| 1. |
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
|
|
| 9. |
|
|
| 10. |
- Dyer, A. H., et al.
(author)
-
Cognitive Outcomes of Long-term Benzodiazepine and Related Drug (BDZR) Use in People Living With Mild to Moderate Alzheimer's Disease: Results From NILVAD
- 2020
-
In: Journal of the American Medical Directors Association. - : Elsevier BV. - 1525-8610. ; 21:2, s. 194-200
-
Journal article (peer-reviewed)abstract
- Objective: Benzodiazepines and related drugs (BDZRs) have been associated with an increased risk of Alzheimer's disease (AD) in later life. Despite this, it remains unclear whether ongoing BDZR use may further accelerate cognitive decline in those diagnosed with mild to moderate AD. Design: This study was embedded within NILVAD, a randomized controlled trial of nilvadipine in mild to moderate AD. Cognition was measured at baseline and 18 months using the Alzheimer Disease Assessment Scale, Cognitive Subsection (ADAS-Cog). We assessed predictors of long-term BDZR use and analyzed the effect of ongoing BDZR use on ADAS-Cog scores at 18 months. Additionally, the impact of BDZR use on adverse events, incident delirium, and falls over 18-month follow-up was assessed adjusting for relevant covariates. Setting and Participants: 448 participants with mild to moderate AD recruited from 23 academic centers in 9 European countries. Results: Overall, 14% (62/448) were prescribed an ongoing BDZR for the study duration. Increasing total number of (non-BDZR) medications was associated with a greater likelihood of BDZR prescription (odds ratio 1.16, 95% confidence interval 1.05-1.29). At 18 months, BDZR use was not associated with greater cognitive decline on the ADAS-Cog controlling for baseline ADAS-Cog scores, age, gender, study arm, and other clinical covariates (beta = 1.62, -1.34 to 4.56). However, ongoing BDZR use was associated with a greater likelihood of adverse events [incidence rate ratio (IRR) 1.19, 1.05-1.34], incident delirium (IRR 2.31, 1.45-3.68), and falls (IRR 1.66, 1.02-2.65) over 18 months that persisted after robust adjustment for covariates. Conclusions and Implications: This study found no effect of ongoing BDZR use on ADAS-Cog scores in those with mild to moderate AD over 18 months. However, ongoing use of these medications was associated with an increased risk of adverse events, delirium, and falls. Thus, BDZR use should be avoided where possible and deprescribing interventions should be encouraged in older adults with AD. (C) 2019 AMDA - The Society for Post-Acute and Long-Term Care Medicine.
|
|
| 11. |
|
|
| 12. |
- de Heus, R. A. A., et al.
(author)
-
Blood Pressure Lowering With Nilvadipine in Patients With Mild-to-Moderate Alzheimer Disease Does Not Increase the Prevalence of Orthostatic Hypotension
- 2019
-
In: Journal of the American Heart Association. - : Ovid Technologies (Wolters Kluwer Health). - 2047-9980. ; 8:10
-
Journal article (peer-reviewed)abstract
- Background-Hypertension is common among patients with Alzheimer disease. Because this group has been excluded from hypertension trials, evidence regarding safety of treatment is lacking. This secondary analysis of a randomized controlled trial assessed whether antihypertensive treatment increases the prevalence of orthostatic hypotension (OH) in patients with Alzheimer disease. Methods and Results-Four hundred seventy-seven patients with mild-to-moderate Alzheimer disease were randomized to the calcium-channel blocker nilvadipine 8 mg/day or placebo for 78 weeks. Presence of OH (blood pressure drop >= 20/>= 10 mm Hg after 1 minute of standing) and OH-related adverse events (dizziness, syncope, falls, and fractures) was determined at 7 follow-up visits. Mean age of the study population was 72.2 +/- 8.2 years and mean Mini-Mental State Examination score was 20.4 +/- 3.8. Baseline blood pressure was 137.8 +/- 14.0/77.0 +/- 8.6 mm Hg. Grade I hypertension was present in 53.4% (n=255). After 13 weeks, blood pressure had fallen by -7.8/-3.9 mm Hg for nilvadipine and by -0.4/-0.8 mm Hg for placebo (P<0.001). Across the 78-week intervention period, there was no difference between groups in the proportion of patients with OH at a study visit (odds ratio [95% CI] 1.1 [0.8-1.5], P 0.62), nor in the proportion of visits where a patient met criteria for OH, corrected for number of visits (7.7 +/- 13.8% versus 7.3 +/- 11.6%). OH-related adverse events were not more often reported in the intervention group compared with placebo. Results were similar for those with baseline hypertension. Conclusions-This study suggests that initiation of a low dose of antihypertensive treatment does not significantly increase the risk of OH in patients with mild-to-moderate Alzheimer disease.
