Direct activation of KCC2 arrests benzodiazepine refractory status epilepticus and limits the subsequent neuronal injury in mice

Hyperpolarizing GABAAR currents, the unitary events that underlie synaptic inhibition, are dependent upon efficient Cl− extrusion, a process that is facilitated by the neuronal specific K+/Cl− co-transporter KCC2. Its activity is also a determinant of the anticonvulsant efficacy of the canonical GABAAR-positive allosteric: benzodiazepines (BDZs). Compromised KCC2 activity is implicated in the pathophysiology of status epilepticus (SE), a medical emergency that rapidly becomes refractory to BDZ (BDZ-RSE). Here, we have identified small molecules that directly bind to and activate KCC2, which leads to reduced neuronal Cl− accumulation and excitability. KCC2 activation does not induce any overt effects on behavior but prevents the development of and terminates ongoing BDZ-RSE. In addition, KCC2 activation reduces neuronal cell death following BDZ-RSE. Collectively, these findings demonstrate that KCC2 activation is a promising strategy to terminate BDZ-resistant seizures and limit the associated neuronal injury

Regression spline bivariate probit models: A practical approach to testing for exogeneity

Bivariate probit models can deal with a problem usually known as endogeneity. This issue is likely to arise in observational studies when confounders are unobserved. We are concerned with testing the hypothesis of exogeneity (or absence of endogeneity) when using regression spline recursive and sample selection bivariate probit models. Likelihood ratio and gradient tests are discussed in this context and their empirical properties investigated and compared with those of the Lagrange multiplier and Wald tests through a Monte Carlo study. The tests are illustrated using two datasets in which the hypothesis of exogeneity needs to be tested

Age and race/ethnicity differences in decisional conflict in women diagnosed with ductal carcinoma in situ

Abstract Purpose Women diagnosed with ductal carcinoma in situ (DCIS) face confusion and uncertainty about treatment options. The objective of this study was to determine whether there are differences in decisional conflict about treatment by age and race/ethnicity. Methods A cross-sectional survey was conducted of women (age ≥ 18) diagnosed with DCIS enrolled at Kaiser Permanente of Southern California. The Decisional Conflict Scale (DCS) measured personal perceptions of decision uncertainty, values clarity, and effective decision-making. We used a multivariable regression to study whether age, race, and ethnicity were associated with patient-reported DCS. Results 45% (N = 1395) of women who received the online survey, participated. The mean age was 56 (± 9.6) years, the majority were white. Compared to women younger than 50, women aged 60–69 reported lower overall DCS scores (-5.4; 95% CI -1.5 to -9.3). Women > 70 had lower values clarity scores (-9.0; 95% CI -2.8 to -15.2) about their treatment compared to women aged 50–59 and 60–69 (-7.1; 95% CI -2.9 to -11.3 and − 7.2; 95% CI -2.9 to -11.5) and likewise, lower effective decision-making scores (-5.4; 95% CI -1.7 to -9.2 and − 5.2; 95% CI -1.4 to -9.0) compared to women  70). Age based tailored discussions about treatment options, health education, and supportive decision-making interventions/tools may reduce decision conflict in future DCIS patients. Trade registration The IRB number is 10678

Ductal Carcinoma in Situ Treatment Decision-Making and Patient-Reported Outcomes: A Review of the Literature

Background/Aims: The treatment for ductal carcinoma in situ (DCIS) is similar to invasive breast cancer despite evidence of low 10-year recurrence rates and mortality. Patient preferences and involvement with decision-making should play a key role in treatment decisions; however, little are known about how decision-making about the type of treatment influences patient-reported outcomes. The objective is to review the recent literature to determine how decision-making for treatment of DCIS influences patient-reported outcomes and to make recommendations on future studies to improve decision-making practices. Methods: A search of PubMed database was conducted for manuscripts published 2009–2014. Search terms included “ductal carcinoma in situ” and “satisfaction with treatment” (n=33), “decisional conflict” (n=1) or “patient decision making” (n=137). Only articles that included patient-reported decision-making were included in the review. Articles were excluded if they aggregated patients with invasive or metastatic breast cancer. Results: There were a total of 11 articles included in the review. We found that decisional conflict among patients was common. Physicians play an important role in women understanding the disease; however, there is controversy about treatment of DCIS among experts. Decisional conflict was related to a lack of knowledge about the disease, which led to confusion, anxiety, fear and depression. The studies showed that conflicting messages from health care professionals negatively impacted patient’s abilities to make informed treatment decisions and patient-reported outcomes. In terms of health disparities, one study found that a lack of understanding about DCIS was greater in women from non-English speaking backgrounds. Recommendations for future research include: 1) improve knowledge of DCIS and its complexities among health care professionals and patients, 2) address knowledge gaps by developing and testing the efficacy of “decision aids” to improve patients comfort in making informed treatment choices, 3) evaluate why various messages about DCIS exist among health care professionals, and 4) address the need to establish consensus on guidelines. Discussion: The literature suggests that patients often have a lack of knowledge and experience adverse psychological outcomes associated with a diagnosis of DCIS. More research is needed to improve informed treatment decisions about the disease for patients diagnosed with DCIS

Cost-Effectiveness of Taxanes in the Treatment of Metastatic Breast Cancer: A Review of the Literature

