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National and international guidelines recommend the use of 1 dose of intravesical chemotherapy immediately following surgery for nonmuscle invasive bladder cancer, which is performed infrequently on a population level. We sought to understand the importance of potential environmental and clinical dimensions involved in the decision to offer this therapy.Urologists from the Michigan Urological Surgery Improvement Collaborative (MUSIC) rated 8 distinct clinical vignettes involving patients with nonmuscle invasive bladder cancer. A ratings-based conjoint analysis method was used to evaluate the clinical vignette responses. Each vignette included 4 clinical dimensions and 2 environmental dimensions, with each dimension consisting of 2 possible attributes. The relative importance of each attribute was derived from the regression model and ranked in order.A total of 58 urologists answered the clinical vignettes which represents75% of MUSIC sites. The median age of urologists was 53, most were male, and median years in practice was 20 years post residency. An environmental attribute, having a recovery room protocol for instilling and disposing of the chemotherapy, ranked as the most influential attribute for giving postoperative chemotherapy (utility=8.6). The clinical attribute yielding the strongest preference for giving chemotherapy was tumor grade (utility=4.9). These preferences varied by different subgroups of urologists, particularly regarding the type of practice a urologist was in.This study demonstrates that urologists have clear preferences for when they offer postoperative immediate chemotherapy. Factors beyond just clinical variables play a role in this decision making process such as the structure of the recovery room.

The purpose of the program WeCare was to provide a personalized approach to addressing the wide array of psycho-social-cultural-fiscal needs to reduce risk factors for infant mortality (IM) by supporting maternal and infant health through health coaching by community health workers (CHWs). A prospective cohort study of 1,513 women from highest risk ZIP codes for IM in central Indiana were followed over three years. The WeCare program focused on training and deploying CHWs to provide evidence-based, patient-centered social care and support to pregnant and postpartum women and tracked outcomes in health risk categories (mental health, nutrition, safe sleep, breastfeeding) targeted for behavioral change. The low birth weight rate among program participants was lower (8.9%) than Marion County's rate (10%) (p=0.23) with statistically significant improvement in many risk behaviors. Despite limitations, the personalized coaching provided by the CHWs provided an effective, practical approach to maternal and child health disparities.

Few studies have assessed the long-term functional outcomes of traumatic brain injury (TBI) in large, well-characterized samples. Using the Traumatic Brain Injury Model Systems cohort, this study assessed the maintenance of independence between years 5 and 15 post-injury and risk factors for decline. The study sample included 1381 persons with TBI who received inpatient rehabilitation, survived to 15 years post-injury, and were available for data collection at 5 or 10 years and 15 years post-injury. The Functional Independence Measure (FIM) and Disability Rating Scale (DRS) were used to measure functional outcomes. The majority of participants had no changes during the 10-year time frame. For FIM, only 4.4% showed decline in Self-Care, 4.9% declined in Mobility, and 5.9% declined in Cognition. Overall, 10.4% showed decline in one or more FIM subscales. Decline was detected by DRS Level of Function (24% with >1-point change) and Employability (6% with >1-point change). Predictors of decline factors across all measures were age >25 years and, across most measures, having less than or equal to a high school education. Additional predictors of FIM decline included male sex (FIM Mobility and Self-Care) and longer rehabilitation length of stay (FIM Mobility and Cognition). In contrast to studies reporting change in the first 5 years post-TBI inpatient rehabilitation, a majority of those who survive to 15 years do not experience functional decline. Aging and cognitive reserve appear to be more important drivers of loss of function than original severity of the injury. Interventions to identify those at risk for decline may be needed to maintain or enhance functional status as persons age with a TBI.

BackgroundCD-30 is highly expressed in some patients with non-seminomatous germ-cell tumors. Brentuximab vedotin is an antibody-drug conjugate directed to CD-30. We report a phase 2 trial of brentuximab vedotin in patients with chemo-refractory GCT.Patients and Methods This is a single arm, two cohort phase 2 trial investigating brentuximab vedotin 1.8 mg/kg IV every 3 weeks until disease progression or intolerable toxicities in patients with relapsed GCT who have no curative options. Patients with mGCT who progressed after first line cisplatin-based chemotherapy and after at least 1 salvage regimen (high-dose or standard-dose chemotherapy) were eligible. CD30 expression was assessed and two cohorts defined: CD30 positive and CD30 negative/unknown.Results18 patients were enrolled. Median age 34.7 (range, 23-56). All patients had non-seminoma. Median AFP 4.9 (range, 1-219,345) and hCG 282 (range, 0.6-172,064). Five patients had late relapse (>2years). Median number of previous chemotherapy regimens was 3 (range, 2-7). Ten patients received prior high-dose chemotherapy. Seven patients had positive CD30 staining. There were two grade 3 treatment-related adverse events. No partial or complete responses were observed. 6 patients achieved radiographic stable disease (range, 9-14.9 weeks), 5 had elevated AFP or hCG at trial entry and all 5 had transient >50% decline in baseline AFP/hCG: 4 had CD30 -ve and 2 had CD30 +ve staining; 10 patients had progression of disease as their best response; 2 were not evaluable for response.ConclusionBrentuximab vedotin does not appear to have clinically meaningful single-agent activity in patients with refractory GCT. Trial Registration Number: NCT02689219Date of registration: February 12, 2016

Purpose: Fatty acid synthase (FASN) is overexpressed in 70% of operable triple-negative breast cancer (TNBC) and is associated with poor prognosis. Proton pump inhibitors selectively inhibit FASN activity and induce apoptosis in TNBC cell lines. Patients and Methods: Patients with operable TNBC were enrolled in this single-arm phase II study. Patients began omeprazole 80 mg orally twice daily for 4–7 days prior to neoadjuvant anthracycline–taxane-based chemotherapy (AC-T) and continued until surgery. The primary endpoint was pathologic complete response (pCR) in patients with baseline FASN overexpression (FASN+). Secondary endpoints included pCR in all surgery patients, change in FASN expression, enzyme activity, and downstream protein expression after omeprazole monotherapy, safety, and limited omeprazole pharmacokinetics. Results: Forty-two patients were recruited with a median age of 51 years (28–72). Most patients had ≥cT2 (33, 79%) and ≥N1 (22, 52%) disease. FASN overexpression prior to AC-T was identified in 29 of 34 (85%) evaluable samples. The pCR rate was 72.4% [95% confidence interval (CI), 52.8–87.3] in FASN+ patients and 74.4% (95% CI, 57.9–87.0) in all surgery patients. Peak omeprazole concentration was significantly higher than the IC50 for FASN inhibition observed in preclinical testing; FASN expression significantly decreased with omeprazole monotherapy [mean change 0.12 (SD, 0.25); P = 0.02]. Omeprazole was well tolerated with no grade ≥ 3 toxicities. Conclusions: FASN is commonly expressed in early TNBC. Omeprazole can be safely administered in doses that inhibit FASN. The addition of omeprazole to neoadjuvant AC-T yields a promising pCR rate that needs further confirmation in randomized studies.

VEGF blockade does not uniformly result in clinical benefit. We evaluated safety, dose-limiting toxicities (DLT), recommended phase II dose (RP2D), antitumor efficacy, and exploratory biomarkers including pharmacogenomics and pharmacokinetics with sorafenib, bevacizumab, and paclitaxel in patients with refractory cancers. The study had a “3 + 3” design, using paclitaxel 80 mg/m2 every week for 3 weeks, in every 4 week cycles, bevacizumab 5 mg/kg every 2 weeks, and sorafenib 200 or 400 mg twice a day, 5 or 7 days/week (5/7, 7/7). The MTD cohort was expanded. Twenty-seven patients enrolled in 3 cohorts: sorafenib 200 mg twice a day 5/7, 200 mg twice a day 7/7, and 400 mg twice a day 5/7. DLTs were grade 3 neutropenia >7 days (cohort 1, 1), grade 3 hypertension (cohort 2, 1), grade 3 hand–foot skin reaction (HFSR; cohort 3, 2). MTD was sorafenib 200 mg twice a day 7/7. Six DLTs occurred in cohort 2 expansion: grade 3 HFSR (2), grade 2 HFSR with sorafenib delay >7 days (2), grade 4 cerebrovascular accident (1), grade 3 neutropenia >7 days (1). RP2D was sorafenib 200 mg twice a day 5/7. Most patients (62%) dose reduced sorafenib to 200 mg daily 5/7 after a median 3 (range, 2–17) cycles. Response rates were 48% overall (27) and 64% for ovarian cancers (14). VEGF-A-1154AA and -7TT recessive homozygous genotypes conferred worse overall survival versus alternative genotypes (7 vs. 22 months). Intermittent, low-dose sorafenib (200 mg twice a day 5/7) combined with bevacizumab and paclitaxel was tolerable and had high antitumor efficacy in patients with refractory cancer (NCT00572078).

