Glucagon-like peptide-1 receptor agonists use for type 2 diabetes mellitus in end-stage renal disease.

BACKGROUND: Management of type 2 diabetes mellitus (T2DM) in patients with end-stage renal disease (ESRD) remains a challenge given limited data. Although current guidelines recommend use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for the treatment of T2DM in patients with concomitant chronic kidney disease, supporting safety and efficacy evidence is lacking for patients with ESRD or hemodialysis. OBJECTIVE: This retrospective study was conducted to evaluate the efficacy and safety of GLP-1 RAs for the treatment of T2DM in patients with ESRD. DESIGN, SETTING, AND PARTICIPANTS: This is a single-centered, multifacility retrospective cohort analysis. Patients were included if they had a diagnosis of T2DM and ESRD and were prescribed a GLP-1 RA. Patients were excluded if the GLP-1 RA was prescribed solely for weight loss. OUTCOME MEASURES: The primary outcome was change in A1C. Secondary outcomes included (1) incidence of acute kidney injury (AKI), (2) change in weight, (3) change in estimated glomerular filtration rate, (4) ability to discontinue basal or bolus insulin, and (5) incidence of emergent hypoglycemia. RESULTS: There were 46 unique patients and 64 individual GLP-1 RA prescriptions included. The mean reduction in A1C was 0.8%. There were 10 incidences of AKI, although none occurred in the semaglutide cohort. Emergent hypoglycemia occurred in 3 patients who were all prescribed concomitant insulin. CONCLUSION: Results from this retrospective review provide additional real-world data on use of GLP-1 RAs in this unique population. Prospective studies to control for confounding factors are warranted given that GLP-1RAs are a safer alternative to insulin in this high-risk population.

Clinical pharmacy specialists providing consistent comprehensive medication management with increased efficiency through telemedicine during the COVID19 pandemic.

INTRODUCTION: The Veterans Affairs (VA) has been at the forefront of harnessing the skills of clinical pharmacy specialists (CPS) in patient-aligned care teams (PACT) to improve patient care outcomes and create access for veterans. With the unfortunate arrival of Coronavirus disease 2019 (COVID19), PACT CPS were duty-bound to expand telehealth services at an accelerated rate. The purpose of this quality improvement analysis is to compare CPS efficiency as well as some objective patient metrics to assess for a change in the quality of care. This is the first study to compare the efficiency and quality of care by CPS in the VA pre-COVID19 and during the COVID19 pandemic. METHODS: This is a retrospective review of PACT CPS comprehensive medication management from 3/10/19 to 11/30/19 and 3/10/20 to 11/30/20. Data points focused on clinic encounters, patient accountability to appointments, disease state expansion, and markers of disease-state management. Given diabetes and hypertension are the main disease states managed by most PACT CPS', the study evaluated changes in hemoglobin A1c (HbA1c) and blood pressure (BP) between the two cohorts as well. Data were analyzed using GraphPad Software or Microsoft Excel. A student T-test was used for continuous data and Chi-squared or Fishers Exact for nominal data. RESULTS: The total number of PACT CPS encounters increased 32% in 2020, and the number of unique patients increased by 12%. There were a statistically significant increase in telephone and direct-to-consumer (DCT) video visits. The rates of no shows and cancellations significantly decreased between 2019 and 2020. There was no difference in the average change in HbA1c or average blood pressure between the two study groups. CONCLUSIONS: When PACT CPS services transitioned from primarily face-to-face visits to all virtual care, the consistency of care improved, and the quality of care was not compromised.

Promotion of virus assembly and organization by the measles virus matrix protein.

Measles virus (MeV) remains a major human pathogen, but there are presently no licensed antivirals to treat MeV or other paramyxoviruses. Here, we use cryo-electron tomography (cryo-ET) to elucidate the principles governing paramyxovirus assembly in MeV-infected human cells. The three-dimensional (3D) arrangement of the MeV structural proteins including the surface glycoproteins (F and H), matrix protein (M), and the ribonucleoprotein complex (RNP) are characterized at stages of virus assembly and budding, and in released virus particles. The M protein is observed as an organized two-dimensional (2D) paracrystalline array associated with the membrane. A two-layered F-M lattice is revealed suggesting that interactions between F and M may coordinate processes essential for MeV assembly. The RNP complex remains associated with and in close proximity to the M lattice. In this model, the M lattice facilitates the well-ordered incorporation and concentration of the surface glycoproteins and the RNP at sites of virus assembly.

Perceptions of Integration of the Clinical Pharmacist into the Patient Care Medical Home Model.

