Association between pre-dementia psychiatric diagnoses and all-cause dementia is independent from polygenic dementia risks in the UK Biobank.

BACKGROUND: Psychiatric disorders have been associated with higher risk for future dementia. Understanding how pre-dementia psychiatric disorders (PDPD) relate to established dementia genetic risks has implications for dementia prevention. METHODS: In this retrospective cohort study, we investigated the relationships between polygenic risk scores for Alzheimer's disease (AD PRS), PDPD, alcohol use disorder (AUD), and subsequent dementia in the UK Biobank (UKB) and tested whether the relationships are consistent with different causal models. FINDINGS: Among 502,408 participants, 9352 had dementia. As expected, AD PRS was associated with greater risk for dementia (odds ratio (OR) 1.62, 95% confidence interval (CI), 1.59-1.65). A total of 94,237 participants had PDPD, of whom 2.6% (n = 2519) developed subsequent dementia, compared to 1.7% (n = 6833) of 407,871 participants without PDPD. Accordingly, PDPD were associated with 73% greater risk of incident dementia (OR 1.73, 1.65-1.83). Among dementia subtypes, the risk increase was 1.5-fold for AD (n = 3365) (OR 1.46, 1.34-1.59) and 2-fold for vascular dementia (VaD, n = 1823) (OR 2.08, 1.87-2.32). Our data indicated that PDPD were neither a dementia prodrome nor a mediator for AD PRS. Shared factors for both PDPD and dementia likely substantially account for the observed association, while a causal role of PDPD in dementia could not be excluded. AUD could be one of the shared causes for PDPD and dementia. INTERPRETATION: Psychiatric diagnoses were associated with subsequent dementia in UKB participants, and the association is orthogonal to established dementia genetic risks. Investigating shared causes for psychiatric disorders and dementia would shed light on this dementia pathway. FUNDING: US NIH (K08AG054727).

Global Prevalence of Pancreatic Cystic Lesions in the General Population on Magnetic Resonance Imaging: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Understanding the burden of pancreatic cystic lesions (PCLs) in the general population is important for clinicians and policymakers. In this systematic review, we sought to estimate the global prevalence of PCLs using magnetic resonance imaging (MRI) and to investigate factors that contribute to its variation. METHODS: We searched MEDLINE, EMBASE, and Cochrane Central, from database inception through February 2023. We included full-text articles that reported the prevalence of PCLs using MRI in the general population. A proportional meta-analysis was performed, and the prevalence of PCLs was pooled using a random-effects model. RESULTS: Fifteen studies with 65,607 subjects were identified. The pooled prevalence of PCLs was 16% (95% confidence interval [CI], 13%-18%; I2 = 99%), most of which were under 10 mm. Age-specific prevalence of PCLs increased from 9% (95% CI, 7%-12%) at 50 to 59 years, to 18% (95% CI, 14%-22%) at 60 to 69 years, 26% (95% CI, 20%-33%) at 70 to 79 years, and 38% at 80 years and above (95% CI, 25%-52%). There was no difference in prevalence between sexes. Subgroup analysis showed higher PCL prevalence when imaging findings were confirmed by independent radiologist(s) (25%; 95% CI, 16%-33%) than when chart review alone was used (5%; 95% CI, 4%-7%; P < .01). There was no independent association of PCL prevalence with geographic location (Europe, North America, or Asia), MRI indication (screening vs evaluation of non-pancreatic pathology), enrollment period, sample size, magnet strength (1.5 vs 3 tesla), and MRI sequence (magnetic resonance cholangiopancreatography vs no magnetic resonance cholangiopancreatography). CONCLUSION: In this systematic review, the global prevalence of PCLs using a highly sensitive noninvasive imaging modality ranged between 13% and 18%.

Prevalence of electronic cigarette use and its determinants in us persons of Hispanic/Latino background: The Hispanic community health study / study of Latinos (HCHS/SOL).

Objective: To determine the prevalence and determinants of electronic nicotine delivery systems (ENDS) use among Hispanic/Latino adults from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Methods: Cross-sectional data collected between the years 2015-2017 were analyzed to assess ENDS use (ever (current: use ≤ past 30 days; former: use > past 30 days) and never) among 11,623 adults (mean age 47 years±0.3 years; 52% women). Weighted prevalence estimates were reported, and age-adjusted logistic regression models were used to examine associations between sociodemographic and clinical exposures with ENDS use. Results: The prevalence of current and former ENDS use was 2.0% and 10.4%, respectively. Having ever used ENDS was associated with prevalent coronary artery disease. Current ENDS use was higher in males and associated with higher education, English language preference, and Puerto Rican background compared with nonsmokers and cigarette-only smokers (all p<0.05). Conclusions: Hispanic/Latino individuals who are young adults, male, US-born, and have high acculturation were more likely to report current ENDS use. These findings could inform preventive and regulatory interventions targeted to Hispanics/Latinos.

