Reduced Cortical Thickness Correlates of Cognitive Dysfunction in Post-COVID-19 Condition: Insights from a Long-Term Follow-up.

BACKGROUND AND PURPOSE: There is a paucity of data on long-term neuroimaging findings from individuals who have developed the post-coronavirus 2019 (COVID-19) condition. Only 2 studies have investigated the correlations between cognitive assessment results and structural MR imaging in this population. This study aimed to elucidate the long-term cognitive outcomes of participants with the post-COVID-19 condition and to correlate these cognitive findings with structural MR imaging data in the post-COVID-19 condition. MATERIALS AND METHODS: A cohort of 53 participants with the post-COVID-19 condition underwent 3T brain MR imaging with T1 and FLAIR sequences obtained a median of 1.8 years after Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) infection. A comprehensive neuropsychological battery was used to assess several cognitive domains in the same individuals. Correlations between cognitive domains and whole-brain voxel-based morphometry were performed. Different ROIs from FreeSurfer were used to perform the same correlations with other neuroimaging features. RESULTS: According to the Frascati criteria, more than one-half of the participants had deficits in the attentional (55%, n = 29) and executive (59%, n = 31) domains, while 40% (n = 21) had impairment in the memory domain. Only 1 participant (1.89%) showed problems in the visuospatial and visuoconstructive domains. We observed that reduced cortical thickness in the left parahippocampal region (t(48) = 2.28, P = .03) and the right caudal-middle-frontal region (t(48) = 2.20, P = .03) was positively correlated with the memory domain. CONCLUSIONS: Our findings suggest that cognitive impairment in individuals with the post-COVID-19 condition is associated with long-term alterations in the structure of the brain. These macrostructural changes may provide insight into the nature of cognitive symptoms.

Protective role of SARS-CoV-2 anti-S IgG against breakthrough infections among European healthcare workers during pre and post-Omicron surge-ORCHESTRA project.

PURPOSE: Anti SARS-CoV-2 vaccination initially showed high effectiveness in preventing COVID-19. However, after the surge of variants of concern, the effectiveness dropped. Several studies investigated if this was related to the decrease of the humoral response over time; however, this issue is still unclear. The aim of this study was to understand whether SARS-CoV-2 anti-S IgG levels can be used to predict breakthrough infection risk and define the timing for further booster doses administration. METHOD: Within the framework of the ORCHESTRA Project, over 20,000 health workers from 11 European centers were enrolled since December 2020. We performed two Cox proportional hazards survival analyses regarding pre-Omicron (from January to July 2021) and Omicron (December 2021-May 2022) periods. The serological response was classified as high (above the 75th percentile), medium (25th-75th), or low (< 25th). RESULTS: Seventy-four (0.33%) and 2122 (20%) health workers were infected during the first and second periods, respectively. Both Cox analyses showed that having high anti-S titer was linked to a significantly lower risk of infection as compared to having medium serological response [HR of high vs medium anti-S titer = 0.27 (95% CI 0.11-0.66) during the first phase, HR = 0.76 (95% CI 0.62-0.93) during the second phase]. CONCLUSION: Vaccine effectiveness wanes significantly after new variants surge, making anti-S titer unsuitable to predict optimal timing for further booster dose administration. Studies on other immunological indicators, such as cellular immunity, are therefore needed to better understand the mechanisms and duration of protection against breakthrough infection risk.

Determinants of Anti-S Immune Response at 12 Months after SARS-CoV-2 Vaccination in a Multicentric European Cohort of Healthcare Workers-ORCHESTRA Project.