|
|
| 13. |
|
|
| 14. |
|
|
| 15. |
|
|
| 16. |
- Lawlor, B., et al.
(author)
-
Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial
- 2018
-
In: Plos Medicine. - : Public Library of Science (PLoS). - 1549-1676. ; 15:9
-
Journal article (peer-reviewed)abstract
- Background This study reports the findings of the first large-scale Phase III investigator-driven clinical trial to slow the rate of cognitive decline in Alzheimer disease with a dihydropyridine (DHP) calcium channel blocker, nilvadipine. Nilvadipine, licensed to treat hypertension, reduces amyloid production, increases regional cerebral blood flow, and has demonstrated antiinflammatory and anti-tau activity in preclinical studies, properties that could have diseasemodifying effects for Alzheimer disease. We aimed to determine if nilvadipine was effective in slowing cognitive decline in subjects with mild to moderate Alzheimer disease. NILVAD was an 18-month, randomised, placebo-controlled, double-blind trial that randomised participants between 15 May 2013 and 13 April 2015. The study was conducted at 23 academic centres in nine European countries. Of 577 participants screened, 511 were eligible and were randomised (258 to placebo, 253 to nilvadipine). Participants took a trial treatment capsule once a day after breakfast for 78 weeks. Participants were aged > 50 years, meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's disease Criteria (NINCDS-ADRDA) for diagnosis of probable Alzheimer disease, with a Standardised Mini-Mental State Examination (SMMSE) score of >= 12 and < 27. Participants were randomly assigned to 8 mg sustained-release nilvadipine or matched placebo. The a priori defined primary outcome was progression on the Alzheimer's Disease Assessment Scale Cognitive Subscale-12 (ADAS-Cog 12) in the modified intention-to-treat (mITT) population (n = 498), with the Clinical Dementia Rating Scale sum of boxes (CDR-sb) as a gated co-primary outcome, eligible to be promoted to primary end point conditional on a significant effect on the ADAS-Cog 12. The analysis set had a mean age of 73 years and was 62% female. Baseline demographic and Alzheimer disease +/- specific characteristics were similar between treatment groups, with reported mean of 1.7 years since diagnosis and mean SMMSE of 20.4. The prespecified primary analyses failed to show any treatment benefit for nilvadipine on the co-primary outcome (p = 0.465). Decline from baseline in ADASCog 12 on placebo was 0.79 (95% CI, -0.07 +/- 1.64) at 13 weeks, 6.41 (5.33 +/- 7.49) at 52 weeks, and 9.63 (8.33 +/- 10.93) at 78 weeks and on nilvadipine was 0.88 (0.02 +/- 1.74) at 13 weeks, 5.75 (4.66 +/- 6.85) at 52 weeks, and 9.41 (8.09 +/- 10.73) at 78 weeks. Exploratory analyses of the planned secondary outcomes showed no substantial effects, including on the CDR-sb or the Disability Assessment for Dementia. Nilvadipine appeared to be safe and well tolerated. Mortality was similar between groups (3 on nilvadipine, 4 on placebo); higher counts of adverse events (AEs) on nilvadipine (1,129 versus 1,030), and serious adverse events (SAEs; 146 versus 101), were observed. There were 14 withdrawals because of AEs. Major limitations of this study were that subjects had established dementia and the likelihood that non-Alzheimer subjects were included because of the lack of biomarker confirmation of the presence of brain amyloid. The results do not suggest benefit of nilvadipine as a treatment in a population spanning mild to moderate Alzheimer disease.
|
|
| 17. |
|
|
| 18. |
|
|
| 19. |
- Lawlor, B., et al.
