Health-related quality of life in patients with a germline BRCA mutation and metastatic pancreatic cancer receiving maintenance olaparib.

BACKGROUND: Patients with metastatic pancreatic cancer often have a detriment in health-related quality of life (HRQoL). In the randomized, double-blind, phase III POLO trial progression-free survival was significantly longer with maintenance olaparib, a poly(ADP-ribose) polymerase inhibitor, than placebo in patients with a germline BRCA1 and/or BRCA2 mutation (gBRCAm) and metastatic pancreatic cancer whose disease had not progressed during first-line platinum-based chemotherapy. The prespecified HRQoL evaluation is reported here. PATIENTS AND METHODS: Patients were randomized to receive maintenance olaparib (300 mg b.i.d.; tablets) or placebo. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item module at baseline, every 4 weeks until disease progression, at discontinuation, and 30 days after last dose. Scores ranged from 0 to 100; a ≥10-point change or difference between arms was considered clinically meaningful. Adjusted mean change from baseline was analysed using a mixed model for repeated measures. Time to sustained clinically meaningful deterioration (TSCMD) was analysed using a log-rank test. RESULTS: Of 154 randomized patients, 89 of 92 olaparib-arm and 58 of 62 placebo-arm patients were included in HRQoL analyses. The adjusted mean change in Global Health Status (GHS) score from baseline was <10 points in both arms and there was no significant between-group difference [-2.47; 95% confidence interval (CI) -7.27, 2.33; P = 0.31]. Analysis of physical functioning scores showed a significant between-group difference (-4.45 points; 95% CI -8.75, -0.16; P = 0.04). There was no difference in TSCMD for olaparib versus placebo for GHS [P = 0.25; hazard ratio (HR) 0.72; 95% CI 0.41, 1.27] or physical functioning (P = 0.32; HR 1.38; 95% CI 0.73, 2.63). CONCLUSIONS: HRQoL was preserved with maintenance olaparib treatment with no clinically meaningful difference compared with placebo. These results support the observed efficacy benefit of maintenance olaparib in patients with a gBRCAm and metastatic pancreatic cancer. CLINCALTRIALS.GOV NUMBER: NCT02184195.

Foundation doctors working at night: what training opportunities exist?

INTRODUCTION: Foundation Training is designed for doctors in their first two years of post-graduation. The number of foundation doctors (FD) in the UK working nights has reduced because of a perception that clinical supervision at night is unsatisfactory and that minimal training opportunities exist. We aimed to assess the value of night shifts to FDs and hypothesised that removing FDs from nights may be detrimental to training. METHODS: Using a survey, we assessed the number of FDs working nights in London, FDs views on working nights and their supervision at night. We evaluated whether working at night, compared to daytime working provided opportunities to achieve foundation competencies. RESULTS: 83% (N = 2157/2593) of FDs completed the survey. Over 90% of FDs who worked nights felt that the experience they gained improved their ability to prioritise, make decisions and plan. FDs who worked nights reported higher scores for achieving competencies in history taking (2.67 vs. 2.51; p = 0.00), examination (2.72 vs. 2.59; p = 0.01) and resuscitation (2.27 vs. 1.96; p = 0.00). The majority (65%) felt adequately supervised. CONCLUSIONS: Our survey has demonstrated that FDs find working nights a valuable experience, providing important training opportunities, which are additional to those encountered during daytime working.

Quality of life after involuntary psychiatric admission.

Studies seeking predictors of outcomes after involuntary admission, including quality of life (QoL), are limited and results inconsistent. We aimed to describe QoL 3 months after involuntary psychiatric admission and to investigate associated factors. One hundred and fifty-three involuntarily admitted inpatients were assessed for a range of sociodemographic and clinical variables. Structured scales included the Brief Psychiatric Rating Scale (BPRS), the MacArthur Admission Experience Survey, the Heinrichs Quality of Life Scale and the World Health Organisation Quality of Life Brief Assessment (WHOQOL-BREF, n = 124). The mean total score on the Heinrichs QoL scale at 3 months was 69.3 (SD = 24.1). Predictors of higher 3 month QoL after involuntary admission in a multiple regression model (adjusted R2 = 0.37, F = 7.1 (14, 138), p ≤0.001) were less severe negative symptoms on the BPRS at baseline (B = -4.56, p < 0.001), improvement in negative symptom scores between baseline and follow up (B = 4.58, p < 0.001) and higher current social class (B = -14.31, p = 0.001). Events during involuntary admission, such as being subject to coercive experiences, were not significantly associated with QoL after admission. The results suggest that a core determinant of service users' QoL after involuntary admission is negative symptom severity and change over time.

