Baseline Diagnosis Research Articles

Tonometry by Ocular Response Analyzer in Keratoconic and Warpage Eyes in Comparison with Normal Eyes.

Purpose:To compare intraocular pressure (IOP) values measured by ocular response analyzer (ORA) in contact lens-induced corneal warpage, normal, and keratoconic eyes.Methods:In a prospective, observational case–control study, 94 eyes of 47 warpage-suspected cases and 46 eyes of 23 keratoconic patients were enrolled. Warpage-suspected cases were followed until a definite diagnosis was made (warpage, nonwarpage normal, or keratoconus). ORA tonometry and corneal biomechanics testing were performed for all cases in each visit. We had 2–3 measured corneal-compensated IOP (IOPcc) and Goldmann-correlated IOP (IOPg) for each patient (based on group) with at least 2-week interval.Results:After following up of warpage-suspected patients, finally 44 eyes of 22 patients had confirmed soft contact lens-related corneal warpage. Forty-six eyes of 23 people were finally diagnosed as nonwarpage normal eyes. Forty-six eyes of 23 known keratoconus patients were also included for comparison. The demographic and refractive data were not different between the warpage and nonwarpage normal groups but were different in the keratoconus group. Both IOPcc and IOPg were statistically different with the highest value in the warpage group followed by normal and keratoconus groups; the same trend was observed in central corneal thickness (CCT). The mean of IOPg was 14.94 ± 2.65, 13.7 ± 2.33, and 10.86 ± 3 and IOPcc was 15.73 ± 2.4, 15.28 ± 2.43, and 14.08 ± 2.55 in the warpage, normal, and keratoconus groups, respectively. IOPg and IOPcc in the warpage group (based on baseline diagnosis) did not regress to become closer to IOP of normal eyes after discontinuation of contact lens in their follow-up visits (P value for IOPg and IOPcc trends in the warpage group was 0.07 and 0.09 controlling for CCT, respectively). Both IOPcc and IOPg were significantly lower in keratoconic eyes in comparison with normal eyes. After correction for the confounding effect of CCT, a lower IOPcc in keratoconus versus warpage remained significant (P = 0.02).Conclusion:Both IOPcc and IOPg were statistically different with the highest value in the warpage group followed by normal and keratoconus groups, just like their CCT. After correction for the confounding effect of CCT, there was no statistically significant difference between the three groups in their measured IOPcc and IOPg except for IOPcc in keratoconus versus warpage (P = 0.02).

Peripheral Markers of Vascular Endothelial Dysfunction Show Independent but Additive Relationships with Brain-Based Biomarkers in Association with Functional Impairment in Alzheimer's Disease.

Background:Cerebrovascular dysfunction confers risk for functional decline in Alzheimer’s disease (AD), yet the clinical interplay of these two pathogenic processes is not well understood.Objective:We utilized Alzheimer’s Disease Neuroimaging Initiative (ADNI) data to examine associations between peripherally derived soluble cell adhesion molecules (CAMs) and clinical diagnostic indicators of AD.Methods:Using generalized linear regression models, we examined cross-sectional relationships of soluble plasma vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-Selectin to baseline diagnosis and functional impairment (clinical dementia rating sum-of-boxes, CDR-SB) in the ADNI cohort (n = 112 AD, n = 396 mild cognitive impairment (MCI), n = 58 cognitively normal). We further analyzed associations of these biomarkers with brain-based AD biomarkers in a subset with available cerebrospinal fluid (CSF) data (n = 351). p-values derived from main effects and interaction terms from the linear regressions were used to assess the relationship between independent and dependent variables for significance (significance level was set at 0.05 a priori for all analysis).Results:Higher mean VCAM-1 (p = 0.0026) and ICAM-1 (p = 0.0189) levels were found in AD versus MCI groups; however, not in MCI versus cognitively normal groups. Only VCAM-1 was linked with CDR-SB scores (p = 0.0157), and APOE ɛ4 genotype modified this effect. We observed independent, additive associations when VCAM-1 and CSF amyloid-β (Aβ42), total tau, phosphorylated tau (P-tau), or P-tau/Aβ42 (all < p = 0.01) were combined in a CDR-SB model; ICAM-1 showed a similar pattern, but to a lesser extent.Conclusion:Our findings indicate independent associations of plasma-based vascular biomarkers and CSF biomarkers with AD-related clinical impairment.

Inhibitory effects of biofeedback electrostimulation therapy on pain and cortisol levels in chronic neuropathic pain: A randomized-controlled trial.