INTRODUCTION: The patient-centered medical home (PCMH) model is a multidisciplinary, team-based approach to healthcare that focuses on actively involving the patient in clinical decision making. The Veterans Health Administration (VA), while desiring to be a national leader in the delivery of primary care services, used the principles of the PCMH model to design the patient-aligned care team (PACT). The purpose of this study, was to explore the perception of the PACT members after integration of a clinical pharmacist to the PACT. METHODS: This was a single-center cross-sectional study conducted at an integrated Veterans Health Administration system. We electronically surveyed PACT staff practicing within VA-Tennessee Valley Health Care System as of October 1, 2016 using a modified version of the Medicine Medication Use Processes Matrix (MUPM) containing 19 items on five theoretical grouping of processes (evaluation and management, monitoring, medication review, documentation, and education) and two groupings(clinician satisfaction and access). RESULTS: Ninety-one complete responses were received. Perceptions were positive, with 79% rated as either 4 ("moderate contribution") or 5 ("major contribution"). Individual responses based on discipline, with the exception of the medical support assistant were rated positive, specifically job satisfaction. CONCLUSIONS: This study evaluated the perceptions of clinical pharmacist integration into the PACT model. Respondents perceived clinical pharmacist beneficial.

Replication-Competent Influenza Virus and Respiratory Syncytial Virus Luciferase Reporter Strains Engineered for Co-Infections Identify Antiviral Compounds in Combination Screens.

Myxoviruses such as influenza A virus (IAV) and respiratory syncytial virus (RSV) are major human pathogens, mandating the development of novel therapeutics. To establish a high-throughput screening protocol for the simultaneous identification of pathogen- and host-targeted hit candidates against either pathogen or both, we have attempted co-infection of cells with IAV and RSV. However, viral replication kinetics were incompatible, RSV signal window was low, and an IAV-driven minireplicon reporter assay used in initial screens narrowed the host cell range and restricted the assay to single-cycle infections. To overcome these limitations, we developed an RSV strain carrying firefly luciferase fused to an innovative universal small-molecule assisted shut-off domain, which boosted assay signal window, and a hyperactive fusion protein that synchronized IAV and RSV reporter expression kinetics and suppressed the identification of RSV entry inhibitors sensitive to a recently reported RSV pan-resistance mechanism. Combined with a replication-competent recombinant IAV strain harboring nanoluciferase, the assay performed well on a human respiratory cell line and supports multicycle infections. Miniaturized to 384-well format, the protocol was validated through screening of a set of the National Institutes of Health Clinical Collection (NCC) in quadruplicate. These test screens demonstrated favorable assay parameters and reproducibility. Application to a LOPAC library of bioactive compounds in a proof-of-concept campaign detected licensed antimyxovirus therapeutics, ribavirin and the neuraminidase inhibitor zanamivir, and identified two unexpected RSV-specific hit candidates, Fenretinide and the opioid receptor antagonist BNTX-7. Hits were evaluated in direct and orthogonal dose-response counterscreens using a standard recRSV reporter strain expressing Renilla luciferase.

Implementation of a pharmacotherapy clinic into the patient centered medical home model by a second year pharmacy resident.

OBJECTIVE: Evaluate the impact a post graduate year 2 (PGY-2) pharmacy resident run clinic incorporated into the patient centered medical home (PCMH) model may have on achieving reduction in glycosylated hemoglobin (A1c), low density lipoprotein (LDL), and systolic and diastolic blood pressures (SBP and DBP) over six months in type 2 diabetics within the Veterans Health Administration (VHA). METHODS: This was a prospective, quasi-experimental study enrolling type 2 diabetics referred to the pharmacist-run clinic not meeting American Diabetes Association (ADA) treatment goals for A1c less than 7%, and/or LDL less than 100 mg/dL, and/or blood pressure (BP) less than 130/80 mmHg. Once signed informed consent was obtained, veterans were followed according to usual standards of care for six months with visits and lab follow-up at baseline, three, and six months (±45 days). The primary endpoint was the change in HbA1c, LDL, and BP from baseline to six months. Secondary endpoints included the change from baseline to three months in A1c, LDL, and BP and the percentage of patients who achieved ADA treatment goals for A1c, LDL, and BP at six months. RESULTS: Among the 24 patients included in the data analysis (100% male, 92% Caucasian), A1c decreased significantly from 7.56% to 7.19% (p = 0.0122) as well as LDL from 92.9 to 68.5 mg/dL (p = 0.0023), SBP from 131 to 124 mmHg (p = 0.0302), and DBP from 71.5 to 64.8 mmHg (p = 0.0012). The proportion of patients at recommended goal A1c <7% rose from 17% to 38%, as did the percentage of patients meeting ADA goals for LDL (75% to 96%), SBP (46% to 71%), and DBP (79% to 92%). CONCLUSION: Patients followed in a resident run pharmacotherapy clinic in the PCMH model with interventions over six months showed significant improvements in clinical endpoints including A1c, LDL, SBP, and DBP.

