Chlorthalidone vs. Hydrochlorothiazide for Hypertension-Cardiovascular Events.

BACKGROUND: Whether chlorthalidone is superior to hydrochlorothiazide for preventing major adverse cardiovascular events in patients with hypertension is unclear. METHODS: In a pragmatic trial, we randomly assigned adults 65 years of age or older who were patients in the Department of Veterans Affairs health system and had been receiving hydrochlorothiazide at a daily dose of 25 or 50 mg to continue therapy with hydrochlorothiazide or to switch to chlorthalidone at a daily dose of 12.5 or 25 mg. The primary outcome was a composite of nonfatal myocardial infarction, stroke, heart failure resulting in hospitalization, urgent coronary revascularization for unstable angina, and non-cancer-related death. Safety was also assessed. RESULTS: A total of 13,523 patients underwent randomization. The mean age was 72 years. At baseline, hydrochlorothiazide at a dose of 25 mg per day had been prescribed in 12,781 patients (94.5%). The mean baseline systolic blood pressure in each group was 139 mm Hg. At a median follow-up of 2.4 years, there was little difference in the occurrence of primary-outcome events between the chlorthalidone group (702 patients [10.4%]) and the hydrochlorothiazide group (675 patients [10.0%]) (hazard ratio, 1.04; 95% confidence interval, 0.94 to 1.16; P = 0.45). There were no between-group differences in the occurrence of any of the components of the primary outcome. The incidence of hypokalemia was higher in the chlorthalidone group than in the hydrochlorothiazide group (6.0% vs. 4.4%, P<0.001). CONCLUSIONS: In this large pragmatic trial of thiazide diuretics at doses commonly used in clinical practice, patients who received chlorthalidone did not have a lower occurrence of major cardiovascular outcome events or non-cancer-related deaths than patients who received hydrochlorothiazide. (Funded by the Veterans Affairs Cooperative Studies Program; ClinicalTrials.gov number, NCT02185417.).

Molnupiravir and Nirmatrelvir-Ritonavir: Oral Coronavirus Disease 2019 Antiviral Drugs.

At a crucial time with rapid spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant globally, the United States Food and Drug Administration has issued an emergency use authorization for 2 oral antivirals, molnupiravir (in persons aged ≥18 years) and nirmatrelvir-ritonavir (Paxlovid) (in persons aged ≥12 years weighing ≥40 kg), for the outpatient treatment of patients with mild to moderate coronavirus disease 2019 (COVID-19) who are at risk for progression. Molnupiravir is a nucleoside analogue, whereas nirmatrelvir is a SARS-CoV-2 main protease inhibitor, and ritonavir is a human immunodeficiency virus type 1 protease inhibitor. Drug interactions are a major concern for nirmatrelvir-ritonavir. Nirmatrelvir-ritonavir demonstrated a greater risk reduction in hospitalization and death than molnupiravir compared to placebo. Both drugs need to be started within 5 days of symptoms onset and given for 5 days' duration. This article reviews the 2 oral COVID-19 antiviral drugs including the mechanisms of action, antiviral activity, pharmacokinetics, drug interactions, clinical experience including trials, adverse events, recommended indications, and formulary considerations.

Individual astrocyte morphology in the collagenous lamina cribrosa revealed by multicolor DiOlistic labeling.

