Associations of plasma proteomics and age-related outcomes with brain age in a diverse cohort.

Machine learning models are increasingly being used to estimate "brain age" from neuroimaging data. The gap between chronological age and the estimated brain age gap (BAG) is potentially a measure of accelerated and resilient brain aging. Brain age calculated in this fashion has been shown to be associated with mortality, measures of physical function, health, and disease. Here, we estimate the BAG using a voxel-based elastic net regression approach, and then, we investigate its associations with mortality, cognitive status, and measures of health and disease in participants from Atherosclerosis Risk in Communities (ARIC) study who had a brain MRI at visit 5 of the study. Finally, we used the SOMAscan assay containing 4877 proteins to examine the proteomic associations with the MRI-defined BAG. Among N = 1849 participants (age, 76.4 (SD 5.6)), we found that increased values of BAG were strongly associated with increased mortality and increased severity of the cognitive status. Strong associations with mortality persisted when the analyses were performed in cognitively normal participants. In addition, it was strongly associated with BMI, diabetes, measures of physical function, hypertension, prevalent heart disease, and stroke. Finally, we found 33 proteins associated with BAG after a correction for multiple comparisons. The top proteins with positive associations to brain age were growth/differentiation factor 15 (GDF-15), Sushi, von Willebrand factor type A, EGF, and pentraxin domain-containing protein 1 (SEVP 1), matrilysin (MMP7), ADAMTS-like protein 2 (ADAMTS), and heat shock 70 kDa protein 1B (HSPA1B) while EGF-receptor (EGFR), mast/stem-cell-growth-factor-receptor (KIT), coagulation-factor-VII, and cGMP-dependent-protein-kinase-1 (PRKG1) were negatively associated to brain age. Several of these proteins were previously associated with dementia in ARIC. These results suggest that circulating proteins implicated in biological aging, cellular senescence, angiogenesis, and coagulation are associated with a neuroimaging measure of brain aging.

Multi-omics Analyses Identify AKR1A1 as a Biomarker for Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease. As many genes associate with DKD, multi-omics approaches were employed to narrow the list of functional genes, gene products and related pathways providing insights into the pathophysiological mechanisms of DKD. The Kidney Precision Medicine Project human kidney single-cell RNA-sequencing (scRNAseq) dataset and Mendeley Data on human kidney cortex biopsy proteomics were utilized. R package Seurat was used to analyze scRNAseq and subset proximal tubule cells. PathfindR was applied for pathway analysis in cell type-specific differentially expressed genes and R limma package was used to analyze differential protein expression in kidney cortex. A total of 790 differentially expressed genes were identified in proximal tubule cells, including 530 upregulated and 260 downregulated transcripts. Compared with differentially expressed proteins, 24 genes/proteins were in common. An integrated analysis combining protein quantitative trait loci (pQTL), GWAS hits (estimated glomerular filtration rate) and a plasma metabolomics analysis was performed using baseline metabolites predictive of DKD progression in our longitudinal Diabetes Heart Study samples. Aldo-keto reductase family 1 member A1 gene (AKR1A1) was revealed as a potential molecular hub for DKD cellular dysfunction in several cross-linked pathways featured by deficiency of this enzyme.

Genome-Wide Association Studies of 3 Distinct Recovery Phenotypes in Mild Ischemic Stroke.

