University of Connecticut Health Center

In the original publication [...].

ATP-binding cassette (ABC) transporters are transmembrane proteins involved in the translocation of bilirubin, bile acids, phospholipids, and cholesterol into bile canaliculi. Mutations in particular genes encoding these transporters—including BSEP (ABCB11 gene), MDR3 (ABCB4 gene), sterolin-1 and sterolin-2 (ABCG5/8 genes), and MRP2 (ABCC2 gene)—result in a wide spectrum of liver diseases, ranging from benign conditions such as Dubin-Johnson syndrome to more severe presentations like progressive familial intrahepatic cholestasis. The severity of disease is influenced by many factors, including zygosity, mutation type, and environmental modifiers such as hormones, consanguinity, and founder effects. Homozygous and compound heterozygous mutations typically result in severe and early-onset diseases, while heterozygous single-allelic mutants generally result in milder diseases. Next-generation genetic testing has proven to have high diagnostic value and is important for prognostication. With knowledge of the underlying specific mutations, there is also potential for future targeted therapy for many severe diseases. The aim of this review is to update and discuss the hepatic diseases associated with ABC transporter mutations, the genetic and environmental effects that influence the severity of disease, typical presentations of these cholestatic hepatic diseases, diagnostic considerations, and treatment options.

Pseudomonas aeruginosa is an opportunistic pathogen of significant clinical interest. When susceptible cultures of P. aeruginosa are treated with fluoroquinolone (FQ) antibiotics, some cells survive treatment and regrow in a phenomenon termed antibiotic persistence. Studies in Escherichia coli and other bacterial species suggest that FQ persisters survive by repairing DNA double-stranded breaks (DSBs) after antibiotic removal. In this study, we show that most stationary-phase P. aeruginosa survive by avoiding DSBs rather than repairing them.

BackgroundPsychological conditions are significant health concerns among older adults. However, limited evidence exists on how different cognition levels are associated with various psychological conditions. This study examines the associations of cognition levels with anxiety, perceived stress, and depressive symptoms among older adults.MethodUsing logistic regression and generalized linear models, we analyzed cross‐sectional data from 2,730 participants (age ≥ 65) in the Health and Retirement Study (HRS) 2020 interviews. Cognition was assessed with the 27‐point HRS cognition scale; Psychological outcomes were measured with the 5‐item Beck Anxiety Inventory, Perceived Stress Scale, and the Center for Epidemiological Studies Depression Scale.ResultCognitive impairment and dementia were strongly associated with the burden of psychological conditions. Individuals with cognitive impairment have 39% higher odds of anxiety, 0.99‐point higher perceived stress, and 0.33‐point higher depressive symptoms than individuals with normal cognition. Individuals with dementia were 91% more likely to experience anxiety, have 2.5‐point higher perceived stress, and 0.37‐point higher depressive symptoms than those with normal cognition. Women had significantly higher rates of anxiety, stress, and depressive symptoms than men. Hispanic individuals had higher anxiety and higher depressive symptoms than non‐Hispanic individuals, while their perceived stress scores were not significantly different. Multimorbidity with two or more chronic conditions, functional difficulty, and lower income were also significant predictors of poorer psychological health.ConclusionFindings highlight the disproportionate burden of psychological conditions for older adults with cognitive impairment and dementia, emphasizing the need for tailored intervention to improve psychological well‐being in the continuum of Alzheimer's Disease and Related Dementias.

Abstract Heterogeneity in aging is defined as variability in characteristics associated with chronological age. The concept of increased heterogeneity of health-related characteristics with increasing age has long been recognized as a tenet of geriatric medicine. However, a surprisingly limited amount of research has tested this concept. We used grip strength, an objective measure of physical function and frailty, to explore patterns of grip strength variability in population-based age-sex cohorts cross-sectionally and longitudinally. We constructed a study cohort from the UK Biobank database consisting of adults (52% female) with two measures of grip strength (n = 73,134). Age groups at initial measurement were: 40-44, 45-49, 50-54, 55-59, 60-64, and 65-69. In females and males separately, we compared: (1) patterns of grip strength variability across successively older age groups at one time point; and (2) changes over time in grip strength variability for individuals within the same age group cohort. Cross-sectional results revealed that, for females, grip strength variability did not differ significantly between pairs of successively older age groups; for males, we found statistically significant decreases in grip strength variability across successively older age groups. Longitudinal results showed that grip strength variability did not change over time within age group cohorts among females. In contrast, grip strength variability increased over time within nearly all age group cohorts among males. We conclude that heterogeneity in grip strength with aging operates differently for females and males, and that patterns of heterogeneity for males are strikingly different depending on whether age is explored cross-sectionally or longitudinally.

