Faculty Bibliography

Blood pressure variability (BPV) predicts cardiovascular events independent of mean blood pressure. BPV is defined as short-term (24-h), medium or long- term (weeks, months or years). Standard deviation, coefficient of variation and variation independent of the mean have been used to quantify BPV. High BPV is associated with increasing age, diabetes, smoking and vascular disease and is a consequence of premature ageing of the vasculature. Long-term BPV has been incorporated into cardiovascular risk models (QRISK) and elevated BPV confers an increased risk of cardiovascular outcomes even in subjects with controlled blood pressure. Long-acting dihydropyridine calcium channel blockers and thiazide diuretics are the only drugs that reduce BPV and for the former explains their beneficial effects on cardiovascular outcomes. We believe that BPV should be incorporated into blood pressure management guidelines and based on current evidence, long-acting dihydropyridines should be preferred drugs in subjects with elevated BPV.

INTRODUCTION/BACKGROUND:Family history of cardiovascular disease (CVD) is an independent risk factor for coronary heart disease, and the risk increases with number of family members affected. It offers insights into shared genetic, environmental and lifestyle factors that influence heart disease risk. In this study, we aimed to estimate the association of family history of CVD and its risk factors, as well as the number of affected parents or siblings, with the prevalence of major cardiometabolic risk factors (CRFs) such as hypertension, dysglycemia, dyslipidemia and obesity in a sample of young adults. METHODS:The study utilized a cross-sectional analysis of baseline data from the UAE Healthy Future Study (UAEHFS), involving 5,058 respondents below the age of 40 years. Information on parental and sibling health regarding heart disease and stroke, hypertension, type 2 diabetes (T2D), high cholesterol and obesity, was gathered through a self-completed questionnaire. CRFs were estimated based on body measurements, biochemical markers and self-reported conditions. Multivariate regression analyses were used to examine the associations between categories of family history and the estimated CRFs. RESULTS:More than half (58%) of the sample reported having a positive family history of CVD or its risk factors. The most common family history reported was T2D and hypertension, which accounted for 39.8% and 35% of the sample, respectively. The prevalence of all CRFs was significantly higher among those with a positive family history compared to those without family-history (P < 0.001). The prevalence and likelihood of having a CRF increased as the number of parents and/or siblings affected increased, indicating a potential dose-response trend. The odds were highest among individuals with both parental-and-sibling family history of disease, where they increased to 2.36 (95% CI 1.68-3.32) for hypertension, 2.59 (95% CI 1.86-3.60) for dysglycemia, 1.9 (95% CI 1.29-2.91) for dyslipidemia and 3.79 (95% CI 2.83-5.06) for obesity. CONCLUSION/CONCLUSIONS:In this study, we addressed the effect of family history as an independent risk factor on the major CRFs for the first time in the region. We observed that the majority of young Emirati adults had a positive family history of CVD-related diseases. Family history showed a strong association with the increased prevalence of CRFs. Additionally, having more relatives with specific diseases was associated with a higher risk of developing CRFs. Identifying people with a history of these conditions can help in early intervention and personalized risk assessments.