BACKGROUND AND OBJECTIVES: Stroke genetic research has made substantial progress in the past decade. Its recovery application, however, remains behind, in part due to its reliance on the modified Rankin Scale (mRS) score as a measure of poststroke outcome. The mRS does not map well to biological processes because numerous psychosocial factors drive much of what the mRS captures. Second, the mRS contains multiple disparate biological events into a single measure further limiting its use for biological discovery. This led us to investigate the effect of distinct stroke recovery phenotypes on genetic variation associations with Genome-Wide Association Studies (GWASs) by repurposing the NIH Stroke Scale (NIHSS) and its subscores. METHODS: In the Vitamin Intervention for Stroke Prevention cohort, we estimated changes in cognition, motor, and global impairments over 2 years using specific measures. We included genotyped participants with a total NIHSS score greater than zero at randomization and excluded those with recurrent stroke during the trial. A GWAS linear mixed-effects model predicted score changes, with participant as a random effect, and included initial score, age, sex, treatment group, and the first 5 ancestry principal components. RESULTS: In total, 1,270 participants (64% male) were included with a median NIHSS score of 2 (interquartile range [IQR] 1-3) and median age 68 (IQR 59-75) years. At randomization, 20% had cognitive deficits (NIHSS Cog-4 score >0) and 70% had ≥1 motor deficits (impairment score >1). At 2 years, these percentages improved to 7.2% with cognitive deficits and 30% with motor deficits. GWAS identified novel suggestive gene-impairment associations (p < 5e-6) for cognition (CAMK2D, EVX2, LINC0143, PTPRM, SGMS1, and SMAD2), motor (ACBD6, KDM4B, MARK4, PTPRS, ROBO1, and ROBO2), and global (MSR1 and ROBO2) impairments. DISCUSSION: Defining domain-specific stroke recovery phenotypes and using longitudinal clinical trial designs can help detect novel genes associated with chronic recovery. These data support the use of granular endpoints to identify genetic associations related to stroke recovery.

A Dynamic Model for Estimating the Retention Duration of Neutralizing Antibody Titers After Vaccination in a COVID-19 Convalescent Population.

We measured neutralizing antibodies (nAbs) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a cohort of 235 convalescent patients (representing 384 analytic samples). They were followed for up to 588 days after the first report of onset in Taiwan. A proposed Bayesian approach was used to estimate nAb dynamics in patients postvaccination. This model revealed that the titer reached its peak (1819.70 IU/mL) by 161 days postvaccination and decreased to 154.18 IU/mL by day 360. Thus, the nAb titers declined in 6 months after vaccination. Protection, against variant B.1.1.529 (ie, Omicron) may only occur during the peak period.

Evaluation of pain related behaviors and disease related outcomes in an immunocompetent mouse model of prostate cancer induced bone pain.

Cancer-induced bone pain (CIBP) is the most common and devastating symptom of bone metastatic cancer that substantially disrupts patients' quality of life. Currently, there are few effective analgesic treatments for CIBP other than opioids which come with severe side effects. In order to better understand the factors and mechanisms responsible for CIBP it is essential to have clinically relevant animal models that mirror pain-related symptoms and disease progression observed in patients with bone metastatic cancer. In the current study, we characterize a syngeneic mouse model of prostate cancer induced bone pain. We transfected a prostate cancer cell line (RM1) with green fluorescent protein (GFP) and luciferase reporters in order to visualize tumor growth longitudinally in vivo and to assess the relationship between sensory neurons and tumor cells within the bone microenvironment. Following intra-femoral injection of the RM1 prostate cancer cell line into male C57BL/6 mice, we observed a progressive increase in spontaneous guarding of the inoculated limb between 12 and 21 days post inoculation in tumor bearing compared to sham operated mice. Daily running wheel performance was evaluated as a measure of functional impairment and potentially movement evoked pain. We observed a progressive reduction in the distance traveled and percentage of time at optimal velocity between 12 and 21 days post inoculation in tumor bearing compared to sham operated mice. We utilized histological, radiographic and µCT analysis to examine tumor induced bone remodeling and observed osteolytic lesions as well as extra-periosteal aberrant bone formation in the tumor bearing femur, similar to clinical findings in patients with bone metastatic prostate cancer. Within the tumor bearing femur, we observed reorganization of blood vessels, macrophage and nerve fibers within the intramedullary space and periosteum adjacent to tumor cells. Tumor bearing mice displayed significant increases in the injury marker ATF3 and upregulation of the neuropeptides SP and CGRP in the ipsilateral DRG as well as increased measures of central sensitization and glial activation in the ipsilateral spinal cord. This immunocompetent mouse model will be useful when combined with cell type selective transgenic mice to examine tumor, immune cell and sensory neuron interactions in the bone microenvironment and their role in pain and disease progression associated with bone metastatic prostate cancer.

Structured Moderate Exercise and Biomarkers of Kidney Health in Sedentary Older Adults: The Lifestyle Interventions and Independence for Elders Randomized Clinical Trial.