Abstract Gait speed is a simple and robust predictor of outcomes in older persons including disability and falls. Yet, despite widespread acceptance as an important clinical indicator, it is not routinely assessed during office visits. We sought to implement gait speed assessment into Medicare Annual Wellness Visit (AWV) workflow at four clinical practices across two healthcare systems. Gait speed was assessed using a previously-validated, radio frequency identification (RFID) technology-based system. Patients complete a 4-meter walk while wearing an armband containing an RFID tag. Wall-mounted antennae identify the tag and a computer program calculates gait speed (meters per second). We assessed implementation feasibility and fidelity using a mixed methods approach informed by the Consolidated Framework for Implementation Research 2.0. Implementation strategies included: identifying clinical champions; developing a gait speed field in Epic, the electronic medical record system; training medical assistants to conduct gait speed assessments before “rooming” patients; and assessing the proportion of AWVs where the system worked as intended. Preliminary results are available from the first clinic. Over the first 6 weeks of the 12-week implementation period, we observed 35 AWVs. In the 3-week first phase, medical assistants successfully assessed gait speed and recorded results into Epic during 16/23 (70%) of AWVs. After medical assistant re-training and re-programming range adjustment to optimize tag detection, gait speed was successfully assessed in 100% of the 12 visits observed in the 3-week second phase. Our findings provide encouraging evidence indicating that gait speed assessment using RFID technology can be implemented into AWV workflow.

Background: Meniscal preservation has been demonstrated to contribute to long-term knee health and has been a successful intervention in isolation and in patients with anterior cruciate ligament reconstruction (ACLR). The long-term results of meniscal repair in the setting of revision ACLR have yet to be documented. Purpose: To report the incidence of meniscal repair failures at the 6-year follow-up in a cohort of patients who underwent concurrent revision ACLR and primary meniscal repair. Study Design: Prospective cohort study; Level of evidence, 2. Methods: All revision ACLRs with concomitant primary meniscal repair cases from a multicenter group between 2006 and 2011 were selected. Six-year follow-up was obtained to determine whether any subsequent surgery had occurred since their initial revision ACLR. If so, operative reports were obtained, whenever possible, to verify pathological condition and treatment. Results: In total, 221 patients from 1234 revision ACLRs underwent concurrent primary meniscal repairs (18% of the cohort). There were 238 repairs performed: 173 medial and 65 lateral. The majority of these repairs (n = 181; 76%) were performed with an all-inside technique. Six-year surgical follow-up was obtained in 77% (171/221) of the cohort, or 189 of 238 (79%) of the repairs (136 medial, 53 lateral). The meniscal repair failure rate, defined as reoperation, was 16% (31/189) at 6 years. Of the 31 failures, 28 were medial (24 all-inside, 4 inside-out; 28/136 = 20.6% failure rate) and 3 were lateral (2 all-inside, 1 inside-out; 3/53 = 5.7% failure rate). Three medial failures were treated in conjunction with a subsequent repeat revision ACLR. Medial tears underwent reoperation for failure at a significantly higher rate than lateral tears (20.6% vs 5.7%; P = .01) and had a significantly shorter survival time compared with lateral tears (P = .02). No difference was found between the failure and nonfailure groups when it came to tear type, tear length, repair technique utilized, suture/implant type, or number of sutures used between the 2 groups. Conclusion: Meniscal repair in the revision ACLR setting has a 16% failure rate at 6 years. Failure rates for medial tears (20.6%) were found to be higher than that for lateral tears (5.7%), which aligns with previous studies in both the revision and primary ACLR setting.

BTB/POZ domain-containing proteins are increasingly recognized for their context-dependent roles in cancer, acting as either tumor suppressors or oncogenic drivers depending on the cancer type. Among them, the function of ankyrin repeat and BTB domain-containing protein 2 (ABTB2) in pancreatic ductal adenocarcinoma (PDAC), a highly lethal malignancy, has remained unexplored. In this study, we employed comprehensive functional genomics approaches—siRNA/shRNA knockdown, CRISPR-Cas9 knockout, plasmid-based overexpression, and a Cre-LoxP transgenic mouse model—to systemically modulate ABTB2 expression in human and murine PDAC cell lines, as well as in the KPC mouse model of PDAC. Our gain- and loss-of-function studies revealed that ABTB2 plays a pivotal tumor-suppressive role, significantly impairing PDAC cell oncogenicity in vitro and tumorigenesis in vivo. Importantly, therapeutic targeting of ABTB2 using adeno-associated virus serotype 2 (AAV2) and lipid nanoparticles (LNPs) demonstrated marked anti-tumor efficacy and synergized with 5-fluorouracil (5-FU) to enhance treatment outcomes. Transcriptomic analysis, immunoprecipitation, and functional assays demonstrated that ABTB2 interacts with tumour necrosis factor receptor-associated protein 1 (TRAP1), promoting its ubiquitin-dependent degradation and thereby suppressing key oncogenic Wnt/β-catenin and PI3K/Akt signaling pathways. Notably, TRAP1 inhibitors are currently in phase I clinical trials as potential anticancer agents. Our findings provide mechanistic insight and underscore the ABTB2/TRAP1 axis as a promising therapeutic target for PDAC treatment.

