Mapping Neutralizing and Immunodominant Sites on the SARS-CoV-2 Spike Receptor-Binding Domain by Structure-Guided High-Resolution Serology.

Analysis of the specificity and kinetics of neutralizing antibodies (nAbs) elicited by SARS-CoV-2 infection is crucial for understanding immune protection and identifying targets for vaccine design. In a cohort of 647 SARS-CoV-2-infected subjects, we found that both the magnitude of Ab responses to SARS-CoV-2 spike (S) and nucleoprotein and nAb titers correlate with clinical scores. The receptor-binding domain (RBD) is immunodominant and the target of 90% of the neutralizing activity present in SARS-CoV-2 immune sera. Whereas overall RBD-specific serum IgG titers waned with a half-life of 49 days, nAb titers and avidity increased over time for some individuals, consistent with affinity maturation. We structurally defined an RBD antigenic map and serologically quantified serum Abs specific for distinct RBD epitopes leading to the identification of two major receptor-binding motif antigenic sites. Our results explain the immunodominance of the receptor-binding motif and will guide the design of COVID-19 vaccines and therapeutics.

Social determinants of health but not global genetic ancestry predict dementia prevalence in Latin America.

INTRODUCTION: Leveraging the nonmonolithic structure of Latin America, which represents a large variability in social determinants of health (SDoH) and high levels of genetic admixture, we aim to evaluate the relative contributions of SDoH and genetic ancestry in predicting dementia prevalence in Latin American populations. METHODS: Community-dwelling participants aged 65 and older (N = 3808) from Cuba, Dominican Republic, Mexico, and Peru completed the 10/66 protocol assessments. Dementia was diagnosed using the cross-culturally validated 10/66 algorithm. Multivariate linear regression models adjusted for SDoH were used in the main analysis. This study used cross-sectional data from the 1066 population-based study. RESULTS: Individuals with higher proportions of Native American (>70%) and African American (>70%) ancestry were more likely to exhibit factors contributing to worse SDoH, such as lower educational levels (p < 0.001), lower socioeconomic status (p < 0.001), and higher frequency of vascular risk factors (p < 0.001). After adjusting for measures of SDoH, there was no association between ancestry proportion and dementia probability, and ancestry proportions no longer significantly accounted for the variance in cognitive performance (African predominant p = 0.31 [-0.19, 0.59] and Native predominant p = 0.74 [-0.24, 0.33]). DISCUSSION: The findings suggest that social and environmental factors play a more crucial role than genetic ancestry in predicting dementia prevalence in Latin American populations. This underscores the need for public health strategies and policies that address these social determinants to effectively reduce dementia risk in these communities. HIGHLIGHTS: Countries in Latin America express a large variability in social determinants of health and levels of admixture. After adjustment for downstream societal factors linked to SDoH, genetic ancestry shows no link to dementia. Population ancestry profiles alone do not influence cognitive performance. SDoH are key drivers of racial disparities in dementia and cognitive performance.

Seroprevalence trends of anti-SARS-CoV-2 antibodies and associated risk factors: a population-based study.

PURPOSE: We aimed to assess the seroprevalence trends of SARS-CoV-2 antibodies in several Swiss cantons between May 2020 and September 2021 and investigate risk factors for seropositivity and their changes over time. METHODS: We conducted repeated population-based serological studies in different Swiss regions using a common methodology. We defined three study periods: May-October 2020 (period 1, prior to vaccination), November 2020-mid-May 2021 (period 2, first months of the vaccination campaign), and mid-May-September 2021 (period 3, a large share of the population vaccinated). We measured anti-spike IgG. Participants provided information on sociodemographic and socioeconomic characteristics, health status, and adherence to preventive measures. We estimated seroprevalence with a Bayesian logistic regression model and the association between risk factors and seropositivity with Poisson models. RESULTS: We included 13,291 participants aged 20 and older from 11 Swiss cantons. Seroprevalence was 3.7% (95% CI 2.1-4.9) in period 1, 16.2% (95% CI 14.4-17.5) in period 2, and 72.0% (95% CI 70.3-73.8) in period 3, with regional variations. In period 1, younger age (20-64) was the only factor associated with higher seropositivity. In period 3, being aged ≥ 65 years, with a high income, retired, overweight or obese or with other comorbidities, was associated with higher seropositivity. These associations disappeared after adjusting for vaccination status. Seropositivity was lower in participants with lower adherence to preventive measures, due to a lower vaccination uptake. CONCLUSIONS: Seroprevalence sharply increased over time, also thanks to vaccination, with some regional variations. After the vaccination campaign, no differences between subgroups were observed.

