Diabetes and pancreatic cancer risk in a multiracial cohort.

AIMS: To determine the relationship of diabetes with pancreatic cancer incidence among African American and Whites of similar socio-economic status. METHODS: Using the Southern Community Cohort Study, we conducted a follow-up during 2002-2015 of pancreatic cancer incidence of 73,378 mostly low-income participants aged 40-79 years; 15,913 reported diabetes at baseline. Multivariable Cox analysis controlling for sex, family history of pancreatic cancer, BMI, smoking status, alcohol consumption, education, income and other important covariates, and with age as the timescale was used. RESULTS: Totally, 265 incident pancreatic cancer cases were observed. Pancreatic cancer risk was increased among those with diabetes (HR 1.54, CI 1.16-2.05), with similar increases among African Americans (HR 1.51, CI 1.08-2.11) and Whites (HR 1.78, CI 1.00-3.16). No trend in risk was observed for diabetes duration among those with diabetes, with HRs of 1.39 (0.91-2.11), 2.31 (1.51-3.54) and 1.23 (0.80-1.89) for <5, 5-9 and 10+ years duration, respectively. African Americans were at increased risk of pancreatic cancer (HR = 1.40, 95% CI 1.05-1.87), which persisted after adjusting for diabetes (HR 1.36, CI 1.02-1.81). The effect sizes for other pancreatic cancer risk factors with pancreatic cancer were similar by diabetes status, although a stronger association with low BMI was evident among those with diabetes. CONCLUSIONS: Diabetes increases pancreatic cancer risk similarly among African Americans and Whites in this Southern U.S.

Longitudinal Assessment of Multimorbidity Medication Patterns among Smokers in the COPDGene Cohort.

Background and objectives: Chronic obstructive pulmonary disease (COPD) is usually comorbid with other chronic diseases. We aimed to assess the multimorbidity medication patterns and explore if the patterns are similar for phase 1 (P1) and 5-year follow-up phase 2 (P2) in the COPDGene cohort. Materials and Methods: A total of 5564 out of 10,198 smokers from the COPDGene cohort who completed 2 visits, P1 and P2 visits, with complete medication use history were included in the study. We conducted latent class analysis (LCA) among the 27 categories of chronic disease medications, excluding COPD treatments and cancer medications at P1 and P2 separately. The best number of LCA classes was determined through both statistical fit and interpretation of the patterns. Results: We found four classes of medication patterns at both phases. LCA showed that both phases shared similar characteristics in their medication patterns: LC0: low medication; LC1: hypertension (HTN) or cardiovascular disease (CVD)+high cholesterol (Hychol) medication predominant; LC2: HTN/CVD+type 2 diabetes (T2D) +Hychol medication predominant; LC3: Hychol medication predominant. Conclusions: We found similar multimorbidity medication patterns among smokers at P1 and P2 in the COPDGene cohort, which provides an understanding of how multimorbidity medication clustered and how different chronic diseases combine in smokers.

Prostate-specific membrane antigen (PSMA)-mediated laminin proteolysis generates a pro-angiogenic peptide.

Prostate-specific membrane antigen (PSMA) is a membrane-bound glutamate carboxypeptidase expressed in a number of tissues. PSMA participates in various biological functions depending on the substrate available in the particular tissue; in the brain, PSMA cleaves the abundant neuropeptide N-acetyl-aspartyl-glutamate to regulate release of key neurotransmitters, while intestinal PSMA cleaves polyglutamated peptides to supply dietary folate. PSMA expression is also progressively upregulated in prostate cancer where it correlates with tumor progression as well as in tumor vasculature, where it regulates angiogenesis. The previous research determined that PSMA cleavage of small peptides generated via matrix metalloprotease-mediated proteolysis of the extracellular matrix protein laminin potently activated endothelial cells, integrin signaling and angiogenesis, although the specific peptide substrates were not identified. Herein, using enzymatic analyses and LC/MS, we unequivocally demonstrate that several laminin-derived peptides containing carboxy-terminal glutamate moieties (LQE, IEE, LNE) are bona fide substrates for PSMA. Subsequently, the peptide products were tested for their effects on angiogenesis in various models. We report that LQ, the dipeptide product of PSMA cleavage of LQE, efficiently activates endothelial cells in vitro and enhances angiogenesis in vivo. Importantly, LQE is not cleaved by an inactive PSMA enzyme containing an active site mutation (E424S). Endothelial cell activation by LQ was dependent on integrin beta-1-induced activation of focal adhesion kinase. These results characterize a novel PSMA substrate, provide a functional rationale for the upregulation of PSMA in cancer cells and tumor vasculature and suggest that inhibition of PSMA could lead to the development of new angiogenic therapies.