BACKGROUND: The effectiveness of the immunity provided by SARS-CoV-2 vaccines is an important public health issue. We analyzed the determinants of 12-month serology in a multicenter European cohort of vaccinated healthcare workers (HCW). METHODS: We analyzed the sociodemographic characteristics and levels of anti-SARS-CoV-2 spike antibodies (IgG) in a cohort of 16,101 vaccinated HCW from eleven centers in Germany, Italy, Romania, Slovakia and Spain. Considering the skewness of the distribution, the serological levels were transformed using log or cubic standardization and normalized by dividing them by center-specific standard errors. We fitted center-specific multivariate regression models to estimate the cohort-specific relative risks (RR) of an increase of one standard deviation of log or cubic antibody level and the corresponding 95% confidence interval (CI) for different factors and combined them in random-effects meta-analyses. RESULTS: We included 16,101 HCW in the analysis. A high antibody level was positively associated with age (RR = 1.04, 95% CI = 1.00-1.08 per 10-year increase), previous infection (RR = 1.78, 95% CI 1.29-2.45) and use of Spikevax [Moderna] with combinations compared to Comirnaty [BioNTech/Pfizer] (RR = 1.07, 95% CI 0.97-1.19) and was negatively associated with the time since last vaccine (RR = 0.94, 95% CI 0.91-0.98 per 30-day increase). CONCLUSIONS: These results provide insight about vaccine-induced immunity to SARS-CoV-2, an analysis of its determinants and quantification of the antibody decay trend with time since vaccination.

Prediction models using artificial intelligence and longitudinal data from electronic health records: a systematic methodological review.

OBJECTIVE: To describe and appraise the use of artificial intelligence (AI) techniques that can cope with longitudinal data from electronic health records (EHRs) to predict health-related outcomes. METHODS: This review included studies in any language that: EHR was at least one of the data sources, collected longitudinal data, used an AI technique capable of handling longitudinal data, and predicted any health-related outcomes. We searched MEDLINE, Scopus, Web of Science, and IEEE Xplorer from inception to January 3, 2022. Information on the dataset, prediction task, data preprocessing, feature selection, method, validation, performance, and implementation was extracted and summarized using descriptive statistics. Risk of bias and completeness of reporting were assessed using a short form of PROBAST and TRIPOD, respectively. RESULTS: Eighty-one studies were included. Follow-up time and number of registers per patient varied greatly, and most predicted disease development or next event based on diagnoses and drug treatments. Architectures generally were based on Recurrent Neural Networks-like layers, though in recent years combining different layers or transformers has become more popular. About half of the included studies performed hyperparameter tuning and used attention mechanisms. Most performed a single train-test partition and could not correctly assess the variability of the model's performance. Reporting quality was poor, and a third of the studies were at high risk of bias. CONCLUSIONS: AI models are increasingly using longitudinal data. However, the heterogeneity in reporting methodology and results, and the lack of public EHR datasets and code sharing, complicate the possibility of replication. REGISTRATION: PROSPERO database (CRD42022331388).

Multimorbidity and Serological Response to SARS-CoV-2 Nine Months after 1st Vaccine Dose: European Cohort of Healthcare Workers-Orchestra Project.

Understanding antibody persistence concerning multimorbidity is crucial for vaccination policies. Our goal is to assess the link between multimorbidity and serological response to SARS-CoV-2 nine months post-first vaccine. We analyzed Healthcare Workers (HCWs) from three cohorts from Italy, and one each from Germany, Romania, Slovakia, and Spain. Seven groups of chronic diseases were analyzed. We included 2941 HCWs (78.5% female, 73.4% ≥ 40 years old). Multimorbidity was present in 6.9% of HCWs. The prevalence of each chronic condition ranged between 1.9% (cancer) to 10.3% (allergies). Two regression models were fitted, one considering the chronic conditions groups and the other considering whether HCWs had diseases from ≥2 groups. Multimorbidity was present in 6.9% of HCWs, and higher 9-months post-vaccine anti-S levels were significantly associated with having received three doses of the vaccine (RR = 2.45, CI = 1.92-3.13) and with having a prior COVID-19 infection (RR = 2.30, CI = 2.15-2.46). Conversely, lower levels were associated with higher age (RR = 0.94, CI = 0.91-0.96), more time since the last vaccine dose (RR = 0.95, CI = 0.94-0.96), and multimorbidity (RR = 0.89, CI = 0.80-1.00). Hypertension is significantly associated with lower anti-S levels (RR = 0.87, CI = 0.80-0.95). The serological response to vaccines is more inadequate in individuals with multimorbidity.

