Khadija Rantell

A 6.4 Mb Duplication of the α-Synuclein Locus Causing Frontotemporal Dementia and Parkinsonism: Phenotype-Genotype Correlations

IMPORTANCE α-Synuclein (SNCA) locus duplications are associated with variable clinical features and reduced penetrance but the reasons underlying this variability are unknown. OBJECTIVES To report a novel family carrying a heterozygous 6.4 Mb duplication of the SNCA locus with an atypical clinical presentation strongly reminiscent of frontotemporal dementia and late-onset pallidopyramidal syndromes and study phenotype-genotype correlations in SNCA locus duplications. DESIGN, SETTING, AND PARTICIPANTS We report the clinical and neuropathologic features of a family carrying a 6.4 Mb duplication of the SNCA locus. To identify candidate disease modifiers, we completed a genetic analysis of the family and conducted statistical analysis on previously published cases carrying SNCA locus duplications using regression modeling with robust standard errors to account for clustering at the family level. MAIN OUTCOMES AND MEASURES We assessed whether length of the SNCA locus duplication influences disease penetrance and severity and whether extraduplication factors have a disease-modifying role. RESULTS We identified a large 6.4 Mb duplication of the SNCA locus in this family. Neuropathological analysis showed extensive α-synuclein pathology with minimal phospho-tau pathology. Genetic analysis showed an increased burden of Parkinson disease-related risk factors and the disease-predisposing H1/H1 microtubule-associated protein tau haplotype. Statistical analysis of previously published cases suggested there is a trend toward increasing disease severity and disease penetrance with increasing duplication size. The corresponding odds ratios from the univariable analyses were 1.17 (95% CI, 0.81-1.68) and 1.34 (95% CI, 0.78-2.31), respectively. Sex was significantly associated with both disease risk and severity; men compared with women had increased disease risk and severity and the corresponding odds ratios from the univariable analyses were 8.36 (95% CI, 1.97-35.42) and 5.55 (95% CI, 1.39-22.22), respectively. CONCLUSIONS AND RELEVANCE These findings further expand the phenotypic spectrum of SNCA locus duplications. Increased dosage of genes located within the duplicated region probably cannot increase disease risk and disease severity without the contribution of additional risk factors. Identification of disease modifiers accounting for the substantial phenotypic heterogeneity of patients with SNCA locus duplications could provide insight into molecular events involved in α-synuclein aggregation.

Bereavement by suicide as a risk factor for suicide attempt: a cross-sectional national UK-wide study of 3432 young bereaved adults

Objectives US and UK suicide prevention strategies suggest that bereavement by the suicide of a relative or friend is a risk factor for suicide. However, evidence is lacking that the risk exceeds that of any sudden bereavement, is specific to suicide, or applies to peer suicide. We conducted the first controlled UK-wide study to test the hypothesis that young adults bereaved by suicide have an increased risk of suicidal ideation and suicide attempt compared with young adults bereaved by other sudden deaths. Design National cross-sectional study. Setting Staff and students at 37 UK higher educational institutions in 2010. Participants 3432 eligible respondents aged 18–40 exposed to sudden bereavement of a friend or relative after the age of 10. Exposures Bereavement by suicide (n=614), by sudden unnatural causes (n=712) and by sudden natural causes (n=2106). Primary outcome measures Incident suicidal ideation and suicide attempt. Findings Adults bereaved by suicide had a higher probability of attempting suicide (adjusted OR (AOR)=1.65; 95% CI 1.12 to 2.42; p=0.012) than those bereaved by sudden natural causes. There was no such increased risk in adults bereaved by sudden unnatural causes. There were no group differences in probability of suicidal ideation. The effect of suicide bereavement was similar whether bereaved participants were blood-related to the deceased or not. The significant association between bereavement by suicide and suicide attempt became non-significant when adding perceived stigma (AOR=1.11; 95% CI 0.74 to 1.67; p=0.610). When compared with adults bereaved by sudden unnatural causes, those bereaved by suicide did not show significant differences in suicide attempt (AOR=1.48; 95% CI 0.94 to 2.33; p=0.089). Conclusions Bereavement by suicide is a specific risk factor for suicide attempt among young bereaved adults, whether related to the deceased or not. Suicide risk assessment of young adults should involve screening for a history of suicide in blood relatives, non-blood relatives and friends.