Prostate specific membrane antigen produces pro-angiogenic laminin peptides downstream of matrix metalloprotease-2.

Prostate specific membrane antigen (PSMA) is a pro-angiogenic cell-surface protease that we previously demonstrated regulates blood vessel formation in a laminin and integrin ß1-dependent manner. Here, we examine the principal mechanism of PSMA activation of integrin ß1. We show that digesting laminin sequentially with recombinant matrix metalloprotease-2 (MMP-2) and PSMA generates small peptides that enhance endothelial cell adhesion and migration in vitro. We also provide evidence that these laminin peptides activate adhesion via integrin α6ß1 and focal adhesion kinase. Using an in vivo Matrigel implant assay, we show that these MMP/PSMA-derived laminin peptides also increase angiogenesis in vivo. Together, our results reveal a novel mechanism of PSMA activation of angiogenesis by processing laminin downstream of MMP-2.

How is Aging Perceived to Affect Well-being in Women Older than 50 Years Living With HIV? A Qualitative Systematic Review.

ABSTRACT: Advances in HIV treatment have led to more people with HIV living to 50 years and older. No reviews have qualitatively analyzed and synthesized the literature relevant to theory and practice for well-being specifically in Women living with HIV (WLWH) aged 50 years and older. Sixteen eligible qualitative studies were critically appraised and thematically synthesized to investigate how aging was perceived to affect well-being in WLWH aged 50 years and older. Six themes demonstrated how HIV-related stigmas negatively affected social well-being, and how adjusting to living and aging with HIV negatively affected psychological and physical well-being of older WLWH. Holding caring roles also negatively affected physical well-being of WLWH. Globally, majority women aging with HIV were found to experience additional stigmas. Further research could elucidate how HIV-related stigma affects the well-being of global majority women living and aging with HIV. Recommendations are made for future HIV-related clinical practice and theory development.

Youth-Onset Type 2 Diabetes: The Epidemiology of an Awakening Epidemic.

In this narrative review, we describe the epidemiology (prevalence, incidence, temporal trends, and projections) of type 2 diabetes among children and adolescents (<20 years), focusing on data from the U.S. and reporting global estimates where available. Secondarily, we discuss the clinical course of youth-onset type 2 diabetes, from prediabetes to complications and comorbidities, drawing comparisons with youth type 1 diabetes to highlight the aggressive course of this condition, which, only recently, has become recognized as a pediatric disease by health care providers. Finally, we end with an overview of emerging topics in type 2 diabetes research that have potential to inform strategies for effective preventive action at the community and individual levels.

Racial Disparities in Diabetes Technology Adoption and Their Association with HbA1c and Diabetic Ketoacidosis.

Aim: Poorer glycemic control and higher diabetic ketoacidosis (DKA) rates are seen in racial/ethnic minorities with type 1 diabetes (T1D). Use of diabetes technologies such as continuous glucose monitors (CGM), continuous subcutaneous insulin infusion (CSII) and automated insulin delivery (AID) systems has been shown to improve glycemic control and reduce DKA risk. We examined race/ethnicity differences in diabetes technology use and their relationship with HbA1c and DKA. Methods: Data from patients aged ≥12 years with T1D for ≥1 year, receiving care from a single diabetes center, were examined. Patients were classified as Non-Hispanic White (n=3945), Non-Hispanic Black (Black, n=161), Hispanic (n=719), and Multiracial/Other (n=714). General linear models and logistic regression were used. Results: Black (OR=0.22, 0.15-0.32) and Hispanic (OR=0.37, 0.30-0.45) patients were less likely to use diabetes technology. This disparity was greater in the pediatric population (p-interaction=0.06). Technology use associated with lower HbA1c in each race/ethnic group. Among technology users, AID use associated with lower HbA1c compared to CGM and/or CSII (HbA1c of 8.4% vs 9.2%, respectively), with the greatest difference observed for Black adult AID users. CSII use associated with a lower odds of DKA in the past year (OR=0.73, 0.54-0.99), a relationship that did not vary by race (p-interaction =0.69); this inverse association with DKA was not observed for CGM or AID. Conclusion: Disparities in diabetes technology use, DKA, and glycemic control were apparent among Black and Hispanic patients with T1D. Differences in technology use ameliorated but did not fully account for disparities in HbA1c or DKA.

