Protective effects of peri-menopausal oestrogen replacement: A test of the critical period hypothesis

New director of studies: Prof Jackie AndradeFull version unavailable due to 3rd party copyright restrictions.Oestrogen decline during the menopause leads to decline in cognitive performance because oestrogen receptor sites are found in the prefrontal cortex and hippocampus of the female brain, areas associated with memory and attention functions. Extensive research over the past two decades has tested the effects of administering Hormone Replacement Therapy (HRT) to maintain oestrogen levels. MRI studies have shown improvements in hippocampal volume and frontal functions with HRT, but evidence for associated improvements in verbal memory performance has been mixed. Some studies have even found detrimental effects of HRT, leading to the suggestion of a critical period for HRT administration relative to menopause. Oestrogen receptor sites are found in frontal brain regions associated with working memory (WM) functions including attention. These functions have been researched less than verbal memory, but with similarly mixed findings. The research reported in this thesis tested the critical period hypothesis in relation to WM. Study one tested the prediction that HRT will benefit WM if the therapy is initiated during the peri-menopause, and will harm it if initiated post-menopause. A naturalistic sample of 121 women were recruited, comprising women who varied in the time they had begun taking HRT, and menopausal status-matched controls who had never taken HRT. Participants completed three tests of WM span and the Sustained Attention to Response Task (SART) on two occasions 12 months apart. WM performance supported the critical period hypothesis, with women who had begun the therapy after the menopause displayed worsened WM capacity when compared to peri-menopausal initiators and post-menopausal women with no history of HRT use. At one year follow up, postmenopausal HRT users were still underperforming compared to peri-HRT initiators and those in the post-menopausal stage with no history of HRT use. No significant differences were identified between groups on the SART. The effects of natural supplements on physical symptoms of the menopause have been researched, but there is little research on their effects on cognitive symptoms and none specifically testing the critical period hypothesis. Study two tested the effects of soya isoflavones on WM during peri- and post-menopausal stages. One hundred and twelve peri- and post-menopausal women were randomly allocated to receive either placebo or 100mg soya supplement in capsules daily for three months. Participants and researcher were blind to this allocation. Participants completed two tests of WM span and two Sustained Attention (SA) tasks at baseline, after three months of soya/placebo, and after a further three months without supplement. There was no effect of isoflavones on cognition, regardless of time of initiation of the supplement. This thesis offers a unique contribution to the literature, by establishing empirically that HRT may have long-lasting benefits for WM if administered in the peri-menopause period, and detriments if taken post-menopause. There was no evidence that administration of soya-based phytoestrogens for three months peri- or post-menopause replicated these effects of HRT on cognition

Variation in referral and access to new psychological therapy services by age: an empirical quantitative study.

Background: Older people with common mental health problems (CMHPs) are known to have reduced rates of referral to psychological therapy. Aim: We aimed to assess referral rates to the Improving Access to Psychological Therapies (IAPT) service, contact with a therapist and clinical outcome by age. Design and Setting: Empirical research using patient episodes of care from South West IAPT. Method: By analysing 82,513 episodes of care (2010-2011), referral rates and clinical improvement were compared to both total population and estimated prevalence in each age group using IAPT data. Probable recovery of those completing treatment were calculated for each group. Results: Estimated prevalence of CMHPs peaks in 45–49 year olds (20.59% of population). The proportions of patients identified with CMHPs being referred peaks at 20-24 years (22.95%) and reduces with increase in age thereafter to 6.00% for 70-74 year olds. Once referred, the proportion of those attending first treatment increases with age between 18 years (57.64%) and 64 years (76.97%). In addition, the percentage of those having a clinical improvement gradually increases from the age 20 years (12.94%) to 69 years (20.74%). Conclusion: Younger adults are more readily referred to IAPT services. However, as a proportion of those referred, probabilities of attending once, attending more than once, and clinical improvement, increase with age. It is uncertain whether optimum levels of referral have been reached for young adults. It is important to establish whether changes to service configuration, treatment options, and GP behaviour can increase referrals for middle-aged and older adults