BACKGROUND/UNASSIGNED:COVID-19 has caused over 46,000 deaths in New York City, with a disproportional impact on certain communities. As part of the COVID-19 response, the city has directly administered over 6 million COVID-19 tests (in addition to millions of indirectly administered tests not covered in this analysis) at no cost to individuals, resulting in nearly half a million positive results. Given that the prevalence of testing, throughout the pandemic, has tended to be higher in more affluent areas, these tests were targeted to areas with fewer resources. OBJECTIVE/UNASSIGNED:This study aimed to evaluate the impact of New York City's COVID-19 testing program; specifically, we aimed to review its ability to provide equitable testing in economically, geographically, and demographically diverse populations. Of note, in addition to the brick-and-mortar testing sites evaluated herein, this program conducted 2.1 million tests through mobile units to further address testing inequity. METHODS/UNASSIGNED:Testing data were collected from the in-house Microsoft SQL Server Management Studio 18 Clarity database, representing 6,347,533 total tests and 449,721 positive test results. These tests were conducted at 48 hospital system locations. Per capita testing rates by zip code tabulation area (ZCTA) and COVID-19 positivity rates by ZCTA were used as dependent variables in separate regressions. Median income, median age, the percentage of English-speaking individuals, and the percentage of people of color were used as independent demographic variables to analyze testing patterns across several intersecting identities. Negative binomial regressions were run in a Jupyter Notebook using Python. RESULTS/UNASSIGNED:Per capita testing inversely correlated with median income geographically. The overall pseudo r2 value was 0.1101 when comparing hospital system tests by ZCTA against the selected variables. The number of tests significantly increased as median income fell (SE 1.00000155; P<.001). No other variables correlated at a significant level with the number of tests (all P values were >.05). When considering positive test results by ZCTA, the number of positive test results also significantly increased as median income fell (SE 1.57e-6; P<.001) and as the percentage of female residents fell (SE 0.957; P=.001). The number of positive test results by ZCTA rose at a significant level alongside the percentage of English-only speakers (SE 0.271; P=.03). CONCLUSIONS/UNASSIGNED:New York City's COVID-19 testing program was able to improve equity through the provision of no-cost testing, which focused on areas of the city that were disproportionately impacted by COVID-19 and had fewer resources. By detecting higher numbers of positive test results in resource-poor neighborhoods, New York City was able to deploy additional resources, such as those for contact tracing and isolation and quarantine support (eg, free food delivery and free hotel stays), early during the COVID-19 pandemic. Equitable deployment of testing is feasible and should be considered early in future epidemics or pandemics.

BACKGROUND:Guidance technology in total joint arthroplasty has gained popularity over the last few decades. Computer-assisted navigation (CAN) was recently introduced for glenoid implantation in total shoulder arthroplasty (TSA). However, utilization trends of CAN TSA are not currently known. This study aims to determine the prevalence and trends of CAN usage in TSA from its introduction in 2017 until 2023. METHODS:A retrospective review was performed of all TSAs (anatomic TSA [aTSA] or reverse TSA [rTSA]) implanted using a single computer navigation shoulder system (ExactechGPS; Gainseville, FL, USA). Intraoperative navigation was performed for the glenoid component only. Utilization of CAN was reported per year to determine trends in the prevalence of CAN cases, number of users, new users, dropped users, high-volume users (>50 CAN cases/year), and the number of cases completed by high-volume users. The data was also stratified by type of TSA (aTSA vs. rTSA) and type of glenoid component used (augmented or non-augmented). RESULTS:From 2017 to 2023, navigated TSAs increased from 654 to 9777 cases per year, with a greater increase in navigated rTSA than aTSA volume. The number of CAN cases using augmented implants grew 1435% while non-augmented implants grew 1352%. By 2023, the overall number of CAN users increased from 79 to 667 users. High-volume CAN surgeons increased to 50 users by 2023. Over this period, the number of CAN TSA performed by high-volume surgeons increased more rapidly than the actual number of high-volume surgeons per year. CONCLUSIONS:This study demonstrates an exponential increase in the use of CAN for TSA in the last eight years. This increase is driven by progressive growth in both the volume of new users as well as CAN TSAs performed by existing users by several hundred folds. These upwards trends in utilization of guidance technology for TSA are likely to continue in future.

BACKGROUND/UNASSIGNED:Statistical significance currently defines superiority in phase III oncology trials. However, this practice is increasingly questioned. Here, we estimated the fragility of phase III oncology trials. METHODS/UNASSIGNED:) until the interpretation was changed according to the significance threshold of each trial. Severe fragility was defined by SIFI ≤1%. RESULTS/UNASSIGNED:value-but not its binary significance interpretation-was associated with fragility and severe fragility. Trials with subsequent FDA approval had lower odds of severe fragility. Lastly, the underlying survival model had differential effects on SIFI estimation. CONCLUSIONS/UNASSIGNED:Even among phase III oncology trials, which directly inform patient care, changes in the outcomes of few patients are often sufficient to change statistical significance and trial interpretation. These findings imply that current definitions of statistical significance used in phase III oncology are inadequate to identify replicable findings.

