Clinic-based Cohort Research Articles

Behavioral and Psychological Symptoms of Dementia and Mortality Risk Among People With Cognitive Impairment: An 8-year Longitudinal Study From the NCGG-STORIES.

Behavioral and psychological symptoms of dementia (BPSD) are common among people with dementia from the early stages and can appear even in mild cognitive impairment (MCI). However, the prognostic impact of BPSD is unclear. This study examined the association between BPSD and mortality among people with cognitive impairment. This longitudinal study involved 1,065 males and 1,681 females (mean age: 77.1 years for males and 78.6 years for females) with MCI or dementia diagnosis from the National Center for Geriatrics and Gerontology-Life Stories of People with Dementia (NCGG-STORIES), a single-center memory clinic-based cohort study in Japan that registered first-time outpatients from 2010-2018. Information about death was collected through a mail survey returned by participants or their close relatives, with an up to 8-year follow-up. BPSD was assessed using the Dementia Behavior Disturbance Scale (DBD) at baseline. During the follow-up period, 229 (28.1%) male and 254 (15.1%) female deaths occurred. Cox proportional hazards regression analysis showed that higher DBD scores were significantly associated with increased mortality risk among males, but not females (compared with the lowest quartile score group, hazard ratios for the highest quartile score group were 1.59; 95% confidence interval, [CI] 1.11-2.29 for males and 1.06; 95% CI, 0.66-1.70 for females). Among the DBD items, lack of interest in daily living, excessive daytime sleep, and refusal to receive care had a higher mortality risk. The findings suggest a potential association between BPSD and poor prognosis among males with cognitive impairment.

Using Geographic Momentary Assessment to Explore Spatial Environment Influences on Wellbeing in People With HIV.

Place-based socio-economic and racial inequities contribute to health disparities among people with HIV (PWH). We used geographic ecological momentary assessment (GEMA) methodologies to explore the interplay between psychosocial outcomes in daily diaries and community spatial measures among PWH in New Orleans. PWH (N = 69) were recruited from a clinic-based cohort study. Micro-longitudinal data were collected via smartphone-based daily diaries and geospatial tracking over 14 days. First, correlations were run between diary derived outcomes (e.g., feeling safe in current location, stress), and spatial measures (e.g., violent crime, alcohol outlets, and vacant lots) within a half-mile buffer around each diary point to understand the real time associations between mood and space. Next, we fit multilevel models, controlling for between-person effects, to assess within-person associations between accumulative spatial daily violence exposure (50m, 100m and 200m buffers), and measures of daily mood and coping. Violent crime, alcohol outlets and vacant lots were inversely correlated with feeling safe and positively correlated with perceived ease of obtaining drugs. Vacant lots were positively associated with stress and inversely correlated with positive mood. Within individuals, higher daily accumulated violence exposure was associated with increased rumination at the 50m buffer level, decreased trust in oneself and others at the 100m buffer, and decreased ratio of positive/negative mood at all buffers. Our results emphasize the intricate interplay between mental wellness, coping mechanisms, and spatial measures in PWH. Future research and interventions for PWH should consider how spatial factors may influence PWH in terms of mental health and care engagement.

Automated breast density assessment for full-field digital mammography and digital breast tomosynthesis.

Mammographic density is a strong risk factor for breast cancer (BC) and is reported clinically as part of Breast Imaging Reporting and Data System (BI-RADS) results issued by radiologists. Automated assessment of density is needed that can be used for both full-field digital mammography (FFDM) and digital breast tomosynthesis (DBT) as both types of exams are acquired in standard clinical practice. We trained a deep learning model to automate the estimation of BI-RADS density from a prospective Washington University (WashU) clinic-based cohort of 9,714 women, entering into the cohort in 2013 with follow-up through, October 31, 2020. The cohort included 27% non-Hispanic Black women. The trained algorithm was assessed in an external validation cohort that included 18,360 women screened at Emory from January 1, 2013 and followed through December 31, 2020 that included 42% non-Hispanic Black women. Our model-estimated BI-RADS density demonstrated substantial agreement with the density as assessed by radiologist. In the external validation, the agreement with radiologists for category B 81% and C 77% for FFDM and B 83% and C 74% for DBT show important distinction for separation of women with dense breast. We obtained a Cohen's κ of 0.72 (95% CI, 0.71, 0.73) in FFDM and 0.71 (95% CI 0.69, 0.73) in DBT. We provided a consistent and fully automated BI-RADS estimation for both FFDM and DBT using a deep learning model. The software can be easily implemented anywhere for clinical use and risk prediction.

