Randomized Trial of Ceftazidime-Avibactam vs Meropenem for Treatment of Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia (REPROVE): Analyses per US FDA-Specified End Points

Background: Hospital-acquired and ventilator-associated pneumonia (HAP/VAP; nosocomial pneumonia) due to Gram-negative pathogens are associated with significant morbidity and mortality; treatment options for multidrug-resistant infections are limited. The pivotal phase III REPROVE trial evaluated the efficacy of ceftazidime-avibactam (CAZ-AVI) vs meropenem in the treatment of patients with HAP/VAP. Study results for prespecified analyses per US Food and Drug Administration-recommended trial end points are reported here. Methods: Hospitalized adults with HAP/VAP proven or suspected to be caused by a Gram-negative pathogen were randomized 1:1 to receive CAZ-AVI or meropenem for 7 to 14 days. The primary outcome was 28-day all-cause mortality in the intent-to-treat (ITT) population. Secondary outcomes included clinical cure at test of cure (TOC) in the ITT and microbiological ITT (micro-ITT) populations, and safety and tolerability throughout the study. Results: hundred seventy randomized patients received treatment and were included in the ITT population (CAZ-AVI, n = 436; meropenem, n = 434). CAZ-AVI was noninferior to meropenem for the primary end point (28-day all-cause mortality; ITT) based on the prespecified 10% noninferiority margin (CAZ-AVI, 9.6%; meropenem, 8.3%; difference, 1.5%; 95% confidence interval [CI], -2.4% to 5.3%) and for the clinical cure end point in the ITT population based on a prespecified -10% noninferiority margin (CAZ-AVI, 67.2%; meropenem, 69.1%; difference, −1.9%; 95% CI, -8.1% to 4.3%). Clinical cure rates at TOC for patients infected with CAZ-nonsusceptible pathogens were similar (CAZ-AVI, 75.5%; meropenem, 71.2%; micro-ITT). Safety data were consistent with established safety profiles for both agents. Conclusions: CAZ-AVI provides an important new treatment option for HAP/VAP due to Gram-negative pathogens, including CAZ-nonsusceptible strains

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Tumor Necrosis Factor Alpha-Induced Apoptosis in Human Neuronal Cells: Protection by the Antioxidant \u3ci\u3eN\u3c/i\u3e-Acetylcysteine and the Genes \u3ci\u3ebcl-2\u3c/i\u3e and \u3ci\u3ecrmA\u3c/i\u3e

Tumor necrosis factor alpha (TNF-α) is a candidate human immunodeficiency virus type 1-induced neurotoxin that contributes to the pathogenesis of AIDS dementia complex. We report here on the effects of exogenous TNF-α on SK-N-MC human neuroblastoma cells differentiated to a neuronal phenotype with retinoic acid. TNF-α caused a dose-dependent loss of viability and a corresponding increase in apoptosis in differentiated SK-N-MC cells but not in undifferentiated cultures. Importantly, intracellular signalling via TNF receptors, as measured by activation of the transcription factor NF-kB, was unaltered by retinoic acid treatment. Finally, overexpression of bcl-2 or crmA conferred resistance to apoptosis mediated by TNF-α, as did the addition of the antioxidant N-acetylcysteine. These results suggest that TNF-a induces apoptosis in neuronal cells by a pathway that involves formation of reactive oxygen intermediates and which can be blocked by specific genetic interventions

State-level impulsivity, affect, and alcohol: a psychometric evaluation of the Momentary Impulsivity Scale across two intensive longitudinal samples.

We reexamined the psychometric properties of the Momentary Impulsivity Scale (MIS) in two young adult samples using daily diary (=77) and ecological momentary assessment (=147). A one-factor between- and within-person structure was supported, though "I felt impatient" loaded poorly within-person. MIS scores consistently related to emotion-driven trait impulsivity; however, MSSDs of MIS scores were unrelated to outcomes after accounting for aggregate MIS scores. We observed positive, within-person correlations with negative, but not positive, affect. Between-person MIS scores correlated with alcohol problems, though within-person MIS-alcohol relations were inconsistent. MIS scores were unrelated to laboratory-based impulsivity tasks. Findings inform the assessment of state-level impulsivity in young adults. Future research should prioritize expanding the MIS to capture the potential multidimensionality of state-level impulsivity

<em>P. falciparum</em> Enhances HIV Replication in an Experimental Malaria Challenge System

<div><p>Co-infection with HIV and <em>P. falciparum</em> worsens the prognosis of both infections; however, the mechanisms driving this adverse interaction are not fully delineated. To evaluate this, we studied HIV-1 and <em>P. falciparum</em> interactions <em>in vitro</em> using peripheral blood mononuclear cells (PBMCs) from human malaria naïve volunteers experimentally infected with <em>P. falciparum</em> in a malaria challenge trial.PBMCs collected before the malaria challenge and at several time points post-infection were infected with HIV-1 and co-cultured with either <em>P. falciparum</em> infected (iRBCs) or uninfected (uRBCs) red blood cells. HIV p24Ag and TNF-α, IFN-γ, IL-4, IL-6, IL-10, IL-17, and MIP-1α were quantified in the co-culture supernatants. In general, iRBCs stimulated more HIV p24Ag production by PBMCs than did uRBCs. HIV p24Ag production by PBMCs in the presence of iRBCs (but not uRBCs) further increased during convalescence (days 35, 56, and 90 post-challenge). In parallel, iRBCs induced higher secretion of pro-inflammatory cytokines (TNF-α, IFN-γ, and MIP-1α) than uRBCs, and production increased further during convalescence. Because the increase in p24Ag production occurred after parasitemia and generalized immune activation had resolved, our results suggest that enhanced HIV production is related to the development of anti-malaria immunity and may be mediated by pro-inflammatory cytokines.</p> </div

Safety and comparability of controlled human Plasmodium falciparum infection by mosquito bite in malaria-naïve subjects at a new facility for sporozoite challenge.