Background/Aims: Metastatic breast cancer (MBC) is an incurable disease in which regardless of treatment, total survival time is often less than a year. In these patients suffering from MBC, mitigation of symptoms, reducing side effects of therapy and enhancing quality of life are the major issues in selecting a treatment. Taxanes have been shown to be efficacious as single agents or in combination with other agents as compared to other chemotherapy regimens. Docetaxel has received more support over paclitaxel in many analyses that have compared the two drugs indirectly. A direct comparison of both docetaxel and paclitaxel has not been possible until recently due to a lack of randomized trials. Little is known in reference to cost-effectiveness of taxanes in the treatment of MBC when compared directly. The objective of this literature review was to assess cost-effectiveness literature comparing docetaxel and paclitaxel in MBC. Methods: PubMed was used to conduct a search for manuscripts published 2005–2014. Search terms included “metastatic breast cancer” in addition to “cost-effectiveness” (n=96), “cost-utility” (n=9), “docetaxel” (n=332) and “paclitaxel” (n=336). Only articles that included cost-effectiveness analyses and a direct comparison among the taxanes were included. Results: A total of three cost-effectiveness studies were identified and included in the final review. Two of the three studies utilized data from a randomized controlled trial. The cost-effectiveness analyses reported incremental cost-effectiveness ratios (ICER) and quality adjusted life-years (QALY) and concluded that docetaxel, compared to paclitaxel, was superior and improved QALYs by 0.33–0.75. It is important to note that all three analyses were conducted outside of the United States. Discussion: In North America, breast cancer remains the most frequently diagnosed cancer in women. Yet, there are no new comprehensive economic analyses comparing the two taxanes published recently in the United States. Literature reflecting such comparisons has been published within the United Kingdom, Spain and Canada (reflected in this review). However, with the prevalence for the disease growing, it is important to continuously develop models assessing cost-effectiveness among patients with MBC

Ductal Carcinoma in Situ Treatment Decision-Making and Patient-Reported Outcomes: A Review of the Literature

Background/Aims: The treatment for ductal carcinoma in situ (DCIS) is similar to invasive breast cancer despite evidence of low 10-year recurrence rates and mortality. Patient preferences and involvement with decision-making should play a key role in treatment decisions; however, little are known about how decision-making about the type of treatment influences patient-reported outcomes. The objective is to review the recent literature to determine how decision-making for treatment of DCIS influences patient-reported outcomes and to make recommendations on future studies to improve decision-making practices. Methods: A search of PubMed database was conducted for manuscripts published 2009–2014. Search terms included “ductal carcinoma in situ” and “satisfaction with treatment” (n=33), “decisional conflict” (n=1) or “patient decision making” (n=137). Only articles that included patient-reported decision-making were included in the review. Articles were excluded if they aggregated patients with invasive or metastatic breast cancer. Results: There were a total of 11 articles included in the review. We found that decisional conflict among patients was common. Physicians play an important role in women understanding the disease; however, there is controversy about treatment of DCIS among experts. Decisional conflict was related to a lack of knowledge about the disease, which led to confusion, anxiety, fear and depression. The studies showed that conflicting messages from health care professionals negatively impacted patient’s abilities to make informed treatment decisions and patient-reported outcomes. In terms of health disparities, one study found that a lack of understanding about DCIS was greater in women from non-English speaking backgrounds. Recommendations for future research include: 1) improve knowledge of DCIS and its complexities among health care professionals and patients, 2) address knowledge gaps by developing and testing the efficacy of “decision aids” to improve patients comfort in making informed treatment choices, 3) evaluate why various messages about DCIS exist among health care professionals, and 4) address the need to establish consensus on guidelines. Discussion: The literature suggests that patients often have a lack of knowledge and experience adverse psychological outcomes associated with a diagnosis of DCIS. More research is needed to improve informed treatment decisions about the disease for patients diagnosed with DCIS

A Systematic Review of the Measurement Properties of the European Organization for Research and Treatment of Cancer QLQ-BR23 Quality-of-Life Instrument

Background/Aims: The objective of this literature review was to analyze the measurement properties of the European Organization for Research and Treatment of Cancer’s (EORTC) breast cancer-specific quality-of-life questionnaire (QLQ-BR23). Methods: A PubMed search was conducted using the search terms “breast neoplasm,” “quality of life,” and “EORTC” to identify all the articles using the EORTC QLQ-BR23 questionnaire. The search was limited to studies published in the English language from 2005 to 2014. Articles were also searched on HEALTHSTAR and Google Scholar Search and the websites of organizations like the Centers for Disease Control and Prevention, the National Cancer Institute and the EORTC Quality-of-Life group. This study primarily focused on articles looking solely at measurement properties such as discriminative and evaluative properties, reliability, validity and interpretability of the EORTC QLQ-BR23 instrument. Articles that did not report any measure of reliability, such as intraclass correlation coefficient or Cronbach’s alpha, were excluded from the review. Results: Of the 101 articles obtained from the initial search, 18 were relevant and 15 met the inclusion criteria. The QLQ-BR23 instrument had suitable face and content validity. Of those 15 articles that met the inclusion criteria, only 6 established support for convergent-divergent validity. Acceptable convergent-divergent validity was seen in the body image, sexual functioning, systemic therapy side effects, breast symptoms and arm symptoms domains. Construct validity for all domains was supported using the method of known groups in 3 culturally diverse populations when the QLQ-BR23 was used as a discriminating tool. Overall, the instrument exhibited high internal consistency in the diverse populations. Reliability, interpretability and evaluative properties were inadequately studied in the published studies. Discussion: The EORTC QLQ-BR23 instrument is proven to be valid cross-culturally and readily accepted as having high internal consistency. Consequently, it is a suitable instrument for measuring patient-reported outcomes in breast cancer patients. It has good discriminative properties, but evaluative properties need more empirical support. Considerations for future research may include using the QLQ-BR23 module in studies designed to better assess the instrument’s evaluative properties