Influence of BMI on virtual coronary artery calcium scoring.

PURPOSE: Virtual non-contrast (VNC) coronary artery calcium scoring (CAC) may obviate the need for traditional non-contrast (TNC) CAC. There is no data on the influence of body mass index (BMI) on VNC reliability. We aimed to evaluate the influence of BMI on VNC CAC agreement with TNC. MATERIALS AND METHODS: All patients who underwent sequential CAC and coronary CT angiography (CCTA) using spectral CT with TNC CAC > 0 between August 2020 and December 2021 were included. Agatston CAC scores were calculated manually by 2 blinded readers from VNC scans. A correction factor was calculated from the slope of the linear regression using the method of least squares and applied to the VNC scores. Bland-Altman plots and Cohen's weighted Kappa were utilized. RESULTS: We included 174 patients (57.5% female). Mean BMI was 32.6 ± 7.02 kg/m2 [BMI < 30 (39.7%); BMI 30-40 (45.4%); and BMI > 40 kg/m2 (14.9%)]. Mean TNC CAC was 177.8 ± 316.86 and mean VNC CAC after applying the correction factor 149.34 ± 296.73. The TNC value strongly correlated with VNC (r = 0.94; p < 0.0001). As BMI increased there was a progressive reduction in signal-to-noise ratio, contrast-to-noise ratio and coronary enhancement (p < 0.05). The degree of agreement between VNC and TNC CAC decreased as BMI increased (agreement = 91.79 (weighted Kappa = 0.72), 91.14 (weighted Kappa = 0.58) and 88.46% (weighted Kappa = 0.48) (all P values < 0.001) for BMI < 30; 30-40 and > 40 kg/m2, respectively). CONCLUSION: BMI has a significant influence on the accuracy of VNC CAC. VNC CAC shows substantial agreement in non-obese patients but performs poorly in BMI > 40 kg/m2. This is the first study to evaluate the influence of body mass index (BMI) on virtual non-contrast (VNC) coronary artery calcium scoring (CAC) as compared to traditional non-contrast (TNC). We retrospectively evaluated 174 patients with TNC CAC and two blinded reviewers manually calculated the VNC CAC. All cases were included without specific selection for quality. The ratio between the two directly proportional values was determined using the slope from the linear regression through the method of least squares. This correction factor of 2.65 was applied to the calcium scores obtained from VNC images. We found that VNC CAC shows substantial risk-class agreement with TNC in non-obese patients (agreement = 91.79 and weighted Kappa = 0.72) but performs poorly in BMI > 40 kg/m2 (agreement: 88.46% and weighted Kappa = 0.48). These findings show the potential use of VNC CAC to avoid additional radiation in non-obese patients. However, further research on potential improvement strategies for VNC CAC in obese patients is needed.

Race-Ethnic Differences of ST-Elevation Myocardial Infarction: Findings from a New York Health System Registry.

Background: Race and ethnicity are major considerations in the incidence, management, and long-term outcome of ST-elevation myocardial infarction (STEMI) in the United States, but there is limited existing comparative data. Methods: We assembled a registry in a health system serving Bronx, NY of STEMI patients from 2008-2014 and analyzed differences in presentation, treatment and mortality between Hispanic/Latino (H/L), non-Hispanic Black (NHB) and non-Hispanic White (NHW). Upon discharge post-treatment for STEMI, all patients were followed for a median of 4.4 years (interquartile range 2.5, 6.0). Out of 966 STEMI patients, mean age was 61 years, 46% were H/L and 65% were male. H/Ls and NHBs had a higher prevalence of hypertension and diabetes mellitus than their NHW counterparts, coinciding with a lower socioeconomic status (SES). Results: The number of critically diseased vessels found at cardiac catheterization and mean troponin levels did not vary by race-ethnicity; neither did the adjusted hazard ratios (HR) for death. However, age-sex adjusted rates of general hospital readmission were higher in NHBs vs NHWs (HR 1.30, P=.03). Age-sex adjusted cardiovascular readmissions rates were higher in H/Ls than NHWs (HR 1.42, P=.03). Age-sex adjusted heart failure readmissions were increased for both H/Ls (HR 2.14, P=.01) and NHBs (HR 2.12, P=.02) over NHWs. Conclusions: Among STEMI patients, a higher prevalence of modifiable cardiovascular risk factors and a lower SES was seen among NHBs and H/Ls compared to NHWs. Despite similar coronary disease severity and in-hospital death, NHBs and H/Ls had a greater risk of general, cardiovascular and heart failure readmissions post-STEMI compared to NHWs.