Objectives This study aims to investigate the effectiveness of biofeedback electrostimulation therapy (BEST) in chronic neuropathic pain and to evaluate changes in perceived level of pain and level of blood cortisol before and after treatment. Patients and methods This single-blind, prospective, randomized-controlled study included a total of 20 patients (8 males, 12 females; mean age: 53.5±13.8; range, 31 to 82 years) with chronic neuropathic pain between January 2014 and June 2014. The patients were randomized to BEST (n=10) or placebo (n=10) group. Pain was measured using the Visual Analog Scale, and serum cortisol levels were measured before and after treatment. Results There was no significant difference in the baseline demographics, diagnosis, and treatment modalities between the groups. Approximately 50% patients in the treatment group reported that the treatment was effective, compared to 30% in the placebo group. Pain score reduction after treatment in the BEST group was significant (p<0.05), while it was not significant in the placebo group (p=0.4). Cortisol levels significantly reduced only in the BEST group after treatment (p=0.013). Conclusion The BEST yields reduction in pain severity and cortisol levels. Based on these results, it seems to be effective in the treatment of chronic neuropathic pain after a single treatment and may be more effective for long-term management.

The association between manic symptoms in adolescence and preschool symptoms: The importance of family history.

First, to investigate whether specific manic symptoms in preschool predict manic symptom severity in adolescence. Second, to investigate the interaction between family history (FH) of bipolar disorder (BP) and preschool manic symptoms in predicting later adolescent manic symptom severity. This analysis utilized data from the Preschool Depression Study (PDS) which followed 306 preschoolers aged 3-6years over time since 2003. Only subjects who had data both at baseline (age 3-6years) and at or after age 12 were included (n=122). Baseline manic symptom severity scores and diagnoses were assessed by the Preschool Age Psychiatric Assessment (PAPA). Manic symptoms severity at age ≥12 was assessed by the Kiddie Mania Rating Scale (KMRS). FH were ascertained by Family Interview for Genetic Studies (FIGS). Multilevel models of KMRS total score at age ≥12 by preschool mania symptoms with gender, baseline age, baseline ADHD, as well as baseline MDD diagnosis as covariates, and false discovery rate correction were used in statistical analysis. Hypertalkativity, flight of ideas, uninhibited gregariousness, decreased need for sleep (DNFS), and increased motor pressure/ motor activity/ energy in preschool were associated with increased KMRS score at age ≥12. Racing thoughts, inappropriate laughing, and DNFS in early childhood were associated with higher manic symptoms in adolescence in subjects with FH of BP compared to those without FH. The longitudinal clinical importance of displaying manic symptoms (racing thoughts, inappropriate laughing, and DNFS) in early childhood varies by FH. Among the aforementioned symptoms, DNFS was a robust predictor of later manic symptoms. Assessing FH of BP is very important in clinical risk prediction from early childhood.

Quantitative Evaluation of COVID-19 Pneumonia Lung Extension by Specific Software and Correlation with Patient Clinical Outcome.

Lung infection named as COVID-19 is an infectious disease caused by the most recently discovered coronavirus 2 (SARS-CoV-2). CT (computed tomography) has been shown to have good sensitivity in comparison with RT-PCR, particularly in early stages. However, CT findings appear to not always be related to a certain clinical severity. The aim of this study is to evaluate a correlation between the percentage of lung parenchyma volume involved with COVID-19 infection (compared to the total lung volume) at baseline diagnosis and correlated to the patient’s clinical course (need for ventilator assistance and or death). All patients with suspected COVID-19 lung disease referred to our imaging department for Chest CT from 24 February to 6 April 2020were included in the study. Specific CT features were assessed including the amount of high attenuation areas (HAA) related to lung infection. HAA, defined as the percentage of lung parenchyma above a predefined threshold of −650 (HAA%, HAA/total lung volume), was automatically calculated using a dedicated segmentation software. Lung volumes and CT findings were correlated with patient’s clinical course. Logistic regressions were performed to assess the predictive value of clinical, inflammatory and CT parameters for the defined outcome. In the overall population we found an average infected lung volume of 31.4 ± 26.3% while in the subgroup of patients who needed ventilator assistance and who died as well as the patients who died without receiving ventilator assistance the volume of infected lung was significantly higher 41.4 ± 28.5 and 72.7 ± 36.2 (p < 0.001). In logistic regression analysis best predictors for ventilation and death were the presence of air bronchogram (p = 0.006), crazy paving (p = 0.007), peripheral distribution (p < 0.001), age (p = 0.002), fever at admission (p = 0.007), dyspnea (p = 0.002) and cardiovascular comorbidities (p < 0.001). In multivariable analysis, quantitative CT parameters and features added incremental predictive value beyond a model with only clinical parameters (area under the curve, 0.78 vs. 0.74, p = 0.02). Our study demonstrates that quantitative evaluation of lung volume involved by COVID-19 pneumonia helps to predict patient’s clinical course.

Rethinking the course of psychotic disorders: modelling long-term symptom trajectories.