Incidence and Determinants of Symptomatic and Asymptomatic SARS-CoV-2 Breakthrough Infections After Booster Dose in a Large European Multicentric Cohort of Health Workers-ORCHESTRA Project.

BACKGROUND: SARS-CoV-2 breakthrough infections (BI) after vaccine booster dose are a relevant public health issue. METHODS: Multicentric longitudinal cohort study within the ORCHESTRA project, involving 63,516 health workers (HW) from 14 European settings. The study investigated the cumulative incidence of SARS-CoV-2 BI after booster dose and its correlation with age, sex, job title, previous infection, and time since third dose. RESULTS: 13,093 (20.6%) BI were observed. The cumulative incidence of BI was higher in women and in HW aged < 50 years, but nearly halved after 60 years. Nurses experienced the highest BI incidence, and administrative staff experienced the lowest. The BI incidence was higher in immunosuppressed HW (28.6%) vs others (24.9%). When controlling for gender, age, job title and infection before booster, heterologous vaccination reduced BI incidence with respect to the BNT162b2 mRNA vaccine [Odds Ratio (OR) 0.69, 95% CI 0.63-0.76]. Previous infection protected against asymptomatic infection [Relative Risk Ratio (RRR) of recent infection vs no infection 0.53, 95% CI 0.23-1.20] and even more against symptomatic infections [RRR 0.11, 95% CI 0.05-0.25]. Symptomatic infections increased from 70.5% in HW receiving the booster dose since < 64 days to 86.2% when time elapsed was > 130 days. CONCLUSIONS: The risk of BI after booster is significantly reduced by previous infection, heterologous vaccination, and older ages. Immunosuppression is relevant for increased BI incidence. Time elapsed from booster affects BI severity, confirming the public health usefulness of booster. Further research should focus on BI trend after 4th dose and its relationship with time variables across the epidemics.

Universal screening programme for cytomegalovirus infection in the first trimester of pregnancy: study protocol for an observational multicentre study in the area of Barcelona (CITEMB study).

INTRODUCTION: Congenital cytomegalovirus (cCMV) is the leading cause of non-genetic sensorineural hearing loss and one of the main causes of neurological disability. Despite this, no universal screening programme for cCMV has been implemented in Spain. A recent study has shown that early treatment with valaciclovir, initiated in the first trimester and before the onset of signs in the fetus, reduces the risk of fetal infection. This finding favours the implementation of a universal screening programme for cCMV.The aim of this study is to evaluate the performance of a universal screening programme for cCMV during the first trimester of pregnancy in a primary care setting. METHODS AND ANALYSIS: This is an observational multicentre cohort study. The study will be conducted in four primary care settings from the Northern Metropolitan Barcelona area and three related hospitals and will last 3 years and will consist of a recruitment period of 18 months.In their first pregnancy visit, pregnant women will be offered to add a CMV serology test to the first trimester screening tests. Pregnant women with primary infection will be referred to the reference hospital, where they will continue treatment and follow-up according to the clinical protocol of the referral hospital, which includes treatment with valacyclovir. A CMV-PCR will be performed at birth on newborns of mothers with primary infection, and those who are infected will undergo neonatal follow-up for at least 12 months of life.For the analysis, the acceptance rate, the prevalence of primary CMV infections and the CMV seroprevalence in the first trimester of pregnancy will be studied. ETHICS AND DISSEMINATION: Ethical approval was obtained from the University Institute Foundation for Primary Health Care Research Jordi Gol i Gurina Ethics Committee 22/097-P dated 27 April 2022.