Changes in Lens Structure in Pathological Myopia, Cataract Surgery and Special Situations

Pathological myopia is a major cause of low vision and blindness worldwide. In patients with pathological myopia, there are changes such as thinning of the lens and increase in equatorial diameter. In various population and clinic-based cohort, case-control and cross-sectional studies, it has been reported that myopic patients have a higher risk of posterior subcapsular cataract, cortical and nuclear cataract. It is known that the modern technique of phacoemulsification and intraocular lens implantation is effective in highly myopic eyes and provides significant improvement in visual acuity. However, complications related to phacoemulsification such as posterior capsule rupture, retinal detachment, progression of existing maculopathy, capsular phimosis, late lens dislocation and transient intraocular pressure elevation occur more frequently in highly myopic patients. As a result, it is extremely important that cataract surgeries of these patients are performed by experienced surgeons and that attention is paid to perioperative and postoperative complications.

Abstract C060: Social isolation and secondary appraisal mediate the association between race and functional well-being among prostate cancer survivors

Abstract Background: Disparities in prostate cancer (PCa) incidence and mortality persist among African Americans. Functional well-being plays a crucial role in the prognosis and survival of PCa patients. Prior studies show the association between African American race and health-related quality of life among PCa patients. However, no studies have examined possible mediational processes linking race to functional well-being in this population. Objective: To assess the association between race and functional well-being and the mediating pathways of clinical, social determinants, and psychological factors in PCa patients. Methods: We used clinic-based cohort data of PCa patients treated with radical prostatectomy from April 2017 through September 2021. We measured functional well-being, socioeconomic factors, social stressors, perceived stress, and primary and secondary appraisal by self-report. We obtained clinical variables such as disease stage, prostate-specific antigen (PSA) levels, and comorbidities through electronic medical records. We first conducted a path analysis based on linear regression to test the direct association between race and functional well-being, adjusting for age, marital status, education level, employment status, and income. We concurrently examined the mediational pathways linking race to functional well-being via mediators, including stage, PSA, primary appraisal, secondary appraisal, perceived stress, and social isolation. Results: A total of 163 participants (48 African American, 115 White) with a mean age of 66.7 years (SD=6.31) were included in the study. Participants' mean score of functional well-being was 20.32 (SD=6.70; Range=0-28). Compared to White individuals, African American participants exhibited significantly lower levels of functional well-being (b [95% CI] = -3.09 [-5.48, -0.72]). Mediation analyses linking race to functional well-being revealed that, compared to Whites, African Americans displayed significantly lower levels of secondary appraisal (b [95% CI] = -1.45 [-2.85, -0.05]), which, in turn, were associated with higher levels of functional well-being (b [95% CI] = 0.27 [0.01, 0.53]). In addition, African Americans also displayed higher levels of social isolation (b [95% CI] = 0.55 [0.14, 0.97]), which were significantly associated with lower levels of functional well-being (b [95% CI] = -0.91 [-1.64, -0.17]). Both indirect effects of race → secondary appraisal → functional well-being (b [95% CI] = -0.39 [-0.88, -0.01]) and race → social isolation → functional well-being (b [95% CI] = -0.50 [-1.06, -0.02]) were significant and explained 12.6% and 16.2%, respectively, of the total relationship between race and functional well-being. Conclusion: Social isolation and secondary appraisal mediate the association between race and functional well-being among prostate cancer survivors. There is a need to understand the lived experiences of Black men and develop interventions that mitigate the impact of social barriers and psychological stressors on functional well-being to advance health equity. Citation Format: Fatimata Sanogo, Junhan Cho, Trista Beard, Chanita Hughes Halbert. Social isolation and secondary appraisal mediate the association between race and functional well-being among prostate cancer survivors [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C060.

Hepatitis B prevalence and risk factors among adults living with HIV in South Africa: a clinic-based cohort study

BackgroundPeople living with HIV (PLHIV) may have concurrent Hepatitis B Virus (HBV) infection, and certain antiretroviral therapies are recommended for HBV-HIV co-infected individuals. Routine screening for Hepatitis B virus may influence management of antiretroviral therapy for PLHIV, but risk factors for co-infection have not been well defined. The objective of this study was to identify risk factors for HBV infection among PLHIV in South Africa.MethodsWe conducted a cross-sectional analysis of a prospective, clinic-based cohort study of adults seeking HIV testing from 2013–2017 in Umlazi township, South Africa. Patients newly diagnosed with HIV were enrolled and subsequently tested for Hepatitis B surface antigen positive (HBsAg +). We used a Poisson linear regression model to assess which factors, pertaining to sociodemographic status, medical history, clinical symptoms, mental health were associated with HBV.ResultsAmong 3,105 PLHIV participants in South Africa, 6% were positive for HBV. Males had a higher HBV prevalence (10.4%) than females (5.2%). Within the HBV-positive group, the mean age was 33.2 years, with 38.3% females and 43.9% having completed high school or higher. About 39.9% reported alcohol use, 24.7% had a smoking history, and 8.3% reported substance use in the past year. Older participants born before 1995, when routine infant HBV vaccination was introduced, were more likely to have HBV. In multivariable analyses, smoking history increased HBV risk in females (aPR = 2.58; 95% CI 1.47–2.52), while alcohol use decreased HBV risk in males (aPR = 0.36; 95% CI 0.19–0.70).ConclusionsIn a South African cohort, roughly one in 16 PLHIV had HBV co-infection, and this rate was higher in males. The most prominent risk factors for HBV infection in PLHIV were alcohol use, higher income, and smoking history, which may help inform targeted treatment and prevention strategies. Creating HBV-specific screening and prevention strategies for PLHIV may be useful for reducing HBV infections.

