The TERT promoter is polycomb-repressed in neuroblastoma cells with long telomeres.

Acquiring a telomere maintenance mechanism is a hallmark of high-risk neuroblastoma and commonly occurs by expressing telomerase (TERT). Telomerase-negative neuroblastoma has long telomeres and utilize the telomerase-independent alternative lengthening of telomeres (ALT) mechanism. Conversely, no discernable telomere maintenance mechanism is detected in a fraction of neuroblastoma with long telomeres. Here, we show, unlike most cancers, DNA of the TERT promoter is broadly hypomethylated in neuroblastoma. In telomerase-positive neuroblastoma cells, the hypomethylated DNA promoter is approximately 1.5-kb. The TERT locus shows active chromatin marks with low enrichment for the repressive mark, H3K27me3. MYCN, a commonly amplified oncogene in neuroblstoma, binds to the promoter and induces TERT expression. Strikingly, in neuroblastoma with long telomeres, the hypomethylated region spans the entire TERT locus, including multiple nearby genes with enrichment for the repressive H3K27me3 chromatin mark. Furthermore, subtelomeric regions showed enrichment of repressive chromatin marks in neuroblastomas with long telomeres relative to those with short telomeres. These repressive marks were even more evident at the genic loci, suggesting a telomere position effect. Inhibiting H3K27 methylation by three different EZH2 inhibitors induced the expression of TERT in cell lines with long telomeres and H3K27me3 marks in the promoter region. EZH2 inhibition facilitated MYCN binding to the TERT promoter in neuroblastoma cells with long telomeres. Taken together, these data suggest that epigenetic regulation of TERT expression differs in neuroblastoma depending on the telomere maintenance status, and H3K27 methylation is important in repressing TERT expression in neuroblastoma with long telomeres.

Breaking barriers, building faculty: A qualitative analysis to exploring faculty development in academic hospital medicine.

BACKGROUND: Hospital medicine (HM) continues to be primarily composed of junior hospitalists and research has highlighted a paucity of mentors and academic output. Faculty advancement programs have been identified as a means to support junior hospitalists in their career trajectories and to advance the field. The optimal approach to supporting faculty development (FD) efforts is not known. OBJECTIVE: To understand hospitalist groups' approaches to FD, including efforts that were perceived to be effective, and to identify barriers as well as potential future directions for FD. DESIGN: Rapid qualitative methods were utilized including templated summaries and matrix analysis to identify major themes. SETTING AND PARTICIPANTS: Virtual focus groups with hospitalists in the Hospital Medicine Reengineering Network (HOMERuN). MAIN OUTCOME AND MEASURES: Qualitative themes RESULTS: Nineteen individuals from 17 unique institutions from across the United States in May 2022 participated in seven focus groups. Four key themes emerged from the study and included (1) academic hospitalist programs face multifaceted challenges and barriers to FD in HM, (2) groups have embraced a diversity of structures and frameworks, (3) due to clinical volumes, FD programs have had to adapt and evolve to meet FD needs, and (4) participants identified multiple areas for improvement, including defining tangible outcomes of FD programs and creating a repository of FD material which can be shared widely.

Comparative simulation of intraperitoneal aminoglycoside regimens for patients with peritonitis on automated peritoneal dialysis.

BACKGROUND: Intraperitoneal (IP) aminoglycosides (AGs) continue to be the cornerstone of empiric management of peritonitis. AG dosing during automated peritoneal dialysis (APD), however, has not been well studied in patients with peritonitis. We sought to identify differences in AG exposure in the peritoneum and plasma for two different dosing regimens with little supporting evidence in patients on APD with peritonitis. METHODS: A retrospective design that utilised the peritoneal and plasma concentration-time data from a prior study of 18 continuous ambulatory peritoneal dialysis (CAPD) patients with peritonitis to generate an in silico peritoneal and plasma PK model. This model was then used to compare via simulation using Phoenix© WinNonlin Software with IP AG dosing for a loading-dose regimen (1.5 mg/kg first dose) versus a fixed-dose regimen (0.6 mg/kg/d) in patients on APD with peritonitis. RESULTS: Outcome measures were (1) percentage of time where peritoneal peak concentrations/minimal inhibitory concentration (MIC) ratio >10, (2) AUC/MIC > 74 and (3) plasma Cmin concentrations. Both regimens resulted in > 90% optimal peak/MIC ratio and AUC/MIC ratios on days 1 and 5 of the dose protocol. The loading-dose regimen resulted in IP exposures that were 2.5 times greater in the peritoneal compartment on day 1. By day 5, both protocols resulted in similar accumulation of AG plasma Cmin concentrations of 2.5-3.4 mg/L versus 2.4-3.3 mg/L, respectively, for the loading-dose regimen versus fixed-dose regimen. CONCLUSIONS: The current international guidelines for the treatment of peritoneal dialysis-associated peritonitis can continue to recommend the fixed-dose regimen for those on APD with the addition of plasma Cmin monitoring after 3 days to assess for drug accumulation.