Astrocytes in the lamina region of the optic nerve head play vital roles in supporting retinal ganglion cell axon health. In glaucoma, these astrocytes are implicated as early responders to stressors, undergoing characteristic changes in cell function as well as cell morphology. Much of what is currently known about individual lamina astrocyte morphology has been learned from rodent models which lack a defining feature of the human optic nerve head, the collagenous lamina cribrosa (LC). Current methods available for evaluation of collagenous LC astrocyte morphology have significant shortcomings. We aimed to evaluate Multicolor DiOlistic labeling (MuDi) as an approach to reveal individual astrocyte morphologies across the collagenous LC. Gold microcarriers were coated with all combinations of three fluorescent cell membrane dyes, DiI, DiD, and DiO, for a total of seven dye combinations. Microcarriers were delivered to 150 µm-thick coronal vibratome slices through the LC of pig, sheep, goat, and monkey eyes via MuDi. Labeled tissues were imaged with confocal and second harmonic generation microscopy to visualize dyed cells and LC collagenous beams, respectively. GFAP labeling of DiOlistically-labeled cells with astrocyte morphologies was used to investigate cell identity. 3D models of astrocytes were created from confocal image stacks for quantification of morphological features. DiOlistic labeling revealed fine details of LC astrocyte morphologies including somas, primary branches, higher-order branches, and end-feet. Labeled cells with astrocyte morphologies were GFAP+. Astrocytes were visible across seven distinct color channels, allowing high labeling density while still distinguishing individual cells from their neighbors. MuDi was capable of revealing tens to hundreds of collagenous LC astrocytes, in situ, with a single application. 3D astrocyte models allowed automated quantification of morphological features including branch number, length, thickness, hierarchy, and straightness as well as Sholl analysis. MuDi labeling provides an opportunity to investigate morphologies of collagenous LC astrocytes, providing both qualitative and quantitative detail, in healthy tissues. This approach may open doors for research of glaucoma, where astrocyte morphological alterations are thought to coincide with key functional changes related to disease progression.

"Toll"-erance in the skin.

Interactions between potentially pathogenic commensal bacteria and cutaneous immunity are poorly understood. In this issue of Immunity, Skabytska et al. (2014) show that S. aureus-derived TLR2/6 heterodimer ligands can recruit myeloid-derived suppressor cells into the skin, countering rather than promoting inflammation.

Skin codelivery of contact sensitizers and neurokinin-1 receptor antagonists integrated in microneedle arrays suppresses allergic contact dermatitis.

BACKGROUND: Allergic contact dermatitis (CD) is a chronic inflammatory skin disease caused by type 1 biased adaptive immunity for which there is an unmet need for antigen (Ag)-specific immunotherapies. Exposure to skin sensitizers stimulates secretion of the proinflammatory neuropeptides substance P and hemokinin 1, which signal via the neurokinin-1 receptor (NK1R) to promote the innate and adaptive immune responses of CD. Accordingly, mice lacking the NK1R develop impaired CD. Nonetheless, the role and therapeutic opportunities of targeting the NK1R in CD remain to be elucidated. OBJECTIVE: We sought to develop an Ag-specific immunosuppressive approach to treat CD by skin codelivery of hapten and NK1R antagonists integrated in dissolvable microneedle arrays (MNA). METHODS: In vivo mouse models of contact hypersensitivity and ex vivo models of human skin were used to delineate the effects and mechanisms of NK1R signaling and the immunosuppressive effects of the contact sensitizer NK1R antagonist MNA in CD. RESULTS: We demonstrated in mice that CD requires NK1R signaling by substance P and hemokinin 1. Specific deletion of the NK1R in keratinocytes and dendritic cells, but not in mast cells, prevented CD. Skin codelivery of hapten or Ag MNA inhibited neuropeptide-mediated skin inflammation in mouse and human skin, promoted deletion of Ag-specific effector T cells, and increased regulatory T cells, which prevented CD onset and relapses locally and systemically in an Ag-specific manner. CONCLUSIONS: Immunoregulation by engineering localized skin neuroimmune networks can be used to treat cutaneous diseases that like CD are caused by type 1 immunity.

A single subcutaneous or intranasal immunization with adenovirus-based SARS-CoV-2 vaccine induces robust humoral and cellular immune responses in mice.

Optimal vaccines are needed for sustained suppression of SARS-CoV-2 and other novel coronaviruses. Here, we developed a recombinant type 5 adenovirus vector encoding the gene for the SARS-CoV-2 S1 subunit antigen (Ad5.SARS-CoV-2-S1) for COVID-19 immunization and evaluated its immunogenicity in mice. A single immunization with Ad5.SARS-CoV-2-S1 via S.C. injection or I.N delivery induced robust antibody and cellular immune responses. Vaccination elicited significant S1-specific IgG, IgG1, and IgG2a endpoint titers as early as 2 weeks, and the induced antibodies were long lasting. I.N. and S.C. administration of Ad5.SARS-CoV-2-S1 produced S1-specific GC B cells in cervical and axillary LNs, respectively. Moreover, I.N. and S.C. immunization evoked significantly greater antigen-specific T-cell responses compared to unimmunized control groups with indications that S.C. injection was more effective than I.N. delivery in eliciting cellular immune responses. Mice vaccinated by either route demonstrated significantly increased virus-specific neutralization antibodies on weeks 8 and 12 compared to control groups, as well as BM antibody forming cells (AFC), indicative of long-term immunity. Thus, this Ad5-vectored SARS-CoV-2 vaccine candidate showed promising immunogenicity following delivery to mice by S.C. and I.N. routes of administration, supporting the further development of Ad-based vaccines against COVID-19 and other infectious diseases for sustainable global immunization programs.

