Clonal Lineage Tracing with Somatic Delivery of Recordable Barcodes Reveals Migration Histories of Metastatic Prostate Cancer.

The patterns by which primary tumors spread to metastatic sites remain poorly understood. Here, we define patterns of metastatic seeding in prostate cancer (PCa) using a novel injection-based mouse model - EvoCaP (Evolution in Cancer of the Prostate), featuring aggressive metastatic cancer to bone, liver, lungs, and lymph nodes. To define migration histories between primary and metastatic sites, we used our EvoTraceR pipeline to track distinct tumor clones containing recordable barcodes. We detected widespread intratumoral heterogeneity from the primary tumor in metastatic seeding, with few clonal populations (CPs) instigating most migration. Metastasis-to-metastasis seeding was uncommon, as most cells remained confined within the tissue. Migration patterns in our model were congruent with human PCa seeding topologies. Our findings support the view of metastatic PCa as a systemic disease driven by waves of aggressive clones expanding their niche, infrequently overcoming constraints that otherwise keep them confined in the primary or metastatic site.

Pregnancy outcomes as related to in utero exposure to air pollution and greenness: The Life-GAP Project.

Background: Lower birth weight and preterm birth may increase the risk of adverse health outcomes later in life. We examined whether maternal exposure to air pollution and greenness during pregnancy is associated with offspring birth weight and preterm birth. Methods: We analyzed data on 4286 singleton births from 2358 mothers from Respiratory Health in Northern Europe, a prospective questionnaire-based cohort study (1990-2010). Mixed-effects regression models with random intercepts for mothers and centers were used to estimate the association of exposures to particulate matter (PM2.5 and PM10), nitrogen dioxide (NO2), ozone (O3), black carbon (BC), and greenness (Normalized Difference Vegetation Index in 300m-buffers [NDVI300m]) with birth outcomes, adjusting for potential confounders. Results: Median (interquartile range [IQR]) exposures to PM2.5, PM10, NO2, O3, BC, and NDVI300m during pregnancy were 8.4(5.0) µg/m3, 14.4(8.3) µg/m3, 14.0(11.0) µg/m3, 54.7(10.2) µg/m3, 0.47(0.41) µg/m3, and 0.31(0.20), respectively. IQR increases in air pollution exposures during pregnancy were associated with decreased birth weight and the strongest association was seen for PM2.5 (-49g; 95% confidence interval [CI] = -83, -16). However, O3 showed an opposite association. IQR increase in NDVI300m was associated with an increase in birth weight of 25 g (95% CI = 7, 44). Preterm birth was not associated with the exposures. Conclusion: Increased greenness and decreased air pollution may contribute to healthier pregnancies and improve overall health in the next generation. This emphasizes the need to adopt policies that target the reduction of air pollution emissions and exposure of the population.

Effect of using the Simple Erosion Narrowing Score or Sharp/van der Heijde score on power of rheumatoid arthritis clinical trials to detect differences in radiographic progression.

OBJECTIVES: The Simple Erosion Narrowing Score (SENS) is a simplification of the Sharp/van der Heijde score (SHS). Previous studies found SENS and SHS to have very similar measurement properties, but suggest that SENS has a lower discriminative ability that may result in reduced power. Therefore, we aimed to quantify the effect of using SENS rather than SHS on the power to show between-group differences in radiographic progression. METHODS: Using data from two clinical trials in rheumatoid arthritis (DRESS and BeSt), SENS was derived from the SHS. Criterion validity of the SENS in relation to the SHS was assessed by calculating the Spearman correlation. The power of both scores to show a difference between groups was compared using bootstrapping to generate 10.000 replications of each study. Then, the number of replications with a significant difference in progression (using ANCOVA adjusted for baseline scores) were compared. RESULTS: Correlations between SENS and SHS were all >0.9, indicating high criterion validity of SENS compared with SHS as a reference standard. There was one exception, the DRESS study showed a somewhat lower correlation for the change score at 18 months (0.787). The loss in power of SENS over SHS was limited to at most 19% (BeSt year 5). In addition, the difference in power between SENS and SHS is smaller at higher levels of power. CONCLUSION: SENS appears to be a reasonable alternative to SHS, with only a limited loss of power to show between-group differences in radiographic progression.