Changes in socioeconomic resources and mental health after the second COVID-19 wave (2020-2021): a longitudinal study in Switzerland.

BACKGROUND: During the 2020/2021 winter, the labour market was under the impact of the COVID-19 pandemic. Changes in socioeconomic resources during this period could have influenced individual mental health. This association may have been mitigated or exacerbated by subjective risk perceptions, such as perceived risk of getting infected with SARS-CoV-2 or perception of the national economic situation. Therefore, we aimed to determine if changes in financial resources and employment situation during and after the second COVID-19 wave were prospectively associated with depression, anxiety and stress, and whether perceptions of the national economic situation and of the risk of getting infected modified this association. METHODS: One thousand seven hundred fifty nine participants from a nation-wide population-based eCohort in Switzerland were followed between November 2020 and September 2021. Financial resources and employment status were assessed twice (Nov2020-Mar2021, May-Jul 2021). Mental health was assessed after the second measurement of financial resources and employment status, using the Depression, Anxiety and Stress Scale (DASS-21). We modelled DASS-21 scores with linear regression, adjusting for demographics, health status, social relationships and changes in workload, and tested interactions with subjective risk perceptions. RESULTS: We observed scores above thresholds for normal levels for 16% (95%CI = 15-18) of participants for depression, 8% (95%CI = 7-10) for anxiety, and 10% (95%CI = 9-12) for stress. Compared to continuously comfortable or sufficient financial resources, continuously precarious or insufficient resources were associated with worse scores for all outcomes. Increased financial resources were associated with higher anxiety. In the working-age group, shifting from full to part-time employment was associated with higher stress and anxiety. Perceiving the Swiss economic situation as worrisome was associated with higher anxiety in participants who lost financial resources or had continuously precarious or insufficient resources. CONCLUSION: This study confirms the association of economic stressors and mental health during the COVID-19 pandemic and highlights the exacerbating role of subjective risk perception on this association.

Prevalence and association of frailty with SARS-CoV-2 infection in older adults in Southern Switzerland-Findings from the Corona Immunitas Ticino Study.

BACKGROUND: Frailty is an age-associated state of increased vulnerability to stressors that strongly predicts poor health outcomes. Epidemiological evidence on frailty is limited during the COVID-19 pandemic, and whether frailty is associated with the risk of infection is unknown. OBJECTIVES: We derived a robust Frailty Index (FI) to measure the prevalence of frailty and its risk factors in community-dwelling older adults in Southern Switzerland (Ticino), and we explored the association between frailty and serologically confirmed SARS-CoV-2 infection. METHODS: In September 2020, we recruited a random sample of community-dwelling older adults (65 +) in the Corona Immunitas Ticino prospective cohort study (CIT) and assessed a variety of lifestyle and health characteristics. We selected 30 health-related variables, computed the Rockwood FI, and applied standard thresholds for robust (FI < 0.1), pre-frail (0.1 ≤ FI < 0.21), and frail (FI ≥ 0.21). RESULTS: Complete data for the FI was available for 660 older adults. The FI score ranged between zero (no frailty) and 0.59. The prevalence of frailty and pre-frailty were 10.3% and 48.2% respectively. The log-transformed FI score increased by age similarly in males and females, on average by 2.8% (p < 0.001) per one-year increase in age. Out of 481 participants with a valid serological test, 11.2% were seropositive to either anti-SARS-CoV-2 IgA or IgG. The frailty status and seropositivity were not statistically associated (p = 0.236). CONCLUSION: Advanced age increases the risk of frailty. The risk of COVID-19 infection in older adults may not differ by frailty status.

Associations of multilingualism and language proficiency with cognitive functioning: epidemiological evidence from the SwissDEM study in community dwelling older adults and long-term care residents.

