In utero exposure to antidepressant medication and neonatal and child outcomes: a systematic review.

OBJECTIVE: The aim of this study is to systematically review published studies, reporting outcomes to offspring following in utero exposure to antidepressant medications, which used an untreated depressed comparison group. METHODS: OVID, Scopus, EBSCO Collections, the Cochrane Library and Web of Science databases were searched for relevant publications published between January 1950 and May 2018 and a total of 188 potentially eligible studies were identified. RESULTS: Following review, 16 primary studies were eligible for inclusion. Antidepressant exposure was associated with an increased risk of lower gestational age, preterm birth, but not low birthweight or being small for gestational age compared to untreated depression. There is some evidence that congenital defects are associated with antidepressant use, particularly between cardiac defects and paroxetine use. There is conflicting evidence regarding neurodevelopment in offspring, with some reports of increased incidence of autistic spectrum disorders and depression, but also reports of no problems when measuring emotional symptoms, peer problems, conduct problems and hyperactivity-inattention scores. CONCLUSION: When compared with an untreated depressed group, antidepressant exposure was associated with adverse outcomes at birth, while there is insufficient data to determine whether the association between antidepressants and congenital defects or developmental disorders is a true association. However, although we compared treated vs. untreated depression there still may be residual confounding as an untreated depressed group is likely to have less severe depression.

General health status in young people with intellectual disabilities with and without Down syndrome in, and transitioning from, special education: findings from the National Longitudinal Transitions Study-2.

BACKGROUND: There has been little prior investigation of the general health of young people with intellectual disabilities across transition, nor separately for youth with intellectual disabilities with or without Down syndrome, despite general health being a strong predictor of subsequent health service use, hospital admissions and mortality in the general population. We aimed to investigate general health status in youth with intellectual disabilities with and without Down syndrome over the transitional period and quantify the extent to which personal characteristics, parental relationship and household income are associated with general health status. METHODS: The National Longitudinal Transitions Study-2 includes a nationally representative sample of youth receiving special education services aged 13-17 years at wave 1, followed up over 10 years in five waves of data collection. Data on general health status of youth with intellectual disabilities with and without Down syndrome were obtained from parent reports. We summarised overall demographics and general health status and plotted general health status for those who had health data available for all five waves. We then used random-effects ordered logistic regression to investigate whether wave of data collection, age, sex, Down syndrome, ethnicity, parental relationship status and household income are associated with general health status. RESULTS: At wave 1, data on intellectual disabilities were available on 9008/9576 (94.1%) young people, and 871/9008 (9.7%) of them had intellectual disabilities, of whom 125/871 (14.4%) had Down syndrome. Youth with intellectual disabilities with or without Down syndrome had low rates of excellent or very good health. Across waves 1-5, there was a shallow gradient in the proportion of youth with intellectual disabilities reporting excellent/very good health, from 57.7% at 13-17 years to 52.6% at 21-25 years, being more marked for those without Down syndrome (57.8% at 13-17 years to 51.8% at 21-25 years). However, contrary to our expectations, an ordinal measure of general health status did not decline over this transitional period and did not differ between youth with and without Down syndrome. There was a gradient with higher income associated with better health, significantly so over $50 001 (odds ratio = 0.559, 95% confidence interval 0.366-0.854). Poorer health was experienced by youth with Hispanic, Latino or Spanish ethnicity (odds ratio = 1.790, 95% confidence interval 1.051-3.048). Female sex and parental relationship status were not associated with health status. CONCLUSIONS: Young people with intellectual disabilities have bad health, and require support across all ages, including transition. Schools, teachers and staff in transitional services should consider health, and health care and support during transitional planning due to change in service provision and be aware of ethnicity and the stressful effects of low household income. This is important as interventions based on provision of greater support can prevent adverse consequences.

Healthcare Utilisation, Morbidities and Alcohol Use Monitoring Prior to Alcoholic Psychosis Diagnosis.

