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OBJECTIVE Patient-Reported Outcomes Measurement Information System® (PROMIS® ) measures can be administered via computerized adaptive testing (CAT) or fixed short forms (FSF), but the empirical benefits of CAT versus FSF are unknown in juvenile myositis (JM). This study assesses if PROMIS CAT is feasible, precise, correlated with FSF, and less prone to respondent burden and floor/ceiling effects than FSF in JM. METHODS Patients 8-17 yo (self-report and parent proxy) and parents of patients 5-7 yo (only parent proxy) completed PROMIS Fatigue, Pain Interference, Upper Extremity Function, Mobility, Anxiety and Depressive Symptoms measures. Pearson correlations, paired t-tests, and Cohen's D were calculated between PROMIS CAT and FSF. McNemar test assessed floor/ceiling effects between CAT and FSF. Precision and respondent burden were examined across the T-score range. RESULTS Data from 67 patient-parent dyads were analyzed. CAT and FSF mean scores did not significantly differ except in parent proxy Anxiety and Fatigue (effect size: 0.23 and 0.19, respectively). CAT had less pronounced floor/ceiling effects at the less symptomatic extreme in all domains except self-report Anxiety. Increased item burden and higher standard errors were seen in less symptomatic scorers for CAT. Modified stopping rules limiting CAT item administration did not decrease precision. CONCLUSION PROMIS CAT appears to be feasible and correlated with FSF. CAT had less pronounced floor/ceiling effects, allowing detection of individual differences in less symptomatic patients. Modified stopping rules for CAT may decrease respondent burden. CAT can be considered for long-term follow-up of JM patients.

BACKGROUND The COVID-19 pandemic disrupted healthcare in the United States and raised concerns about certain antihypertensives, and may have impacted both prescribing practices and access to blood pressure (BP) medications. METHODS We assessed trends in BP prescription fills before and during the first year of the COVID-19 pandemic, using cross-sectional data for BP fills and tablets in the IQVIA (IMS Health) National Prescription Audit® database. Drugs filled via retail (92% coverage), mail-order (78% coverage), and long-term care (72% coverage) channels from January 2018 through December 2020 were included. Data were projected nationally and by state. RESULTS Between 2.9 and 3.4 billion BP tablets were dispensed monthly until February 2020, increasing sharply to 3.8 billion in March 2020 and declining to 3.5 billion in April, then increasing at 3-month intervals until December 2020. The number of tablets per fill increased slightly over time, with the largest increase (from 66.7 to 68.6) during February–March, 2020. Tablets were dispensed through retail channels (99.7 billion), mail-order (14.7 billion), and long-term care (5.3 billion). Rates of patients initiating new medications decreased during 2020 compared to prior years. Fills did not vary significantly by drug class. CONCLUSIONS A sharp increase in BP fills occurred with COVID-19 emergence, suggesting patients may have secured medications in preparation for potential access limitations. A decrease in new fills, indicating decreased initiation and/or modification of treatment regimens, suggests need for efforts to re-engage patients in the healthcare system and provide alternative ways to obtain medication refills and adjustments.

Purpose: UGT1A1*28 confers a higher risk of toxicity in patients treated with irinotecan. Patients with *1/*1 and *1/*28 genotypes might tolerate higher than standard doses of irinotecan. We aimed to identify the MTD of irinotecan in patients with metastatic colorectal cancer (mCRC) with *1/*1 and *1/*28 genotypes treated with FOLFIRI plus bevacizumab, and to determine whether bevacizumab alters irinotecan pharmacokinetics.Experimental Design: Previously untreated patients with mCRC (25 *1/*1; 23 *1/*28) were given FOLFIRI plus bevacizumab every 2 weeks. The irinotecan dose was escalated using a 3 + 3 design in each genotype group as follows: 260, 310, and 370 mg/m2. The MTD was the highest dose at which Results: For *1/*1 patients, 2 DLTs were observed among 10 patients at 310 mg/m2, while 370 mg/m2 was not tolerated (2 DLTs in 4 patients). For *1/*28 patients, 2 DLTs were observed among 10 patients at 260 mg/m2, while 310 mg/m2 was not tolerated (4 DLTs in 10 patients). Neutropenia and diarrhea were the most common DLTs. Changes in the AUCs of irinotecan and SN-38 associated with bevacizumab treatment were marginal.Conclusions: The MTD of irinotecan in FOLFIRI plus bevacizumab is 310 mg/m2 for UGT1A1 *1/*1 patients and 260 mg/m2 for *1/*28 patients. Bevacizumab does not alter the pharmacokinetics of irinotecan. The antitumor efficacy of these genotype-guided doses should be tested in future studies of patients with mCRC treated with FOLFIRI plus bevacizumab. Clin Cancer Res; 23(4); 918–24. ©2016 AACR.