BACKGROUND: We explored whether number of languages spoken and language proficiency are associated with cognitive performance among older adults living in the community and in long-term care (LTC) in Switzerland. METHODS: Among study participants, 664 lived in the community in the Canton of Zurich (Mean age = 72.97 years; SD = 6.08), 386 lived in the community in Ticino (Mean age = 76.24 years; SD = 6.66), and 176 resided in LTC in Ticino (Mean age = 87.61 years; SD = 6.45). We recorded sociodemographic variables, number of languages spoken, language proficiency, and assessed overall cognitive performance, immediate and delayed memory, and verbal fluency with standardized tests. We used adjusted regression models. RESULTS: A higher number of spoken languages was positively associated with overall cognitive performance, verbal fluency and immediate and delayed memory performance in community-dwelling older adults in the Cantons of Ticino and Zurich, (all p values ≤ 0.012;), but not in in older adults living in LTC homes (all p values ≥ 0.35). Higher language proficiency was associated with better memory performance among individuals living in the community in Ticino (p value = 0.003), and to better performance in verbal fluency and memory tasks in Zurich (p values ≤ 0.002). Among LTC residents, proficiency levels were not associated with cognitive performance. CONCLUSIONS: Multilingualism and greater language proficiency were associated with better cognitive functioning in community-dwelling but not in institutionalized older adults. Multilingualism may contribute to cognitive reserve, as well as protect and delay cognitive decline in late life.

Physician-reported characteristics, representations, and ethical justifications of shared decision-making practices in the care of paediatric patients with prolonged disorders of consciousness.

BACKGROUND: Despite consensus about the importance of implementing shared decision-making (SDM) in clinical practice, this ideal is inconsistently enacted today. Evidence shows that SDM practices differ in the degree of involvement of patients or family members, or in the amount of medical information disclosed to patients in order to "share" meaningfully in treatment decisions. Little is known on which representations and moral justifications physicians hold when realizing SDM. This study explored physicians' experiences of SDM in the management of paediatric patients with prolonged disorders of consciousness (PDOC). Specifically, we focused on physicians' SDM approaches, representations, and ethical justifications for engaging in SDM. METHODS: We used a qualitative approach to explore the SDM experiences of 13 ICU physicians, paediatricians, and neurologists based in Switzerland who have been or were involved in the care of paediatric patients living with PDOC. A semi-structured interview format was used and interviews were audio-recorded and transcribed. Data were analysed through thematic analysis. RESULTS: We found that participants followed three main decision-making approaches: the "brakes" approach, characterized by maximized family's decisional freedom, though conditional to physician's judgment regarding the medical appropriateness of a treatment; the "orchestra director" approach, characterized by a multi-step decision-making process led by the main physician aimed at eliciting the voices of the care team members and of the family; and the "sunbeams" approach, characterized by a process oriented to reach consensus with family members through dialogue, where the virtues of the physician are key to guide the process. We also found that participants differed in the moral justifications sustaining each approach, citing the duty to respect parental autonomy, to invest in an ethics of care, and to employ physicians' virtues to guide the decision-making process. CONCLUSION: Our results show that physicians come to perform SDM in different ways, with several representations, and distinct ethical justifications. SDM training among health care providers should clarify the ductility of SDM and the several ethical motivations underpinning it, rather than insisting on the principle of respect for patient's autonomy as its only moral foundation.

Older adults' experiences of restrictive measures during the early stages of the COVID-19 pandemic in Southern Switzerland: Evidence from the Corona Immunitas Ticino study.

From the outset of the pandemic, Swiss federal authorities implemented numerous public health measures to contain the spread of SARS-CoV-2. In southern Switzerland, Canton Ticino legislated additional measures, some of which specifically targeted people aged 65 and over. We assessed how older adults perceived and experienced the introduction of these age-specific measures using data from a large, randomized sample of community-dwelling older adults aged 65+ collected between October 2020 and February 2021. We analyzed 788 open-ended responses on the experience of the introduction of the measures using a qualitative thematic analysis. At the individual level, 45% of the sample had a mostly positive experience, 29% had a mostly negative experience, 10% identified positive and negative aspects and 16% reported neither. We next assessed factors distinguishing the different types of experiences using bivariate and multivariate models. Older adults who were younger, unpartnered, had lower levels of education and higher levels of depressive symptoms and loneliness were more likely to report negative experiences. Our findings suggest the need to provide clear communication to older adults that accounts for the heterogeneity of this population, and to consider the potential for policies to have negative implications for those with fewer personal resources.