AIMS: The aim of this study was to describe healthcare utilisation, morbidities and monitoring of alcohol use in patients prior to a diagnosis of alcoholic psychosis in order to inform the early identification of patients at risk. METHODS: Using linked general practice and hospitalisation data in England (April 1997 to June 2014), we identified 1731 individuals (≥18 years) with a clinical recorded diagnosis of alcoholic psychosis and 17,310 matched controls without the disorder, we examined all prior general practitioner (family doctor) visits, hospitalisations, medically recorded morbidities and alcohol assessment/interventions records. Poisson regression models were used to compare rates of healthcare utilisation in people with alcoholic psychosis to those without. Logistic regression models were used to evaluate the association between alcoholic psychosis and prior morbidities. RESULTS: Patients with alcoholic psychosis showed increased levels of healthcare utilisation at least 5 years prior to their diagnosis. The most common reasons for prior healthcare visits were seizures and injuries and there was >4-fold higher rate of seizures, unintentional injuries and self-harm incidents among these patients up to 10 years prior to diagnosis, compared to the control population. A high proportion (78%) of patients had their alcohol consumption recorded, 50% had a record of heavy drinking but only one in five had any evidence of receiving an alcohol-related intervention. CONCLUSION: Patients present more often with seizures and injuries than the general population several years prior to a diagnosis of alcoholic psychosis. These visits represent opportunities for preventive action and imply that we may be missing opportunities to intervene.

Experience Focussed Counselling with Voice Hearers as a Trauma-Sensitive Approach. Results of a Qualitative Thematic Enquiry.

The individual approach of the Hearing Voices Movement, Experience Focussed Counselling or Making Sense of Voices, claims a strong life context and trauma focus. This qualitative study represented the first to explore whether Experience Focussed Counselling with voice hearers, when compared to Treatment As Usual, could be considered trauma-sensitive. Twenty-five semi-structured interviews with voice hearers and mental health professionals in routine German mental health settings were analysed as part of an Applied Thematic Analysis. Overall themes identified were: trauma related; dealing with emotions; process of working with voices; intra- and interpersonal life; and coping related. Experience Focussed Counselling was considered helpful in understanding and working on unresolved trauma-related areas of distress. The same did not apply to Treatment As Usual. Findings support Experience Focussed Counselling as a trauma-sensitive intervention in hearing voices. Frontline mental health staff can potentially support voice hearers in identifying and working on trauma-related voices and emotions.

Myasthenia Gravis and Crisis: Evaluation and Management in the Emergency Department.

BACKGROUND: Myasthenia gravis (MG) is an uncommon autoimmune disorder affecting the neuromuscular junction and manifesting as muscle weakness. A multitude of stressors can exacerbate MG. When symptoms are exacerbated, muscle weakness can be severe enough to result in respiratory failure, a condition known as myasthenic crisis (MC). OBJECTIVE: This review discusses risk factors, diagnosis, management, and iatrogenic avoidance of MC. DISCUSSION: MC can affect any age, ethnicity, or sex and can be precipitated with any stressor, infection being the most common. MC is a clinical diagnosis defined by respiratory failure caused by exacerbation of MG. Muscle weakness can involve any voluntary muscle. MC can be differentiated from other neuromuscular junction diseases by the presence of normal reflexes, normal sensation, lack of autonomic symptoms, lack of fasciculations, and worsening weakness with repetitive motion. Treatment should target the inciting event and airway support. All acetylcholinesterase inhibitors should be avoided in crisis, including edrophonium testing and corticosteroids initially. Respiratory support can begin with noninvasive positive-pressure ventilation, as this has been successful even in patients with bulbar weakness. If intubation is necessary, consider avoiding paralytics or use a reduced dose of nondepolarizing agents. CONCLUSIONS: MC should be in the differential of any patient with muscular weakness and respiratory compromise. Emergency department management of MC should focus on ruling out infection and respiratory support. Strong consideration should be given to beginning with noninvasive positive-pressure ventilation for ventilatory support. Corticosteroids, depolarizing paralytics, and acetylcholinesterase inhibitors should be avoided in patients with MC in the emergency department.

Memories of Phil Bryden.

Phil Bryden was a seminal figure in the development of the field of cerebral lateralization in the last half of the twentieth century, and a founding editor of this journal. Here his founding co-editors reminisce about their friend and colleague, and reflect on his wide-ranging influence in the field and in their own careers.