Quantitative in vitro to in vivo extrapolation for developmental toxicity potency of valproic acid analogues.

BACKGROUND: The developmental toxicity potential (dTP) concentration from the devTOX quickPredict (devTOXqP ) assay, a metabolomics-based human induced pluripotent stem cell assay, predicts a chemical's developmental toxicity potency. Here, in vitro to in vivo extrapolation (IVIVE) approaches were applied to address whether the devTOXqP assay could quantitatively predict in vivo developmental toxicity lowest effect levels (LELs) for the prototypical teratogen valproic acid (VPA) and a group of structural analogues. METHODS: VPA and a series of structural analogues were tested with the devTOXqP assay to determine dTP concentration and we estimated the equivalent administered doses (EADs) that would lead to plasma concentrations equivalent to the in vitro dTP concentrations. The EADs were compared to the LELs in rat developmental toxicity studies, human clinical doses, and EADs reported using other in vitro assays. To evaluate the impact of different pharmacokinetic (PK) models on IVIVE outcomes, we compared EADs predicted using various open-source and commercially available PK and physiologically based PK (PBPK) models. To evaluate the effect of in vitro kinetics, an equilibrium distribution model was applied to translate dTP concentrations to free medium concentrations before subsequent IVIVE analyses. RESULTS: The EAD estimates for the VPA analogues based on different PK/PBPK models were quantitatively similar to in vivo data from both rats and humans, where available, and the derived rank order of the chemicals was consistent with observed in vivo developmental toxicity. Different models were identified that provided accurate predictions for rat prenatal LELs and conservative estimates of human safe exposure. The impact of in vitro kinetics on EAD estimates is chemical-dependent. EADs from this study were within range of predicted doses from other in vitro and model organism data. CONCLUSIONS: This study highlights the importance of pharmacokinetic considerations when using in vitro assays and demonstrates the utility of the devTOXqP human stem cell-based platform to quantitatively assess a chemical's developmental toxicity potency.

Corrigendum to "Risk Factor Control Across the Spectrum of Cardiovascular Risk: Findings from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)" [American Journal of Preventive Cardiology, Volume 5, March 2021, 100147].

[This corrects the article DOI: 10.1016/j.ajpc.2021.100147.].

Risk factor control across the spectrum of cardiovascular risk: Findings from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

BACKGROUND: Presence of cardiovascular disease (CVD) risk factors (RFs) should prompt patients and their providers to work aggressively towards controlling those that are modifiable. The extent to which a greater CVD RF burden is related to CVD RF control in a contemporary and diverse Hispanic/Latino population is not well-understood. METHODS: Using multicenter community-based data from the Hispanic Community Health Study/Study of Latinos, we assessed the self-reported prevalence of hypertension, hypercholesterolemia, diabetes, and prevalent CVD (ischemic heart disease or stroke). We used contemporaneous guidelines to define RF control. Multivariable logistic regression for complex survey sampling was used to examine whether having more CVD RFs was associated with CVD RF control (adjusting for age, sex, Hispanic background group, education, and health insurance). RESULTS: Our sample included 8521 participants with at least one CVD RF or prevalent CVD. The mean age in HCHS/SOL target population was 49 (SE 0.3) years and 56% were women. Frequency of one, two, or three self-reported CVD RFs was 57%, 26%, 8%, respectively, and overall 9% of participants had prevalent CVD. After adjusting for sociodemographic factors, compared to those reporting one CVD RF, individuals with three CVD RFs were the least likely to have blood pressure, cholesterol, and glucose optimally controlled (odds ratio [OR]: 0.56; 95% confidence interval [CI]: 0.40-0.80). However, those with prevalent CVD were more likely to have all three risk factors controlled, (OR: 1.43; 95% CI: 1.01-2.01). CONCLUSION: Hispanic/Latino adults with three major CVD RFs represent a group with poor overall CVD RF control. Secondary CVD prevention fares better. The potential contributors to inadequate CVD RF control in this highly vulnerable group warrants further investigation.

Tobacco Use Prevalence and Transitions From 2013 to 2018 Among Adults With a History of Cardiovascular Disease.

