An Ig γ Marker Genotype Is a Strong Risk Factor for Alzheimer Disease, Independent of Apolipoprotein E ε4 Genotype.

Increasing evidence implicates HSV type 1 (HSV1) in the pathogenesis of late-onset Alzheimer disease (AD). HSV1 has evolved highly sophisticated strategies to evade host immunosurveillance. One strategy involves encoding a decoy Fcγ receptor (FcγR), which blocks Fc-mediated effector functions, such as Ab-dependent cellular cytotoxicity. Ig γ marker (GM) allotypes, encoded by highly polymorphic IGHG genes on chromosome 14q32, modulate this immunoevasion strategy, and thus may act as effect modifiers of the HSV1-AD association. In this nested case-control human study, 365 closely matched case-control pairs-whose blood was drawn on average 9.6 y before AD diagnosis-were typed for GM alleles by a TaqMan genotyping assay. APOE genotype and a genetic risk score based on nine additional previously known AD risk genes (ABCA7, BIN1, CD33, CLU, CR1, EPHA1, MS4A4E, NECTIN2, and PICALM) were extracted from a genome-wide association study analysis. Antiviral Abs were measured by ELISA. Conditional logistic regression models were applied. The distribution of GM 3/17 genotypes differed significantly between AD cases and controls, with higher frequency of GM 17/17 homozygotes in AD cases as compared with controls (19.8 versus 10.7%, p = 0.001). The GM 17/17 genotype was associated with a 4-fold increased risk of AD (odds ratio 4.142, p < 0.001). In conclusion, the results of this study demonstrate that Ig GM 17/17 genotype contributes to the risk of later AD development, independent of apolipoprotein ε4 genotype and other AD risk genes, and explain, at least in part, why every HSV1-infected person is not equally likely to develop HSV1-associated AD.

EAES rapid guideline: appendicitis in the elderly.

BACKGROUND: There is a lack of trustworthy evidence-informed guidelines on the diagnosis and management of acute appendicitis in elderly patients. METHODS: We developed a rapid guideline in accordance with GRADE and AGREE II standards. The steering group consisted of general surgeons, members of the EAES Research Committee/Guidelines Subcommittee with expertise and experience in guideline development, advanced medical statistics and evidence synthesis, biostatisticians, and a guideline methodologist. The guideline panel consisted of three general surgeons, an intensive care physician, a geriatrician and a patient advocate. We conducted systematic reviews and the results of evidence synthesis were summarized in evidence tables. Recommendations were authored and published through an online authoring and publication platform (MAGICapp), with the guideline panel making use of an evidence-to-decision framework and a Delphi process to arrive at consensus. RESULTS: This rapid guideline provides a weak recommendation against the use of clinical scoring systems to replace cross-sectional imaging in the diagnostic approach of suspected appendicitis in elderly patients. It provides a weak recommendation against the use of antibiotics alone over surgical treatment in patients who are deemed fit for surgery, and a weak recommendation for laparoscopic over open surgery. Furthermore, it provides a summary of surgery-associated risks in elderly patients. The guidelines, with recommendations, evidence summaries and decision aids in user-friendly formats can also be accessed in MAGICapp: https://app.magicapp.org/#/guideline/4494 . CONCLUSIONS: This rapid guideline provides evidence-informed trustworthy recommendations on the diagnosis and management of acute appendicitis in elderly patients.

Plasma concentrations of free amyloid ß cannot predict the development of Alzheimer's disease.

INTRODUCTION: Biomarkers that identify individuals at risk of Alzheimer's disease (AD) development would be highly valuable. Plasma concentration of amyloid ß (Aß)-central in the pathogenesis of AD-is a logical candidate, but studies to date have produced conflicting results on its utility. METHODS: Plasma samples from 339 preclinical AD cases (76.4% women, mean age 61.3 years) and 339 age- and sex-matched dementia-free controls, taken an average of 9.4 years before AD diagnosis, were analyzed using Luminex xMAP technology and INNO-BIA plasma Aß form assays to determine concentrations of free plasma Aß40 and Aß42. RESULTS: Plasma concentrations of free Aß40 and Aß42 did not differ between preclinical AD cases and dementia-free controls, in the full sample or in subgroups defined according to sex and age group (<60 and ≥ 60 years). The interval between sampling and AD diagnosis did not affect the results. Aß concentrations did not change in the years preceding AD diagnosis among individuals for whom longitudinal samples were available. DISCUSSION: Plasma concentrations of free Aß could not predict the development of clinical AD, and Aß concentrations did not change in the years preceding AD diagnosis in this sample. These results indicate that free plasma Aß is not a useful biomarker for the identification of individuals at risk of developing clinical AD.