Previous miscarriage and the subsequent risk of preterm birth in Scotland, 1980-2008: a historical cohort study.

OBJECTIVE: To determine whether the relationship between previous miscarriage and risk of preterm birth changed over the period 1980-2008, and to determine whether the pattern varied according to the cause of the preterm birth. DESIGN: Linked birth databases. SETTING: All Scottish NHS hospitals. POPULATION: A total of 732 719 nulliparous women with a first live birth between 1980 and 2008. METHODS: Risk was estimated using logistic regression. MAIN OUTCOME MEASURES: Preterm birth, subdivided by cause (spontaneous, induced with a diagnosis of pre-eclampsia, or induced without a diagnosis of pre-eclampsia) and severity [extreme (24-28 weeks of gestation), moderate (29-32 weeks of gestation), and mild (33-36 weeks of gestation)]. RESULTS: Consistent with previous studies, previous miscarriage was associated with an increased risk of all-cause preterm birth (adjusted odds ratio, aOR 1.26; 95% confidence interval, 95% CI 1.22-1.29). This arose from associations with all subtypes. The strongest association was found with extreme preterm birth (aOR 1.73; 95% CI 1.57-1.90). Risk increased with the number of miscarriages. Women with three or more miscarriages had the greatest risk of all-cause preterm birth (aOR 2.14; 95% CI 1.93-2.38), and the strongest association was with extreme preterm birth (aOR 3.87; 95% CI 2.85-5.26). The strength of the association between miscarriage and preterm birth decreased from 1980 to 2008. This was because of weakening associations with spontaneous preterm birth and induced preterm birth without a diagnosis of pre-eclampsia. CONCLUSIONS: The association between a prior history of miscarriage and the risk of preterm birth declined in Scotland over the period 1980-2008. We speculate that changes in the methods of managing incomplete termination of pregnancy might explain the trend, through reduced cervical damage.

Previous caesarean delivery and the risk of unexplained stillbirth: retrospective cohort study and meta-analysis.

OBJECTIVE: To determine whether caesarean delivery in the first pregnancy is a risk factor for unexplained antepartum stillbirth in a second pregnancy. DESIGN: A population-based retrospective cohort study and meta-analysis. SETTING: All maternity units in Scotland. PARTICIPANTS: A cohort of 128 585 second births, 1999-2008. METHODS: Time-to-event analysis and random-effects meta-analysis. MAIN OUTCOME MEASURE: Risk of unexplained antepartum stillbirth in a second pregnancy. RESULTS: There were 88 stillbirths among 23 688 women with a previous caesarean delivery (2.34 per 10 000 women per week) and 288 stillbirths in 104 897 women who had previously delivered vaginally (1.67 per 10 000 women per week, P = 0.002). When analysed by cause, women with a previous caesarean delivery had an increased risk of unexplained stillbirth (hazard ratio, HR 1.47; 95% confidence interval, 95% CI 1.12-1.94; P = 0.006) and, as previously observed, the excess risk was apparent from 34 weeks of gestation onwards. The risk did not differ in relation to the indication of the caesarean delivery, and was independent of maternal characteristics and previous obstetric complications. We identified three other comparable studies (two in North America and one in Europe), and meta-analysis of these studies showed a statistically significant association between previous caesarean delivery and the risk of antepartum stillbirth in the second pregnancy (pooled HR 1.40; 95% CI 1.10-1.77; P = 0.006). CONCLUSIONS: Women who have had a previous caesarean delivery are at increased risk of unexplained stillbirth in the second pregnancy. TWEETABLE ABSTRACT: Caesarean first delivery is associated with an increased risk of unexplained stillbirth in the next pregnancy.

The prevalence of vertebral deformities is increased with higher egg incubation temperatures and triploidy in Atlantic salmon Salmo salar L.