Diabetes and liver cancer risk: A stronger effect in Whites than Blacks?

BACKGROUND: Both diabetes and liver cancer are overrepresented among African Americans, but limited information is available on the interrelationship of these two diseases among African Americans. We examined the association of diabetes with the incidence of liver cancer and whether this varied by participant self-reported race/ethnicity. METHODS: Using the Southern Community Cohort Study, we conducted a cancer follow up (2002-2016) of a cohort of mostly low-income participants aged 40-79 with diabetes (n = 15,879) and without diabetes (n = 59,077) at study baseline. Cox regression was used to compute Hazard Ratios (HR) and 95% CIs for the risk of incident liver cancer. RESULTS: With 790,132 person years of follow up, 320 incident cases of liver cancer were identified. In analyses controlling for age, sex, race, BMI, current and former smoking, total alcohol consumption, family history of liver cancer, any hepatitis infection, hyperlipidemia and socioeconomic factors, the association between diabetes and risk of liver cancer differed significantly (pinteraction = 0.0001) between participants identifying as Black/African American (AA) or White/European American (EA). Diabetes was associated with 5.3-fold increased cancer risk among EAs (HR 5.4, 95% CI 3.2-9.3) vs an 80% increase (HR 1.8, 95% CI 1.3-2.5) among AAs. Furthermore, controlling for diabetes greatly attenuated the higher risk of liver cancer among AAs; indeed, while the cancer risk among those without diabetes was twice as high among AAs than EAs (HR = 2.0, 95% CI = 1.4-2.9), no excess in AAs was observed among those with diabetes (HR = 0.7, 95% CI = 0.4-1.1). CONCLUSION: While liver cancer risk in general is greater in AAs than EAs and diabetes increases this risk in both racial/ethnic groups, diabetes appears to impact liver cancer to a much greater extent among EAs. The findings raise the possibility of racially different mechanisms and impacts of diabetes on this often fatal cancer among AAs and EAs.

Validating the Matching of Patients in the Linkage of a Large Hospital System's EHR with State and National Death Databases.

BACKGROUND: Though electronic health record (EHR) data have been linked to national and state death registries, such linkages have rarely been validated for an entire hospital system's EHR. OBJECTIVES: The aim of the study is to validate West Virginia University Medicine's (WVU Medicine) linkage of its EHR to three external death registries: the Social Security Death Masterfile (SSDMF), the national death index (NDI), the West Virginia Department of Health and Human Resources (DHHR). METHODS: Probabilistic matching was used to link patients to NDI and deterministic matching for the SSDMF and DHHR vital statistics records (WVDMF). In subanalysis, we used deaths recorded in Epic (n = 30,217) to further validate a subset of deaths captured by the SSDMF, NDI, and WVDMF. RESULTS: Of the deaths captured by the SSDMF, 59.8 and 68.5% were captured by NDI and WVDMF, respectively; for deaths captured by NDI this co-capture rate was 80 and 78%, respectively, for the SSDMF and WVDMF. Kappa statistics were strongest for NDI and WVDMF (61.2%) and NDI and SSDMF (60.6%) and weakest for SSDMF and WVDMF (27.9%). Of deaths recorded in Epic, 84.3, 85.5, and 84.4% were captured by SSDMF, NDI, and WVDMF, respectively. Less than 2% of patients' deaths recorded in Epic were not found in any of the death registries. Finally, approximately 0.2% of "decedents" in any death registry re-emerged in Epic at least 6 months after their death date, a very small percentage and thus further validating the linkages. CONCLUSION: NDI had greatest validity in capturing deaths in our EHR. As a similar, though slightly less capture and agreement rate in identifying deaths is observed for SSDMF and state vital statistics records, these registries may be reasonable alternatives to NDI for research and quality assurance studies utilizing entire EHRs from large hospital systems. Investigators should also be aware that there will be a very tiny fraction of "dead" patients re-emerging in the EHR.