FRAMES Elements Associated With Alcohol Treatment Research Assessments and Related Behavior Change.

OBJECTIVE: Assessment reactivity research has contributed substantially to our understanding of alcohol treatment research protocols influencing clinical outcomes. The state of the science is such that relatively little is known about how alcohol treatment research participation influences behavior. The purpose of this study was twofold: (a) to determine the distribution of FRAMES elements (i.e., Feedback, personal Responsibility, Advice, a Menu of options, Empathic style of interaction, and support for Self-efficacy) contained in alcohol treatment research assessment interviews; and (b) to examine their association with subsequent alcohol use among a sample of clients presenting for alcohol use disorder treatment. METHOD: Audiotaped recordings of participant (n = 189) research assessment interviews were converted to digital recordings and reviewed for FRAMES elements using the FRAMES Checklist Instrument. RESULTS: Feedback, personal responsibility, empathic style of interaction, and support for self-efficacy were the more frequently occurring elements across follow-up periods. Alternatively, menu of options and advice occurred infrequently. Feedback and support for self-efficacy predicted subsequent alcohol use, although the association between feedback and alcohol use was unexpectedly positive. CONCLUSIONS: As part of the assessment interview process, alcohol treatment research participants receive multiple instances of feedback and support for self-efficacy specific to their alcohol use that are predictive of changes in alcohol use.

Delayed boosting improves human antigen-specific Ig and B cell responses to the RH5.1/AS01B malaria vaccine.

Modifications to vaccine delivery that increase serum antibody longevity are of great interest for maximizing efficacy. We have previously shown that a delayed fractional (DFx) dosing schedule (0-1-6 month) - using AS01B-adjuvanted RH5.1 malaria antigen - substantially improves serum IgG durability as compared with monthly dosing (0-1-2 month; NCT02927145). However, the underlying mechanism and whether there are wider immunological changes with DFx dosing were unclear. Here, PfRH5-specific Ig and B cell responses were analyzed in depth through standardized ELISAs, flow cytometry, systems serology, and single-cell RNA-Seq (scRNA-Seq). Data indicate that DFx dosing increases the magnitude and durability of circulating PfRH5-specific B cells and serum IgG1. At the peak antibody magnitude, DFx dosing was distinguished by a systems serology feature set comprising increased FcRn binding, IgG avidity, and proportion of G2B and G2S2F IgG Fc glycans, alongside decreased IgG3, antibody-dependent complement deposition, and proportion of G1S1F IgG Fc glycan. Concomitantly, scRNA-Seq data show a higher CDR3 percentage of mutation from germline and decreased plasma cell gene expression in circulating PfRH5-specific B cells. Our data, therefore, reveal a profound impact of DFx dosing on the humoral response and suggest plausible mechanisms that could enhance antibody longevity, including improved FcRn binding by serum Ig and a potential shift in the underlying cellular response from circulating short-lived plasma cells to nonperipheral long-lived plasma cells.

Patient Perceptions of Switching to a Generic Dry Powder Inhaler - Increased Understanding Through Journey Mapping.

