAF V600 mutations. METHODS: Patients received vemurafenib at 550 mg/m2 (maximum 960 mg/dose) orally twice daily for 28-day cycles until progression or intolerable toxicity. The primary aim was to determine the objective response rate and secondary objectives included estimating progression-free survival and assessing the tolerability of vemurafenib. RESULTS: Twenty-two patients matched to the subprotocol and 4 patients (18%) enrolled. Primary reasons for non-enrollment were ineligibility due to exclusions of low-grade glioma (n = 7) and prior BRAF inhibitor therapy (n = 7). Enrolled diagnoses were one each of histiocytosis, ameloblastoma, Ewing sarcoma, and high-grade glioma, all with BRAF V600E mutations. Treatment was overall tolerable with mostly expected grade 1/2 adverse events (AE). Grade 3 or 4 AE on treatment were acute kidney injury, hyperglycemia, and maculopapular rash. One patient came off therapy due to AE. One patient (glioma) had an objective partial response and remained on protocol therapy for 15 cycles. CONCLUSION: There was a low accrual rate on this MATCH subprotocol, with only 18% of those who matched with BRAFV600 mutations enrolling, resulting in early termination, and limiting study results (ClinicalTrials.gov Identifier: NCT03220035).

Insights into gemcitabine resistance in pancreatic cancer: association with metabolic reprogramming and TP53 pathogenicity in patient derived xenografts.

BACKGROUND: With poor prognosis and high mortality, pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. Standard of care therapies for PDAC have included gemcitabine for the past three decades, although resistance often develops within weeks of chemotherapy initiation through an array of possible mechanisms. METHODS: We reanalyzed publicly available RNA-seq gene expression profiles of 28 PDAC patient-derived xenograft (PDX) models before and after a 21-day gemcitabine treatment using our validated analysis pipeline to identify molecular markers of intrinsic and acquired resistance. RESULTS: Using normalized RNA-seq quantification measurements, we first identified oxidative phosphorylation and interferon alpha pathways as the two most enriched cancer hallmark gene sets in the baseline gene expression profile associated with intrinsic gemcitabine resistance and sensitivity, respectively. Furthermore, we discovered strong correlations between drug-induced expression changes in glycolysis and oxidative phosphorylation genes and response to gemcitabine, which suggests that these pathways may be associated with acquired gemcitabine resistance mechanisms. Thus, we developed prediction models using baseline gene expression profiles in those pathways and validated them in another dataset of 12 PDAC models from Novartis. We also developed prediction models based on drug-induced expression changes in genes from the Molecular Signatures Database (MSigDB)'s curated 50 cancer hallmark gene sets. Finally, pathogenic TP53 mutations correlated with treatment resistance. CONCLUSION: Our results demonstrate that concurrent upregulation of both glycolysis and oxidative phosphorylation pathways occurs in vivo in PDAC PDXs following gemcitabine treatment and that pathogenic TP53 status had association with gemcitabine resistance in these models. Our findings may elucidate the molecular basis for gemcitabine resistance and provide insights for effective drug combination in PDAC chemotherapy.

NMR crystallization: in situ NMR strategies for monitoring the evolution of crystallization processes.

We present a discussion of the range of NMR techniques that have been utilized for in situ monitoring of crystallization processes, highlighting the opportunities that now exist for exploiting the versatility of NMR techniques to reveal insights into the changes that occur in both the solid phase and the liquid phase as a function of time during crystallization processes from solution. New results are presented from in situ NMR studies of a range of crystallization processes using the CLASSIC NMR strategy and other techniques, specifically covering the following topics: (i) crystallization of glycine from aqueous solution at low temperature, revealing the relatively long-lived existence of a pure phase of the highly meta-stable ß polymorph, (ii) the complementarity of 1H→13C cross-polarization NMR and direct-excitation 13C NMR techniques in probing the evolution of the solid and liquid phases in in situ NMR studies of crystallization processes, (iii) in situ NMR studies of the process of guest exchange between a crystalline host-guest material in contact with the liquid phase of a more favourable type of guest, and (iv) systematic studies of the influence of magic-angle sample spinning on the behaviour of a crystallization system.