Fracture risk after deprescription of bisphosphonates: Application of real-world data in primary care / Riesgo de fractura después de la desprescripción de bifosfonatos: aplicación de real-world data en atención primaria

Purpose: To compare the effect of discontinuing bisphosphonate treatment on fracture risk in postmenopausal women at high versus low risk of fracture. Design: Retrospective, longitudinal and population-based cohort study. Setting: Barcelona City Primary Care. Catalan Health Institute. Participants: All women attended by primary care teams who in January 2014 had received bisphosphonate treatment for at least five years were included and followed for another five years. Intervention: Patients were classified according to their risk of new fractures, defined as those who had a history of osteoporotic fracture and/or who received treatment with an aromatase inhibitor, and the continuity or deprescription of the bisphosphonate treatment was analyzed over fiver year follow-up. Main measurements: The cumulative incidence of fractures and the incidence density were calculated and analyzed using logistic regression and Cox models. Results: We included 3680 women. There were no significant differences in fracture risk in high-risk women who discontinued versus continued bisphosphonate treatment (hazard ratio [HR] 1.17, 95% confidence interval [CI] 0.87–1.58 for total osteoporotic fractures). However, discontinuers at low risk had a lower incidence of fracture than continuers. This difference was significant for vertebral fractures (HR 0.64, 95% CI 0.47–0.88) and total fractures (HR 0.77, 95% CI 0.64–0.92). Conclusion: Our results suggest that deprescribing bisphosphonates in women who have already received five years of treatment does not increase fracture risk. In low-risk women, continuing this treatment might could even favor the appearance of new osteoporotic fractures.(AU)

Objetivo: Comparar el efecto de la desprescripción de bifosfonatos sobre el riesgo de fractura en mujeres posmenopáusicas con alto y bajo riesgo de fractura. Diseño: Estudio de cohortes retrospectivo, longitudinal y de base poblacional. Emplazamiento: Atención primaria Barcelona. Institut Català de la Salut. Participantes: Se incluyeron todas las mujeres atendidas por los equipos de atención primaria que a enero de 2014 habían recibido tratamiento con bifosfonatos durante al menos cinco años. Intervención: Se clasificó a las pacientes según su riesgo de nuevas fracturas, definido como presencia de antecedentes de fractura osteoporótica y/o tratamiento con un inhibidor de la aromatasa, y se analizó la continuidad o desprescripción del tratamiento con bifosfonatos a lo largo de cinco años de seguimiento. Mediciones principales: La incidencia acumulada de fracturas y la densidad de incidencia se calcularon y analizaron mediante regresión logística y modelos de Cox. Resultados: Se incluyeron 3.680 mujeres. No hubo diferencias significativas en el riesgo de fractura en mujeres de alto riesgo que desprescribieron el bisfosfonato comparado con aquellas que continuaron (hazard ratio [HR] 1,17, intervalo de confianza [IC] de 95% 0,87-1,58 para fracturas osteoporóticas totales). Sin embargo, los que discontinuaron con bajo riesgo tuvieron una menor incidencia de fractura que los que continuaron. Esta diferencia fue significativa para fracturas vertebrales (HR 0,64, IC 95% 0,47-0,88) y fracturas totales (HR 0,77, IC 95% 0,64-0,92). Conclusiones: Nuestros resultados sugieren que la desprescripción de bifosfonatos en mujeres que ya han recibido cinco años de tratamiento no aumenta el riesgo de fractura. En mujeres de bajo riesgo, la continuación de este tratamiento podría incluso favorecer la aparición de nuevas fracturas osteoporóticas.(AU)

Contribution of Frailty to Multimorbidity Patterns and Trajectories: Longitudinal Dynamic Cohort Study of Aging People.