The clinical course of psychotic disorders is highly variable. Typically, researchers have captured different course types using broad pre-defined categories. However, whether these adequately capture symptom trajectories of psychotic disorders has not been fully assessed. Using data from AESOP-10, we sought to identify classes of individuals with specific symptom trajectories over a 10-year follow-up using a data-driven approach. AESOP-10 is a follow-up, at 10 years, of 532 incident cases with a first episode of psychosis initially identified in south-east London and Nottingham, UK. Using extensive information on fluctuations in the presence of psychotic symptoms, we fitted growth mixture models to identify latent trajectory classes that accounted for heterogeneity in the patterns of change in psychotic symptoms over time. We had sufficient data on psychotic symptoms during the follow-up on 326 incident patients. A four-class quadratic growth mixture model identified four trajectories of psychotic symptoms: (1) remitting-improving (58.5%); (2) late decline (5.6%); (3) late improvement (5.4%); (4) persistent (30.6%). A persistent trajectory, compared with remitting-improving, was associated with gender (more men), black Caribbean ethnicity, low baseline education and high disadvantage, low premorbid IQ, a baseline diagnosis of non-affective psychosis and long DUP. Numbers were small, but there were indications that those with a late decline trajectory more closely resembled those with a persistent trajectory. Our current approach to categorising the course of psychotic disorders may misclassify patients. This may confound efforts to elucidate the predictors of long-term course and related biomarkers.

A Systematic Review of Telehealth and Sport-Related Concussion: Baseline Testing, Diagnosis, and Management.

Background: The use of telehealth has increased as a result of the COVID-19 pandemic. As sports at all levels resume, sports medicine physicians may be interested in how telehealth can be used for concussion care. Questions/Purpose: We sought to assess how telehealth has been used in the baseline testing, diagnosis, and/or management of concussion. Secondarily, we sought to assess the strengths and weaknesses of telehealth for concussion care and identify aspects of concussion care for which telehealth has not yet been studied. Methods: A systematic review was performed in September 2020 of PubMed and Embase using the following terms: concuss*, "mild traumatic brain," "head injur*," telehealth, telemedicine, telecare, "mobile health," m-health, virtual. Studies included were original research articles investigating the use of telehealth in the care of concussion (including baseline testing, diagnosis, and management), published in English, and had full text available. Results: A total of 356 articles were screened, of which 5 were determined to meet inclusion criteria. These articles described the use of telehealth for managing concussion in military and rural settings. No articles involved the use of telehealth for baseline concussion testing of athletes or for sideline evaluation. Conclusion: Despite the limited original research on the use of telehealth for concussion care, the articles identified provide a foundation for exploring the potential value of telehealth in the office practice and sports team setting. Telehealth may expand the ability of a sports medicine physician to provide timely and effective concussion care to athletes during the COVID-19 pandemic and beyond. More rigorous research is needed.

A multilayer multimodal detection and prediction model based on explainable artificial intelligence for Alzheimer\u2019s disease

Alzheimer’s disease (AD) is the most common type of dementia. Its diagnosis and progression detection have been intensively studied. Nevertheless, research studies often have little effect on clinical practice mainly due to the following reasons: (1) Most studies depend mainly on a single modality, especially neuroimaging; (2) diagnosis and progression detection are usually studied separately as two independent problems; and (3) current studies concentrate mainly on optimizing the performance of complex machine learning models, while disregarding their explainability. As a result, physicians struggle to interpret these models, and feel it is hard to trust them. In this paper, we carefully develop an accurate and interpretable AD diagnosis and progression detection model. This model provides physicians with accurate decisions along with a set of explanations for every decision. Specifically, the model integrates 11 modalities of 1048 subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) real-world dataset: 294 cognitively normal, 254 stable mild cognitive impairment (MCI), 232 progressive MCI, and 268 AD. It is actually a two-layer model with random forest (RF) as classifier algorithm. In the first layer, the model carries out a multi-class classification for the early diagnosis of AD patients. In the second layer, the model applies binary classification to detect possible MCI-to-AD progression within three years from a baseline diagnosis. The performance of the model is optimized with key markers selected from a large set of biological and clinical measures. Regarding explainability, we provide, for each layer, global and instance-based explanations of the RF classifier by using the SHapley Additive exPlanations (SHAP) feature attribution framework. In addition, we implement 22 explainers based on decision trees and fuzzy rule-based systems to provide complementary justifications for every RF decision in each layer. Furthermore, these explanations are represented in natural language form to help physicians understand the predictions. The designed model achieves a cross-validation accuracy of 93.95% and an F1-score of 93.94% in the first layer, while it achieves a cross-validation accuracy of 87.08% and an F1-Score of 87.09% in the second layer. The resulting system is not only accurate, but also trustworthy, accountable, and medically applicable, thanks to the provided explanations which are broadly consistent with each other and with the AD medical literature. The proposed system can help to enhance the clinical understanding of AD diagnosis and progression processes by providing detailed insights into the effect of different modalities on the disease risk.