In vitro activity of fosfomycin alone and in combination against Staphylococcus aureus with reduced susceptibility or resistance to methicillin, vancomycin, daptomycin or linezolid.

OBJECTIVES: To evaluate the activity of fosfomycin against a group of MRSA strains, including isolates with reduced susceptibility or resistance to vancomycin, daptomycin, linezolid and ceftaroline and to determine the effect of combining various combinations of antimicrobial agents used in the therapy of serious Gram-positive infections. METHODS: Broth microdilution testing was used to determine the MICs of fosfomycin, vancomycin, daptomycin, linezolid, ceftaroline and cefazolin. Isolates were selected for further evaluations to determine in vitro synergy between fosfomycin and select antimicrobial agents using chequerboard broth microdilution testing. Fosfomycin was tested in combination with vancomycin, linezolid, daptomycin, ceftaroline and cefazolin. RESULTS: Fosfomycin maintained activity against 100% of strains of vancomycin-resistant Staphylococcus aureus (VRSA) and linezolid-resistant S. aureus (LRSA), 86% of VISA and 95% of daptomycin-resistant S. aureus (DRSA) strains. The combination of fosfomycin with ceftaroline consistently demonstrated synergy among all 18 isolates against the strains tested. The next most potent combination regimen was linezolid with fosfomycin, which demonstrated synergy in 16 of the 18 strains. Daptomycin demonstrated synergy in only 7 of the 18 strains tested when combined with fosfomycin. Cefazolin demonstrated synergy in 6 of 6 strains and vancomycin demonstrated no interaction in 6 of 6 strains tested. CONCLUSIONS: Fosfomycin demonstrated excellent activity against MRSA as well as isolates with resistance or reduced activity to other anti-MRSA drugs including vancomycin, daptomycin and linezolid. When combined with linezolid or daptomycin, fosfomycin demonstrated synergy for all or most strains tested. Thus, these combinations may have potential clinical utility when treating patients with serious infections caused by MRSA.

Delayed Repeat Contrast Enema for Treatment of Pediatric Intussusception.

INTRODUCTION: Ileocolic intussusception is a common cause of pediatric bowel obstruction. Contrast enema is successful in treating the majority of patients, and if initially unsuccessful, approximately one-third may be reduced with repeat enemas. We sought to study protocol implementation for delayed repeat enema in pediatric patients not reduced completely by an initial contrast enema. Our aims were to assess repeat enema success rates and outcome differences in preprotocol and postprotocol patients with respect to (1) intussusception recurrence, (2) surgical intervention and complication rates, and (3) length of stay. MATERIALS AND METHODS: We performed a retrospective review of treatment and clinical outcomes prior to and following protocol implementation for repeat enema for intussusception at two tertiary pediatric referral hospitals. The preprotocol period was defined from 2/2013 to 2/2016, and the postprotocol period was from 8/2016 to 11/2019. RESULTS: There were 112 patients in the preprotocol group, with 74 (66%) having successful reduction following the first enema. Of the 38 patients without successful reduction, 16 (42%) patients underwent repeat enema, and five were successful (31%). The postprotocol group included 122 patients, with 84 (69%) having successful first reduction. Of the 38 patients that failed, 25 patients (66%) underwent repeat enema, of which 13 (52%) were successful. Compared to preprotocol patients, postprotocol patients had significantly more enemas repeated and a trend toward fewer surgical interventions. CONCLUSIONS: Protocol implementation of repeat delayed enemas was significantly associated with an increased rate of repeat enemas at our institutions and reduced need for operative intervention during the index stay.

Vales+Tú: a cluster-randomized pilot study to reduce workplace injuries among US Latino day laborers.