Nutrition practices in Australia and New Zealand in response to evolving evidence: Results of three point-prevalence audits.

BACKGROUND: The Augmented versus Routine Approach to Giving Energy Trial (TARGET) was a 4000-patient trial in which augmented enteral calorie dose did not influence outcomes. AIM: We aimed to quantify practice change following TARGET. METHODS: Three single-day, prospective, multicentre, point-prevalence audits of adult patients receiving enteral nutrition (EN) in participating Australian and New Zealand intensive care units at 10:00 AM were conducted: (i) 2010 (before conducting TARGET); (ii) 2018 (immediately before publishing TARGET results); and (iii) 2020 (2 years after TARGET publication). Data included baseline characteristics, clinical outcomes, and nutrition data. Data are n (%), mean ± standard deviation, or median [interquartile range]. Differences in enteral calorie prescription between 2018 and 2020 were compared using the Mann-Whitney test. RESULTS: The percentage of patients receiving EN (2010 42%, 2018 38%, 2020 33%; P = 0.012) and the prescription of calorie-dense EN formula (≥1.5 kcal/ml) (2010 33%, 2018 24%, 2020 23%; P = 0.038) decreased over time. However, when comparing prepublication and postpublication (2018-2020), calorie dose and calorie density were similar: 22.9 ± 8.6 versus 23.4 ± 12.8 kcal/kg/day (P = 0.816) and <1.5 kcal/ml: 76 versus 77% (P = 0.650), respectively. CONCLUSION: In Australian and New Zealand intensive care units, enteral calorie dose and calorie density of prescribed EN were similar before TARGET publication and 2 years later.

Patients' experiences of a suppoRted self-manAGeMent pAThway In breast Cancer (PRAGMATIC): quality of life and service use results.

PURPOSE: To describe trends and explore factors associated with quality of life (QoL) and psychological morbidity and assess breast cancer (BC) health service use over a 12-month period for patients joining the supported self-management (SSM)/patient-initiated follow-up (PIFU) pathway. METHODS: Participants completed questionnaires at baseline, 3, 6, 9 and 12 months that measured QoL (FACT-B, EQ 5D-5L), self-efficacy (GSE), psychological morbidity (GHQ-12), roles and responsibilities (PRRS) and service use (cost diary). RESULTS: 99/110 patients completed all timepoints; 32% (35/110) had received chemotherapy. The chemotherapy group had poorer QoL; FACT-B total score mean differences were 8.53 (95% CI: 3.42 to 13.64), 5.38 (95% CI: 0.17 to 10.58) and 8.00 (95% CI: 2.76 to 13.24) at 6, 9 and 12 months, respectively. The odds of psychological morbidity (GHQ12 >4) were 5.5-fold greater for those treated with chemotherapy. Financial and caring burdens (PRRS) were worse for this group (mean difference in change at 9 months 3.25 (95% CI: 0.42 to 6.07)). GSE and GHQ-12 scores impacted FACT-B total scores, indicating QoL decline for those with high baseline psychological morbidity. Chemotherapy patients or those with high psychological morbidity or were unable to carry out normal activities had the highest service costs. Over the 12 months, 68.2% participants phoned/emailed breast care nurses, and 53.3% visited a hospital breast clinician. CONCLUSION: The data suggest that chemotherapy patients and/or those with heightened psychological morbidity might benefit from closer monitoring and/or supportive interventions whilst on the SSM/PIFU pathway. Reduced access due to COVID-19 could have affected service use.

Longitudinal association of prepubertal urinary phthalate metabolite concentrations with pubertal progression among a cohort of boys.