BACKGROUND: Multimorbidity and frailty are characteristics of aging that need individualized evaluation, and there is a 2-way causal relationship between them. Thus, considering frailty in analyses of multimorbidity is important for tailoring social and health care to the specific needs of older people. OBJECTIVE: This study aimed to assess how the inclusion of frailty contributes to identifying and characterizing multimorbidity patterns in people aged 65 years or older. METHODS: Longitudinal data were drawn from electronic health records through the SIDIAP (Sistema d'Informació pel Desenvolupament de la Investigació a l'Atenció Primària) primary care database for the population aged 65 years or older from 2010 to 2019 in Catalonia, Spain. Frailty and multimorbidity were measured annually using validated tools (eFRAGICAP, a cumulative deficit model; and Swedish National Study of Aging and Care in Kungsholmen [SNAC-K], respectively). Two sets of 11 multimorbidity patterns were obtained using fuzzy c-means. Both considered the chronic conditions of the participants. In addition, one set included age, and the other included frailty. Cox models were used to test their associations with death, nursing home admission, and home care need. Trajectories were defined as the evolution of the patterns over the follow-up period. RESULTS: The study included 1,456,052 unique participants (mean follow-up of 7.0 years). Most patterns were similar in both sets in terms of the most prevalent conditions. However, the patterns that considered frailty were better for identifying the population whose main conditions imposed limitations on daily life, with a higher prevalence of frail individuals in patterns like chronic ulcers &peripheral vascular. This set also included a dementia-specific pattern and showed a better fit with the risk of nursing home admission and home care need. On the other hand, the risk of death had a better fit with the set of patterns that did not include frailty. The change in patterns when considering frailty also led to a change in trajectories. On average, participants were in 1.8 patterns during their follow-up, while 45.1% (656,778/1,456,052) remained in the same pattern. CONCLUSIONS: Our results suggest that frailty should be considered in addition to chronic diseases when studying multimorbidity patterns in older adults. Multimorbidity patterns and trajectories can help to identify patients with specific needs. The patterns that considered frailty were better for identifying the risk of certain age-related outcomes, such as nursing home admission or home care need, while those considering age were better for identifying the risk of death. Clinical and social intervention guidelines and resource planning can be tailored based on the prevalence of these patterns and trajectories.

Fracture risk after deprescription of bisphosphonates: Application of real-world data in primary care.

PURPOSE: To compare the effect of discontinuing bisphosphonate treatment on fracture risk in postmenopausal women at high versus low risk of fracture. DESIGN: Retrospective, longitudinal and population-based cohort study. SETTING: Barcelona City Primary Care. Catalan Health Institute. PARTICIPANTS: All women attended by primary care teams who in January 2014 had received bisphosphonate treatment for at least five years were included and followed for another five years. INTERVENTION: Patients were classified according to their risk of new fractures, defined as those who had a history of osteoporotic fracture and/or who received treatment with an aromatase inhibitor, and the continuity or deprescription of the bisphosphonate treatment was analyzed over fiver year follow-up. MAIN MEASUREMENTS: The cumulative incidence of fractures and the incidence density were calculated and analyzed using logistic regression and Cox models. RESULTS: We included 3680 women. There were no significant differences in fracture risk in high-risk women who discontinued versus continued bisphosphonate treatment (hazard ratio [HR] 1.17, 95% confidence interval [CI] 0.87-1.58 for total osteoporotic fractures). However, discontinuers at low risk had a lower incidence of fracture than continuers. This difference was significant for vertebral fractures (HR 0.64, 95% CI 0.47-0.88) and total fractures (HR 0.77, 95% CI 0.64-0.92). CONCLUSION: Our results suggest that deprescribing bisphosphonates in women who have already received five years of treatment does not increase fracture risk. In low-risk women, continuing this treatment might could even favor the appearance of new osteoporotic fractures.

Corrigendum: Temporal trends of COVID-19 antibodies in vaccinated healthcare workers undergoing repeated serological sampling: an individual-level analysis within 13 months in the ORCHESTRA cohort.

[This corrects the article DOI: 10.3389/fimmu.2022.1079884.].

Polypharmacy Patterns in Multimorbid Older People with Cardiovascular Disease: Longitudinal Study.

