Survival with metastatic breast cancer based on initial presentation, de novo versus relapsed.

PURPOSE: We hypothesized different Overall Survival (OS) in metastatic breast cancer (MBC) after relapse vs de novo presentation. METHODS: We identified women in British Columbia with MBC diagnosed between 01/2001 and 12/2009. OS from MBC was calculated for relapsed vs de novo cohorts in 3 subgroups, based on hormone receptors (HR) and HER2 status. Age at MBC, disease-free interval (DFI), de novo vs relapsed, year of MBC diagnosis, and systemic treatment were entered into univariable and multivariable analyses. RESULTS: We identified 3645 pts with known HR of which 2796 had known HER2. Median follow-up was 91 months. Median OS was longer for de novo vs relapsed MBC: HR+/HER2- 34 versus 23 months (mos) (p < 0.0001), HR-/HER2- (TN) 11 versus 8 mos (p = 0.02), HER2+ 29 versus 15 mos (p < 0.0001). For TN disease, no variable independently discriminated a group with increased risk of death. For both the HR +/HER2- and the HER2 + groups, relapsed vs de novo status (HzR 1.4 [95% CI 1.2-1.5; p < 0.0001], and HzR 1.6 [95% CI 1.4-1.9; p < 0.0001], respectively) and age >50 (HzR 1.2 [95% CI 1.1-1.4; p = 0.001] and HzR 1.3 [95% CI 1.1-1.5; p = 0.01], respectively) were associated with increased risk of death on multivariable analysis. CONCLUSION: These data provide information that may guide discussions about prognosis between physicians and patients with MBC. In addition, it highlights the importance of stratifying for initial stage at diagnosis in future MBC therapeutic trials.

Family history, not lack of medication use, is associated with the development of postpartum depression in a high-risk sample.

We sought to determine clinical predictors of postpartum depression (PPD), including the role of medication, in a sample of women followed prospectively during and after pregnancy. Women with a history of mood disorder were recruited and evaluated during each trimester and 1 week, 1 month, and 3 months postpartum. DSM-IV criteria for a major depressive episode were assessed by a psychiatric interview at each time point. Sixty-three women with major depression and 30 women with bipolar disorder entered the study and 75.4 % met DSM-IV criteria for a MDE during pregnancy, postpartum, or both. We modeled depression in a given time period (second trimester, third trimester, or 1 month postpartum) as a function of medication use during the preceding period (first, second, or third trimester). The odds of being depressed for those who did not use medication in the previous period was approximately 2.8 times that of those who used medication (OR 2.79, 95 % CI 1.38-5.66, p = 0.0048). Of 38 subjects who were psychiatrically well during the third trimester, 39.5 % (N = 15) met the criteria for a MDE by 4 weeks postpartum. In women who developed PPD, there was a high rate of a family history of PPD (53.3 %) compared to women who did not develop PPD (11.8 %, p = 0.02). While the use of psychiatric medications during pregnancy reduced the odds of being depressed overall, the use of psychiatric medications during pregnancy may not protect against PPD in women at high risk, particularly those with a family history of PPD.

A Preliminary Evaluation of a Brief Behavioral Parent Training for Challenging Behavior in Autism Spectrum Disorder.

Children with autism spectrum disorder (ASD) often exhibit challenging behaviors. Existing behavioral parent trainings (BPT) address ASD symptomology, but are lengthy and associated with significant attrition. In the current pilot study, a longitudinal randomized controlled trial was used to evaluate a novel brief BPT targeting caregivers of children with ASD ages 5-9. The 6-session BPT, delivered in a group format, focused on high-frequency challenging behaviors (e.g., problem behaviors, feeding and sleep issues). Caregivers who received BPT (n = 29), relative to an active control (psychoeducation/supportive therapy; n = 9), reported higher treatment satisfaction and acceptability. Challenging behaviors were reduced in the BPT and active control groups. The novel BPT was a feasible and acceptable intervention to target challenging behaviors in youth with ASD.