Rationale & Objective: In the Lifestyle Interventions and Independence for Elders (LIFE) trial, a structured exercise intervention slowed kidney function decline in sedentary older adults. Biomarkers of kidney health could distinguish potential mechanisms for this beneficial effect. Study Design: Randomized controlled trial. Setting & Population: A total of 1,381 sedentary adults aged 70-89 years enrolled in the LIFE trial. Intervention: Structured, 2-year, moderate-intensity exercise intervention versus health education. Outcomes: Physical activity was measured by step count. Primary outcomes were changes in 14 serum and urine biomarkers of kidney health collected at baseline, year 1, and year 2. We determined the effect of randomization on changes in kidney measures and then evaluated observational associations of achieved activity on each measure. Results: Participants assigned to exercise walked on average 291 more steps per day than participants assigned to health education. The intervention was not significantly associated with changes in biomarkers of kidney health. In observational analyses, persons in the highest versus lowest quartile of activity (≥3,470 vs <1,568 steps/day) had significant improvement in urine albumin (mean, -0.22 mg albumin/g urine creatinine [interquartile range (IQR), -0.37 to -0.06]), alpha-1-microglobulin (-0.18 mg/L [-0.28 to -0.08]), trefoil factor-3 (-0.24 pg/mL [-0.35 to -0.13]), epidermal growth factor (0.19 pg/mL [0.06-0.32]), uromodulin (0.06 pg/mL [0.00-0.12]), interleukin 18 (-0.09 pg/mL [-0.15 to -0.03]), neutrophil gelatinase-associated lipocalin (-0.16 pg/mL [-0.24 to -0.07]), monocyte chemoattractant protein-1 (-0.25 pg/mL [-0.36 to -0.14]), clusterin (-0.16 pg/mL [-0.30 to -0.02]), serum tumor necrosis factor receptor-1 (-0.25 mg/dL [-0.39 to -0.11]) and tumor necrosis factor receptor-2 (-0.30 mg/dL [-0.44 to -0.16]). In sensitivity analyses, incremental changes in activity were most impactful on urine interleukin 18 and serum tumor necrosis factor-1. Limitations: The original study was not designed to assess the impact on kidney health. Non-white individuals and patients with advanced chronic kidney disease are underrepresented. Conclusions: Randomization to structured exercise did not improve kidney health at a group level. However, higher exercise was associated with concurrent improvements in biomarkers of glomerular injury, tubular function/repair, tubular injury, generalized inflammation, and tubulointerstitial repair/fibrosis. Plain-Language Summary: In the Lifestyle Interventions For Elders (LIFE) study, randomization to an exercise and physical activity intervention improved the slope of estimated glomerular filtration rate over 2 years compared with health education among older adults. In this study, we sought to determine whether there were specific biomarkers of kidney health that were affected by the exercise and physical activity intervention to investigate potential mechanisms for this positive impact on kidney decline. We found that randomization to the intervention did not improve any of the 14 measures of kidney tubule health. However, in observational analyses, higher activity was independently associated with improvements in several domains, especially tubular injury and generalized inflammation. These results help to clarify the impact of physical activity on kidney health.

Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci.

Introduction: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. Methods: A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: "Some College" (yes/no, for any education beyond high school) and "Graduated College" (yes/no, for completing a 4-year college degree). Genome-wide significant (p < 5 × 10-8) and suggestive (p < 1 × 10-6) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). Results: In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (FOXP1, MBOAT4, SKP2, STIM1, STX4), brain (BRI3, FILIP1, FOXP1, LINC00290, LMTK2, MBOAT4, MYO6, SENP6, SRGAP3, STIM1, TMEM167A, TMEM30A), and liver (BRI3, FOXP1) biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. Discussion: Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.

Single Nucleotide Polymorphisms Associated With Motor Recovery in Patients With Nondisabling Stroke: GWAS Study.