Purpose: This qualitative study explored patients' attitudes about and perceptions of generic dry powder inhaler (DPI) substitution for the brand product and patients' views of generic product quality, efficacy, design, and usability. Methods: Forty COPD and asthma patients (36 adults, four adolescents), who were actively using a brand DPI product, participated in one of six focus groups. Participants completed a journey mapping exercise to assess attitudes and opinions about a scenario where they refill their prescription and unexpectedly receive a generic DPI instead of their brand DPI. The focus groups were audio recorded, transcribed, and analyzed thematically. Results: The hypothetical scenario of unexpectedly receiving a generic DPI elicited mixed feelings including: happiness and relief about potential cost savings, confusion, disappointment, anger, and/or frustration with the unexpected switch. Participants in most groups anticipated anxiety or hesitation in using the generic DPI due to concerns about potential differences in usability, uncertainty about correct use, and questions about efficacy. Participants across all groups said they would ask a pharmacist or healthcare provider for information or answers to their questions, and some participants said they would use online resources. When participants held the brand and generic DPI devices, most preferred the brand DPI device and found it easier, less cumbersome, or more convenient to use (due to size and weight). However, many participants reiterated that the potential reduced cost of the generic DPI would be a primary factor in their decision-making related to generic DPI substitution for their brand DPI. Conclusion: Patients experienced a mixture of positive and negative feelings when faced with an unexpected generic DPI substitution. Some patients have doubts about their ability to successfully navigate differences in generic device design, and most expressed the desire to participate in discussions and decision-making with their HCP about generic DPI sameness and substitution.

Treatment of HR+/HER2- breast cancer in urban mainland China: results from the CancerMPact Survey 2019.

PURPOSE: To report the treatment utilization patterns for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer in urban mainland China (CancerMPact®). METHODS: The results presented are from an online survey conducted in September 2019 with 45 physicians treating breast cancer patients from 11 cities in mainland China. RESULTS: Surveyed physicians reported that Stage I HR+/HER2(-) breast cancer patients are often treated with surgery alone (42%), whereas the use of surgery in combination with systemic therapy with or without radiotherapy increases in later stages (Stage II 67%, Stage III 77%). Doxorubicin-cyclophosphamide (AC)-based regimens were the most common in both the neoadjuvant and adjuvant settings in HR+/HER2(-) breast cancer patients, across all stages. In metastatic patients, use of surgery and radiotherapy decreases in favor of utilization of systemic therapy alone. Pre- and post-menopausal metastatic patients were frequently treated with hormone therapy or AC-based regimens in first line. Regardless of the first-line therapy administered, capecitabine-based regimens were commonly used in second line. In third line, chemotherapy regimens containing capecitabine or gemcitabine were given to nearly 40% of HR+/HER2(-) breast cancer patients. There were no standard of care regimens established for fourth or greater lines of treatment. In metastatic HR+/HER2(-) breast cancer, physicians reported 50% objective response rates in first-line settings with a progression-free survival of 16 months. CONCLUSION: HR+/HER2(-) breast cancer patients in urban mainland China were prescribed chemotherapy regimens more frequently than CDK4/6 inhibitors. Treatment practices varied, with physicians reporting the use of multiple modalities and treatment regimens for their patients.

The prostate tissue-based telomere biomarker as a prognostic tool for metastasis and death from prostate cancer after prostatectomy.

Current biomarkers are inadequate prognostic predictors in localized prostate cancer making treatment decision-making challenging. Previously, we observed that the combination of more variable telomere length among prostate cancer cells and shorter telomere length in prostate cancer-associated stromal cells - the telomere biomarker - is strongly associated with progression to metastasis and prostate cancer death after prostatectomy independent of currently used pathologic indicators. Here, we optimized our method allowing for semi-automated telomere length determination in single cells in fixed tissue, and tested the telomere biomarker in five cohort studies of men surgically treated for clinically localized disease (N = 2,255). We estimated the relative risk (RR) of progression to metastasis (N = 311) and prostate cancer death (N = 85) using models appropriate to each study's design adjusting for age, prostatectomy stage, and tumor grade, which then we meta-analyzed using inverse variance weights. Compared with men who had less variable telomere length among prostate cancer cells and longer telomere length in prostate cancer-associated stromal cells, men with the combination of more variable and shorter telomere length had 3.76 times the risk of prostate cancer death (95% confidence interval [CI] 1.37-10.3, p = 0.01) and had 2.23 times the risk of progression to metastasis (95% CI 0.99-5.02, p = 0.05). The telomere biomarker was associated with prostate cancer death in men with intermediate risk disease (grade groups 2/3: RR = 9.18, 95% CI 1.14-74.0, p = 0.037) and with PTEN protein intact tumors (RR = 6.74, 95% CI 1.46-37.6, p = 0.015). In summary, the telomere biomarker is robust and associated with poor outcome independent of current pathologic indicators in surgically treated men.

Therapeutic Vulnerability to ATR Inhibition in Concurrent NF1 and ATRX-Deficient/ALT-Positive High-Grade Solid Tumors.