The Epidemiology of UK Autoimmune Liver Disease Varies With Geographic Latitude

Background & AimsThe epidemiology of autoimmune liver disease (AILD) is challenging to study because of the diseases’ rarity and because of cohort selection bias. Increased incidence farther from the Equator has been reported for multiple sclerosis, another autoimmune disease. We assessed the incidence of primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH) in relation to latitude.MethodsWe performed a retrospective cohort study using anonymized UK primary care records from January 1, 2002, to May 10, 2016. All adults without a baseline diagnosis of AILD were included and followed up until the first occurrence of an AILD diagnosis, death, or they left the database. Latitude was measured as registered general practice rounded down to whole degrees.ResultsThe cohort included 8,590,421 records with 53.3 × 107 years of follow-up evaluation from 694 practices. There were 1314 incident cases of PBC, 396 of PSC, and 1034 of AIH. Crude incidences were as follows: PBC, 2.47 (95% CI, 2.34–2.60); PSC, 0.74 (95% CI, 0.67–0.82); and AIH, 1.94 (95% CI, 1.83–2.06) per 100,000 per year. PBC incidence correlated with female sex, smoking, and deprivation; PSC incidence correlated with male sex and non-smoking; AIH incidence correlated with female sex and deprivation. A more northerly latitude was associated strongly with incidence of PBC: 2.16 (95% CI, 1.79–2.60) to 4.86 (95% CI, 3.93–6.00) from 50°N to 57°N (P = .002) and incidence of AIH: 2.00 (95% CI, 1.65–2.43) to 3.28 (95% CI, 2.53–4.24) (P = .003), but not incidence of PSC: 0.82 (95% CI, 0.60–1.11) to 1.02 (95% CI, 0.64–1.61) (P = .473). Incidence after adjustment for age, sex, smoking, and deprivation status showed similar positive correlations for PBC and AIH with latitude, but not PSC. Incident AIH cases were younger at more northerly latitude.ConclusionsWe describe an association in the United Kingdom between more northerly latitude and the incidence of PBC and AIH that requires both confirmation and explanation.

Comparison of Single and Multitask Learning for Predicting Cognitive Decline Based on MRI Data

The Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog) is a neuropsychological tool that has been designed to assess the severity of cognitive symptoms of dementia. Personalized prediction of the changes in ADAS-Cog scores could help in timing therapeutic interventions in dementia and at-risk populations. In the present work, we compared single and multitask learning approaches to predict the changes in ADAS-Cog scores based on T1-weighted anatomical magnetic resonance imaging (MRI). In contrast to most machine learning-based prediction methods ADAS-Cog changes, we stratified the subjects based on their baseline diagnoses and evaluated the prediction performances in each group. Our experiments indicated a positive relationship between the predicted and observed ADAS-Cog score changes in each diagnostic group, suggesting that T1-weighted MRI has a predictive value for evaluating cognitive decline in the entire AD continuum. We further studied whether correction of the differences in the magnetic field strength of MRI would improve the ADAS-Cog score prediction. The partial least square-based domain adaptation slightly improved the prediction performance, but the improvement was marginal. In summary, this study demonstrated that ADAS-Cog change could be, to some extent, predicted based on anatomical MRI. Based on this study, the recommended method for learning the predictive models is a single-task regularized linear regression due to its simplicity and good performance. It appears important to combine the training data across all subject groups for the most effective predictive models.

951. Weight Gain Associated With Antiretroviral Therapy

BackgroundObesity is a global public health crisis with a growing prevalence in persons with human immunodeficiency virus (PWH) population. In this study, we aimed to investigate factors associated with weight gain in the PWH population.MethodsThis was a single-centered, retrospective cohort study of our clinic patient population from January 1, 2015 to January 1, 2019. Patients with human immunodeficiency virus (HIV) were identified from the electronic health record and a randomized sample of 300 patients who had at least two follow up appointments, were on antiretroviral therapy, and had viral loads less than 200 were evaluated. The primary outcome was weight change over follow up. Cox Proportional Hazards models were used, taking a weight gain > 3 kg as the outcome, and the time on therapy between visits as the time to event. Robust linear regression was used to model mean changes in weight, accounting for influential observations. All analysis were performed in STATA 16.0.Table 1 ResultsAt baseline, 87% were male, 63% were white, and 65% were overweight/obese. 30% were on a protease inhibitor, 46% were on non-nucleoside reverse transcriptase inhibitor, and 37% were on an integrase inhibitor. 64% were on Tenofovir disoproxil (TDF), 8% were on Tenofovir alafenamide (TAF), and 19% were on Abacavir. Mean weight change over follow up was significantly increased at 1.31 kg (95% CI = 0.58 – 2.04 kg, p= 0.0004). TAF use and male gender were significantly associated with risk of weight gain > 3 kg in univariate analysis [respectively, OR = 2.53, 95% CI = 1.30 – 4.92, p = 0.006; OR = 2.60, 95% CI = 1.05 – 6.45, p = 0.04]. In multivariate analysis, TAF use was significantly associated with weight gain > 3 kg, while male gender was of borderline significance [respectively, OR = 2.29, 95% CI = 1.17 – 4.47, p = 0.01; OR = 2.40, 95% CI = 0.96 – 5.97, p=0.060]. Significant factors associated with weight change are noted in Table 1.ConclusionAs PWH are living longer on effective ARV therapy, monitoring for weight gain is required as obesity contributes to morbidity and mortality from cardiovascular disease and metabolic diseases. Key factors for weight gain in our clinic population include male gender, baseline diagnosis of hypertension, use of TAF, bictegravir use, and rilpivirine use.Disclosures Carlos Malvestutto, MD, Gilead Sciences (Advisor or Review Panel member)ViiV Healthcare (Advisor or Review Panel member)