The association of sociodemographic factors with total and item-level semantic fluency metrics.

We aimed to estimate the association of age, education, and sex/gender with semantic fluency performance as measured by the standard total number of words as well as novel item-level metrics and to descriptively compare associations across cohorts with different recruitment strategies and sample compositions. Cross-sectional data from 2,391 individuals from three cohorts were used: Washington Heights/Inwood Columbia Aging Project, a community-based cohort; Second Manifestations of ARTerial disease-Magnetic Resonance, a clinic-based cohort; and African American Alzheimer's Disease Genetics Study, a volunteer-based cohort. Total number of correct words and six item-level semantic fluency metrics were included as main outcomes: average cluster size, number of cluster switches, lexical/Zipf frequency, age of acquisition, and lexical decision response time. General linear models were run separately in each cohort to model the association between sociodemographic variables and semantic fluency metrics. Across cohorts, older age was associated with a lower total score and fewer cluster switches. Higher level of education was associated with naming more words, performing more cluster switches, and naming words with a longer lexical decision response time, lower frequency of occurrence, or later age of acquisition. Being female compared to male was associated with naming fewer words, smaller cluster sizes, naming words with a longer lexical decision response time, and lower age of acquisition. The effects varied in strength but were in a similar direction across cohorts. Item-level semantic fluency metrics-similar to the standard total score-are sensitive to the effects of age, education, and sex/gender. The results suggest geographical, cultural, and cross-linguistic generalizability of these sociodemographic effects on semantic fluency performance. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Real-world performance of plasma p-tau181 in a heterogeneous memory clinic cohort.

In light of clinical trials and disease-modifying therapies, an early identification of patients at-risk of developing Alzheimer's disease (AD) is crucial. Blood-based biomarkers have shown promising results regarding the in vivo detection of the earliest neuropathological changes in AD. Herein, we investigated the ability of plasma p-tau181 to act as a prescreening marker for amyloid positivity in a heterogeneous memory clinic-based cohort. In this retrospective cross-sectional study, we included a total of 115 patients along the clinical AD continuum (mild cognitive impairment [MCI] due to AD, n = 62, probable AD dementia, n = 53). Based on their biomarker status, they were stratified into an amyloid-positive (Aβ+, n = 88) or amyloid-negative cohort (Aβ-, n = 27). Plasma and CSF p-tau181 concentrations were quantified using an ultrasensitive single-molecule array (SIMOA©). Furthermore, age- and sex-adjusted receiver operating characteristic (ROC) curves were calculated and the area under the curve (AUC) of each model was compared using DeLong's test for correlated AUC curves. The median (interquartile range [IQR]) concentration of plasma p-tau181 was significantly higher in Aβ+ patients (3.6 pg/mL [2.5-4.6]), compared with Aβ- patients (1.7 pg/mL [1.2-1.9], p < 0.001). Regarding the distinction between Aβ+ and Aβ- patients and the prediction of amyloid positivity, a high diagnostic accuracy for plasma p-tau181 with an AUC of 0.89 (95% CI = 0.82-0.95) was calculated. Adding the risk factors, age and APOE4, to the model did not significantly improve its performance. Our findings demonstrate that plasma p-tau181 could be a noninvasive and feasible prescreening marker for amyloid positivity in a heterogeneous clinical AD cohort and therefore help in identifying those who would benefit from more invasive assessment of amyloid pathology.

Characteristics of Youth Presenting for Gender Care Compared to Background Populations: Examination of Social Determinants of Health.

Purpose: Transgender and gender diverse (TGD) youth in North American clinical reports are predominantly White with relatively high socioeconomic status suggesting that access to gender-affirming care is inequitable. This study examined whether socioeconomic and social determinant of health discrepancies exist between a clinical population of TGD youth and surrounding communities. Methods: Patient postal codes were used to link the Ontario Marginalization Index (ON-MARG) to a clinic-based TGD youth cohort (n = 298). Using ON-MARG, each patient was assigned a quintile score from 1 (least marginalized) to 5 (most marginalized) on four marginalization measures. Mean quintile scores were compared to background populations. Census-based Toronto neighborhood-level data on ethnic diversity and educational status were also examined. Neighborhoods were categorized as highly represented, less represented, or unrepresented based on representation in the clinic cohort. One-way analysis of covariance was used to determine associations between neighborhood-level variables and the degree of neighborhood representation. Results: ON-MARG data demonstrated that clinic patients hailed from areas with more individuals having paid employment. Patients from Toronto and surrounding areas came, in general, from communities with fewer recent immigrants and visible minorities. Highly represented Toronto neighborhoods had smaller proportions of visible minorities and immigrants compared with less and unrepresented neighborhoods. Educational status, represented by adults with bachelor's degrees, was lower among unrepresented neighborhoods. Conclusion: TGD youth seen in clinic, particularly those from Toronto, are disproportionally White and socioeconomically advantaged. Further research is needed to better understand the underrepresentation of racialized and low-socioeconomic status youth and to inform strategies to improve access to care.