Seclusion and Psychiatric Intensive Care Evaluation Study (SPICES) : Combined qualitative and quantitative approaches to the uses and outcomes of coercive practices in mental health services

BackgroundSeclusion (the isolation of a patient in a locked room) and transfer to a psychiatric intensive care unit (PICU; a specialised higher-security ward with higher staffing levels) are two common methods for the management of disturbed patient behaviour within acute psychiatric hospitals. Some hospitals do not have seclusion rooms or easy access to an on-site PICU. It is not known how these differences affect patient management and outcomes.ObjectivesTo (1) assess the factors associated with the use of seclusion and PICU care, (2) estimate the consequences of the use of these on subsequent violence and costs (study 1) and (3) describe differences in the management of disturbed patient behaviour related to differential availability (study 2).DesignThe electronic patient record system at one trust was used to compare outcomes for patients who were and were not subject to seclusion or a PICU, controlling for variables, including recent behaviours. A cost-effectiveness analysis was performed (study 1). Nursing staff at eight hospitals with differing access to seclusion and a PICU completed attitudinal measures, a video test on restraint-use timing and an interview about the escalation pathway for the management of disturbed behaviour at their hospital. Analyses examined how results differed by access to PICU and seclusion (study 2).ParticipantsPatients on acute wards or PICUs in one NHS trust during the period 2008–13 (study 1) and nursing staff at eight randomly selected hospitals in England, with varying access to seclusion and to a PICU (study 2).Main outcome measuresAggression, violence and cost (study 1), and utilisation, speed of use and attitudes to the full range of containment methods (study 2).ResultsPatients subject to seclusion or held in a PICU were more likely than those who were not to be aggressive afterwards, and costs of care were higher, but this was probably because of selection bias. We could not derive satisfactory estimates of the causal effect of either intervention, but it appeared that it would be feasible to do so for seclusion based on an enriched sample of untreated controls (study 1). Hospitals without seclusion rooms used more rapid tranquillisation, nursing of the patient in a side room accompanied by staff and seclusion using an ordinary room (study 2). Staff at hospitals without seclusion rated it as less acceptable and were slower to initiate manual restraint. Hospitals without an on-site PICU used more seclusion, de-escalation and within-eyesight observation.LimitationsOfficial record systems may be subject to recording biases and crucial variables may not be recorded (study 1). Interviews were complex, difficult, constrained by the need for standardisation and collected in small numbers at each hospital (study 2).ConclusionsClosing seclusion rooms and/or restricting PICU access does not appear to reduce the overall levels of containment, as substitution of other methods occurs. Services considering expanding access to seclusion or to a PICU should do so with caution. More evaluative research using stronger designs is required.FundingThe National Institute for Health Research Health Services and Delivery Research programme

Implicit trust in clinical decision-making by multidisciplinary teams

In clinical practice, decision-making is not performed by individual knowers but by an assemblage of people and instruments in which no one member has full access to every piece of evidence. This is due to decision making teams consisting of members with different kinds of expertise, as well as to organisational and time constraints. This raises important questions for the epistemology of medicine, which is inherently social in this kind of setting, and implies epistemic dependence on others. Trust in these contexts is a highly complex social practice, involving different forms of relationships between trust and reasons for trust: based on reasons, and not based on reasons; based on reasons that are easily accessible to reflection and others that are not. In this paper, we focus on what it means to have reasons to trust colleagues in an established clinical team, collectively supporting or carrying out every day clinical decision-making. We show two important points about these reasons, firstly, they are not sought or given in advance of a situation of epistemic dependence, but are established within these situations; secondly they are implicit in the sense of being contained or nested within other actions that are not directly about trusting another person. The processes of establishing these reasons are directly about accomplishing a task, and indirectly about trusting someone else’s expertise or competence. These processes establish a space of reasons within which what it means to have reasons for trust, or not, gains a meaning and traction in these team-work settings. Based on a qualitative study of decision-making in image assisted diagnosis and treatment of a complex disease called pulmonary hypertension (PH), we show how an intersubjective framework, or ‘space of reasons’ is established through team members forging together a common way of identifying and dealing with evidence. In dealing with images as a central diagnostic tool, this also involves a common way of looking at the images, a common mode or style of perception. These frameworks are developed through many iterations of adjusting and calibrating interpretations in relation to those of others, establishing what counts as evidence, and ranking different kinds of evidence. Implicit trust is at work throughout this process. Trusting the expertise of others in clinical decision-making teams occurs while the members of the team are busy on other tasks, most importantly, building up a framework of common modes of seeing, and common ways of identifying and assessing evidence emerge. It is only in this way that trusting or mistrusting becomes meaningful in these contexts, and that a framework for epistemic dependence is established