Dutch gout patients' perspective on continuation or discontinuation of urate-lowering therapy during remission: a mixed methods study.

BACKGROUND: Long-term gout management is based on reducing serum urate by using urate-lowering therapy (ULT) 1, 2. A lifelong treat-to-target approach is advocated, though a ULT (taper to) stop attempt can be considered (treat-to-avoid symptoms approach) during remission. Exploring gout patients' beliefs on long-term ULT strategies during remission is important for optimising gout management. OBJECTIVE: To identify factors that influence the decision for continuation or discontinuation of ULT and to determine their relative importance according to gout patients in remission. METHODS: A mixed methods design was used. First, semi-structured interviews (substudy 1) were conducted to identify barriers and facilitators for (dis)continuation of ULT using inductive thematic analysis. Afterwards these barriers/facilitators were summarized into neutrally phrased items and used in a Maximum Difference Scaling study (MaxDiff, substudy 2) to determine their relative importance using the rescaled probability score (RPS). RESULTS: Substudies 1 and 2 included 18 and 156 patients, respectively. Substudy 1 yielded 22 items, within 10 overarching themes. Substudy 2 revealed that the perceived risk of joint damage and gout flares and that ULT use gives some assurance of ULT use were the most important items. The costs, ease of receiving ULT and its practical use were the least important items. CONCLUSION: These results can aid shared decision making and provide input for what's important to discuss with gout patients in remission, when they consider ULT discontinuation. Emphasis should be on the risk of having gout flares and joint damage, not so much on facilitating how easily medication is received.

High sugar diet alters immune function and the gut microbiome in juvenile green iguanas (Iguana iguana).

The present work aimed to study whether a high sugar diet can alter immune responses and the gut microbiome in green iguanas. Thirty-six iguanas were split into four treatment groups using a 2×2 design. Iguanas received either a sugar-supplemented diet or a control diet, and either a lipopolysaccharide (LPS) injection or a phosphate-buffered saline (PBS) injection. Iguanas were given their respective diet treatment through the entire study (∼3 months) and received a primary immune challenge 1 and 2 months into the experiment. Blood samples and cloacal swabs were taken at various points in the experiment and used to measure changes in the immune system (bacterial killing ability, lysis and agglutination scores, LPS-specific IgY concentrations), and alterations in the gut microbiome. We found that a sugar diet reduces bacterial killing ability following an LPS challenge, and sugar and the immune challenge temporarily alters gut microbiome composition while reducing alpha diversity. Although sugar did not directly reduce lysis and agglutination following the immune challenge, the change in these scores over a 24-h period following an immune challenge was more drastic (it decreased) relative to the control diet group. Moreover, sugar increased constitutive agglutination outside of the immune challenges (i.e. pre-challenge levels). In this study, we provide evidence that a high sugar diet affects the immune system of green iguanas (in a disruptive manner) and alters the gut microbiome.

Artificial intelligence for family medicine research in Canada: current state and future directions: Report of the CFPC AI Working Group.

