First in-human evaluation of [1-C]pyruvate in DO for hyperpolarized MRI of the brain: A safety and feasibility study.

Purpose: To investigate the safety and value of hyperpolarized (HP) MRI of [1-C]pyruvate in healthy volunteers using deuterium oxide (DO) as a solvent.

Methods: Healthy volunteers (n = 5), were injected with HP [1-C]pyruvate dissolved in DO and imaged with a metabolite-specific 3D dual-echo dynamic EPI sequence at 3T at one site (Site 1). Volunteers were monitored following the procedure to assess safety.

Comparing the CFIR-ERIC matching tool recommendations to real-world strategy effectiveness data: a mixed-methods study in the Veterans Health Administration.

Background: Practical and feasible methods for matching implementation strategies to diagnosed barriers of evidence-based interventions in real-world contexts are lacking. This evaluation compared actual implementation strategies applied with those recommended by an expert opinion-based tool to improve guideline-concordant cirrhosis care in a Veterans Health Administration national learning collaborative effort.

Methods: This convergent parallel mixed-methods study aimed to (1) identify pre-implementation Consolidated Framework for Implementation Research (CFIR) barriers to cirrhosis care through focus groups with frontline providers, (2) generate 20 recommended strategies using focus group identified barriers entered into the CFIR-Expert Recommendations for Implementing Change (ERIC) Implementation Strategy Matching Tool, (3) survey providers over two consecutive years on the actual use of 73 ERIC strategies and determine strategy effectiveness, (4) compare actual versus recommended strategy use, and (5) compare actual versus expected barriers by reverse applying the CFIR-ERIC Matching Tool.

Herpesvirus-induced spermidine synthesis and eIF5A hypusination for viral episomal maintenance.

Spermidine is essential for cellular growth and acts as a prerequisite of hypusination, a post-translational modification of eukaryotic initiation factor 5A (eIF5A), allowing the translation of polyproline-containing proteins. Here, we show that oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV) increases spermidine synthesis and eIF5A hypusination to enhance expression of polyproline-containing latency-associated nuclear antigen (LANA) for viral episomal maintenance. KSHV upregulates intracellular spermidine levels by dysregulating polyamine metabolic pathways in three-dimensional (3D) culture and 2D de novo infection conditions.

Single-cell analysis of Kaposi's sarcoma-associated herpesvirus infection in three-dimensional air-liquid interface culture model.

The oral cavity is the major site for transmission of Kaposi's sarcoma-associated herpesvirus (KSHV), but how KSHV establishes infection and replication in the oral epithelia remains unclear. Here, we report a KSHV spontaneous lytic replication model using fully differentiated, three-dimensional (3D) oral epithelial organoids at an air-liquid interface (ALI). This model revealed that KSHV infected the oral epithelia when the basal epithelial cells were exposed by damage.

Limitations of access to antipsychotics in Canada: loss of the old and unavailability of the new options.

Schizophrenia is a severe, debilitating disorder that is associated with a significant burden of illness. Antipsychotic medications remain the mainstay of treatment for schizophrenia and related disorders. In recent years, a number of new psychotropic medications have been introduced to the market, with some potential differences in the mechanism of action compared to the previous ones.

Core implementation strategies for improving cirrhosis care in the Veterans Health Administration.

Background And Aims: The Veterans Health Administration (VHA) provides care for more than 80,000 veterans with cirrhosis. This longitudinal, multimethod evaluation of a cirrhosis care quality improvement program aimed to (1) identify implementation strategies associated with evidence-based, guideline-concordant cirrhosis care over time, and (2) use qualitative interviews to operationalize strategies for a manualized intervention.

Approach And Results: VHA providers were surveyed annually about the use of 73 implementation strategies to improve cirrhosis care in fiscal years 2018 (FY18) and 2019 (FY19).

Complete blood count inflammatory markers in treatment-resistant schizophrenia: Evidence of association between treatment responsiveness and levels of inflammation.

Accumulating evidence suggests that the variable response to antipsychotic treatment in schizophrenia reflects distinct biological subtypes. The pathophysiology of schizophrenia is associated with alteration in the immune system which can be measured with complete blood count (CBC) markers of systemic inflammation, including the neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR). While previous research suggested a decrease in CBC inflammatory markers following treatment, it is unknown if treatment or response to treatment is associated with CBC markers in treatment-resistant schizophrenia.