BACKGROUND: Epidemiological studies have reported associations of anti-androgenic phthalate metabolite concentrations with later onset of male puberty, but few have assessed associations with progression. OBJECTIVES: We examined the association of prepubertal urinary phthalate metabolite concentrations with trajectories of pubertal progression among Russian boys. METHODS: At enrollment (ages 8-9 years), medical history, dietary, and demographic information were collected. At entry and annually to age 19 years, physical examinations including testicular volume (TV) were performed and spot urines collected. Each boy's prepubertal urine samples were pooled, and 15 phthalate metabolites were quantified by isotope dilution LC-MS/MS at Moscow State University. Metabolites of anti-androgenic parent phthalates were included: butylbenzyl (BBzP), di-n-butyl (DnBP), diisobutyl (DiBP), di(2-ethylhexyl) (DEHP) and diisononyl (DiNP) phthalates. We calculated the molar sums of DEHP, DiNP, and all AAP metabolites. We used group-based trajectory models (GBTMs) to identify subgroups of boys who followed similar pubertal trajectories from ages 8-19 years based on annual TV. We used multinomial and ordinal regression models to evaluate whether prepubertal log-transformed phthalate metabolite concentrations were associated with slower or faster pubertal progression trajectories, adjusting for covariates. RESULTS: 304 boys contributed a total of 752 prepubertal urine samples (median 2, range: 1-6) for creation of individual pools. The median length of follow-up was 10.0 years; 79% of boys were followed beyond age 15. We identified three pubertal progression groups: slower (34%), moderate (43%), and faster (23%) progression. A standard deviation increase in urinary log-monobenzyl phthalate (MBzP) concentrations was associated with higher adjusted odds of being in the slow versus faster pubertal progression trajectory (aOR 1.47, 95% CI 1.06-2.04). None of the other phthalate metabolites were associated with pubertal progression. CONCLUSIONS: On average, boys with higher concentrations of prepubertal urinary MBzP had a slower tempo of pubertal progression, perhaps attributable to the disruption of androgen-dependent biological pathways.

Increasing precision in the measurement of change in pediatric neurodegenerative disease.

Due to the surge in new brain-directed treatments, metrics to detect the alteration in developmental trajectories in cognition and adaptive behavior have become increasingly important. We propose Growth Scale Values (GSVs) as a solution to monitoring children with severe neurologic/neurodegenerative conditions. This report stems from a panel of experts presenting at the Gorlin symposium (WORLD Symposium) and a subsequent open Webinar sponsored by the National MPS Society. Because norm-referenced scores (Standard Scores or Intelligence Quotient, i.e., IQ) do not yield information about gain, stability, or loss of skills, they are not suitable for natural history studies or clinical trials. Age-equivalent (AE) scores have been the standard metric used in natural history studies. While AEs are familiar and interpretable to clinicians and parents, they are imprecise due to lack of standard deviations, standard errors of measurement, and equal intervals between scores. Raw scores also have unequal intervals and are not comparable between ages or ability levels. The GSV, a nonlinear transformation of raw scores using item calibration to make an interval scale score, can be used for accurate measures of within-person change. GSVs have been identified as a useful metric for longitudinal measurement of other conditions involving neurodiversity. These growth scores circumvent inaccurate AEs in infants, are not limited by age and can be used for impaired patients who are chronologically above the normative age range. GSVs have interval properties (a given difference between GSV values represents the same difference in ability at all score levels) and each GSV value has a known standard error of measurement (SEM). GSVs are recommended to measure change in cognitive and adaptive behavior in natural history studies and in clinical trials for children with neurologic disease.

Outcome of Extracorporeal Membrane Oxygenation for Pediatric Patients With Neoplasm: An Extracorporeal Life Support Organization Database Study (2000-2019).