BACKGROUND AND OBJECTIVES: Despite notable advances in genetic understanding of stroke recovery, most studies focus only on candidate genes. To date, only 2 genome-wide association studies (GWAS) have focused on stroke outcomes, but they were limited to the modified Rankin Scale (mRS). The mRS maps poorly to biological processes. Therefore, we performed a GWAS to discover single nucleotide polymorphisms (SNPs) associated with motor recovery poststroke. METHODS: We used the Vitamin Intervention for Stroke Prevention (VISP) data set of 2,100 genotyped participants with nondisabling stroke. We included only participants who had motor impairment at randomization. Participants with a recurrent stroke during the trial were excluded. Genotyped data underwent strict quality control and imputation. The GWAS used logistic regression models with generalized estimating equations to leverage the repeated NIH Stroke Scale motor score measurements spanning 6 time points over 24 months. The primary outcome was a decrease in the motor drift score of ≥1 vs <1 at each time point. Our model estimated the odds ratio (OR) of motor improvement for each SNP after adjusting for age, sex, race, days from stroke to visit, initial motor score, VISP treatment arm, and principal components. RESULTS: A total of 488 (64%) participants with a mean (SD) age of 66 ± 11 years were included in the GWAS. Although no associations reached genome-wide significance (p < 5 × 10-8), our analysis detected 115 suggestive associations (p < 5 × 10-6). Notably, we found multiple SNP clusters near genes with plausible neuronal repair biology mechanisms. The CLDN23 gene had the most convincing association with rs1268196-T as its most significant SNP (OR 0.32; 95% CI 0.21-0.48; p value 6.19 × 10-7). CLDN23 affects blood-brain barrier integrity, neurodevelopment, and immune cell transmigration. DISCUSSION: We identified novel suggestive genetic associations with the first-ever motor-specific poststroke recovery GWAS. The results seem to describe a distinct stroke recovery phenotype compared with prior genetic stroke outcome studies that use outcome measures, such as the mRS. Replication and further mechanistic investigation are warranted. In addition, this study demonstrated a proof-of-principle approach to optimize statistical efficiency with longitudinal data sets for genetic discovery.

Assessment of finite element human body and ATD models in estimating injury risk in far-side impacts using field-based injury risk.

The objective of this study was to assess the ability of finite element human body models (FEHBMs) and Anthropometric Test Device (ATD) models to estimate occupant injury risk by comparing it with field-based injury risk in far-side impacts. The study used the Global Human Body Models Consortium midsize male (M50-OS+B) and small female (F05-OS+B) simplified occupant models with a modular detailed brain, and the ES-2Re and SID-IIs ATD models in the simulated far-side crashes. A design of experiments (DOE) with a total of 252 simulations was conducted by varying lateral ΔV (10-50kph; 5kph increments), the principal direction of force (PDOF 50°, 60°, 65°, 70°, 75°, 80°, 90°), and occupant models. Models were gravity-settled and belted into a simplified vehicle model (SVM) modified for far-side impact simulations. Acceleration pulses and vehicle intrusion profiles used for the DOE were generated by impacting a 2012 Camry vehicle model with a mobile deformable barrier model across the 7 PDOFs and 9 lateral ΔV's in the DOE for a total of 63 additional simulations. Injury risks were estimated for the head, chest, lower extremity, pelvis (AIS 2+; AIS 3+), and abdomen (AIS 3+) using logistic regression models. Combined AIS 3+ injury risk for each occupant was calculated using AIS 3+ injury risk estimations for the head, chest, abdomen, and lower extremities. The injury risk calculated using computational models was compared with field-based injury risk derived from NASS-CDS by calculating their correlation coefficient. The field-based injury risk was calculated using risk curves that were created based on real-world crash data in a previous study (Hostetler et al., 2020). Occupant age (40 years), seatbelt use (belted occupant), collision deformation classification, lateral ΔV, and PDOF of the crash event were used in these curves to estimate field injury risk. Large differences in the kinematics were observed between HBM and ATD models. ATD models tended to overestimate risk in almost every case whereas HBMs yielded better risk estimates overall. Chest and lower extremity risks were the least correlated with field injury risk estimates. The overall risk of AIS 3+ injury risk was the strongest comparison to the field data-based risk curves. The HBMs were still not able to capture all the variance but future studies can be carried out that are focused on investigating their shortfalls and improving them to estimate injury risk closer to field injury risk in far-side crashes.

Living Alone, Physical Health, and Mortality in Breast Cancer Survivors: A Prospective Observational Cohort Study.