Suboptimal egg incubation temperature is a risk factor for the development of skeletal deformities in teleosts. Triplicate diploid and triploid Atlantic salmon, Salmo salar L., egg batches were incubated at 6, 8 and 10 °C up until first feeding, whereupon fish were reared on a natural temperature before examination for externally visible skeletal deformities (jaw and spine) and radiographed for vertebral deformities and morphology at the parr stage. Increasing incubation temperatures and triploidy increased the number of fish showing one or more deformed vertebrae. Triploids had significantly higher mean vertebrae cranio-caudal length (L) and dorsal-ventral height (H) ratio at 6 and 10 °C than diploids, but triploidy had no effect on mean vertebrae centra area. Triploids demonstrated an increase in lower jaw deformities with increased incubation temperature, whereas jaw deformities were rare in diploids. Fish incubated at 10 °C had a significantly lower mean vertebral number than fish incubated at 6 °C, and triploids had lower mean vertebral numbers than diploids. Diploid fish with 58 vertebrae had a significantly higher mean vertebral centra area than fish with 59 vertebrae, but vertebral number did not affect the mean vertebral L/H ratio. The results are discussed with respect to the welfare and production of farmed salmonids.

Applications of pathology-assisted image analysis of immunohistochemistry-based biomarkers in oncology.

Immunohistochemistry-based biomarkers are commonly used to understand target inhibition in key cancer pathways in preclinical models and clinical studies. Automated slide-scanning and advanced high-throughput image analysis software technologies have evolved into a routine methodology for quantitative analysis of immunohistochemistry-based biomarkers. Alongside the traditional pathology H-score based on physical slides, the pathology world is welcoming digital pathology and advanced quantitative image analysis, which have enabled tissue- and cellular-level analysis. An automated workflow was implemented that includes automated staining, slide-scanning, and image analysis methodologies to explore biomarkers involved in 2 cancer targets: Aurora A and NEDD8-activating enzyme (NAE). The 2 workflows highlight the evolution of our immunohistochemistry laboratory and the different needs and requirements of each biological assay. Skin biopsies obtained from MLN8237 (Aurora A inhibitor) phase 1 clinical trials were evaluated for mitotic and apoptotic index, while mitotic index and defects in chromosome alignment and spindles were assessed in tumor biopsies to demonstrate Aurora A inhibition. Additionally, in both preclinical xenograft models and an acute myeloid leukemia phase 1 trial of the NAE inhibitor MLN4924, development of a novel image algorithm enabled measurement of downstream pathway modulation upon NAE inhibition. In the highlighted studies, developing a biomarker strategy based on automated image analysis solutions enabled project teams to confirm target and pathway inhibition and understand downstream outcomes of target inhibition with increased throughput and quantitative accuracy. These case studies demonstrate a strategy that combines a pathologist's expertise with automated image analysis to support oncology drug discovery and development programs.

The effect of ploidy and incubation temperature on survival and the prevalence of aplasia of the septum transversum in Atlantic salmon, Salmo salar L.

Heart deformities are a concern in aquaculture and are linked to egg incubation temperature. Diploid and triploid Atlantic salmon, Salmo salar L., were incubated at 6, 8 and 10 °C and analysed for aplasia of the septum transversum (n = 150 ploidy⁻¹ incubation temperature⁻¹). Heart morphology (size and shape) was assessed in fish incubated at 6 °C and in fish with and without aplasia of the septum transversum (n = 9 group⁻¹) incubated at 10 °C. Egg mortality was significantly higher in triploids than in diploids at all incubation temperatures, and increased egg incubation temperatures increased mortality in both ploidy. Triploids grew quicker than diploids after egg incubation at 10 °C, but not at 6 °C. Aplasia of the septum transversum occurred only in triploid fish after incubation at 6 °C and 8 °C (0.7% and 3.3%, respectively) and was significantly greater (P ≤ 0.05) in triploids after incubation at 10 °C compared with diploids (30% and 18%, respectively). Aplasia of the septum transversum significantly increased heart mass and resulted in a long flat ventricle compared with fish displaying a septum transversum. The results suggest triploid salmon should be incubated below 8 °C.

Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene.

Although disorders of iron metabolism are prevalent, iron transport remains poorly understood. To address this problem, we undertook a positional cloning strategy to identify the causative mutation in mice with microcytic anaemia (mk). Homozygous mk/mk mice have microcytic, hypochromic anaemia due to severe defects in intestinal iron absorption and erythroid iron utilization. We report the identification of a strong candidate gene for mk, and suggest that the phenotype is a consequence of a missense mutation in Nramp2 (ref. 5), a previously identified gene of unknown function. Nramp2 is homologous to Nramp1, a gene activa in host defense. If Nramp2 is mk, as the cumulative evidence suggests, our findings have broad implications for the understanding of iron transport and resistance to intracellular pathogens.