Upregulation of MAPK pathway is associated with survival in castrate-resistant prostate cancer.

BACKGROUND: Recent evidence has implicated the MAP kinase (MAPK) pathway with the development of castrate-resistant prostate cancer (CRPC). We have previously reported gene amplification of critical members of this pathway with the development of castrate-resistant disease. In addition, we have shown that rising Raf-1 expression, with the development of CRPC, influences time to biochemical relapse. We therefore sought to further analyse the role of both Raf-1 and its downstream target MAPK in the molecular pathogenesis of CRPC. METHODS: Protein expression of Raf-1 and MAPK, including their activation status, was analysed using immunohistochemistry in a database of 65 paired tumour specimens obtained before and after the development of CRPC and correlated with other members of the pathway. RESULTS: Patients whose nuclear expression of MAPK rose with the development of CRPC had a significantly shorter median time to death following biochemical relapse (1.40 vs 3.00 years, P=0.0255) as well as reduced disease-specific survival when compared with those whose expression fell or remained unchanged (1.16 vs 2.62 years, P=0.0005). Significant correlations were observed between protein expression of Raf-1 and MAPK with the type 1 receptor tyrosine kinases, Her2 and epidermal growth factor receptor, as well as the transcription factor AP-1 in CRPC tumours. CONCLUSION: We conclude that the Her2/Raf-1/MAPK/AP-1 axis may promote the development of CRPC, leading to early relapse, and reduced disease-specific survival. In addition, members of the pathway may act as novel therapeutic and/or diagnostic targets for prostate cancer.

Pregabalin-induced sexual disinhibition.

INTRODUCTION: Sexual side effects have rarely been reported secondary to treatment with Pregabalin, a structural analogue of the inhibitory neurotransmitter gamma amino butyric acid (GABA). METHOD: We present the case of AB, a 27-year-old single man with a diagnosis of recurrent depressive disorder who was prescribed pregabalin to alleviate the significant anxiety symptoms he was experiencing. RESULTS: A significant amelioration in anxiety symptoms was attained; however, he developed the adverse effects of acute sexual disinhibition and increased libido. These adverse effects were temporally related to treatment with pregabalin and reduced with dose reduction of this agent. CONCLUSIONS: To date, limited published data are available relating such a reaction to pregabalin. A greater clinical recognition of this association between pregabalin and sexual disinhibition, would allow clinicians to intervene at an earlier stage of this adverse effect and potentially as in this case, management may only require dose reduction rather than treatment discontinuation.

The effect of supplementing pony diets with yeast on 2. The faecal microbiome.

There is a need to develop feeding strategies to prevent the adverse effect of concentrate feeding in high-performance horses fed energy-dense diets aiming to maintain their health and welfare. The objective of this study is to determine the effect of a VistaEQ product containing 4% live yeast Saccharomyces cerevisiae (S. cerevisiae), with activity 5 × 108 colony-forming unit/g and fed 2 g/pony per day, on faecal microbial populations when supplemented with high-starch and high-fibre diets using Illumina next generation sequencing of the V3-V4 region of the 16S ribosomal RNA gene. The four treatments were allocated to eight mature Welsh section A pony geldings enrolled in a 4-period × 8 animal crossover design. Each 19-day experimental period consisted of an 18-day adaptation phase and a single collection day, followed by a 7-day wash out period. After DNA extraction from faeces and library preparation, α-diversity and linear discriminant analysis effect size were performed using 16S metagenomics pipeline in Quantitative Insights Into Microbial Ecology (QIIME™) and Galaxy/Hutlab. Differences between the groups were considered significant when linear discriminant analysis score was >2 corresponding to P < 0.05. The present study showed that S. cerevisiae used was able to induce positive changes in the equine microbiota when supplemented to a high-fibre diet: it increased relative abundance (RA) of Lachnospiraceae and Dehalobacteriaceae family members associated with a healthy core microbiome. Yeast supplementation also increased the RA of fibrolytic bacteria (Ruminococcus) when fed with a high-fibre diet and reduced the RA of lactate producing bacteria (Streptococcus) when a high-starch diet was fed. In addition, yeast increased the RA of acetic, succinic acid producing bacterial family (Succinivibrionaceae) and butyrate producing bacterial genus (Roseburia) when fed with high-starch and high-fibre diets, respectively. VistaEQ supplementation to equine diets can be potentially used to prevent acidosis and increase fibre digestibility. It may help to meet the energy requirements of performance horses while maintaining gut health.