Is living in a household with children associated with SARS-CoV-2 seropositivity in adults? Results from the Swiss national seroprevalence study Corona Immunitas.

BACKGROUND: We aimed to determine whether living in a household with children is associated with SARS-CoV-2 seropositivity in adults and investigated interacting factors that may influence this association. METHODS: SARS-CoV-2 serology testing was performed in randomly selected individuals from the general population between end of October 2020 and February 2021 in 11 cantons in Switzerland. Data on sociodemographic and household characteristics, employment status, and health-related history was collected using questionnaires. Multivariable logistic regression was used to examine the association of living with children <18 years of age (number, age group) and SARS-CoV-2 seropositivity. Further, we assessed the influence of reported non-household contacts, employment status, and gender. RESULTS: Of 2393 working age participants (18-64 years), 413 (17.2%) were seropositive. Our results suggest that living with children and SARS-CoV-2 seropositivity are likely to be associated (unadjusted odds ratio (OR) 1.22, 95% confidence interval [0.98-1.52], adjusted OR 1.25 [0.99-1.58]). A pattern of a positive association was also found for subgroups of children aged 0-11 years (OR 1.21 [0.90-1.60]) and 12-17 years (OR 1.14 [0.78-1.64]). Odds of seropositivity were higher with more children (OR 1.14 per additional child [1.02-1.27]). Men had higher risk of SARS-CoV-2 infection when living with children than women (interaction: OR 1.74 [1.10-2.76]). CONCLUSIONS: In adults from the general population living with children seems associated with SARS-CoV-2 seropositivity. However, child-related infection risk is not the same for every subgroup and depends on factors like gender. Further factors determining child-related infection risk need to be identified and causal links investigated. TRIAL REGISTRATION: https://www.isrctn.com/ISRCTN18181860 .

Physicians' decision-making when managing pediatric patients with prolonged disorders of consciousness: A qualitative study.

BACKGROUND AND PURPOSE: Advances in medicine have resulted in treatments that can extend the survival of patients with prolonged disorders of consciousness (PDOC) for several years. However, several diagnostic and prognostic uncertainties remain, particularly in the care of pediatric patients. In the absence of international guidelines, we aimed to explore physicians' decision-making when managing pediatric patients with PDOC. METHODS: We conducted a qualitative study using semistructured, individual interviews and employed an inductive thematic analytical approach to explore physicians' subjective experiences and decision-making when managing pediatric patients with PDOC. We recruited a purposive sample of 19 Italian-speaking physicians currently or previously employed in intensive care units or pediatric, internal medicine, or neurology departments in Switzerland. RESULTS: Participants stated that making clinical decisions involving pediatric patients with PDOC is extremely challenging, because the decisional process requires finding a balance between several contending factors. We found that physicians experienced ambivalence in three domains of care (time, goals of care, and target of care), and that they were aware of the risk of self-fulfilling prophecies for both prognosis and main clinical outcomes. CONCLUSIONS: Our study confirmed that experienced clinicians acknowledge the complex nature and challenge of clinical decision-making in the care of pediatric patients with PDOC. More research is warranted to improve and expand existing guidelines aimed at assisting and facilitating clinical and ethical decision-making, and improving physicians' awareness of the factors affecting their decisions when dealing with patients with PDOC.

Effectiveness of crisis resolution home treatment for the management of acute psychiatric crises in Southern Switzerland: a natural experiment based on geography.