OBJECTIVES: This study update in usage and outcomes of pediatric extracorporeal membrane oxygenation (ECMO) for patients with neoplasm analyzed according to demographics, clinical variables, and complications. DESIGN: Retrospective database review of the Extracorporeal Life Support Organization registry from the last 2 decades (2000-2019). The data were divided between two decades in order to compare patients' backgrounds and outcomes over time. SETTING: ECMO centers reporting to Extracorporeal Life Support Organization. PATIENTS: Patients equal to or younger than 18 years old with International Classification of Diseases, 9th Revision and International Classification of Diseases, 10th Revision codes that referred to neoplasms who were managed with ECMO. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Demographics, cancer subtype, clinical variables, and ECMO complications were assessed in relation to the primary study outcome of survival to hospital discharge. Nine-hundred two patients met inclusion criteria; 699 patients were in the latest decade, which is more than three times the number from the previous decade (203 patients). On univariate analysis, compared with the previous decade, in the later decade, ECMO was more frequently applied in patients with pre-ECMO cardiac arrest (31.3% vs 17.1%; p < 0.001), and/or lower oxygenation index (38.0 vs 48.1; p < 0.001). We failed to identify a difference in survival between the 2 decades (42.8% vs 37.9%; p = 0.218). On multivariable analysis, diagnosis of hematologic malignancy, post-cardiopulmonary resuscitation support type, hematopoietic stem cell transplant, and age older than seven were each associated with greater odds of mortality. CONCLUSIONS: The use of ECMO in children with neoplasm has expanded over the latest decade with changes in patient selection. Mortality remains unchanged. Hence, although the clinician still should stay cautious in its application, ECMO can be considered as an option to rescue pediatric oncologic patients in the setting of worsening cardiopulmonary status in the PICU.

Aligning tumor mutational burden (TMB) quantification across diagnostic platforms: phase II of the Friends of Cancer Research TMB Harmonization Project.

BACKGROUND: Tumor mutational burden (TMB) measurements aid in identifying patients who are likely to benefit from immunotherapy; however, there is empirical variability across panel assays and factors contributing to this variability have not been comprehensively investigated. Identifying sources of variability can help facilitate comparability across different panel assays, which may aid in broader adoption of panel assays and development of clinical applications. MATERIALS AND METHODS: Twenty-nine tumor samples and 10 human-derived cell lines were processed and distributed to 16 laboratories; each used their own bioinformatics pipelines to calculate TMB and compare to whole exome results. Additionally, theoretical positive percent agreement (PPA) and negative percent agreement (NPA) of TMB were estimated. The impact of filtering pathogenic and germline variants on TMB estimates was assessed. Calibration curves specific to each panel assay were developed to facilitate translation of panel TMB values to whole exome sequencing (WES) TMB values. RESULTS: Panel sizes >667 Kb are necessary to maintain adequate PPA and NPA for calling TMB high versus TMB low across the range of cut-offs used in practice. Failure to filter out pathogenic variants when estimating panel TMB resulted in overestimating TMB relative to WES for all assays. Filtering out potential germline variants at >0% population minor allele frequency resulted in the strongest correlation to WES TMB. Application of a calibration approach derived from The Cancer Genome Atlas data, tailored to each panel assay, reduced the spread of panel TMB values around the WES TMB as reflected in lower root mean squared error (RMSE) for 26/29 (90%) of the clinical samples. CONCLUSIONS: Estimation of TMB varies across different panels, with panel size, gene content, and bioinformatics pipelines contributing to empirical variability. Statistical calibration can achieve more consistent results across panels and allows for comparison of TMB values across various panel assays. To promote reproducibility and comparability across assays, a software tool was developed and made publicly available.

TPM, FPKM, or Normalized Counts? A Comparative Study of Quantification Measures for the Analysis of RNA-seq Data from the NCI Patient-Derived Models Repository.