Supplementary Table 1. Toxicities during the first cycle of FOLFIRI plus bevacizumab. Number of patients (%) is indicated. Toxicities were included if they occurred in at least 10% of patients or if they were grade 3 or greater, and if they were at least possibly related to treatment.

Supplementary Figure 1. Progression-free survival (PFS) overall (A), by UGT1A1 genotype (B), and by irinotecan dose (C).

Supplementary Table 2 from In vitro Progression of Human Papillomavirus 16 Episome-Associated Cervical Neoplasia Displays Fundamental Similarities to Integrant-Associated Carcinogenesis

Supplementary Figure 1 from In vitro Progression of Human Papillomavirus 16 Episome-Associated Cervical Neoplasia Displays Fundamental Similarities to Integrant-Associated Carcinogenesis

Supplementary Figure 3 from In vitro Progression of Human Papillomavirus 16 Episome-Associated Cervical Neoplasia Displays Fundamental Similarities to Integrant-Associated Carcinogenesis

An important event in the development of cervical squamous cell carcinoma (SCC) is deregulated expression of high-risk human papillomavirus (HR-HPV) oncogenes, most commonly related to viral integration into host DNA. Mechanisms of development of the ∼15% of SCCs that contain extrachromosomal (episomal) HR-HPV are poorly understood due to limited longitudinal data. We therefore used the W12 model to study mechanisms of cervical carcinogenesis associated with episomal HPV16. In vitro progression of W12 normally occurs through selection of cells containing integrated HPV16. However, in one long-term culture, keratinocytes developed a selective growth advantage and invasive phenotype while retaining HPV16 episomes at increased copy number in the absence of transcriptionally active integrants. Longitudinal investigations revealed similarities between the episome- and integrant-associated routes of neoplastic progression. Most notable were dynamic changes in viral early gene expression in episome-retaining cells, consistent with continually changing selective pressures. An early increase in viral transcription preceded elevated episome copy number and was followed by a reduction to near baseline after the development of invasiveness. Episomal transcriptional deregulation did not require selection of a specific sequence variant of the HPV16 upstream regulatory region, although increased levels of acetylated histone H4 around the late promoter implicated a role for altered chromatin structure. Interestingly, invasive episome-retaining cells showed high levels of HPV16 E2/E6 proteins (despite decreased transcript levels) and reduced expression of IFN-stimulated genes, adaptations that support viral persistence and cell survival. Our findings suggest a unified working model for events important in cervical neoplastic progression regardless of HR-HPV physical state. Cancer Res; 70(10); 4081–91. ©2010 AACR.

Supplementary Figure Legends 1-4 from In vitro Progression of Human Papillomavirus 16 Episome-Associated Cervical Neoplasia Displays Fundamental Similarities to Integrant-Associated Carcinogenesis

Supplementary Figure 4 from In vitro Progression of Human Papillomavirus 16 Episome-Associated Cervical Neoplasia Displays Fundamental Similarities to Integrant-Associated Carcinogenesis

Supplementary Figure 2 from In vitro Progression of Human Papillomavirus 16 Episome-Associated Cervical Neoplasia Displays Fundamental Similarities to Integrant-Associated Carcinogenesis

Supplementary Table 1 from In vitro Progression of Human Papillomavirus 16 Episome-Associated Cervical Neoplasia Displays Fundamental Similarities to Integrant-Associated Carcinogenesis