Genomic instability in non-breast/ovarian malignancies of individuals with germline pathogenic variants in BRCA1/2.

Individuals with germline pathogenic variants (gPVs) in BRCA1 or BRCA2 (BRCA1/2) are at a high risk of breast- and ovarian carcinomas (BOCs) with BRCA1/2-deficiency and homologous recombination deficiency (HRD) that can be detected by analysis of genome-wide genomic instability features such as large-scale state transitions, telomeric allelic imbalances and genomic loss-of-heterozygosity. Malignancies with HRD are more sensitive to platinum-based therapies and PARP inhibitors. Here, we aim to investigate the fraction of non-BOC malignancies that have BRCA1/2-deficiency and genomic instability features. The full tumor history of a large historical clinic-based consecutive cohort of 2,965 individuals with gPVs in BRCA1/2 was retrieved via the Dutch nationwide pathology databank (Palga). In total, 169 non-BOC malignancies were collected and analyzed with targeted next-generation sequencing and shallow whole-genome sequencing to determine somatic second hit alterations and genomic instabilities indicative of HRD, respectively. BRCA1/2-deficiency was detected in 27% (21/79) and 23% (21/90) of 20 different types of non-BOC malignancies of individuals with gPVs in BRCA1 and BRCA2, respectively. These malignancies had a higher genomic instability score than BRCA1- or BRCA2-proficient malignancies (P < .001 and P < .001, respectively). BRCA1/2-deficiency and genomic instability features were found in 27% and 23% of a broad spectrum of non-BOC malignancies in individuals with gPVs in BRCA1 and BRCA2, respectively. Evaluation of the effectivity of PARP-inhibitors in these individuals should be focused on tumors with confirmed absence of a wild type allele.

Abstract PO4-09-01: Survival of patients harboring a germline ATM pathogenic/likely pathogenic variant and diagnosed with breast cancer: A case-control study

Abstract Introduction: Patients harboring a pathogenic/likely pathogenic variant (PV/LPV) in ATM present an increased lifetime risk of developing breast cancer (BC). The survival outcomes of these patients are not well-known. Methods: Retrospective, multicentric case-control study. Case group included patients with stage I-III breast cancer harboring a PV/LPV in ATM. Control group included patients with stage I-III breast cancer with a negative germline BC multigene panel testing including ATM gene analysis. Clinical outcomes defined as locoregional relapse-free survival (RFS), distant RFS and breast cancer specific survival were compared between cases and controls. Case group was obtained from five hereditary cancer units and control group was obtained from a sporadic clinic-based cohort. Cases and controls were matched 1:2 by stage, molecular subtype by immunohistochemistry, age at BC diagnosis and year of BC diagnosis. Baseline continuous variables were presented as mean and standard deviation and comparison was performed with Student´s t-test. Baseline categorical variables were presented with number and percentage and comparison were performed using chi-square test. Survival analyses were estimated by Kaplan-Meier curves, the comparison of survival was tested by stratified log-rank testing. Cox proportional hazards model was used to estimate the hazard ratio and confidence intervals. Results: We identified 64 patients (p) with an ATM PV/LPV and 120 controls. Median age at diagnosis was 47 years (28-84) and 46 years (25-88), respectively. The main tumoral characteristics in both groups were ductal (87.5% and 83.5%), luminal B-HER2 negative (37.5% and 45.8%) with histological grade II (54.7% and 58.5%) tumors. Majority of tumors in both groups were diagnosed at stage II (53.1% and 54.2%). Differences between groups were observed in first-degree BC family history (39p (61.9%) vs 51p (43.6%); p=0.02); frequency of multicentric/multifocal tumors (15p (25%) vs 13p (11.1%); p=0.018); contralateral breast cancer (16p (25%) vs 8p (6.7%); p=0.0004) and type of surgery (46.8% conservative surgery in cases and 69.2% in controls; p&amp;lt; 0.001). The result of the germline genetic study was not available for all patients before surgery. Baseline characteristics are summarized in Table 1. With a median follow-up of 6.7 years, we observed more locoregional recurrence and distant recurrence in the control group (ipsilateral local or lymphatic recurrence: 0p (0%) vs 15p (12.5%); p=0.078; metachronic contralateral breast cancer: 7p (12.7%) vs 3p (2.6%); p=0.02; distance recurrence 5p (7.8%) vs 24p (20%); p=0.03. No differences between groups were observed in BC-specific survival analysis, with a median BC-specific survival of 6.24y (4.67-12.1) in patients with ATM and 6.68y (6.12-7.94) in the control group (HR: 1.21 (0.88-1.65); p=0.24). Conclusions: Patients with BC harboring a germline ATM PV/LPV had more multifocal and multicentric disease at diagnosis; and more synchronous and metachronous contralateral BC compared to controls, with no differences in BC-specific survival. Further studies in a larger cohort are warranted to analyze sensitivity to systemic therapies. Table 1. Baseline characteristics of cases and control groups. ER (Estrogen Receptor) positive if &amp;gt; or equal to 1%; PR (Progesterone Receptor) positive if &amp;gt; or equal to 1%; HER2 (Human epidermal growth factor receptor-2); ChTh: Chemotherapy; SLNB: Sentinel Lymph Node Biopsy; AL: Axillar lymphadenectomy Citation Format: Mara Cruellas, Ariadna Roqué, Nuria Dueñas, Iris Teruel, Noemí Tuset Der-Abrain, Alejandra Rezqallah, Víctor Navarro, Laia Joval-Ramentol, Maite Torres, Cristina Saura, Joan Brunet, Judith Balmaña. Survival of patients harboring a germline ATM pathogenic/likely pathogenic variant and diagnosed with breast cancer: A case-control study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-09-01.