Background Although tobacco product use and transitions have been characterized in the general population, few studies have focused on individuals with established cardiovascular disease (CVD) in a population-based sample. Methods and Results We examined tobacco use prevalence and longitudinal patterns of tobacco product transitions in adults (≥18 years) of the nationally representative PATH (Population Assessment of Tobacco and Health) study, from 2013 to 2014 (Wave 1) through 2016 to 2018 (Wave 4). Prevalent CVD was classified through self-report of having had a heart attack, heart failure, stroke, or other heart condition. Factors associated with tobacco product use and transitions were investigated using survey logistic regression. We examined 2615 participants with self-reported CVD at Wave 1. Overall, 28.9% reported current tobacco use, equating to ≈6.2 million adults in the United States with prevalent CVD and current tobacco use. Among adults with CVD who are current tobacco users, the most commonly used product was cigarettes (82.8%), followed by any type of cigar (23.7%), and e-cigarette use (23.3%). E-cigarette use without concurrent cigarette use among participants with prevalent CVD was uncommon (1.1%). Factors associated with tobacco use were younger age, male sex, had lower education level, and lack of knowledge about the association between smoking and CVD. Men with prevalent CVD were less likely to use e-cigarettes compared with women (odds ratio [OR], 0.7; 95% CI, 0.5-0.9). Among cigarette users with CVD, transition rates between Waves 1 and 4 demonstrated <5% decrease in cigarette, with a 0.5% increase in e-cigarette use. Only ≈10% were in formal tobacco cessation programs. Conclusions Despite known harmful cardiovascular effects, over one fourth of adults with prevalent CVD use tobacco products and few quit smoking over the 4 waves of the PATH data set.

Performance of HepaRG and HepG2 cells in the high-throughput micronucleus assay for in vitro genotoxicity assessment.

The micronucleus (MN) assay is a core test used to evaluate genotoxic potential of xenobiotics. The traditional in vitro MN assay is usually conducted in cells lacking metabolic competency or by supplementing cultures with an exogenous rat S9 metabolic system, which creates a significant assay limitation for detecting genotoxic metabolites. Our previous study demonstrated that compared to HepG2, HepaRG cells exhibited a significantly higher level of CYP450 enzyme activities and detected a greater portion of genotoxic carcinogens requiring metabolic activation using the Comet assay. The aim of this study was to assess the performance of HepaRG cells in the flow cytometry-based MN assay by testing 28 compounds with known genotoxic or carcinogenic modes of action (MoA). HepaRG cells exhibited higher sensitivity (83%) than HepG2 cells (67%) in detecting 12 indirect-acting genotoxicants or carcinogens. The HepaRG MN assay was 100% specific and 93% accurate in detecting genotoxic potential of the 28 compounds. Quantitative comparison of the MN concentration-response data using benchmark dose analysis showed that most of the tested compounds induced higher % MN in HepaRG than HepG2 cells. In addition, HepaRG cells were compatible with the Multiflow DNA damage assay, which predicts the genotoxic MoA of compounds tested. These results suggest that high-throughput flow cytometry-based MN assay may be adapted using HepaRG cells for genotoxicity assessment, and that HepaRG cells appear to be more sensitive than HepG2 cells in detecting genotoxicants or carcinogens that require metabolic activation.

Virulence Characteristics of mecA-Positive Multidrug-Resistant Clinical Coagulase-Negative Staphylococci.

Coagulase-negative staphylococci (CoNS) are an important group of opportunistic pathogenic microorganisms that cause infections in hospital settings and are generally resistant to many antimicrobial agents. We report on phenotypic and genotypic virulence characteristics of a select group of clinical, mecA-positive (encoding penicillin-binding protein 2a) CoNS isolates. All CoNS were resistant to two or more antimicrobials with S. epidermidis strain 214EP, showing resistance to fifteen of the sixteen antimicrobial agents tested. Aminoglycoside-resistance genes were the ones most commonly detected. The presence of megaplasmids containing both horizontal gene transfer and antimicrobial resistance genetic determinants indicates that CoNS may disseminate antibiotic resistance to other bacteria. Staphylococcus sciuri species produced six virulence enzymes, including a DNase, gelatinase, lipase, phosphatase, and protease that are suspected to degrade tissues into nutrients for bacterial growth and contribute to the pathogenicity of CoNS. The PCR assay for the detection of biofilm-associated genes found the eno (encoding laminin-binding protein) gene in all isolates. Measurement of their biofilm-forming ability and Spearman's rank correlation coefficient analyses revealed that the results of crystal violet (CV) and extracellular polymeric substances (EPS) assays were significantly correlated (ρ = 0.9153, P = 3.612e-12). The presence of virulence factors, biofilm-formation capability, extracellular enzymes, multidrug resistance, and gene transfer markers in mecA-positive CoNS clinical strains used in this study makes them powerful opportunistic pathogens. The study also warrants a careful evaluation of nosocomial infections caused by CoNS and may be useful in studying the mechanism of virulence and factors associated with their pathogenicity in vivo and developing effective strategies for mitigation.