The thermal and chemical stability of 24mer ferritins has led to attempts to exploit their naturally occurring nanoscale (8 nm) internal cavities for biotechnological applications. An area of increasing interest is the encapsulation of molecules either for medical or biocatalysis applications. Encapsulation requires ferritin dissociation, typically induced using high temperature or acidic conditions (pH ≥ 2), which generally precludes the inclusion of fragile cargo such as proteins or peptide fragments. Here we demonstrate that minimizing salt concentration combined with adjusting the pH to ≤8.5 (i.e. low proton/metal ion concentration) reversibly shifts the naturally occurring equilibrium between dimeric and 24meric assemblies of Escherichia coli bacterioferritin (Bfr) in favour of the disassembled form. Interconversion between the different oligomeric forms of Bfr is sufficiently slow under these conditions to allow the use of size exclusion chromatography to obtain wild type protein in the purely dimeric and 24meric forms. This control over association state was exploited to bind heme at natural sites that are not accessible in the assembled protein. The potential for biotechnological applications was demonstrated by the encapsulation of a small, acidic [3Fe-4S] cluster-containing ferredoxin within the Bfr internal cavity. The capture of ∼4–6 negatively charged ferredoxin molecules per cage indicates that charge complementarity with the inner protein surface is not an essential determinant of successful encapsulation.

Objective: Spinal cord lesions resulting from spinal cord injury (SCI) and spina bifida (SB) are permanent and cause significant functional impairment. High rates of impaired psychological function and lower health-related quality of life (HRQOL) have been documented in children with SB and their caregivers, but few studies have examined these issues in the pediatric SCI population. Moreover, no research has investigated mental health or HRQOL among children living with spinal cord lesions, or their caregivers, in the developing world. There is reason to suspect that lack of access to medical, rehabilitative, and psychological resources places these individuals at particular risk for compromised psychological functioning. Therefore, the goals of the present study are: 1) to compare psychological functioning and HRQOL of children with SCI or SB to an age-matched comparison group; 2) to compare the psychological functioning, HRQOL, and level of burden in caregivers of children with SCI /SB to that of caregivers of healthy age-matched children; and, 3) to determine the influence of hopefulness on anxious and depressive symptomatology and HRQOL in children with SCI or SB. Participants: Thirty children with spinal cord lesions; 30 age-matched comparison group children; 30 caregivers of children with spinal cord lesions, and 30 caregivers of comparison group children. Methods: Children and caregivers completed a series of questionnaires assessing depressive and anxious symptomatology and HRQOL. Children also completed a questionnaire assessing hopefulness, and caregivers completed a questionnaire assessing levels of burden. Results: Contrary to hypotheses, significant between-group differences were not observed in terms of depressive and anxious symptoms in either children or their caregivers. However, significant differences in HRQOL were observed between children with spinal cord lesions and the comparison group. Finally, results revealed significant differences between caregiver groups on measures of HRQOL and burden. Conclusions: Results therefore highlight the need service delivery in Colombia to children with spinal cord lesions and their caregivers. Access to improved medical, rehabilitative, and psychological care could profoundly impact quality of life in the spinal cord lesion child and caregiver population, particularly with regard to respite services and resources to improve children's ability to attend school and participate in the community. In addition, parents of Colombian children with permanent physical disabilities may not expect their children to achieve normative levels of participation as compared to their healthy peers; psychoeducation would likely assist parents to understand that their children can live full lives despite their different abilities.

The study investigates the affordances of email newsletters as perceived by the general public subscribers of non-profit organizations’ e-newsletters, through analyzing over 17,000 survey responses. An affordance lens acknowledges the possibility of multiple courses of action and forms of engagement in relation to the technology. Findings reveal that email newsletters may be more useful in terms of relationship cultivation than has been generally recognized, but also that perceptions of email affordances varied considerably between segments of the non-profit sector. While finding no strong links between e-newsletter receipt and volunteering or donation activity, the usefulness of email newsletters in terms of building connection between organization and recipient was confirmed at a moderate level. While illuminating the range of affordances offered by email, which has been largely overlooked in the literature, this study also suggests a number of implications for organizations in the non-profit sector.

This study analyses media coverage of two Māori women politicians in Aotearoa New Zealand. This article adopts an intersectional lens to critically examine the discriminatory ideologies at play in mainstream New Zealand media coverage of Metiria Turei and Paula Bennett. The analysis reveals that although the coverage examined in this article presents the Māori heritage of the two women very differently, the coverage pays close attention to both women’s gender and bodies while simultaneously diminishing their individuality by folding them into stereotypes. Classification and disempowerment of ‘stroppy women’/‘stirrer Māori’ are enabled by the intersection of racist, sexist and classist discourses.

