Comparison of Clinical Outcomes among Intensive Care Unit Patients Receiving One or Two Grams of Ceftriaxone Daily.

Intensive care unit (ICU) patients may experience ceftriaxone underexposure, but clinical outcomes data are lacking. The objective of this study was to determine the impact of ceftriaxone dosing on clinical outcomes among ICU patients without central nervous system (CNS) infection. A retrospective study of ICU patients receiving intravenous, empirical ceftriaxone for non-CNS infections was conducted. Patients ≥18 years of age who received ≤2 g of ceftriaxone daily for ≥72 h were included and categorized as receiving ceftriaxone 1 g or 2 g daily. The primary, composite outcome was treatment failure, defined as inpatient mortality and/or antibiotic escalation due to clinical worsening. Propensity score matching was performed based on the probability of receiving 2 g of ceftriaxone daily. Multivariable logistic regression determined the association between ceftriaxone dose and treatment failure in a propensity-matched cohort. A total of 212 patients were included in the propensity-matched cohort. The most common diagnoses (83.0%) were pneumonia and urinary tract infection. Treatment failure occurred in 17.0% and 5.7% of patients receiving 1 g and 2 g daily, respectively (P = 0.0156). Overall inpatient mortality was 8.5%. Ceftriaxone 2 g dosing was associated with a reduced likelihood of treatment failure (adjusted odds ratio [aOR] = 0.190; 95% confidence interval [CI] = 0.059 to 0.607). Other independent predictors of treatment failure included sequential organ failure assessment score (aOR = 1.440; 95% CI = 1.254 to 1.653) and creatinine clearance at 72 h from ceftriaxone initiation (aOR = 0.980; 95% CI = 0.971 to 0.999). Therefore, ceftriaxone at 2 g daily, when used as appropriate antimicrobial coverage, may be appropriate for ICU patients with lower mortality risk.

Vertical Profiles of Droplet Size Distributions Derived from Cloud-Side Observations by the Research Scanning Polarimeter: Tests on Simulated Data.

The Research Scanning Polarimeter (RSP) is an airborne along-track scanner measuring the polarized and total reflectances with high angular resolution. It allows for accurate characterization of liquid water cloud droplet sizes using the rainbow structure in the polarized reflectance. RSP's observations also provide constraints on the cumulus cloud's 2D cross section, yielding estimates of its geometric shape. In this study for the first time we evaluate the possibility to retrieve vertical profiles of microphysical characteristics along the cloud side by combining these micro- and macrophysical retrieval methods. First we constrain cloud's geometric shape, then for each point on the bright side of its surface we collect data from different scans to obtain the multi-angle polarized reflectance at that point. The rainbow structures of the reflectances from multiple points yield the corresponding droplet size distributions (DSDs), which are then combined into vertical profiles. We present the results of testing the proposed profiling algorithm on simulated data obtained using large eddy simulations and 3D radiative transfer computations. The virtual RSP measurements were used for retrieval of DSD profiles, which then were compared to the actual data from the LES-model output. A cumulus congestus cloud was selected for these tests in preparation for analysis of real measurements made during the Cloud, Aerosol and Monsoon Processes Philippines Experiment (CAMP2Ex). We demonstrate that the use of the non-parametric Rainbow Fourier Transform (RFT) allows for adequate retrieval of the complex altitude-dependent bimodal structure of cloud DSDs.

Heat Shock Proteins Are Essential Components in Transformation and Tumor Progression: Cancer Cell Intrinsic Pathways and Beyond.

Heat shock protein (HSP) synthesis is switched on in a remarkably wide range of tumor cells, in both experimental animal systems and in human cancer, in which these proteins accumulate in high levels. In each case, elevated HSP concentrations bode ill for the patient, and are associated with a poor outlook in terms of survival in most cancer types. The significance of elevated HSPs is underpinned by their essential roles in mediating tumor cell intrinsic traits such as unscheduled cell division, escape from programmed cell death and senescence, de novo angiogenesis, and increased invasion and metastasis. An increased HSP expression thus seems essential for tumorigenesis. Perhaps of equal significance is the pronounced interplay between cancer cells and the tumor milieu, with essential roles for intracellular HSPs in the properties of the stromal cells, and their roles in programming malignant cells and in the release of HSPs from cancer cells to influence the behavior of the adjacent tumor and infiltrating the normal cells. These findings of a triple role for elevated HSP expression in tumorigenesis strongly support the targeting of HSPs in cancer, especially given the role of such stress proteins in resistance to conventional therapies.

Remote Sensing of Droplet Number Concentration in Warm Clouds: A Review of the Current State of Knowledge and Perspectives.