Metformin rescues muscle function in BAG3 myofibrillar myopathy models.

Dominant de novo mutations in the co-chaperone BAG3 cause a severe form of myofibrillar myopathy, exhibiting progressive muscle weakness, muscle structural failure, and protein aggregation. To elucidate the mechanism of disease in, and identify therapies for, BAG3 myofibrillar myopathy, we generated two zebrafish models, one conditionally expressing BAG3P209L and one with a nonsense mutation in bag3. While transgenic BAG3P209L-expressing fish display protein aggregation, modeling the early phase of the disease, bag3-/- fish exhibit exercise dependent fiber disintegration, and reduced swimming activity, consistent with later stages of the disease. Detailed characterization of the bag3-/- fish, revealed an impairment in macroautophagic/autophagic activity, a defect we confirmed in BAG3 patient samples. Taken together, our data highlights that while BAG3P209L expression is sufficient to promote protein aggregation, it is the loss of BAG3 due to its sequestration within aggregates, which results in impaired autophagic activity, and subsequent muscle weakness. We therefore screened autophagy-promoting compounds for their effectiveness at removing protein aggregates, identifying nine including metformin. Further evaluation demonstrated metformin is not only able to bring about the removal of protein aggregates in zebrafish and human myoblasts but is also able to rescue the fiber disintegration and swimming deficit observed in the bag3-/- fish. Therefore, repurposing metformin provides a promising therapy for BAG3 myopathy.Abbreviations:ACTN: actinin, alpha; BAG3: BAG cochaperone 3; CRYAB: crystallin alpha B; DES: desmin; DMSO: dimethyl sulfoxide; DNAJB6: DnaJ heat shock protein family (Hsp40) member B6; dpf: days post fertilization; eGFP: enhanced green fluorescent protein; FDA: Food and Drug Administration; FHL1: four and a half LIM domains 1; FLNC: filamin C; hpf: hours post-fertilization; HSPB8: heat shock protein family B [small] member 8; LDB3/ZASP: LIM domain binding 3; MYOT: myotilin; TTN: titin; WT: wild-type.

Pediatric Prevention: Academic Behavior.

Many children in the United States are performing below basic standards in reading, mathematics, and writing. Children at risk for academic problems often have comorbid classroom behavior problems and/or are diagnosed with high-incidence disabilities. Early intervention to prevent academic problems is a key goal of school-wide response-to-intervention models. The goal of school-based instructional intervention is to increase children's strength of responding so basic academic skills can be combined to solve more complex tasks. Parents and caregivers can support intervention efforts at school by engaging in frequent communication with student assistance teams and helping children with academic work completion at home.

Health Beliefs of Nurses in Northern Thailand: A Q-Methodology Study.

Introduction: Northern Thailand has a distinct culture and set of health beliefs. Nurses' beliefs influence approaches to care affecting health care outcomes. This study explored the content, origin, and sociocultural influences on health beliefs of Northern Thai nurses and how they influence clinical practice and education. Method: Q-methodology was used in this study. Data were collected with interviews using Q-cards, Q-sort distribution board, and a semistructured interview guide. Results: Data were collected from 30 clinical nurses and 30 nurses working in academia. Q-factor analysis produced three factors accounting for 48% of variance: personal experience, Thai and Buddhist beliefs, and contemporary beliefs. Discussion: Participants who felt strongly rooted in their culture and beliefs were homogeneous in recognizing the need for evidence-based practice. Nurses aware of the nature and sources of their beliefs and those of patients are well-placed to balance maintenance of cultural traditions with the need to provide evidence-based practice.

Agreement Between Structured Descriptive Assessments and Functional Analyses Conducted Over a Telehealth System.

