Plasma gelsolin as a biomarker of inflammation

The prognostic implications of declining plasma gelsolin levels have been documented after a diverse variety of acute insults. Because gelsolin concentrations fall prior to the development of complications, a pathophysiological role for gelsolin depletion has been postulated in delayed multiorgan failure. The original hypothesis about the function of circulating gelsolin was that it scavenged actin released from cells at the site of injury. Although extracellular actin may be the primary cause of gelsolin depletion, the biologic imperative for gelsolin could entail the modulation of several inflammatory mediators as much as the disposal of actin. Translational research is actively addressing whether replenishment of plasma gelsolin could provide an efficacious and well tolerated therapeutic intervention in selected seriously ill patients

Influence of Sex/Gender and Race on Responses to Raltegravir Combined With Tenofovir-Emtricitabine in Treatment-Naive Human Immunodeficiency Virus-1 Infected Patients: Pooled Analyses of the STARTMRK and QDMRK Studies.

BACKGROUND: Antiretroviral therapy in human immunodeficiency virus (HIV)-infected women and blacks merits particular scrutiny because these groups have been underrepresented in clinical trials. METHODS: To document the effects of raltegravir across sex and racial lines, we conducted a pooled subgroup analysis of the efficacy and safety of raltegravir 400 mg BID plus tenofovir-emtricitabine by sex (women vs men) and self-identified race (black vs non-black) using phase 3 studies in treatment-naive patients. RESULTS: Study participants included 42 black women, 102 non-black women, 48 black men, and 477 non-black men. Clade B infections were less common in women (43.8%) than men (84.6%) and in blacks (45.6%) than non-blacks (80.5%). Baseline CD4 counts were ≤200 cells/µL in 52.2% of blacks and 31.6% of non-blacks. Black men had the largest proportion of patients with baseline CD4 counts/µL and the highest nontreatment-related discontinuation rate among the 4 sex-by-race subgroups. Human immunodeficiency virus-ribonucleic acid levels/mL were achieved at week 48 in 92.7% (95% confidence interval [CI], 80.1-98.5) of black women, 93.6% (95% CI, 86.6-97.6) of non-black women, 82.9% (95% CI, 67.9-92.8) of black men, and 91.4% (95% CI, 88.4-93.8) of non-black men. Serious clinical adverse events were reported in 9.0% of women versus 8.8% of men and in 11.1% of blacks versus 8.5% of non-blacks. CONCLUSIONS: In this post hoc analysis of patients with previously untreated HIV-1 infection receiving raltegravir plus tenofovir-emtricitabine, generally comparable results were achieved across sex and racial subgroups. However, black men had a lower response rate than either black women or non-black men, partially attributable to lower baseline CD4 counts and higher discontinuation rates

Can we prevent antimicrobial resistance by using antimicrobials better?

Since their development over 60 years ago, antimicrobials have become an integral part of healthcare practice worldwide. Recently, this has been put in jeopardy by the emergence of widespread antimicrobial resistance, which is one of the major problems facing modern medicine. In the past, the development of new antimicrobials kept us one step ahead of the problem of resistance, but only three new classes of antimicrobials have reached the market in the last thirty years. A time is therefore approaching when we may not have effective treatment against bacterial infections, particularly for those that are caused by Gram-negative organisms. An important strategy to reduce the development of antimicrobial resistance is to use antimicrobials more appropriately, in ways that will prevent resistance. This involves a consideration of the pharmacokinetic and pharmacodynamics properties of antimicrobials, the possible use of combinations, and more appropriate choice of antimicrobials, which may include rapid diagnostic testing and antimicrobial cycling. Examples given in this review include Mycobacterium tuberculosis, Gram-negative and Gram-positive organisms. We shall summarise the current evidence for these strategies and outline areas for future development

Association of plasma gelsolin with frailty phenotype and mortality among octogenarian community-dwelling men : a cohort study