Withdrawn: Plasma concentrations of free amyloid-ß cannot predict the development of Alzheimer's disease.

The Publisher regrets that this article is an accidental duplication of an article that has already been published, DOI of original article: http://dx.doi.org/10.1016/j.jalz.2016.12.004. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

Herpes simplex infection and the risk of Alzheimer's disease: A nested case-control study.

BACKGROUND: Herpes simplex virus (HSV) is thought to play an etiological role in the development of Alzheimer's disease (AD). METHODS: Plasma samples from 360 AD cases (75.3% women, mean age 61.2 years) and 360 age- and sex-matched dementia-free controls, taken on average 9.6 years before AD diagnosis, were analyzed for anti-HSV antibodies (immunoglobulin G, IgG, and immunoglobulin M, IgM) by enzyme-linked immunosorbent assays. RESULTS: In the complete sample group, the presence of anti-HSV IgG and IgM antibodies did not increase the risk of AD significantly (odds ratio (OR) 1.636, P = .069 and OR 1.368, P = .299, respectively). In cases with 6.6 years or more between plasma sampling and AD diagnosis (n = 270), there was a significant association between presence of anti-HSV IgG antibodies and AD (OR 2.250, P = .019). CONCLUSION: Among persons with a follow-up time of 6.6 years or more, HSV infection was significantly associated with AD.

The Consortium on Health and Ageing: Network of Cohorts in Europe and the United States (CHANCES) project--design, population and data harmonization of a large-scale, international study.

There is a public health demand to prevent health conditions which lead to increased morbidity and mortality among the rapidly-increasing elderly population. Data for the incidence of such conditions exist in cohort studies worldwide, which, however, differ in various aspects. The Consortium on Health and Ageing: Network of Cohorts in Europe and the United States (CHANCES) project aims at harmonizing data from existing major longitudinal studies for the elderly whilst focussing on cardiovascular diseases, diabetes mellitus, cancer, fractures and cognitive impairment in order to estimate their prevalence, incidence and cause-specific mortality, and identify lifestyle, socioeconomic, and genetic determinants and biomarkers for the incidence of and mortality from these conditions. A survey instrument assessing ageing-related conditions of the elderly will be also developed. Fourteen cohort studies participate in CHANCES with 683,228 elderly (and 150,210 deaths), from 23 European and three non-European countries. So far, 287 variables on health conditions and a variety of exposures, including biomarkers and genetic data have been harmonized. Different research hypotheses are investigated with meta-analyses. The results which will be produced can help international organizations, governments and policy-makers to better understand the broader implications and consequences of ageing and thus make informed decisions.

Longitudinal relationships between stress of conscience and concepts of importance.

The aim of this observational longitudinal cohort study was to describe relationships over time between degrees of stress of conscience, perceptions of conscience, burnout scores and assessments of person-centred climate and social support among healthcare personnel working in municipal care of older people. This study was performed among registered nurses and nurse assistants (n = 488). Data were collected on two occasions. Results show that perceiving one's conscience as a burden, having feelings of emotional exhaustion and depersonalization and noticing disturbing conflicts between co-workers were positively associated with stress of conscience. No significant changes were observed during the year under study, but degrees of stress of conscience and burnout scores were higher than in previous studies, suggesting that downsizing and increased workloads can negatively affect healthcare personnel. Following and expressing one's conscience in one's work, and perceiving social support from superiors are of importance in buffering the effects of stress of conscience.

PILRA polymorphism modifies the effect of APOE4 and GM17 on Alzheimer's disease risk.