Native immunogold labeling of cell surface proteins and viral glycoproteins for cryo-electron microscopy and cryo-electron tomography applications.

Numerous methods have been developed for immunogold labeling of thick, cryo-preserved biological specimens. However, most of the methods are permutations of chemical fixation and sample sectioning, which select and isolate the immunolabeled region of interest. We describe a method for combining immunogold labeling with cryo-electron microscopy (cryo-EM) and cryo-electron tomography (cryo-ET) of the surface proteins of intact mammalian cells or the surface glycoproteins of assembling and budding viruses in the context of virus-infected mammalian cells cultured on EM grids. In this method, the cells were maintained in culture media at physiologically relevant temperatures while sequentially incubated with the primary and secondary antibodies. Subsequently, the immunogold-labeled specimens were vitrified and observed under cryo-conditions in the transmission electron microscope. Cryo-EM and cryo-ET examination of the immunogold-labeled cells revealed the association of immunogold particles with the target antigens. Additionally, the cellular structure was unaltered by pre-immunolabeling chemical fixation and retained well-preserved plasma membranes, cytoskeletal elements, and macromolecular complexes. We think this technique will be of interest to cell biologists for cryo-EM and conventional studies of native cells and pathogen-infected cells.

Crystal structures of Klebsiella pneumoniae dihydrofolate reductase bound to propargyl-linked antifolates reveal features for potency and selectivity.

Resistance to the antibacterial antifolate trimethoprim (TMP) is increasing in members of the family Enterobacteriaceae, driving the design of next-generation antifolates effective against these Gram-negative pathogens. The propargyl-linked antifolates are potent inhibitors of dihydrofolate reductases (DHFR) from several TMP-sensitive and -resistant species, including Klebsiella pneumoniae. Recently, we have determined that these antifolates inhibit the growth of strains of K. pneumoniae, some with MIC values of 1 µg/ml. In order to further the design of potent and selective antifolates against members of the Enterobacteriaceae, we determined the first crystal structures of K. pneumoniae DHFR bound to two of the propargyl-linked antifolates. These structures highlight that interactions with Leu 28, Ile 50, Ile 94, and Leu 54 are necessary for potency; comparison with structures of human DHFR bound to the same inhibitors reveal differences in residues (N64E, P61G, F31L, and V115I) and loop conformations (residues 49 to 53) that may be exploited for selectivity.

Propargyl-linked antifolates are dual inhibitors of Candida albicans and Candida glabrata.

Species of Candida, primarily C. albicans and with increasing prevalence, C. glabrata, are responsible for the majority of fungal bloodstream infections that cause morbidity, especially among immune compromised patients. While the development of new antifungal agents that target the essential enzyme, dihydrofolate reductase (DHFR), in both Candida species would be ideal, previous attempts have resulted in antifolates that exhibit inconsistencies between enzyme inhibition and antifungal properties. In this article, we describe the evaluation of pairs of propargyl-linked antifolates that possess similar physicochemical properties but different shapes. All of these compounds are effective at inhibiting the fungal enzymes and the growth of C. glabrata; however, the inhibition of the growth of C. albicans is shape-dependent with extended para-linked compounds proving more effective than compact, meta-linked compounds. Using crystal structures of DHFR from C. albicans and C. glabrata bound to lead compounds, 13 new para-linked compounds designed to inhibit both species were synthesized. Eight of these compounds potently inhibit the growth of both fungal species with three compounds displaying dual MIC values less than 1 µg/mL. Analysis of the active compounds shows that shape and distribution of polar functionality is critical in achieving dual antifungal activity.

Elucidating features that drive the design of selective antifolates using crystal structures of human dihydrofolate reductase.

The pursuit of antimicrobial drugs that target dihydrofolate reductase (DHFR) exploits differences in sequence and dynamics between the pathogenic and human enzymes. Here, we present five crystal structures of human DHFR bound to a new class of antimicrobial agents, the propargyl-linked antifolates (PLAs), with a range of potency (IC50 values of 0.045-1.07 µM) for human DHFR. These structures reveal that interactions between the ligands and Asn 64, Phe 31, and Phe 34 are important for increased affinity for human DHFR and that loop residues 58-64 undergo ligand-induced conformational changes. The utility of these structural studies was demonstrated through the design of three new ligands that reduce the number of contacts with Asn 64, Phe 31, and Phe 34. Synthesis and evaluation show that one of the designed inhibitors exhibits the lowest affinity for human DHFR of any of the PLAs (2.64 µM). Comparisons of structures of human and Staphylococcus aureus DHFR bound to the same PLA reveal a conformational change in the ligand that enhances interactions with residues Phe 92 (Val 115 in huDHFR) and Ile 50 (Ile 60 in huDHFR) in S. aureus DHFR, yielding selectivity. Likewise, comparisons of human and Candida glabrata DHFR bound to the same ligand show that hydrophobic interactions with residues Ile 121 and Phe 66 (Val 115 and Asn 64 in human DHFR) yield selective inhibitors. The identification of residue substitutions that are important for selectivity and the observation of active site flexibility will help guide antimicrobial antifolate development for the inhibition of pathogenic species.