Association of Plasma YKL-40 With MRI, CSF, and Cognitive Markers of Brain Health and Dementia.

Higher YKL-40 levels in the CSF are a known biomarker of brain inflammation. We explored the utility of plasma YKL-40 as a biomarker for accelerated brain aging and dementia risk. We performed cross-sectional and prospective analyses of 4 community-based cohorts in the United States or Europe: the Age, Gene/Environment Susceptibility-Reykjavik Study, Atherosclerosis Risk in the Communities study, Coronary Artery Risk Development in Young Adults study, and Framingham Heart Study (FHS). YKL-40 was measured from stored plasma by a single laboratory using Mesoscale Discovery with levels log transformed and standardized within each cohort. Outcomes included MRI total brain volume, hippocampal volume, and white matter hyperintensity volume (WMHV) as a percentage of intracranial volume, a general cognitive composite derived from neuropsychological testing (SD units [SDU]), and the risk of incident dementia. We sought to replicate associations with dementia in the clinic-based ACE csf cohort, which also had YKL-40 measured from the CSF. Meta-analyses of MRI outcomes included 6,558 dementia-free participants, and for analysis of cognition, 6,670. The blood draw preceded MRI/cognitive assessment by up to 10.6 years across cohorts. The mean ages ranged from 50 to 76 years, with 39%-48% male individuals. In random-effects meta-analysis of study estimates, each SDU increase in log-transformed YKL-40 levels was associated with smaller total brain volume (β = -0.33; 95% CI -0.45 to -0.22; p < 0.0001) and poorer cognition (β = -0.04; 95% CI -0.07 to -0.02; p < 0.01), following adjustments for demographic variables. YKL-40 levels did not associate with hippocampal volume or WMHV. In the FHS, each SDU increase in log YKL-40 levels was associated with a 64% increase in incident dementia risk over a median of 5.8 years of follow-up, following adjustments for demographic variables (hazard ratio 1.64; 95% CI 1.25-2.16; p < 0.001). In the ACE csf cohort, plasma and CSF YKL-40 were correlated (r = 0.31), and both were associated with conversion from mild cognitive impairment to dementia, independent of amyloid, tau, and neurodegeneration status. Higher plasma YKL-40 levels were associated with lower brain volume, poorer cognition, and incident dementia. Plasma YKL-40 may be useful for studying the association of inflammation and its treatment on dementia risk.

Prevalence and risk factors for impaired activities of daily living in patients with neo-vascular age-related macular degeneration who present for anti-VEGF treatment