Purpose To measure the effect of a pharmacist-initiated transitions of care (TOC) program on rates of 30-day all-cause readmissions and primary care follow-up. Methods A retrospective cohort study was conducted to evaluate a pharmacist-initiated TOC program for patients discharged from hospitals of a large health system from September 2015 through July 2016. Discharged patients of 13 primary care physicians (the intervention cohort) received TOC program services, and discharged patients seen by 12 other primary care physicians (the control cohort) received usual care. Patients in both cohorts were followed for 90 days. The primary outcome was 30-day all-cause readmissions, and secondary outcomes were 14-day primary care visits, TOC pharmacist identification and resolution of medication therapy problems (MTPs), and transition care management (TCM) billing. Multivariable modeling was performed to test the associations of patient receipt of TOC services with 30-day readmissions and 14-day primary care visits, with controlling for patient demographics and baseline healthcare utilization. Results A total of 492 patients received the TOC intervention, and 379 were followed in the usual care cohort. Among intervention patients, 960 MTPs were identified, and 85.7% of identified MTPs were resolved. Moreover, 9% of intervention cohort patients were readmitted within 30 days, compared to 15% of control cohort patients, and this effect was significant in the multivariable model (odds ratio, 1.82; 95% confidence interval, 1.15-2.89; P = 0.0108). Rates of primary care visits did not differ significantly between the groups; 65% of intervention group visits were billed using TCM codes. Conclusion A pharmacist-initiated TOC program was effective in reducing 30-day all-cause readmissions.

Patients with advanced cancer often face distressing decisions about chemotherapy. There are conflicting data on the relationships among perceived prognosis, psychological characteristics, and chemotherapy use, which impair the refinement of decision support interventions.Clarify the relationships among patient and oncologist estimates of life expectancy for 6 and 12 months, chemotherapy use, and patient psychological characteristics.Secondary analysis of data from two cross-sectional studies.One hundred sixty-six patients with advanced stage cancer recruited from ambulatory cancer clinics.All data were obtained at study enrollment. Patients completed the Adult Hope Scale, Hospital Anxiety and Depression Scale, and Life Orientation Test-Revised. Patients and their oncologists provided estimates of surviving beyond 6 and 12 months. Chemotherapy use was determined by chart review.There were no significant associations between life-expectancy estimates and chemotherapy use nor patient anxiety, depression, hope, or optimism and chemotherapy use. Patients' life expectancy estimates for 12 months and oncologists' for 6 months were associated with higher patient anxiety and depression. Finally, both oncologist and patient estimates of life expectancy for 6 and 12 months were associated with increased levels of trait hope.Advanced cancer patients who provide less optimistic estimates of life expectancy have increased anxiety and depression, but do not use chemotherapy more often. Increased patient trait hope is associated with more favorable oncologist estimates. These findings highlight the need for interventions to support both patients and oncologists as they clarify prognostic expectations and patients cope with the psychological distress of a limited life expectancy.

SummaryIntroduction: Dual healthcare system use can create gaps and fragments of information for patient care. The Department of Veteran Affairs is implementing a health information exchange (HIE) program called the Virtual Lifetime Electronic Record (VLER), which allows providers to access and share information across healthcare systems. HIE has the potential to improve the safety of medication use. However, data regarding the pattern of outpatient medication use across systems of care is largely unknown. Therefore, the objective of this study is to describe the prevalence of medication dispensing across VA and non-VA health care systems among a cohort Veteran population Methods: This study included all Veterans who had two outpatient visits or one inpatient visit at the Indianapolis VA during a 1-year period prior to VLER enrollment. Source of medication data was assessed at the subject level, and categorized as VA, INPC (non-VA), or both. The primary target was identification of sources for medication data. Then, we compared the mean number of prescriptions, as well as overall and pairwise differences in medication dispensing.Results: Out of 52,444 Veterans, 17.4% of subjects had medication data available in a regional HIE. On average, 40 prescriptions per year were prescribed for Veterans who used both sources compared to 29 prescriptions per year from VA only and 25 prescriptions per year from INPC only sources. The annualized prescription rate of Veterans in the dual use group was 36% higher than those who had only VA data available and 61% higher than those who had only INPC data available.Conclusions: Our data demonstrated that 17.4% of subjects had medication use identified from non-VA sources, including prescriptions for antibiotics, antineoplastics, and anticoagulants. These data support the need for HIE programs to improve coordination of information, with the potential to reduce adverse medication interactions and improve medication safety.

BACKGROUND: Completion rates for medication therapy management (MTM) services have been lower than desired and the Centers for Medicare and Medicaid Services has added MTM comprehensive medication review (CMR) completion rates as a Part D plan star measure. Over half of plans utilize community pharmacists via contracts with MTM vendors. OBJECTIVES: The primary objective of this survey study was to identify factors associated with the CMR completion rates of community pharmacies contracted with a national MTM vendor. METHODS: Representatives from 27,560 pharmacy locations contracted with a national MTM vendor were surveyed. The dependent variable of interest was the pharmacies’ CMR completion rate. Independent variables included the pharmacy’s progressiveness stratum and number of CMRs assigned by the MTM vendor during the time period, as well as self-reported data to characterize MTM facilitators, barriers, delivery strategies, staffing, selected items from a modified Assessment of Chronic Illness care, and pharmacist/pharmacy demographics. Univariate negative binomial models were fit for each independent variable, and variables significant at p < 0.05 were entered into a multivariable model. RESULTS: Representatives from 3836 (13.9%) pharmacy locations responded; of these, 90.9% (n =3486) responses were usable. The median CMR completion rate was 0.42. Variables remaining significant at p < 0.05 in the multivariable model included: progressiveness strata; pharmacy type; scores on the facilitators scale; responses to two potential barriers items; scores on the patient/caregiver delivery strategies sub-scale; providing MTM at multiple locations; reporting that the MTM vendor sending the survey link is the primary MTM vendor for which the respondent provides MTM; and the number of hours per week that the pharmacy is open. CONCLUSIONS: Factors at the respondent (e.g., responses to facilitators scale) and pharmacy (e.g., pharmacy type) levels were associated with CMR completion rates. These findings could be used by MTM stakeholders to improve CMR completion rates.

Knowledge is a prerequisite for changing behavior, and is useful for improving outcomes and reducing mortality rates in patients diagnosed with chronic kidney disease (CKD). The purpose of this article is to describe baseline CKD knowledge and awareness obtained as part of a larger study testing the feasibility of a self-management intervention. Thirty patients were recruited who had CKD Stage 3 with coexisting diabetes and hypertension. Fifty-four percent of the sample were unaware of their CKD diagnosis. Participants had a moderate amount of CKD knowledge. This study suggests the need to increase knowledge in patients with CKD Stage 3 to aid in slowing disease progression.

Introduction: Palliative sedation for refractory existential distress (PS-ED) is ethically troubling but potentially critical to quality end-of-life (EOL) care. Physicians’ in postgraduate training support toward PS-ED is unknown nor is it known how empathy, hope, optimism, or intrinsic religious motivation (IRM) affect their support. These knowledge gaps hinder efforts to support physicians who struggle with patients’ EOL care preferences. Methods: One hundred thirty-four postgraduate physicians rated their support of PS for refractory physical pain (PS-PP) or PS-ED, ranked the importance of patient preferences in ethically challenging situations, and completed measures of empathy, hope, optimism, and IRM. Predictors of PS-ED and PS-PP support were examined using binary and multinomial logistic regression. Results: Only 22.7% of residents were very supportive of PS-ED, and 82.0% were very supportive of PS-PP. Support for PS-PP or PS-ED did not correlate with levels of empathy, hope, optimism, or IRM; however, for residents with lower IRM, greater optimism was associated with greater PS-ED support. In contrast, among residents with higher IRM, optimism was not associated with PS-ED support. Conclusions: Comparing current results to published surveys, a similar proportion of residents and practicing physicians support PS-ED and PS-PP. In contrast to practicing physicians, however, IRM does not directly influence residents’ supportiveness. The interaction between optimism and IRM suggests residents’ beliefs and characteristics are salient to their EOL decisions. End-of-life curricula should provide physicians opportunities to reflect on the personal and ethical factors that influence their support for PS-ED.

OBJECTIVE We tested whether an elevation in the serum proinsulin–to–C-peptide ratio (PI:C), a biomarker of β-cell endoplasmic reticulum (ER) dysfunction, was associated with progression to type 1 diabetes. RESEARCH DESIGN AND METHODS Fasting total PI and C levels were measured in banked serum samples obtained from TrialNet Pathway to Prevention (PTP) participants, a cohort of autoantibody-positive relatives without diabetes of individuals with type 1 diabetes. Samples were obtained ∼12 months before diabetes onset from PTP progressors in whom diabetes developed (n = 60), and were compared with age-, sex-, and BMI-matched nonprogressors who remained normoglycemic (n = 58). PI:C ratios were calculated as molar ratios and were multiplied by 100% to obtain PI levels as a percentage of C levels. RESULTS Although absolute PI levels did not differ between groups, PI:C ratios were significantly increased in antibody-positive subjects in whom there was progression to diabetes compared with nonprogressors (median 1.81% vs. 1.17%, P = 0.03). The difference between groups was most pronounced in subjects who were ≤10 years old, where the median progressor PI:C ratio was nearly triple that of nonprogressors; 90.0% of subjects in this age group within the upper PI:C quartile progressed to the development of diabetes. Logistic regression analysis, adjusted for age and BMI, demonstrated increased odds of progression for higher natural log PI:C ratio values (odds ratio 1.44, 95% CI 1.02, 2.05). CONCLUSIONS These data suggest that β-cell ER dysfunction precedes type 1 diabetes onset, especially in younger children. Elevations in the serum PI:C ratio may have utility in predicting the onset of type 1 diabetes in the presymptomatic phase.