(1) Introduction: Cardiovascular disease is associated with high mortality, especially in older people. This study aimed to characterize the evolution of combined multimorbidity and polypharmacy patterns in older people with different cardiovascular disease profiles. (2) Material and methods: This longitudinal study drew data from the Information System for Research in Primary Care in people aged 65 to 99 years with profiles of cardiovascular multimorbidity. Combined patterns of multimorbidity and polypharmacy were analysed using fuzzy c-means clustering techniques and hidden Markov models. The prevalence, observed/expected ratio, and exclusivity of chronic diseases and/or groups of these with the corresponding medication were described. (3) Results: The study included 114,516 people, mostly men (59.6%) with a mean age of 78.8 years and a high prevalence of polypharmacy (83.5%). The following patterns were identified: Mental, behavioural, digestive and cerebrovascular; Neuropathy, autoimmune and musculoskeletal; Musculoskeletal, mental, behavioural, genitourinary, digestive and dermatological; Non-specific; Multisystemic; Respiratory, cardiovascular, behavioural and genitourinary; Diabetes and ischemic cardiopathy; and Cardiac. The prevalence of overrepresented health problems and drugs remained stable over the years, although by study end, cohort survivors had more polypharmacy and multimorbidity. Most people followed the same pattern over time; the most frequent transitions were from Non-specific to Mental, behavioural, digestive and cerebrovascular and from Musculoskeletal, mental, behavioural, genitourinary, digestive and dermatological to Non-specific. (4) Conclusions: Eight combined multimorbidity and polypharmacy patterns, differentiated by sex, remained stable over follow-up. Understanding the behaviour of different diseases and drugs can help design individualised interventions in populations with clinical complexity.

12-year evolution of multimorbidity patterns among older adults based on Hidden Markov Models.

BACKGROUND: The evolution of multimorbidity patterns during aging is still an under-researched area. We lack evidence concerning the time spent by older adults within one same multimorbidity pattern, and their transitional probability across different patterns when further chronic diseases arise. The aim of this study is to fill this gap by exploring multimorbidity patterns across decades of age in older adults, and longitudinal dynamics among these patterns. METHODS: Longitudinal study based on the Swedish National study on Aging and Care in Kungsholmen (SNAC-K) on adults ≥60 years (N=3,363). Hidden Markov Models were applied to model the temporal evolution of both multimorbidity patterns and individuals' transitions over a 12-year follow-up. FINDINGS: Within the study population (mean age 76.1 years, 66.6% female), 87.2% had ≥2 chronic conditions at baseline. Four longitudinal multimorbidity patterns were identified for each decade. Individuals in all decades showed the shortest permanence time in an Unspecific pattern lacking any overrepresented diseases (range: 4.6-10.9 years), but the pattern with the longest permanence time varied by age. Sexagenarians remained longest in the Psychiatric-endocrine and sensorial pattern (15.4 years); septuagenarians in the Neuro-vascular and skin-sensorial pattern (11.0 years); and octogenarians and beyond in the Neuro-sensorial pattern (8.9 years). Transition probabilities varied across decades, sexagenarians showing the highest levels of stability. INTERPRETATION: Our findings highlight the dynamism and heterogeneity underlying multimorbidity by quantifying the varying permanence times and transition probabilities across patterns in different decades. With increasing age, older adults experience decreasing stability and progressively shorter permanence time within one same multimorbidity pattern.

Kinetics of humoral immune response over 17 months of COVID-19 pandemic in a large cohort of healthcare workers in Spain: the ProHEpiC-19 study.