Opinions of key stakeholders concerning involuntary admission of patients under the Mental Health Act 2001.

OBJECTIVES: To evaluate and compare the opinions of key stakeholders involved in the involuntary admission and treatment of patients under the Mental Health Act (MHA) 2001 regarding their views towards the operation of the legislation. METHODS: We employed a descriptive survey design. A questionnaire was distributed to stakeholders involved in the operation of the MHA 2001 (except service users, whose views were explored in a separate qualitative study) via paper or online versions evaluating their opinions regarding the operation of the MHA 2001 in relation to assessment, care, rights, transfer and information available. RESULTS: Stakeholders agreed that in their opinion that patients generally benefit from the care they receive (79%) and that the MHA 2001 ensures an independent and fair review of the person's detention (65%). However, only 23% of stakeholders were satisfied with the process of transferring patients to hospital and with the clinical assessment procedures therein (37%), with the greatest levels of dissatisfaction amongst Gardai (Police), general practitioners (GPs) and family members. CONCLUSIONS: While the introduction of the MHA 2001 has assisted delivery of care to patients with improved adherence to international human rights frameworks applicable at the time of its enactment, substantial dissatisfaction with the implementation of the MHA 2001 in practice is experienced by stakeholders particularly at the distressing phase of clinical assessment and transfer to hospital.

Service users' experiences of mental health tribunals in Ireland: a qualitative analysis.

OBJECTIVES: To explore the mental health tribunal experiences of people admitted involuntarily under the Mental Health Act 2001. METHODS: Employing a qualitative descriptive study design, data were collected from 23 service users who had experienced mental health tribunals during a recent involuntary admission. Face-to-face semi-structured interviews were conducted ~3 months post-revocation of their involuntary admission order. Data were analysed using an inductive thematic process. RESULTS: The majority of participants reported mixed experiences comprising positive and negative aspects in relation to information provision, emotional support and an inclusive atmosphere. Some participants reported receiving accessible information about the tribunal process, felt emotionally supported throughout, and encountered respectful and dignifying practices during the tribunal proceedings. However, many participants described experiencing non-inclusive practices, reported feeling ill-informed regarding the tribunal process, emotionally unsupported during and after the tribunal, and distressed by what they perceived as adversarial tribunal proceedings. CONCLUSIONS: Systemic changes could ensure that the positive experiences encountered by the minority of participants in this study are more consistently experienced. Ongoing education and training of stakeholders in the provision of inclusive tribunal practices, and the provision of accessible information and emotional support to service users through the stages of the involuntary admission process appear likely to be beneficial. Service users should automatically be offered the option of having a support person of their choosing present during tribunals.

Lateral asymmetry: hard or simple-minded?

A letter or a three-dimensional shape was presented in the center of the visual field. Following the off-set of this stimulus either a comparison letter or a three-dimensional shape was flashed briefly in either the right or left visual field. The subject's task was to respond SAME, or DIFFERENT. The stimuli could be in the same plane, rotated in two dimensions (letters) or in three dimensions (three-dimensional shapes). The left visual field presentations (right hemisphere) of same-pair matches for letters only produced faster reaction times and fewer errors. In all other conditions reaction time measures showed no hemisphere effects. By contrast, error score data indicated that the left hemisphere was overwhelmingly more accurate.

Statistical analysis of highly skewed immune response data.