Incidental detection of colorectal malignancies using FDG PET-CT.

The aim of this study was to evaluate the detection rate of incidental colorectal malignancies using whole-body 18FDG-PET/CT at an Irish teaching hospital. We performed a retrospective review of the records of 800 consecutive patients undergoing PET-CT scans at our institution from January 2009 - August 2009. The radiologic reports were analysed and all scans with focal colonic FDG uptake were audited. The colonoscopic and histologic records of the patients who underwent further investigation were reviewed for cancerous and pre-cancerous histology. A total of 643 patients were included in the study. Forty-eight patients (7.5%) had scans which demonstrated focal colonic FDG uptake. Of the 21 patients who underwent further investigation with endoscopy, 14 (66.7%) had biopsies which were positive for dysplasia, this represented 2.2% of the total patients undergoing PET-CT. Eight of these fourteen patients (1.2% of the total) had biopsies demonstrating adenocarcinoma. Four of these patients (50%) had TNM stage 1 or 2 colorectal carcinoma and underwent subsequent curative surgical resection. We found a 2.2% rate of incidentally-diagnosed colorectal malignant and premalignant lesions in patients undergoing PET-CT at our institution. A 1.2% rate of adenocarcinoma was identified. This rate is higher than previously described in the literature.

Randomized phase II trial of docetaxel plus prednisone in combination with placebo or AT-101, an oral small molecule Bcl-2 family antagonist, as first-line therapy for metastatic castration-resistant prostate cancer.

BACKGROUND: AT-101 (A), a small molecule oral inhibitor of the Bcl-2 family, has activity alone and in combination with docetaxel (Taxotere) and prednisone (DP) in metastatic castration-resistant prostate cancer (mCRPC). A randomized, double-blind, placebo-controlled phase II trial compared DP combined with either AT-101 (A) or placebo in chemonaive mCRPC. PATIENTS AND METHODS: Men with progressive mCRPC despite androgen deprivation were eligible and randomized 1:1. Patients received docetaxel (75 mg/m2 day 1) and prednisone 5 mg orally twice daily every 21 days with either AT-101 (40 mg) or placebo twice daily orally on days 1-3. The primary end point was overall survival (OS). RESULTS: Two hundred and twenty-one patients were randomly assigned. Median OS for AT-101 plus docetaxel-prednisone (ADP) and placebo-DP was 18.1 versus 17.8 months [hazard ratio (HR) 1.07, 95% confidence interval 0.72-1.55, P=0.63]. Secondary end points were also not statistically different. Grade 3/4 toxic effects for ADP versus placebo-DP were cardiac events (5% versus 2%), lymphopenia (23% versus 16%), neutropenia (47% versus 40%), ileus (2% versus 0%) and pulmonary embolism (6% versus 2%). In a subgroup of high-risk mCRPC (n=34), outcomes appeared to favor ADP (median OS 19 versus 14 months). CONCLUSIONS: AT-101 was tolerable but did not extend OS when combined with DP in mCRPC; a potential benefit was observed in high-risk patients.

Somnolence in adult craniopharyngioma patients is a common, heterogeneous condition that is potentially treatable.