RATIONALE & OBJECTIVE/OBJECTIVE:Arterial stiffness is associated with prevalent chronic kidney disease (CKD). Whether arterial stiffness is prospectively associated with incident CKD is inconclusive. STUDY DESIGN/METHODS:Longitudinal cohort study. SETTING & PARTICIPANTS/METHODS:Using data from the Atherosclerosis Risk in Communities (ARIC) Study, the primary analysis included 3,161 participants without prevalent CKD at visit 5; a secondary analysis studied 4,341 participants with any estimated glomerular filtration rate (eGFR) record across visits 5 to 7. EXPOSURE/METHODS:Carotid-femoral pulse wave velocity (cfPWV), heart-femoral PWV (hfPWV), heart-ankle PWV (haPWV), brachial-ankle PWV (baPWV), heart-carotid PWV (hcPWV), and femoral-ankle PWV (faPWV). OUTCOMES/RESULTS:accompanied by >25% decline eGFR or CKD hospitalization. Secondary analysis - eGFR slope. ANALYTICAL APPROACH/METHODS:Primary analysis - Cox regression models to calculate hazard ratio (HR). Secondary analysis - multilevel mixed effects models to estimate the eGFR slope across visits. RESULTS:/year [95% CI, -0.56 to -0.33] in Q4 versus -0.37 [95% CI, -0.48 to -0.26] in Q1). All p-value <0.05. faPWV was not associated with incident CKD or eGFR slope. LIMITATIONS/CONCLUSIONS:Residual confounding. CONCLUSIONS:Greater arterial stiffness, especially higher cfPWV, hfPWV, and haPWV, was prospectively associated with a higher risk of incident CKD and faster decline in eGFR among community-dwelling older adults, supporting a pathophysiological contribution of arterial stiffness to the development of CKD.

Polygenic scores (PGSs) are being rapidly adopted for trait prediction in the clinic and beyond. PGSs are often thought of as capturing the direct genetic effect of one's genotype on their phenotype. However, because PGSs are constructed from population-level associations, they are influenced by factors other than direct genetic effects, including stratification, assortative mating, and dynastic effects ("SAD effects"). Our interpretation and application of PGSs may hinge on the relative impact of SAD effects, since they may often be environmentally or culturally mediated. We developed a method that estimates the proportion of variance in a PGS (in a given sample) that is driven by direct effects, SAD effects, and their covariance. We leverage a comparison of a PGS of interest based on a standard GWAS with a PGS based on a sibling GWAS-which is largely immune to SAD effects-to quantify the relative contribution of each type of effect to variance in the PGS of interest. Our method, Partitioning Genetic Scores Using Siblings (PGSUS, pron. "Pegasus"), breaks down variance components further by axes of genetic ancestry, allowing for a nuanced interpretation of SAD effects. In particular, PGSUS can detect stratification along major axes of ancestry as well as SAD variance that is "isotropic" with respect to axes of ancestry. Applying PGSUS, we found evidence of stratification in PGSs constructed using large meta-analyses of height and educational attainment as well as in a range of PGSs constructed using the UK Biobank. In some instances, a given PGS appears to be stratified along a major axis of ancestry in one prediction sample but not in another (for example, in comparisons of prediction in samples from different countries, or in ancient DNA vs. contemporary samples). Finally, we show that different approaches for adjustment for population structure in GWASs have distinct advantages with respect to mitigation of ancestry-axis-specific and isotropic SAD variance in PGS. Our study illustrates how family-based designs can be combined with standard population-based designs to guide the interpretation and application of genomic predictors.