Predictors of Change in Skin Intrinsic Fluorescence in Type 1 Diabetes: The Epidemiology of Diabetes Complications Study.

BACKGROUND: Skin intrinsic fluorescent (SIF) scores are indirect measures of advanced glycation end-products (AGEs). SIF scores are cross-sectionally associated with type 1 diabetes (T1D) complications such as increased albumin excretion rate (AER), coronary artery calcification (CAC) and neuropathy. We assessed predictors of SIF score change in those with T1D. METHODS: Data from the 30-year longitudinal Epidemiology of Diabetes Complications (EDC) study of childhood-onset T1D were used to assess AGEs measured with a SIF score produced by the SCOUT DS® device. SIF scores were assessed twice in 83 participants: between 2007-08 and again between 2010-14. Regression analyses were used to assess independent predictors of SIF score change. RESULTS: At baseline, mean age was 47.9 ± 6.9 years, diabetes duration was 36.7 ± 6.4 years, and median glycosylated hemoglobin (HbA1c) was 7.1 (interquartile range: 6.5, 8.5). During a mean follow-up of 5.2 ± 0.9 years, mean change in SIF score was 2.9 ± 2.8 arbitrary units. In multivariable linear regression models, log HbA1c (P < 0.001), log estimated glomerular filtration rate (eGFR) (P < 0.001), overt nephropathy (defined as AER ≥ 200 µg/min, P = 0.06), and multiple daily insulin shots/pump use (MDI) exposure years (P = 0.02) were independent predictors of SIF score change. CONCLUSIONS: Increases in SIF score over 5 years were related to increased glycemic levels and decreased kidney function (eGFR). MDI and glomerular damage were related to a decreased SIF score. This is one of the first studies with repeated SIF assessments in T1D and provides unique, albeit preliminary, insight about these associations.

Racial Differences in Hepatocellular Carcinoma Incidence and Risk Factors among a Low Socioeconomic Population.

The purpose of this study was to examine differences in risk factors associated with hepatocellular carcinoma (HCC) among White and African Americans from low socioeconomic backgrounds in the Southern Community Cohort Study (SCCS). The SCCS is a prospective cohort study with participants from the southeastern US. HCC incidence rates were calculated. Multivariable Cox regression was used to calculate HCC-adjusted hazard ratios (aHR) associated with known baseline HCC risk factors for White and African Americans, separately. There were 294 incident HCC. The incidence rate ratio for HCC was higher (IRR = 1.4, 95%CI: 1.1-1.9) in African Americans compared to White Americans. White Americans saw a stronger association between self-reported hepatitis C virus (aHR = 19.24, 95%CI: 10.58-35.00) and diabetes (aHR = 3.55, 95%CI: 1.96-6.43) for the development of HCC compared to African Americans (aHR = 7.73, 95%CI: 5.71-10.47 and aHR = 1.48, 95%CI: 1.06-2.06, respectively) even though the prevalence of these risk factors was similar between races. Smoking (aHR = 2.91, 95%CI: 1.87-4.52) and heavy alcohol consumption (aHR = 1.59, 95%CI: 1.19-2.11) were significantly associated with HCC risk among African Americans only. In this large prospective cohort, we observed racial differences in HCC incidence and risk factors associated with HCC among White and African Americans.

Racial Variation in the Relationship of Glycemic Control with Fracture Risk in Elderly Patients with Diabetes.

We investigated racial variation in glycemic control (glycated hemoglobin A1c [HbA1c]) with fracture risk in geriatric patients with diabetes. Compared to an HbA1c of 7.0-7.9% [53-63 mmol/mol], HbA1c ≥9.0% [≥75 mmol/mol] was associated with increased fracture risk among Blacks and those of Unknown race only. This increase was attenuated in Blacks after accounting for the relative frequency of patient-provider interaction.

Physical Activity, Mental and Personal Well-Being, Social Isolation, and Perceptions of Academic Attainment and Employability in University Students: The Scottish and British Active Students Surveys.