Latino day laborers (LDL) are a vulnerable population of workers facing considerable risk for occupational injury. Under the guidance of our Community Advisory Board, we developed and tested the feasibility, acceptability and preliminary effects of Vales+Tú (You Are Worth More), a workplace injury risk-reduction program implemented by promotores on street-corners where LDL seek employment. The program was informed by theoretical perspectives emphasizing individual and group agency and self-determination. A pilot three-arm cluster-randomized community trial was conducted among 75 LDL. The intervention arms consisted of an individualized Brief Motivational Interview, a Group Problem Solving activity and a standard of care control (OSHA safety cards). We met our study goal of 25 LDL per intervention arm, and contacted 88% of participants post intervention. Participants evaluated the interventions favorably. At post-test, the Brief Motivational Interview group reported significant reductions in exposure to workplace hazards and increases in risk-reduction practices. The Group Problem Solving participants showed significant reductions in exposure to hazards (t-test -4.16, p < 0.001). Both intervention groups increased their reliance on corner peers, a measure of social support. Standard of care participants increased in self-efficacy to work safely. Overall, the only significant different between the three study conditions was in self-efficacy. These findings provide evidence of the feasibility and acceptability of Vales+Tú and show preliminary program efficacy. A large-scale replication trial will permit a more formal modeling of the study findings. Clinical Trial Registration (ClinicalTrials.gov): NCT04378348.

This pilot-randomized trial tested the feasibility and initial efficacy of an injury risk-reduction program among Latino day laborers (LDL). The study tested two alternative interventions consisting of a Brief Motivational Interview (Individual) and a Group Problem Solving (Group) conditions that were compared with a Standard-of-Care control group receiving safety cards. We then tested the extent to which the study conditions reduced exposure to workplace hazards and increased safety practices at work. Results indicate that intervening at day labor corners is a feasible intervention strategy acceptable to these immigrant workers. Initial results also indicate that there were multiple within-group significant differences in risk reduction, mostly in the individual condition, and that there was one significant between-group difference in safety self-efficacy at post-test. A larger more rigorous trial can further test the stability of these results and determine the extent to which these intervention approaches can reduce the risk for injury that LDL confront at work.

The American Board of Internal Medicine's New Longitudinal Assessment Option and What It Means for Infectious Disease Specialists.

As members of the American Board of Internal Medicine's (ABIM) Infectious Disease (ID) Board we've heard from many of our colleagues asking for greater flexibility in maintaining their ABIM Board Certification. The ID Board-and ABIM as a whole-has engaged with the physician community over the past several years to gain a deeper understanding of what is most important to them, and how an enhanced Maintenance of Certification (MOC) program could support their commitment to keeping up with advances in medical knowledge. This article serves as an update about how ABIM has evolved its assessments over time and on our progress in developing a new longitudinal pathway that is anticipated to become available in most specialties in 2022, and will launch in ID in 2023.

Development and Pilot Screen of Novel High Content Assay for Down Regulators of Expression of Heterogenous Nuclear Ribonuclear Protein H2.

BACKGROUND/AIMS: Despite recent advances in melanoma drug discovery, the average overall survival of patients with late-stage metastatic melanoma is approximately 3 years, suggesting a need for new approaches and melanoma therapeutic targets. Previously we identified heterogeneous nuclear ribonucleoprotein H2 as a potential target of anti-melanoma compound 2155-14 (Palrasu et al., Cell Physiol Biochem 2019;53:656-686). In the present study, we endeavored to develop an assay to enable a high throughput screening campaign to identify drug-like molecules acting via down regulation of heterogeneous nuclear ribonucleoprotein H2 that can be used for melanoma therapy and research. METHODS: We established a cell-based platform using metastatic melanoma cell line WM266-4 expressing hnRNPH2 conjugated with green fluorescent protein to enable assay development and screening. High Content Screening assay was developed and validated in 384 well plate format, followed by miniaturization to 1,536 well plate format. RESULTS: All plate-based QC parameters were acceptable: %CV = 6.7±0.3, S/B = 21±2.1, Z' = 0.75±0.04. Pilot screen of FDA-approved drug library (n=1,400 compounds) demonstrated hit rate of 0.5%. Two compounds demonstrated pharmacological response and were authenticated by western blot analysis. CONCLUSION: We developed a highly robust HTS-amenable high content screening assay capable of monitoring down regulation of hnRNPH2. This assay is thus capable of identifying authentic down regulators of hnRNPH1 and 2 in a large compound collection and, therefore, is amenable to a large-scale screening effort.