Objective: Levels of chitotriosidase (CHIT1) are increased in the cerebrospinal fluid (CSF) of amyotrophic lateral sclerosis (ALS) patients reflecting microglial activation. Here, we determine the diagnostic and prognostic potential of CHIT1 for early symptomatic ALS. Methods: Overall, 275 patients from 8 European neurological centers were examined. We included ALS with 6 months from symptom onset, other motoneuron diseases (oMND), ALS mimics (DCon) and non-neurodegenerative controls (Con). CSF CHIT1 levels were analyzed for diagnostic power and association with progression and survival in comparison to the benchmark neurofilament. The 24-bp duplication polymorphism of CHIT1 was analyzed in a subset of patients (N=65). Results: Homozygous CHIT1 duplication mutation carriers (9%) invariably had undetectable CSF CHIT1 levels, while heterozygous carriers had similar levels as patients with wildtype CHIT1 (p=0.414). In both early and late symptomatic ALS CHIT1 levels was increased, did not correlate with patients’ progression rates, and was higher in patients diagnosed with higher diagnostic certainty. Neurofilament levels correlated with CHIT1 levels and prevailed over CHIT1 regarding diagnostic performance. Both CHIT1 and neurofilaments were identified as independent predictors of survival in late but not early symptomatic ALS. Evidence is provided that CHIT1 predicts progression in El Escorial diagnostic category in the group of ALS cases with a short duration. Conclusions: CSF CHIT1 level may have additional value in the prognostication of ALS patients with a short history of symptoms classified in diagnostic categories of lower clinical certainty. To fully interpret apparently low CHIT1 levels knowledge of CHIT1 genotype is needed.

The aim of the study was to evaluate whether there are clinical subtypes in children with functional nausea based on comorbidities and responses to the Nausea Profile questionnaire.Patients from the Neurointestinal and Motility Program clinical registry at Lurie Children's Hospital were included if they met Rome IV criteria for functional nausea. Patients completed the Nausea Profile, a multidimensional measure of nausea with gastrointestinal, emotional, and somatic subscales. Comorbidities were assessed by chart review and self-report measures. Latent class analysis was used to identify patient groups based on comorbidities. To assess if model-identified groups were predictive of differences in nausea quality, Nausea Profile subscale means were compared between groups and used to predict group membership. Conversely, k-means analysis was used to divide the sample into groups based upon Nausea Profile subscale scores, to determine if identified groups had different comorbidities.Seventy-two patients (n = 53 girls) with a mean age (±SD) 14.5 ± 2.9 were included. Two clinical subtypes were identified based on comorbidities, with responses on the emotional subscale of the Nausea Profile predicting group membership (P 0.04). When patients were grouped by nausea quality, the resulting clusters differed on psychiatric comorbidities (P 0.001).Our findings support the existence of nausea subtypes within the broad diagnosis of functional nausea. One such subtype is an emotional predominant nausea supporting the notion that anxiety and depression constitute a subset of patients with nausea. Thus, patients may benefit from a treatment approach that integrates both GI assessment and psychiatric support in their care.

Background Diabetic retinopathy (DR) may be asymptomatic in both mild and advanced stages. A patient's accurate perception of their DR severity may therefore be critical for effective self-management behaviors and understanding the need for timely intervention and follow-up. Purpose To evaluate the relationship between self-reported and actual retinopathy severity in diabetic patients. Methods This study was a single-center cross-sectional survey. Diabetic patients identified by enterprise data warehouse were sent an online questionnaire where they were asked to self-assess for presence of DR and grade their severity. Actual DR grading was determined via chart review. The primary outcome measures were patient-assessed DR severity and agreement with actual DR severity. Results Of 3208 invitations sent, 324 (10%) patients responded and 319 responses were analyzed. The data showed that 39 of 253 (15%) with no DR, 26 of 40 (65%) with mild/moderate DR, and 24 of 26 (92%) with severe DR believed they had DR (p