Subsets of Neurofibromatosis Type 1 (NF1)-associated solid tumors have been shown to display high frequencies of ATRX mutations and the presence of alternative lengthening of telomeres (ALT). We studied the phenotype of combined NF1 and ATRX deficiency in malignant solid tumors. Cell lines derived from NF1-deficient sporadic glioblastomas (U251, SF188), an NF1-associated ATRX mutant glioblastoma cell line (JHH-NF1-GBM1), an NF1-derived sarcoma cell line (JHH-CRC65), and two NF1-deficient MPNST cell lines (ST88-14, NF90.8) were utilized. Cancer cells were treated with ATR inhibitors, with or without a MEK inhibitor or temozolomide. In contrast to the glioma cell line SF188, combined ATRX knockout (KO) and TERC KO led to ALT-like properties and sensitized U251 glioma cells to ATR inhibition in vitro and in vivo. In addition, ATR inhibitors sensitized U251 cells to temozolomide, but not MEK inhibition, irrespective of ATRX level manipulation; whereas, the JHH-NF1-GBM1 cell line demonstrated sensitivity to ATR inhibition, but not temozolomide. Similar effects were noted using the MPNST cell line NF90.8 after combined ATRX knockdown and TERC KO; however, not in ST88-14. Taken together, our study supports the feasibility of targeting the ATR pathway in subsets of NF1-deficient and associated tumors.

Alcohol Treatment Research Contributing to Changes in Substance Use Behavior and Related Negative Consequences.

OBJECTIVE: The purpose of this study was to investigate the extent to which two of the more salient characteristics of a treatment research assessment protocol (i.e., the comprehensiveness of the assessment battery and the frequency of its administration) for alcohol use disorder contribute to reductions in substance use and related negative consequences. METHOD: Study participants were recruited from two hospital-administered substance use disorder outpatient clinics. Two hundred thirty-five individuals presenting for outpatient alcohol treatment screened study eligible and provided informed consent. Study participants were randomized to one of four research assessment conditions (i.e., frequent-comprehensive, frequent-brief, infrequent-comprehensive, and infrequent-brief) based on the crossing of a 2 (i.e., assessment comprehensiveness: comprehensive vs. brief) by 2 (i.e., assessment frequency: frequent vs. infrequent) factorial design. RESULTS: Individuals assigned to the frequent assessment conditions reported greater reductions in substance use and substance use-related negative consequences relative to their counterparts assigned to the infrequent assessment conditions. In addition, a greater proportion of individuals assigned to the frequent assessment conditions reported abstinence from both alcohol and other substances. CONCLUSIONS: The improvements in substance use and related negative consequences associated with more frequent research assessments were statistically significant and clinically meaningful.

Next Generation Identification system: Latent print matching algorithm and casework practices.

The development of automated fingerprint identification systems (AFIS) revolutionized casework in the friction ridge community. Through the evolution of AFIS development, algorithms have become increasingly sensitive and specific. Internal validation studies conducted by the Federal Bureau of Investigation Laboratory Division's Latent Print Units (LPU) assessed the performance of the Next Generation Identification (NGI) system's latent print matching algorithm under the various encoding methods of the Multi-Biometric Identification System (MBIS) platform for the purpose of casework implementation. Based on the results of these studies, casework practices in the LPU have become more streamlined and efficient. The increase in accuracy of the latent print matching algorithm has reduced the number of candidates compared per search. For fingerprints, the results showed the best indicator for the correct mate being the number one candidate was the difference in score between the first and second candidate. When the score difference was 1200 or higher, the first candidate was mated in 99.3% of the trials. This understanding may allow for additional quality assurance measures to be implemented in casework.

Patterns of Care and Outcomes for Non-Metastatic Prostate Cancer in the United States: Results of the CancerMPact® Survey 2018.