The cloud droplet number concentration (N d) is of central interest to improve the understanding of cloud physics and for quantifying the effective radiative forcing by aerosol-cloud interactions. Current standard satellite retrievals do not operationally provide N d, but it can be inferred from retrievals of cloud optical depth (τ c) cloud droplet effective radius (r e) and cloud top temperature. This review summarizes issues with this approach and quantifies uncertainties. A total relative uncertainty of 78% is inferred for pixel-level retrievals for relatively homogeneous, optically thick and unobscured stratiform clouds with favorable viewing geometry. The uncertainty is even greater if these conditions are not met. For averages over 1° ×1° regions the uncertainty is reduced to 54% assuming random errors for instrument uncertainties. In contrast, the few evaluation studies against reference in situ observations suggest much better accuracy with little variability in the bias. More such studies are required for a better error characterization. N d uncertainty is dominated by errors in r e, and therefore, improvements in r e retrievals would greatly improve the quality of the N d retrievals. Recommendations are made for how this might be achieved. Some existing N d data sets are compared and discussed, and best practices for the use of N d data from current passive instruments (e.g., filtering criteria) are recommended. Emerging alternative N d estimates are also considered. First, new ideas to use additional information from existing and upcoming spaceborne instruments are discussed, and second, approaches using high-quality ground-based observations are examined.

On the role of ice-nucleating aerosol in the formation of ice particles in tropical mesoscale convective systems.

Over decades, the cloud physics community has debated the nature and role of aerosol particles in ice initiation. The present study shows that the measured concentration of ice crystals in tropical mesoscale convective systems exceeds the concentration of ice nucleating particles (INPs) by several orders of magnitude. The concentration of INPs was assessed from the measured aerosol particles concentration in the size range of 0.5 to 1 µm. The observations from this study suggest that primary ice crystals formed on INPs make only a minor contribution to the total concentration of ice crystals in tropical mesoscale convective systems. This is found by comparing the predicted INP number concentrations with in-situ ice particle number concentrations. The obtained measurements suggest that ice multiplication is the likely explanation for the observed high concentrations of ice crystals in this type of convective system.

Vertical variation of ice particle size in convective cloud tops.

A novel technique is used to estimate derivatives of ice effective radius with respect to height near convective cloud tops (dre /dz) from airborne shortwave reflectance measurements and lidar. Values of dre /dz are about -6 µm/km for cloud tops below the homogeneous freezing level, increasing to near 0 µm/km above the estimated level of neutral buoyancy. Retrieved dre /dz compares well with previously documented remote sensing and in situ estimates. Effective radii decrease with increasing cloud top height, while cloud top extinction increases. This is consistent with weaker size sorting in high, dense cloud tops above the level of neutral buoyancy where fewer large particles are present, and with stronger size sorting in lower cloud tops that are less dense. The results also confirm that cloud-top trends of effective radius can generally be used as surrogates for trends with height within convective cloud tops. These results provide valuable observational targets for model evaluation.

Radiative flux and forcing parameterization error in aerosol-free clear skies.

Radiation parameterizations in GCMs are more accurate than their predecessorsErrors in estimates of 4 ×CO2 forcing are large, especially for solar radiationErrors depend on atmospheric state, so global mean error is unknown.

Monitoring of the Heat Shock Response with a Real-Time Luciferase Reporter.

The heat shock response (HSR) is a cellular mechanism for counteracting acute proteotoxic stress. In eukaryotes, transcriptional activation of the HSR is regulated by heat shock factor 1 (HSF1). Activation of HSF1 induces the expression of heat shock proteins (HSPs) that function as molecular chaperones to fold and maintain the three-dimensional structure of misfolded proteins. The regulation of the degree and duration of the HSR is controlled by multiple biochemical mechanisms that include posttranslational modification of HSF1 and numerous protein-protein interactions. In this chapter, we describe a method to evaluate the activation and deactivation of the HSR at the transcriptional level using a short half-life luciferase reporter assay. This assay can be used to further characterize the HSR or as a screen for small molecule inducers, amplifiers, or repressors.

High-Dimensional Contact Network Epidemiology.

Contact network models are recent alternatives to equation-based models in epidemiology. In this paper, the spread of disease is modeled on contact networks using bond percolation. The weight of the edges in the contact graphs is determined as a function of several variables in which case the weight is the product of the probabilities of independent events involving each of the variables. In the first experiment, the weight of the edges is computed from a single variable involving the number of passengers on flights between two cities within the United States, and in the second experiment, the weight of the edges is computed as a function of several variables using data from 2012 Kenyan household contact networks. In addition, the paper explored the dynamics and adaptive nature of contact networks. The results from the contact network model outperform the equation-based model in estimating the spread of the 1918 Influenza virus.

Quantifying the Value of the Molecular Tumor Board: Discordance Recommendation Rate and Drug Cost Avoidance.