This paper considers methods of statistical analysis for highly skewed immune response data. Observations from population studies of immunological variables are rarely normally distributed between individuals; typically the distribution shows extreme levels of skewness. In some situations, skewness remains considerable even after transforming the data. Using resampling techniques, applied to several actual datasets of ELISA assay data, we consider the robustness of normal parametric methods, e.g. t tests and linear regression. Despite the skewness of the transformed data, we demonstrate that such methods are quite robust depending on the number of observations, type of analysis and severity of skewness. We also illustrate how bootstrap resampling can be used to provide a valid alternative method of analysis that can be used either for checking normal parametric analysis or as a direct method of analysis. We illustrate this combined approach by analysing real data to test for association between human serum antibodies to malaria merozoite surface proteins, MSP1 and MSP2, and resistance to clinical malaria, and confirm the protective effect of antibodies to MSP1 and demonstrated a similar protective effect for some antibodies to MSP2.

Delayed puberty in males with beta-thalassemia major: pulsatile gonadotropin-releasing hormone administration induces changes in gonadotropin isoform profiles and an increase in sex steroids.

Patients with beta-thalassemia major often have pubertal delay, the etiology of which has not been fully elucidated. We investigated the pituitary-gonadal response to short-term subcutaneous pulsatile gonadotropin-releasing hormone (GnRH) administration (150 ng/kg body weight every 120 min for 7 days) in five young males (aged 13.6-19.0 years) affected by beta-thalassemia major and presenting signs of delayed puberty. Immunoreactive and bioactive gonadotropin levels were determined and their isoform profiles were examined, before and after GnRH treatment, in a pool of samples collected every 15 min for 240 min. Testosterone, androstenedione, 17-hydroxyprogesterone, dehydroepiandrosterone and 17 beta-estradiol were measured as markers of gonadal function on days 0, 1, 3, 5 and 7 of treatment. Five patients (aged 16.9-26.8 years) with confirmed diagnosis of idiopathic hypogonadotropic hypogonadism who were starting pulsatile GnRH therapy were also studied in the same protocol. Increased sex steroid levels were observed in both groups as a result of treatment. On day 7, the thalassemic patients had increased bioactive luteinizing hormone (LH) and follide-stimulating hormone (FSH), although immunoreactive LH and FSH were comparable to day 0. Moreover, fewer acidic and more basic immunoreactive and bioactive isoforms were noted in LH profiles on day 7. Similar results were observed in hypogonadal patients, who also had increased immunoreactive LH and FSH values. We suggest that the early stage of delayed puberty in thalassemia might be characterized by a neuroendocrine dysfunction resulting in an impaired hypothalamic GnRH release, which is inadequate for a proper pituitary stimulation. Pulsatile GnRH treatment seems to re-establish partially the correct pituitary-gonadal function.

Attention and para-attentional processing. Event-related brain potentials as tests of a model.

In 1972 when we began to analyze the vast amount of material from the laboratories of physiological psychologists, we had only a vague conceptualization of what a model of attention might look like. We began where everyone else had, with the view that everything had something to do with "arousal" but with Lacey's (1967) warning in mind that all of the dependent variables might not actually be measuring aspects of the same process. With this warning in mind, we were forced by the data to organize them into a three-systems mode. Since the first publication of this model in 1975, we have found increasing amounts of evidence to support and extend it. This evidence is briefly reviewed in the present paper in terms of the techniques employed in various types of investigation. Further, the current review of data has made it possible to specify the para-attentional substrate (the extrinsic lemniscal primary projection systems) upon which the three systems described in the earlier model operate. The earlier model was based on psychophysiological, neurobehavioral and neurochemical analyses while the current specification results from the results of recordings of event-related brain electrical responses. The conclusions derived from these results can be summarized as follows: First. It has become possible to distinguish controlled attention from the para-attentional pre- and post-attentive automatic processes upon which controls operate. Second. The pre- and post-attentive processes appear to be coordinate with activity in the extrinsic lemniscal primary sensory projection systems. Processing in these systems is reflected in the early components of event-related brain electrical potentials. These extrinsic systems are, however, not just throughputs for further processing. Rather, they are sensitive to the history of reinforcement which the subject has experienced. The concept of a limited channel capacity must, therefore, be modified to encompass this ability of organisms to improve, through practice, their competence to process a great deal of information in parallel. Competence, not capacity, limits central processing span. Third. A set of intrinsic extralemniscal processing systems has been identified to operate via a tecto-tegmental pathway to the reticular nucleus of the thalamus. The later components (N2P3, etc.) of event-related potentials have been shown to reflect processing in these systems and those that control them. Activity in these systems has been related to targeted conscious awareness.(ABSTRACT TRUNCATED AT 400 WORDS)