Implicit trust in clinical decision-making by multidisciplinary teams

In clinical practice, decision-making is not performed by individual knowers but by an assemblage of people and instruments in which no one member has full access to every piece of evidence. This is due to decision making teams consisting of members with different kinds of expertise, as well as to organisational and time constraints. This raises important questions for the epistemology of medicine, which is inherently social in this kind of setting, and implies epistemic dependence on others. Trust in these contexts is a highly complex social practice, involving different forms of relationships between trust and reasons for trust: based on reasons, and not based on reasons; based on reasons that are easily accessible to reflection and others that are not. In this paper, we focus on what it means to have reasons to trust colleagues in an established clinical team, collectively supporting or carrying out every day clinical decision-making. We show two important points about these reasons, firstly, they are not sought or given in advance of a situation of epistemic dependence, but are established within these situations; secondly they are implicit in the sense of being contained or nested within other actions that are not directly about trusting another person. The processes of establishing these reasons are directly about accomplishing a task, and indirectly about trusting someone else’s expertise or competence. These processes establish a space of reasons within which what it means to have reasons for trust, or not, gains a meaning and traction in these team-work settings. Based on a qualitative study of decision-making in image assisted diagnosis and treatment of a complex disease called pulmonary hypertension (PH), we show how an intersubjective framework, or ‘space of reasons’ is established through team members forging together a common way of identifying and dealing with evidence. In dealing with images as a central diagnostic tool, this also involves a common way of looking at the images, a common mode or style of perception. These frameworks are developed through many iterations of adjusting and calibrating interpretations in relation to those of others, establishing what counts as evidence, and ranking different kinds of evidence. Implicit trust is at work throughout this process. Trusting the expertise of others in clinical decision-making teams occurs while the members of the team are busy on other tasks, most importantly, building up a framework of common modes of seeing, and common ways of identifying and assessing evidence emerge. It is only in this way that trusting or mistrusting becomes meaningful in these contexts, and that a framework for epistemic dependence is established

Glycaemic control in people with type 2 diabetes mellitus during and after cancer treatment: A systematic review and meta-analysis

Background Cancer and Diabetes Mellitus (DM) are leading causes of death worldwide and the prevalence of both is escalating. People with co-morbid cancer and DM have increased morbidity and premature mortality compared with cancer patients with no DM. The reasons for this are likely to be multifaceted but will include the impact of hypo/hyperglycaemia and diabetes therapies on cancer treatment and disease progression. A useful step toward addressing this disparity in treatment outcomes is to establish the impact of cancer treatment on diabetes control. Aim The aim of this review is to identify and analyse current evidence reporting glycaemic control (HbA1c) during and after cancer treatment. Methods Systematic searches of published quantitative research relating to comorbid cancer and type 2 diabetes mellitus were conducted using databases, including Medline, Embase, PsychINFO, CINAHL and Web of Science (February 2017). Full text publications were eligible for inclusion if they: were quantitative, published in English language, investigated the effects of cancer treatment on glycaemic control, reported HbA1c (%/mmols/mol) and included adult populations with diabetes. Means, standard deviations and sample sizes were extracted from each paper; missing standard deviations were imputed. The completed datasets were analysed using a random effects model. A mixed-effects analysis was undertaken to calculate mean HbA1c (%/mmols/mol) change over three time periods compared to baseline. Results The available literature exploring glycaemic control post-diagnosis was mixed. There was increased risk of poor glycaemic control during this time if studies of surgical treatment for gastric cancer are excluded, with significant differences between baseline and 12 months (p < 0.001) and baseline and 24 months (p = 0.002). Conclusion We found some evidence to support the contention that glycaemic control during and/or after non-surgical cancer treatment is worsened, and the reasons are not well defined in individual studies. Future studies should consider the reasons why this is the case