Developmental effects in physiological stress in early adolescents with and without autism spectrum disorder

IntroductionHumans place high value on how they are socially evaluated by others. The Trier Social Stress Test (TSST) is a well-established measure of social evaluative threat that promotes activation of the hypothalamic pituitary adrenal (HPA) axis and release of cortisol. Higher cortisol responses in typically developing (TD) adolescents are influenced by age and pubertal development especially in later stages. Children with ASD have been shown to exhibit blunted cortisol in response to the TSST although adults with ASD show a more prototypical response. The current study examined physiological stress in early adolescents with ASD and TD. It was hypothesized that TD youth would show elevated cortisol in response to the TSST influenced by age and pubertal stage. In contrast, youth with ASD would show a more diminished stress response yet still show effects for age and pubertal development MethodsThe sample included 241 youth, 138 with ASD (median age=11.25) and 103 TD (median age=11.67). Standardized diagnostic and pubertal development (genital/breast (GB), and pubic hair (PH) stage) physical exams were performed. Salivary cortisol was collected before and after the TSST. Linear mixed effects models examined the effects of baseline cortisol, time, age, sex, pubertal stage, and diagnosis. ResultsWe did not find an effect of early pubertal development stage (GB or PH) on cortisol response. There was an interaction between age and TSST timepoint, showing stronger effects for older children across the timeline especially during the stressor. Finally, there was a significant diagnosis by TSST timepoint interaction characterized by a blunted cortisol stress response in youth with ASD compared to TD participants who showed higher cortisol. DiscussionWe found evidence that age contributes to an increase in cortisol in response to social evaluative threat during early adolescence. TD youth exhibit an adaptive elevated stress response to psychosocial threat whereas youth with ASD do not. There may exist a developmental lag in the perception of and stress responsivity to social evaluation which may emerge in older adolescents with ASD.

Spatial and Temporal Heterogeneity of PD-L1 Expression and Tumor Mutational Burden in Gastroesophageal Adenocarcinoma at Baseline Diagnosis and after Chemotherapy.

Intrapatient heterogeneity of programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB) in gastroesophageal adenocarcinoma (GEA) could influence their roles as predictive biomarkers for response to immune checkpoint inhibitors (ICI). In this retrospective analysis, we evaluated the spatiotemporal heterogeneity and prognostic relevance of PD-L1 expression and TMB in GEA. A cohort of 211 patients with stage II-IV GEA was retrospectively reviewed for a total of 407 tumor samples with PD-L1 expression data and 319 tumor samples with TMB data. PD-L1 status was defined as positive if combined positive score (CPS) ≥1 using the 22C3 pharmDx assay. TMB levels were categorized as low, intermediate, or high (≤5, 5-15, or >15 mutations/Mb), or using a single threshold (<10 or ≥10 mutation/Mb), determined by next-generation sequencing using a targeted gene panel. Of 407 tumors, 56% were PD-L1 negative and 44% PD-L1 positive. Of 319 tumors, 50% were TMB-low, 45% TMB-intermediate, and 5% TMB-high; 86% had <10 and 14% ≥10 mutations/Mb. TMB level was significantly associated with MSI-status. PD-L1 expression and TMB exhibited marked spatial heterogeneity between baseline primary and metastatic tumors (61% and 69% concordance), and temporal heterogeneity between tumors before and after chemotherapy (57%-63% and 73%-75% concordance). PD-L1 expression and TMB were not significantly associated with overall survival. PD-L1 expression and TMB exhibit marked spatial and temporal heterogeneity in GEA. This heterogeneity should be considered when obtaining tumor samples for molecular testing and when deciding whether ICI therapy is appropriate.See related commentary by Klempner et al., p. 6401.

The Breast Cancer Cohort Study in Chinese Women: research design and preliminary results of clinical multi-center cohort

Objective: The incidence of breast cancer in Chinese women continues to rise. The large breast cancer cohort studies in China are relatively scarce. There are many bottlenecks in the construction of large clinical cohort for breast cancer diagnosis, treatment, and prognoses, such as inconsistent standards, high rates of lost follow-up, repeated construction, and inability to share. To better solving the difficulties and problems faced by large-scale clinical cohort research in China, this project will cooperate with several tertiary A hospitals to establish a breast cancer cohort in Chinese women. It also provides a data platform and technical support for breast cancer multi-center clinical cohort research. Methods: Based on the evidence-based medicine and expert opinion and consensus, we established a breast cancer cohort standardized indicator set-recording baseline information, diagnosis and treatment-related information of the enrolled patients, and collecting biological specimens. According to the technical specification of long-term follow-up for the endpoint, data management, and data security and in the large population-based cohort study, a standardized follow-up system for the diagnosis, treatment, and prognosis of breast cancer prospective cohorts is formed. Results: Based on standardized data sets and the computer discipline's advantage from the University of Science and Technology Beijing, we integrate the new information technology methods, including dynamic information collection terminals and social networks. Thus, the quality of control programs on compliance and intelligence data was improved, and a Chinese women breast cancer cohort database was developed. By February 2020, 12 147 patients were included in the clinical cohort database. Biological specimens'resources in cohort construction were collected and cooperated with Shandong University to research the multi-center quality control system and shared evaluation system of biobanks. Building an open and shared biobank network and forming a full chain of breast cancer research platform. Conclusion: With the implementation of the "13(th) Five-Year Plan" precision medicine research, this study provides a research foundation for precision diagnosis and treatment of breast cancer and provides data support for the country to formulate relevant medical policies.