This study examined whether experimental functional analyses (FAs) conducted by parents at home with coaching via telehealth would produce differentiated results, and compared these results to the functions identified from structured descriptive assessments (SDAs) also conducted by parents at home via telehealth. Four boys between the ages of 4- and 8-years old with intellectual and developmental disabilities and their parents participated. All assessments were conducted in the children's homes with their parents serving as intervention agents and with coaching from remote behavior therapists using videoconferencing technology. Parent-implemented FAs produced differentiated results for all 4 children in the study. Overall, analyzing antecedent-behavior (A-B) and behavior-consequence (B-C) relations from the SDA videos identified only half of the functions identified by the FAs. For children whose SDA results were differentiated, analyzing A-B relations correctly identified 4 of 5 functions. Analyzing B-C relations correctly identified 5 of 6 functions identified by the experimental FA, but overidentified attention for all children. Implications for conducting functional analyses and interpreting structured descriptive assessment via telehealth are discussed.

Effects of word overlap on generalized gains from a repeated readings intervention.

We compared children's gains in oral reading fluency after applying a standard fluency-building intervention to three training passages that differed in word overlap (high, low, and multiple exemplar) with an untrained generalization passage. Participants were 132 White and Hispanic third-grade children from two schools in the northeast and mountain west. Children were randomly assigned within classrooms to the three word overlap conditions, pre-tested on their assigned training and a common generalization passage, received a fluency-building intervention on their assigned training passage, and then post-tested on the same two passages. Regression analyses were conducted to examine the effects of word overlap condition on the children's fluency gains after controlling for pre-test fluency and classroom. Results revealed significantly larger priming and generalization effects for the multiple exemplar versus both the low- and high-word overlap conditions. Survival curves showed that a significantly larger proportion of children in the multiple exemplar condition survived as generalized responders at all generalization levels relative to the other two conditions. Implications for assessing and promoting generalized oral reading fluency in response-to-intervention models and directions for future research are discussed.

Renewal during functional communication training.

Functional communication training (FCT) is one of the most commonly prescribed interventions for the treatment of severe destructive behavior exhibited by individuals with intellectual disabilities. Although highly effective, FCT has been shown to fail in some cases when treatment is introduced into the child's typical environment. Basic and translational research on renewal provides a model for studying the relapse of destructive behavior following successful response to treatment in clinic settings using FCT. In the present study, we evaluated whether relapse of destructive behavior could be attributed to the discriminative control of the home context, which was historically correlated with reinforcement for destructive behavior. We implemented baseline contingencies in the home setting with caregivers acting as interventionists (i.e., Context A). We then implemented FCT in a treatment clinic with trained therapists (i.e., Context B). Finally, we introduced FCT in the home setting with caregivers implementing the treatment procedures (i.e., return to Context A). For three of four participants we observed the relapse of destructive behavior consistent with operant renewal. We discuss the implications of these findings with respect to strategies designed to promote generalization of FCT across settings during the treatment of severe destructive behavior.

Abundance, distribution and diversity of gelatinous predators along the northern Mid-Atlantic Ridge: A comparison of different sampling methodologies.

The diversity and distribution of gelatinous zooplankton were investigated along the northern Mid-Atlantic Ridge (MAR) from June to August 2004.Here, we present results from macrozooplankton trawl sampling, as well as comparisons made between five different methodologies that were employed during the MAR-ECO survey. In total, 16 species of hydromedusae, 31 species of siphonophores and four species of scyphozoans were identified to species level from macrozooplankton trawl samples. Additional taxa were identified to higher taxonomic levels and a single ctenophore genus was observed. Samples were collected at 17 stations along the MAR between the Azores and Iceland. A divergence in the species assemblages was observed at the southern limit of the Subpolar Frontal Zone. The catch composition of gelatinous zooplankton is compared between different sampling methodologies including: a macrozooplankton trawl; a Multinet; a ringnet attached to bottom trawl; and optical platforms (Underwater Video Profiler (UVP) & Remotely Operated Vehicle (ROV)). Different sampling methodologies are shown to exhibit selectivity towards different groups of gelatinous zooplankton. Only ~21% of taxa caught during the survey were caught by both the macrozooplankton trawl and the Multinet when deployed at the same station. The estimates of gelatinous zooplankton abundance calculated using these two gear types also varied widely (1.4 ± 0.9 individuals 1000 m-3 estimated by the macrozooplankton trawl vs. 468.3 ± 315.4 individuals 1000 m-3 estimated by the Multinet (mean ± s.d.) when used at the same stations (n = 6). While it appears that traditional net sampling can generate useful data on pelagic cnidarians, comparisons with results from the optical platforms suggest that ctenophore diversity and abundance are consistently underestimated, particularly when net sampling is conducted in combination with formalin fixation. The results emphasise the importance of considering sampling methodology both when planning surveys, as well as when interpreting existing data.