Objective Parent variables (stigma, mood, unmet needs for information and support, and worry) are associated with behavioral difficulties in children with seizures; however, it is not known how this relationship is influenced by additional seizures. This study followed children (ages 4–14 years) and their parents over a 24-month period (with data collected at baseline and 6, 12, and 24 months) and investigated the effect of an additional seizure on the relationship between parenting variables and child behavior difficulties. Methods The sample was parents of 196 children (104 girls and 92 boys) with a first seizure within the past 6 weeks. Child mean age at baseline was 8 years, 3 months (SD 3 years). Data were analyzed using t-tests, chi-square tests, and repeated measures analyses of covariance. Results Relationships between parent variables, additional seizures, and child behavior problems were consistent across time. Several associations between parent variables and child behavior problems were stronger in the additional seizure group than in the no additional seizure group. Conclusions Findings suggest that interventions that assist families to respond constructively to the reactions of others regarding their child's seizure condition and to address their needs for information and support could help families of children with continuing seizures to have an improved quality of life.

Background and Aims Locally advanced pancreatic cancer (LAPC) has a poor prognosis. There are limited data describing the use of photodynamic therapy (PDT) for pancreatic cancer in humans. We hypothesized that EUS-guided PDT for LAPC is safe, technically feasible, and produces a dose- and time-dependent increasing degree of image-defined tumor necrosis. Methods In a single-center, prospective, dose-escalation phase 1 study, patients with treatment-naive LAPC received intravenous porfimer sodium (Concordia Laboratories Inc, St Michael, Barbados) followed 2 days later by EUS-PDT. EUS-PDT was performed by puncture with a 19-gauge needle and insertion of a 1.0-cm light diffuser (Pioneer Optics, Bloomfield, Conn) and illumination with a 630-nm light (Diomed Inc, Andover, Mass). A CT scan 18 days after PDT was done to assess for change in pancreatic necrosis. Nab-paclitaxel (125 mg/ m2 intravenously) and gemcitabine (1000 mg /m2 intravenously) were initiated 7 days after CT and given weekly for 3 of 4 weeks (1 cycle) until disease progression or unacceptable toxicity. Results Twelve patients (mean age, 67 ± 6 years; 8 male) with tumors (mean diameter, 45.2 ± 12.9 mm) in the head and/or neck (8) or body and/or tail (4) underwent EUS-PDT. Compared with baseline imaging, increased volume and percentage of tumor necrosis were observed in 6 of 12 patients (50%) after EUS-PDT. The mean overall increases in volume and percentage necrosis were 10 ± 26 cm3 (P = .20) and 18% ± 22% (P = .016), respectively. After a median follow-up of 10.5 months (range, 1.0-37.4 months), median progression-free (PFS) and overall survival (OS) were 2.6 months (95% confidence interval, 0.7, not estimable) and 11.5 months (95% confidence interval, 1.1, 16.9), respectively. Surgical resection was attempted in 2 patients, and pathology showed a complete response (n = 1) and residual 2-mm tumor (n = 1). There were 8 serious adverse events and none related to EUS or EUS-PDT. Conclusion EUS-PDT for LAPC appears to be safe and produces measurable imaged-defined tumor necrosis. Phase 2 studies are warranted. (Clinical trial registration number: NCT01770132 .)

Objective: Guidelines recommend that decision aids provide quantitative information about risks and benefits of available options. Impact of providing this information is unknown. Methods: Randomized trial comparing two decision aids about colorectal cancer (CRC) screening with colonoscopy or fecal immunochemical test (FIT). 688 primary care patients due for CRC screening viewed a decision aid that uses words only (Verbal arm) vs. one that provides quantitative information (Quantitative arm). Main outcomes included perceived CRC risk, intent to be screened, and test preference, measured before and after viewing decision aid, and screening uptake at six months. Analyses were performed with ANCOVA and logistic regression. Results: Compared to the Verbal arm, those in the Quantitative arm had a larger increase in intent to undergo FIT (p = 0.011) and were more likely to switch their preferred test from non-FIT to FIT (28% vs. 19%, p = .010). There were decreases in perceived risk in the Verbal Arm but not the Quantitative Arm (p = 0.004). There was no difference in screening uptake. Numeracy did not moderate any effects. Conclusions: Quantitative information had relatively minor impact and no clearly negative effects, such as reducing uptake. Practice implications: Quantitative information may be useful but not essential for patients viewing decision aids.

Background The majority of estrogen receptor-positive (ERα+) breast cancers respond to endocrine therapies. However, resistance to endocrine therapies is common in 30% of cases, which may be due to altered ERα signaling and/or enhanced plasticity of cancer cells leading to breast cancer subtype conversion. The mechanisms leading to enhanced plasticity of ERα-positive cancer cells are unknown. Methods We used short hairpin (sh)RNA and/or the CRISPR/Cas9 system to knockdown the expression of the dependence receptor UNC5A in ERα+ MCF7 and T-47D cell lines. RNA-seq, quantitative reverse transcription polymerase chain reaction, chromatin immunoprecipitation, and Western blotting were used to measure the effect of UNC5A knockdown on basal and estradiol (E2)-regulated gene expression. Mammosphere assay, flow cytometry, and immunofluorescence were used to determine the role of UNC5A in restricting plasticity. Xenograft models were used to measure the effect of UNC5A knockdown on tumor growth and metastasis. Tissue microarray and immunohistochemistry were utilized to determine the prognostic value of UNC5A in breast cancer. Log-rank test, one-way, and two-way analysis of variance (ANOVA) were used for statistical analyses. Results Knockdown of the E2-inducible UNC5A resulted in altered basal gene expression affecting plasma membrane integrity and ERα signaling, as evident from ligand-independent activity of ERα, altered turnover of phosphorylated ERα, unique E2-dependent expression of genes effecting histone demethylase activity, enhanced upregulation of E2-inducible genes such as BCL2, and E2-independent tumorigenesis accompanied by multiorgan metastases. UNC5A depletion led to the appearance of a luminal/basal hybrid phenotype supported by elevated expression of basal/stem cell-enriched ∆Np63, CD44, CD49f, epidermal growth factor receptor (EGFR), and the lymphatic vessel permeability factor NTN4, but lower expression of luminal/alveolar differentiation-associated ELF5 while maintaining functional ERα. In addition, UNC5A-depleted cells acquired bipotent luminal progenitor characteristics based on KRT14+/KRT19+ and CD49f+/EpCAM+ phenotype. Consistent with in vitro results, UNC5A expression negatively correlated with EGFR expression in breast tumors, and lower expression of UNC5A, particularly in ERα+/PR+/HER2− tumors, was associated with poor outcome. Conclusion These studies reveal an unexpected role of the axon guidance receptor UNC5A in fine-tuning ERα and EGFR signaling and the luminal progenitor status of hormone-sensitive breast cancers. Furthermore, UNC5A knockdown cells provide an ideal model system to investigate metastasis of ERα+ breast cancers. Electronic supplementary material The online version of this article (10.1186/s13058-018-0963-5) contains supplementary material, which is available to authorized users.

Background Supportive music and imagery and music listening interventions have been effective in decreasing distress and improving mood in cancer patients receiving chemotherapy, but it is unclear whether the two interventions differ in their treatment benefits. Furthermore, previous studies have not examined moderators to determine which subgroup(s) of patients may benefit most from each intervention. Objective To examine the effects of supportive music and imagery compared with preferred music listening on responsiveness to music therapy, distress, anxiety and depression, and benefit finding. A secondary purpose was to explore sense of coherence and locus of control as potential moderators of intervention effectiveness. Methods A single-session, two-group comparative effectiveness randomized trial in two cancer centers. Patients were randomized to supportive music and imagery or preferred music listening during outpatient chemotherapy treatment. Data were collected at baseline and immediately after the 45-minute session. ANCOVA models were used to determine main effects of intervention as well as pairing potential moderators with group assignment to explore differences in intervention effects by moderator. Results There were differential effects between the two interventions with the supportive music and imagery group scoring higher in responsiveness to music therapy and benefit finding. The music listening group scores indicated lower distress. The exploratory moderating analyses suggested Health Locus of Control-Internal and Sense of Coherence influenced intervention effectiveness. Conclusions Music and imagery and preferred music listening experiences may serve different therapeutic purposes, access and activate different patient resources, and may be helpful at different stages of treatment.