Telomere length, brain tau deposition and cognitive decline: Two‐year follow‐up study

AbstractBackgroundTelomere length (TL) is known to be associated with aging and various age‐related diseases. However, previous studies on the relationship between the TL and Alzheimer’s disease (AD) yielded inconsistent results, and the association between TL and in vivo AD pathologies such as cerebral beta‐amyloid (Aβ) and tau deposition remains unclear. We investigated whether TL is related to in vivo AD pathologies and predicts future cognitive decline.MethodTotal 132 older adults recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease were included for analysis. For all participants, absolute TL values (aTL) were measured by a quantitative PCR method using DNA extracted from whole blood at baseline, as aTL can provide more direct comparison between experiments and laboratories compared to traditional TL assays. Global PiB retention measured 11C‐PiB‐PET and global tau deposition in the regions corresponding to Braak stages measured by 18F‐AV‐1451 PET were used in this study. For clinical outcome, conversion of clinical diagnosis and change of MMSE score assessed at baseline and 2‐year follow‐up was used.ResultAmong 132 older adults, 71 of them were cognitively normal and 51 of them were cognitively impaired (39 MCI and 22 AD dementia) at baseline and total 20 individuals converted to MCI or AD dementia during 2 year follow‐up period. No significant group difference in aTL was observed between diagnostic groups at baseline. However, aTL at baseline was significantly longer in converters (N=20) compared to non‐converters (N=112) even after adjusting age, sex, APOE4 positivity and baseline diagnosis. In addition, the difference of MMSE score between baseline and 2‐year follow‐up showed positive association with baseline aTL after adjusting age, sex, education, APOE4 and baseline diagnosis. With regard to in vivo AD pathologies, baseline aTL had a significant positive association with global tau deposition, but not with global Aβ deposition.ConclusionOur finding suggests that longer TL relates to greater tau deposition in brain and more rapid cognitive decline in older adults. Further studies to elucidate mechanism underlying the association of TL with tau deposition and cognitive decline will be necessary.

Subjective cognitive decline is associated with longitudinal cerebral blood flow reductions and gray matter atrophy in older adults

AbstractBackgroundSubjective cognitive decline (SCD), a potential harbinger of Alzheimer’s disease (AD), has been cross‐sectionally associated with neurodegeneration and cerebrovascular disease markers on brain MRI. However, longitudinal associations are less clear with few existing studies that yield inconsistent findings. Here, we related baseline SCD to longitudinal structural and hemodynamic markers of brain health in older adults free of clinical dementia and stroke.MethodsVanderbilt Memory &amp; Aging Project participants (n=299,72±7 years, 58% male) completed a baseline SCD protocol and multimodal 3T brain MRI, including T 1‐weighted imaging (grey matter volumes) and pseudo‐continuous arterial spin labeling (cerebral blood flow (CBF)) at baseline and multiple follow‐ups (18‐months, 3‐years, 5‐years). Baseline SCD (total and subdomain memory, language, and executive functioning scores) was longitudinally related to global and regional grey matter volumes and CBF (mL/100g/min). Linear mixed effects models, with random intercepts and slopes and a follow‐up time interaction, covaried for baseline age, sex, race/ethnicity, education, diagnosis, mood, and apolipoprotein E (APOE)‐e4 status. Grey matter volume models covaried for intracranial volume. CBF models covaried for associated tissue volume.ResultsMean follow‐up time was 3.8 years. Higher total SCD predicted hippocampal volume reductions (p=0.04), increased inferior lateral ventricular volume (p&lt;0.001; Figure 1A), and global CBF reductions (p&lt;0.001; Figure 1B). Higher scores within each SCD domain predicted hippocampal volume reductions, increased inferior lateral ventricular volume, and global CBF reductions (p‐values&lt;0.04). Higher executive functioning‐SCD related only to frontal and occipital CBF reductions (p‐values&lt;0.003; Figure 1C) but not temporal CBF or lobar atrophy (p‐values&gt;0.07). Language‐SCD predicted reduced frontal CBF (p=0.01; Figure 1D) and temporal lobe volume (p=0.02). Surprisingly, memory‐SCD was not associated with temporal lobe volume or CBF (p‐values&gt;0.05). Sensitivity analyses excluding outliers revealed the same associations.ConclusionsHigher baseline SCD predicted multiple pathways of longitudinal brain changes, including cerebral hemodynamics and volume loss within areas first affected by AD. Executive functioning‐SCD predicted hemodynamic changes and language‐SCD related to alterations within the frontal and temporal lobes. Results suggest the relevance of considering the type of SCD, as specific domains may predict different pathologies over time with important prognostic implications. Future research is needed to understand the clinical consequences of these findings.