Cardiopulmonary Exercise Testing and Prognosis in Hypertrophic Cardiomyopathy

Background—Exercise testing is performed in patients with hypertrophic cardiomyopathy to evaluate blood pressure response, a risk factor for sudden cardiac death. The prognostic role of exercise gas exchange variables is unknown. Methods and Results—Between 1998 and 2010, 1898 patients (age 47±15 years, range 16–86 years; 67% male) with hypertrophic cardiomyopathy underwent cardiopulmonary exercise testing. A total of 178 (9.4%) patients reached the primary end point of all-cause mortality or heart transplant (death/transplant) during a median follow-up of 5.6 years (interquartile range 2.6–8.9), giving an annual event rate of 1.6% per person year. Peak oxygen consumption (adjusted hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.77–0.88, P<0.001), ventilatory efficiency (adjusted HR 1.10, 95% CI 1.00–1.22, P=0.049), and ventilatory anaerobic threshold (adjusted HR 0.82, 95% CI 0.70–0.96, P=0.016) were predictors of the primary outcome after correction for age, sex, left atrial size, nonsustained ventricular tachycardia, and ejection fraction. The overall adjusted death/transplant estimates for patients in the lowest quartile with peak oxygen consumption ⩽15.3 mL/kg/min were 14% at 5 years and 31% at 10 years. Peak oxygen consumption (HR 0.81, 95% CI 0.77–0.86, P<0.01) and ventilation to carbon dioxide production (HR 1.10, 95% CI 1.08–1.13, P<0.001) were predictors of death because of heart failure or transplantation but not sudden cardiac death or implantable cardioverter defibrillator shocks. Conclusions—Cardiopulmonary exercise testing provides prognostic information in patients with hypertrophic cardiomyopathy. Submaximal exercise parameters, such as ventilatory efficiency and anaerobic threshold, measured alone or in combination with peak oxygen consumption, predict death from heart failure.

The stigma perceived by people bereaved by suicide and other sudden deaths: A cross-sectional UK study of 3432 bereaved adults

Objective To test the hypothesis that perceived stigma scores in young adults bereaved by suicide are significantly higher than in young adults bereaved by other sudden deaths, whether blood-related to the deceased or not. Methods We conducted a cross-sectional study of all staff and students aged 18–40 at 37 UK higher educational institutions in 2010, and identified 3432 respondents who had experienced a sudden bereavement of a close contact since reaching the age of 10, either due to sudden natural causes, sudden unnatural causes, or suicide. We used multivariable regression to compare scores on the stigma, shame, responsibility and guilt subscales of the Grief Experience Questionnaire, adjusting for socio-demographic factors and pre-bereavement psychopathology. Results People bereaved by suicide (n = 614) had higher stigma scores than people bereaved by sudden natural death (n = 2106; adjusted coefficient = 2.52; 95% CI = 2.13–2.90; p = < 0.001) and people bereaved by sudden unnatural death (n = 712; adjusted coefficient = 1.69; 95% CI = 1.25–2.13; p = < 0.001). Shame, responsibility and guilt scores were also significantly higher in people bereaved by suicide, whether compared with bereavement by sudden natural death or sudden unnatural death. Associations were not modified by whether the bereaved was blood-related to the deceased or not. Conclusions Stigma was perceived more acutely by the relatives and friends of those who died by suicide than those bereaved by other causes of sudden natural or sudden unnatural death. Their high levels of perceived stigma, shame, responsibility and guilt require qualitative investigation to identify whether these grief dimensions limit social functioning, help-seeking behaviour and/or support offered.