BACKGROUND: In order to correctly decode phenotypic information from RNA-sequencing (RNA-seq) data, careful selection of the RNA-seq quantification measure is critical for inter-sample comparisons and for downstream analyses, such as differential gene expression between two or more conditions. Several methods have been proposed and continue to be used. However, a consensus has not been reached regarding the best gene expression quantification method for RNA-seq data analysis. METHODS: In the present study, we used replicate samples from each of 20 patient-derived xenograft (PDX) models spanning 15 tumor types, for a total of 61 human tumor xenograft samples available through the NCI patient-derived model repository (PDMR). We compared the reproducibility across replicate samples based on TPM (transcripts per million), FPKM (fragments per kilobase of transcript per million fragments mapped), and normalized counts using coefficient of variation, intraclass correlation coefficient, and cluster analysis. RESULTS: Our results revealed that hierarchical clustering on normalized count data tended to group replicate samples from the same PDX model together more accurately than TPM and FPKM data. Furthermore, normalized count data were observed to have the lowest median coefficient of variation (CV), and highest intraclass correlation (ICC) values across all replicate samples from the same model and for the same gene across all PDX models compared to TPM and FPKM data. CONCLUSION: We provided compelling evidence for a preferred quantification measure to conduct downstream analyses of PDX RNA-seq data. To our knowledge, this is the first comparative study of RNA-seq data quantification measures conducted on PDX models, which are known to be inherently more variable than cell line models. Our findings are consistent with what others have shown for human tumors and cell lines and add further support to the thesis that normalized counts are the best choice for the analysis of RNA-seq data across samples.

Associations Between Patterns of Alcohol Use and Viral Load Suppression Amongst Women Living with HIV in South Africa.

This study aimed to identify alcohol use patterns associated with viral non-suppression among women living with HIV (WLWH) and the extent to which adherence mediated these relationships. Baseline data on covariates, alcohol consumption, ART adherence, and viral load were collected from 608 WLWH on ART living in the Western Cape, South Africa. We defined three consumption patterns: no/light drinking (drinking ≤ 1/week and ≤ 4 drinks/occasion), occasional heavy episodic drinking (HED) (drinking > 1 and ≤ 2/week and ≥ 5 drinks/occasion) and frequent HED (drinking ≥ 3 times/week and ≥ 5 drinks/occasion). In multivariable analyses, occasional HED (OR 3.07, 95% CI 1.78-5.30) and frequent HED (OR 7.11, 95% CI 4.24-11.92) were associated with suboptimal adherence. Frequent HED was associated with viral non-suppression (OR 2.08, 95% CI 1.30-3.28). Suboptimal adherence partially mediated the relationship between frequent HED and viral non-suppression. Findings suggest a direct relationship between frequency of HED and viral suppression. Given the mediating effects of adherence on this relationship, alcohol interventions should be tailored to frequency of HED while also addressing adherence.

High-level psychotropic polypharmacy: a retrospective comparison of children in foster care to their peers on Medicaid.

BACKGROUND: The use of antipsychotic medication and psychotropic polypharmacy has increased in the United States over the last two decades especially for children from low-income families and those in foster care. Although attention has been paid to providing greater insight, prescribing patterns remain concerning since there is a lack of evidence related to safety and efficacy. High-level psychotropic polypharmacy has not been described. We aim to compare the use of HLPP for children receiving Medicaid services and those in foster care and identify factors associated with the duration of use of high-level psychotropic polypharmacy. Additionally, we will examine the frequency of laboratory metabolic screening and emergency department, inpatient, and outpatient visits. METHODS: A cross-sectional, secondary analysis of statewide data describes trends in high-level psychotropic polypharmacy from 2012 to 2017 and the prevalence and predictors of high-level psychotropic polypharmacy duration and resource use in 2017 for all children on Medicaid and those in foster care. High-level psychotropic polypharmacy included concurrent use, at least four classes of medications including an antipsychotic, and at least 30 days duration. RESULTS: High-level psychotropic polypharmacy increased from 2012 to 2014 for both groups but stabilized in 2015-2016. Children in foster care showed a slight increase compared to their peers in 2017. There was no association between duration and demographic characteristics or foster care status. Diagnoses predicted duration. Neither group received metabolic monitoring at an acceptable rate. CONCLUSIONS: Concerning patterns of high-level psychotropic polypharmacy and metabolic monitoring were identified. Cautious use of high-level psychotropic polypharmacy and greater oversight to ensure that these children are receiving comprehensive services like behavioral health, primary care, and primary prevention.