Background/ObjectivesTo assess the prevalence and correlates of impaired activities of daily living (ADLs) in patients with neovascular age-related macular degeneration (nAMD) who present for anti-vascular endothelial growth factor (VEGF) therapy.MethodsIn a clinic-based cohort of 437 patients with nAMD who presented for anti-VEGF therapy, the Older American Resources and Services Scale (OARS) was administered to assess for impairments in basic, instrumental and total ADL. Logistic regression analyses were conducted to determine odds ratios (OR) and 95% confidence intervals (CI) for factors associated with ADL impairment.ResultsThe prevalence of impaired basic, instrumental and total ADL was 37.76%, 67.82% and 39.59%, respectively. In multivariate-adjusted models, moderate visual impairment [OR 5.65, 95% CI (2.31–13.83) and blindness [OR 5.43, 95% CI (2.09–14.12)] were associated with greater odds of impaired total ADL. Depressive symptoms [OR 2.08, 95% CI (1.08–4.00)], the presence of any disability [OR 3.16, 95% CI (1.64–0.07)] and never driving [OR 4.00, 95% CI (1.60–10.00)] were also positively associated with total ADL impairment. Better vision-related quality of life (QoL) was inversely associated with impaired instrumental ADL whilst higher health-related QoL scores were associated with decreased odds of total ADL impairment.ConclusionsThere is a high prevalence rate of ADL impairment among nAMD patients presenting for therapy. Visual impairment, never driving, poor physical and mental health increased the odds of experiencing ADL impairment whilst better VRQoL and HRQoL reduced the odds of impairment.

Genomic disparity impacts variant classification of cancer susceptibility genes in Turkish breast cancer patients.

Turkish genome is underrepresented in large genomic databases. This study aims to evaluate the effect of allele frequency in the Turkish population in determining the clinical utility of germline findings in breast cancer, including invasive lobular carcinoma (ILC), mixed invasive ductal and lobular carcinoma (IDC-L), and ductal carcinoma (DC). Two clinic-based cohorts from the Umraniye Research and Training Hospital (URTH) were used in this study: a cohort consisting of 132 women with breast cancer and a non-cancer cohort consisting of 492 participants. The evaluation of the germline landscape was performed by analysis of 27 cancer genes. The frequency and type of variants in the breast cancer cohort were compared to those in the non-cancer cohort to investigate the effect of population genetics. The variant allele frequencies in Turkish Variome and gnomAD were statistically evaluated. The genetic analysis identified 121 variants in the breast cancer cohort (actionable = 32, VUS = 89) and 223 variants in the non-cancer cohort (actionable = 25, VUS = 188). The occurrence of 21 variants in both suggested a possible genetic population effect. Evaluation of allele frequency of 121 variants from the breast cancer cohort showed 22% had a significantly higher value in Turkish Variome compared to gnomAD (p < 0.0001, 95% CI) with a mean difference of 60 times (ranging from 1.37-354.4). After adjusting for variant allele frequency using the ancestry-appropriate database, 6.7% (5/75) of VUS was reclassified to likely benign. To our knowledge, this is the first study of population genetic effects in breast cancer subtypes in Turkish women. Our findings underscore the need for a large genomic database representing Turkish population-specific variants. It further highlights the significance of the ancestry-appropriate population database for accurate variant assessment in clinical settings.

Protocol for preliminary, multicenteric validation of "PoCOsteo device": A point of care tool for proteomic and genomic study of osteoporosis.

One of the goals of the HORIZON 2020 project PoCOsteo was to develop a medical device, which would measure and/or quantify proteomic as well as genomic factors as present in whole blood samples collected through finger prick. After validating the tool in the clinical setting, the next step would be its clinical validation based on the existing guidelines. This article presents the protocol of a validation study to be carried out independently at two different centers (Division of Endocrinology and Diabetology at the Medical University of Graz as a clinic-based cohort, and the Endocrinology and Metabolism Research Institute at the Tehran University of Medical Sciences as a population-based cohort). It aims to assess the tool according to the Clinical & Laboratory Standards Institute guidelines, confirming if the proteomics and genomics measurements provided by the tool are accurate and reproducible compared with the existing state-of-the-art tests. This is the first time that such a detailed protocol for lab validation of a medical tool for proteomics and genomic measurement is designed based on the existing guidelines and thus could be used as a template for clinical validation of future point-of-care tools. Moreover, the multicentric cohort design will allow the study of a large number of diverse individuals, which will improve the validity and generalizability of the results for different settings.

Individuals from Memory Clinic were Associated with Severer Amyloid Deposition in the Chinese Population in Urban Cities