Synthetic fluorescent MYC probe: Inhibitor binding site elucidation and development of a high-throughput screening assay.

We report the discovery of a fluorescent small molecule probe. This probe exhibits an emission increase in the presence of the oncoprotein MYC that can be attenuated by a competing inhibitor. Hydrogen-deuterium exchange mass spectrometry analysis, rationalized by induced-fit docking, suggests it binds to the "coiled-coil" region of the leucine zipper domain. Point mutations of this site produced functional MYC constructs resistant to inhibition in an oncogenic transformation assay by compounds that displace the probe. Utilizing this probe, we have developed a high-throughput assay to identify MYC inhibitor scaffolds. Screening of a diversity library (N = 1408, 384-well) and a library of pharmacologically active compounds (N = 1280, 1536-well) yielded molecules with greater drug-like properties than the probe. One lead is a potent inhibitor of oncogenic transformation and is specific for MYC relative to resistant mutants and transformation-inducing oncogenes. This method is simple, inexpensive, and does not require protein modification, DNA binding, or the dimer partner MAX. This assay presents an opportunity for MYC inhibition researchers to discover unique scaffolds.

Tocilizumab: A retrospective multi-center cohort study of critically ill patients with COVID-19.

BACKGROUND: Coronavirus disease 19 (COVID-19) can have a severe presentation characterized by a dysregulated immune response requiring admission to the intensive care unit (ICU). Immunomodulatory treatments like tocilizumab were found to improve inflammatory markers and lung injury over time. We aim to evaluate the effectiveness of tocilizumab treatment on critically ill patients with severe COVID-19. MATERIALS AND METHODS: We conducted a multi-center retrospective cohort study of 154 adult patients admitted to the ICU for severe COVID-19 pneumonia between March 15 and May 8, 2020. Data were obtained by electronic medical record (EMR) review. The primary outcome of interest was mortality. RESULTS: Of 154 patients, 34 (21.4%) received tocilizumab. Compared to the non-treated group, the treated group was significantly younger, had fewer comorbidities, lower creatinine and procalcitonin levels, and higher alanine aminotransferase levels on admission. The treated group was more likely to receive supportive measures in the context of critical illness. The overall case fatality rate was 71.4%, and it was significantly lower in the treated than the non-treated (52.9 vs. 76.7%, p = 0.007). In multivariable survival analysis, tocilizumab treatment was associated with a 2.1 times lower hazard of mortality when compared to those who were not treated (hazard ratio: 0.47; 95% CI: 0.27, 0.83; p = 0.009). The prevalence of secondary infection was higher in the treated group compared to the non-treated without significant difference (p = 0.17). CONCLUSION: Tocilizumab treatment for critically ill patients with COVID-19 resulted in a lower likelihood of mortality.

Body composition outcomes of Healthy Fit and the role of acculturation among low-income Hispanics on the US-Mexico border.

BACKGROUND: Hispanic immigrants continue to experience higher rates of overweight and obesity compared to their non-Hispanic counterparts. Acculturation may contribute to unhealthy weight gain among immigrant populations by shifting dietary patterns from high fruit and vegetable consumption to unhealthier high fat diets. Healthy Fit, a culturally tailored community health worker (CHW) intervention, aims to reduce obesity related outcomes by providing physical activity and nutrition education and resources in a low-income Hispanic population. This study aims to evaluate outcomes of Healthy Fit participants and examine changes in body composition in relation to level of acculturation at baseline and follow-up. METHOD: In this longitudinal observational study, CHWs recruited 514 participants from community events and agencies serving low-income Hispanic populations in El Paso, Texas from 2015 to 2016. Following an in-person health screening, eligible participants received nutrition and physical activity education guided by fotonovelas, comic-like educational books. Telephone follow-ups made at 1, 3, and 6 months by CHWs encouraged follow-through on referrals. 288 participants completed the screening again during the 12-month follow-up. RESULTS: The sample was predominantly Hispanic (96%), female (82%), uninsured (79%), had a household income of less than $19,999 (70%), foreign-born (79%), preferred Spanish (86%) and few rated themselves as good or excellent for English proficiency (27%). Overall, Healthy Fit participants significantly improved (i.e., decreased) BFP by 0.71% (t = 2.47, p = 0.01) but not BMI (b = .01, t = - 0.14, p = .89). Contrary to expectations, acculturation was not associated with lower BMI (b = 0.09, p = 0.84) or BFP (b = 0.13, p = 0.85) at baseline. However, acculturation predicted changes in both BMI (b = 0.30, p = 0.03) and BFP (b = 1.33, p = 0 .01) from baseline to follow-up. Specifically, the low acculturation group improved in body composition measures over time and the high acculturation group did not improve in either measure. CONCLUSION: Findings suggest Healthy Fit was most effective among less acculturated individuals. The influence of acculturation on the efficacy of nutrition and exercise interventions suggests that Hispanics should not be treated as a homogenous subgroup.