A comparison of ultrasound guided bilateral single injection shot Erector Spinae Plane blocks versus wound infiltration for post-operative analgesia in laparoscopic assisted colonic surgery- a prospective randomised study.

BACKGROUND: Both wound infiltration (WI) with local anaesthetic and Erector Spinae Plane block (ESPB) have been described for post-operative analgesia after abdominal surgery. This study compared the efficacy of WI versus ESPB for post-operative analgesia after laparoscopic assisted colonic surgery. METHODS: Seventy-two patients between 18 and 85 years of age undergoing elective surgery were randomised to receive either WI or ESPB. In the WI group a 40 ml bolus of 0.5% Ropivacaine, infiltrated at the ports and minimally invasive wound at subcutaneous and fascia layers. In the ESPB group at T8 level, under ultrasound guidance, a 22-gauge nerve block needle was passed through the Erector Spinae muscle to reach its fascia. A dose up to 40 ml of 0.5% Ropivacaine, divided into two equal volumes, was injected at each side. Both groups had a multimodal analgesic regime, including regular Paracetamol, dexamethasone and patient-controlled analgesia (PCA) with Fentanyl. The primary end point was a post-operative pain score utilising a verbal Numerical Rating Score (NRS, 0-10) on rest and coughing in the post anaesthetic care unit (PACU) and in the first 24 h. Secondary outcomes measured were: opioid usage, length of stay and any clinical adverse events. RESULTS: There was no significant treatment difference in PACU NRS at rest and coughing (p-values 0. 382 and 0.595respectively). Similarly, there were no significant differences in first 24 h NRS at rest and coughing (p-values 0.285 and 0.431 respectively). There was no significant difference in Fentanyl use in PACU or in the first 24 h (p- values 0.900 and 0.783 respectively). Neither was there a significant difference found in mean total Fentanyl use between ESPB and WI groups (p-value 0.787). CONCLUSION: Our observations found both interventions had an overall similar efficacy. TRIAL REGISTRATION: The study was registered with the Australian New Zealand Clinical Trial Registry (ACTRN: 12619000113156 ).

Boron-Nitrogen-Doped Nanographenes: A Synthetic Tale from Borazine Precursors.

In this work, a comprehensive account of the authors' synthetic efforts to prepare borazino-doped hexabenzocoronenes by using the Friedel-Crafts-type electrophilic aromatic substitution is reported. Hexafluoro-functionalized aryl borazines, bearing an ortho fluoride leaving group on each of the N- and B-aryl rings, was shown to lead to cascade-type electrophilic aromatic substitution events in the stepwise C-C bond formation, giving higher yields of borazinocoronenes than those obtained with borazine precursors bearing fluoride leaving groups at the ortho positions of the B-aryl substituents. By using this pathway, an unprecedented boroxadizine-doped PAH featuring a gulf-type periphery could be isolated, and its structure proven by single-crystal X-ray diffraction analysis. Mechanistic studies on the stepwise Friedel-Crafts-type cyclization suggest that the mechanism of the planarization reaction proceeds through extension of the π system. To appraise the doping effect of the boroxadizine unit on the optoelectronic properties of topology-equivalent molecular graphenes, the all-carbon and pyrylium PAH analogues, all featuring a gulf-type periphery, were also prepared. As already shown for the borazino-doped hexabenzocoronene, the replacement of the central benzene ring by its B3 N2 O congener widens the HOMO-LUMO gap and dramatically enhances the fluorescence quantum yield.

Magnesium isotopes of the bulk solar wind from Genesis diamond-like carbon films.

