Search

Background: The CHARIOT PRO Main study is a prospective, non-interventional study evaluating cognitive trajectories in participants at the preclinical stage of Alzheimer’s disease (AD) classified by risk levels for developing mild cognitive impairment due to AD (MCI-AD). Objectives: The study aimed to characterize factors and markers influencing cognitive and functional progression among individuals at-risk for developing MCI-AD, and examine data for more precise predictors of cognitive change, particularly in relation to APOE ε4 subgroup. Design: This single-site study was conducted at the Imperial College London (ICL) in the United Kingdom. Participants 60 to 85 years of age were classified as high, medium (amnestic or non-amnestic) or low risk for developing MCI-AD based on RBANS z-scores. A series of clinical outcome assessments (COAs) on factors influencing baseline cognitive changes were collected in each of the instrument categories of cognition, lifestyle exposure, mood, and sleep. Data collection was planned to occur every 6 months for 48 months, however the median follow-up time was 18.1 months due to early termination of study by the sponsor. Results: 987 participants were screened, among them 690 participants were actively followed-up post baseline, of whom 165 (23.9%) were APOE ε4 carriers; with at least one copy of the allele. The mean age was 68.73 years, 94.6% were white, 57.4% were female, and 34.8% had a Family History of Dementia with a somewhat larger percentage in the APOE ε4 carrier group (42.4%) compared to the non-carrier group (32.4%). Over half of the participants were married and 53% had a Bachelor’s or higher degree. Most frequently, safety events typical for this population consisted of upper respiratory tract infection (10.4%), falls (5.2%), hypertension (3.5%) and back pain (3.0%). Conclusion (clinical relevance): AD-related measures collected during the CHARIOT PRO Main study will allow identification and evaluation of AD risk factors and markers associated with cognitive performance from the pre-clinical stage. Evaluating the psycho-biological characteristics of these pre-symptomatic individuals in relation to their natural neurocognitive trajectories will enhance current understanding on determinants of the initial signs of cognitive changes linked to AD.

The following compilation of letters date from between 1845 and 1854; they form part of a larger collection of papers relating to Christina Gordon and her descendants, which are currently in the author's possession.1 The bulk of the letters included in this article were written by a Scottish priest, Donald Carmichael, to his great-nephew and namesake whilst the latter was a seminarian in Europe and are full of kindly advice and news from home for the young student.2 also offer a fascinating snapshot of Scottish religious and social history in the 1840s and 1850s. The correspondence is fundamentally a personal and family based one, reflecting as it does the mentoring relationship of great-uncle to his protégé. However, there is also much to interest historians in the post-emancipation but pre-reestablishment of the Scottish Catholic hierarchy era.

Lack of standardization across sites and raters, poor interrater reliability, and possible scoring bias affecting the primary outcome measure contribute to a high failure rate in anxiety trials. Remote centralized raters who are blinded to protocol inclusion and exclusion criteria as well as visit number may standardize assessments across raters and eliminate scoring bias, decreasing placebo response and thereby increasing signal detection. The purpose of the primary study was to test the safety and efficacy of an anxiolytic in a double-blind, placebo-controlled (no active comparator), multicenter trial. However, there was an additional prospective objective to explore site ratings compared with remote centralized ratings in the cohort of subjects on placebo. Site raters assessed subjects 6 times over an 8-week period. The primary outcome measure was the week 8 site-rated Hamilton Anxiety Scale (HAM-A). Remote centralized raters by telephone independently rated these subjects on the HAM-A at baseline and week 6. Of the 122 subjects selected by site raters and therefore randomized, remote centralized raters would have admitted 59 (48%) and excluded 63 (52%), based on their HAM-A ratings. The mean change from baseline in HAM-A total score in the placebo group admitted to the study by site raters was 9.3, significantly higher than the 5.9 point mean change on placebo as measured by the remote centralized raters.The data are consistent with the potential for qualification bias at baseline when rated by sites. The results make a strong case for using strategies to ensure that baseline scoring is truly independent of the pressure to enroll.