Living alone, particularly for individuals with poor physical health, can increase the likelihood of mortality. This study aimed to explore the individual and joint associations of living alone and physical health with overall mortality among breast cancer survivors in the Women's Healthy Eating and Living (WHEL). We collected baseline, 12-month and 48-month data among 2869 women enrolled in the WHEL cohort. Living alone was assessed as a binary variable (Yes, No), while scores of physical health were measured using the RAND Short Form-36 survey (SF-36), which include four domains (physical function, role limitation, bodily pain, and general health perceptions) and an overall summary score of physical health. Cox proportional hazard models were used to evaluate associations. No significant association between living alone and mortality was observed. However, several physical health measures showed significant associations with mortality (p-values < 0.05). For physical function, the multivariable model showed a hazard ratio (HR) of 2.1 (95% CI = 1.02-4.23). Furthermore, the study examined the joint impact of living alone and physical health measures on overall mortality. Among women with better physical function, those living alone had a 3.6-fold higher risk of death (95% CI = 1.01-12.89) compared to those not living alone. Similar trends were observed for pain. However, regarding role limitation, the pattern differed. Breast cancer survivors living alone with worse role limitations had the highest mortality compared to those not living alone but with better role limitations (HR = 2.6, 95% CI = 1.11-5.95). Similar trends were observed for general health perceptions. Our findings highlight that living alone amplifies the risk of mortality among breast cancer survivors within specific health groups.

Association Between Child Sugary Drink Consumption and Serum Lipid Levels in Electronic Health Records.

Sugar-sweetened beverage (SSB) and fruit juice (FJ) consumption may promote lipid abnormalities in childhood. We examined the association between SSB/FJ intake and lipid levels using electronic health record data for 2816 adolescents. Multivariable logistic regression models treated clinical cutpoints for abnormal lipid levels (triglycerides [TG], high-density lipoprotein (HDL), low-density lipoprotein [LDL], and total cholesterol) as dependent variables. In models not adjusted for adiposity, elevated SSB and FJ consumption was associated with increased odds of having abnormally high TG (SSB: odds ratio [OR] = 1.28 (95% confidence interval [CI] = [1.07-1.52], P = .007); FJ: 1.35 ([1.09-1.69], P = .007)) and abnormally low HDL (SSB: 1.47 ([1.17-1.86], P = .001); FJ: 1.35 ([1.02-1.78], P = .03)). Adjusting for adiposity, a likely mediator of the relationship, attenuated these associations. These findings support the need for identifying unhealthy beverage consumption habits during childhood health care visits as a modifiable behavior associated with cardiometabolic risk.

Methods for estimating insulin resistance from untargeted metabolomics data.

CONTEXT: Insulin resistance is associated with multiple complex diseases; however, precise measures of insulin resistance are invasive, expensive, and time-consuming. OBJECTIVE: Develop estimation models for measures of insulin resistance, including insulin sensitivity index (SI) and homeostatic model assessment of insulin resistance (HOMA-IR) from metabolomics data. DESIGN: Insulin Resistance Atherosclerosis Family Study (IRASFS). SETTING: Community based. PARTICIPANTS: Mexican Americans (MA) and African Americans (AA). MAIN OUTCOME: Estimation models for measures of insulin resistance, i.e. SI and HOMA-IR. RESULTS: Least Absolute Shrinkage and Selection Operator (LASSO) and Elastic Net regression were used to build insulin resistance estimation models from 1274 metabolites combined with clinical data, e.g. age, sex, body mass index (BMI). Metabolite data were transformed using three approaches, i.e. inverse normal transformation, standardization, and Box Cox transformation. The analysis was performed in one MA recruitment site (San Luis Valley, Colorado (SLV); N = 450) and tested in another MA recruitment site (San Antonio, Texas (SA); N = 473). In addition, the two MA recruitment sites were combined and estimation models tested in the AA recruitment sample (Los Angeles, California; N = 495). Estimated and empiric SI were correlated in the SA (r2 = 0.77) and AA (r2 = 0.74) testing datasets. Further, estimated and empiric SI were consistently associated with BMI, low-density lipoprotein cholesterol (LDL), and triglycerides. We applied similar approaches to estimate HOMA-IR with similar results. CONCLUSIONS: We have developed a method for estimating insulin resistance with metabolomics data that has the potential for application to a wide range of biomedical studies and conditions.