OBJECTIVE: To understand the current landscape of artificial intelligence (AI) for family medicine (FM) research in Canada, identify how the College of Family Physicians of Canada (CFPC) could support near-term positive progress in this field, and strengthen the community working in this field. COMPOSITION OF THE COMMITTEE: Members of a scientific planning committee provided guidance alongside members of a CFPC staff advisory committee, led by the CFPC-AMS TechForward Fellow and including CFPC, FM, and AI leaders. METHODS: This initiative included 2 projects. First, an environmental scan of published and gray literature on AI for FM produced between 2018 and 2022 was completed. Second, an invitational round table held in April 2022 brought together AI and FM experts and leaders to discuss priorities and to create a strategy for the future. REPORT: The environmental scan identified research related to 5 major domains of application in FM (preventive care and risk profiling, physician decision support, operational efficiencies, patient self-management, and population health). Although there had been little testing or evaluation of AI-based tools in practice settings, progress since previous reviews has been made in engaging stakeholders to identify key considerations about AI for FM and opportunities in the field. The round-table discussions further emphasized barriers to and facilitators of high-quality research; they also indicated that while there is immense potential for AI to benefit FM practice, the current research trajectory needs to change, and greater support is needed to achieve these expected benefits and to avoid harm. CONCLUSION: Ten candidate action items that the CFPC could adopt to support near-term positive progress in the field were identified, some of which an AI working group has begun pursuing. Candidate action items are roughly divided into avenues where the CFPC is well-suited to take a leadership role in tackling priority issues in AI for FM research and specific activities or initiatives the CFPC could complete. Strong FM leadership is needed to advance AI research that will contribute to positive transformation in FM.

Rheumatoid arthritis patients' perspective on the use of prediction models in clinical decision-making.

OBJECTIVES: A rapidly expanding number of prediction models is being developed aiming to improve rheumatoid arthritis (RA) diagnosis and treatment. However, few are actually implemented in clinical practice. This study explores factors influencing the acceptance of prediction models in clinical decision-making by RA patients. METHODS: A qualitative study design was used with thematic analysis of semi-structured interviews. Purposive sampling was applied to capture a complete overview of influencing factors. The interview topic list was based on pilot data. RESULTS: Data saturation was reached after 12 interviews. Patients were generally positive about the use of prediction models in clinical decision-making. Six key themes were identified from the interviews. First, patients have the need for information on prediction models. Second, factors influencing trust in model-supported treatment are described. Third, patients envision the model to have a supportive role in clinical decision-making. Fourth, patients hope to personally benefit from model-supported treatment in various ways. Fifth, patients are willing to contribute time and effort to contribute to model input. And lastly, we discuss the theme on effects of the relationship with the caregiver in model-supported treatment. CONCLUSION: Within this study RA patients were generally positive about the use of prediction models in their treatment given some conditions were met and concerns addressed. The results of this study can be used during the development and implementation in RA care of prediction models in order to enhance patient acceptability.

Monthly average air pollution models using geographically weighted regression in Europe from 2000 to 2019.

Detailed spatial models of monthly air pollution levels at a very fine spatial resolution (25 m) can help facilitate studies to explore critical time-windows of exposure at intermediate term. Seasonal changes in air pollution may affect both levels and spatial patterns of air pollution across Europe. We built Europe-wide land-use regression (LUR) models to estimate monthly concentrations of regulated air pollutants (NO2, O3, PM10 and PM2.5) between 2000 and 2019. Monthly average concentrations were collected from routine monitoring stations. Including both monthly-fixed and -varying spatial variables, we used supervised linear regression (SLR) to select predictors and geographically weighted regression (GWR) to estimate spatially-varying regression coefficients for each month. Model performance was assessed with 5-fold cross-validation (CV). We also compared the performance of the monthly LUR models with monthly adjusted concentrations. Results revealed significant monthly variations in both estimates and model structure, particularly for O3, PM10, and PM2.5. The 5-fold CV showed generally good performance of the monthly GWR models across months and years (5-fold CV R2: 0.31-0.66 for NO2, 0.4-0.79 for O3, 0.4-0.78 for PM10, 0.46-0.87 for PM2.5). Monthly GWR models slightly outperformed monthly-adjusted models. Correlations between monthly GWR model were generally moderate to high (Pearson correlation >0.6). In conclusion, we are the first to develop robust monthly LUR models for air pollution in Europe. These monthly LUR models, at a 25 m spatial resolution, enhance epidemiologists to better characterize Europe-wide intermediate-term health effects related to air pollution, facilitating investigations into critical exposure time windows in birth cohort studies.