NASA's Genesis Mission returned solar wind (SW) to the Earth for analysis to derive the composition of the solar photosphere from solar material. SW analyses control the precision of the derived solar compositions, but their ultimate accuracy is limited by the theoretical or empirical models of fractionation due to SW formation. Mg isotopes are "ground truth" for these models since, except for CAIs, planetary materials have a uniform Mg isotopic composition (within ≤1‰) so any significant isotopic fractionation of SW Mg is primarily that of SW formation and subsequent acceleration through the corona. This study analyzed Mg isotopes in a bulk SW diamond-like carbon (DLC) film on silicon collector returned by the Genesis Mission. A novel data reduction technique was required to account for variable ion yield and instrumental mass fractionation (IMF) in the DLC. The resulting SW Mg fractionation relative to the DSM-3 laboratory standard was (-14.4‰, -30.2‰) ± (4.1‰, 5.5‰), where the uncertainty is 2Æ¡ SE of the data combined with a 2.5‰ (total) error in the IMF determination. Two of the SW fractionation models considered generally agreed with our data. Their possible ramifications are discussed for O isotopes based on the CAI nebular composition of McKeegan et al. (2011).

Feed-derived iodine overrides environmental contribution to cow milk.

Diets worldwide are deficient in iodine, leading to a range of undesirable health effects at the population level. Dairy products are a primary source of iodine in diets for those populations in which iodized salt is not systematically used or available. However, the flows of iodine through dairy agroecosystems are not well understood. The aim of this research was to investigate iodine flows though the dairy agroecosystem, including the influence of atmospheric depositional inputs, environmental variables, season, husbandry, and diet. Three farm-based sampling campaigns were carried out in this investigation, with milk, soil, silage, grass, and feed iodine determined by inductively coupled plasma mass spectroscopy, and nonparametric statistical analysis tests were conducted on data sets obtained. Natural iodine inputs into the environment are dominated by atmospheric deposition, which mainly from sea spray, and thus the location of farms relative to the coast and prevailing wind direction. Herbage and silage produced from grass-based systems strongly correlated with soil iodine, yet there was a strong disconnect between soil, forage, and feed and the milk that results. This was due to the levels of iodine in supplemental feeds being approximately 10-fold higher than those in forage-derived feeds. The practice of feed supplementation, accentuated by summer housing of cows, led to elevated milk iodine.

Patterns of Growth and Decline in Lung Function in Persistent Childhood Asthma.

BACKGROUND: Tracking longitudinal measurements of growth and decline in lung function in patients with persistent childhood asthma may reveal links between asthma and subsequent chronic airflow obstruction. METHODS: We classified children with asthma according to four characteristic patterns of lung-function growth and decline on the basis of graphs showing forced expiratory volume in 1 second (FEV1), representing spirometric measurements performed from childhood into adulthood. Risk factors associated with abnormal patterns were also examined. To define normal values, we used FEV1 values from participants in the National Health and Nutrition Examination Survey who did not have asthma. RESULTS: Of the 684 study participants, 170 (25%) had a normal pattern of lung-function growth without early decline, and 514 (75%) had abnormal patterns: 176 (26%) had reduced growth and an early decline, 160 (23%) had reduced growth only, and 178 (26%) had normal growth and an early decline. Lower baseline values for FEV1, smaller bronchodilator response, airway hyperresponsiveness at baseline, and male sex were associated with reduced growth (P<0.001 for all comparisons). At the last spirometric measurement (mean [±SD] age, 26.0±1.8 years), 73 participants (11%) met Global Initiative for Chronic Obstructive Lung Disease spirometric criteria for lung-function impairment that was consistent with chronic obstructive pulmonary disease (COPD); these participants were more likely to have a reduced pattern of growth than a normal pattern (18% vs. 3%, P<0.001). CONCLUSIONS: Childhood impairment of lung function and male sex were the most significant predictors of abnormal longitudinal patterns of lung-function growth and decline. Children with persistent asthma and reduced growth of lung function are at increased risk for fixed airflow obstruction and possibly COPD in early adulthood. (Funded by the Parker B. Francis Foundation and others; ClinicalTrials.gov number, NCT00000575.).