BACKGROUND: Crisis Resolution Home Treatment (CRHT) is an alternative to inpatient treatment for acute psychiatric crises management. However, evidence on CRHT effectiveness is still limited. In the Canton of Ticino (Southern Switzerland), in 2016 the regional public psychiatric hospital replaced one acute ward with a CRHT. The current study was designed within this evaluation setting to assess the effectiveness of CRHT compared to standard inpatient treatment. METHODS: CRHT was offered to patients aged 18 to 65 with an acute psychiatric crisis that would have required hospitalization. We used a natural experiment based on geography, where intervention and control groups were formed according to the place of residence. Primary endpoints were reduction of psychiatric symptoms at discharge measured using the Health of the Nation Outcome Scales, treatment duration in days, and rate and length of readmissions during a two-year follow-up period after discharge. Safety during the treatment period was measured with the number of serious adverse events (suicide/suicide attempts, major self-harm episodes, acute alcohol/drug intoxications, aggressions to caregivers or family members). We used linear, log-linear and logistic regression models with propensity scores for the main analysis. RESULTS: We enrolled 321 patients; 67 were excluded because the treatment period was too short and 17 because they were transferred before the end of the treatment. Two hundred thirty-seven patients were available for data analysis, 93 in the intervention group and 144 in the control group. No serious adverse event was observed during the treatment period in both groups. Reduction of psychiatric symptoms at discharge (p-value = 0.359), readmission rates (p-value = 0.563) and length of readmissions (p-value = 0.770) during the two-year follow-up period did not differ significantly between the two groups. Treatment duration was significantly higher in the treatment group (+ 29.6% on average, p-value = 0.002). CONCLUSIONS: CRHT was comparable to standard hospitalization in terms of psychiatric symptoms reduction, readmission rates and length of readmissions, but it was also characterized by a longer first treatment period. However, observational evidence following the study indicated that CRHT duration constantly lowered over time since its introduction in 2016 and became comparable to hospitalization, showing therefore to be an effective alternative also in terms of treatment length. TRIAL REGISTRATION: ISRCTN38472626 (17/11/2020, retrospectively registered).

Caregivers of people with dementia and mental health during COVID-19: findings from a cross-sectional study.

BACKGROUND: There is sparse evidence on the impact on vulnerable populations of the COVID-19 pandemic. The aim of our study was to explore burden and mental wellbeing (including depressive, anxiety, and stress symptoms) in caregivers of people with dementia during the first wave of the pandemic in Italy and southern Switzerland, two bordering regions severely hit by the COVID-19 pandemic. METHODS: We conducted an online cross-sectional survey with family carers of people with dementia between May and June 2020. We registered socio-demographic characteristics, and information about the relationship with the care recipient, dementia subtype, care inputs from others, and the need of care of the person with dementia. We measured caregiver burden with the Zarit Burden Interview (ZBI), psychological distress with the Depression, Anxiety and Stress Scale (DASS-21), and perceived isolation with the 3-item UCLA Loneliness Scale (UCLALS3). RESULTS: Caregivers (N =571) reported moderate to severe care-related burden (mean=54.30; SD=18.33), moderate anxiety symptoms (mean=10.04; SD=6.93), mild depressive symptoms (mean=11.79; SD=6.12) and mild stress (mean=12.95; SD=5.53), and 72.3% of participants reported to feel lonely. All scores were significantly more severe in Swiss compared to Italian caregivers (all p values<0.001). CONCLUSIONS: We found that caregivers' burden, anxiety symptoms, depression and perceived loneliness were marked during the first wave of the COVID-19 pandemic, in two severely hit bordering countries. Regional differences in the impact of the epidemic on caregivers could be due to contextual, societal, and cultural circumstances. As the pandemic endures, support to caregivers of people with dementia should be proportionate and tailored to needs and adapted to contextual factors.

Dementia is (not) a natural part of ageing: a cross-sectional study on dementia knowledge and misconceptions in Swiss and Italian young adults, adults, and older adults.

BACKGROUND: Increasing public awareness and understanding of dementia is the second key action area of the 2017 WHO Global action plan on a public health response to dementia. To achieve this aim, the first indispensable step is to understand the average level of dementia knowledge and to identify areas of low dementia knowledge. We aimed to quantify dementia knowledge in the general population, and to explore the extent to which it differs by age, sex, education, and indirect experience with dementia. METHODS: We conducted an online cross-sectional survey in two Italian-speaking sites, south Switzerland (Ticino) and northern Italy (Piedmont). The survey was distributed between September and December 2019. We registered socio-demographic characteristics including whether the participant had contact with a person living with dementia, and measured dementia knowledge with the Dementia Knowledge Assessment Survey (DKAS). RESULTS: Misconceptions about dementia were common among respondents, and lack of knowledge has been identified in dementia causes, characteristics, risk factors, and health promotion. Our results point out the lack of knowledge about how to communicate and relate with, and take care of a person living with dementia. The overall DKAS score was significantly and positively associated with female sex (ß = 0.21; p < 0.001), educational level (ß = 0.15; p < 0.001) and contact with a person living with dementia (ß = 0.17; p < 0.001), but not with age (ß = -0.01; p = 0.57). CONCLUSION: Our results confirmed that general population's knowledge of dementia is thin. Interventional studies that rely on participatory action research methods are warranted to co-design interventions aimed at improving dementia knowledge and understanding in the public.