Age-related phenotypes in breast cancer: A population-based study.

Breast cancer in young (<40 years) is associated with a higher frequency of aggressive tumor types and poor prognosis. It remains unclear if there is an underlying age-related biology that contributes to the unfavorable outcome. We aim to investigate the relationship between age and breast cancer biology, with emphasis on proliferation. Clinico-pathologic information, immunohistochemical markers and follow-up data were obtained for all patients aged <50 (Bergen cohort-1; n = 355, not part of a breast screening program) and compared to previously obtained information on patients aged 50 to 69 years (Bergen cohort-2; n = 540), who participated in the Norwegian Breast Cancer Screening Program. Young breast cancer patients presented more aggressive tumor features such as hormone receptor negativity, HER2 positivity, lymph-node metastasis, the HER2-enriched and triple-negative subtypes and shorter survival. Age <40 was significantly associated with higher proliferation (by Ki67). Ki67 showed weaker prognostic value in young patients. We point to aggressive phenotypes and increased tumor cell proliferation in breast cancer of the young. Hence, tumors of young breast cancer patients may present unique biological features, also when accounting for screen/interval differences, that may open for new clinical opportunities, stratifying treatment by age.

Antibody-dependent enhancement of toxicity of myotoxin II from Bothrops asper.

Improved therapies are needed against snakebite envenoming, which kills and permanently disables thousands of people each year. Recently developed neutralizing monoclonal antibodies against several snake toxins have shown promise in preclinical rodent models. Here, we use phage display technology to discover a human monoclonal antibody and show that this antibody causes antibody-dependent enhancement of toxicity (ADET) of myotoxin II from the venomous pit viper, Bothrops asper, in a mouse model of envenoming that mimics a snakebite. While clinical ADET related to snake venom has not yet been reported in humans, this report of ADET of a toxin from the animal kingdom highlights the necessity of assessing even well-known antibody formats in representative preclinical models to evaluate their therapeutic utility against toxins or venoms. This is essential to avoid potential deleterious effects as exemplified in the present study.

Treat-to-target vs fixed interval retreatment strategy with rituximab in rheumatoid arthritis: a retrospective cohort study.

To compare the effectiveness of retreatment of rheumatoid arthritis (RA) patients with rituximab (RTX) following the treat-to-target retreatment (TTr) or fixed interval retreatment (FIr) strategy. RA patients starting RTX treatment between January 2008 and June 2016, and receiving at least three infusion cycles were grouped by strategy (TTr, FIr or both). Primary outcome (between strategy difference in DAS28-CRP (Disease Activity Score in 28 joints calculated with C-reactive protein)) and secondary outcomes (flares, use of co-medication and mean yearly dose of RTX) were analyzed by group using linear mixed models to account for different strategies within patients. A total of 213 patients, 59 TTr (of whom 32 switched from TTr to FIr) and 186 FIr were included. No between-group difference in mean DAS28-CRP was found (0.10 DAS28-CRP point (95% CI - 0.07 to 0.26)). The TTr strategy did not result in more flares (IRR 1.13, 95%CI 0.87 to 1.47), conventional synthetic disease-modifying antirheumatic drug use (difference - 11.7%, 95%CI - 26.3% to 2.9%), or lower mean yearly RTX dose (difference 172 mg/yr, 95%CI - 355 to 11.7 mg/yr). RTX retreatment with either a TTr or FIr strategy does not seem to lead to better disease control and/or less drug use when used in a DAS28-CRP treat-to-target context. Choice of either strategy can, therefore, be made based on patient and physician preferences and logistical context.

Staphylococcus aureus induces drug resistance in cancer T cells in Sézary syndrome.