Ado-trastuzumab emtansine (T-DM1) in patients with HER2-amplified tumors excluding breast and gastric/gastroesophageal junction (GEJ) adenocarcinomas: results from the NCI-MATCH trial (EAY131) subprotocol Q.

BACKGROUND: The National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) is a national precision medicine study incorporating centralized genomic testing to direct refractory cancer patients to molecularly targeted treatment subprotocols. This treatment subprotocol was designed to screen for potential signals of efficacy of ado-trastuzumab emtansine (T-DM1) in HER2-amplified histologies other than breast and gastroesophageal tumors. METHODS: Eligible patients had HER2 amplification at a copy number (CN) >7 based on targeted next-generation sequencing (NGS) with a custom Oncomine AmpliSeq™ (ThermoFisher Scientific) panel. Patients with prior trastuzumab, pertuzumab or T-DM1 treatment were excluded. Patients received T-DM1 at 3.6 mg/kg i.v. every 3 weeks until toxicity or disease progression. Tumor assessments occurred every three cycles. The primary end point was centrally assessed objective response rate (ORR). Exploratory end points included correlating response with HER2 CN by NGS. The impact of co-occurring genomic alterations and PTEN loss by immunohistochemistry were also assessed. RESULTS: Thirty-eight patients were enrolled and 36 included in efficacy analysis. Median prior therapies in the metastatic setting was 3 (range 0-9; unknown in one patient). Median HER2 CN was 17 (range 7-139). Partial responses were observed in two (5.6%) patients: one mucoepidermoid carcinoma of parotid gland and one parotid gland squamous cell cancer. Seventeen patients (47%) had stable disease including 8/10 (80%) with ovarian and uterine carcinomas, with median duration of 4.6 months. The 6-month progression-free survival rate was 23.6% [90% confidence interval 14.2% to 39.2%]. Common toxicities included fatigue, anemia, fever and thrombocytopenia with no new safety signals. There was a trend for tumor shrinkage with higher levels of gene CN as determined by the NGS assay. CONCLUSION: T-DM1 was well tolerated. While this subprotocol did not meet the primary end point for ORR in this heavily pre-treated diverse patient population, clinical activity was seen in salivary gland tumors warranting further study in this tumor type in dedicated trials.

Longitudinal Trends in the Diagnosis of Attention-Deficit/Hyperactivity Disorder and Stimulant Use in Preschool Children on Medicaid.

OBJECTIVES: To describe trends in the diagnosis of attention-deficit/hyperactivity disorder (ADHD) and prescribing of stimulants in preschool-age children receiving Medicaid and to identify factors associated with the receipt of psychosocial care. STUDY DESIGN: Data were extracted from 2012-2016 Kentucky Medicaid claims for children aged <6 years. ADHD was identified using International Classification of Diseases, Tenth Revision codes F90.0, F90.1, F90.2, F90.8, and F90.9. Psychosocial therapy was defined as having at least 1 relevant Current Procedural Terminology code in a claim within the year. A generalized linear model with a logit link and binomial distribution was used to assess factors associated with receipt of psychosocial treatment in 2016. RESULTS: More than 2500 (1.24%) preschool-aged children receiving Medicaid had a diagnosis of ADHD in 2016, with 988 (38.2%) of those receiving a stimulant medication. Children in foster care were diagnosed with and/or treated for ADHD 4 times more often than other Medicaid recipients. Of the 1091 preschoolers receiving stimulants, 99 (9%) did not have a diagnosis of ADHD. There were no significant differences in diagnoses by race/ethnicity, but children reported to be black, Hispanic, or other race/ethnicity received stimulants at a lower rate than white children. Positive predictors for receiving psychosocial therapy in 2016 included having the diagnosis but not receiving a stimulant, having at least 1 prescription written by a psychiatrist, having comorbidities, and age. The use of stimulants in children aged <6 years declined from 0.9% in 2012 to 0.5% in 2016. CONCLUSIONS: Promising trends demonstrate a decreasing use of stimulants in preschoolers; however, continued vigilance is needed to promote the optimal use of psychosocial interventions.