Centralizing Telehealth Test-to-Treat Through a Regional Clinical Contact Center: A Veterans Health Administration Pilot.

Background: This project describes a Veterans Health Administration telehealth pilot to facilitate COVID-19 oral antiviral treatment as part of the national test-to-treat (T2T) strategy. The pilot was operationalized for two pilot VA medical centers by the regional clinical contact center (CCC) for a Veteran Integrated Service Network, which offers multiple services through several virtual modalities. Methods: Nurse triage and medical provider evaluation templates were developed for the CCC to standardize clinical interventions with veteran callers reporting positive home COVID-19 test results. When veterans were determined eligible and consented to treatment with an emergency use authorization (EUA) antiviral medication, CCC providers used secure direct messaging for synchronous communication with local pharmacy services to facilitate adjudication and dispensing. Templates for pharmacy documentation and primary care follow-up monitoring were also developed and disseminated. Results: In total, 198 veterans (mean age 65 years, 89% male, 88% non-Hispanic White) were evaluated through telehealth by regional CCC providers using the T2T process and 96% were prescribed an antiviral medication. Primary care follow-up occurred in 86% of cases, a median of 3 days after the telehealth evaluation. The 30-day all-cause hospitalization rate was 1.5% and there were no deaths within 30 days of treatment initiation. Conclusions: Veterans Integrated Service Network's CCC telehealth triage and evaluation processes enabled safe EUA-compliant care delivery, improved evaluator experience and efficiency, and augmented existing EUA processes in place by front-line pharmacy and primary care teams.

Pre-endoscopy coronavirus disease 2019 screening and severe acute respiratory syndrome coronavirus-2 nucleic acid amplification testing in the Veterans Affairs healthcare system: clinical practice patterns, outcomes, and relationship to procedure volume.

BACKGROUND AND AIMS: The coronavirus disease 2019 (COVID-19) pandemic has had profound impacts worldwide, including on the performance of GI endoscopy. We aimed to describe the performance and outcomes of pre-endoscopy COVID-19 symptom and exposure screening and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) nucleic acid amplification testing (NAAT) across the national Veterans Affairs healthcare system and describe the relationship of SARS-CoV-2 NAAT use and resumption of endoscopy services. METHODS: COVID-19 screening and NAAT results from March 2020 to April 2021 were analyzed to determine use, performance characteristics of screening, and association between testing and endoscopic volume trends. RESULTS: Of 220,891 completed endoscopies identified, 115,890 (52.5%) had documented preprocedure COVID-19 symptom and exposure screenings and 154,127 (69.8%) had preprocedure NAAT results within 7 days before scheduled endoscopy. Of 131,894 total canceled endoscopies, 26,475 (20.1%) had screening data and 28,505 (21.6%) had SARS-CoV-2 NAAT results. Overall, positive NAAT results were reported in 1.8% of all individuals tested and in 1.3% of those who screened negative. Among completed and canceled endoscopies, COVID-19 screening had a 34.6% sensitivity (95% confidence interval [CI], 32.4%-36.8%) and 96.4% specificity (95% CI, 96.2%-96.5%) when compared with NAAT. COVID-19 screening had a positive predictive value of 15.0% (95% CI, 14.0%-16.1%) and a negative predictive value of 98.7% (95% CI, 98.7%-98.8%). There was a very weak correlation between monthly testing and monthly endoscopy volume by site (Spearman rank correlation coefficient = .09). CONCLUSIONS: These findings have important implications for decisions about preprocedure testing, especially given breakthrough infections among vaccinated individuals during the SARS-CoV-2 delta and omicron variant surge.

Synergistic premalignant effects of chronic ethanol exposure and insulin receptor substrate-1 overexpression in liver.