(author)
-
NILVAD protocol: A European multicentre double-blind placebo-controlled trial of nilvadipine in mild-to-moderate Alzheimer's disease
- 2014
-
In: BMJ Open. - : BMJ Publishing Group. - 2044-6055. ; 4:10
-
Journal article (peer-reviewed)abstract
- Introduction: This study is a European multicentre, randomised, double-blind, placebo-controlled trial investigating the efficacy and safety of nilvadipine as a disease course modifying treatment for mild-to-moderate Alzheimer's disease (AD) in a phase III study that will run for a period of 82 weeks with a treatment period of 78 weeks. Methods and analysis: Adult patients, males and females over 50 years with mild-to-moderate AD as defined by the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's disease and Related Disorders Association (NINCDSADRDA) criteria, will be included in the study. It aims to recruit a total of 500 patients with AD; 250 in the nilvadipine group and 250 in the placebo group. Participants will be randomised to receive nilvadipine, an 8 mg overencapsulated, sustained release capsule, or a matching overencapsulated placebo (sugar pill) for a period of 78 weeks of treatment. The primary efficacy outcome measure in this study is the change in cognitive function as assessed by the Alzheimer's disease Assessment Scale (ADASCog 12) from baseline to the end of treatment duration (78 weeks). There are two key secondary outcome measures, the Clinical Dementia Rating Scale Sum of Boxes (CDRsb) and the Disability Assessment for Dementia (DAD). If a statistically significant effect is seen in the primary outcome, CDRsb will be considered to be a coprimary end point and only the DAD will contribute to the secondary outcome analysis. Ethics and dissemination: The study and all subsequent amendments have received ethical approval within each participating country according to national regulations. Each participant will provide written consent to participate in the study. All participants will remain anonymised throughout and the results of the study will be published in an international peerreviewed journal. Trial registration number EUDRACT Reference Number: 201200276427.
|
|
| 20. |
- Mason, L., et al.
(author)
-
Preference for biological motion is reduced in ASD : implications for clinical trials and the search for biomarkers
- 2021
-
In: Molecular Autism. - : Springer Nature. - 2040-2392. ; 12
-
Journal article (peer-reviewed)abstract
- Background: The neurocognitive mechanisms underlying autism spectrum disorder (ASD) remain unclear. Progress has been largely hampered by small sample sizes, variable age ranges and resulting inconsistent findings. There is a pressing need for large definitive studies to delineate the nature and extent of key case/control differences to direct research towards fruitful areas for future investigation. Here we focus on perception of biological motion, a promising index of social brain function which may be altered in ASD. In a large sample ranging from childhood to adulthood, we assess whether biological motion preference differs in ASD compared to neurotypical participants (NT), how differences are modulated by age and sex and whether they are associated with dimensional variation in concurrent or later symptomatology.Methods: Eye-tracking data were collected from 486 6-to-30-year-old autistic (N = 282) and non-autistic control (N = 204) participants whilst they viewed 28 trials pairing biological (BM) and control (non-biological, CTRL) motion. Preference for the biological motion stimulus was calculated as (1) proportion looking time difference (BM-CTRL) and (2) peak look duration difference (BM-CTRL).Results: The ASD group showed a present but weaker preference for biological motion than the NT group. The nature of the control stimulus modulated preference for biological motion in both groups. Biological motion preference did not vary with age, gender, or concurrent or prospective social communicative skill within the ASD group, although a lack of clear preference for either stimulus was associated with higher social-communicative symptoms at baseline.Limitations: The paired visual preference we used may underestimate preference for a stimulus in younger and lower IQ individuals. Our ASD group had a lower average IQ by approximately seven points. 18% of our sample was not analysed for various technical and behavioural reasons.Conclusions: Biological motion preference elicits small-to-medium-sized case–control effects, but individual differences do not strongly relate to core social autism associated symptomatology. We interpret this as an autistic difference (as opposed to a deficit) likely manifest in social brain regions. The extent to which this is an innate difference present from birth and central to the autistic phenotype, or the consequence of a life lived with ASD, is unclear.
|
|
| 21. |
- Meulenbroek, O., et al.
