Primary care physicians' perceptions of barriers and facilitators to management of chronic kidney disease: A mixed methods study.

BackgroundGiven the high prevalence of chronic kidney disease (CKD), primary care physicians (PCPs) frequently manage early stage CKD. Nonetheless, there are challenges in providing optimal CKD care in the primary care setting. This study sought to understand PCPs' perceptions of barriers and facilitators to the optimal management of CKD.Study designMixed methods study.Settings and participantsCommunity-based PCPs in four US cities: Baltimore, MD; St. Louis, MO; Raleigh, NC and San Francisco, CA.MethodologyWe used a self-administered questionnaire and conducted 4 focus groups of PCPs (n = 8 PCPs/focus group) in each city to identify key barriers and facilitators to management of patients with CKD in primary care.Analytic approachWe conducted descriptive analyses of the survey data. Major themes were identified from audio-recorded interviews that were transcribed and coded by the research team.ResultsOf 32 participating PCPs, 31 (97%) had been in practice for >10 years, and 29 (91%) practiced in a non-academic setting. PCPs identified multiple barriers to managing CKD in primary care including at the level of the patient (e.g., low awareness of CKD, poor adherence to treatment recommendations), the provider (e.g., staying current with CKD guidelines), and the health care system (e.g., inflexible electronic medical record, limited time and resources). PCPs desired electronic prompts and lab decision support, concise guidelines, and healthcare financing reform to improve CKD care.ConclusionsPCPs face substantial but modifiable barriers in providing care to patients with CKD. Interventions that address these barriers and promote facilitative tools may improve PCPs' effectiveness and capacity to care for patients with CKD

The effects of metformin on endogenous androgens and SHBG in women : a systematic review and meta-analysis

Objectives Elevated circulating androgens are risk factors for several chronic, metabolic and reproductive disorders. Metformin is an insulin-sensitizing agent that may lower androgen levels. To evaluate the effects of metformin on endogenous androgens and SHBG levels in women, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing metformin with placebo or no treatment. Data source We used OVID to search MEDLINE, EMBASE and CENTRAL until March 2007. Review methods Two reviewers independently extracted data on methodological quality, participants, interventions and outcomes of interest. Our a priori primary outcome was post-treatment measurements. In a secondary analysis, we evaluated the difference between the pre- and post-treatment levels. We computed the weighted mean difference (WMD) as a measure of effect for each outcome using the DerSimonian-Laird random effects method. We used the I2 statistic to assess heterogeneity and explored its causes in subgroup analyses of features related to participants' characteristics and study design. Based on a regression model, we conducted sensitivity analyses by investigating the use of placebo as a predictor of effect size. Results Twenty RCTs fulfilled the inclusion criteria. Pooled WMDs in post-treatment levels between the metformin and control group were -0\ub731 nmol/l (95% CI -0\ub765 to 0\ub703) for total testosterone (TT), 0\ub710 pmol/l (95% CI -0\ub789 to 1\ub710) for free testosterone (FT), 0\ub714 \u3bcmol/l (95% CI -0\ub734 to 0\ub762) for dehydroepiandrosteronesulfate (DHEAS), -0\ub760 nmol/l (95% CI -1\ub767 to 0\ub746) for androstenedione (AND) and 5\ub788 nmol/l (95% CI 2\ub701-9\ub775) for SHBG. Pooled WMDs of the pre- to post-treatment differences (i.e. with adjustment for baseline hormone levels) were -0\ub738 (95% CI -0\ub751 to -0\ub725) for TT, -2\ub771 (95% CI -10\ub735 to 4\ub793) for FT, -0\ub750 (95% CI -0\ub783 to -0\ub716) for DHEAS, -1\ub739 (95% CI -2\ub730 to -0\ub749) for AND and 6\ub763 (95% CI 2\ub732-10\ub794) for SHBG. In subgroup analyses, features related to the administered treatment (i.e. metformin as a single agent or as part of combined regimens) partly explained the heterogeneity. Sensitivity analyses of studies using placebo showed similar results to those not using placebo. Conclusions Our systematic review and meta-analysis provides evidence of metformin-induced changes in circulating androgens and SHBG levels in women but the quality of evidence is not high. However, there are no data from RCTs regarding these effects in postmenopausal women or healthy premenopausal women. High-quality RCTs are required to evaluate whether metformin has effects on surrogate markers and patient-important outcomes in these patient groups

Analysis of the ATR-Chk1 and ATM-Chk2 pathways in male breast cancer revealed the prognostic significance of ATR expression