PURPOSE: We describe patterns of care and treatment outcomes for non-metastatic PCa (nmPCA), either hormone-sensitive or castration-resistant, in the United States of America (USA) in 2018. METHODS: A survey (CancerMPact®) recruited physicians nationwide to answer an online questionnaire about how they treated patients with nmPCA. Questions covered aspects of treatment at all disease stages. Board-certified urologists and oncologists with at least five years of clinical practice and who treated at least 30 PCa patients monthly were included. RESULTS: The survey included responses from ninety-four physicians with an average of 17.5 years of clinical practice, who had treated a combined average of 4415 patients with nmPCA per month in 2018. Approximately 40% of patients in stage I were managed with either active surveillance or observation/no therapy, decreasing to 20%, 8% and 6% in stages II, III and IV(M0), respectively. Intensity-modulated radiotherapy was favored over other radiotherapy modalities, with rates of use ranging between 60% and 69% depending on disease stage. Leuprolide as monotherapy or in combination with enzalutamide, abiraterone or bicalutamide were the most common systemic treatment options for non-metastatic hormone-sensitive PCa (nmHSPC) patients with the first or second recurrence. Only 16.5% of non-metastatic castration-resistant PCa (nmCRPC) patients did not relapse within five years of initial therapy for nmCRPC. CONCLUSION: While PCa treatment recommendations are rapidly changing due to advances in treatment, we observed great concordance between their most current versions and real-world data treatment patterns reported by US physicians.

COVID-19 mRNA vaccines drive differential antibody Fc-functional profiles in pregnant, lactating, and nonpregnant women.

Substantial immunological changes occur throughout pregnancy to render the mother immunologically tolerant to the fetus and allow fetal growth. However, additional local and systemic immunological adaptations also occur, allowing the maternal immune system to continue to protect the dyad against pathogens both during pregnancy and after birth through lactation. This fine balance of tolerance and immunity, along with physiological and hormonal changes, contributes to increased susceptibility to particular infections in pregnancy, including more severe coronavirus disease 2019 (COVID-19). Whether these changes also make pregnant women less responsive to vaccination or induce altered immune responses to vaccination remains incompletely understood. To define potential changes in vaccine response during pregnancy and lactation, we undertook deep sequencing of the humoral vaccine response in a group of pregnant and lactating women and nonpregnant age-matched controls. Vaccine-specific titers were comparable between pregnant women, lactating women, and nonpregnant controls. However, Fc receptor (FcR) binding and antibody effector functions were induced with delayed kinetics in both pregnant and lactating women compared with nonpregnant women after the first vaccine dose, which normalized after the second dose. Vaccine boosting resulted in high FcR-binding titers in breastmilk. These data suggest that pregnancy promotes resistance to generating proinflammatory antibodies and indicates that there is a critical need to follow prime-boost timelines in this vulnerable population to ensure full immunity is attained.

Treatment patterns in non-small-cell lung cancer in China: Results from the CancerMPact survey 2020.

PURPOSE: To report the treatment patterns of non-small-cell lung cancer (NSCLC) patients in China based on a survey of physicians (CancerMPact). METHODS: 117 Chinese physicians from 27 cities in mainland China were recruited for an online survey in October 2020, reporting on how they treat their patients across all disease stages, including histology and relevant biomarkers in advanced or metastatic NSCLC. RESULTS: Surveyed physicians indicated that almost half of their stage I patients were treated with surgery only. For stage II patients, it is more common to treat with surgery in combination with radiation and/or systemic therapy (44.5%), whereas the use of surgery decreases for stage III patients and the overall use of systemic therapy increases (63.4%-68.8%). Physicians are more likely to use systemic therapy alone for stage IV patients (31.4%). Chosen treatment regimens for stage IV NSCLC varied by histology and biomarkers, and several observed treatment patterns differed from the USA. In China, platinum-based chemotherapy is standard of care for treating stage IV NSCLC patients, unlike the USA, where checkpoint inhibitors are the dominant choice in first-line. Further, Chinese physicians reported prescribing biomarker-targeted agents for one-third or less of their patients with EGFR, ALK, ROS-1, or BRAF driver mutations, compared to 60-95% in the USA. CONCLUSION: As treatment options expand in NSCLC in China, physicians face complex decisions for the treatment of their patients. Treatment patterns often vary, including by disease histology and clinically relevant biomarkers. The standard of care for NSCLC in China also differs from the USA.

SMARCAL1 loss and alternative lengthening of telomeres (ALT) are enriched in giant cell glioblastoma.