Treatment patterns, clinical outcomes, and healthcare resource use associated with advanced/metastatic lung cancer in China: protocol for a retrospective observational study.

BackgroundLung cancer (LC) is the most common cancer worldwide. The prevalence of LC and rate of associated mortality are high and increasing faster in China than in Western countries. Non-small cell lung cancer (NSCLC) accounts for most LCs. This study aims to be the first large, multi-center, non-interventional retrospective study of treatment patterns (type/duration, number of lines, completion rate), real-world outcomes, and medical costs among Chinese patients with advanced/metastatic NSCLC (IIIb/IV) or extensive-stage small cell LC (ES-SCLC).MethodsThis study will enroll 8,800 patients (≥18 years, with a diagnosis of advanced/metastatic NSCLC made between 1 December 2013 to 30 November 2014) from 35 to 50 Chinese sites. Hospital information systems (HIS) and electronic medical records will be retrospectively reviewed, in adherence with regulatory and ethical requirements. Early-stage treatment (starting from 1 December 2010) of patients with recurrent disease or early disease progression will be examined. Data will be collected at baseline (diagnosis) and 6 and 12 months after this. Observation will end after 3 years or death. Data will be stratified by histology, staging, age, region, health insurance, and epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) mutation status. Treatment duration and overall survival will be estimated using Kaplan-Meier curves. Descriptive statistics will be used for disease characteristics and patient demographics. Cox-proportional hazards models will be used to examine the impact of demographics/treatment on survival. Treatment patterns and outcome predictors will be explored using multivariate logistic regression.DiscussionThis protocol describes the methodology for collecting real-world data to guide evidence-based clinical practice and inform unmet needs in NSCLC treatment, with potential to identify gaps between guidelines and current practice.Trial registrationNCT03505515; data registered on ClinicalTrials.gov: 12h Apr., 2018.

Natural history of apathy in Alzheimer’s disease

AbstractBackgroundApathy is a common behavioral symptom of dementia, yet information on its impact dementia is limited. This study examines prevalence, incidence, and persistence of apathy longitudinally.MethodSample was drawn from the National Alzheimer's Coordinating Center Uniform Data Set (NACC‐UDS) including participants enrolled 9/2005‐5/2019 with at least one follow‐up, with baseline diagnosis of MCI or AD. Presence of apathy was defined using clinician judgment within the NACC‐UDS protocol, indicating whether the participant currently manifests meaningful change in behavior in apathy (yes=1/no=0). Incidence of apathy was defined as the proportion of participants who did not have an endorsement of apathy at baseline but had a new endorsement of apathy at that visit. Persistence of apathy was defined as the proportion of participants who had an endorsement of apathy between two consecutive visits.ResultSample included 9,607 participants with baseline CDR=0.5 (n=5,323), 1 (n=3,115), 2/3 (n=1169). Apathy was endorsed in 59.4% of participants at some point during follow‐up (CDR=0.5: 46.6%, CDR=1: 72.9%, CDR=2/3: 81.2%). Participants with apathy differed from those who never had apathy in: being male (49.0% vs. 44.7%), education (14.6±3.7 vs. 14.9±3.6), reporting depression in the past 2 years (42.7% vs. 26.6%), having at least one APOE e4 allele (58.7% vs. 52.9%), follow‐up years (4.1± 2.1 vs 3.8±2.2), MMSE (21.5±6.3 vs. 24.2±5.1), and FAQ (13.8±9.0 vs. 7.6±8.2) (all p&lt;0.01). Differences in baseline age and comorbidities were statistically insignificant. Presence of apathy increased over time in participants with baseline CDR=0.5 (baseline to visit 5: 19.8% to 33.8%) and CDR=1 (43.9% to 59.9%), but fluctuated around 62.4% in CDR=2/3. Incidence of apathy fluctuated around 12.5%, 15.7% and 13.4 % for each baseline CDR group. Persistence of apathy between consecutive visits increased over time in participants with baseline CDR=0.5 (baseline to visit 5: 12.6% to 21.4%) and CDR=1 (33.2% to 44.8%), but fluctuated around 49.2% in CDR=2/3.ConclusionPrevalence and persistence of apathy increased over time and correlated with disease severity. Incident apathy appears to plateau after CDR=1. The increasing impact of apathy over the course of dementia has clinical relevance and should be considered in designing intervention studies.