Single-nucleotide variants (SNVs) in key T cell genes can drive clinical pathologies and could be repurposed to improve cellular cancer immunotherapies. Here, we perform massively parallel base-editing screens to generate thousands of variants at gene loci annotated with known or potential clinical relevance. We discover a broad landscape of putative gain-of-function (GOF) and loss-of-function (LOF) mutations, including in PIK3CD and the gene encoding its regulatory subunit, PIK3R1, LCK, SOS1, AKT1 and RHOA. Base editing of PIK3CD and PIK3R1 variants in T cells with an engineered T cell receptor specific to a melanoma epitope or in different generations of CD19 chimeric antigen receptor (CAR) T cells demonstrates that discovered GOF variants, but not LOF or silent mutation controls, enhanced signaling, cytokine production and lysis of cognate melanoma and leukemia cell models, respectively. Additionally, we show that generations of CD19 CAR T cells engineered with PIK3CD GOF mutations demonstrate enhanced antigen-specific signaling, cytokine production and leukemia cell killing, including when benchmarked against other recent strategies.

PURPOSE/OBJECTIVE:Medication nonadherence is common among patients with breast cancer (BC) and increases BC mortality and complications from comorbidities. There is growing interest in mobile health interventions such as smartphone applications (apps) to promote adherence. METHODS:Use of Medisafe, a medication reminder and tracking app, was tested over 12 weeks among patients on BC treatment and at least one oral medication. Study participants were instructed to generate adherence reports every 4 weeks through Medisafe and were deemed to have completed the intervention if >50% of reports were generated. The primary end point was feasibility of the intervention, defined as a completion rate of ≥75% of consented patients. Secondary end points included changes in self-reported nonadherence from baseline to 12 weeks and patient-reported outcomes including reasons for nonadherence and satisfaction with Medisafe. We conducted univariable and multivariable analyses to evaluate demographic and clinical factors associated with intervention completion. RESULTS:Among 100 patients enrolled, 78 (78.0%) completed the intervention. Age, race, ethnicity, clinical stage, and type of medication were not associated with odds of intervention completion. Self-reported nonadherence rates did not improve from baseline to postintervention in the overall study population. However, among patients with self-reported nonadherence at baseline, 26.3% reported adherence postintervention; these patients frequently reported logistical barriers to adherence. Study participants reported high levels of satisfaction with Medisafe, noting that the app was highly functional and provided high-quality information. CONCLUSION/CONCLUSIONS:Smartphone apps such as Medisafe are feasible and associated with high patient satisfaction. They may improve adherence in nonadherent patients and those who face logistical challenges interfering with medication-taking. Future trials of mobile health interventions should target patients at high risk for medication nonadherence.

Colorectal cancer (CRC) remains a leading cause of cancer death due to metastatic spread. LIN28B is overexpressed in 30% of CRCs and promotes metastasis, yet its mechanisms remain unclear. In this study, we genetically modified CRC cell lines to overexpress LIN28B, resulting in enhanced PI3K/AKT pathway activation and liver metastasis in mice. We developed genetically modified mouse models with constitutively active Pik3ca that form intestinal tumors progressing to liver metastases with an intact immune system, addressing the limitations of previous Pik3ca-mutant models, including long tumor latency, mixed histology, and lack of distant metastases. The PI3Kα-specific inhibitor alpelisib reduced migration and invasion in vitro and metastasis in vivo. We present the first comprehensive analysis of vertical inhibition of the PI3K/AKT pathway in CRC using FDA-approved drugs alpelisib and capivasertib (an AKT inhibitor) in combination with LY2584702 (an S6K inhibitor) in CRC cell lines and mouse- and patient-derived organoids (PDOs). Tissue microarrays from CRC patients confirmed that LIN28B and PI3K/AKT pathway activation correlate with CRC progression. These findings highlight the critical role of the LIN28B-mediated PI3K/AKT pathway in CRC metastasis, the therapeutic potential of targeted inhibition, and the promise of PDOs in precision medicine in metastatic CRC.