A Technology-Driven, Healthcare-Based Intervention to Improve Family Beverage Choices: Results from a Pilot Randomized Trial in the United States.

Background: Healthcare-based interventions to address sugary beverage intake could achieve broad reach, but intensive in-person interventions are unsustainable in clinical settings. Technology-based interventions may provide an alternative, scalable approach. Methods: Within an academic health system in the United States that already performs electronic health record-based sugary drink screening, we conducted a pilot randomized trial of a technology-driven family beverage choice intervention. The goal of the intervention was to reduce sugar-sweetened beverage (SSB) and fruit juice (FJ) consumption in 60 parent-child dyads, in which children were 1-8 years old. The pediatrician-initiated intervention consisted of a water promotion toolkit, a video, a mobile phone application, and 14 interactive voice-response phone calls to parents over 6 months. The study was conducted between June 2021 and May 2022. The aim of the pilot study was to assess the potential feasibility and efficacy of the newly developed intervention. Results: Intervention fidelity was excellent, and acceptability was high for all intervention components. Children in both the intervention and the control groups substantially decreased their consumption of SSB and FJ over follow-up (mean combined baseline 2.5 servings/day vs. 1.4/day at 6 months) and increased water consumption, but constrained linear mixed-effects models showed no differences between groups on these measures. Compared to parents in the control group, intervention parents had larger decreases in SSB intake at 3 months (-0.80 (95% CI: -1.54, -0.06, p = 0.03) servings daily), but these differences were not sustained at 6 months. Conclusion: These findings suggest that, though practical to implement in a clinical care setting and acceptable to a diverse participant group, our multicomponent intervention may not be universally necessary to achieve meaningful behavior changes around family beverage choice. A lower-intensity intervention, such as EHR-based clinical screening alone, might be a less resource-intense way for health systems to achieve similar behavioral outcomes. Future studies might therefore explore whether, instead of applying a full intervention to all families whose children overconsume SSB or FJ, a stepped approach, starting with clinical screening and brief counseling, could be a better use of health system resources.

Examining the Impact of Cholecystectomy on Tumor Recurrence in Breast Cancer Patients.

Previous studies have found that bile acids influence the growth of breast cancer cells in vitro, suggesting that naturally occurring bile acids may also influence the growth of human breast cancer cells. Cholecystectomy alters modulation of bile acid metabolites, and therefore postcholecystectomy women could be at an increased risk of cancer development and recurrence. This study examined the breast cancer outcome in women who underwent cholecystectomy as compared to those with intact gallbladder. Ninety-three patients diagnosed with Stage I-III invasive mammary carcinoma in 2014 were retrospectively identified and patient demographics, treatment, and outcomes were collected and statistically analyzed. Results revealed 36% of patients who underwent cholecystectomy had recurrence compared to 25% recurrence in patients with intact gallbladders (p = .30). Forty-six percent of cholecystectomy patients were deceased, and 23% of those with intact gallbladder were deceased (p = .024). The effect of cholecystectomy on bile acid modulation and breast cancer recurrence requires further investigation.

Pivotal Role of Genetic Counselors in the Uptake of Germline Genetic Testing in Non-Metastatic Breast Cancer and the Impact of Testing on Surgical Decision Making.

BACKGROUND: Genetic testing is increasingly utilized in breast cancer patients; however, testing rates remain low. We aimed to evaluate the rate of genetic testing at a tertiary academic medical center utilizing a multidisciplinary clinic model including genetic counselor. METHODS: A single-center retrospective chart review was performed on a cohort of newly diagnosed breast cancer patients from January 2018 through February 2019. Patients were reviewed for genetic screening eligibility, consultation with a genetic counselor, and test results. RESULTS: Final analysis included 426 patients. 261 (61.3%) were found to meet National Comprehensive Cancer Network guidelines for genetic testing, of which 178 patient (68.2%) underwent testing and 32 patients (12.3%) declined testing. Of the 165 not eligible for testing, 5 patients were tested. A total of 183 patients underwent testing and 116 (63.4%) had a negative result, 17 (9.3%) were positive for at least one gene mutation and 50 (27.3%) were identified to have a variant of unknown significance (VUS). There was a positive association between those patients who met with a genetic counselor and eligibility for testing (OR 31.1, 95% CI 16.0-60.5). CONCLUSIONS: Genetic testing result has become an increasingly important factor when defining optimal surgical treatment for breast cancer patients. Increasing the availability of genetic consultation for breast cancer patients can improve testing rates and patient selection.

