Screening over Speech in Unselected Populations for Clinical Trials in AD (PROSPECT-AD): Study Design and Protocol.

BACKGROUND: Speech impairments are an early feature of Alzheimer's disease (AD) and consequently, analysing speech performance is a promising new digital biomarker for AD screening. Future clinical AD trials on disease modifying drugs will require a shift to very early identification of individuals at risk of dementia. Hence, digital markers of language and speech may offer a method for screening of at-risk populations that are at the earliest stages of AD, eventually in combination with advanced machine learning. To this end, we developed a screening battery consisting of speech-based neurocognitive tests. The automated test performs a remote primary screening using a simple telephone. OBJECTIVES: PROSPECT-AD aims to validate speech biomarkers for identification of individuals with early signs of AD and monitor their longitudinal course through access to well-phenotyped cohorts. DESIGN: PROSPECT-AD leverages ongoing cohorts such as EPAD (UK), DESCRIBE and DELCODE (Germany), and BioFINDER Primary Care (Sweden) and Beta-AARC (Spain) by adding a collection of speech data over the telephone to existing longitudinal follow-ups. Participants at risk of dementia are recruited from existing parent cohorts across Europe to form an AD 'probability-spectrum', i.e., individuals with a low risk to high risk of developing AD dementia. The characterization of cognition, biomarker and risk factor (genetic and environmental) status of each research participants over time combined with audio recordings of speech samples will provide a well-phenotyped population for comparing novel speech markers with current gold standard biomarkers and cognitive scores. PARTICIPANTS: N= 1000 participants aged 50 or older will be included in total, with a clinical dementia rating scale (CDR) score of 0 or 0.5. The study protocol is planned to run according to sites between 12 and 18 months. MEASUREMENTS: The speech protocol includes the following neurocognitive tests which will be administered remotely: Word List [Memory Function], Verbal Fluency [Executive Functions] and spontaneous free speech [Psychological and/ or behavioral symptoms]. Speech features on the linguistic and paralinguistic level will be extracted from the recordings and compared to data from CSF and blood biomarkers, neuroimaging, neuropsychological evaluations, genetic profiles, and family history. Primary candidate marker from speech will be a combination of most significant features in comparison to biomarkers as reference measure. Machine learning and computational techniques will be employed to identify the most significant speech biomarkers that could represent an early indicator of AD pathology. Furthermore, based on the analysis of speech performances, models will be trained to predict cognitive decline and disease progression across the AD continuum. CONCLUSION: The outcome of PROSPECT-AD may support AD drug development research as well as primary or tertiary prevention of dementia by providing a validated tool using a remote approach for identifying individuals at risk of dementia and monitoring individuals over time, either in a screening context or in clinical trials.

Subspecialisation in cardiology care and outcome: should clinical services be redesigned, again?

BACKGROUND: Inpatient management of cardiac patients by cardiologists results in reduced mortality and hospitalisation. With increasing subspecialisation of the field because of growing management complexity and use of technological innovations, the impact of sub-specialisation on patient outcomes is unclear. AIM: To investigate whether management by subspecialty cardiologists impacts the outcomes of patients with subspecialty-specific diseases. METHODS: All patients admitted to a tertiary centre over nine years with a diagnosis of heart failure, acute coronary syndrome (ACS) or primary arrhythmia were reviewed. The outcomes of these patients managed by cardiologists subspecialised in their admission diagnosis (heart failure specialists, interventionalists and electrophysiologists) were compared with those treated by general cardiologists. RESULTS: Heart failure was diagnosed in 1704 patients, ACS in 7763 and arrhythmia in 4398. There was no difference in length of stay (LOS) (P = 0.26), mortality (P = 0.57) or cardiovascular readmissions (P = 0.50) in heart failure patients treated by general cardiologists compared with subspecialists. In ACS patients, subspecialty management was associated with reduced LOS, cardiovascular readmissions and mortality (all P < 0.05). This reduction in mortality was seen mainly in lower risk patients (P < 0.05). There was a reduction in LOS and cardiovascular readmissions in arrhythmia patients receiving subspecialty management (both P < 0.05) but no difference in mortality (P = 0.14). ACS patients managed by interventionalists were more likely to undergo coronary intervention (P < 0.05). Electrophysiologists more frequently referred patients for catheter ablation and pacemaker implantation than general cardiologists (P < 0.05). CONCLUSIONS: The benefits of subspecialty care seem attributable to the appropriate selection of patients who would benefit from technological innovations in care. These results suggest that the development of healthcare systems which align cardiovascular disease with the subspecialist may be more effective.