Occupational therapy consultation for case managers in community mental health: exploring strategies to improve job satisfaction and self-efficacy.

UNLABELLED: The purpose of this study was 2-fold: (1) to examine to what extent case managers' job satisfaction and self-efficacy were impacted by the addition of an occupational therapy consultation model and (2) to identify factors that both positively and negatively impacted the occupational therapy consultation services. PRIMARY PRACTICE SETTING: The study was conducted at a mental health community support program in a local homeless center. METHODOLOGY AND SAMPLE: In a 2-year study, a mixed-methods design was used to study changes over time in job satisfaction and perceived self-efficacy among 14 case managers who received ongoing occupational therapy consultation. Job satisfaction and self-efficacy data were obtained using standardized questionnaires. Qualitative data related to factors impacting the consultation program were obtained using open-ended written questions, focus groups, and individual interviews. RESULTS: Statistically significant differences in job satisfaction and perceptions of self-efficacy were found 18 months into the study, when case managers were more actively seeking occupational therapy consultation services and were reporting improved client outcomes from occupational therapy intervention. In addition, themes related to both positive and negative factors impacting the occupational therapy consultation program were identified and provided useful data for development of future consultation services. IMPLICATION FOR CASE MANAGEMENT PRACTICE: Results suggest that ongoing training and professional support for case managers who are paraprofessionals and/or new to mental health practice may improve job satisfaction and efficacy. Occupational therapy consultation may be helpful in developing services for health promotion, including self-care management, cognitive assessments, activity-based programming, and home safety evaluation and modification. In addition, new graduates and paraprofessional case managers working with clients who are high utilizers of services may benefit from smaller caseloads and support from clinical professionals.

Training and dissemination of cognitive behavior therapy for depression in adults: a preliminary examination of therapist competence and client outcomes.

OBJECTIVE: In this study, the authors examined the feasibility and effectiveness of training community therapists to deliver cognitive behavior therapy (CBT) for depression. METHOD: Participants were therapists (n = 12) and clients (n = 116; mean age = 41 years, 63% women) presenting for treatment of depression at a not-for-profit and designated community mental health center for St. Joseph County, Indiana. The training model included a 2-day workshop followed by 1 year of phone consultations. CBT competence ratings from the Cognitive Therapy Scale were obtained prior to training and at 6 and 12 months posttraining. Two different groups of clients, a treatment-as-usual (TAU) group (n = 74) and a CBT group (n = 42), were compared with respect to decrease in symptoms of depression (assessed with the Beck Depression Inventory) and anxiety (assessed with the Beck Anxiety Inventory). RESULTS: Therapists showed significant increases in total scores from pretraining to 6 months posttraining, increases that were maintained at 12 months. The increase in the total score reflected gains on items that specifically measure CBT skills and structure. Although both TAU and CBT resulted in a significant decrease in depressive symptoms, the CBT clients showed significantly greater change than the TAU clients, F(2, 113) = 53.40, p < .001. The CBT clients also showed a significant decrease in anxiety symptoms, whereas the TAU clients did not. CONCLUSIONS: Although there remains a significant amount to learn to guide researchers' mission of improving the availability and effectiveness of treatment for individuals with depression, this study demonstrates that an empirically supported treatment can be implemented in a community mental health center and may result in improved outcomes.

Structure of a Venezuelan equine encephalitis virus assembly intermediate isolated from infected cells.

Venezuelan equine encephalitis virus (VEEV) is a prototypical enveloped ssRNA virus of the family Togaviridae. To better understand alphavirus assembly, we analyzed newly formed nucleocapsid particles (termed pre-viral nucleocapsids) isolated from infected cells. These particles were intermediates along the virus assembly pathway, and ultimately bind membrane-associated viral glycoproteins to bud as mature infectious virus. Purified pre-viral nucleocapsids were spherical with a unimodal diameter distribution. The structure of one class of pre-viral nucleocapsids was determined with single particle reconstruction of cryo-electron microscopy images. These studies showed that pre-viral nucleocapsids assembled into an icosahedral structure with a capsid stoichiometry similar to the mature nucleocapsid. However, the individual capsomers were organized significantly differently within the pre-viral and mature nucleocapsids. The pre-viral nucleocapsid structure implies that nucleocapsids are highly plastic and undergo glycoprotein and/or lipid-driven rearrangements during virus self-assembly. This mechanism of self-assembly may be general for other enveloped viruses.