Mapping the road to elimination: a 5-year evaluation of implementation strategies associated with hepatitis C treatment in the veterans health administration.

Background: While few countries and healthcare systems are on track to meet the World Health Organization's hepatitis C virus (HCV) elimination goals, the US Veterans Health Administration (VHA) has been a leader in these efforts. We aimed to determine which implementation strategies were associated with successful national viral elimination implementation within the VHA.

Methods: We conducted a five-year, longitudinal cohort study of the VHA Hepatic Innovation Team (HIT) Collaborative between October 2015 and September 2019.

The Hepatic Innovation Team Collaborative: A Successful Population-Based Approach to Hepatocellular Carcinoma Surveillance.

After implementing a successful hepatitis C elimination program, the Veterans Health Administration's (VHA) Hepatic Innovation Team (HIT) Collaborative pivoted to focus on improving cirrhosis care. This national program developed teams of providers across the country and engaged them in using systems redesign methods and population health approaches to improve care. The HIT Collaborative developed an Advanced Liver Disease (ALD) Dashboard to identify Veterans with cirrhosis who were due for surveillance for hepatocellular carcinoma (HCC) and other liver care, promoted the use of an HCC Clinical Reminder in the electronic health record, and provided training and networking opportunities.

Development and validation of a patient face-mounted, negative-pressure antechamber for reducing exposure of healthcare workers to aerosolized particles during endonasal surgery.

Objective: The authors developed a negative-pressure, patient face-mounted antechamber and tested its efficacy as a tool for sequestering aerated particles and improving the safety of endonasal surgical procedures.

Methods: Antechamber prototyping was performed with 3D printing and silicone-elastomer molding. The lowest vacuum settings needed to meet specifications for class I biosafety cabinets (flow rate ≥ 0.

Molecular Signatures of Inflammatory Profile and B-Cell Function in Patients with Severe Fever with Thrombocytopenia Syndrome.

Dabie bandavirus (severe fever with thrombocytopenia syndrome virus [SFTSV]) induces an immunopathogenic disease with a high fatality rate; however, the mechanisms underlying its clinical manifestations are largely unknown. In this study, we applied targeted proteomics and single-cell transcriptomics to examine the differential immune landscape in SFTS patient blood. Serum immunoprofiling identified low-risk and high-risk clusters of SFTS patients based on inflammatory cytokine levels, which corresponded to disease severity.

Exploring the landscape of sustainability performance management systems in U.S. local governments.

Municipalities around the globe are increasingly adopting and integrating sustainability goals into their service functions. As with many public programs, local sustainability initiatives benefit from regular and systematic assessment aimed at determining the extent to which efforts are achieving their performance goals. However, there currently is little understanding of how local governments are collecting and tracking data on their sustainability-related performance and to what extent they integrate its lessons into their sustainability management practice.

The Commissions Paid to Brokers for Fully Insured Health Insurance Plans.

Insurance agents and brokers play an important role in facilitating the contracting of fully insured health insurance and pharmacy benefit plans for U.S. employers.

Getting to implementation: a protocol for a Hybrid III stepped wedge cluster randomized evaluation of using data-driven implementation strategies to improve cirrhosis care for Veterans.

Background: Cirrhosis is a rapidly increasing cause of global mortality. To improve cirrhosis care, the Veterans Health Administration (VHA) developed the Hepatic Innovation Team (HIT) Collaborative to support VA Medical Centers (VAMCs) to deliver evidence-based cirrhosis care. This randomized HIT program evaluation aims to develop and assess a novel approach for choosing and applying implementation strategies to improve the quality of cirrhosis care.

Characterizing patient-reported outcomes in veterans with cirrhosis.

Background And Aims: The Veterans Health Administration (VA) cares for over 80,000 Veterans with cirrhosis annually. Given the importance of understanding patient reported outcomes in this complex population, we aimed to assess the associations between attitudes towards care, disease knowledge, and health related quality of life (HRQoL) in a national sample.

Methods: In this cross-sectional study, we mailed paper surveys to a random sample of Veterans with cirrhosis, oversampling those with decompensated disease.