Digital Platform Uses for Help and Support Seeking of Parents With Children Affected by Disabilities: Scoping Review.

BACKGROUND: Receiving a diagnosis that leads to severe disability in childhood can cause a traumatic experience with long-lasting emotional stress for patients and family members. In recent decades, emerging digital technologies have transformed how patients or caregivers of persons with disabilities manage their health conditions. As a result, information (eg, on treatment and resources) has become widely available to patients and their families. Parents and other caregivers can use digital platforms such as websites or social media to derive social support, usually from other patients and caregivers who share their lived experiences, challenges, and successes on these platforms. However, gaps remain in our understanding of platforms that are most frequently used or preferred among parents and caregivers of children with disabilities. In particular, it is not clear what factors primarily drive or discourage engagement with these digital tools and what the main ethical considerations are in relation to these tools. OBJECTIVE: We aimed to (1) identify prominent digital platforms used by parents or caregivers of children with disabilities; (2) explore the theoretical contexts and reasons for digital platform use, as well as the experiences made with using these platforms reported in the included studies; and (3) identify any privacy and ethical concerns emerging in the available literature in relation to the use of these platforms. METHODS: We conducted a scoping review of 5 academic databases of English-language articles published within the last 10 years for diseases with childhood onset disability and self-help or parent/caregiver-led digital platforms. RESULTS: We identified 17 papers in which digital platforms used by parents of affected children predominantly included social media elements but also search engines, health-related apps, and medical websites. Information retrieval and social support were the main reasons for their utilization. Nearly all studies were exploratory and applied either quantitative, qualitative, or mixed methods. The main ethical concerns for digital platform users included hampered access due to language barriers, privacy issues, and perceived suboptimal advice (eg, due to missing empathy of medical professionals). Older and non-college-educated individuals and ethnic minorities appeared less likely to access information online. CONCLUSIONS: This review showed that limited scientifically sound knowledge exists on digital platform use and needs in the context of disabling conditions in children, as the evidence consists mostly of exploratory studies. We could highlight that affected families seek information and support from digital platforms, as health care systems seem to be insufficient for satisfying knowledge and support needs through traditional channels.

Functional immunity against SARS-CoV-2 in the general population after a booster campaign and the Delta and Omicron waves, Switzerland, March 2022.

Functional immunity (defined here as serum neutralising capacity) critically contributes to conferring protection against SARS-CoV-2 infection and severe COVID-19. This cross-sectional analysis of a prospective, population-based cohort study included 1,894 randomly-selected 16 to 99-year-old participants from two Swiss cantons in March 2022. Of these, 97.6% (95% CI: 96.8-98.2%) had anti-spike IgG antibodies, and neutralising capacity was respectively observed for 94%, 92% and 88% against wild-type SARS-CoV-2, Delta and Omicron variants. Studying functional immunity to inform and monitor vaccination campaigns is crucial.

Harmonizing neuropsychological assessment for mild neurocognitive disorders in Europe.

INTRODUCTION: Harmonized neuropsychological assessment for neurocognitive disorders, an international priority for valid and reliable diagnostic procedures, has been achieved only in specific countries or research contexts. METHODS: To harmonize the assessment of mild cognitive impairment in Europe, a workshop (Geneva, May 2018) convened stakeholders, methodologists, academic, and non-academic clinicians and experts from European, US, and Australian harmonization initiatives. RESULTS: With formal presentations and thematic working-groups we defined a standard battery consistent with the U.S. Uniform DataSet, version 3, and homogeneous methodology to obtain consistent normative data across tests and languages. Adaptations consist of including two tests specific to typical Alzheimer's disease and behavioral variant frontotemporal dementia. The methodology for harmonized normative data includes consensus definition of cognitively normal controls, classification of confounding factors (age, sex, and education), and calculation of minimum sample sizes. DISCUSSION: This expert consensus allows harmonizing the diagnosis of neurocognitive disorders across European countries and possibly beyond.