Subsets of high-grade gliomas, including glioblastoma (GBM), are known to utilize the alternative lengthening of telomeres (ALT) pathway for telomere length maintenance. However, the telomere maintenance profile of one subtype of GBM-giant cell GBM-has not been extensively studied. Here, we investigated the prevalence of ALT, as well as ATRX and SMARCAL1 protein loss, in a cohort of classic giant cell GBM and GBM with giant cell features. To determine the presence of ALT, a telomere-specific fluorescence in situ hybridization assay was performed on 15 cases of classic giant cell GBM, 28 additional GBMs found to have giant cell features, and 1 anaplastic astrocytoma with giant cell features. ATRX, SMARCAL1, and IDH1 protein status were assessed in a proportion of cases by immunohistochemistry and were compared to clinical-pathologic and molecular characteristics. In the overall cohort of 44 cases, 19 (43%) showed evidence of ALT. Intriguingly, of the ALT-positive cases, only 9 (47.4%) displayed loss of the ALT suppressor ATRX by immunohistochemistry. Since inactivating mutations in SMARCAL1 have been identified in ATRX wild-type ALT-positive gliomas, we developed an immunohistochemistry assay for SMARCAL1 protein expression using genetically validated controls. Of the 19 ALT-positive cases, 6 (31.5%) showed loss or mis-localization of SMARCAL1 by immunohistochemistry. Of these cases, four retained ATRX protein expression, while two cases also displayed ATRX loss. Additionally, we assessed five cases from which multiple temporal samples were available and ALT status was concordant between both tumor biopsies. In summary, we have identified a subset of giant cell GBM that utilize the ALT telomere maintenance mechanism. Importantly, in addition to ATRX loss, ALT-positive tumors harboring SMARCAL1 alterations are prevalent in giant cell GBM.

COVID-19 mRNA vaccines drive differential Fc-functional profiles in pregnant, lactating, and non-pregnant women.

Significant immunological changes occur throughout pregnancy to tolerize the mother and allow growth of the fetal graft. However, additional local and systemic immunological adaptations also occur, allowing the maternal immune system to continue to protect the dyad against foreign invaders both during pregnancy and after birth through lactation. This fine balance of tolerance and immunity, along with physiological and hormonal changes, contribute to increased susceptibility to particular infections in pregnancy, including more severe COVID-19 disease. Whether these changes also make pregnant women less responsive to vaccination or induce altered immune responses to vaccination remains incompletely understood. To holistically define potential changes in vaccine response during pregnancy and lactation, we deeply profiled the humoral vaccine response in a group of pregnant and lactating women and non-pregnant age-matched controls. Vaccine-specific titers were comparable, albeit slightly lower, between pregnant and lactating women, compared to non-pregnant controls. Among pregnant women, we found higher antibody titers and functions in those vaccinated with the Moderna vaccine. FcR-binding and antibody effector functions were induced with delayed kinetics in both pregnant and lactating women compared to non-pregnant women. Antibody boosting resulted in high FcR-binding titers in breastmilk. These data point to an immune resistance to generate highly inflammatory antibodies during pregnancy and lactation, and a critical need to follow prime/boost timelines in this vulnerable population to ensure full immunity is attained.

Safety and Efficacy of 7 Days on/7 Days off Versus 14 Days on/7 Days off Schedules of Capecitabine in Patients with Metastatic Colorectal Cancer: A Retrospective Review.

INTRODUCTION/BACKGROUND: The administration schedule of capecitabine for the treatment of metastatic colorectal cancer (mCRC) in clinical trials has been 14 days of drug with 7 days off in a 21 day cycle (14/7). In an effort to improve tolerability, an alternative every other week treatment (7/7) is often administered. The purpose of this study was to determine the safety and efficacy of administering 7/7 compared with 14/7 capecitabine dosing. MATERIALS AND METHODS: In this retrospective study, mCRC patients received capecitabine on a 7/7 or 14/7 schedule. The primary objective was to determine the tolerability of the respective dosing schedules, defined according to frequency of dose reductions and treatment delays. Secondary objectives included comparisons of objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety of dosing strategies. RESULTS: Of 175 included patients, 73 (41.7%) received the capecitabine 7/7 schedule and 102 (58.3%) received the 14/7 schedule. There was a statistically significant difference between the 7/7 and 14/7 groups with regard to dose reductions (4% vs. 29%; P < .001) and treatment delays (22% vs. 43%; P = .004). The incidence of any adverse effects (45% vs. 72%; P < .001) and specifically, palmar-plantar erythrodysesthesia (18% vs. 45%; P < .001), were significantly higher in the 14/7 group. No significant difference was seen with regard to ORR, PFS, or OS. CONCLUSION: Patients with mCRC who received the 7/7 schedule had significantly fewer dose reductions and treatment delays compared with patients who received the 14/7 schedule. Although no difference in efficacy outcomes were observed, prospective studies are needed to confirm these findings.