AbstractBackgroundAmyloid deposition is considered the initial pathology in Alzheimer’s disease (AD), investigation of amyloid pathology and the risk factor for amyloid pathology and cognitive declines in the Chinese population is critical for personalized management. However, the prevalence of amyloid deposition and the risk factors for amyloid pathology are unknown in the Chinese population.MethodParticipants were recruited from urban communities and memory clinics in Shanghai and Zhengzhou, China. A total of 246 AD individuals, 274 Mild cognitive impairment (MCI) individuals, and 506 Normal cognition (NC) individuals were identified: 106 AD, 156 MCI and 506 NC from the Community‐based cohort (COMC) as well as 140 AD and 118 MCI from the Clinic‐based cohort (CLIC). Amyloid positivity and deposition were analyzed based on amyloid positron emission tomography (PET) scans. We also performed a partial least squares (PLS) analysis to evaluate the associations of cohort, age, sex, education level, and ApoE genotype with amyloid qualification, quantification results and global cognition in all 1026 participants.ResultAcross the two cohorts, the AD group displayed the significantly highest rate of amyloid positivity (211/246, 85.8%), followed by the MCI (122/274, 44.5%) and NC groups (136/506, 26.9%, all P &lt; 0.001). Participants from the CLIC displayed a higher rate of amyloid positivity than those from the COMC in the MCI (68/118, 57.6% vs. 54/156, 34.6%, P &lt; 0.001) and AD groups (128/140, 91.4% vs. 83/106, 78.3%, P = 0.006). MCI (SUVr: 1.37 ± 0.25 vs. 1.25 ± 0.18, P &lt; 0.001), Aβ+ MCI (SUVr: 1.48 ± 0.27 vs. 1.37 ± 0.24, P = 0.03) and AD individuals (SUVr: 1.47 ± 0.23 vs. 1.39 ± 0.23, P = 0.01) in the CLIC displayed significantly greater amyloid deposition than those in the COMC. According to the PLS model, we found that the CLIC was significantly associated with positive amyloid deposition and severer amyloid deposition.ConclusionWe found that individuals from CLIC displayed a higher amyloid positive rate and severer amyloid deposition. Specifically, in a PLS model, The CLIC, was strongly associated with amyloid pathology.

Individuals from Memory Clinic were Associated with Severer Amyloid Deposition in the Chinese Population in Urban Cities

AbstractBackgroundAmyloid deposition is considered the initial pathology in Alzheimer’s disease (AD), investigation of amyloid pathology and the risk factor for amyloid pathology and cognitive declines in the Chinese population is critical for personalized management. However, the prevalence of amyloid deposition and the risk factors for amyloid pathology are unknown in the Chinese population.MethodParticipants were recruited from urban communities and memory clinics in Shanghai and Zhengzhou, China. A total of 246 AD individuals, 274 Mild cognitive impairment (MCI) individuals, and 506 Normal cognition (NC) individuals were identified: 106 AD, 156 MCI and 506 NC from the Community‐based cohort (COMC) as well as 140 AD and 118 MCI from the Clinic‐based cohort (CLIC). Amyloid positivity and deposition were analyzed based on amyloid positron emission tomography (PET) scans. We also performed a partial least squares (PLS) analysis to evaluate the associations of cohort, age, sex, education level, and ApoE genotype with amyloid qualification, quantification results and global cognition in all 1026 participants.ResultAcross the two cohorts, the AD group displayed the significantly highest rate of amyloid positivity (211/246, 85.8%), followed by the MCI (122/274, 44.5%) and NC groups (136/506, 26.9%, all P &lt; 0.001). Participants from the CLIC displayed a higher rate of amyloid positivity than those from the COMC in the MCI (68/118, 57.6% vs. 54/156, 34.6%, P &lt; 0.001) and AD groups (128/140, 91.4% vs. 83/106, 78.3%, P = 0.006). MCI (SUVr: 1.37 ± 0.25 vs. 1.25 ± 0.18, P &lt; 0.001), Aß+ MCI (SUVr: 1.48 ± 0.27 vs. 1.37 ± 0.24, P = 0.03) and AD individuals (SUVr: 1.47 ± 0.23 vs. 1.39 ± 0.23, P = 0.01) in the CLIC displayed significantly greater amyloid deposition than those in the COMC. According to the PLS model, we found that the CLIC was significantly associated with positive amyloid deposition and severer amyloid deposition.ConclusionWe found that individuals from CLIC displayed a higher amyloid positive rate and severer amyloid deposition. Specifically, in a PLS model, The CLIC, was strongly associated with amyloid pathology.

Clinical Application of the Multicomponent Grading System for Sleep Apnea Classification and Incident Cardiovascular Mortality.

Objective To evaluate the clinical utility of the Baveno classification in predicting incident cardiovascular mortality after five years of follow-up in a clinic-based cohort of patients with obstructive sleep apnea (OSA). Materials and Methods We evaluated the reproducibility of the Baveno classification using data from the Santiago Obstructive Sleep Apnea (SantOSA) study. The groups were labeled Baveno A (minor symptoms and comorbidities), B (severe symptoms and minor comorbidities), C (minor symptoms and severe comorbidities), and D (severe symptoms and comorbidities). Within-group comparisons were performed using analysis of variance (ANOVA) and post hoc tests. The associations between groups and incident cardiovascular mortality were determined through the Mantel-Cox and Cox proportional hazard ratios (HRs) adjusted by covariables. Results A total of 1,300 OSA patients were included (Baveno A: 27.7%; B: 28%; C: 16.8%; and D: 27.5%). The follow-up was of 5.4 years. Compared to Baveno A, the fully-adjusted risk of cardiovascular mortality with Baveno B presented an HR of 1.38 (95% confidence interval [95%CI]: 0.14-13.5; p = 0.78); with Baveno C, it was of 1.71 (95%CI: 0.18-16.2; p = 0.63); and, with Baveno D, of 1.04 (95%CI: 0.12-9.2; p = 0.98). We found no interactions involving Baveno group, sex and OSA severity. Discussion Among OSA patients, the Baveno classification can describe different subgroups. However, its utility in identifying incident cardiovascular mortality is unclear. Long-term follow-up studies and the inclusion of demographic variables in the classification could improve its ability to detect a high-risk phenotype associated with cardiovascular mortality. Conclusion The Baveno classification serves as a valuable method for categorizing varying groups of patients afflicted with OSA. Nevertheless, its precision in identifying occurrence of cardiovascular mortality is still unclear.