(author)
-
European multicentre double-blind placebo-controlled trial of Nilvadipine in mild-to-moderate Alzheimer's disease - The substudy protocols: NILVAD frailty; NILVAD blood and genetic biomarkers; NILVAD cerebrospinal fluid biomarkers; NILVAD cerebral blood flow
- 2016
-
In: BMJ Open. - : BMJ. - 2044-6055. ; 6:7
-
Journal article (peer-reviewed)abstract
- Introduction: In conjunction with the NILVAD trial, a European Multicentre Double-Blind Placebo Controlled trial of Nilvadipine in Mild-to-Moderate Alzheimer's disease (AD), there are four NILVAD substudies in which eligible NILVAD patients are also invited to participate. The main NILVAD protocol was previously published in BMJ Open (2014). The objectives of the NILVAD substudies are to determine whether frailty, cerebrospinal fluid (CSF), blood biomarker profile and Apolipoprotein E (APOE) status predict response to Nilvadipine, and to investigate the effect of Nilvadipine on cerebral blood flow and blood biomarkers. Methods and analysis: All participants who fulfil criteria for the main NILVAD study are eligible for participation in the NILVAD substudies. Participation is subject to informed consent and whether the substudy is available at a particular NILVAD study site. Each substudy entails extra measurements during the course of the main NILVAD study. For example, in the blood and genetic biomarkers substudy, extra blood (30 mL) will be collected at week 0, week 13, week 52 and week 78, while in the cerebral blood flow substudy, participants will receive an MRI and transcranial Doppler measurements at week 0, week 26 and week 78. In the CSF substudy, 10 mL CSF is collected at week 0 and week 78. Ethics and dissemination: All NILVAD substudies and all subsequent amendments have received ethical approval within each participating country, according to national regulations. Each participant provides written consent to participate. All participants remain anonymised throughout and the results of each substudy will be published in an international peer reviewed journal. © 2016 Published by the BMJ Publishing Group Limited.
|
|
| 22. |
|
|
| 23. |
- Duff, S E, et al.
(author)
-
Dysplasia in the ileoanal pouch.
- 2002
-
In: Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland. - 1462-8910. ; 4:6, s. 420-9
-
Journal article (peer-reviewed)abstract
- Formation of an ileo-anal pouch is an accepted technique following colectomy in the surgical management of ulcerative colitis (UC) and familial adenomatous polyposis (FAP). The configuration of pouches and anastomotic techniques has varied over the last two decades. The increased use of stapling devices in formation of the pouch-anal anastomosis avoids the need for endoanal mucosal stripping and may contribute to improved functional results, but leaves a 'columnar cuff' of residual rectal mucosa in situ. Concerns regarding the long-term safety of the ileo-anal pouch have been raised by reports of the occurrence of dysplasia in the pouch mucosa and 15 cases of adenocarcinoma. In UC, persistence of underlying disease in the residual rectal mucosa, anal transition zone and columnar cuff provides the site for development of dysplasia and malignancy. Pouchitis is unlikely to be a major cause of dysplasia or malignancy, as long-term follow-up of patients with Koch pouches has demonstrated. In FAP, any persistent rectal mucosa and mucosa of the small intestine is at risk of adenomatous dysplasia due to the genetic alterations causing the disease. Long-term surveillance should focus on all FAP pouch patients, and in UC patients should be directed towards the diagnosis of residual rectal mucosa in the area distal to the pouch anastomosis. Specialist histopathological opinion is essential in the diagnosis of dysplasia in the ileo-anal pouch.
|
|
| 24. |
- Eklof, B., et al.