BACKGROUND: Arformoterol tartrate (arformoterol, 15 μg bid) is a nebulized long-acting β 2 -agonist approved for maintenance treatment of COPD. METHODS: This was a multicenter, double-blind, randomized, placebo-controlled study. Patients (aged ≥ 40 years with baseline FEV 1 ≤ 65% predicted, FEV 1 > 0.50 L, FEV 1 /FVC ≤ 70%, and ≥ 15 pack-year smoking history) received arformoterol (n = 420) or placebo (n = 421) for 1 year. The primary assessment was time from randomization to respiratory death or first COPD exacerbation-related hospitalization. RESULTS: Among 841 patients randomized, 103 had ≥ 1 primary event (9.5% vs 15.0%, for arformoterol vs placebo, respectively). Patients who discontinued treatment for any reason (39.3% vs 49.9%, for arformoterol vs placebo, respectively) were followed for up to 1 year postrandomization to assess for primary events. Fewer patients receiving arformoterol than placebo experienced COPD exacerbation-related hospitalizations (9.0% vs 14.3%, respectively). Twelve patients (2.9%) receiving arformoterol and 10 patients (2.4%) receiving placebo died during the study. Risk for first respiratory serious adverse event was 50% lower with arformoterol than placebo ( P = .003). Numerically more patients on arformoterol (13; 3.1%) than placebo (10; 2.4%) experienced cardiac serious adverse events; however, time-to-first cardiac serious adverse event was not significantly different. Improvements in trough FEV 1 and FVC were greater with arformoterol (least-squares mean change from baseline vs placebo: 0.051 L, P = .030 and 0.075 L, P = .018, respectively). Significant improvements in quality of life (overall St. George's Hospital Respiratory Questionnaire and Clinical COPD Questionnaire) were observed with arformoterol vs placebo ( P CONCLUSIONS: Arformoterol demonstrated an approximately 40% lower risk of respiratory death or COPD exacerbation-related hospitalization over 1 year vs placebo. Arformoterol was well-tolerated and improved lung function vs placebo. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00909779; URL:www.clinicaltrials.gov

Background: Connecting willing patients with dementia to suitable clinical research studies has been historically challenging. The United Kingdom Dementia and Neurodegenerative Research Network (DeNDRoN) was established to link patients into high-quality studies. One component is DemReg, a register of dementia patients and their carers who have agreed to be approached regarding future research studies. The limited literature highlights the predominance of altruism mediating research register participation. The objective of this study was to understand the motivations of patients and carers to participate in DemReg.Methods: There were 107 participants in the study, interviewed using a questionnaire to determine which factors were important in their decision to be on the register. The study compared the proportion of the altruistic motivations articulated with the proportion of the other answers offered.Results: The two most important motivators for registering on DemReg were to help others (44%; p < 0.001) or themselves (29%; p < 0.001) and altruistic motives took precedence over those for personal benefit. Participants were not motivated by the prospect of payment or by concern that they would be letting down their clinician if they did not register.Conclusions: There are currently major projects within the United Kingdom to increase the number of patients on dementia registers and to further involvement in dementia research. This study, to the best of our knowledge, is the first to assess the motivations of patients and carers for joining a dementia research register in the United Kingdom, and the findings highlight the importance of altruistic motives.