CONTEXT AND OBJECTIVE: Somnolence and obesity are prevalent in craniopharyngioma patients. We hypothesized that somnolence was because of obstructive sleep apnoea in craniopharyngioma patients. DESIGN, PATIENTS AND MEASUREMENTS: We assessed prevalence of somnolence and sleep apnoea in 28 craniopharyngioma and 23 obese controls attending a tertiary referral centre, by means of the Epworth Sleepiness Score (ESS) and polysomnography. All subjects with sleep apnoea were offered continuous positive airway pressure therapy (CPAP) or modafinil. All craniopharyngioma patients, with unexplained somnolence, were offered modafinil. RESULTS: Somnolence was reported by 20/28 (71·5%) craniopharyngioma patients and 4/23 (17%) obese subjects (P < 0·001). Median ESS was 7·5 (IQR 6, 10·7) in craniopharyngioma patients and 4·0 (4,8) in controls, P < 0·01. Eleven somnolent craniopharyngioma patients had obstructive sleep apnoea, in whom treatment led to a reduction in ESS by 6·4 ± 1·4, P = 0·01. Among the remaining nine patients, five were offered modafinil therapy, of whom four had benefit, three were not compliant with hormone replacement, and one died before intervention. There was no difference in the prevalence of obstructive sleep apnoea between craniopharyngioma (n = 13, 46%) and obese subjects (n = 14, 61%, P = 0·4). Body mass index (BMI) does not correlate with apnoea hypopnoea index [apnoea - hypopnoea index (AHI), r = 0·25, P = 0·08], which suggests that obesity alone does not explain the prevalence of sleep apnoea in craniopharyngioma patients. CONCLUSIONS: Somnolence is common in craniopharyngioma patients and in the majority is because of obstructive sleep apnoea. An additional group of somnolent craniopharyngioma patients benefits from modafinil.

Molecular analysis of original antigenic sin. I. Clonal selection, somatic mutation, and isotype switching during a memory B cell response.

To determine how the memory B cell population elicited to one epitope might be used in immune responses to other, structurally related epitopes, we explored the phenomenon of original antigenic sin. Strain A/J mice reproducibly respond to immunization with p-azophenylarsonate (Ars) by production of anti-Ars antibodies encoded predominantly by a single VH gene segment (VHIdCR). The structural analogue of Ars p-azophenylsulfonate (Sulf) fails alone to elicit such V regions, but can do so in A/J mice previously immunized with Ars, providing a means to specifically examine B cells capable of responding secondarily to a crossreactive antigen (i.e., memory cells). VHIdCR-expressing hybridomas were derived from the Ars-primed, Sulf-boosted original antigenic sin response of A/J mice at various times after Ars priming, and the properties of the antibodies they express and the structure of the genes encoding these antibodies were characterized. The data obtained support the following conclusions: (a) The Ars-induced memory B cell population capable of being crossreactively stimulated by Sulf is largely formed from a small fraction of all B cells participating in the anti-Ars primary response that express somatically mutated V regions; (b) the antibody repertoire and clonal composition of this population are stable over long periods of time; (c) memory B cells are capable of clonal expansion in the absence of a high rate of V gene somatic mutation; (d) the activation requirements for clonal selection of memory, versus naive B cells appear to differ; and (e) a major fraction of Ars-induced memory B cells express either IgM or IgG3 prior to and during the initial stages of the sin response.

Different epitope structures select distinct mutant forms of an antibody variable region for expression during the immune response.

Antibody variable (V) regions that initially differ from one another by only single amino acid residues at VH-D and D-JH segment junctions (termed canonical V regions) can be elicited in strain A/J mice by three different haptens. Among such V regions an amino acid substitution due to somatic mutation is recurrently observed at VH CDR2 position 58, regardless of which of these haptens is used for immunization. This substitution confers upon a canonical V region a generic increase in affinity for all the haptens. Conversely, the type of amino acid substitution at VH position 59 resulting from somatic mutation that is recurrently observed among such V regions changes with the eliciting hapten, in a manner that correlates directly with the cognate affinity increases (or decreases) for hapten conferred by the observed substitutions. This small subregion of VH CDR2 therefore plays a major role in determining both affinity and specificity for antigen. The data confirm that affinity for antigen is of pivotal importance in determining the degree of selection of different mutant forms of a V region. Moreover, during an immune response a sufficiently diverse mutant repertoire can be generated from a single canonical V region to allow adaptation to increase affinity for three different epitopes.

Sunitinib malate for metastatic castration-resistant prostate cancer following docetaxel-based chemotherapy.

