Isavuconazole in the Treatment of Invasive Aspergillosis and Mucormycosis Infections

We have a limited arsenal with which to treat invasive fungal infections caused by Aspergillus and Mucorales. The morbidity and mortality for both pathogens remains high. A triazole antifungal, isavuconazole, was recently granted approval by the US Food and Drug Administration and the European Medicines Agency for the treatment of invasive aspergillosis and mucormycosis. A randomized double-blind comparison trial for the treatment of invasive aspergillosis found isavuconazole noninferior to voriconazole. A separate, open-label study evaluating the efficacy of isavuconazole in the treatment of mucormycosis found comparable response rates to amphotericin B and posaconazole treated historical controls. The prodrug isavuconazonium sulfate is commercially available in both an oral and intravenous formulation and is generally well tolerated. Isavuconazole’s broad spectrum of activity, limited side effect profile, and favorable pharmacokinetics will likely solidify its place in therapy

Diabetes Mellitus Type 2 as a Risk Factor and Outcome Modifier for Cryptococcosis in HIV Negative, Non-transplant Patients, a Propensity Score Match Analysis

Cryptococcosis is an opportunistic fungal infection of worldwide distribution with significant associated morbidity and mortality. HIV, organ transplantation, malignancy, cirrhosis, sarcoidosis, and immunosuppressive medications are established risk factors for cryptococcosis. Type 2 diabetes mellitus (DM2) has been hypothesized as a risk factor and an outcome modifier for cryptococcosis. We aimed to compare outcomes among HIV-negative, non-transplant (NHNT) patients with and without DM2. We queried a global research network to identify NHNT patients (n = 3280). We performed a propensity score-matched (PSM) analysis comparing clinical outcomes among cryptococcosis patients by DM status. We also characterize adults with cryptococcosis and DM2 as the only risk factor. After PSM, NHNT patients with DM2 were more likely to develop cognitive dysfunction [9% vs. 6%, OR 1.6; 95% CI (1.1–2.3); P = 0.01] but had similar mortality, hospitalization, ICU, and stroke risk after acquiring cryptococcosis when compared to NHNT patients without DM2. Pulmonary cryptococcosis was the most common site of infection. Among 44 cryptococcosis patients with DM2 as the only identifiable risk factor for disease, the annual incidence of cryptococcosis was 0.001%, with a prevalence of 0.002%. DM2 is associated with increased cognitive dysfunction risk in NHNT patients with cryptococcosis. It is rare for DM2 to be the only identified risk factor for developing cryptococcosis. Kidney disease, hyperglycemia, and immune dysfunction can increase the risk of cryptococcosis in patients with DM2

Diagnosis of Breakthrough Fungal Infections in the Clinical Mycology Laboratory: An ECMM Consensus Statement.

Breakthrough invasive fungal infections (bIFI) cause significant morbidity and mortality. Their diagnosis can be challenging due to reduced sensitivity to conventional culture techniques, serologic tests, and PCR-based assays in patients undergoing antifungal therapy, and their diagnosis can be delayed contributing to poor patient outcomes. In this review, we provide consensus recommendations on behalf of the European Confederation for Medical Mycology (ECMM) for the diagnosis of bIFI caused by invasive yeasts, molds, and endemic mycoses, to guide diagnostic efforts in patients receiving antifungals and support the design of future clinical trials in the field of clinical mycology. The cornerstone of lab-based diagnosis of breakthrough infections for yeast and endemic mycoses remain conventional culture, to accurately identify the causative pathogen and allow for antifungal susceptibility testing. The impact of non-culture-based methods are not well-studied for the definite diagnosis of breakthrough invasive yeast infections. Non-culture-based methods have an important role for the diagnosis of breakthrough invasive mold infections, in particular invasive aspergillosis, and a combination of testing involving conventional culture, antigen-based assays, and PCR-based assays should be considered. Multiple diagnostic modalities, including histopathology, culture, antibody, and/or antigen tests and occasionally PCR-based assays may be required to diagnose breakthrough endemic mycoses. A need exists for diagnostic tests that are effective, simple, cheap, and rapid to enable the diagnosis of bIFI in patients taking antifungals.S