Background Arformoterol is a single-isomer ( R , R -formoterol) nebulized long-acting β 2 -agonist approved for use in patients with chronic obstructive pulmonary disease (COPD). Exposure (plasma concentrations of ( R , R )-formoterol) and forced expiratory volume in 1 s (FEV 1 ) were compared for 15 μg nebulized arformoterol and 12 and 24 μg racemic formoterol (containing 6 and 12 μg ( R , R )-formoterol, respectively) delivered by dry powder inhaler (DPI). Methods An open-label, randomized, three-way crossover study in 39 subjects with COPD (FEV 1 1.4 L, 44.4% predicted). Twice-daily treatments included nebulized arformoterol (15 μg) and racemic formoterol DPI (12 and 24 μg) for 14 days. Plasma concentrations of ( R , R )- and ( S , S )-formoterol were determined on days 1 and 14 of each treatment period. Airway function efficacy endpoints included the percent change in trough FEV 1 from baseline on day 14 of each treatment period. Results At steady state, exposure to ( R , R )-formoterol was similar following nebulized 15 μg arformoterol ( C max : 6.5 pg/mL; AUC(0− τ ): 56.5 pg h/mL) and 12 μg racemic formoterol DPI ( C max : 6.2 pg/mL; AUC (0− τ ) : 46.3 pg h/mL). The geometric mean ratios between these two treatments (90% confidence intervals) for C max and AUC (0− τ ) were 0.91 (0.76, 1.09) and 1.16 (1.00, 1.35), respectively. Treatment with 24 μg racemic formoterol DPI resulted in dose proportionally higher ( R,R )-formoterol: C max (10.8 pg/mL) and AUC (0− τ ) (83.6 pg h/mL). Detectable ( S , S )-formoterol was consistently measured only after treatment with racemic formoterol. The mean percent increase in trough FEV 1 was 19.1% in the arformoterol group, and 16.0% and 18.2% in the 12 and 24 μg racemic formoterol groups, respectively. Changes in ( R , R )-formoterol concentrations over time paralleled changes in FEV 1 . Conclusions In this study, plasma exposure to ( R , R )-formoterol was similar for nebulized 15 μg arformoterol and 12 μg racemic formoterol DPI, and 40% lower than 24 μg racemic formoterol DPI. There was no evidence of chiral interconversion following treatment with arformoterol. Finally, temporal changes in airway function in all treatment groups corresponded to changes in ( R , R )-formoterol plasma concentrations.

The inflammatory cytokines tumor necrosis factor-alpha (TNF alpha) and interleukin-1 alpha (IL-1 alpha) have angiogenic properties but generally inhibit cultured endothelial cell (EC) proliferation. Investigations into the growth-regulatory effects of these two agents on a variety of cultured EC types showed that they exert mitogenic, anti-proliferative or cytotoxic effects depending upon cell type and cytokine combinations. The anti-proliferative effect was distinct from cytotoxicity. Nitric oxide (NO) release from EC, examined as a potential mechanism underlying some of these effects, did not appear to mediate the anti-proliferative effects of these cytokines. However, NO also seemed to have a bimodal effect on EC proliferation depending upon whether the NO was endogenous or exogenous. These data underscore the diversity in cytokine and NO effects on cultured EC which, if reproducible in vivo, may be partly responsible for the variable and sometimes contradictory results obtained with regards to the role of inflammatory cytokines and NO on angiogenesis.

Summary.-This research examined the validity of the short form of the Need for Cognition Scale. Contrary to expectation, the scale was not related to private self-consciousness or a self-directed problem-solving strategy. Consistent with expectation, however, the scale was related to preferences for various activities, both intellectual and social, that reflect an underlying need for cognition. These results are seen as supporting the validity of the short form of the scale. Cadoppo and Petty (1) developed a "need for cognition" scale designed to assess differences in the desire to engage in and enjoy effortful cognitive activities. Research with the scale has tended to support its validity (1, 3). Later, a short form (2) which has impressive convergent validity with the full version (r= .95) and excellent reliability estimated by theta of .90 (2) was developed. As relatively little work has been done with this version, the present research was designed to address this deficit. People high in need for cognition should be "thinkers" who enjoy mental activities and have high need to understand. Based on this rationale, we expected scores on the short form of the scale to correlate positively with a measure of individual differences in tendencies toward introspection, self-reflection, and a general awareness of one's inner thoughts, the Private self-consciousness scale (4). We also predicted that scores on the short form would correlate positively with a measure of self-directed religious problem-solving style (5), i.e., a problem-solving approach which emphasizes personal freedom from God, agency, and active coping. The present study also addressed relatively neglected research on validity with the Need for Cognition Scale: behavior and activity preferences. If the short form is a valid measure of tendencies toward the enjoyment of cognition, then the scale should correlate in predicted ways with measures of intellectual and social activities that differ in their cognitive requirements. The present research developed a questionnaire requesting people to imagine themselves in six different situations, a waiting room with magazines, a library (only nonfiction book options were provided), a gift certificate for a bookstore (fiction books), selecting a movie to rent, watching TV, and a free weekend without studying (choice among various social activities). A final section asked for a global ranking of the previous six activities (e.g., magazines, movies, etc.). To convey more dearly the stimulus materials, the first situation is presented in detail. This situation stated "Imagine you are in a waiting room and there are many people ahead of you. Please rank order the following magazines in the order you would be most likely to look at them to occupy your time." The choices were: GQ or Mademoiselle, Newsweek, Psychology Today, Omni, National Inquirer, and Scientific American. Within each of the six vicarious situations, subjects were asked to rank order their preferences for the activities specified. It was predicted that scores on the short form would be positively correlated with preferences for high need for cognition activities in each of the six situations, as well as in the global category.'