Objectives Thymic malignancies are rare, and options are limited for metastatic disease. Src plays a role in normal thymic epithelial maturation, and its inhibition with the oral compound saracatinib was postulated to be effective in controlling thymic malignancy. Materials and methods Patients with unresectable thymic malignancy were treated with saracatinib 175 mg by mouth daily in 28 days cycles with radiographic evaluation at cycle 2 day 1 for safety, then cycle 3 day 1 and every 8 weeks thereafter. Response was evaluated by RECIST 1.0. A two-stage optimal design was used, powered to detect a true response rate of 20%. Results 21 patients were enrolled at two institutions, 12 of them with thymoma, 9 with thymic carcinoma. Thymoma patients received a median of 4.5 cycles and thymic carcinoma patients a median of 1 cycle. There were no responses, so accrual was halted after the first stage per protocol. 9 patients had stable disease beyond the first assessment. Median time to progression was 5.7 months for thymoma patients and 3.6 months for thymic carcinoma patients. Saracatinib was well tolerated. Conclusion Src inhibition by saracatinib did not produce any radiographic responses, though some patients did experience stable disease. Though negative, this study shows the feasibility of completing a trial in this rare disease, and of accruing reasonably significant numbers of thymic carcinoma patients. More clinical trials are required for this population ( NCT00718809 ).

Objective To assess the effects of amantadine on anger and aggression among individuals with a chronic traumatic brain injury (TBI). Methods A cohort of 118 persons with chronic TBI (>6 months postinjury) and moderate-severe aggression selected from a larger cohort of 168 participants enrolled in a parallel-group, randomized, double-blind, placebo-controlled trial of amantadine 100 mg twice daily (n = 82) versus placebo (n = 86) for treatment of irritability were studied. Anger and aggression were measured at treatment days 0, 28, and 60 using observer-rated and participant-rated State-Trait Anger Expression Inventory-2 (STAXI-2) and Neuropsychiatric Inventory-Agitation/Aggression domain (NPI-A) Most Problematic and Distress scores. Results Participant-rated day 60 NPI-A Most Problematic (adjusted P = .0118) and NPI-A Distress (adjusted P = .0118) were statistically significant between the 2 groups, but STAXI-2 differences were not significant after adjustment for multiple comparisons. Substantial improvements were noted in both amantadine and placebo groups (70% vs 56% improving at least 3 points on day 60 Observer NPI-A; P = .11). Conclusion Amantadine 100 mg twice daily in this population with chronic TBI appears to be beneficial in decreasing aggression from the perspective of the individual with TBI. No beneficial impact on anger was found. Trial registration clinicaltrials.gov Identifier: NCT00779324; http://www.clinicaltrials.gov/ct2/show/NCT00779324?term=irritability&rank=6.

DNA methylation aberrations have been implicated in acquired resistance to platinum drugs in ovarian cancer. In this study, we elucidated an epigenetic signature associated with platinum drug resensitization that may offer utility in predicting the outcomes of patients who are coadministered a DNA methyltransferase inhibitor. The ovarian cancer specimens we analyzed were derived from a recent clinical trial that compared the responses of patients with recurrent platinum-resistant ovarian cancer who received carboplatin plus the DNA methyltransferase inhibitor guadecitabine or a standard-of-care chemotherapy regimen selected by the treating physician. Tumor biopsies or malignant ascites were collected from patients before treatment (day 1, cycle 1) or after treatment (after 2 cycles) for epigenomic and transcriptomic profiling using the Infinium HumanMethylation450 BeadChip (HM450). We defined 94 gene promoters that were hypomethylated significantly by guadecitabine, with 1,659 genes differentially expressed in pretreatment versus posttreatment tumors. Pathway analysis revealed that the experimental regimen significantly altered immune reactivation and DNA repair pathways. Progression-free survival correlated with baseline expression levels of 1,155 genes involved in 25 networks. In functional investigations in ovarian cancer cells, engineered upregulation of certain signature genes silenced by promoter methylation (DOK2, miR-193a, and others) restored platinum drug sensitivity. Overall, our findings illuminate how inhibiting DNA methylation can sensitize ovarian cancer cells to platinum drugs, in large part by altering gene expression patterns related to DNA repair and immune activation, with implications for improving the personalized care and survival outcomes of ovarian cancer patients. Significance: Epigenomic targeting may improve therapeutic outcomes in platinum-resistant and recurrent ovarian cancer in part by effects on DNA repair and antitumor immune responses. Cancer Res; 78(3); 631–44. ©2017 AACR.

Oxidative stress suppresses host immunity by generating oxidized lipid agonists of the platelet-activating factor receptor (PAF-R). Because many classical chemotherapeutic drugs induce reactive oxygen species (ROS), we investigated whether these drugs might subvert host immunity by activating PAF-R. Here, we show that PAF-R agonists are produced in melanoma cells by chemotherapy that is administered in vitro, in vivo, or in human subjects. Structural characterization of the PAF-R agonists induced revealed multiple oxidized glycerophosphocholines that are generated nonenzymatically. In a murine model of melanoma, chemotherapeutic administration could augment tumor growth by a PAF-R–dependent process that could be blocked by treatment with antioxidants or COX-2 inhibitors or by depletion of regulatory T cells. Our findings reveal how PAF-R agonists induced by chemotherapy treatment can promote treatment failure. Furthermore, they offer new insights into how to improve the efficacy of chemotherapy by blocking its heretofore unknown impact on PAF-R activation. Cancer Res; 74(23); 7069–78. ©2014 AACR.

BACKGROUND: “Systems of care” are strengths-based approaches to treating adolescents and others with disruptive disorders. However, little is known about why some adolescents improve and others do not. OBJECTIVE: To examine changes in personal strengths and family functioning as predictors of behavioral and social functioning among adolescents with disruptive disorders who participated in a system of care program. DESIGN: Secondary analyses of data from 114 adolescents (12-17 years of age) with disruptive disorders and their caregivers who participated in the Dawn Project Evaluation Study. Caregivers completed in-depth interviews conducted by trained data collectors using standardized questionnaires. Baseline and 12- month data are reported here. RESULTS: Improvement in personal strengths was a significant predictor of improvement in adolescent behavioral and social functioning, controlling for demographics ( p < .001). CONCLUSION: In adolescents with disruptive disorders, psychiatric nurses should focus on enhancing adolescents’ personal strengths to improve behavioral and social functioning.

Building Our Solutions and Connections (BOSC) focused on enhancing problem-solving skills (PSS) of primary caregivers of children with mental health problems. Aims were determining feasibility, acceptability, and effect size ( ES ) estimates for depression, burden, personal control, and PSS. Methods: Caregivers were randomized to BOSC ( n = 30) or wait-list control (WLC) groups ( n = 31). Data were collected at baseline, post-intervention, and 3 and 6 months post-intervention. Results: Three-months post-intervention, ES for burden and personal control were .07 and .08, respectively. ES for depressed caregivers for burden and personal control were 0.14 and 0.19, respectively. Conclusions: Evidence indicates that the intervention had desired effects.

Background Communication problems between family surrogates and intensive care unit (ICU) clinicians have been documented, but few interventions are effective. Nurses have the potential to play an expanded role in ICU communication and decision making. Objectives To conduct a pilot randomized controlled trial of the family navigator (FN), a distinct nursing role to address family members' unmet communication needs early in an ICU stay. Methods An interprofessional team developed the FN protocol. A randomized controlled pilot intervention trial of the FN was performed in a tertiary referral hospital's ICU to test the feasibility and acceptability of the intervention. The intervention addressed informational and emotional communication needs through daily contact by using structured clinical updates, emotional and informational support modules, family meeting support, and follow-up phone calls. Results Twenty-six surrogate/patient pairs (13 per study arm) were enrolled. Surrogates randomized to the intervention had contact with the FN on 90% or more of eligible patient days. All surrogates agreed that they would recom mend the FN to other families. Open-ended comments from both surrogates and clinicians were uniformly positive. Conclusions Having a fully integrated nurse empowered to facilitate decision making is a feasible intervention in an ICU and is well-received by ICU families and staff. A larger randomized controlled trial is needed to demonstrate impact on important outcomes, such as surrogates' well-being and decision quality.