Self-Assembled Monolayer for Low-Power-Consumption, Long-Term-Stability, and High-Efficiency Quantum Dot Light-Emitting Diodes.

Quantum dot light-emitting diodes (QLEDs) are an emerging class of optoelectronic devices with a wide range of applications. However, there still exist several drawbacks preventing their applications, including long-term stability, electron leakage, and large power consumption. To circumvent the difficulties, QLEDs based on a self-assembled hole transport layer (HTL) with reduced device complexity are proposed and demonstrated. The self-assembled HTL is prepared from poly[3-(6-carboxyhexyl)thiophene-2,5-diyl] (P3HT-COOH) solution in N,N-dimethylformamide (DMF) forming a well-ordered monolayer on an indium-tin-oxide (ITO) anode. The P3HT-COOH monolayer has a smaller HOMO band offset and a sufficiently large electron barrier with respect to the CdSe/ZnS quantum dot (QD) emission layer, and thus it is beneficial for hole injection into and electron leakage blocking from the QD layer. Interestingly, the QLEDs exhibit an excellent conversion efficiency (97%) in turning the injected electron-hole pairs into light emission. The performance of the resulting QLEDs possesses a low turn-on voltage of +1.2 V and a maximum external quantum efficiency of 25.19%, enabling low power consumption with high efficiency. Additionally, those QLEDs also exhibit excellent long-term stability without encapsulation with over 90% luminous intensity after 200 days and superior durability with over 70% luminous intensity after 2 h operation under the luminance of 1000 cd m-2. The outstanding device features of our proposed QLEDs, including low turn-on voltage, high efficiency, and long-term stability, can advance the development of QLEDs toward facile large-area mass production and cost-effectiveness.

Longitudinal neutralizing antibody responses after SARS-CoV-2 infection: A convalescent cohort study in Taiwan.

BACKGROUND: Understanding the neutralizing antibody (NAb) titer against COVID-19 over time is important to provide information for vaccine implementation. The longitudinal NAb titer over one year after SARS-CoV-2 infection is still unclear. The purposes of this study are to evaluate the duration of the neutralizing NAb titers in COVID-19 convalescents and factors associated with the titer positive duration. METHODS: A cohort study followed COVID-19 individuals diagnosed between 2020 and 2021 May 15th from the COVID-19 database from the Taiwan Centers for Disease Control. We analyzed NAb titers from convalescent SARS-CoV-2 individuals. We used generalized estimating equations (GEE) and a Cox regression model to summarize the factors associated with NAb titers against COVID-19 decaying in the vaccine-free population. RESULTS: A total of 203 convalescent subjects with 297 analytic samples were followed for a period of up to 588 days. Our study suggests that convalescent COVID-19 in individuals after more than a year and four months pertains to only 25% of positive titers. The GEE model indicates that longer follow-up duration was associated with a significantly lower NAb titer. The Cox regression model indicated the disease severity with advanced condition was associated with maintaining NAb titers (adjusted hazard ratio: 2.01, 95% CI: 1.11-3.63) and that smoking was also associated with higher risk of negative NAb titers (adjusted hazard ratio: 0.55, 95% CI: 0.33-0.92). CONCLUSIONS: Neutralizing antibody titers diminished after more than a year. The antibody titer response against SARS-CoV-2 in naturally convalescent individuals provides a reference for vaccinations.

Five-year survivors from brain metastases treated with stereotactic radiosurgery: Biology, improving treatments, or just plain luck?