Epilepsy surgery in children with drug-resistant epilepsy, a long-term follow-up.

OBJECTIVES: In this follow-up study, we wanted to present the long-term outcome (5-21 years) in terms of seizure freedom, seizure reduction, and the cognitive development in the first 47 children who underwent epilepsy surgery at the University Hospital in Lund from 1991 to 2007. MATERIALS AND METHODS: All children who underwent epilepsy surgery in the southern region of Sweden were assessed for cognitive function before surgery and at follow-up. A review of medical documents for demographic data and seizure-related characteristics was made by retrospectively examining the clinical records. RESULTS: Forty-seven children with a median age at surgery of 8 years (range 0.5-18.7 years) were included. Twenty-three children achieved seizure freedom, six demonstrated >75% improvement in seizure frequency, and none of the children experienced an increase in seizure frequency. Twenty-one children required a reoperation to achieve satisfactory seizure outcomes. Cognitive functional level was preserved, and the majority of patients, 34 (76%), followed their expected cognitive trajectory. The patients who became seizure free significantly improved their cognitive processing speed, even after long-term follow-up. CONCLUSIONS: Epilepsy surgery in children offers suitable candidates a good chance of significantly improved outcome and low rates of complications. Several children, however, required a reoperation to achieve satisfactory seizure outcomes. Cognitive level was preserved, and the majority of patients followed their expected cognitive trajectory. Cognitive improvements in processing speed appear to occur in parallel with seizure control and were even more pronounced in subjects with no anti-epilepsy drugs. These improvements persisted even after long-term follow-up.

Prevalence, detection and drug treatment of hypertension in a rural Australian population: the Greater Green Triangle risk factor study 2004-2006.

BACKGROUND: Hypertension is an important risk factor for cardiovascular disease; however, limited findings are available on its detection and management in rural Australia. AIM: To assess the prevalence, awareness and treatment of hypertension in a rural South-East Australian population. METHODS: Three cross-sectional surveys in Limestone Coast, Corangamite Shire and Wimmera regions during 2004-2006 using a random population sample (n = 3320, participation rate 49%) aged 25-74 years. Blood pressure was measured by trained nurses. Information on history of hypertension and medication was obtained by questionnaires. Hypertension was defined as systolic blood pressure >or=140 mmHg and/or diastolic blood pressure >or=90 mmHg and/or on antihypertensive drug treatment. RESULTS: Overall, one-third of participants had hypertension; of these, two-thirds, 54% (95% confidence interval (CI) 47-60) of men and 71% (95% CI 65-77) of women, were aware of their condition. Half of the participants with hypertension were treated and nearly half of these were controlled. Both treatment and control were more common in women (60%, 95% CI 54-67 and 55%, 95% CI 47-64) compared with men (42%, 95% CI 36-49 and 35%, 95% CI 26-44). Monotherapy was used by 55% (95% CI 48-61) of treated hypertensives. Angiotensin-converting enzyme inhibitors were the most frequently used class of antihypertensive drugs in men, whereas angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists and diuretics were all widely used among women. CONCLUSION: This study emphasizes suboptimal detection and treatment of hypertension, especially in men, in rural Australia.

Antithrombins and the importance of good control.

The generation of thrombin and the formation of platelet rich intra-coronary thrombus in response to atherosclerotic plaque rupture is pathognomonic of acute coronary syndromes. An understanding of the process of thrombin generation and the unique relationship between the structure and function of thrombin is essential to developing more effective anti-thrombotic strategies than the use of standard unfractionated heparin in the acute coronary syndromes. The mechanisms of action of heparin, low molecular weight heparins (LMWHs) and the newer direct anti-thrombins, recombinant hirudin and Hirulog, are reviewed. Evidence from the currently available phase 2 and 3 trials of these drugs regarding their efficacy in the acute coronary syndromes is also reviewed.

Intervention with PTCA and CABG following thrombolysis for acute myocardial infarction. Australian data from GUSTO 1 (1991-3) and International Study Group r-TPA-Streptokinase Mortality (1989) trials. Global Utilisation of Streptokinase and Tissue.

The patterns of revascularisation with percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass graft (CABG) surgery in the GUSTO 1 trial patients in Australia are described. In comparison with rates documented in earlier trials of thrombolytic therapy in Australia, the rates of revascularisation post-thrombolysis increased by 50%, primarily due to a doubling in the rate of use of PTCA. However, the rates were low by international comparisons. There were marked variations in the rates of revascularisation between States, but no correlation with differences in mortality between States. The main predictors of post thrombolysis PTCA were prior angina, mild infarction and access to PTCA facilities.