The ATR-Chk1 and ATM-Chk2 pathways are central in DNA damage repair (DDR) and their over-activation may confer aggressive molecular features, being an adaptive response to endogenous DNA damage and oncogene-induced replication stress. Herein we investigated the ATR-Chk1 and ATM-Chk2 signalings in male breast cancer (MBC). The expression of DDR kinases (pATR, pATM, pChk1, pChk2, and pWee1) and DNA damage markers (pRPA32 and γ-H2AX) was evaluated by immunohistochemistry in 289 MBC samples to assess their association. Survival analyses were carried out in 112 patients. Survival curves were estimated with the Kaplan-Meier method and compared by log-rank test. Cox proportional regression models were generated to identify variables impacting survival outcomes. The expression of pATR conferred poorer survival outcomes (log rank p = 0.013, p = 0.007 and p = 0.010 for overall, 15- and 10-year survival, respectively). Multivariate Cox models of 10-year survival and overall indicated that pATR expression, alone or combined with pChk2, was an independent predictor of adverse outcomes (10-year survival: pATR: HR 2.74, 95% CI: 1.23–6.10; pATR/pChk2: HR 2.92, 95% CI: 1.35–6.33; overall survival: pATR: HR 2.58, 95% CI: 1.20–5.53; pATR/pChk2: HR 2.89, 95% CI: 1.37–6.12). Overall, the ATR/ATM-initiated molecular cascade seems to be active in a fraction of MBC patients and may represent a negative prognostic factor

Control of replication stress and mitosis in colorectal cancer stem cells through the interplay of PARP1, MRE11 and RAD51

Cancer stem cells (CSCs) are tumor subpopulations driving disease development, progression, relapse and therapy resistance, and their targeting ensures tumor eradication. CSCs display heterogeneous replication stress (RS), but the functionality/relevance of the RS response (RSR) centered on the ATR-CHK1 axis is debated. Here, we show that the RSR is efficient in primary CSCs from colorectal cancer (CRC-SCs), and describe unique roles for PARP1 and MRE11/RAD51. First, we demonstrated that PARP1 is upregulated in CRC-SCs resistant to several replication poisons and RSR inhibitors (RSRi). In these cells, PARP1 modulates replication fork speed resulting in low constitutive RS. Second, we showed that MRE11 and RAD51 cooperate in the genoprotection and mitosis execution of PARP1-upregulated CRC-SCs. These roles represent therapeutic vulnerabilities for CSCs. Indeed, PARP1i sensitized CRC-SCs to ATRi/CHK1i, inducing replication catastrophe, and prevented the development of resistance to CHK1i. Also, MRE11i + RAD51i selectively killed PARP1-upregulated CRC-SCs via mitotic catastrophe. These results provide the rationale for biomarker-driven clinical trials in CRC using distinct RSRi combinations

The role of motor simulation in action perception: a neuropsychological case study

Research on embodied cognition stresses that bodily and motor processes constrain how we perceive others. Regarding action perception the most prominent hypothesis is that observed actions are matched to the observer’s own motor representations. Previous findings demonstrate that the motor laws that constrain one’s performance also constrain one’s perception of others’ actions. The present neuropsychological case study asked whether neurological impairments affect a person’s performance and action perception in the same way. The results showed that patient DS, who suffers from a frontal brain lesion, not only ignored target size when performing movements but also when asked to judge whether others can perform the same movements. In other words DS showed the same violation of Fitts’s law when performing and observing actions. These results further support the assumption of close perception action links and the assumption that these links recruit predictive mechanisms residing in the motor system

Quality-sensitive foraging by a robot swarm through virtual pheromone trails

Large swarms of simple autonomous robots can be employed to find objects clustered at random locations, and transport them to a central depot. This solution offers system parallelisation through concurrent environment exploration and object collection by several robots, but it also introduces the challenge of robot coordination. Inspired by ants’ foraging behaviour, we successfully tackle robot swarm coordination through indirect stigmergic communication in the form of virtual pheromone trails. We design and implement a robot swarm composed of up to 100 Kilobots using the recent technology Augmented Reality for Kilobots (ARK). Using pheromone trails, our memoryless robots rediscover object sources that have been located previously. The emerging collective dynamics show a throughput inversely proportional to the source distance. We assume environments with multiple sources, each providing objects of different qualities, and we investigate how the robot swarm balances the quality-distance trade-off by using quality-sensitive pheromone trails. To our knowledge this work represents the largest robotic experiment in stigmergic foraging, and is the first complete demonstration of ARK, showcasing the set of unique functionalities it provides