Recent studies have suggested that plasma-derived proteins may be potential biomarkers relevant for graft-versus-host disease and/or non-relapse mortality occurring after allogeneic blood or marrow transplantation. However, none of these putative biomarkers have been assessed in patients treated either with human leukocyte antigen-haploidentical blood or marrow transplantation or with post-transplantation cyclophosphamide, which has been repeatedly associated with low rates of severe acute graft-versus-host disease, chronic graft-versus-host disease, and non-relapse mortality. We explored whether seven of these plasma-derived proteins, as measured by enzyme-linked immunosorbent assays, were predictive of clinical outcomes in post-transplantation cyclophosphamide-treated patients using plasma samples collected at serial predetermined timepoints from patients treated on prospective clinical studies of human leukocyte antigen-haploidentical (n=58; clinicaltrials.gov Identifier: 00796562) or human leukocyte antigen-matched-related or -unrelated (n=100; clinicaltrials.gov Identifiers: 00134017 and 00809276) T-cell-replete bone marrow transplantation. Day 30 levels of interleukin-2 receptor α, tumor necrosis factor receptor 1, serum STimulation-2 (IL1RL1 gene product), and regenerating islet-derived 3-α all had high areas under the curve of 0.74-0.97 for predicting non-relapse mortality occurrence by 3 months post-transplant in both the human leukocyte antigen-matched and human leukocyte antigen-haploidentical cohorts. In both cohorts, all four of these proteins were also predictive of subsequent non-relapse mortality occurring by 6, 9, or 12 months post-transplant and were significantly associated with non-relapse mortality in univariable analyses. Furthermore, day 30 elevations of interleukin-2 receptor α were associated with grade II-IV and III-IV acute graft-versus-host disease occurring after day 30 in both cohorts. These data confirm that plasma-derived proteins previously assessed in other transplantation platforms appear to retain prognostic and predictive utility in patients treated with post-transplantation cyclophosphamide.

Objective: To characterize patients who voluntarily enrolled in an electronic health information exchange (HIE) program designed to share data between Veterans Health Administration (VHA) and non-VHA institutions.Materials and Methods: Patients who agreed to participate in the HIE program were compared to those who did not. Patient characteristics associated with HIE enrollment were examined using a multivariable logistic regression model. Variables selected for inclusion were guided by a health care utilization model adapted to explain HIE enrollment. Data about patients’ sociodemographics (age, gender), comorbidity (Charlson index score), utilization (primary and specialty care visits), and access (distance to VHA medical center, insurance, VHA benefits) were obtained from VHA and HIE electronic health records.Results: Among 57 072 patients, 6627 (12%) enrolled in the HIE program during its first year. The likelihood of HIE enrollment increased among patients ages 50–64, of female gender, with higher comorbidity, and with increasing utilization. Living in a rural area and being unmarried were associated with decreased likelihood of enrollment.Discussion and Conclusion: Enrollment in HIE is complex, with several factors involved in a patient’s decision to enroll. To broaden HIE participation, populations less likely to enroll should be targeted with tailored recruitment and educational strategies. Moreover, inclusion of special populations, such as patients with higher comorbidity or high utilizers, may help refine the definition of success with respect to HIE implementation.

The study objective was to examine factors that influence African American (AA) family members' end-of-life care decision outcomes for a relative who recently died from serious illness.A cross-sectional descriptive study design was used. Binary logistic and linear regressions were used to identify factors associated with decision regret and decisional conflict. Forty-nine bereaved AA family members of AA decedents with serious illness who died two to six months prior to enrollment were recruited from the palliative care program in a safety net hospital and a metropolitan church in the Midwest. Measurements used were the Decisional Conflict, Decision Regret, Beliefs and Values, and Quality of Communication scales.Family members who reported higher quality of communication with health care providers had lower decisional conflict. Family members of decedents who received comfort-focused care (CFC) had significantly less decision regret than family members of those who received life-prolonging treatment (LPT). Family members who reported stronger beliefs and values had higher quality of communication with providers and lower decisional conflict.This research adds to a small body of literature on correlates of end-of-life decision outcomes among AAs. Although AAs' preference for aggressive end-of-life care is well-documented, we found that receipt of CFC was associated with less decision regret. To reduce decisional conflict and decision regret at the end of life, future studies should identify strategies to improve family member-provider communication, while considering relevant family member and decedent characteristics.

// James Haley 1 , Sunil Tomar 1 , Nicholas Pulliam 1 , Sen Xiong 1 , Susan M. Perkins 2 , Adam R. Karpf 3 , Sumegha Mitra 1, 4 , Kenneth P. Nephew 1, 5, 6 , Anirban K. Mitra 1, 5, 7 1 Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN 47405, USA 2 Department of Biostatistics, Indiana University, Indianapolis, IN 46202, USA 3 Eppley Institute and Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA 4 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA 5 Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN 46202, USA 6 Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA 7 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA Correspondence to: Anirban K. Mitra, email: anmitra@indiana.edu Keywords: ovarian cancer, migration, invasion, proliferation, clonogenicity Received: January 27, 2016 Accepted: April 10, 2016 Published: April 27, 2016 ABSTRACT Genomic analysis of ovarian cancer cell lines has revealed a panel that best represents the most common ovarian cancer subtype, high-grade serous ovarian cancer (HGSOC). However, these HGSOC-like cell lines have not been extensively applied by ovarian cancer researchers to date, and the most commonly used cell lines in the ovarian cancer field do not genetically resemble the major clinical type of the disease. For the HGSOC-like lines to serve as suitable models, they need to be characterized for common functional assays. To achieve that objective, we systematically studied a panel of HGSOC cells CAOV3, COV362, Kuramochi, OVCAR4, OVCAR5, OVCAR8, OVSAHO and SNU119 for migration, invasion, proliferation, clonogenicity, EMT phenotype and cisplatin resistance. They exhibited a range of efficacies and OVCAR5, OVCAR8 and Kuramochi were the most aggressive. SNU119 and OVSAHO cells demonstrated the lowest functional activities. Wide differences in expression of EMT markers were observed between cell lines. SNU119 were the most epithelial and OVCAR8 had the most mesenchymal phenotype. COV362 was the most resistant to cisplatin while CAOV3 was the most sensitive. Taken together, our systematic characterization represents a valuable resource to help guide the application of HGSOC cells by the cancer research community.

The Virtual Lifetime Electronic Record (VLER) Health program provides the Veterans Health Administration (VHA) a framework whereby VHA providers can access the veterans’ electronic health record information to coordinate healthcare across multiple sites of care. As an early adopter of VLER, the Indianapolis VHA and Regenstrief Institute implemented a regional demonstration program involving bi-directional health information exchange (HIE) between VHA and non-VHA providers. The aim of the study is to determine whether implementation of VLER HIE reduces 1 year VHA medical costs. A cohort evaluation with a concurrent control group compared VHA healthcare costs using propensity score adjustment. A CHEERs compliant checklist was used to conduct the cost evaluation. Patients were enrolled in the VLER program onsite at the Indianapolis VHA in outpatient clinics or through the release-of-information office. VHA cost data (in 2014 dollars) were obtained for both enrolled and nonenrolled (control) patients for 1 year prior to, and 1 year after, the index date of patient enrollment. There were 6104 patients enrolled in VLER and 45,700 patients in the control group. The annual adjusted total cost difference per patient was associated with a higher cost for VLER enrollees $1152 (95% CI: $807–1433) (P

In the study we describe adaptive functioning in children with epilepsy whose primary caregivers identified them as having learning problems. This was a cross-sectional study of 50 children with epilepsy and learning problems. Caregivers supplied information regarding the child’s adaptive functioning and behavior problems. Children rated their self-concept and completed a battery of neuropsychological tests. Mean estimated IQ (PPVT-III) in the participant children was 72.8 (SD = 18.3). On average, children scored 2 standard deviations below the norm on the Vineland Adaptive Behavior Scale–II and this was true even for children with epilepsy who had estimated IQ in the normal range. In conclusion, children with epilepsy and learning problems had relatively low adaptive functioning scores and substantial neuropsychological and mental health problems. In epilepsy, adaptive behavior screening can be very informative and guide further evaluation and intervention, even in those children whose IQ is in the normal range.

Objectives The purposes of this 36-month study of children with first recognized seizures were: (1) to describe baseline differences in behavior problems between children with and without prior unrecognized seizures; (2) to identify differences over time in behavior problems between children with seizures and their healthy siblings; (3) to identify the proportions of children with seizures and healthy siblings who were consistently at risk for behavior problems for 36 months; and (4) to identify risk factors for behavior problems 36 months following the first recognized seizure. Risk factors explored included demographic (child age and gender, caregiver education), neuropsychological (IQ, processing speed), seizure (epileptic syndrome, use of antiepileptic drug, seizure recurrence), and family (family mastery, satisfaction with family relationships, parent response) variables. Methods Participants were 300 children aged 6 through 14 years with a first recognized seizure and 196 healthy siblings. Data were collected from medical records, structured interviews, self-report questionnaires, and neuropsychological testing. Behavior problems were measured using the Child Behavior Checklist and the Teacher's Report Form. Data analyses included descriptive statistics and linear mixed models. Results Children with prior unrecognized seizures were at higher risk for behavior problems at baseline. As a group, children with seizures showed a steady reduction in behavior problems over time. Children with seizures were found to have significantly more behavior problems than their siblings over time, and significantly more children with seizures (11.3%) than siblings (4.6%) had consistent behavior problems over time. Key risk factors for child behavior problems based on both caregivers and teachers were: less caregiver education, slower initial processing speed, slowing of processing speed over the first 36 months, and a number of family variables including lower levels of family mastery or child satisfaction with family relationships, lower parent support of the child's autonomy, and lower parent confidence in their ability to discipline their child. Conclusions Children with new-onset seizures who are otherwise developing normally have higher rates of behavior problems than their healthy siblings; however, behavior problems are not consistently in the at-risk range in most children during the first 3 years after seizure onset. When children show behavior problems, family variables that might be targeted include family mastery, parent support of child autonomy, and parents’ confidence in their ability to handle their children's behavior.