High incidence of asymptomatic malara infections in a birth cohort of children less than one year of age in Ghana, detected by multicopy gene polymerase chain reaction.

The incidence of Plasmodium falciparum infection has been followed in a birth cohort of 71 infants in southern Ghana, an area of perennial malaria transmission. Parasite DNA detection established the presence of a high rate of infection in newborns (13.6%), a low level of infection from two to 26 weeks (1.5-9.7%) and a steadily increasing parasite rate from 26 weeks of age. The median age to first infection was 42 weeks. Five cases of fever (temperature > or = 37.5 degrees C) and parasite density greater than 1,000 parasites/microl of blood, all in children more than 18 weeks of age, were considered possible cases of clinical malaria. The risk of infection was almost three times higher in the wet season than in the dry season and increased significantly from the age of 18 weeks. The level of malaria-specific IgG at birth was positively correlated with risk of infection in children 6-12 months of age, indicating that maternally derived anti-malarial IgG is correlated with exposure to malaria infection. There was no association between malaria-specific IgG at birth and risk of infection in children 0-6 months of age. However, infants do appear to possess mechanisms to limit parasite growth and a role for maternal antibody cannot be ruled out.

Independence of childhood life events and chronic adversities: a comparison of two patient groups and controls.

OBJECTIVE: To examine the differences between independent and behavior-dependent stressful life events and chronic adversities in child psychiatric patients, community controls, and children with asthma. METHOD: The Psychosocial Assessment of Childhood Experiences was used to assess recent severe events (life events with high long-term threat) and major adversities (long-term experiences with high negative impact on child) in children attending a psychiatric clinic (n = 99), community controls (n = 26), and children with chronic asthma (n = 94). RESULTS: In the previous year, the psychiatric patients had, on average, experienced significantly more independent and behavior-dependent severe events and major adversities than either the controls or the asthmatic patients. The differences were most pronounced in relation to behavior-dependent high-threat life events and long-term-experiences. Among the psychiatric patients, one third of all severe events and one quarter of all major adversities were dependent on the child's behavior. The corresponding proportions in the controls and children with asthma were between one fifth and one twelfth. CONCLUSIONS: Psychiatrically disturbed children have an increased risk of experiencing behavior-dependent life events and long-term adversities compared with their peers in the community at large and compared with children suffering from a chronic physical illness such as asthma. Future studies need to examine the possible contributions of such experiences to the development and maintenance of psychiatric and physical illness in children.

Differential regulation in the release of bioactive versus immunoactive gonadotropins from cultured rat pituitary cells by inhibin and androgens.

Using in vitro bioassays and radioimmunoassays, the authors examined the interactions between purified 32kD ovine inhibin, testosterone, and dihydrotestosterone on basal and GnRH-stimulated secretion of gonadotropins in primary rat pituitary cell cultures. This study demonstrates that inhibin and androgens: 1) differentially regulate gonadotropin levels, 2) cause changes in the amounts of bioactive and immunoactive FSH and LH released. In conclusion, differences in bio- and immuno-FSH and LH secretion suggest that the endocrine milieu results in not only quantitative but qualitative changes in the secreted gonadotropin isoforms.

Clinical case definitions for malaria: clinical malaria associated with very low parasite densities in African infants.