BACKGROUND: Physical activity (PA) promotes health and well-being. For students, university represents a transitional period, including increased independence over lifestyle behaviors, in addition to new stressors and barriers to engaging in PA. It is, therefore, important to monitor PA trends in students to gain a greater understanding about the role it might play in physical and mental well-being, as well as other factors, such as attainment and employability. METHODS: Cross-sectional surveys were conducted in 2016 in Scottish universities and colleges, and in 2017 in universities and colleges across the United Kingdom, and the data were pooled for the present study (N = 11,650). Cumulative ordinal logistic regression was used to model the association between PA levels and mental and personal well-being, social isolation, and perceptions of academic attainment and employability. RESULTS: Only 51% of the respondents met the recommended levels of moderate to vigorous PA per week. There was a linear relationship between PA levels and all outcomes, with better scores in more active students. CONCLUSIONS: UK university students are insufficiently active compared with the general population of 16- to 24-year olds. Yet, students with higher PA report better outcomes for mental and personal well-being, social isolation, and perceptions of academic attainment and employability.

Differences in Endothelin B Receptor Isoforms Expression and Function in Breast Cancer Cells.

The endothelins and their receptors are best known for their regulation of the vascular system. Their widespread expression in epithelial cells and their overexpression in some tumors has prompted investigation into their ability to regulate cancer progression. In this study, we assessed the mRNA expression of the major endothelin B receptor gene (EDNRB) isoforms and found differences in both mRNA and protein expression in normal breast cells and breast cancer cell lines. Knocking down the EDNRB gene in breast cancer cells altered invasiveness toward endothelin 3 (ET3), and we observed EDNRB isoform-specific regulation of breast cancer cell invasion and cell signaling, as well as isoform- and subtype-specific differences in breast cancer patient survival. The results reported in this study emphasize the importance of the endothelin B receptor in breast cancer. To our knowledge, this study is the first to clarify the differential expression and roles of specific EDNRB isoforms in breast cancer.

Prostate-specific membrane antigen regulates angiogenesis by modulating integrin signal transduction.

The transmembrane peptidase prostate-specific membrane antigen (PSMA) is universally upregulated in the vasculature of solid tumors, but its functional role in tumor angiogenesis has not been investigated. Here we show that angiogenesis is severely impaired in PSMA-null animals and that this angiogenic defect occurs at the level of endothelial cell invasion through the extracellular matrix barrier. Because proteolytic degradation of the extracellular matrix is a critical component of endothelial invasion in angiogenesis, it is logical to assume that PSMA participates in matrix degradation. However, we demonstrate a novel and more complex role for PSMA in angiogenesis, where it is a principal component of a regulatory loop that is tightly modulating laminin-specific integrin signaling and GTPase-dependent, p21-activated kinase 1 (PAK-1) activity. We show that PSMA inhibition, knockdown, or deficiency decreases endothelial cell invasion in vitro via integrin and PAK, thus abrogating angiogenesis. Interestingly, the neutralization of beta(1) or the inactivation of PAK increases PSMA activity, suggesting that they negatively regulate PSMA. This negative regulation is mediated by the cytoskeleton as the disruption of interactions between the PSMA cytoplasmic tail and the anchor protein filamin A decreases PSMA activity, integrin function, and PAK activation. Finally, the inhibition of PAK activation enhances the PSMA/filamin A interaction and, thus, boosts PSMA activity. These data imply that PSMA participates in an autoregulatory loop, wherein active PSMA facilitates integrin signaling and PAK activation, leading to both productive invasion and downregulation of integrin beta(1) signaling via reduced PSMA activity. Therefore, we have identified a novel role for PSMA as a true molecular interface, integrating both extracellular and intracellular signals during angiogenesis.

Does change in isolated lumbar extensor muscle function correlate with good clinical outcome? A secondary analysis of data on change in isolated lumbar extension strength, pain, and disability in chronic low back pain.