Background Biomarkers are needed for frailty, a common phenotype often associated with muscle loss in older people. Plasma gelsolin (pGSN) is a protein largely synthesized and secreted by skeletal muscle. Aims To investigate whether pGSN could be a biomarker of the frailty phenotype and predict mortality. Methods A homogenous cohort of males (born 1919-1934, baseline n = 3490) has been followed since the 1960s. In 2010/11, frailty phenotypes by modified Fried criteria were assessed. pGSN was measured in a convenience subset (n = 469, mean age 83) and re-measured in survivors (n = 127) in 2017. Mortality through December 31, 2018 was retrieved from national registers. Regression models were used for analyses. Results Of 469 males, 152 (32.4%) were robust, 284 (60.6%) prefrail, and 33 (7.0%) frail in 2010/11. There was a graded (p = 0.018) association between pGSN (mean 58.1 ug/mL, SD 9.3) and frailty. After multivariable adjustment, higher pGSN levels were associated with lower odds of having contemporaneous phenotypic prefrailty (OR per 1 SD 0.73, 95% CI 0.58-0.92) and frailty (OR per 1 SD 0.70, 95% CI 0.44-1.11). By 2018, 179 males (38.2%) had died, and higher baseline pGSN predicted a lower 7-year mortality rate (HR per 1 SD 0.85, 95% CI 0.72-1.00). pGSN concentrations in 2010/11 and 2017 were correlated (n = 127, r = 0.34, p < 0.001). Discussion Higher baseline pGSN concentrations were associated with a persistently robust phenotype and lower mortality rate over 7 years in a cohort of octogenarian males with high socioeconomic status and may be a promising laboratory biomarker for the development of a frailty phenotype.Peer reviewe

Delayed Therapy with Plasma Gelsolin Improves Survival in Murine Pneumococcal Pneumonia

Abstract Background: Innate immune responses contribute to successful resolution of bacterial pneumonia. Bolstering host defense with immunomodulators might be increasingly needed to improve outcomes in antibiotic-resistant infections. One candidate molecule is recombinant human plasma gelsolin (rhu-pGSN), an abundant normal blood protein whose levels fall proportionally with disease severity. Pretreatment with rhu-pGSN has beneficial effects in many pre-clinical models of inflammation and injury, including pneumonia. We evaluated the effects of delaying therapy with rhu-pGSN up to 48 hours after lethal intra-nasal pneumococcal challenge in a mouse model to more closely mimic realistic clinical circumstances. Methods: Adult Bl/6 mice were inoculated intra-nasally with S. pneumoniae serotype 3 on day 0, followed by subcutaneous rhu-pGSN 24 hours later for evaluation of bacterial clearance in lavage fluids. To assess effects on survival, rhu-pGSN was administered on days 2 and 3 after infection and effects monitored for 10 days. No antibiotics or other interventions were given. Results: Treatment with rhu-pGSN at 24 hours after infection improved bacterial clearance, seen as reduction of bacterial CFU in bronchoalveolar lavage fluid at 48 hours (% of initial inoculum, vehicle vs.. rhu-pGSN (dose range 0.5–2 mg): 30 ± 13 vs. 11 ± 7, n = 6 trials using inocula ranging 0.3–1.8 x 106 CFU, 3 mice/group/trial, P = .001). In 3 separate trials, pGSN (0.5 mg s.c.) reduced weight loss and mortality (% survival, vehicle vs. pGSN: 40 vs. 80, 0 vs. 25, 17 vs. 43; n ≥ 16/group, P =.02). Increasing the dose to 1 mg further improved survival from 17 to 71%. Conclusion: Rhu-pGSN can substantially improve survival in a murine model of fatal pneumococcal pneumonia, even when administered as single doses on days 2 and 3 after infection without antibiotics. The data support further evaluation of pGSN as adjunctive therapy for serious infections with diverse pathogens and in models of antibiotic-resistant pneumonia. Disclosures Z. Yang, BioAegis: Shared NIH grant to study plasma gelsolin, we receive plasma gelsolin for our lab studies; S. Levinson, BioAegis: BIoAegis shares a grant to investigate plasma gelsolin with HSPH, Employee and Shareholder, Salary; T. Stossel, BioAegis: Consultant and Shareholder, portion of royalties from Hospital IP licensed to BioAegis; M. DiNubile, BioAegis: Employee and Shareholder, Consulting fee; L. Kobzik, BioAegis: Collaborator and We share a NIH grant on pGSN with BioAegis, we receive plasma gelsolin for our lab studie

Efficacy of the Pentavalent Rotavirus Vaccine, RotaTeq (RV5), Between Doses of a 3-Dose Series and With Less Than 3 Doses (Incomplete Regimen)