Functional recovery in a cohort of ECMO and non-ECMO acute respiratory distress syndrome survivors

BackgroundThe mortality benefit of VV-ECMO in ARDS has been extensively studied, but the impact on long-term functional outcomes of survivors is poorly defined. We aimed to assess the association between ECMO and functional outcomes in a contemporaneous cohort of survivors of ARDS.MethodsMulticenter retrospective cohort study of ARDS survivors who presented to follow-up clinic. The primary outcome was FVC% predicted. Univariate and multivariate regression models were used to evaluate the impact of ECMO on the primary outcome.ResultsThis study enrolled 110 survivors of ARDS, 34 of whom were managed using ECMO. The ECMO cohort was younger (35 [28, 50] vs. 51 [44, 61] years old, p < 0.01), less likely to have COVID-19 (58% vs. 96%, p < 0.01), more severely ill based on the Sequential Organ Failure Assessment (SOFA) score (7 [5, 9] vs. 4 [3, 6], p < 0.01), dynamic lung compliance (15 mL/cmH20 [11, 20] vs. 27 mL/cmH20 [23, 35], p < 0.01), oxygenation index (26 [22, 33] vs. 9 [6, 11], p < 0.01), and their need for rescue modes of ventilation. ECMO patients had significantly longer lengths of hospitalization (46 [27, 62] vs. 16 [12, 31] days, p < 0.01) ICU stay (29 [19, 43] vs. 10 [5, 17] days, p < 0.01), and duration of mechanical ventilation (24 [14, 42] vs. 10 [7, 17] days, p < 0.01). Functional outcomes were similar in ECMO and non-ECMO patients. ECMO did not predict changes in lung function when adjusting for age, SOFA, COVID-19 status, or length of hospitalization.ConclusionsThere were no significant differences in the FVC% predicted, or other markers of pulmonary, neurocognitive, or psychiatric functional recovery outcomes, when comparing a contemporaneous clinic-based cohort of survivors of ARDS managed with ECMO to those without ECMO.

Subjective cognitive complaints and blood biomarkers of neurodegenerative diseases: a longitudinal cohort study

BackgroundSubjective cognitive complaints (SCC) have been mostly studied in the context of Alzheimer’s disease in memory clinic settings. The potential of combining SCC with genetic information and blood biomarkers of neurodegenerative diseases for risk assessment of dementia and depression in the absence of dementia among community-dwelling older adults has so far not been explored.MethodsData were based on a population-based cohort of 6357 participants with a 17-year follow-up (ESTHER study) and a clinic-based cohort of 422 patients. Participants of both cohorts were grouped according to the diagnosis of dementia (yes/no) and the diagnosis of depression in the absence of dementia (yes/no). Participants without dementia included both cognitively unimpaired participants and cognitively impaired participants. Genetic information (APOE ε4 genotype) and blood-based biomarkers of neurodegenerative diseases (glial fibrillary acidic protein; GFAP, neurofilament light chain; NfL, phosphorylated tau181; p-tau181) were available in the ESTHER study and were determined with Simoa Technology in a nested case–control design. Logistic regression models adjusted for relevant confounders were run for the outcomes of all-cause dementia and depression in the absence of dementia.ResultsThe results showed that persistent SCC were associated both with increased risk of all-cause dementia and of depression without dementia, independently of the diagnostic setting. However, the results for the ESTHER study also showed that the combination of subjective complaints with APOE ε4 and with increased GFAP concentrations in the blood yielded a substantially increased risk of all-cause dementia (OR 5.35; 95%CI 3.25–8.81, p-value < 0.0001 and OR 7.52; 95%CI 2.79–20.29, p-value < 0.0001, respectively) but not of depression. Associations of NfL and p-tau181 with risk of all-cause dementia and depression were not statistically significant, either alone or in combination with SCC, but increased concentrations of p-tau181 seemed to be associated with an increased risk for depression.ConclusionIn community and clinical settings, SCC predict both dementia and depression in the absence of dementia. The addition of GFAP could differentiate between the risk of all-cause dementia and the risk of depression among individuals without dementia.