Objectives Children with long-standing epilepsy have a significantly increased risk of academic underachievement compared with healthy controls. We prospectively followed children from seizure onset to assess the relationship between change in neuropsychological functioning and change in academic achievement and to explore the risk and protective moderating effects of demographic, seizure, and family variables. Methods As part of a larger study, neuropsychological and academic data were collected at both baseline and 36 months for 219 children 6–14 years of age with seizures. Prior factor analysis of results from a battery of well-standardized neuropsychological tests yielded four factors: language, processing speed, attention/executive/construction, and verbal memory/learning. Academic achievement was measured with the Woodcock–Johnson Revised Achievement Test Battery. Correlation coefficients and linear mixed models were used for analysis. Results The reading and math scores of children with seizures and siblings did not differ at baseline, but children with seizures had lower scores than siblings at 36 months. Writing scores were significantly lower for affected children than siblings at both times. Among children with seizures, there were positive correlations between neuropsychological functioning and academic achievement at baseline and 36 months. Changes in language and in verbal memory/learning were positively correlated with change in reading achievement ( r = 0.25 and r = 0.17, respectively). Age at onset moderated the association between change in neuropsychological functioning and change in reading and writing achievement ( P ≤ 0.006), with stronger relationships among younger children (β = 0.25–0.44). The association between change in language and change in writing achievement was moderated by caregiver anxiety ( P = 0.04; stronger for more anxious parents, β = 0.40), and the association between change in processing speed and change in math achievement was moderated by etiology ( P = 0.02; stronger for symptomatic/cryptogenic vs idiopathic, β = 0.29). Gender and other family variables did not have significant moderating effects. Conclusions Changes in neuropsychological function were associated with changes in academic achievement following onset of seizures, with risk factors being younger age at onset, lower caregiver education, high parental anxiety, and symptomatic/cryptogenic etiology. Academic performance should be closely monitored in children with early-onset seizures.

Background: Identifying methods to accurately measure the glomerular filtration rate (GFR) in obese individuals without kidney overt kidney disease is necessary to understanding the pathophysiology and natural history of obesity-related kidney disease. Methods: Using a cross-sectional design, iohexol clearance and disposition was measured, an optimal sampling schedule was identified, and the reliability of GFR-estimating methods was described in 29 obese individuals with normal serum creatinine levels. Iohexol disposition was measured using population pharmacokinetics. The agreement with GFR-estimating equations was assessed by intraclass coefficients. Results: Mean age was 44 ± 10 years, body mass index 45 ± 10, creatinine 0.7 ± 0.2 mg/dl (62 ± 18 µmol/l) , and cystatin C 0.83 ± 0.18 mg/dl (8.3 ± 1.8 mg/l). Iohexol disposition fit a two-compartment model and 5 sampling windows were identified over a 4-hour period to optimize model accuracy and minimize blood draws. Precision was not compromised with this sampling design. Neither creatinine nor cystatin C were linearly correlated with the measured GFR though cystatin C was independent of body composition. Agreement was fair to poor between the measured GFR and GFR-estimating equations. Conclusion: This study offers a rigorous method to study obesity-related kidney disease and improve upon suboptimal GFR-estimating methods.

Background Patients with chronic heart failure (HF) have cognitive deficits in memory, psychomotor speed, and executive function and poor health-related quality of life (HRQL), but the association between cognitive deficits and HRQL is unknown. Objectives The objectives of this study were to (1) evaluate the relationship between HF severity, age, comorbidities, and cognitive deficits and HRQL among patients with chronic HF and (2) examine whether cognitive deficits mediated the relationship between HF severity and HRQL. Design and sample This study was part of a larger explanatory study; 249 patients with HF completed face-to-face interviews. Methods Measures of HF severity, comorbidity (multiple comorbid conditions, hypertension, and depressive symptoms), cognitive function (domains of language, working memory, memory, psychomotor speed, and executive function), and HRQL were obtained. Clinical variables were abstracted from patients' records. Statistical analyses were conducted using descriptive statistics, Pearson correlation coefficients, and multiple linear regression analyses. Results Overall, the HRQL of patients was moderately poor. Heart failure severity, age, depressive symptoms, and total recall memory explained 55% of the variance in HRQL, but the contribution of memory was minimal (1%). Patients with more severe HF, younger age, and more depressive symptoms had poorer HRQL. Other cognitive function variables, multiple comorbidity, and hypertension were not significant explanatory variables for HRQL. Cognitive deficits did not mediate the relationship between HF severity and HRQL. Conclusions Novel interventions targeted at improving HRQL continue to be urgently needed, particularly among younger patients and patients with depressive symptoms. Measures of HRQL are not sufficient as outcomes when investigating cognitive deficits in HF. Investigators need to include outcome measures of patients' actual abilities to perform daily activities and HF self-care.

► Background: Patients with heart failure (HF) have been found to have cognitive deficits, but it remains unclear whether these deficits are associated with HF or with aging or comorbid conditions common in HF. ► Objectives: The purpose of this study was (a) to determine the types, the frequency, and the severity of cognitive deficits among patients with chronic HF compared with age-and education-matched healthy participants and participants with major medical conditions other than HF, and (b) to evaluate the relationships between HF severity, age, and comorbidities and cognitive deficits. ► Methods: A sample of 414 participants completed the study (249 HF patients, 63 healthy and 102 medical participants). The HF patients completed measures of HF severity, comorbidity (multiple comorbidity, depressive symptoms), and neuropsychological functioning. Blood pressure and oxygen saturation were assessed at interview; clinical variables were abstracted from records. Participants in the comparison groups completed the same measures as the HF patients except those specific to HF. ► Results: Compared with the healthy and medical participants, HF patients had poorer memory, psychomotor speed, and executive function. Significantly more HF patients (24%) had deficits in three or more domains. Higher (worse) HF severity was associated with more cognitive deficits; HF severity interacted with age to explain deficits in executive function. Surprisingly, men with HF had poorer memory, psychomotor speed, and visuospatial recall ability than women. Multiple comorbidity, hypertension, depressive symptoms, and medications were not associated with cognitive deficits in this sample. ► Discussion: HF results in losses in memory, psychomotor speed, and executive function in almost one fourth of patients. Patients with more severe HF are at risk for cognitive deficits. Older patients with more severe HF may have more problems in executive function, and men with HF may be at increased risk for cognitive deficits. Studies are urgently needed to identify the mechanisms for the cognitive deficits in HF and to test innovative interventions to prevent cognitive loss and decline.

This study characterized structural abnormalities associated with onset of seizures in children, using magnetic resonance imaging and a standardized classification system in a large prospective cohort. Two hundred eighty-one children aged 6-14 years completed magnetic resonance imaging within 6 months of their first recognized seizure. Most examinations were performed with a standardized, dedicated seizure protocol; all were scored using a standard scoring system. At least one magnetic resonance imaging abnormality was identified in 87 of 281 (31%) children with a first recognized seizure. Two or more abnormalities were identified in 34 (12%). The commonest abnormalities were ventricular enlargement (51%), leukomalacia/gliosis (23%), gray-matter lesions such as heterotopias and cortical dysplasia (12%), volume loss (12%), other white-matter lesions (9%), and encephalomalacia (6%). Abnormalities defined as significant, or potentially related to seizures, occurred in 40 (14%). Temporal lobe and hippocampal abnormalities were detected at a higher frequency than in previous studies (13/87). Magnetic resonance imaging and a standardized, reliable, valid scoring system demonstrated a higher rate of abnormal findings than previously reported, including findings formerly considered incidental. Practice parameters may need revision, to expand the definition of significant abnormalities and support wider use of magnetic resonance imaging in children with newly diagnosed seizures.

SUMMARY Purpose: To define seizure recurrence rates in normal children who had had a single seizure and to define electroencephalography (EEG) or magnetic resonance imaging (MRI) utility in predicting seizure recurrence. Methods: We studied 150 children (6 to 14 years) with a first afebrile, unprovoked seizure. Inclusion criteria were: Normal physical and neurological examination, undergone EEG and MRI studies of the brain, and followed for at least 27 months. These children participated in an ongoing prospective study of new onset seizures in childhood. Results:The seizure recurrence rate was 66.4%. An abnormal EEG had no association with seizure recurrence at 9, 18, or 27 months (p ¼ 0.1806, p ¼ 0.2792, and p ¼ 0.2379, respectively). A ‘‘significant’’ MRI abnormality, which occurred in 16.0% of patients, was associated with an increased seizure recurrence risk at 9 months (p ¼ 0.0389) but not at 18 or 27 months. Discussion: EEG findings poorly predict recurrence after a single seizure. The high rate of MRI abnormalities suggests that MRI may need consideration as a routine test to evaluate epilepsy in normal children.