ABSTRACT: Patients with Sézary syndrome (SS), a leukemic variant of cutaneous T-cell lymphoma (CTCL), are prone to Staphylococcus aureus infections and have a poor prognosis due to treatment resistance. Here, we report that S aureus and staphylococcal enterotoxins (SE) induce drug resistance in malignant T cells against therapeutics commonly used in CTCL. Supernatant from patient-derived, SE-producing S aureus and recombinant SE significantly inhibit cell death induced by histone deacetylase (HDAC) inhibitor romidepsin in primary malignant T cells from patients with SS. Bacterial killing by engineered, bacteriophage-derived, S aureus-specific endolysin (XZ.700) abrogates the effect of S aureus supernatant. Similarly, mutations in major histocompatibility complex (MHC) class II binding sites of SE type A (SEA) and anti-SEA antibody block induction of resistance. Importantly, SE also triggers resistance to other HDAC inhibitors (vorinostat and resminostat) and chemotherapeutic drugs (doxorubicin and etoposide). Multimodal single-cell sequencing indicates T-cell receptor (TCR), NF-κB, and JAK/STAT signaling pathways (previously associated with drug resistance) as putative mediators of SE-induced drug resistance. In support, inhibition of TCR-signaling and Protein kinase C (upstream of NF-κB) counteracts SE-induced rescue from drug-induced cell death. Inversely, SE cannot rescue from cell death induced by the proteasome/NF-κB inhibitor bortezomib. Inhibition of JAK/STAT only blocks rescue in patients whose malignant T-cell survival is dependent on SE-induced cytokines, suggesting 2 distinct ways SE can induce drug resistance. In conclusion, we show that S aureus enterotoxins induce drug resistance in primary malignant T cells. These findings suggest that S aureus enterotoxins cause clinical treatment resistance in patients with SS, and antibacterial measures may improve the outcome of cancer-directed therapy in patients harboring S aureus.

Prioritization of Adverse Consequences After Total Knee Arthroplasty Contributing to a Poor Response: A Best-Worst Scaling Exercise Among Total Knee Arthroplasty Patients and Knee Specialists.

BACKGROUND: Total knee arthroplasty (TKA) can have a number of adverse consequences for patients that might contribute to a poor outcome. This study aimed to prioritize these consequences, from the perspective of patients and knee specialists. METHODS: There were 95 TKA patients and 63 knee specialists who prioritized a set of 29 adverse consequences, based on a previous qualitative study, using a Maximum Difference Scaling method. A hierarchical Bayesian analysis was used to calculate relative importance scores. Differences and agreements between patients versus knee specialists and satisfied versus dissatisfied patients were analyzed using Mann-Whitney-U tests and Kendall's coefficients of concordance. RESULTS: There were 4 out of 5 items in the top-5 of both patients and knee specialists that were similar, however, the ranking was different. The highest-ranked consequence for patients was: "Inability to do normal activities such as walking, cycling, swimming and heavy household chores", while knee specialists ranked: "No improvement in pain during the day" as the highest. "No improvement in walking" was in the patients' top-5, but was not ranked in the top-5 of knee specialists. For satisfied and dissatisfied patients, the top-5 of consequences was similar. CONCLUSION: Comparable perspectives were found for patients versus knee specialists and satisfied versus dissatisfied patients on the importance of adverse consequences after TKA. However, when looking in more detail, differences in ranking of specific subitems suggest that patients place slightly more importance on the inability to perform valued activities, while knee specialists prioritize lack of pain relief to a higher degree.

Concomitant exposure to air pollution, green space and noise, and risk of myocardial infarction: a cohort study from Denmark.