Children's preference for mixed- versus fixed-ratio schedules of reinforcement: A translational study of risky choice.

Laboratory research has shown that when subjects are given a choice between fixed-ratio and bi-valued mixed-ratio schedules of reinforcement, preference typically emerges for the mixed-ratio schedule even with a larger ratio requirement. The current study sought to replicate and extend these findings to children's math problem completion. Using an ABCBC reversal design, four fourth-grade students were given the choice of completing addition problems reinforced on either a fixed-ratio 5 schedule or one of three mixed-ratio schedules; an equivalent mixed-ratio (1, 9) schedule, a mixed-ratio (1, 11) schedule with a 20% larger ratio requirement, and an equally lean mixed-ratio (5, 7) schedule without the small fixed-ratio 1 component. This was followed by a reversal back to the preceding phase in which preference for the mixed-ratio schedule had been observed, and a final reversal back to the mixed-ratio (5, 7) phase. Findings were consistent with previous research in that all children preferred the mixed-ratio (1, 9) schedule over the equivalent fixed-ratio 5 schedule. Preference persisted for the leaner mixed-ratio (1, 11) schedule for three of the four children. Indifference or preference for the fixed-ratio 5 alternative was observed in phases containing the mixed-ratio (5, 7) schedule. These results extend previous research on risky choice to children's math problem completion and highlight the importance of a small ratio component in the emergence of preference for bi-valued mixed-ratio schedules. Implications of these results for arranging reinforcement to increase children's academic responding are discussed.

Choice in transition: Replication and extension to preschool children in a naturalistic setting.

This study replicated previous basic research into the dynamics of choice and extended this analysis to children's behavior in a naturalistic setting. Two preschoolers with disabilities were observed interacting with their teachers at baseline and during an experimental analysis involving four pairs of concurrent variable-interval schedules of adult attention implemented by an experimenter. Each child was exposed to four experimental phases in which the relative reinforcer rates for on- and off-task behavior were 10:1, 1:1, 1:10, and reversed back to 10:1. The 10:1 phase was designed to mimic the same schedules and types of adult attention observed at baseline. We used the generalized matching equation to model steady-state behavior at the end of the transition phases and to evaluate changes in sensitivity at various points throughout the phases. Choice in transition was evaluated by plotting log behavior ratios by session, cumulated time on- and off-task and cumulated attention for on- and off-task behavior by session, and interreinforcer behavior ratios following different sequences of the first four reinforcer deliveries. The generalized matching equation accounted for a large proportion of variance in steady-state responding, sensitivity values increased steadily throughout the phases, patterns of choice in transition were similar to those reported in basic research, and interreinforcer preference generally shifted toward the just-reinforced alternative. These findings are consistent with previous basic research and support the generality of the dynamics of choice to children's on- and off-task behavior reinforced by adult attention.

Radical trimodality therapy for patients with locally advanced bladder cancer: The British Columbia Cancer Agency experience.