The presence of moderate extrapyramidal signs predicts poorer outcomes in a community‐based cohort of multi‐ethnic demented elders

AbstractBackgroundExtrapyramidal signs (EPS) are a common feature of Alzheimer's Disease (AD) associated with worse outcomes in observational studies of dementia. Prior studies have been primarily conducted in predominately white, clinic‐based samples. Less is known regarding the role of EPS in the disease course of dementia in ethnic minority and non‐clinic‐based populations.MethodPredictors 3 (P3) is a multi‐ethnic community‐based cohort study of dementia. Recruitment began in 2011 and is ongoing. Participants are evaluated annually by trained investigators. 142 P3 participants with a baseline diagnosis of probable dementia were selected for this study. Moderate EPS was defined as a score of 2 or more on selected items from the Unified Parkinson's Disease Rating Scale. The cognitive endpoint was defined as a score of &lt;= 10 on the Folstein MMSE, the functional endpoint as a score of &gt;= 10 on the 17‐point Blessed Dementia Rating Scale, and the institutional equivalent endpoint as need for equivalent to nursing home care. Adjusted Cox models were fitted for time to death and cognitive, functional, and institutional equivalent endpoints with baseline moderate EPS as predictor. Effect modification was assessed by fitting cross‐product terms for moderate EPS by ethnicity, sex, age, education, and APOE polymorphism.ResultMean follow‐up time was 3.61 years (range: 0.29 ‐ 7.50, SD = 1.95). 33 participants (23.2%) had moderate EPS at baseline. 53 died (37.3%), 23 (17.2%) reached the cognitive endpoint, 45 (36.3%) the functional endpoint, and 44 (37.9%) the institutional equivalent endpoint post‐baseline. Moderate EPS at baseline was significantly associated with an increased hazard of death (HR = 2.57, 95% CI = 1.30, 5.10) and of reaching the functional endpoint (5.59, 95% CI = 2.36, 13.27). Associations between moderate EPS and the cognitive and institutional equivalent endpoints were not statistically significant. No evidence was found for effect modification of associations on either additive or multiplicative scales.ConclusionIn a multi‐ethnic community‐dwelling cohort of demented elders, we found that baseline moderate EPS significantly predicted time to death and time to functional endpoint, but not time to cognitive and institutional equivalent care endpoints. These findings confirm those of previous studies conducted on predominately white, clinic‐based samples.

Medial temporal lobe (MTL) ‐ default‐mode network (DMN) functional connectivity disruption in the progression of Alzheimer’s disease

AbstractBackgroundA multi‐modal analysis of resting‐state functional connectivity disruption (fMRI) and morphometric changes characteristic of neurodegeneration (T1 structural MRI) in Alzheimer's disease (AD) was performed to develop biomarkers for the transition from cognitively normal (CN) to significant memory concern (SMC) to early and late mild cognitive impairment (EMCI, LMCI).MethodsFalse Detection Rate (FDR) corrected (q=0.005) parallel group‐level one‐way four‐factor (CN, SMC, EMCI, LMCI) ANOVA and post hoc pairwise t tests of ROI pairs [1]; same‐session functional connectivity (AFNI) and morphometry (FreeSurfer); ADNI‐3 sub‐population with baseline diagnosis CN (N=33), SMC (N=35), EMCI (N=13), and LMCI (N=14) matched for age (p=0.33), education (p=0.63), and gender (p=0.127).ResultsA 3‐mm grid of ROI seeds (r=6mm) in left MTL yielded 435 ROI “anchors”. 3D (Fisher Z‐transformed) correlation maps were computed for each subject for each anchor ROI and input to a group‐level one‐way four‐factor 3D ANOVA. Cluster analysis (N vox 20; p=0.02; P=3.45) of the 3D F Statistic maps yielded 4,185 target ROIs. An r=6mm ROI was placed at the center of mass of each target cluster. ROI anchor‐target pair correlations were input to a group‐level one‐way four‐factor ANOVA and FDR corrected (q=0.005; p*=0.003) (estimated by permutation, N=1000) which identified 2,420 significant tests (ROI pairs). Post hoc pairwise t tests only on the significant ANOVA tests were FDR‐corrected (q=0.005) and yielded 31 significant SMC‐CN tests (p*=6.3x10‐5); 54 EMCI‐CN tests (p*=1.1x10‐4); and 209 LMCI‐CN tests (p*=4.2x10‐4). The spatial distribution of target ROIs included (bilaterally) MTL and DMN‐associated regions. Of the significant SMC‐CN tests, 39% were positive (increased connectivity). In the significant EMCI‐CN tests, 100% were positive. However, in the significant LMCI‐CN comparisons, the pattern reversed and only 5% were positive. An independent analysis of right hemisphere yielded similar results.ConclusionsAn hybrid a priori data‐driven approach identified a population of MTL‐anchored ROI pairs whose spatial distribution of target ROIs included regions associated with DMN and MTL, and whose functional connectivity revealed a striking pattern of change with clinical progression when compared to CN: SMC, a mixture of hyper‐ and hypo‐connectivity; EMCI, widespread hyper‐connectivity; and LMCI, widespread hypo‐connectivity. Reference: (1) Grajski, K. A., Bressler, S., and ADNI. (2019). Neuroimage Clin. 2019;23:101860.