AIMS: The three correlated environmental exposures (air pollution, road traffic noise, and green space) have all been associated with the risk of myocardial infarction (MI). The present study aimed to analyse their independent and cumulative association with MI. METHODS AND RESULTS: In a cohort of all Danes aged 50 or older in the period 2005-17, 5-year time-weighted average exposure to fine particles (PM2.5), ultrafine particles, elemental carbon, nitrogen dioxide (NO2), and road traffic noise at the most and least exposed façades of residence was estimated. Green space around residences was estimated from land use maps. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence interval (CI), and cumulative risk indices (CRIs) were calculated. All expressed per interquartile range. Models were adjusted for both individual and neighbourhood-level socio-demographic covariates. The cohort included 1 964 702 persons. During follow-up, 71 285 developed MI. In single-exposure models, all exposures were associated with an increased risk of MI. In multi-pollutant analyses, an independent association with risk of MI was observed for PM2.5 (HR: 1.026; 95% CI: 1.002-1.050), noise at most exposed façade (HR: 1.024; 95% CI: 1.012-1.035), and lack of green space within 150 m of residence (HR: 1.018; 95% CI: 1.010-1.027). All three factors contributed significantly to the CRI (1.089; 95% CI: 1.076-1.101). CONCLUSION: In a nationwide cohort study, air pollution, noise, and lack of green space were all independently associated with an increased risk of MI. The air pollutant PM2.5 was closest associated with MI risk.

The present study aimed to analyse their independent and cumulative association of the three correlated environmental exposures: air pollution, road traffic noise, and green space with MI. Air pollution, noise, and lack of green space were all independently associated with MI.Risk estimates for air pollution, noise, and lack of green space were similar, indicating that all may be equally relevant targets for regulatory measures.

Exposure to air pollution and risk of respiratory tract infections in the adult Danish population-a nationwide study.

OBJECTIVES: The association between air pollution and risk of respiratory tract infection (RTI) in adults needs to be clarified in settings with low to moderate levels of air pollution. We investigated this in the Danish population between 2004 and 2016. METHODS: We included 3 653 490 persons aged 18-64 years in a nested case-control study. Exposure was defined as the average daily concentration at the individual's residential address of CO, NOX, NO2, O3, SO2, NH3, PPM2.5, black carbon, organic carbon, mineral dust, sea salt, secondary inorganic aerosols, SO42-, NO3-, NH4+, secondary organic aerosols, PM2.5, and PM10 during a 3-month exposure window. RTIs were defined by hospitalization for RTIs. Incidence rate ratios (IRRs) and 95% CIs were estimated comparing highest with lowest decile of exposure using conditional logistic regression models. RESULTS: In total, 188 439 incident cases of RTI were identified. Exposure to most air pollutants was positively associated with risk of RTI. For example, NO2 showed an IRR of 1.52 (CI: 1.48-1.55), and PM2.5 showed an IRR of 1.45 (CI: 1.40-1.50). In contrast, exposure to sea salt, PM10, NH3, and O3 was negatively associated with a risk of RTIs. DISCUSSION: In this nationwide study comprising adults, exposure to air pollution was associated with risk of RTIs and subgroups hereof. Sea salt, PM10, NH3, and O3 may be proxies for rural areas, as the levels of these species in Denmark are higher near the western coastlines and/or in rural areas with fewer combustion sources.

The Use of Remote Consultations and Associated Factors in Rheumatology: A Large Retrospective Cohort Study of Follow-Up Consultations Before, During, and After COVID-19.

OBJECTIVE: To investigate the use of remote consultations (RCs) and the influence of consultation, health care provider (HCP), and patient characteristics on the choice for remote or face-to-face consultation. METHODS: A monocenter retrospective cohort study was conducted on follow-up consultations of patients with rheumatic diseases from January 1, 2019 to January 16, 2023, using data from electronic health records. Trends in the proportion of RCs before, during, and after COVID-19 were studied. Cross-classified multilevel logistic regression models were built to account for clustering of consultations (level 1) within both patients and HCPs (level 2). The influence of consultation, patient, and HCP characteristics on the type of consultation was assessed. RESULTS: 157,028 consultations of 30,215 unique patients seen by 64 HCPs were included in the data set. After an initial sharp increase in RC use at the beginning of the COVID-19 pandemic, the proportion of RCs decreased toward a seemingly steady state at around 30%. 90% of the variance in the use of RCs can be attributed to the consultation level, whereas 4% and 6% can be attributed to the patient and HCP level. Longer consultation durations and time since last consultation decreased the odds for a RC, as did higher patient age, shared care, and longer disease duration. Higher travel distance, consultation density, and patient digital access increased the odds for a RC. CONCLUSION: The COVID pandemic resulted in a structural increase in the use of RCs. Although several patient characteristics are associated with the type of consultation, most variance resulted from consultation characteristics compared with patients and HCPs.