PILRA (rs1859788 A > G) has been suggested to be a protective variant for Alzheimer's disease (AD) and is an entry co-receptor for herpes simplex virus-1. We conducted a nested case-control study of 360 1:1-matched AD subjects. Interactions between the PILRA-A allele, APOE risk variants (ε3/ε4 or ε4/ε4) and GM17 for AD risk were modelled. The associations were cross-validated using two independent whole-genome sequencing datasets. We found negative interactions between PILRA-A and GM17 (OR 0.72, 95% CI 0.52-1.00) and between PILRA-A and APOE risk variants (OR 0.56, 95% CI 0.32-0.98) in the discovery dataset. In the replication cohort, a joint effect of PILRA and PILRA × GM 17/17 was observed for the risk of developing AD (p .02). Here, we report a negative effect modification by PILRA on APOE and GM17 high-risk variants for future AD risk in two independent datasets. This highlights the complex genetics of AD.

Plasma Amyloid-ß in Relation to Antibodies Against Herpes Simplex Virus, Cytomegalovirus, and Chlamydophila pneumoniae.

BACKGROUND: Amyloid-ß (Aß), the key constituent of Alzheimer's disease (AD) plaques, has antimicrobial properties. OBJECTIVE: To investigate the association between plasma Aß and antibodies against the AD-related pathogens herpes simplex virus (HSV), cytomegalovirus (CMV), and C. pneumoniae. METHODS: Plasma from 339 AD cases, obtained on average 9.4 years (±4.00) before diagnosis, and their matched controls were analyzed for Aß40 and Aß42 concentrations with Luminex xMAP technology and INNOBIA plasma Aß-form assays. Enzyme-linked immunosorbent assays were utilized for analyses of anti-HSV immunoglobulin (Ig) G, anti-HSV1 IgG, anti-HSV2 IgG, anti-CMV IgG, and anti-C. pneumoniae IgG. Follow-up samples were available for 150 of the cases. RESULTS: Presence and levels of anti-HSV1 IgG, anti-HSV2 IgG, anti-CMV IgG, and anti-C. pneumoniae IgG did not correlate with concentrations of Aß42 or Aß40 in cases or controls. CONCLUSION: Levels of plasma Aß were not associated with antibodies against different AD-related pathogens.

Acute hyperglycaemia leads to altered frontal lobe brain activity and reduced working memory in type 2 diabetes.

How acute hyperglycaemia affects memory functions and functional brain responses in individuals with and without type 2 diabetes is unclear. Our aim was to study the association between acute hyperglycaemia and working, semantic, and episodic memory in participants with type 2 diabetes compared to a sex- and age-matched control group. We also assessed the effect of hyperglycaemia on working memory-related brain activity. A total of 36 participants with type 2 diabetes and 34 controls (mean age, 66 years) underwent hyperglycaemic clamp or placebo clamp in a blinded and randomised order. Working, episodic, and semantic memory were tested. Overall, the control group had higher working memory (mean z-score 33.15 ± 0.45) than the group with type 2 diabetes (mean z-score 31.8 ± 0.44, p = 0.042) considering both the placebo and hyperglycaemic clamps. Acute hyperglycaemia did not influence episodic, semantic, or working memory performance in either group. Twenty-two of the participants (10 cases, 12 controls, mean age 69 years) were randomly invited to undergo the same clamp procedures to challenge working memory, using 1-, 2-, and 3-back, while monitoring brain activity by blood oxygen level-dependent functional magnetic resonance imaging (fMRI). The participants with type 2 diabetes had reduced working memory during the 1- and 2-back tests. fMRI during placebo clamp revealed increased BOLD signal in the left lateral frontal cortex and the anterior cingulate cortex as a function of working memory load in both groups (3>2>1). During hyperglycaemia, controls showed a similar load-dependent fMRI response, whereas the type 2 diabetes group showed decreased BOLD response from 2- to 3-back. These results suggest that impaired glucose metabolism in the brain affects working memory, possibly by reducing activity in important frontal brain areas in persons with type 2 diabetes.

Perceptions of conscience, stress of conscience and burnout among nursing staff in residential elder care.