Background: Improvements in therapies have led to an increasing number of long-term survivors of brain metastases. The present series compares a population of 5-year survivors of brain metastases to a generalized brain metastases population to assess for factors attributable to long-term survival. Methods: A single institution retrospective review was performed to identify 5-year survivors of brain metastases who received stereotactic radiosurgery (SRS). A historical control population of 737 patients with brain metastases was used to assess similarities and differences between the long-term survivor population and the general population treated with SRS. Results: A total of 98 patients with brain metastases were found to have survived over 60 months. No differences between long-term survivors and controls were identified with regards to the age at first SRS (P = .19), primary cancer distribution (P = .80), and the number of metastases at first SRS (P = .90). Cumulative incidence of neurologic death at 6, 8 and 10 years for the long-term survivor cohort was 4.8%, 16%, and 16% respectively. In the historical controls, cumulative incidence of neurologic death reached a plateau at 40% after 4.9 years. A significant difference in the distribution of burden of disease at the time of the first SRS was found between the 5-year survivors and the control (P = .0049). 58% of 5-year survivors showed no evidence of clinical disease at the last follow-up. Conclusion: Five-year survivors of brain metastases represent a diverse histologic population, suggesting a small population of oligometastatic and indolent cancers exist for each cancer type.

Shorter screw lengths in dynamic Dynesys fixation have less screw loosening: From clinical investigation to finite-element analysis.

BACKGROUND: The dynamic Dynesys Stabilization System preserves lumbar mobility at instrumented levels. This study investigated the effect of screw length on screw loosening (SL) after dynamic Dynesys fixation and screw displacement during lumbar motion, using clinical investigation and finite-element (FE) analysis. METHODS: Clinical data of 50 patients with degenerative spondylolisthesis treated with decompression and Dynesys fixation in 2011 were analyzed retrospectively. Horizontal sliding displacement and vertical displacement of screw tips at L4 were analyzed postoperatively using displacement-controlled FE analysis at the L4-L5 level with screw lengths 45 (long screw), 36 (median screw), and 27 (short screw), and 6.4 mm in diameter, under flexion, extension, lateral bending, and rotation. RESULTS: In 13 patients (13/50, 26%), 40 screws (40/266, 15%) were loose at mean follow-up of 101.3 ± 4.4 months. Radiographic SL at 35, 40, 45, and 50 mm were 7.7%, 10.7%, 12.1%, and 37.5%, respectively, regardless of the fixation level ( p = 0.009). FE analysis revealed that the long screw model with corresponding longer lever arm had maximal horizontal sliding displacement under all directions and maximal vertical displacement, except for lateral bending. CONCLUSION: Shorter screws in Dynesys fixation may help avoid dynamic SL. Clinically, 50 mm screws showed the greatest SL and median screw screws demonstrated the least displacement biomechanically.

Post Stroke Motor Recovery Genome Wide Association Study: A Domain-Specific Approach.

Background: In this genome wide association study (GWAS) we aimed to discover single nucleotide polymorphisms (SNPs) associated with motor recovery post-stroke. Methods: We used the Vitamin Intervention for Stroke Prevention (VISP) dataset of 2,100 genotyped patients with non-disabling stroke. Of these, 488 patients had motor impairment at enrollment. Genotyped data underwent strict quality control and imputation. The GWAS utilized logistic regression models with generalized estimating equations (GEE) to leverage the repeated NIH Stroke Scale (NIHSS) motor score measurements spanning 6 time points over 24 months. The primary outcome was a decrease in the motor drift score of ≥ 1 vs. < 1 at each timepoint. Our model estimated the odds ratio of motor improvement for each SNP after adjusting for age, sex, race, days from stroke to visit, initial motor score, VISP treatment arm, and principal components. Results: Although no associations reached genome-wide significance (p < 5 × 10 -8 ), our analysis detected 115 suggestive associations (p < 5 × 10 -6 ). Notably, we found multiple SNP clusters near genes with plausible neuronal repair biology mechanisms. The CLDN23 gene had the most convincing association which affects blood-brain barrier integrity, neurodevelopment, and immune cell transmigration. Conclusion: We identified novel suggestive genetic associations with the first ever motor-specific post stroke recovery GWAS. The results seem to describe a distinct stroke recovery phenotype compared to prior genetic stroke outcome studies that use outcome measures, like the mRS. Replication and further mechanistic investigation are warranted. Additionally, this study demonstrated a proof-of-principle approach to optimize statistical efficiency with longitudinal datasets for genetic discovery.