PURPOSE: Secondary analysis of data from studies utilising isolated lumbar extension exercise interventions for correlations among changes in isolated lumbar extension strength, pain, and disability. MATERIALS AND METHODS: Studies reporting isolated lumbar extension strength changes were examined for inclusion criteria including: (1) participants with chronic low back pain, (2) intervention ≥ four weeks including isolated lumbar extension exercise, (3) outcome measures including isolated lumbar extension strength, pain (Visual Analogue Scale), and disability (Oswestry Disability Index). Six studies encompassing 281 participants were included. Correlations among change in isolated lumbar extension strength, pain, and disability. Participants were grouped as "met" or "not met" based on minimal clinically important changes and between groups comparisons conducted. RESULTS: Isolated lumbar extension strength and Visual Analogue Scale pooled analysis showed significant weak to moderate correlations (r = -0.391 to -0.539, all p < 0.001). Isolated lumbar extension strength and Oswestry Disability Index pooled analysis showed significant weak correlations (r = -0.349 to -0.470, all p < 0.001). For pain and disability, isolated lumbar extension strength changes were greater for those "met" compared with those "not met" (p < 0.001-0.008). CONCLUSIONS: Improvements in isolated lumbar extension strength may be related to positive and meaningful clinical outcomes. As many other performance outcomes and clinical outcomes are not related, isolated lumbar extension strength change may be a mechanism of action affecting symptom improvement. Implications for Rehabilitation Chronic low back pain is often associated with deconditioning of the lumbar extensor musculature. Isolated lumbar extension exercise has been shown to condition this musculature and also reduce pain and disability. This study shows significant correlations between increases in isolated lumbar extension strength and reductions in pain and disability. Strengthening of the lumbar extensor musculature could be considered an important target for exercise interventions.

The relationship between balance performance, lumbar extension strength, trunk extension endurance, and pain in participants with chronic low back pain, and those without.

BACKGROUND: Chronic low back pain is associated with lumbar extensor deconditioning. This may contribute to decreased neuromuscular control and balance. However, balance is also influenced by the hip musculature. Thus, the purpose of this study was to examine balance in both asymptomatic participants and those with chronic low back pain, and to examine the relationships among balance, lumbar extension strength, trunk extension endurance, and pain. METHODS: Forty three asymptomatic participants and 21 participants with non-specific chronic low back pain underwent balance testing using the Star Excursion Balance Test, lumbar extension strength, trunk extension endurance, and pain using a visual analogue scale. FINDINGS: Significant correlations were found between lumbar extension strength and Star Excursion Balance Test scores in the chronic low back pain group (r = 0.439-0.615) and in the asymptomatic group (r = 0.309-0.411). Correlations in the chronic low back pain group were consistently found in posterior directions. Lumbar extension strength explained ~19.3% to ~37.8% of the variance in Star Excursion Balance Test scores for the chronic low back pain group and ~9.5% to ~16.9% for the asymptomatic group. INTERPRETATION: These results suggest that the lumbar extensors may be an important factor in determining the motor control dysfunctions, such as limited balance, that arise in chronic low back pain. As such, specific strengthening of this musculature may be an approach to aid in reversing these dysfunctions.

A Comparison of Isolated Lumbar Extension Strength Between Healthy Asymptomatic Participants and Chronic Low Back Pain Participants Without Previous Lumbar Spine Surgery.

STUDY DESIGN: Cross-sectional case-control study. OBJECTIVE: To compare isolated lumbar extension strength between healthy asymptomatic participants and participants with chronic low back pain (CLBP), while controlling for previous lumbar spine surgery. SUMMARY OF BACKGROUND DATA: Deconditioning of the lumbar musculature is common in those with previous lumbar surgery, resulting in decreased strength and endurance. Evidence is required to support whether this is the case for participants with CLBP yet no previous surgery compared with asymptomatic participants. METHODS: Forty-two healthy (25 males and 17 females) asymptomatic participants, and 53 participants with non-specific CLBP (30 males and 23 females) aged between 19 and 76 years were recruited. Maximal isometric isolated lumbar extension (ILEX) strength was examined. RESULTS: A Mann-Whitney U test indicated that ILEX strength was significantly greater in the asymptomatic group compared with the CLBP group (Z = 1441.00, P = 0.014). Post-hoc effect size was calculated to be d = 0.56, showing a moderate effect. CONCLUSION: These results indicate that ILEX weakness and lumbar extensor deconditioning is present independent of surgery and may be a factor involved in CLBP. As such, lumbar extensor deconditioning would appear to be a reasonable target for interventions in CLBP. LEVEL OF EVIDENCE: 3.