The aims of this study were to develop an instrument to measure parents' responses and perceptions related to the onset of either seizures or asthma in a child (aged 4-14) and to assess the initial reliability and validity of the instrument. The 35-item scale developed comprised five subscales: Child Support, Family Life/Leisure, Condition Management, Child Autonomy, and Child Discipline. Subjects were parents of 224 children with new-onset seizures and 104 parents of children with new-onset asthma. Internal consistency reliabilities were stronger for Child Support, Family Life/Leisure, and Condition Management than for Child Autonomy and Child Discipline for both samples. Test-retest reliability ranged from good to fair for both samples. The associations between parent positive mood and all of the subscales for both samples in the predicted directions provided key empirical support for validity. The scale has potential for use in research and in the clinical setting. In addition, the scale has potential to be used with other conditions.

Little is known about the bases of parental worry about adolescents' risk for acquiring a sexually transmitted infection (STI). Parents ( N = 247) of adolescents 12—17 years endorsed reasons that explained their worry or nonworry. Parents' past experience of an STI, perception of the child's sexual activity, and racial self-identification were predictors of worry. Cluster analyses identified five groups of worriers and four groups of nonworriers. Worriers tended to select reasons reflecting an external parental locus of control or child-specific reasons. Nonworriers endorsed reasons consistent with internal parental locus of control. Findings suggest that preventive health communication should be tailored to parents' perceptions of risk and protective factors.

Objective To evaluate the acceptability to Latino parents of having their adolescent children vaccinated against sexually transmitted infections, and to identify potential demographic correlates of acceptability. Methods We applied established methodology to a sample of 119 Latino parents who accompanied their children (51% female, aged 12–17 years) to medical appointments. The parents used computer-based questionnaires to rate 9 hypothetical vaccine scenarios. The scenarios had 4 dimensions: mode of transmission (sexually transmitted or not sexually transmitted), severity of infection (curable, chronic, or fatal), vaccine efficacy (50%, 70%, or 90%), and availability of behavioral methods for prevention (available or not available). Willingness by parents to vaccinate their adolescents under each vaccine scenario was assessed on a scale (range, 0–100). Conjoint analysis was used to determine the relative contribution of each dimension to the ratings. Results The study sample consisted of predominantly Mexican immigrant parents, 94% of whom chose to complete the Spanish version of the computerized interview. The mean value of the parents' willingness to accept vaccination for their adolescent children was exceptionally high. For example, the mean score of the Latino parents for the 6 sexually transmitted infection (STI) vaccine scenarios (score 86.2; SD 21.1) was far higher than the mean score in previous studies (81.3, SD 21.1). Conjoint analysis revealed that the dimensions of vaccine efficacy and severity of infection were equal in terms of their influence on vaccine ratings for the Latino parents. The next most influential dimension on vaccine ratings was the availability of behavioral prevention, followed by the sexual transmissibility of the infection. Conclusions Our sample of predominantly Mexican parents was accepting of the concept of STI vaccination for their adolescent children. Important issues for parents include vaccine efficacy and severity of infection, followed by vaccines for infections that had no method of behavioral prevention available. Overall, there is little difference in the relative preference of a STI versus non-STI vaccine for their adolescent children.

Background The treatment of primary mediastinal nonseminomatous germ cell tumors (PMNSGCT) with cisplatin-based chemotherapy, followed by surgical resection of residual disease, has been established. We reviewed our institution's 25-year experience in the cisplatin era to determine surgical risks and predictors of survival after surgery for PMNSGCT. Methods A total of 158 patients (mean age, 29 ± 8 years) who underwent postchemotherapy operations for PMNSGCT were reviewed and multiple variables analyzed. Results Ten (6%) operative deaths occurred, nine of which were attributed to respiratory failure, and 26 (18%) patients experienced postoperative complications, including 9 with respiratory failure. None of 17 recent patients who received chemotherapy regimens that did not contain bleomycin experienced pulmonary complications ( p = 0.12 vs patients who received bleomycin). Operative survivors were followed up a median of 34 months (range, 1 to 194 months). Multivariable analysis demonstrated that the postchemotherapy pathologic category of complete necrosis vs teratoma), persistent germ cell or nongerm cell cancer, and elevated serum tumor markers after operation were independently predictive of survival. Conclusions Operative risks for PMNSGCT appear to be improved with the use of chemotherapy regimens that do not contain bleomycin. Patients pathologically demonstrating complete tumor necrosis in the residual mass after chemotherapy have excellent long-term survival, with decreasing survival after resection of teratoma and persistent germ cell or nongerm cell cancer. Patients pathologically demonstrating persistent germ cell or nongerm cell cancer have poor but possible long-term survival, which justifies an aggressive surgical approach in patients who are deemed operable.

Structural brain abnormalities of various types can lead to epilepsy, and many are associated with delays in cognitive development or specific cognitive deficits. Genetic cortical malformations (e.g., lissencephaly, schizencephaly, heterotopias, and polymicrogyria) are often characterized by seizure disorders, typically with significant delays in broad cognitive development (Guerrini, 2005). Similarly, tuberous sclerosis is characteristically associated with seizures and developmental delays. More importantly, the degree of intellectual deficit appears to be related to the degree of structural abnormality (i.e., the number of tubers) (Jambaque et al., 1991). Hippocampal sclerosis, a common finding in temporal lobe epilepsy in adults, has been associated with specific deficits in verbal memory and language or spatial memory in a manner consistent with the hemisphere affected (e.g., Baxendale et al., 1998); intelligence and other functions are relatively spared (e.g., Bourgeois et al., 1983; Ellenberg et al., 1986; Martin et al., 1999; Rodin et al., 1986). The degree of neuropsychological deficit is related to hippocampal volumes in adulthood (Baxendale et al., 1998; Hermann et al., 2002). The nature and extent of these neuropsychological deficits appear to be related to age of seizure onset, with lower memory scores and smaller hippocampal volumes observed among individuals with childhood onset (Baxendale et al., 1998). Furthermore, these effects might even be moderated by age of onset, with earlier age of onset being associated with not only hippocampal volume loss but an additional reduction in total brain volume, together with broader neuropsychological deficits that extend outside of the memory domain (Hermann et al., 2002). These findings support an association between the presence of structural brain abnormalities and cognitive deficits in children with epilepsy. For some conditions (e.g. tuberous sclerosis complex), the extent of the structural abnormalities is related to the severity of neuropsychological dysfunction (Jambaque et al., 1991; O’Callaghan et al., 2003; Weber et al., 2000). Moreover, the type and location of the structural abnormalities can be related to the nature of neuropsychological deficits affecting specific cognitive domains (e.g., Hermann et al., 2002). Shinnar and colleagues followed 411 children in New York City after their first unprovoked afebrile seizure (Shinnar et al., 2001). That study helped to characterize a new onset sample with regard to structural brain abnormalities; however, there are potential limitations that could affect the conclusions and generalizability of those findings. First, although the sample was large, only 27% (n = 59) of the children had MRIs; the majority (73%) had CT scans. As would be expected, abnormalities were detected in higher proportions of children using MRI (34%) compared to CT (22%). Therefore, that study likely underestimated the extent of structural brain abnormalities in this population. Second, there was no differentiation between abnormalities that seemed to be related to the seizure disorder versus those that were not related. In addition, imaging data were collected over the course of the children’s disorder in order to use the most sensitive imaging study for each participant that was available at the time of the 2001 publication (Shinnar, 2006). Consequently, many of the children in that sample completed their imaging studies many years after onset. In a subsequent and parallel study, Berg and colleagues followed 613 children in Connecticut following a second unprovoked seizure (Berg et al., 2000). The Connecticut study improved on many of the limitations in the New York City study. The majority of children in the Connecticut study completed MRI studies (vs. CT), and the imaging was obtained in conjunction with the initial evaluation at onset. Consequently, the lower proportion of children showing abnormalities in the Connecticut sample (12.7%, using more sensitive imaging but closer to onset) versus the New York City sample (21%, using less sensitive imaging but more chronic seizures) raises the possibility that some of these abnormalities might develop or become more detectable over the course of the disorder. However, it is possible that differences in exclusion criteria and/or definitions of onset also contributed to the differences in rates of abnormalities. In an effort to start addressing these differences, it would be beneficial to replicate these findings in a new sample with many of the strengths of the Connecticut study. All of these imaging studies have documented the potential for structural abnormalities at the onset of seizures in children. However, it is unclear if these abnormalities are related to cognitive function. Neuropsychological data were not reported for any of these studies. Neuropsychological deficits have been well documented in children with epilepsy (see Fastenau et al., 2003, for brief review), but there have been mixed findings in children at the onset of the disorder. Williams and colleagues (Williams et al., 1998) examined a small cohort (n = 37) of children newly diagnosed with epilepsy prior to initiation of antiepileptic drug therapy and found no differences in neuropsychological performance compared to children newly diagnosed with diabetes. However, others have documented subtle deficits at onset in children. Oostrom and colleagues (Oostrom et al., 2003) compared 51 children with new onset of epilepsy (i.e., at least two seizures) to a group of 48 healthy same age classmates with nearly identical IQ. At baseline they found that children with epilepsy showed deficits in attention and learning compared to the control group. None of these studies examined the relationship between structural abnormalities and neuropsychological deficits at the onset of the disorder. In this study, we explored the relationships between MRI abnormalities of the brain and neuropsychological functioning in children who were evaluated following their first recognized seizure. In the analyses we separated the MRI abnormalities into those that seemed to be related to the seizure disorder and into those that were not related.