BACKGROUND: Understanding the immune response to the SARS-CoV-2 virus is critical for efficient monitoring and control strategies. The ProHEpic-19 cohort provides a fine-grained description of the kinetics of antibodies after SARS-CoV-2 infection with an exceptional resolution over 17 months. METHODS: We established a cohort of 769 healthcare workers including healthy and infected with SARS-CoV-2 in northern Barcelona to determine the kinetics of the IgM against the nucleocapsid (N) and the IgG against the N and spike (S) of SARS-CoV-2 in infected healthcare workers. The study period was from 5 May 2020 to 11 November 2021.We used non-linear mixed models to investigate the kinetics of IgG and IgM measured at nine time points over 17 months from the date of diagnosis. The model included factors of time, gender, and disease severity (asymptomatic, mild-moderate, severe-critical) to assess their effects and their interactions. FINDINGS: 474 of the 769 participants (61.6%) became infected with SARS-CoV-2. Significant effects of gender and disease severity were found for the levels of all three antibodies. Median IgM(N) levels were already below the positivity threshold in patients with asymptomatic and mild-moderate disease at day 270 after the diagnosis, while IgG(N and S) levels remained positive at least until days 450 and 270, respectively. Kinetic modelling showed a general rise in both IgM(N) and IgG(N) levels up to day 30, followed by a decay with a rate depending on disease severity. IgG(S) levels remained relatively constant from day 15 over time. INTERPRETATION: IgM(N) and IgG(N, S) SARS-CoV-2 antibodies showed a heterogeneous kinetics over the 17 months. Only the IgG(S) showed a stable increase, and the levels and the kinetics of antibodies varied according to disease severity. The kinetics of IgM and IgG observed over a year also varied by clinical spectrum can be very useful for public health policies around vaccination criteria in adult population. FUNDING: Regional Ministry of Health of the Generalitat de Catalunya (Call COVID19-PoC SLT16_04; NCT04885478).

Dynamics of multimorbidity and frailty, and their contribution to mortality, nursing home and home care need: A primary care cohort of 1 456 052 ageing people.

Background: Prevalence of both multimorbidity and frailty increases with age, but more evidence is needed to elucidate their relationship and their association with other health-related outcomes. We analysed the dynamics of both conditions as people age and calculate the associated risk of death, nursing home admission, and need for home care. Methods: Data were drawn from the primary care electronic health records of a longitudinal cohort of people aged 65 or older in Catalonia in 2010-2019. Frailty and multimorbidity were measured using validated instruments (eFRAGICAP, a cumulative deficit model; and SNAC-K, respectively), and their longitudinal evolution was described. Cox regression models accounted for the competing risk of death and adjusted by sex, socioeconomical status, and time-varying age, alcohol and smoking. Findings: We included 1 456 052 patients. Prevalence of multimorbidity was consistently high regardless of age, while frailty almost quadrupled from 65 to 99 years. Frailty worsened and also changed with age: up to 84 years, it was more related to concurrent diseases, and afterwards, to frailty-related deficits. While concurrent diseases contributed more to mortality, frailty-related deficits increased the risk of institutionalisation and the need for home care. Interpretation: The nature of people's multimorbidity and frailty vary with age, as does their impact on health status. People become frailer as they age, and their frailty is more characterised by disability and other symptoms than by diseases. Mortality is most associated with the number of comorbidities, whereas frailty-related deficits are associated with needing specialised care. Funding: Instituto de Salud Carlos III through PI19/00535, and the PFIS Grant FI20/00040 (Co-funded by European Regional Development Fund/European Social Fund).

Silent brain infarcts, peripheral vascular disease and the risk of cardiovascular events in patients with hypertension.