PURPOSE: To assess the outcomes of patients with locally advanced bladder cancer (clinically T3b-T4 or N+and M0) who were referred to the British Columbia Cancer Agency and treated with radical trimodality therapy (RTMT). RTMT consists of transurethral resection of the tumor, followed by both chemotherapy and radiation. METHODS: Between 1997 and 2007, 380 patients with cT3b-cT4 or N+ M0 bladder cancer were referred to the British Columbia Cancer Agency. Of these patients, 50 (13%) were treated using RTMT (all with platin-based chemotherapy and median radiation dose of 60Gy). Patient and disease characteristics as well as treatment data were retrospectively recorded through a chart review. Study end points included overall survival (OS), bladder cancer-specific survival (BCSS), and local relapse-free survival (LRFS). RESULTS: Median follow-up period for surviving patients was 8.53 years. At 5 and 10 years, OS was 30% and 17%, BCSS was 31% and 27%, and LRFS was 60% and 50%, respectively. Complete local response on first cystoscopy following treatment was the only significant predictor of OS, BCSS, and LRFS on univariate analysis, and it was also a significant predictor for LRFS on multivariable analysis. CONCLUSIONS: RTMT is a reasonable alternative to radical cystectomy in patients with locally advanced disease who are either unfit for or unwilling to undergo cystectomy.

The response of Thalassiosira pseudonana to long-term exposure to increased CO2 and decreased pH.

The effect of ocean acidification conditions has been investigated in cultures of the diatom Thalassiosira pseudonana CCMP1335. Expected end-of-the-century pCO(2) (aq) concentrations of 760 µatm (equivalent to pH 7.8) were compared with present-day condition (380 µatm CO(2), pH 8.1). Batch culture pH changed rapidly because of CO(2) (aq) assimilation and pH targets of 7.8 and 8.1 could not be sustained. Long-term (∼100 generation) pH-auxostat, continuous cultures could be maintained at target pH when cell density was kept low (<2×10(5) cells mL(-1)). After 3 months continuous culture, the C:N ratio was slightly decreased under high CO(2) conditions and red fluorescence per cell was slightly increased. However, no change was detected in photosynthetic efficiency (F(v)/F(m)) or functional cross section of PS II (σ(PSII)). Elevated pCO(2) has been predicted to be beneficial to diatoms due to reduced cost of carbon concentration mechanisms. There was reduced transcription of one putative δ-carbonic anhydrase (CA-4) after 3 months growth at increased CO(2) but 3 other δ-CAs and the small subunit of RUBISCO showed no change. There was no evidence of adaptation or clade selection of T. pseudonana after ∼100 generations at elevated CO(2). On the basis of this long-term culture, pH change of this magnitude in the future ocean may have little effect on T. pseudonana in the absence of genetic adaption.

Gill damage to Atlantic salmon (Salmo salar) caused by the common jellyfish (Aurelia aurita) under experimental challenge.

BACKGROUND: Over recent decades jellyfish have caused fish kill events and recurrent gill problems in marine-farmed salmonids. Common jellyfish (Aurelia spp.) are among the most cosmopolitan jellyfish species in the oceans, with populations increasing in many coastal areas. The negative interaction between jellyfish and fish in aquaculture remains a poorly studied area of science. Thus, a recent fish mortality event in Ireland, involving Aurelia aurita, spurred an investigation into the effects of this jellyfish on marine-farmed salmon. METHODOLOGY/PRINCIPAL FINDINGS: To address the in vivo impact of the common jellyfish (A. aurita) on salmonids, we exposed Atlantic salmon (Salmo salar) smolts to macerated A. aurita for 10 hrs under experimental challenge. Gill tissues of control and experimental treatment groups were scored with a system that rated the damage between 0 and 21 using a range of primary and secondary parameters. Our results revealed that A. aurita rapidly and extensively damaged the gills of S. salar, with the pathogenesis of the disorder progressing even after the jellyfish were removed. After only 2 hrs of exposure, significant multi-focal damage to gill tissues was apparent. The nature and extent of the damage increased up to 48 hrs from the start of the challenge. Although the gills remained extensively damaged at 3 wks from the start of the challenge trial, shortening of the gill lamellae and organisation of the cells indicated an attempt to repair the damage suffered. CONCLUSIONS: Our findings clearly demonstrate that A. aurita can cause severe gill problems in marine-farmed fish. With aquaculture predicted to expand worldwide and evidence suggesting that jellyfish populations are increasing in some areas, this threat to aquaculture is of rising concern as significant losses due to jellyfish could be expected to increase in the future.