Diabetes is a crucial health issue affecting people all over the world due to its increasing rates and huge socio-economic impact. This chapter discusses the epidemiology of diabetes by indicating that both Type-I and Type-II diabetes cases are on a sharp rise globally. The multifactorial nature of the epidemics and their susceptibility is presented in terms of genetic, behavioral, and environmental factors that have contributed to the pervasive nature of the illness. Further, in this chapter, some of the major limitations in the management of Diabetes Mellitus, such as factors related to early detection of the disease, compliance to treatment, and management of complications are presented. This is further demonstrated through the necessity of different approaches and therapies in various regions, due to differences in access to healthcare services and their outcomes. The chapter also analyzes the modern treatment strategies, which include recent advancements in drug treatment where new oral and injectable drugs have been introduced and innovations in insulin delivery devices such as continuous glucose monitoring and insulin pump systems. Also, the paper discusses in detail the role of lifestyle changes and education of the patient on diabetes control. As such, these new treatments will be grouped into ranges that include gene manipulation strategies, regenerative technologies, and healthcare information and communication technologies. These cutting-edge treatment modalities are expected to enhance disease management and treatment possibilities. The concluding section of the chapter provides an overview of potential treatments and research opportunities within the public health system to mitigate the burden of diabetes in the population. The significance of collaboration in addressing this intricate, demanding, and dynamic issue is also emphasized.

Abstract Background Kapp and lambda, serum free light chain (FLC) measurements are pivotal analytes for the diagnosis and monitoring of monoclonal gammopathy or AL amyloidosis. The calculated FLC ratio (kappa/lambda) is strongly recommended for disease diagnosis, risk stratification, and management of plasma dyscrasias. UConn Health Center Laboratory Medicine validated Diazyme’s human kappa and lambda FLC assays to meet the need of quantifying serum FLC in patients suspected of monoclonal gammopathies. UConn Laboratory utilized Abbott’s Alinity c as an automated platform to validate Diazyme’s assay in-house, in place of reference laboratory’s Optilite® Freelite, a quantitative immunoturbidometric assay. Methods Within-run precision, between-run precision, method comparison, and reference range were conducted using CLSI guidelines. For within-run precision, QC levels 1 and 2 were run 10 times each while between-run precision was carried out for 20 days. Method comparison included quantitative evaluation by Deming regression between Optilite® Freelite and Diazyme kappa/lambda assay. For the reference range study, 26 samples were originally obtained for verification of the manufacturer suggested reference range. This eventually turned into establishing a reference range using 122 samples. Results The linearity of kappa FLC (KFLC)assay was measured between 0.00 to 191.20 mg/L, with lambda FLC (LFLC) over a measured range of 0.03 to 213.90 mg/L. KFLC level 1 was found to have a mean of 16.47 mg/L, with a CV 4.2%. KFLC level 2 mean 28.41 mg/dL, with a CV 1.8%. LFLC level 1 mean 24.48 mg/dL, with a CV 2.1%. LFLC level 2 mean of 42.40 mg/dL , CV 1.7%. Quantitative comparison between Optilite® Freelite and Alinity c Diazyme kappa/lambda assay indicated a -1.423 bias for KFLC and 3.212 bias for LFLC. 26 samples were used to verify Diazyme suggested reference range 2.37-20.73 mg/L for KFLC and 4.23-27.69 mg/dL for LFLC. The reference range passed for LFLC, however, failed for KFLC with 23.1% outside the given reference range. 122 samples were used to establish reference range for KFLC and LFLC. Through transformed parametric, reference range for KFLC and LFLC is 6.8-32.2 mg/L and 4.7-24.3 mg/L respectively. The reference range for k/l ratio is 0.61-2.58. Conclusion The median KFLC in normal population in UConn Health was 15.85 mg/L and median LFLC was 11.95 mg/L with k/l ratio median of 1.42. Other studies have shown the need for establishing local reference range for free light chains. However, the dominance of known reference range of 0.26-1.65 creates a problem for clinicians to adopt local reference range. Many laboratories using Diazyme have adopted Diazyme reference range when switching from Optilite to Diazyme kappa/lambda assay. Our continued discussion with hematology and oncology clinicians have geared us towards adopting Diazyme reference range although the established reference range would be different. For future direction, we will analyze local reference range with patient outcome seen at UConn Health through kappa/lambda measurements to understand if reference range revision is needed.