Visual images of prescription drug benefits in direct-to-consumer television advertisements.

OBJECTIVE: Images demonstrating a prescription drug's efficacy are often included in direct-to-consumer television advertisements. The current research assessed whether exaggerated efficacy images can mislead individuals, and whether providing accurate quantitative information can reduce these misperceptions. METHODS: We conducted two experimental studies with internet panelists 60 years and older testing drug efficacy images in television ads for wet age-related macular degeneration (N = 901) and plaque psoriasis (N = 902). In each study, participants viewed one of six ads that varied in the efficacy images included (no image, accurate image, exaggerated image) and the presentation of quantitative information (absent, present). Measures included recall, perceptions, and numeracy. RESULTS: In both studies, participants who saw exaggerated images were more likely than those who saw no image or accurate images to overestimate efficacy. Presenting quantitative information increased participants' gist and verbatim recall of drug efficacy, and in some cases, led participants to have more accurate perceptions of the drug's efficacy even in the presence of exaggerated images. Higher numeracy was associated with better gist and verbatim recall. CONCLUSIONS: These results support visual persuasion theory. Moreover, they show that exaggerating benefits visually can mislead viewers. PRACTICE IMPLICATIONS: Stakeholders should ensure that images in direct-to-consumer promotion are accurate and non-misleading.

Qualitative Examination of Voting Empowerment and Participation Among People Living With Traumatic Brain Injury.

OBJECTIVE: To examine political participation after traumatic brain injury (TBI). DESIGN: Qualitative, participatory research via interviews and observations. Each participant was interviewed to discuss their experience of voting in 2007 or 2008. Data were coded using Grounded Theory to develop themes, metacodes, and theories. SETTING: Community. PARTICIPANTS: A total of 57 individuals with history of TBI and 28 family members (N=85). MAIN OUTCOME MEASURES: Not applicable. RESULTS: Four themes emerged from the data: (1) people with TBI have barriers to voting; (2) the voting process can be improved for people with TBI; (3) voting is the responsibility of members of society; and (4) voting is one way we have a voice in society. CONCLUSIONS: The data support the importance of voting as an American right regardless of the presence of disability. While persons with TBI report voting represents their freedom and voice, there may be barriers that can threaten or limit their voice.

Obesity is Associated with Shorter Telomere Length in Prostate Stromal Cells in Men with Aggressive Prostate Cancer.

In our prior studies, obesity was associated with shorter telomeres in prostate cancer-associated stromal (CAS) cells, and shorter CAS telomeres were associated with an increased risk of prostate cancer death. To determine whether the association between obesity and shorter CAS telomeres is replicable, we conducted a pooled analysis of 790 men who were surgically treated for prostate cancer, whose tissue samples were arrayed on five tissue microarray (TMA) sets. Telomere signal was measured using a quantitative telomere-specific FISH assay and normalized to 4',6-diamidino-2-phenylindole for 351 CAS cells (mean) per man; men were assigned their median value. Weight and height at surgery, collected via questionnaire or medical record, were used to calculate body mass index (BMI; kg/m2) and categorize men as normal (<25), overweight (25 ≤ BMI < 30), or obese (≥30). Analyses were stratified by grade and stage. Men were divided into tertiles of TMA- (overall) or TMA- and disease aggressiveness- (stratified) specific distributions; short CAS telomere status was defined by the bottom two tertiles. We used generalized linear mixed models to estimate the association between obesity and short CAS telomeres, adjusting for age, race, TMA set, pathologic stage, and grade. Obesity was not associated with short CAS telomeres overall, or among men with nonaggressive disease. Among men with aggressive disease (Gleason≥4+3 and stage>T2), obese men had a 3-fold increased odds of short CAS telomeres (OR: 3.06; 95% confidence interval: 1.07-8.75; P trend = 0.045) when compared with normal weight men. Telomere shortening in prostate stromal cells may be one mechanism through which lifestyle influences lethal prostate carcinogenesis. PREVENTION RELEVANCE: This study investigates a potential mechanism underlying the association between obesity and prostate cancer death. Among men with aggressive prostate cancer, obesity was associated with shorter telomeres prostate cancer associated stromal cells, and shorter CAS telomeres have been associated with an increased risk of prostate cancer death.