Ancient Lowland Maya neighborhoods: Average Nearest Neighbor analysis and kernel density models, environments, and urban scale

Many humans live in large, complex political centers, composed of multi-scalar communities including neighborhoods and districts. Both today and in the past, neighborhoods form a fundamental part of cities and are defined by their spatial, architectural, and material elements. Neighborhoods existed in ancient centers of various scales, and multiple methods have been employed to identify ancient neighborhoods in archaeological contexts. However, the use of different methods for neighborhood identification within the same spatiotemporal setting results in challenges for comparisons within and between ancient societies. Here, we focus on using a single method—combining Average Nearest Neighbor (ANN) and Kernel Density (KD) analyses of household groups—to identify potential neighborhoods based on clusters of households at 23 ancient centers across the Maya Lowlands. While a one-size-fits all model does not work for neighborhood identification everywhere, the ANN/KD method provides quantifiable data on the clustering of ancient households, which can be linked to environmental zones and urban scale. We found that centers in river valleys exhibited greater household clustering compared to centers in upland and escarpment environments. Settlement patterns on flat plains were more dispersed, with little discrete spatial clustering of households. Furthermore, we categorized the ancient Maya centers into discrete urban scales, finding that larger centers had greater variation in household spacing compared to medium-sized and smaller centers. Many larger political centers possess heterogeneity in household clustering between their civic-ceremonial cores, immediate hinterlands, and far peripheries. Smaller centers exhibit greater household clustering compared to larger ones. This paper quantitatively assesses household clustering among nearly two dozen centers across the Maya Lowlands, linking environment and urban scale to settlement patterns. The findings are applicable to ancient societies and modern cities alike; understanding how humans form multi-scalar social groupings, such as neighborhoods, is fundamental to human experience and social organization

Ancient Lowland Maya neighborhoods: Average Nearest Neighbor analysis and kernel density models, environments, and urban scale

Many humans live in large, complex political centers, composed of multi-scalar communities including neighborhoods and districts. Both today and in the past, neighborhoods form a fundamental part of cities and are defined by their spatial, architectural, and material elements. Neighborhoods existed in ancient centers of various scales, and multiple methods have been employed to identify ancient neighborhoods in archaeological contexts. However, the use of different methods for neighborhood identification within the same spatiotemporal setting results in challenges for comparisons within and between ancient societies. Here, we focus on using a single method—combining Average Nearest Neighbor (ANN) and Kernel Density (KD) analyses of household groups—to identify potential neighborhoods based on clusters of households at 23 ancient centers across the Maya Lowlands. While a one-size-fits all model does not work for neighborhood identification everywhere, the ANN/KD method provides quantifiable data on the clustering of ancient households, which can be linked to environmental zones and urban scale. We found that centers in river valleys exhibited greater household clustering compared to centers in upland and escarpment environments. Settlement patterns on flat plains were more dispersed, with little discrete spatial clustering of households. Furthermore, we categorized the ancient Maya centers into discrete urban scales, finding that larger centers had greater variation in household spacing compared to medium-sized and smaller centers. Many larger political centers possess heterogeneity in household clustering between their civic-ceremonial cores, immediate hinterlands, and far peripheries. Smaller centers exhibit greater household clustering compared to larger ones. This paper quantitatively assesses household clustering among nearly two dozen centers across the Maya Lowlands, linking environment and urban scale to settlement patterns. The findings are applicable to ancient societies and modern cities alike; understanding how humans form multi-scalar social groupings, such as neighborhoods, is fundamental to human experience and social organization

Coherent J/psi photoproduction in ultra-peripheral PbPb collisions at root s(NN)=2.76 TeV with the CMS experiment

Peer reviewe

Upsilon (nS) polarizations versus particle multiplicity in pp collisions at root s=7 TeV