HIV-1 Protease and Reverse Transcriptase Control the Architecture of Their Nucleocapsid Partner

The HIV-1 nucleocapsid is formed during protease (PR)-directed viral maturation, and is transformed into pre-integration complexes following reverse transcription in the cytoplasm of the infected cell. Here, we report a detailed transmission electron microscopy analysis of the impact of HIV-1 PR and reverse transcriptase (RT) on nucleocapsid plasticity, using in vitro reconstitutions. After binding to nucleic acids, NCp15, a proteolytic intermediate of nucleocapsid protein (NC), was processed at its C-terminus by PR, yielding premature NC (NCp9) followed by mature NC (NCp7), through the consecutive removal of p6 and p1. This allowed NC co-aggregation with its single-stranded nucleic-acid substrate. Examination of these co-aggregates for the ability of RT to catalyse reverse transcription showed an effective synthesis of double-stranded DNA that, remarkably, escaped from the aggregates more efficiently with NCp7 than with NCp9. These data offer a compelling explanation for results from previous virological studies that focused on i) Gag processing leading to nucleocapsid condensation, and ii) the disappearance of NCp7 from the HIV-1 pre-integration complexes. We propose that HIV-1 PR and RT, by controlling the nucleocapsid architecture during the steps of condensation and dismantling, engage in a successive nucleoprotein-remodelling process that spatiotemporally coordinates the pre-integration steps of HIV-1. Finally we suggest that nucleoprotein remodelling mechanisms are common features developed by mobile genetic elements to ensure successful replication

Interrelation of Personality Measurements

The purpose of this paper is to investigate one method of understanding why man behaves as he does--personality tests

Glycaemic control in people with type 2 diabetes mellitus during and after cancer treatment: A systematic review and meta-analysis

Background Cancer and Diabetes Mellitus (DM) are leading causes of death worldwide and the prevalence of both is escalating. People with co-morbid cancer and DM have increased morbidity and premature mortality compared with cancer patients with no DM. The reasons for this are likely to be multifaceted but will include the impact of hypo/hyperglycaemia and diabetes therapies on cancer treatment and disease progression. A useful step toward addressing this disparity in treatment outcomes is to establish the impact of cancer treatment on diabetes control. Aim The aim of this review is to identify and analyse current evidence reporting glycaemic control (HbA1c) during and after cancer treatment. Methods Systematic searches of published quantitative research relating to comorbid cancer and type 2 diabetes mellitus were conducted using databases, including Medline, Embase, PsychINFO, CINAHL and Web of Science (February 2017). Full text publications were eligible for inclusion if they: were quantitative, published in English language, investigated the effects of cancer treatment on glycaemic control, reported HbA1c (%/mmols/mol) and included adult populations with diabetes. Means, standard deviations and sample sizes were extracted from each paper; missing standard deviations were imputed. The completed datasets were analysed using a random effects model. A mixed-effects analysis was undertaken to calculate mean HbA1c (%/mmols/mol) change over three time periods compared to baseline. Results The available literature exploring glycaemic control post-diagnosis was mixed. There was increased risk of poor glycaemic control during this time if studies of surgical treatment for gastric cancer are excluded, with significant differences between baseline and 12 months (p < 0.001) and baseline and 24 months (p = 0.002). Conclusion We found some evidence to support the contention that glycaemic control during and/or after non-surgical cancer treatment is worsened, and the reasons are not well defined in individual studies. Future studies should consider the reasons why this is the case