The strategic biomarker roadmap for the validation of Alzheimer's diagnostic biomarkers: methodological update.

BACKGROUND: The 2017 Alzheimer's disease (AD) Strategic Biomarker Roadmap (SBR) structured the validation of AD diagnostic biomarkers into 5 phases, systematically assessing analytical validity (Phases 1-2), clinical validity (Phases 3-4), and clinical utility (Phase 5) through primary and secondary Aims. This framework allows to map knowledge gaps and research priorities, accelerating the route towards clinical implementation. Within an initiative aimed to assess the development of biomarkers of tau pathology, we revised this methodology consistently with progress in AD research. METHODS: We critically appraised the adequacy of the 2017 Biomarker Roadmap within current diagnostic frameworks, discussed updates at a workshop convening the Alzheimer's Association and 8 leading AD biomarker research groups, and detailed the methods to allow consistent assessment of aims achievement for tau and other AD diagnostic biomarkers. RESULTS: The 2020 update applies to all AD diagnostic biomarkers. In Phases 2-3, we admitted a greater variety of study designs (e.g., cross-sectional in addition to longitudinal) and reference standards (e.g., biomarker confirmation in addition to clinical progression) based on construct (in addition to criterion) validity. We structured a systematic data extraction to enable transparent and formal evidence assessment procedures. Finally, we have clarified issues that need to be addressed to generate data eligible to evidence-to-decision procedures. DISCUSSION: This revision allows for more versatile and precise assessment of existing evidence, keeps up with theoretical developments, and helps clinical researchers in producing evidence suitable for evidence-to-decision procedures. Compliance with this methodology is essential to implement AD biomarkers efficiently in clinical research and diagnostics.

Returning individual-specific results of a dementia prevalence study: insights from prospective participants living in Switzerland.

OBJECTIVES: To explore prospective participants' preferences regarding the return of their individual-specific results from a dementia prevalence study (a probabilistic diagnosis of dementia). METHODS/DESIGN: We conducted a qualitative study with 22 individuals aged 45 to 86 and resident in the Canton of Ticino (Switzerland). Participants had previously joined the validation phase of an epidemiological study into dementia and its impact. RESULTS: We found that individuals welcome the return of their individual-specific results, provided these meet a number of validity, clinical, and personal utility criteria. They justify researchers' duty to return study findings with the principles of beneficence (eg, providing information that can help participants' medical decision-making) and justice (eg, acknowledging participants' efforts to help research by sharing their personal information). Furthermore, individuals anticipate societal benefits of the return of individual specific study findings, including improved interpersonal relationships among individuals and decreased dementia-related stigma. CONCLUSIONS: Our findings suggest that researchers should address the return of individual-specific study results early on during study design and involve prospective participants in identifying both the conditions under which results should be offered and the perceived individual and societal benefits returning can have.

Redesigning care for older people to preserve physical and mental capacity: WHO guidelines on community-level interventions in integrated care.

Islene Araujo de Carvalho and coauthors discuss the WHO guidelines on integrated care for older people.

Population Neuroscience: Dementia Epidemiology Serving Precision Medicine and Population Health.

Over recent decades, epidemiology has made significant contributions to our understanding of dementia, translating scientific discoveries into population health. Here, we propose reframing dementia epidemiology as "population neuroscience," blending techniques and models from contemporary neuroscience with those of epidemiology and biostatistics. On the basis of emerging evidence and newer paradigms and methods, population neuroscience will minimize the bias typical of traditional clinical research, identify the relatively homogenous subgroups that comprise the general population, and investigate broader and denser phenotypes of dementia and cognitive impairment. Long-term follow-up of sufficiently large study cohorts will allow the identification of cohort effects and critical windows of exposure. Molecular epidemiology and omics will allow us to unravel the key distinctions within and among subgroups and better understand individuals' risk profiles. Interventional epidemiology will allow us to identify the different subgroups that respond to different treatment/prevention strategies. These strategies will inform precision medicine. In addition, insights into interactions between disease biology, personal and environmental factors, and social determinants of health will allow us to measure and track disease in communities and improve population health. By placing neuroscience within a real-world context, population neuroscience can fulfill its potential to serve both precision medicine and population health.