(author)
-
The role of self-reported stressors in recovery from Exhaustion Disorder: a longitudinal study
- 2022
-
In: Bmc Psychiatry. - : Springer Science and Business Media LLC. - 1471-244X. ; 22
-
Journal article (peer-reviewed)abstract
- Background Exhaustion disorder (ED) is a stress-induced disorder characterized by physical and mental symptoms of exhaustion that can be long-lasting. Although stress exposure is essential for the development of ED, little is known regarding the role of stressors in the maintenance of ED. The aim of the study was to investigate the role of work-related stressors, private-related stressors, and adverse childhood experiences in long-term recovery from ED. Methods A mixed methods design was used. The design was sequential, and data analysis was performed in two parts, where the first part consisted of qualitative analysis of patient records, and the second part consisted of statistical analysis of the data retrieved from the qualitative coding. Patient records from 150 patients with ED was analysed regarding work-related stressors, private-related stressors, and adverse childhood experiences. For each patient, two patient records were analysed, one from the time of diagnosis (baseline) and one from the follow-up clinical assessment, 7-12 years after diagnosis (follow-up). Out of the 150 patients, 51 individuals still fulfilled the diagnostic criteria for ED at follow-up (ED group) and 99 individuals no longer fulfilled the diagnostic criteria and were thus considered recovered (EDrec). Percentages in each group (ED and EDrec) reporting each stressor at baseline and follow-up were calculated as well as the differences in percentage points between the groups along with the 95% confidence intervals for the differences. Results At baseline, significantly more EDrec patients reported quantitative demands (73% EDrec, 53% ED) and managerial responsibilities (14% EDrec, 2% ED). Private-related stressors did not differ at baseline. At follow-up, significantly more ED patients reported managerial responsibilities (8 ED, 0% EDrec) and caregiver stress (child) (24% ED, 6% EDrec) and significantly more EDrec patients reported caregiver stress (parent) (6% EDrec, 0% ED). There were no differences regarding adverse childhood experiences. Conclusions The main conclusion is that neither adverse childhood experiences nor any of the stressors at baseline are associated with long-term ED. Ongoing stressors related to having responsibility for other people, such as managerial responsibilities or caring for a child with a chronic disease or psychiatric disorder, may be associated with long-term exhaustion.
|
|
| 25. |
|
|
| 26. |
|
|
| 27. |
|
|
| 28. |
|
|
| 29. |
|
|
| 30. |
|
|
| 31. |
|
|
| 32. |
|
|
| 33. |
|
|
| 34. |
|
|
| 35. |
|
|
| 36. |
- Daly, J, et al.
(author)
-
Targeting hypersialylation in multiple myeloma represents a novel approach to enhance NK cell-mediated tumor responses
- 2022
-
In: Blood advances. - : American Society of Hematology. - 2473-9537 .- 2473-9529. ; 6:11, s. 3352-3366
-
Journal article (peer-reviewed)abstract
- Abnormal glycosylation is a hallmark of cancer, and the hypersialylated tumor cell surface facilitates abnormal cell trafficking and drug resistance in several malignancies, including multiple myeloma (MM). Furthermore, hypersialylation has also been implicated in facilitating evasion of natural killer (NK) cell–mediated immunosurveillance but not in MM to date. In this study, we explore the role of hypersialylation in promoting escape from NK cells. We document strong expression of sialic acid-derived ligands for Siglec-7 (Siglec-7L) on primary MM cells and MM cell lines, highlighting the possibility of Siglec-7/Siglec-7L interactions in the tumor microenvironment. Interactomics experiments in MM cell lysates revealed PSGL-1 as the predominant Siglec-7L in MM. We show that desialylation, using both a sialidase and sialyltransferase inhibitor (SIA), strongly enhances NK cell–mediated cytotoxicity against MM cells. Furthermore, MM cell desialylation results in increased detection of CD38, a well-validated target in MM. Desialylation enhanced NK cell cytotoxicity against CD38+ MM cells after treatment with the anti-CD38 monoclonal antibody daratumumab. Additionally, we show that MM cells with low CD38 expression can be treated with all trans-retinoic acid (ATRA), SIA and daratumumab to elicit a potent NK cell cytotoxic response. Finally, we demonstrate that Siglec-7KO potentiates NK cell cytotoxicity against Siglec-7L+ MM cells. Taken together, our work shows that desialylation of MM cells is a promising novel approach to enhance NK cell efficacy against MM, which can be combined with frontline therapies to elicit a potent anti-MM response.
|
|
| 37. |
|
|
| 38. |
- Gustafson, Yngve, et al.