Controlled human malaria infection (CHMI) studies which recapitulate mosquito-borne infection are a critical tool to identify protective vaccine and drug candidates for advancement to field trials. In partnership with the Walter Reed Army Institute of Research, the CHMI model was established at the Seattle Biomedical Research Institute's Malaria Clinical Trials Center (MCTC). Activities and reagents at both centers were aligned to ensure comparability and continued safety of the model. To demonstrate successful implementation, CHMI was performed in six healthy malaria-naïve volunteers.All volunteers received NF54 strain Plasmodium falciparum by the bite of five infected Anopheles stephensi mosquitoes under controlled conditions and were monitored for signs and symptoms of malaria and for parasitemia by peripheral blood smear. Subjects were treated upon diagnosis with chloroquine by directly observed therapy. Immunological (T cell and antibody) and molecular diagnostic (real-time quantitative reverse transcriptase polymerase chain reaction [qRT-PCR]) assessments were also performed.All six volunteers developed patent parasitemia and clinical malaria. No serious adverse events occurred during the study period or for six months post-infection. The mean prepatent period was 11.2 days (range 9-14 days), and geometric mean parasitemia upon diagnosis was 10.8 parasites/µL (range 2-69) by microscopy. qRT-PCR detected parasites an average of 3.7 days (range 2-4 days) earlier than blood smears. All volunteers developed antibodies to the blood-stage antigen merozoite surface protein 1 (MSP-1), which persisted up to six months. Humoral and cellular responses to pre-erythrocytic antigens circumsporozoite protein (CSP) and liver-stage antigen 1 (LSA-1) were limited.The CHMI model was safe, well tolerated and characterized by consistent prepatent periods, pre-symptomatic diagnosis in 3/6 subjects and adverse event profiles as reported at established centers. The MCTC can now evaluate candidates in the increasingly diverse vaccine and drug pipeline using the CHMI model.ClinicalTrials.gov NCT01058226

General inflammation in the periphery does not correlate to HIV production in co-cultures.

<p>Generalized immunological activation as assessed by C-Reactive Protein (CRP) levels in the plasma collected at the time of PBMC isolation in the five malaria challenge participants. CRP was detected by ELISA. The light pink bars correspond to the early visits (baseline, liver stage, time of first parasitemia) and the burgundy bars correspond to the three post-exposure time points (day 35, day 56, and day 90). The bars show the average CRP levels in the plasma at the time of PBMCs isolation for the 5 participants. Error bars represent the SEM for the triplicate wells run at each time point. Levels of CRP in the plasma did not increase at the post-exposure time points when the increase in HIV production was observed, suggesting that the increase in HIV production was specific to malaria antigen re-exposure and not a result of generalized immune activation.</p

<i>Plasmodium falciparum</i> stimulates enhanced secretion of TNF-α, IFN-γ, and MIP-1α, but not IL-6.

<p>PBMCs from the malaria challenge trial participants were infected with HIV and co-cultured with iRBC and uRBC at the 6 visits as described earlier. Cytokine secretion in the iRBC (red lines) and uRBC (black lines) co-culture supernatants was measured using the BioPlex platform. Cytokine production was measured at days 1, 4, 6, and 8 post initiation of co-culture and the area under the curve was calculated for each participant at each visit and plotted in A – D as the average for the 5 participants, error bars represent the 95% CI. Repeated measures ANOVA was used to determine significance in the difference in amount of cytokines secreted (iRBC-uRBC) at the post-exposure time points compared to the difference in amount of cytokine secreted (iRBC-uRBC) at baseline. p-values have been corrected for multiple comparisons: TNF-α day 35 p = 0.013, day 56 p = 0.29, day 90 p = 0.19; IFN-γ day 35 p<0.001, day 56 p = 0.019, day 90 p<0.001; MIP-1α day 35 p<0.001, day 56 p = 0.002, day 90 p<0.001. There was an increase in TNF-α, IFN-γ, and MIP-1α (A–C) secretion in the iRBC co-cultures compared to the uRBC co-cultures at all time points and an enhanced secretion at the convalescent time points. There was no difference in IL-6 secretion (D).</p

Mutations in the P. falciparum Digestive Vacuole Transmembrane Protein PfCRT and Evidence for Their Role in Chloroquine Resistance

The determinant of verapamil-reversible chloroquine resistance (CQR) in a Plasmodium falciparum genetic cross maps to a 36 kb segment of chromosome 7. This segment harbors a 13-exon gene, pfcrt, having point mutations that associate completely with CQR in parasite lines from Asia, Africa, and South America. These data, transfection results, and selection of a CQR line harboring a novel K761 mutation point to a central role for the PfCRT protein in CQR. This transmembrane protein localizes to the parasite digestive vacuole (DV), the site of CQ action, where increased compartment acidification associates with PfCRT point mutations. Mutations in PfCRT may result in altered chloroquine flux or reduced drug binding to hematin through an effect on DV pH