AIM: This paper is a report of a study of patterns of perceptions of conscience, stress of conscience and burnout in relation to occupational belonging among Registered Nurses and nursing assistants in municipal residential care of older people. BACKGROUND: Stress and burnout among healthcare personnel and experiences of ethical difficulties are associated with troubled conscience. In elder care the experience of a troubled conscience seems to be connected to occupational role, but little is known about how Registered Nurses and nursing assistants perceive their conscience, stress of conscience and burnout. METHOD: Results of previous analyses of data collected in 2003, where 50 Registered Nurses and 96 nursing assistants completed the Perceptions of Conscience Questionnaire, Stress of Conscience Questionnaire and Maslach Burnout Inventory, led to a request for further analysis. In this study Partial Least Square Regression was used to detect statistical predictive patterns. RESULT: Perceptions of conscience and stress of conscience explained 41.9% of the variance in occupational belonging. A statistical predictive pattern for Registered Nurses was stress of conscience in relation to falling short of expectations and demands and to perception of conscience as demanding sensitivity. A statistical predictive pattern for nursing assistants was perceptions that conscience is an authority and an asset in their work. Burnout did not contribute to the explained variance in occupational belonging. CONCLUSION: Both occupational groups viewed conscience as an asset and not a burden. Registered Nurses seemed to exhibit sensitivity to expectations and demands and nursing assistants used their conscience as a source of guidance in their work. Structured group supervision with personnel from different occupations is needed so that staff can gain better understanding about their own occupational situation as well as the situation of other occupational groups.

Burnout and perceptions of conscience among health care personnel: a pilot study.

Although organizational and situational factors have been found to predict burnout, not everyone employed at the same workplace develops it, suggesting that becoming burnt out is a complex, multifaceted phenomenon. The aim of this study was to elucidate perceptions of conscience, stress of conscience, moral sensitivity, social support and resilience among two groups of health care personnel from the same workplaces, one group on sick leave owing to medically assessed burnout (n = 20) and one group who showed no indications of burnout (n = 20). The results showed that higher levels of stress of conscience, a perception of conscience as a burden, having to deaden one's conscience in order to keep working in health care and perceiving a lack of support characterized the burnout group. Lower levels of stress of conscience, looking on life with forbearance, a perception of conscience as an asset and perceiving support from organizations and those around them (social support) characterized the non-burnout group.

Sociotechnical integration of decision support in the dementia domain.

The need for improving dementia care has driven the development of the clinical decision support system DMSS (Dementia Management and Support System). A sociotechnical approach to design and development has been applied, with an activity-centered methodology and user participation throughout the process. Prototypes have been developed based on the characteristics of clinical practice and domain knowledge, while clinical practice has been subjected to different efforts for development such as education and organizational change. This paper addresses the lessons learned and role and impact DMSS has had, and is expected to have on the clinical assessment of dementia in different clinics in Sweden, South Korea and Japan. Furthermore, it will be described in what way the development of DMSS and the development of dementia care in these three areas are interlinked. Results indicate that the most important contribution of DMSS at the point of care, is the educational support that DMSS provides, part from the tailored explanatory support related to a patient case. This effect was partly manifested in a change of routines in the encounter with patients.

A genetic signature including apolipoprotein Eε4 potentiates the risk of herpes simplex-associated Alzheimer's disease.

INTRODUCTION: Herpes simplex virus type 1 (HSV1) in combination with genetic susceptibility has previously been implicated in Alzheimer's disease (AD) pathogenesis. METHODS: Plasma from 360 AD cases, obtained on average 9.6 years before diagnosis, and their age- and sex-matched controls, were analyzed for anti-HSV1 immunoglobulin (Ig) G with enzyme-linked immunosorbent assays (ELISAs). A POE genotype and nine other selected risk genes for AD were extracted from a genome-wide association study analysis by deCODE genetics, Reykjavik, Iceland. RESULTS: The interaction between APOEε4 heterozygosity (APOEε2/ε4 or ε3/ε4) and anti-HSV1 IgG carriage increased the risk of AD (OR 4.55, P = .02). A genetic risk score based on the nine AD risk genes also interacted with anti-HSV1 IgG for the risk of developing AD (OR 2.35, P = .01). DISCUSSION: The present findings suggest that the APOEε4 allele and other AD genetic risk factors might potentiate the risk of HSV1-associated AD.

The Combined Effect of Cancer and Cardiometabolic Conditions on the Mortality Burden in Older Adults.

