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MSTPublications: February 2024

Posted by on Thursday, February 29, 2024 in New Publications .

Relative predictive value of sociodemographic factors for chronic diseases among All of Us participants: a descriptive analysis.
Kunnath AJ, Sack DE, Wilkins CH.
BMC Public Health. 2024 Feb 8;24(1):405. doi: 10.1186/s12889-024-17834-1.

Background: Although sociodemographic characteristics are associated with health disparities, the relative predictive value of different social and demographic factors remains largely unknown. This study aimed to describe the sociodemographic characteristics of All of Us participants and evaluate the predictive value of each factor for chronic diseases associated with high morbidity and mortality.
Methods: We performed a cross-sectional analysis using de-identified survey data from the All of Us Research Program, which has collected social, demographic, and health information from adults living in the United States since May 2018. Sociodemographic data included self-reported age, sex, gender, sexual orientation, race/ethnicity, income, education, health insurance, primary care provider (PCP) status, and health literacy scores. We analyzed the self-reported prevalence of hypertension, coronary artery disease, any cancer, skin cancer, lung disease, diabetes, obesity, and chronic kidney disease. Finally, we assessed the relative importance of each sociodemographic factor for predicting each chronic disease using the adequacy index for each predictor from logistic regression.
Results: Among the 372,050 participants in this analysis, the median age was 53 years, 59.8% reported female sex, and the most common racial/ethnic categories were White (54.0%), Black (19.9%), and Hispanic/Latino (16.7%). Participants who identified as Asian, Middle Eastern/North African, and White were the most likely to report annual incomes greater than $200,000, advanced degrees, and employer or union insurance, while participants who identified as Black, Hispanic, and Native Hawaiian/Pacific Islander were the most likely to report annual incomes less than $10,000, less than a high school education, and Medicaid insurance. We found that age was most predictive of hypertension, coronary artery disease, any cancer, skin cancer, diabetes, obesity, and chronic kidney disease. Insurance type was most predictive of lung disease. Notably, no two health conditions had the same order of importance for sociodemographic factors.
Conclusions: Age was the best predictor for the assessed chronic diseases, but the relative predictive value of income, education, health insurance, PCP status, race/ethnicity, and sexual orientation was highly variable across health conditions. Identifying the sociodemographic groups with the largest disparities in a specific disease can guide future interventions to promote health equity.


Prognostic Value of Multiplexed Assays of Variant Effect and Automated Patch-clamping for KCNH2-LQTS Risk Stratification.
O’Neill MJ, Ng CA, Aizawa T, Sala L, Bains S, Denjoy I, Winbo A, Ullah R, Shen Q, Tan CY, Kozek K, Vanags LR, Mitchell DW, Shen A, Wada Y, Kashiwa A, Crotti L, Dagradi F, Musu G, Spazzolini C, Neves R, Bos JM, Giudicessi JR, Bledsoe X, Lancaster M, Glazer AM, Roden DM, Leenhardt A, Salem JE, Earle N, Stiles R, Agee T, Johnson CN, Horie M, Skinner J, Extramiana F, Ackerman MJ, Schwartz PJ, Ohno S, Vandenberg JI, Kroncke BM.
medRxiv [Preprint]. 2024 Feb 5:2024.02.01.24301443. doi: 10.1101/2024.02.01.24301443.

Background: Long QT syndrome (LQTS) is a lethal arrhythmia condition, frequently caused by rare loss-of-function variants in the cardiac potassium channel encoded by KCNH2. Variant-based risk stratification is complicated by heterogenous clinical data, incomplete penetrance, and low-throughput functional data.
Objective: To test the utility of variant-specific features, including high-throughput functional data, to predict cardiac events among KCNH2 variant heterozygotes.
Methods: We quantified cell-surface trafficking of 18,323 variants in KCNH2 and recorded potassium current densities for 506 KCNH2 variants. Next, we deeply phenotyped 1150 KCNH2 missense variant patients, including ECG features, cardiac event history (528 total cardiac events), and mortality. We then assessed variant functional, in silico, structural, and LQTS penetrance data to stratify event-free survival for cardiac events in the study cohort.
Results: Variant-specific current density (HR 0.28 [0.13-0.60]) and estimates of LQTS penetrance incorporating MAVE data (HR 3.16 [1.59-6.27]) were independently predictive of severe cardiac events when controlling for patient-specific features. Risk prediction models incorporating these data significantly improved prediction of 20 year cardiac events (AUC 0.79 [0.75-0.82]) over patient-only covariates (QTc and sex) (AUC 0.73 [0.70-0.77]).
Conclusion: We show that high-throughput functional data, and other variant-specific features, meaningfully contribute to both diagnosis and prognosis of a clinically actionable monogenic disease.


Mapping niche-specific two-component system requirements in uropathogenic Escherichia coli.
Brannon JR, Reasoner SA, Bermudez TA, Comer SL, Wiebe MA, Dunigan TL, Beebout CJ, Ross T, Bamidele A, Hadjifrangiskou M.
Microbiol Spectr. 2024 Feb 22:e0223623. doi: 10.1128/spectrum.02236-23. Online ahead of print.