Oligotrophic Media Compared with a Tryptic Soy Agar or Broth for the Recovery of Burkholderia cepacia Complex from Different Storage Temperatures and Culture Conditions.

The Burkholderia cepacia complex (BCC) is capable of remaining viable in low-nutrient environments and harsh conditions, posing a contamination risk in non-sterile pharmaceutical products as well as a challenge for detection. To develop optimal recovery methods to detect BCC, three oligotrophic media were evaluated and compared with nutrient media for the recovery of BCC from autoclaved distilled water or antiseptic solutions. Serial dilutions (10-1 to 10-12 CFU/ml) of 20 BCC strains were inoculated into autoclaved distilled water and stored at 6°C, 23°C and 42°C for 42 days. Six suspensions of Burkholderia cenocepacia were used to inoculate aqueous solutions containing 5 µg/ml and 50 µg/ml chlorhexidine gluconate (CHX) and 10 µg/ml benzalkonium chloride (BZK), and stored at 23°C for a further 199 days. Nutrient media such as Tryptic Soy Agar (TSA) or Tryptic Soy Broth (TSB), oligotrophic media (1/10 strength TSA or TSB, Reasoner's 2nd Agar [R2A] or Reasoner's 2nd Broth [R2AB], and 1/3 strength R2A or R2AB) were compared by inoculating these media with BCC from autoclaved distilled water and from antiseptic samples. The recovery of BCC in water or antiseptics was higher in culture broth than on solid media. Oligotrophic medium showed a higher recovery efficiency than TSA or TSB for the detection of 20 BCC samples. Results from multiple comparisons allowed us to directly identify significant differences between TSA or TSB and oligotrophic media. An oligotrophic medium pre-enrichment resuscitation step is offered for the United States Pharmacopeia (USP) proposed compendial test method for BCC detection.

Prognostic and predictive signatures for treatment decisions.

AIM: We develop a subgroup selection procedure using both prognostic and predictive biomarkers to identify four patient subpopulations: low- and high-risk responders, and low- and high-risk nonresponders. METHODS: We utilize three regression models to identify three sets of biomarkers: S, prognostic biomarkers; T, predictive biomarkers; and U, prognostic and predictive biomarkers. The prognostic signature C(S) combines with a predictive signature, either C(T) or C(U), to develop two procedures C(S,T) and C(S,U) for identification of four subgroups. RESULTS: Simulation experiment showed that proposed models for identifying the biomarker sets S and U performed well, as did the procedure C(S,U) for subgroup identification. CONCLUSION: The proposed model provides more comprehensive characterization of patient subpopulations, and better accuracy in patient treatment assignment.

Development of predictive signatures for treatment selection in precision medicine with survival outcomes.

For survival endpoints in subgroup selection, a score conversion model is often used to convert the set of biomarkers for each patient into a univariate score and using the median of the univariate scores to divide the patients into biomarker-positive and biomarker-negative subgroups. However, this may lead to bias in patient subgroup identification regarding the 2 issues: (1) treatment is equally effective for all patients and/or there is no subgroup difference; (2) the median value of the univariate scores as a cutoff may be inappropriate if the sizes of the 2 subgroups are differ substantially. We utilize a univariate composite score method to convert the set of patient's candidate biomarkers to a univariate response score. We propose applying the likelihood ratio test (LRT) to assess homogeneity of the sampled patients to address the first issue. In the context of identification of the subgroup of responders in adaptive design to demonstrate improvement of treatment efficacy (adaptive power), we suggest that subgroup selection is carried out if the LRT is significant. For the second issue, we utilize a likelihood-based change-point algorithm to find an optimal cutoff. Our simulation study shows that type I error generally is controlled, while the overall adaptive power to detect treatment effects sacrifices approximately 4.5% for the simulation designs considered by performing the LRT; furthermore, the change-point algorithm outperforms the median cutoff considerably when the subgroup sizes differ substantially.