Post-hoc analyses of the Rotavirus Efficacy and Safety Trial (RES T) were conducted to determine whether the pentavalent rotavirus vaccine (RV5) confers early protection against rotavirus gastroenteritis (RVGE) before completion of the 3-dose regimen. To evaluate the efficacy of RV5 between doses in reducing the rates of RVGE-related hospitalizations and emergency department (ED) visits in infants who ultimately received all 3 doses of RV5/placebo, events occurring from 2 weeks after the first and second doses to receipt of the subsequent dose (Analysis A) and events occurring from 2 weeks after the first and second doses to 2 weeks after the subsequent dose (Analysis B) were analyzed. In Analysis A, RV5 reduced the rates of combined hospitalizations and ED visits for G1-G4 RVGE or RVGE regardless of serotype between doses 1 and 2 by 100% [95% confidence interval (CI): 72-100%] or 82% (95% CI: 39-97%), respectively, and between doses 2 and 3, RV5 reduced the rates of combined hospitalizations and ED visits for G1-G4 RVGE or RVGE regardless of serotype by 91% (95% CI: 63-99%) or 84% (95% CI: 54-96%), respectively. Similar rate reductions were observed in Analysis B. These data suggest that RV5 provides a high level of protection between doses against hospitalizations and ED visits for RVGE starting as early as 14 days after the first dose

Long-Term Efficacy, Safety, and Tolerability of Indinavir-Based Therapy in Protease Inhibitor—Naive Adults with Advanced HIV Infection

A double-blind, randomized study of zidovudine-experienced, PI- and lamivudine-naive adults with baseline CD4 cell counts of ⩽50 cells/mm3 had demonstrated that the HIV suppression achieved with zidovudine, lamivudine, and indinavir therapy was superior to that achieved with dual-nucleoside or indinavir-only regimens after 24 weeks of therapy. In a 192-week extension of the study, 371 participants received open-label indinavir with or without other antiretroviral drugs. One hundred and eight subjects were originally randomized to receive triple therapy. After 216 weeks, the proportion of subjects with HIV RNA levels of <500 copies/mL were 34%, according to a general estimating equation analysis, 92%, according to an observed data analysis, and 24%, according to an intention-to-treat analysis counting noncompleters as failures; the proportions of subjects with HIV RNA levels of <50 copies/mL were 31%, 85%, and 22%, respectively. Hyperbilirubinemia (experienced by 31% of subjects), nausea (17%), abdominal pain (14%), and nephrolithiasis (13%) were the most common drug-related adverse events during the extensio

Targeted simplification versus antipseudomonal broad-spectrum beta-lactams in patients with bloodstream infections due to Enterobacteriaceae (SIMPLIFY): a study protocol for a multicentre, open-label, phase III randomised, controlled, non-inferiority clinical trial

INTRODUCTION: Within the context of antimicrobial stewardship programmes, de-escalation of antimicrobial therapy is one of the proposed strategies for reducing the unnecessary use of broad-spectrum antibiotics (BSA). The empirical treatment of nosocomial and some healthcare-associated bloodstream infections (BSI) frequently includes a beta-lactam with antipseudomonal activity as monotherapy or in combination with other drugs, so there is a great opportunity to optimise the empirical therapy based on microbiological data. De-escalation is assumed as standard of care for experts in infectious diseases. However, it is less frequent than it would desirable. METHODS AND ANALYSIS: The SIMPLIFY trial is a multicentre, open-label, non-inferiority phase III randomised controlled clinical trial, designed as a pragmatic 'real-practice' trial. The aim of this trial is to demonstrate the non-inferiority of de-escalation from an empirical beta-lactam with antipseudomonal activity to a targeted narrow-spectrum antimicrobial in patients with BSI due to Enterobacteriaceae. The primary outcome is clinical cure, which will be assessed at the test of cure visit. It will be conducted at 19 Spanish public and university hospitals. ETHICS AND DISSEMINATION: Each participating centre has obtained the approval of the ethics review committee, the agreement of the directors of the institutions and authorisation from the Spanish Regulatory Agency (Agencia Española del Medicamento y Productos Sanitarios). Data will be presented at international conferences and published in peer-reviewed journals. DISCUSSION: Strategies to reduce the use of BSA should be a priority. Most of the studies that support de-escalation are observational, retrospective and heterogeneous. A recent Cochrane review stated that well-designed clinical trials should be conducted to assess the safety and efficacy of de-escalation