Sensory systems allow pathogens to differentiate between different niches and respond to stimuli within them. A major mechanism through which bacteria sense and respond to stimuli in their surroundings is two-component systems (TCSs). TCSs allow for the detection of multiple stimuli to lead to a highly controlled and rapid change in gene expression. Here, we provide a comprehensive list of TCSs important for the pathogenesis of uropathogenic Escherichia coli (UPEC). UPEC accounts for >75% of urinary tract infections (UTIs) worldwide. UTIs are most prevalent among people assigned female at birth, with the vagina becoming colonized by UPEC in addition to the gut and the bladder. In the bladder, adherence to the urothelium triggers E. coli invasion of bladder cells and an intracellular pathogenic cascade. Intracellular E. coli are safely hidden from host neutrophils, competition from the microbiota, and antibiotics that kill extracellular E. coli. To survive in these intimately connected, yet physiologically diverse niches E. coli must rapidly coordinate metabolic and virulence systems in response to the distinct stimuli encountered in each environment. We hypothesized that specific TCSs allow UPEC to sense these diverse environments encountered during infection with built-in redundant safeguards. Here, we created a library of isogenic TCS deletion mutants that we leveraged to map distinct TCS contributions to infection. We identify-for the first time-a comprehensive panel of UPEC TCSs that are critical for infection of the genitourinary tract and report that the TCSs mediating colonization of the bladder, kidneys, or vagina are distinct.IMPORTANCEWhile two-component system (TCS) signaling has been investigated at depth in model strains of Escherichia coli, there have been no studies to elucidate-at a systems level-which TCSs are important during infection by pathogenic Escherichia coli. Here, we report the generation of a markerless TCS deletion library in a uropathogenic E. coli (UPEC) isolate that can be leveraged for dissecting the role of TCS signaling in different aspects of pathogenesis. We use this library to demonstrate, for the first time in UPEC, that niche-specific colonization is guided by distinct TCS groups.


A programmable arthritis-specific receptor for guided articular cartilage regenerative medicine.
Walton BL, Shattuck-Brandt R, Hamann CA, Tung VW, Colazo JM, Brand DD, Hasty KA, Duvall CL, Brunger JM.
bioRxiv [Preprint]. 2024 Feb 15:2024.01.31.578281. doi: 10.1101/2024.01.31.578281.

Structural optimization of siRNA conjugates for albumin binding achieves effective MCL1-directed cancer therapy.
Hoogenboezem EN, Patel SS, Lo JH, Cavnar AB, Babb LM, Francini N, Gbur EF, Patil P, Colazo JM, Michell DL, Sanchez VM, McCune JT, Ma J, DeJulius CR, Lee LH, Rosch JC, Allen RM, Stokes LD, Hill JL, Vickers KC, Cook RS, Duvall CL.
Nat Commun. 2024 Feb 21;15(1):1581. doi: 10.1038/s41467-024-45609-0.

An update on clinical presentation and responses to therapy of patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH).
Zhu Z, Bo-Ran Ho B, Chen A, Amrhein J, Apetrei A, Carpenter TO, Lazaretti-Castro M, Colazo JM, McCrystal Dahir K, Geßner M, Gurevich E, Heier CA, Simmons JH, Hunley TE, Hoppe B, Jacobsen C, Kouri A, Ma N, Majumdar S, Molin A, Nokoff N, Ott SM, Peña HG, Santos F, Tebben P, Topor LS, Deng Y, Bergwitz C.
Kidney Int. 2024 Feb 14:S0085-2538(24)00097-8. doi: 10.1016/j.kint.2024.01.031. Online ahead of print.

Integration of metabolic flux with hepatic glucagon signaling and gene expression profiles in the conscious dog.
Coate KC, Ramnanan CJ, Smith M, Winnick JJ, Kraft G, Irimia-Dominguez J, Farmer B, Donahue EP, Roach PJ, Cherrington AD, Edgerton DS.
Am J Physiol Endocrinol Metab. 2024 Feb 7. doi: 10.1152/ajpendo.00316.2023. Online ahead of print.

Combined Anterior-Posterior vs. Posterior-Only Approach in Adult Spinal Deformity Surgery: Which Strategy Is Superior?
Younus I, Chanbour H, Chen JW, Johnson GW, Metcalf T, Lyons AT, Jonzzon S, Liles C, Roth SG, Abtahi AM, Stephens BF, Zuckerman SL.
J Clin Med. 2024 Jan 24;13(3):682. doi: 10.3390/jcm13030682.

Brain-wide human oscillatory local field potential activity during visual working memory.
Singh B, Wang Z, Madiah LM, Gatti SE, Fulton JN, Johnson GW, Li R, Dawant BM, Englot DJ, Bick SK, Roberson SW, Constantinidis C.
iScience. 2024 Feb 5;27(3):109130. doi: 10.1016/j.isci.2024.109130. eCollection 2024 Mar 15.

Lactate utilization enables metabolic escape to confer resistance to BET inhibition in acute myeloid leukemia.
Monteith AJ, Ramsey HE, Silver AJ, Brown D, Greenwood D, Smith BN, Wise AD, Liu J, Olmstead SD, Watke J, Arrate MP, Gorska AE, Fuller L, Locasale JW, Stubbs MC, Rathmell JC, Savona MR.
Cancer Res. 2024 Jan 29. doi: 10.1158/0008-5472.CAN-23-0291. Online ahead of print.

LNK/SH2B3 loss of function increases susceptibility to murine and human atrial fibrillation.
Murphy MB, Yang Z, Subati T, Farber-Eger E, Kim K, Blackwell DJ, Fleming MR, Stark JM, Van Amburg JC, Woodall KK, Van Beusecum JP, Agrawal V, Smart CD, Pitzer A, Atkinson JB, Fogo AB, Bastarache JA, Kirabo A, Wells QS, Madhur MS, Barnett JV, Murray KT.
Cardiovasc Res. 2024 Feb 20:cvae036. doi: 10.1093/cvr/cvae036. Online ahead of print.

Engineering approaches for RNA-based and cell-based osteoarthritis therapies.
DeJulius CR, Walton BL, Colazo JM, d’Arcy R, Francini N, Brunger JM, Duvall CL.
Nat Rev Rheumatol. 2024 Feb;20(2):81-100. doi: 10.1038/s41584-023-01067-4. Epub 2024 Jan 22. Review.