AIM: Insulin receptor substrate, type 1 (IRS-1) transmits growth and survival signals, and is overexpressed in more than 90% of hepatocellular carcinomas (HCCs). However, experimental overexpression of IRS-1 in the liver was found not to be sufficient to cause HCC. Since chronic alcohol abuse is a risk factor for HCC, we evaluated potential interactions between IRS-1 overexpression and chronic ethanol exposure by assessing premalignant alterations in gene expression. METHODS: Wild-type (wt) or IRS-1 transgenic (Tg) mice, constitutively overexpressing the human (h) transgene in the liver, were pair-fed isocaloric liquid diets containing 0% or 24% ethanol for 8 weeks. The livers were used for histopathologic study and gene expression analysis, focusing on insulin, insulin-like growth factor (IGF) and wingless (WNT)-Frizzled (FZD) pathways, given their known roles in HCC. RESULTS: In wt mice, chronic ethanol exposure caused hepatocellular microsteatosis with focal chronic inflammation, reduced expression of proliferating cell nuclear antigen (PCNA) and increased expression of IGF-I and IGF-I receptor. In hIRS-1 Tg mice, chronic ethanol exposure caused hepatic micro- and macrosteatosis, focal chronic inflammation, apoptosis and disordered lobular architecture. These effects of ethanol in hIRS-1 Tg mice were associated with significantly increased expression of IGF-II, insulin, IRS-4, aspartyl-asparaginyl beta hydroxylase (AAH), WNT-1 and FZD 7, as occurs in HCC. CONCLUSION: In otherwise normal liver, chronic ethanol exposure mainly causes liver injury and inflammation with impaired DNA synthesis. In contrast, in the context of hIRS-1 overexpression, chronic ethanol exposure may serve as a cofactor in the pathogenesis of HCC by promoting expression of growth factors, receptors and signaling molecules known to be associated with hepatocellular transformation.

Physician support of HPV vaccination school-entry requirements.

School-entry requirements in the US have led to high coverage for several vaccines, but few states and jurisdictions have adopted these policies for human papillomavirus (HPV) vaccination. Because physicians play a key role in advocating for vaccination policies, we assessed physician support of requiring HPV vaccine for school entry and correlates of this support. Participants were a national sample of 775 physicians who provide primary care, including vaccines, to adolescents. Physicians completed an online survey in 2014 that assessed their support for school-entry requirements for HPV vaccination of 11 and 12 y olds. We used multivariable logistic regression to assess correlates of support for these requirements. The majority of physicians (74%) supported some form of school-entry requirements, with or without opt-out provisions. When opt-out provisions were not specified, 47% agreed that laws requiring HPV vaccination for school attendance were a "good idea." Physicians more often agreed with requirements, without opt-out provisions, if they: had more years in practice (OR=1.49; 95% CI: 1.09-2.04), gave higher quality HPV vaccine recommendations (OR=2.06; 95% CI: 1.45-2.93), believed that having requirements for Tdap, but not HPV, vaccination undermined its importance (OR=3.33; 95% CI: 2.26-4.9), and believed HPV vaccination was as or more important than other adolescent vaccinations (OR=2.30; 95% CI: 1.65-3.18). In conclusion, we found that many physicians supported school-entry requirements for HPV vaccination. More research is needed to investigate the extent to which opt-out provisions might weaken or strengthen physician support of HPV vaccination school-entry requirements.

Left ventricular assist device-associated infections.

The left ventricular assist device (LVAD) is a mechanical pump that supplements or replaces the function of a damaged left ventricle. Although LVAD support is associated with improved survival and quality of life, infectious complications remain a major limitation. The authors examine the epidemiology of LVAD-associated infections and review current diagnostic, treatment, and management strategies. Novel evidence-based approaches to infection prevention remain critical because the number of patients receiving long-term mechanical support continues to burgeon.

Aspartyl-(asparaginyl)-beta-hydroxylase regulates hepatocellular carcinoma invasiveness.