Potentially Inappropriate Prescribing in Long-Term Care and its Relationship With Probable Delirium.

OBJECTIVES: This study examined potentially inappropriate prescribing (PIP) of medication and its association with probable delirium among long-term care (LTC) residents in Ontario, Canada. DESIGN: Population-based cross-sectional study using provincial health administrative data, including LTC assessment data via the Resident Assessment Instrument-Minimum Dataset version 2.0 (RAI-MDS 2.0). SETTING AND PARTICIPANTS: LTC residents in Ontario between January 1, 2016, and December 31, 2019. METHODS: We used residents' first RAI-MDS 2.0 assessment in the study period as the index assessment. Probable delirium was identified via the delirium Clinical Assessment Protocol. Medication use in the 2 weeks preceding assessment was captured using medication claims data. PIP was measured using the STOPP/START criteria and 2015 Beers criteria, with residents classified as having 0, 1, 2, or 3+ instances of PIP. Relationships between PIP and probable delirium was assessed via bivariate and multivariable logistic regression models. RESULTS: The study population included 171,190 LTC residents (mean age 84.5 years, 66.8% female, 62.9% with dementia). More than half (51.8%) of residents had 1+ instances of PIP and 21% had 3+ instances of PIP according to the STOPP/START criteria; PIP prevalence was slightly lower when assessed using Beers criteria (36.5% with 1+, 11.1% with 3+). Overall, 3.7% of residents had probable delirium. The prevalence of probable delirium increased as the number of instances of PIP increased, with residents with 3+ instances of STOPP/START PIP being 1.66 times more likely (95% CI 1.56-1.77) to have probable delirium compared to those with no instances of PIP. Similar findings were observed when PIP was measured using the Beers criteria. Central nervous system (CNS)-related PIP criteria showed a stronger association with probable delirium than non-CNS-related PIP criteria. CONCLUSIONS AND IMPLICATIONS: This population-based study highlighted that PIP was highly prevalent in long-term care residents and was associated with an increased prevalence of probable delirium.

The CEPH aging cohort and biobank: a valuable collection of biological samples from exceptionally long-lived French individuals and their offspring for longevity studies.

The increasing aging of the human population is currently and for the coming decades a major public health issue in many countries, requiring the implementation of global public health policies promoting healthy and successful aging. Individuals are not equal in the face of aging and some can present exceptional healthspan and/or lifespan, which are notably influenced by both genetic and environmental factors. Research and studies on human aging, healthy aging and longevity should rely in particular on cohorts of long-lived individuals, also including biological samples allowing studies on the biology of aging and longevity. In this manuscript, we provide for the first time a complete description of the CEPH (Centre d'Etude du Polymophisme Humain) Aging cohort, an exceptional cohort recruited during the 90s to 2000s, including more than 1700 French long-lived individuals (≥ 90 years old) born between 1875 and 1916 as well as for some of them their siblings and offspring. Among the participants, 1265 were centenarians, including 255 semi-supercentenarians ([105-110] years old) and 25 supercentenarians (≥ 110 years old). The available anthropometric, epidemiologic and clinical data for the cohort participants are described and especially the collection of blood-derived biological samples associated with the cohort which includes DNA, cryopreserved cells and cell lines, plasma, and serum. This biological collection from the first cohort of centenarians in the world is an inestimable resource for ongoing and future molecular, cellular, and functional studies aimed at deciphering the mechanisms of human (successful) aging and longevity.