(author)
-
Depression in old age in Austria, Ireland, Portugal and Sweden
- 2013
-
In: European Geriatric Medicine. - : Elsevier BV. - 1878-7649 .- 1878-7657. ; 4:3, s. 202-208
-
Journal article (peer-reviewed)abstract
- Depression is the third leading cause of disease burden worldwide and the most frequent psychiatric disorder in the older adult population. Depression in old age is disabling, both psychosocially and physically, decreases quality of life and increases mortality. This paper explores the epidemiology, screening, diagnosis and management of depression in old age in four European countries in an attempt to gain a better understanding of the issues contributing to the variability in clinical practice. The prevalence of depression in community dwelling older individuals is high, but studies in the oldest population and in specific settings (like nursing homes) are few. Depression may go undiagnosed, and wide screening programs for early identification of this disease are uncommon. Depression screening is consistently included in comprehensive geriatric assessment, and most geriatricians appear to be confident in its diagnosis and management. Old age psychiatry is still largely underdeveloped, except for Ireland. Primary care physicians start treatment of depression in most countries, referring only complex cases for specialised care. SSRIs seem to be the first line treatment, but choice of antidepressants is widely variable in different countries. Availability of non-pharmacological therapies is still low, and only highly skilled centres use a multifaceted approach to depression care. Attitudes towards depression and mental illness are still mostly negative, which may hinder identification and management of this highly prevalent geriatric problem.
|
|
| 39. |
|
|
| 40. |
- Kamiya, T., et al.
(author)
-
A quantitative review of MHC-based mating preference: the role of diversity and dissimilarity
- 2014
-
In: Molecular Ecology. - : Wiley. - 0962-1083. ; 23:21, s. 5151-5163
-
Research review (peer-reviewed)abstract
- Sexual selection hypotheses stipulate that the major histocompatibility complex genes (MHC) constitute a key molecular underpinning for mate choice in vertebrates. The last four decades saw growing empirical literature on the role of MHC diversity and dissimilarity in mate choice for a wide range of vertebrate animals, but with mixed support for its significance in natural populations. Using formal phylogenetic meta-analysis and meta-regression techniques, we quantitatively review the existing literature on MHC-dependent mating preferences in nonhuman vertebrates with a focus on the role of MHC diversity and dissimilarity. Overall, we found small, statistically nonsignificant, average effect sizes for both diversity- and dissimilarity-based mate choice (r=0.113 and 0.064, respectively). Importantly, however, meta-regression models revealed statistically significant support regarding female choice for diversity, and choice for dissimilarity (regardless of choosy sex) only when dissimilarity is characterized across multiple loci. Little difference was found among vertebrate taxa; however, the lack of statistical power meant statistically significant effects were limited to some taxa. We found little sign of publication bias; thus, our results are likely to be robust. In light of our quantitative assessment, methodological improvements and fruitful future avenues of research are highlighted.
|
|
| 41. |
|
|
| 42. |
|
|
| 43. |
- Wijnhoven, T. M. A., et al.
(author)
-
WHO European Childhood Obesity Surveillance Initiative 2008: weight, height and body mass index in 6-9-year-old children
- 2013
-
In: Pediatric Obesity. - : Wiley. - 2047-6310 .- 2047-6302. ; 8:2, s. 79-97
-
Journal article (peer-reviewed)abstract
- Background Nutritional surveillance in school-age children, using measured weight and height, is not common in the European Region of the World Health Organization (WHO). The WHO Regional Office for Europe has therefore initiated the WHO European Childhood Obesity Surveillance Initiative. Objective To present the anthropometric results of data collected in 2007/2008 and to investigate whether there exist differences across countries and between the sexes. Methods Weight and height were measured in 69-year-old children in 12 countries. Prevalence of overweight, obesity, stunting, thinness and underweight as well as mean Z-scores of anthropometric indices of height, weight and body mass index were calculated. Results A total of 168832 children were included in the analyses and a school participation rate of more than 95% was obtained in 8 out of 12 countries. Stunting, underweight and thinness were rarely prevalent. However, 19.349.0% of boys and 18.442.5% of girls were overweight (including obesity and based on the 2007 WHO growth reference).The prevalence of obesity ranged from 6.0 to 26.6% among boys and from 4.6 to 17.3% among girls. Multi-country comparisons suggest the presence of a northsouth gradient with the highest level of overweight found in southern European countries. Conclusions Overweight among 69-year-old children is a serious public health concern and its variation across the European Region highly depends on the country. Comparable monitoring of child growth is possible across Europe and should be emphasized in national policies and implemented as part of action plans.
|
|
| 44. |
|
|