Translating the REACH OUT dementia caregiver intervention into a primary care setting: a pilot study.

OBJECTIVE: The current study translated the Resources for Enhancing Alzheimer's Caregiver Health: Offering Useful Treatments (REACH OUT), a skills-building stress and burden intervention, for the primary care setting and pilot the resulting intervention. METHODS: The 16-week intervention consisted of a combination of clinic-based group and one-on-one sessions offered within a medical home, geriatrics clinic. A quasi-experimental pre- and post-test study design without a control group tested the resulting intervention. Semi-structured qualitative exit interviews evaluated program satisfaction. RESULTS: Twenty-five caregivers participated in one of four intervention groups; 21 caregivers completed the intervention (attended at least five of six group sessions). Caregiver burden on standardized assessments was significantly reduced between pre- and post-intervention, specifically for physical/emotional strain and caregiving uncertainty. Significant reductions were found in the frequency of reported disruptive behaviors; increased caregiver confidence in handling behavior problem frequency, depressive symptoms, disruptive behaviors, and memory-related problems; and decreased bother with respect to behavioral problem frequency and care recipient depression. Program satisfaction was high. CONCLUSION: This work suggests that the REACH OUT program can be successfully modified for use within a primary-care medical home setting.

Utilization of Asynchronous and Synchronous Teledermatology in a Large Health Care System During the COVID-19 Pandemic.

Background: Teledermatology offers an opportunity to continually deliver care during the coronavirus disease 2019 pandemic. Objective: To provide quantitative data about the use of teledermatology. Methods: Retrospective analysis of teledermatology consultations was performed from March 16 to May 1, 2020. The number/type of encounters, differences in diagnoses, and prescriptions between asynchronous and synchronous teledermatology visits were analyzed. Results: A total of 951 visits (36.2%) were asynchronous whereas 1,672 visits (63.8%) were synchronous. Only 131 (<5%) visits required an acute in-person follow-up. The diagnosis of acne was more frequent with asynchronous visits (p < 0.002, Bonferroni corrected). Antibiotics and nonretinoid acne medications were prescribed more with asynchronous visits, whereas immunomodulators and biologics were more commonly prescribed with synchronous visits (p < 0.02, Bonferroni corrected). Providers at our institution were split on preferred mode (54.2% synchronous, 45.8% asynchronous); however, synchronous visits were preferred for complex medical dermatology patients and return patients (p < 0.05). Limitations: This study is limited by being a single-center study. Conclusions: Asynchronous teledermatology was used more for acne management, whereas synchronous teledermatology was preferable to providers for complex medical dermatology. Postanalysis of the data collected led us to institute a hybridization of our asynchronous and synchronous teledermatology.

Chrysin Ameliorates Cyclosporine-A-Induced Renal Fibrosis by Inhibiting TGF-ß1-Induced Epithelial-Mesenchymal Transition.