Global epigenomic analysis of KSHV-infected primary effusion lymphoma identifies functional superenhancers and enhancer RNAs.

Enhancers play indispensable roles in cell proliferation and survival through spatiotemporally regulating gene transcription. Active enhancers and superenhancers often produce noncoding enhancer RNAs (eRNAs) that precisely control RNA polymerase II activity. Kaposi's sarcoma-associated herpesvirus (KSHV) is a human oncogenic gamma-2 herpesvirus that causes Kaposi's sarcoma and primary effusion lymphoma (PEL).

Oncogenic human herpesvirus hijacks proline metabolism for tumorigenesis.

Three-dimensional (3D) cell culture is well documented to regain intrinsic metabolic properties and to better mimic the in vivo situation than two-dimensional (2D) cell culture. Particularly, proline metabolism is critical for tumorigenesis since pyrroline-5-carboxylate (P5C) reductase (PYCR/P5CR) is highly expressed in various tumors and its enzymatic activity is essential for in vitro 3D tumor cell growth and in vivo tumorigenesis. PYCR converts the P5C intermediate to proline as a biosynthesis pathway, whereas proline dehydrogenase (PRODH) breaks down proline to P5C as a degradation pathway.

Strategy Configurations Directly Linked to Higher Hepatitis C Virus Treatment Starts: An Applied Use of Configurational Comparative Methods.

Background: The Department of Veterans Affairs (VA) cares for more patients with hepatitis C virus (HCV) than any other US health care system. We tracked the implementation strategies that VA sites used to implement highly effective new treatments for HCV with the aim of uncovering how combinations of implementation strategies influenced the uptake of the HCV treatment innovation. We applied Configurational Comparative Methods (CCMs) to uncover causal dependencies and identify difference-making strategy configurations, and to distinguish higher from lower HCV treating sites.

Discovery of Selective SIRT2 Inhibitors as Therapeutic Agents in B-Cell Lymphoma and Other Malignancies.

Genetic ablation as well as pharmacological inhibition of sirtuin 2 (SIRT2), an NAD-dependent protein deacylase, have therapeutic effects in various cancers and neurodegenerative diseases. Previously, we described the discovery of a dual SIRT1/SIRT2 inhibitor called cambinol (IC 56 and 59 µM, respectively), which showed cytotoxic activity against cancer cells in vitro and a marked anti-proliferative effect in a Burkitt lymphoma mouse xenograft model. A number of recent studies have shown a protective effect of SIRT1 and SIRT3 in neurodegenerative and metabolic diseases as well as in certain cancers prompting us to initiate a medicinal chemistry effort to develop cambinol-based SIRT2-specific inhibitors devoid of SIRT1 or SIRT3 modulating activity.

Frequency and Predictors of Polypharmacy in US Medicare Patients: A Cross-Sectional Analysis at the Patient and Physician Levels.

Background: Polypharmacy in older patients increases the risk of medication-related adverse events and can be a marker of unnecessary care.

Objectives: The aim of this study was to describe the frequency of polypharmacy among patients 65 years of age or older and identify factors associated with the occurrence of patient-level and physician-level polypharmacy.

Methods: We performed a cross-sectional analysis of 100% Medicare claims data from January 1, 2016 to December 31, 2016.

Significant physician practice variability in the utilization of endovenous thermal ablation in the 2017 Medicare population.

Background: There has been a substantial increase in the use of procedures to treat lower extremity venous disease in the United States over the past decade. A specialty society-selected metric was applied to evaluate the use of endovenous thermal ablation (EVTA) in Medicare beneficiaries and factors associated with physician practice variations. We used confidential physician reports of this benchmark data to increase physician recognition of individualized usage relative to their peers.

Initial medical and surgical management of inflammatory bowel disease in the biologic era: A comparison between the United States and China.

Background And Aims: We compared the initial medical and surgical management of Crohn's disease (CD) and ulcerative colitis (UC) between the United States and China, with aims to better characterize the global variation in the treatment patterns of inflammatory bowel disease (IBD).

Methods: Participants from the United States and China completed a questionnaire on demographic and clinical characteristics, medications (biologics, immunomodulators, aminosalicylates, steroids), and IBD-related surgical history. Patients diagnosed in 2006 and later were eligible.