BACKGROUND AND AIMS: We aimed to study the relationship between cerebral small vessel disease (cSVD) lesions, as markers of subclinical target organ damage (TOD) in the brain, and incident cardiovascular events (CVE). METHODS: Data from the ISSYS (Investigating Silent Strokes in hYpertensives Study), which is a longitudinal and observational study conducted in patients with hypertension aged 50-70 years, and stroke-free at the inclusion. At the baseline visit, participants underwent a clinical interview, a brain MRI, urine and blood sampling collection and vascular testing studies. Therefore, we obtained markers of TOD from the brain [white matter hyperintensities, silent brain infarcts (SBI), cerebral microbleeds and enlarged perivascular spaces (EPVS)], from kidney (microalbuminuria, glomerular filtration) and regarding large vessels [ankle-to-brachial index (ABI), carotid-femoral pulse wave velocity]. Survival analyses were used to assess the relationship between these predictors and the incidence of cardiovascular events (CVE). RESULTS: We followed-up 964 individuals within a median time of 5 years (4.7-5), representing 4377.1 persons-year. We found 73 patients presenting incident CVE, which corresponds to a rate of 8.2%. We found ABI less than 0.9 [hazard ratio, 2.2; 95% confidence interval (CI) 1.17-4.13, P value = 0.014] and SBI (hazard ratio, 2.9; 95% CI 1.47-5.58, P value = 0.002) independently associated with higher risk of incident CVE. The inclusion of both variables in a clinical model resulted in an increased discrimination of individuals with new CVE of 4.72%, according to the integrated discrimination index. CONCLUSION: Assessment of SBI and ABI less than 0.9 may refine the cardiovascular risk stratification in patients with hypertension.

Neurocognitive Profile of the Post-COVID Condition in Adults in Catalonia-A Mixed Method Prospective Cohort and Nested Case-Control Study: Study Protocol.

The diagnosis of the post-COVID condition is usually achieved by excluding other diseases; however, cognitive changes are often found in the post-COVID disorder. Therefore, monitoring and treating the recovery from the post-COVID condition is necessary to establish biomarkers to guide the diagnosis of symptoms, including cognitive impairment. Our study employs a prospected cohort and nested case-control design with mixed methods, including statistical analyses, interviews, and focus groups. Our main aim is to identify biomarkers (functional and structural neural changes, inflammatory and immune status, vascular and vestibular signs and symptoms) easily applied in primary care to detect cognitive changes in post-COVID cases. The results will open up a new line of research to inform diagnostic and therapeutic decisions with special considerations for cognitive impairment in the post-COVID condition.

Validation of an electronic frailty index with electronic health records: eFRAGICAP index.

OBJECTIVE: To create an electronic frailty index (eFRAGICAP) using electronic health records (EHR) in Catalunya (Spain) and assess its predictive validity with a two-year follow-up of the outcomes: homecare need, institutionalization and mortality in the elderly. Additionally, to assess its concurrent validity compared to other standardized measures: the Clinical Frailty Scale (CFS) and the Risk Instrument for Screening in the Community (RISC). METHODS: The eFRAGICAP was based on the electronic frailty index (eFI) developed in United Kingdom, and includes 36 deficits identified through clinical diagnoses, prescriptions, physical examinations, and questionnaires registered in the EHR of primary health care centres (PHC). All subjects > 65 assigned to a PHC in Barcelona on 1st January, 2016 were included. Subjects were classified according to their eFRAGICAP index as: fit, mild, moderate or severe frailty. Predictive validity was assessed comparing results with the following outcomes: institutionalization, homecare need, and mortality at 24 months. Concurrent validation of the eFRAGICAP was performed with a sample of subjects (n = 333) drawn from the global cohort and the CFS and RISC. Discrimination and calibration measures for the outcomes of institutionalization, homecare need, and mortality and frailty scales were calculated. RESULTS: 253,684 subjects had their eFRAGICAP index calculated. Mean age was 76.3 years (59.5% women). Of these, 41.1% were classified as fit, and 32.2% as presenting mild, 18.7% moderate, and 7.9% severe frailty. The mean age of the subjects included in the validation subsample (n = 333) was 79.9 years (57.7% women). Of these, 12.6% were classified as fit, and 31.5% presented mild, 39.6% moderate, and 16.2% severe frailty. Regarding the outcome analyses, the eFRAGICAP was good in the detection of subjects who were institutionalized, required homecare assistance, or died at 24 months (c-statistic of 0.841, 0.853, and 0.803, respectively). eFRAGICAP was also good in the detection of frail subjects compared to the CFS (AUC 0.821) and the RISC (AUC 0.848). CONCLUSION: The eFRAGICAP has a good discriminative capacity to identify frail subjects compared to other frailty scales and predictive outcomes.