Objective To evaluate the CSF levels of chitinase proteins during the presymptomatic and early symptomatic phases of amyotrophic lateral sclerosis (ALS). Methods CSF samples were obtained from 16 controls, 55 individuals at‐risk for ALS (including 18 carrying a mutation in C9ORF72 , 33 in SOD1 ), 12 ALS patients, and 7 phenoconverters (individuals diagnosed with ALS during follow‐up). At‐risk individuals and phenoconverters were enrolled through the Pre‐fALS study, which includes individuals carrying an ALS‐associated gene mutation without disease manifestations at initial assessment. Longitudinal CSF collections, where possible, took place every 3‐12 months for ALS patients and every 1‐2 years for others. CSF levels of chitotriosidase 1 (CHIT1), chitinase‐3‐like protein 1 (CHI3L1, YKL‐40) and chitinase‐3‐like protein 2 (CHI3L2, YKL‐39) were measured by ELISA, along with CHIT1 activity. Longitudinal changes in at‐risk individuals and phenoconverters were fitted to linear mixed effects models. Results Slowly rising levels of CHIT1 were observed over time in the at‐risk individuals (slope 0.059 log10[CHIT1] per year, P < 0.001). Among phenoconverters, CHIT1 levels and activity rose more sharply (0.403 log10[CHIT1] per year, P = 0.005; 0.260 log10[CHIT1 activity] per year, P = 0.007). Individual levels of both CHI3L1 and CHI3L2 remained relatively stable over time in all participant groups. Interpretation The CHIT1 neuroinflammatory response is a feature of the late presymptomatic to early symptomatic phases of ALS. This study does not suggest a long prodrome of upregulated glial activity in ALS pathogenesis, but strengthens the place of CHIT1 as part of a panel of biomarkers to objectively assess the impact of immune‐modulatory therapeutic interventions in ALS.

To identify risk factors associated with intubation and time to extubation in hospitalized patients with coronavirus disease 2019 (COVID-19).Retrospective observational study.Ten hospitals in the Chicago metropolitan area.Patients with laboratory-confirmed COVID-19 admitted between March 1 and April 8, 2020, were included. We evaluated sociodemographic and clinical characteristics associated with intubation and prolonged intubation for acute respiratory failure secondary to COVID-19 infection.Of the 486 hospitalized patients included in the study, the median age was 59 years (interquartile range, 47-69); 271 (55.8%) were male; and the median body mass index was 30.6 (interquartile range, 26.5-35.6). During the hospitalization, 138 (28.4%) patients were intubated; 78 (56.5%) were eventually extubated; 21 (15.2%) died; and 39 (28.3%) remained intubated at a mean ± SD follow-up of 19.6 ± 6.7 days. Intubated patients had a significantly higher median age (65 vs 57 years,In addition to clinical signs of respiratory distress, patients with COVID-19 who are older, male, or diabetic are at higher risk of requiring intubation. Among intubated patients, older and more obese patients are at higher risk for prolonged intubation. Otolaryngologists consulted for airway management should consider these factors in their decision making.

Background During the last 20 years, 50% of adults with sun-sensitive skin have sunburned annually. Reducing the proportion of people who sunburn requires understanding the circumstances and outdoor activities during which at-risk people sunburn. Methods A 7-day observational study of melanoma survivors (n = 20) and young adult first-degree relatives of melanoma survivors (FDRs) (n = 20) captured daily UV exposure, sun protection, and sunburns during spring and summer in the Midwest of the United States (latitude 41.8°N). Participants wore UV and physical activity sensors and completed a daily self-reported survey of sun protection, sunburn, and physical activities. The estimated protection-adjusted UV dose was calculated for each body area by integrating self-reported sun protection with UV sensor dose. Results In 254 days, at least one body area in 9 of 20 (45%) melanoma survivors and 11 of 20 (55%) FDRs was sunburned (erythema at 24 hours). Sunburns were associated with spring and walking for transportation or leisure, especially walking the dog. Melanoma survivors used sunscreen daily on the face; however, forearms and lower legs were not protected during walking. Young adults did not use sun protection on the face, forearms or lower legs during walking for transportation and use was ineffective during sports. Conclusion The sun protection patterns of daily living identified in this study may promote recognition of erythema as sunburn and inform the development of tailored sun protection mobile applications promoting self-monitoring with wearable UV sensors.