Diagnostic rates and treatment of dementia before and after launch of a national dementia policy: an observational study using English national databases

Objectives To assess the 2009 National Dementia Strategys (NDS) impact on dementia diagnosis and treatment. Setting and participants Primary care data for England before and after launch of the NDS. Primary outcome measures We used nationally available data to estimate the trends over time in rates of dementia diagnoses recorded on the Quality Outcomes Framework (QOF) in Primary Care Trusts (PCT) and antidementia medication prescriptions from 2006/2007 (the first available figures) and the associated increase in cost relative to all other prescriptions. To establish PCT general practitioner (GP) QOF dementia recording validity, we correlated it with medication prescription using the NIC (net ingredient cost). Results Regression analysis showed that dementia diagnosis rate was lower prior to launch of the NDS and increased significantly after it was launched. The number of antidementia prescriptions and the cost of antidementia drugs relative to total PCT prescribing costs increased significantly after 2009. GP recording of dementia diagnosis correlated highly with prescription of cholinesterase inhibitors and memantine in the same area (p<0.001 each year). Conclusions The launch of the NDS was associated with a significant increase in dementia diagnosis rates and prescriptions of antidementia drugs. We cannot establish the causality but this was a change from the prelaunch pattern. Further assessment of any intervention to increase the diagnoses should include an assessment of harm as well as potential benefit.

Standardised patients with intellectual disabilities in training tomorrow’s doctors

Aims and method To develop a programme to help undergraduate medical students and postgraduate trainees to improve their skills in communicating with people with intellectual disabilities through teaching sessions that had input from simulated patients with intellectual disabilities. We conducted four sessions of training for 47 undergraduate 4th-year medical students. The training involved a multiprofessional taught session followed by a clinical scenario role-play with simulated patients who were people with intellectual disabilities. The training was assessed by completing the healthcare provider questionnaire before and after the training. Results There were improvements in the students’ perceived skill, comfort and the type of clinical approach across all three scenarios. Clinical implications By involving people with intellectual disabilities in training medical students there has been a significant improvement in students’ communication skills in areas of perceived skills, comfort and type of clinical approach which will raise the quality of care provided by them in the future.

Support received after bereavement by suicide and other sudden deaths: a cross-sectional UK study of 3432 young bereaved adults

Objective To test the hypothesis that people bereaved by suicide are less likely to receive formal or informal support than people bereaved by other causes of sudden death. Design National cross-sectional study. Setting Adults working or studying at any UK higher education institution (HEI) in 2010. Participants A total of 3432 eligible respondents aged 18–40 years bereaved by the sudden death of a close friend or relative, sampled from approximately 659 572 bereaved and non-bereaved staff and students at 37 of 164 UK HEIs invited to participate. Exposures Bereavement by suicide (n=614; 18%), by sudden unnatural causes (n=712; 21%) and by sudden natural causes (n=2106; 61%). Main outcome measures Receipt of formal and informal support postbereavement; timing of valued support. Results 21% (725/3432) of our sample of bereaved adults reported receiving no formal or informal bereavement support, with no evidence for group differences. People bereaved by suicide were less likely to have received informal support than those bereaved by sudden natural causes (adjusted OR (AOR)=0.79; 95% CI 0.64 to 0.98) or unnatural causes (AOR=0.74; 95% CI 0.58 to 0.96) but did not differ from either comparison group on receipt of formal support. People bereaved by suicide were less likely to have received immediate support (AOR=0.73; 95% CI 0.59 to 0.90) and more likely to report delayed receipt of support (AOR=1.33; 95% CI 1.08 to 1.64) than people bereaved by sudden natural causes. Associations were not modified by gender, or age bereaved, but became non-significant when adjusting for stigma. Conclusions People bereaved by suicide are less likely to receive informal support than people bereaved by other causes of sudden death and are more likely to perceive delays in accessing any support. This is concerning given their higher risk of suicide attempt and the recommendations within suicide prevention strategies regarding their need for support. Study registration http://www.ucl.ac.uk/psychiatry/bereavementstudy/

Trends in family planning and counselling for women with sickle cell disease in the UK over two decades