In areas endemic for Plasmodium falciparum, clinical malaria is believed to be less common in infants than in older children, but specific case definitions have rarely been determined for this age group. As malaria case definitions are known to be both age- and site-specific, assessment of the risk of disease in infancy requires the development of appropriate diagnostic criteria. In southern Ghana, 154 children were recruited at birth and monitored for fever and malaria infection until 2 years of age. Logistic regression was used to model fever risk as a continuous function of parasite density to determine case definitions for the diagnosis of clinical malaria, and to determine age- and season-specific estimates of the fraction of fevers attributable to malaria (AF); 2360 observations were made on 154 children. For fevers defined by a measured temperature > or = 37.5 degrees C, the estimated population AF was 44% (95% confidence interval 34-53). Estimates of AF varied with age and season. For infants, AF was 51% during the wet season and 22% during the dry season; for children over one year of age, AF was 89% during the wet season and 36% during the dry season. The estimated parasite density threshold for initiation of a febrile episode was 100 parasites per microL of blood in infants, compared with 3500 parasites per microL for children over one year of age. Using these case definitions, the incidence of clinical malaria was estimated at 0.09 cases per child-year at risk for children less than 6 months of age, 0.40 for children aged 6-11 months, and 0.69 for children aged 12-23 months. Of 66 cases of clinical malaria, only 3 were observed in children under 5 months of age. We concluded that, although most fevers in infants are not due to malaria, infant clinical malaria may occur at extremely low parasite densities. This may be indicative of a lack of anti-disease immunity in this age group. In southern Ghana, an infant with axillary temperature > or = 37.5 degrees C and parasitaemia > or = 100/microL should be considered to have clinical malaria. Nevertheless, the incidence of clinical malaria is very low in children under 6 months of age, confirming that they are significantly protected from clinical malaria compared to older children.

The effect of chronic anxiety level upon self control of heart rate.

A sample of 90 subjects were rated on the IPAT anxiety scale and 5 subjects (3 male and 2 female) per group were selected from each of the high and low anxiety categories. All subjects were naive participants in heart rate biofeedback sessions utilising analogue visual feedback. Following a heart rate baseline (no feedback) session, all subjects were required to raise their heart rate and lower their heart rate in two separate trials, a visual "target" criteria being provided. The data collected consisted of a resting baseline heart rate value, mean heart rate increase, and mean heart decrease values expressed as beats per minute. Results indicated a marked ability for highly anxious subjects to self-induce heart rate increases only and for low anxious subjects to decrease their heart rate only.

Phono-Graphix(TM): A new method for remediating reading difficulties.

Eighty-seven children, 6 to 16 years of age, with reading and/or spelling difficulties were trained in a new program (Phono-Graphix(TM)) that emphasizes phoneme awareness training, sound-to-print orientation, curriculum design sequenced by orthographic complexity, and active parental supervision in homework assignments. The children's initial level of competence to access the alphabet code was revealed by diagnostic testing, and individualized sequences of instruction were developed. The children received 12 hours or less of one-to-one training, one hour per week. Children gained an average of 13.7 standard score points on word recognition (1.70 points per clinical hour) and 19.34 standard score points on nonsense word decoding (2.57 points per clinical hour).

Experiences of involuntary admission in an approved mental health centre.

The aim of this qualitative study was to gain an understanding of what it means to have an involuntary hospital admission. A sample of six people who were detained at an approved Irish mental health centre consented to recount their experiences were interviewed. The interview transcripts were analysed using Interpretative Phenomenological Analysis. Three superordinate themes were identified: 'The early days', 'Experiences of treatment' and 'Moving on?'. 'The early days' represented participants' initial feelings and opinions of the experience of coming into the approved centre. 'Experiences of treatment' refers to participants' experiences of medication and relationships with staff. Finally, the theme 'Moving on?' represented participants' views on how they adjusted to involuntary admission. 'Learning the way' was central to the participants' notion of moving on. The findings suggest that the meaning of detention is a varied one that evokes an array of emotional responses for participants and highlights the need for a renewed way of thinking and doing concerning those subject to involuntary.

Methylphenidate-induced erections in a prepubertal child.

Methylphenidate is a medication used routinely in the management of attention deficit hyperactivity disorder. We report a case of a prepubertal child who developed unwanted erections after commencing a response-adjusted dosing regimen of sustained release methylphenidate. Despite priapism being a rare adverse reaction associated with methylphenidate, physicians and parents need to be aware as it can have significant long-term complications.