Peer reviewe

Measurement of the prompt J/psi and psi(2S) polarizations in pp collisions at sqrt(s) = 7 TeV

The polarizations of prompt J/psi and psi(2S) mesons are measured in proton-proton collisions at sqrt(s) = 7 TeV, using a dimuon data sample collected by the CMS experiment at the LHC, corresponding to an integrated luminosity of 4.9 inverse femtobarns. The prompt J/psi and psi(2S) polarization parameters lambda[theta], lambda[phi], and lambda[theta, phi], as well as the frame-invariant quantity lambda(tilde), are measured from the dimuon decay angular distributions in three different polarization frames. The J/psi results are obtained in the transverse momentum range 14 < pt < 70 GeV, in the rapidity intervals abs(y) < 0.6 and 0.6 < abs(y) < 1.2. The corresponding psi(2S) results cover 14 < pt < 50 GeV and include a third rapidity bin, 1.2 < abs(y) < 1.5. No evidence of large transverse or longitudinal polarizations is seen in these kinematic regions, which extend much beyond those previously explored

Multiplicity and rapidity dependence of strange hadron production in pp, pPb, and PbPb collisions at the LHC

Peer reviewe

Geoeconomic variations in epidemiology, ventilation management, and outcomes in invasively ventilated intensive care unit patients without acute respiratory distress syndrome: a pooled analysis of four observational studies

Background: Geoeconomic variations in epidemiology, the practice of ventilation, and outcome in invasively ventilated intensive care unit (ICU) patients without acute respiratory distress syndrome (ARDS) remain unexplored. In this analysis we aim to address these gaps using individual patient data of four large observational studies. Methods: In this pooled analysis we harmonised individual patient data from the ERICC, LUNG SAFE, PRoVENT, and PRoVENT-iMiC prospective observational studies, which were conducted from June, 2011, to December, 2018, in 534 ICUs in 54 countries. We used the 2016 World Bank classification to define two geoeconomic regions: middle-income countries (MICs) and high-income countries (HICs). ARDS was defined according to the Berlin criteria. Descriptive statistics were used to compare patients in MICs versus HICs. The primary outcome was the use of low tidal volume ventilation (LTVV) for the first 3 days of mechanical ventilation. Secondary outcomes were key ventilation parameters (tidal volume size, positive end-expiratory pressure, fraction of inspired oxygen, peak pressure, plateau pressure, driving pressure, and respiratory rate), patient characteristics, the risk for and actual development of acute respiratory distress syndrome after the first day of ventilation, duration of ventilation, ICU length of stay, and ICU mortality. Findings: Of the 7608 patients included in the original studies, this analysis included 3852 patients without ARDS, of whom 2345 were from MICs and 1507 were from HICs. Patients in MICs were younger, shorter and with a slightly lower body-mass index, more often had diabetes and active cancer, but less often chronic obstructive pulmonary disease and heart failure than patients from HICs. Sequential organ failure assessment scores were similar in MICs and HICs. Use of LTVV in MICs and HICs was comparable (42\ub74% vs 44\ub72%; absolute difference \u20131\ub769 [\u20139\ub758 to 6\ub711] p=0\ub767; data available in 3174 [82%] of 3852 patients). The median applied positive end expiratory pressure was lower in MICs than in HICs (5 [IQR 5\u20138] vs 6 [5\u20138] cm H2O; p=0\ub70011). ICU mortality was higher in MICs than in HICs (30\ub75% vs 19\ub79%; p=0\ub70004; adjusted effect 16\ub741% [95% CI 9\ub752\u201323\ub752]; p<0\ub70001) and was inversely associated with gross domestic product (adjusted odds ratio for a US$10 000 increase per capita 0\ub780 [95% CI 0\ub775\u20130\ub786]; p<0\ub70001). Interpretation: Despite similar disease severity and ventilation management, ICU mortality in patients without ARDS is higher in MICs than in HICs, with a strong association with country-level economic status. Funding: No funding