Background Pregnancies in women with sickle cell disease (SCD) are known to have high rates of maternal and fetal mortality and morbidity. Given these pregnancy-associated problems for women with SCD, advice both about pregnancy planning and about effective contraception are of paramount importance. This study sought to discover the contraception methods used by women with SCD, what complications women with SCD encounter with contraception, and their experiences of pre-pregnancy counselling and pregnancy planning, and how such issues may have changed over the past two decades. Method The study was a multicentre, interview-based, cross-sectional study. Interviews were carried out with 102 women with SCD, in north and central London during 2010, concerning their current and previous contraceptive use, their pregnancy history, their menstrual history, and the advice they received concerning pregnancy planning and contraception. Patient information was anonymised and ethical approval was obtained. These data were compared with data from a similar study undertaken in 1993. Results There were significant differences in a number of key areas: the number of unplanned pregnancies decreased from 64% in 1993 to 53% in 2010. The number of women with SCD who were advised not to become pregnant also fell, from 36% to 15%. The use of combined oral contraceptive pills declined, from 45% of the women in 1993 to 31% in 2010. Conversely the use of depot medroxyprogesterone acetate contraception (DMPA) and the levonorgestrel intrauterine system (LNG-IUS) both increased. Conclusions Significant changes in the contraceptive methods used by women with SCD are demonstrated in the London population. LNG-IUS use in SCD has not been investigated before. There has been an encouraging decrease in the number of women with SCD who are advised not to become pregnant, perhaps reflecting an improvement in their overall health. Although the number of unplanned pregnancies has fallen, it remains high – emphasising the continuing need for women with SCD to have access to informed advice about pregnancy-associated issues and contraception.

The effects of absence of stereopsis on performance of a simulated surgical task in two-dimensional and three-dimensional viewing conditions.

Background Stereopsis is believed to be advantageous for surgical tasks that require precise hand-eye coordination. We investigated the effects of short-term and long-term absence of stereopsis on motor task performance in three-dimensional (3D) and two-dimensional (2D) viewing conditions. Methods 30 participants with normal stereopsis and 15 participants with absent stereopsis performed a simulated surgical task both in free space under direct vision (3D) and via a monitor (2D), with both eyes open and one eye covered in each condition. Results The stereo-normal group scored higher, on average, than the stereo-absent group with both eyes open under direct vision (p<0.001). Both groups performed comparably in monocular and binocular monitor viewing conditions (p=0.579). Conclusions High-grade stereopsis confers an advantage when performing a fine motor task under direct vision. However, stereopsis does not appear advantageous to task performance under 2D viewing conditions, such as in video-assisted surgery.

Perceived Stigma of Sudden Bereavement as a Risk Factor for Suicidal Thoughts and Suicide Attempt: Analysis of British Cross-Sectional Survey Data on 3387 Young Bereaved Adults

The sudden death of a friend or relative, particularly by suicide, is a risk factor for suicide. People who experience sudden bereavement report feeling highly stigmatised by the loss, potentially influencing access to support. We assessed whether perceived stigma following sudden bereavement is associated with suicidal thoughts and suicide attempt. We analysed cross-sectional survey data on 3387 young adults bereaved by the sudden death of a close contact. We tested the association of high versus low perceived stigma (on the stigma sub-scale of the Grief Experience Questionnaire) with post-bereavement suicidal ideation and suicide attempt, using random effects logistic regression, adjusting for socio-demographic factors, pre-bereavement psychopathology, and mode of sudden bereavement (natural causes/unnatural causes/suicide). Subjects with high perceived stigma scores were significantly more likely to report post-bereavement suicidal thoughts (adjusted odds ratio (AOR) = 2.74; 95% confidence interval (CI) = 1.93–3.89) and suicide attempt (AOR = 2.73; 95% CI = 2.33–3.18) than those with low stigma scores. People who feel highly stigmatised by a sudden bereavement are at increased risk of suicidal thoughts and suicide attempt, even taking into account prior suicidal behaviour. General practitioners, bereavement counsellors, and others who support people bereaved suddenly, should consider inquiring about perceived stigma, mental wellbeing, and suicidal thoughts, and directing them to appropriate sources of support.