BACKGROUND: The number of older people living with cancer and cardiometabolic conditions is increasing, but little is known about how specific combinations of these conditions impact mortality. METHODS: A total of 22,692 participants aged 65 years and older from four international cohorts were followed-up for mortality for an average of 10 years (8,596 deaths). Data were harmonized across cohorts and mutually exclusive groups of disease combinations were created for cancer, myocardial infarction (MI), stroke, and diabetes at baseline. Cox proportional hazards models for all-cause mortality were used to estimate the age- and sex-adjusted hazard ratio and rate advancement period (RAP) (in years). RESULTS: At baseline, 23.6% (n = 5,116) of participants reported having one condition and 4.2% (n = 955) had two or more conditions. Data from all studies combined showed that the RAP increased with each additional condition. Diabetes advanced the rate of dying by the most years (5.26 years; 95% confidence interval [CI], 4.53-6.00), but the effect of any single condition was smaller than the effect of disease combinations. Some combinations had a significantly greater impact on the period by which the rate of death was advanced than others with the same number of conditions, for example, 10.9 years (95% CI, 9.4-12.6) for MI and diabetes versus 6.4 years (95% CI, 4.3-8.5) for cancer and diabetes. CONCLUSIONS: Combinations of cancer and cardiometabolic conditions accelerate mortality rates in older adults differently. Although most studies investigating mortality associated with multimorbidity used disease counts, these provide little guidance for managing complex patients as they age.

Stress of conscience and perceptions of conscience in relation to burnout among care-providers in older people.

AIMS: The aim was to study the relationship between conscience and burnout among care-providers in older care, exploring the relationship between stress of conscience and burnout, and between perceptions of conscience and burnout. BACKGROUND: Everyday work in healthcare presents situations that influence care-providers' conscience. How care-providers perceive conscience has been shown to be related to stress of conscience (stress related to troubled conscience), and in county council care, an association between stress of conscience and burnout has been found. METHOD: A questionnaire study was conducted in municipal housing for older people. A total of 166 care-providers were approached, of which 146 (50 registered nurses and 96 nurses' aides/enrolled nurses) completed a questionnaire folder containing the stress of conscience questionnaire, the perceptions of conscience questionnaire and the maslach burnout inventory. Multivariate canonical correlation analysis was used to explore relationships. RESULT: The relationship between stress of conscience and burnout indicates that experiences of shortcomings and of being exposed to contradictory demands are strongly related to burnout (primarily to emotional exhaustion). The relationship between perceptions of conscience and burnout indicates that a deadened conscience is strongly related to burnout. CONCLUSION: Conscience seems to be of importance in relation to burnout, and suppressing conscience may result in a profound loss of wholeness, integrity and harmony in the self. RELEVANCE TO CLINICAL PRACTICE: The results from our study could be used to raise awareness of the importance of conscience in care.

Factors associated with 'stress of conscience' in healthcare.

AIM: The main purpose of this study was to examine factors related to 'stress of conscience' i.e. stress related to a troubled conscience in healthcare. METHODS: A series of questionnaires was completed by 423 healthcare employees in northern Sweden as part of this cross-sectional study. The series of questionnaires comprised the 'Stress of Conscience Questionnaire', 'Perception of Conscience Questionnaire', 'Revised Moral Sensitivity Questionnaire', Social Interactions Scale, Resilience Scale and a Personal/Work Demographic form. RESULTS: Nonautomatic stepwise regression analysis with forward inclusion resulted in a model that explained approximately 39.6% of the total variation in stress of conscience. Individual items associated with stress of conscience were; perceiving that conscience warns us against hurting others while at the same time not being able to follow one's conscience at work and having to deaden one's conscience to keep working in healthcare. In addition moral sensitivity items belonging to the factor 'sense of moral burden' were; one's ability to sense patient's needs means that one is doing more than one has strength for, having difficulty to deal with feelings aroused when a patient is suffering and one's ability to sense patient's needs means feeling inadequate all added significantly to the model. In addition, deficient social support from superiors, low levels of resilience and working in internal medicine wards were all associated with stress of conscience. CONCLUSION: Healthcare employees seem to experience stress of conscience in their everyday practise. Particular contributing factors are not being able to follow one's conscience at work, and the 'negative' dimension of moral sensitivity - moral burden - which is an inability to deal with moral problems. Thus, in order for conscience and moral sensitivity to become an asset instead of a burden, healthcare employees need to be able to express their moral concerns.