BACKGROUND: Systemic therapy options are limited for metastatic castration-resistant prostate cancer (CRPC) patients who progress following docetaxel (Taxotere). This phase II trial evaluated sunitinib malate in patients with progressing metastatic CRPC following prior docetaxel. PATIENTS AND METHODS: Patients with metastatic CRPC progressing following one to two chemotherapy regimens including docetaxel were included. The primary end point was progression-free survival (PFS) per radiographic and clinical evaluations. Oral sunitinib was administered 50 mg/day 4-weeks on followed by 2-weeks off per cycle up to a maximum of eight cycles or until clinical progression or intolerable toxicity. RESULTS: Thirty-six patients with a median age of 69.5 years were accrued. The median PFS was 19.4 weeks with a 12-week PFS of 75.8%. Four patients (12.1%) had a > or =50% prostate-specific antigen (PSA) decline and seven (21.2%) had a > or =30% PSA decline. Two of 18 patients (11.1%) with measurable disease demonstrated 30% declines by RECIST and eight (44.4%) displayed some shrinkage. A decline in pain score > or =2 points occurred in 13.6% of 22 assessable patients. Drug discontinuation due to toxic effects occurred in 52.8% of patients. CONCLUSION: Sunitinib malate demonstrated promising activity in metastatic CRPC progressing after prior docetaxel.

Hepcidin is not essential for mediating testosterone's effects on erythropoiesis.

BACKGROUND: We have shown that testosterone administration suppresses hepcidin, stimulates iron-dependent erythropoiesis, and increases hemoglobin and hematocrit. OBJECTIVE: We investigated whether testosterone-mediated suppression of hepcidin plays an essential role in mediating testosterone's stimulatory effects on erythropoiesis. METHODS: We utilized two mouse models to elucidate the role of hepcidin as a mediator of testosterone's effects on erythropoiesis: First, we used a whole-body hepcidin knockout (HepKO) mouse. Because testosterone's effects on hepcidin expression are mediated through androgen receptor, we also utilized a liver-specific androgen receptor knockout mouse (L-ArKO). Effects of 6 weeks of testosterone (50 mg/kg weekly) administration relative to vehicle on hemoglobin and hematocrit, red blood cell indices, and markers of iron stores and availability were compared between wild-type (WT) and the two genetically modified mouse models. RESULTS: HepKO mice had significantly higher baseline levels of hemoglobin, hematocrit, serum and liver iron, and ferritin than WT mice. Compared to vehicle group, testosterone administration was associated with significant increases in hematocrit, hemoglobin, red cell counts, reticulocyte count, reticulocyte hemoglobin, and serum iron levels in both HepKO and WT mice. Baseline hematocrit levels did not differ between WT and L-ArKO mice. Compared to vehicle, testosterone treatment was associated with significantly greater increase in hematocrit, hemoglobin, red cell count, reticulocyte count, reticulocyte hemoglobin, and serum iron in WT and L-ArKO mice. CONCLUSION: Although hepcidin suppression by testosterone increases iron availability and erythropoiesis, hepcidin suppression is not essential for mediating testosterone's effects on erythropoiesis in healthy mice.

Seven ways to get a grip on implementing Competency-Based Medical Education at the program level.

Competency-based medical education (CBME) curricula are becoming increasingly common in graduate medical education. Put simply, CBME is focused on educational outcomes, is independent of methods and time, and is composed of achievable competencies.1 In spite of widespread uptake, there remains much to learn about implementing CBME at the program level. Leveraging the collective experience of program leaders at Queen's University, where CBME simultaneously launched across 29 specialty programs in 2017, this paper leverages change management theory to provide a short summary of how program leaders can navigate the successful preparation, launch, and initial implementation of CBME within their residency programs.

Les programmes de formation médicale fondée sur les compétences (FMFC) sont de plus en plus répandus dans les études supérieures en médecine. En termes simples, la FMFC est centrée sur les résultats scolaires, elle est indépendante des méthodes et du temps, et est constituée de compétences réalisables.1 Malgré cette adoption généralisée, il reste encore beaucoup à apprendre sur la mise en œuvre de la FMFC au niveau des programmes. Tirant profit de l'expérience collective des responsables de programmes à l'Université Queen, où la FMFC a été lancée simultanément dans 29 programmes de spécialité en 2017,le présent article s'appuie sur la théorie de la gestion du changement pour produire un court résumé de la manière dont les responsables de programmes peuvent gérer avec succès la préparation, le lancement et la mise en œuvre initiale de la FMFC au sein de leurs programmes de résidence.