Cyclosporine A (CsA) is a nephrotoxicant that causes fibrosis via induction of epithelial-mesenchymal transition (EMT). The flavonoid chrysin has been reported to have anti-fibrotic activity and inhibit signaling pathways that are activated during EMT. This study investigated the nephroprotective role of chrysin in the prevention of CsA-induced renal fibrosis and elucidated a mechanism of inhibition against CsA-induced EMT in proximal tubule cells. Treatment with chrysin prevented CsA-induced renal dysfunction in Sprague Dawley rats measured by blood urea nitrogen (BUN), serum creatinine and creatinine clearance. Chrysin inhibited CsA-induced tubulointerstitial fibrosis, characterized by reduced tubular damage and collagen deposition. In vitro, chrysin significantly inhibited EMT in LLC-PK1 cells, evidenced by inhibition of cell migration, decreased collagen expression, reduced presence of mesenchymal markers and elevated epithelial junction proteins. Furthermore, chrysin co-treatment diminished CsA-induced TGF-ß1 signaling pathways, decreasing Smad 3 phosphorylation which lead to a subsequent reduction in Snail expression. Chrysin also inhibited activation of the Akt/ GSK-3ß pathway. Inhibition of both pathways diminished the cytosolic accumulation of ß-catenin, a known trigger for EMT. In conclusion, flavonoids such as chrysin offer protection against CsA-induced renal dysfunction and interstitial fibrosis. Chrysin was shown to inhibit CsA-induced TGF-ß1-dependent EMT in proximal tubule cells by modulation of Smad-dependent and independent signaling pathways.

Plazomicin: A New Aminoglycoside.

Plazomicin (ACHN-490) is a novel parenteral aminoglycoside developed to target multidrug-resistant Enterobacteriaceae. It has recently been approved by the Food and Drug Administration for the management of complicated urinary tract infections and pyelonephritis caused by susceptible organisms. When compared with meropenem, plazomicin was not inferior. The adverse-event profile for plazomicin was comparable to meropenem except for an increased additional rise in serum creatinine in the plazomicin arm compared with the meropenem arm. This review focuses on the mode of action, antimicrobial activity, pharmacokinetics, clinical indications, and safety profile of this drug. Considerations for formulary addition and its place in therapy are also discussed.

Baloxavir: A Novel Antiviral Agent in the Treatment of Influenza.

Baloxavir marboxil (formerly S-033188) is a prodrug of baloxavir acid (S-033447) and inhibits cap-dependent endonuclease, an essential protein involved in the initiation of viral transcription by cleaving capped mRNA bound to PB2. Its adverse event profile is comparable to oseltamivir but is still vulnerable to resistance. The single-dose baloxavir marboxil is an appealing antiviral regimen for the treatment of influenza among outpatients when compared with longer, twice-daily regimens of oral and inhaled neuraminidase inhibitors. This review focuses on the mode of action, antiviral activity, pharmacokinetics, clinical indications, and safety profiles of this drug. Considerations for formulary addition and its place in therapy are also discussed.

Delafloxacin activity against Staphylococcus aureus with reduced susceptibility or resistance to methicillin, vancomycin, daptomycin or linezolid.

BACKGROUND: Delafloxacin is a recently approved anionic fluoroquinolone antibiotic with broad-spectrum activity against Gram-positive and Gram-negative organisms. The drug has been approved for patients with acute bacterial skin and skin structure infections including those caused by MRSA. There are limited data available against MRSA blood isolates (MRSABIs), vancomycin-intermediate strains (VISA), vancomycin-resistant strains (VRSA), daptomycin-non-susceptible strains (DNSSA) and linezolid-resistant Staphylococcus aureus (LRSA). METHODS: Antimicrobial activity of delafloxacin, levofloxacin, vancomycin, daptomycin and linezolid was determined against 110 MRSABIs, 15 VRSA, 35 VISA, 40 DNSSA and 6 LRSA. Microdilution testing using CAMHB was used to determine MIC according to CLSI guidelines. FDA breakpoints were used to determine delafloxacin susceptibility, and CLSI breakpoints were used for all other antibiotics. PCR testing for molecular markers was performed. RESULTS: Delafloxacin demonstrated activity against MRSABIs with an MIC90 of 1 mg/L and 68% susceptibility. Against the other groups the MIC90 and susceptibility were 1 mg/L and 40%, respectively, for VISA, 4 mg/L and 7% for VRSA and 1 mg/L and 38% for DNSSA. None of the LRSA isolates was susceptible to delafloxacin. Delafloxacin was active against 94% of MRSA blood isolates that were genotype SCC IVa. For MRSABIs with a levofloxacin MIC ≥8 mg/L (55/110), suggesting multiple mutations in the QRDR, delafloxacin MIC90 was 1 mg/L with a 36.4% susceptibility rate. CONCLUSIONS: Delafloxacin demonstrates superior activity to levofloxacin against recent MRSA blood isolates, VISA, VRSA and DNSSA, and demonstrates good activity against blood isolates most commonly found in the community.