Aims: Our main objective was to determine the neuropathological correlates of dementia in patients with Lewy body disease (LBD). Furthermore, we used data derived from clinical, neuropathological and genetic studies to investigate boundary issues between Dementia with Lewy bodies (DLB) and Parkinson's disease with (PDD) and without (PDND) dementia. Methods: One hundred and twenty-one cases with a neuropathological diagnosis of LBD and clinical information on dementia status were included in the analysis (55 PDD, 17 DLB and 49 PDND). We carried out topographical and semi-quantitative assessment of Lewy bodies (LB), Aβ plaques and tau-positive neuropil threads (NT). The APOE genotype and MAPT haplotype status were also determined. Results: The cortical LB (CLB) burden was the only independent predictor of dementia (OR: 4.12, P < 0.001). The total cortical Aβ plaque burden was an independent predictor of a shorter latency to dementia from onset of motor signs (P = 0.001). DLB cases had a higher LB burden in the parietal and temporal cortex, compared to PDD. Carrying at least one APOE ϵ4 allele was associated with a higher cortical LB burden (P = 0.02), particularly in the neocortical frontal, parietal and temporal regions. Conclusions: High CLB burden is a key neuropathological substrate of dementia in LBD. Elevated cortical LB pathology and Aβ plaque deposition are both correlated with a faster progression to dementia. The higher CLB load in the temporal and parietal regions, which seems to be a distinguishing feature of DLB, may account for the shorter latency to dementia and could be mediated by the APOE ϵ4 allele.

Aim To describe the development of a dementia research registry, outlining the conceptual, practical and ethical challenges, and to report initial experiences of recruiting people with dementia to it from primary and secondary care. Background Women, the oldest old and ethnic minorities have been under-represented in clinical trials in dementia. Such under-representation biases estimates of absolute effect, absolute harm and cost-effectiveness. Research on dementia should include patient populations that more exactly reflect the population at risk. One of the impediments to this is the lack of a suitable tool for identification of patients suitable for studies. Construction & contents A technology development methodology was used to develop a registry of people with dementia and their carers. This involved phases of modelling and prototype creation, 'bench testing' the prototype with experts and then 'field testing' the refined prototype in exemplar sites. The evaluation of the field testing described here is based on a case study methodology. Utility This case study suggests that construction and population of a dementia research registry is feasible, but initial development is complex because of the ethical and organisational difficulties. Recruitment from primary care is particularly costly in terms of staff time and only identifies a very small number of people with dementia who were not already known to specialist services. Recruiting people with dementia through secondary care is a resource intensive process that takes up to six months to complete. Identifying the components of a minimum dataset was easy but its usefulness for pre-screening potential research populations has yet to be established. Acceptance rates are very high in the first clinic to recruit to the registry, but this may reflect the efforts of registry 'champions'. Discussion and Conclusions Easier recruitment may perpetuate potential selection biases and we are not yet able to assess the representativeness of the research-ready population recruited to the registry. The need to recruit from wider populations, through primary and social care, remains. The success of this registry will be measured by the proportion of people from it who are recruited to research projects, and its impact on overall accrual to studies.