The purpose of this study was to compare teachers' ratings of academic performance over 24 months between children with new-onset seizures (N=121) and those with new-onset asthma (N=54) aged 4 to 14. At each data collection point (baseline, 12 months, 24 months), children with seizures were placed into two groups according to their recurrent seizure status (yes/no) during that period. Longitudinal linear mixed models were used to explore differences between the asthma group and the two seizure groups and to determine if differences in teachers' ratings of performance in children with seizures were associated with age, gender, or use of medication. In the seizure sample, scores for children in both groups (with and without recurrent seizures) initially declined at 12 months; however, at 24 months, children who did not have recurrent seizures improved, whereas children who continued to have recurrent seizures declined. There was a trend for younger children to decline more than older children.

Recurrence and death in a significant number of patients with ERα-positive breast cancer occurs 10–20 years after diagnosis. Prognostic markers for late events have been more elusive. TFAP2C (AP2γ) regulates the expression of ERα, the ERα pioneer factors FOXA1 and GATA3, and controls ERα-dependent transcription. The purpose of this investigation is to determine the long-term prognostic value of TFAP2C. A tissue microarray (TMA) consisting of breast tumors from 451 patients with median follow-up time of 10.3 years was created and tested for the expression of TFAP2C by immunohistochemistry. Wilcoxon Rank-Sum and Kruskal–Wallis tests were used to determine if TFAP2C H-scores correlate with other tumor markers. Cox proportional hazards regression models were used to determine whether TFAP2C H-scores and other tumor markers were related to overall and disease-free survival in univariate and multivariable models. TFPAC2 overexpression did not impact overall survival during the first 10 years after diagnosis, but was associated with a shorter survival after 10 years (HR 3.40, 95 % CI 1.58, 7.30; p value = 0.002). This late divergence persisted in ER-positive (HR 2.86, 95 % CI 1.29, 6.36; p value = 0.01) and endocrine therapy-positive subgroups (HR 4.19, 95 % CI 1.72, 10.23; p value = 0.002). For the ER+ and endocrine therapy subgroup, the HR was 3.82 (95 % CI 1.53, 9.50; p value = 0.004). TFAP2C H-scores were not correlated with other tumor markers or related to disease-free survival. In this hypothesis-generating study, we show that higher TFAP2C scores correlate with poor overall survival after 10 years of diagnosis in ERα-positive and endocrine therapy-treated subgroups.

Background Previous research has demonstrated modest benefits from music-based interventions, specifically music and imagery interventions, during cancer care. However, little attention has been paid to measuring the benefits of music-based interventions using measurement instruments specifically designed to account for the multidimensional nature of music-imagery experiences. Objective The purpose of this study was to describe the development of, and psychometrically evaluate, the Music Therapy Self-Rating Scale (MTSRS) as a measure for cancer patients engaged in supportive music and imagery interventions. Methods An exploratory factor analysis using baseline data from 76 patients who consented to participate in a music-based intervention study during chemotherapy. Results Factor analysis of 14 items revealed four domains: Awareness of Body, Emotionally Focused, Personal Resources, and Treatment Specific. Internal reliability was excellent (Cronbach alphas ranging from 0.75 to 0.88) and construct and divergent-discriminant validity supported. Conclusions The MTSRS is a psychometrically sound, brief instrument that captures essential elements of patient experience during music and imagery interventions.

Blood levels of the anti-inflammatory and cardioprotective omega-3 eicosapentaenoic (EPA) and docosahexaenoic (DHA) fatty acids are determined primarily by dietary consumption. There is reason to believe that hemodialysis patients are at risk for inadequate omega-3 intake and, consequently, low blood levels.This question was tested in 75 long-term hemodialysis patients and 25 matched controls by measuring fasting, predialysis plasma and red blood cell (RBC) fatty acid levels using gas chromatography and performing a fish-consumption survey.Sixty-seven percent of patients did not meet American Heart Association fish-consumption guidelines for healthy persons. Compared with controls, patients had lower plasma omega-3 levels (mean % wt: DHA, 1.33 +/- 0.38 [SD] versus 1.51 +/- 0.36; P = 0.0370; omega-3 index [ie, EPA plus DHA], 1.67 +/- 0.49 versus 1.92 +/- 0.40; P = 0.0249). RBC levels, which estimate more long-term consumption, showed mixed results (EPA, 0.29 +/- 0.08 versus 0.33 +/- 0.11; P = 0.0816; DHA, 4.65 +/- 0.92 versus 3.16 +/- 1.15; P0.0001; omega-3 index, 4.95 +/- 0.95 versus 3.49 +/- 1.22; P0.0001). RBC omega-3 levels in patients roughly reflected fish consumption. Independent predictors of plasma and RBC omega-3 levels at the 0.05 level of significance included age, race, sex, alcohol use, and fish servings.Hemodialysis patients consumed fish in quantities far below current American Heart Association recommendations and manifested suboptimal omega-3 levels given their high heart disease risk. These results identify a potentially modifiable cardiovascular risk factor.

Heart failure is nearing epidemic proportions and there is a need for innovative approaches to care that facilitate learning and behavioral change in order to improve health outcomes. This article discusses the development and pilot testing of the PUMP UP program, a tailored computerized intervention, designed to improve 4 health outcomes. The development phases included evaluation of knowledge and design and computerization of the intervention. Pilot testing was completed with 12 patients recruited from primary medicine clinics. Patients completed a baseline telephone interview; follow-up data were obtained immediately after the intervention clinic visit and at 4, 8, and 26 weeks after the visit. Four of the 12 patients met the outcome of improved provider adherence to guidelines. Health-related quality of life scores improved at 26 weeks after baseline. The PUMP UP program was informative and feasible to deliver. It is now ready for testing in intervention studies with larger samples.

Adverse consequences are known to occur in family members responsible for providing care to stroke survivors. However, the differential effect of aphasic versus nonaphasic stroke on caregivers has not been well studied. This study compares selected outcomes (e.g., perceived task difficulty, depressive symptoms, and other negative stroke-related outcomes) among caregivers of aphasic (n = 46) and nonaphasic (n = 113) stroke survivors. Results indicated that caregivers of aphasic survivors perceived greater difficulty with tasks and had more negative stroke-related outcomes than caregivers of nonaphasic survivors. Communication with the survivor was rated as most upsetting and difficult by caregivers in the aphasic group, followed by managing behaviors. Lack of time for family and friends was evident. Female caregivers and caregivers of survivors with self-care deficits also perceived greater difficulty with tasks and negative outcomes. Comprehensive assessment of the unique needs of caregivers of aphasic survivors is suggested for more individualized nursing interventions.

An analysis was performed on patients enrolled in a phase 1-2 trial using stereotactic body radiation therapy for hepatocellular carcinoma evaluating variables influencing liver toxicity.Thirty-eight Child-Pugh class A (CPC-A) (39 lesions) and 21 CPC-B patients (26 lesions) were followed for ≥6 months. Six months local control using modified Response Evaluation Criteria in Solid Tumors criteria, progression-free survival, overall survival, and grade III/IV treatment-related toxicity at 3 months were analyzed.Median follow-up was 33.3 months (2.8-61.1 months) for CPC-A and 46.3 months (3.7-70.4 months) for CPC-B patients. Local control at 6 months was 92% for CPC-A and 93% for CPC-B. Kaplan-Meier estimated 2- and 3-year local control was 91% for CPC-A and 82% for CPC-B (P = .61). Median overall survival was 44.8 months and 17.0 months for CPC-A and CPC-B. Kaplan-Meier estimated 2- and 3-year overall survival was 72% and 61% for CPC-A and 33% and 26% for CPC-B (P = .03). Four (11%) CPC-A patients and 8 CPC-B patients (38%) experienced grade III/IV liver toxicity. Overall, CPC-A patients with ≥grade III liver toxicity had 4.59 (95% confidence interval, 1.19-17.66) times greater risk of death than those without toxicity (P = .0268). No such correlation was seen for CPC-B patients; however, 3 of these CPC-B patients underwent orthotopic liver transplant. CPC-B patients experiencing grade III/IV liver toxicity had significantly higher mean liver dose, higher dose to one-third normal liver, and larger volumes of liver receiving doses2.5 to 15 Gy in 2.5-Gy increments. For CPC-A patients, there was no critical liver dose or volume constraint correlated with toxicity.In our experience, liver stereotactic body radiation therapy is a safe therapy for patients with hepatocellular carcinoma in the context of liver cirrhosis; however, for CPC-B patients, careful attention should be paid to low-dose volumes that could potentially result in increased liver toxicity.