BACKGROUND/AIMS: We measured aspartyl (asparaginyl)-beta-hydroxylase (AAH) gene expression in human hepatocelluar carcinoma and surrounding uninvolved liver at both the mRNA and protein level and examined the regulation and function of this enzyme. METHODS: Since growth of HCC is mediated by signaling through the insulin-receptor substrate, type 1 (IRS-1), we examined-if AAH is a downstream gene regulated by insulin and IGF-1 in HCC cells. In addition, IRS-1 regulation of AAH was examined in a transgenic (Tg) mouse model in which the human (h) IRS-1 gene was over-expressed in the liver, and an in vitro model in which a C-terminus truncated dominant-negative hIRS-1 cDNA (hIRS-DeltaC) was over-expressed in FOCUS HCC cells. The direct effects of AAH on motility and invasiveness were examined in AAH-transfected HepG2 cells. RESULTS: Insulin and IGF-1 stimulation increased AAH mRNA and protein expression and motility in FOCUS and Hep-G2 cells. These effects were mediated by signaling through the Erk MAPK and PI3 kinase-Akt pathways. Over-expression of hIRS-1 resulted in high levels of AAH in Tg mouse livers, while over-expression of hIRS-DeltaC reduced AAH expression, motility, and invasiveness in FOCUS cells. Finally, over-expression of AAH significantly increased motility and invasiveness in HepG2 cells, whereas siRNA inhibition of AAH expression significantly reduced directional motility in FOCUS cells. CONCLUSIONS: The results suggest that enhanced AAH gene activity is a common feature of human HCC and growth factor signaling through IRS-1 regulates AAH expression and increases motility and invasion of HCC cells. Therefore, AAH may represent an important target for regulating tumor growth in vivo.

Oncogenic role of the frizzled-7/beta-catenin pathway in hepatocellular carcinoma.

BACKGROUND/AIMS: The molecular mechanisms of hepatocarcinogenesis remain largely unknown. Previous studies suggest that activation of the Wnt/beta-catenin pathway is important during hepatocyte transformation but the role of Frizzled receptor (FZD) in this process has not been defined. Here we investigate activation of this pathway by FZD using transgenic hepatocellular carcinoma (HCC) murine models. METHODS: We employed single (c-myc, SV40-Tag) and established double [insulin receptor substrate-1 (IRS-1/c-myc) and hepatitis Bx protein (X/c-myc)] transgenic lines and all developed HCC. Expression of 9 FZD was measured by real time RT-PCR and Western blot analysis. Phosphorylation and cellular accumulation of beta-catenin were assessed in both dysplastic tissue and tumors. We investigated the effect of a dominant negative (DN) FZD7 on TCF transcriptional activity in a SV40 derived HCC cell line. RESULTS: FZD7 was highly overexpressed at the mRNA and protein level(s) in HCC and occurred in dysplasia. Upregulation of FZD7 was associated with reduced phosphorylation of beta-catenin and led to nuclear accumulation in HCC tumors. Ectopic expression of a DN FZD7 construct decreased TCF transcriptional activity in tumor cells. CONCLUSIONS: These observations suggest that upregulation of FZD7 receptors in association with activation of the canonical Wnt/beta-catenin pathway is a common molecular event in HCC.

Potential role of PTEN phosphatase in ethanol-impaired survival signaling in the liver.

Chronic ethanol consumption can cause sustained hepatocellular injury and inhibit the subsequent regenerative response. These effects of ethanol may be mediated by impaired hepatocyte survival mechanisms. The present study examines the effects of ethanol on survival signaling in the intact liver. Adult Long Evans rats were maintained on ethanol-containing or isocaloric control liquid diets for 8 weeks, after which the livers were harvested to measure mRNA levels, protein expression, and kinase or phosphatase activity related to survival or proapoptosis mechanisms. Chronic ethanol exposure resulted in increased hepatocellular labeling for activated caspase 3 and nuclear DNA damage as demonstrated using the TUNEL assay. These effects of ethanol were associated with reduced levels of tyrosyl phosphorylated (PY) IRS-1 and PI3 kinase, Akt kinase, and Erk MAPK activities and increased levels of phosphatase tensin homologue deleted on chromosome 10 (PTEN) mRNA, protein, and phosphatase activity in liver tissue. In vitro experiments demonstrated that ethanol increases PTEN expression and function in hepatocytes. However, analysis of signaling cascade pertinent to PTEN function revealed increased levels of nuclear p53 and Fas receptor mRNA but without corresponding increases in GSK-3 activity or activated BAD. Although fork-head transcription factor levels were increased in ethanol-exposed livers, virtually all of the fork-head protein detected by Western blot analysis was localized within the cytosolic fraction. In conclusion, chronic ethanol exposure impairs survival mechanisms in the liver because of inhibition of signaling through PI3 kinase and Akt and increased levels of PTEN. However, uncoupling of the signaling cascade downstream of PTEN that mediates apoptosis may account for the relatively modest degrees of ongoing cell loss observed in livers of chronic ethanol-fed rats.