PURPOSE: Molecular tumor boards (MTBs) provide interventions that assist the patient's primary oncologist's interpretation and application of precision oncology and avoid clinical and financial toxicities of prescribing inappropriate targeted therapy. In this article, we describe a novel method for illustrating MTBs value and recommendation discordance rate and report associated drug cost avoidance data. METHODS: From January 1, 2021, to December 31, 2021, patients assessed by our program's MTB were retrospectively evaluated. Recommendation discordance was defined as any disagreement between MTB therapeutic recommendations and those provided in the next-generation sequencing vendor's report. RESULTS: In 2021, our program processed 1,119 next-generation sequencing orders via external vendors for 1,029 unique patients with a variety of solid tumor and hematologic malignancies. During this period, 962 patients were reviewed through our MTB process. MTB recommendation discordance rate was high (229 of 502; 45.6%) and varied across test vendors. Rationales for discordance included the following: low level of evidence (88% of patients), alternative standard of care available (60%), and tolerability concerns (42%), among others. Discordance was highest for Vendor C (30%), followed by Vendor A (24%) and Vendor B (8%). The most common drug classes not supported were mTOR, PARP, MEK, and PIK3CA inhibitors when recommended by vendors in off-label settings. MTB interventions accounted for $3,209,070 in US dollars in potential drug cost avoidance. CONCLUSION: Therapeutic recommendation discordance rates can provide quantitative insight into the benefit of MTB. Discordance-associated drug cost avoidance further demonstrates MTB's financial value. These measures may be used as part of the justification for this service line within a cancer care program.

The impact of humidity above stratiform clouds on indirect aerosol climate forcing.

Some of the global warming from anthropogenic greenhouse gases is offset by increased reflection of solar radiation by clouds with smaller droplets that form in air polluted with aerosol particles that serve as cloud condensation nuclei. The resulting cooling tendency, termed the indirect aerosol forcing, is thought to be comparable in magnitude to the forcing by anthropogenic CO2, but it is difficult to estimate because the physical processes that determine global aerosol and cloud populations are poorly understood. Smaller cloud droplets not only reflect sunlight more effectively, but also inhibit precipitation, which is expected to result in increased cloud water. Such an increase in cloud water would result in even more reflective clouds, further increasing the indirect forcing. Marine boundary-layer clouds polluted by aerosol particles, however, are not generally observed to hold more water. Here we simulate stratocumulus clouds with a fluid dynamics model that includes detailed treatments of cloud microphysics and radiative transfer. Our simulations show that the response of cloud water to suppression of precipitation from increased droplet concentrations is determined by a competition between moistening from decreased surface precipitation and drying from increased entrainment of overlying air. Only when the overlying air is humid or droplet concentrations are very low does sufficient precipitation reach the surface to allow cloud water to increase with droplet concentrations. Otherwise, the response of cloud water to aerosol-induced suppression of precipitation is dominated by enhanced entrainment of overlying dry air. In this scenario, cloud water is reduced as droplet concentrations increase, which diminishes the indirect climate forcing.

HSF1: Primary Factor in Molecular Chaperone Expression and a Major Contributor to Cancer Morbidity.

Heat shock factor 1 (HSF1) is the primary component for initiation of the powerful heat shock response (HSR) in eukaryotes. The HSR is an evolutionarily conserved mechanism for responding to proteotoxic stress and involves the rapid expression of heat shock protein (HSP) molecular chaperones that promote cell viability by facilitating proteostasis. HSF1 activity is amplified in many tumor contexts in a manner that resembles a chronic state of stress, characterized by high levels of HSP gene expression as well as HSF1-mediated non-HSP gene regulation. HSF1 and its gene targets are essential for tumorigenesis across several experimental tumor models, and facilitate metastatic and resistant properties within cancer cells. Recent studies have suggested the significant potential of HSF1 as a therapeutic target and have motivated research efforts to understand the mechanisms of HSF1 regulation and develop methods for pharmacological intervention. We review what is currently known regarding the contribution of HSF1 activity to cancer pathology, its regulation and expression across human cancers, and strategies to target HSF1 for cancer therapy.

GISS-E2.1: Configurations and Climatology.

This paper describes the GISS-E2.1 contribution to the Coupled Model Intercomparison Project, Phase 6 (CMIP6). This model version differs from the predecessor model (GISS-E2) chiefly due to parameterization improvements to the atmospheric and ocean model components, while keeping atmospheric resolution the same. Model skill when compared to modern era climatologies is significantly higher than in previous versions. Additionally, updates in forcings have a material impact on the results. In particular, there have been specific improvements in representations of modes of variability (such as the Madden-Julian Oscillation and other modes in the Pacific) and significant improvements in the simulation of the climate of the Southern Oceans, including sea ice. The effective climate sensitivity to 2 × CO2 is slightly higher than previously at 2.7-3.1°C (depending on version) and is a result of lower CO2 radiative forcing and stronger positive feedbacks.

Persistent Supercooled Drizzle at Temperatures below -25°C Observed at McMurdo Station, Antarctica.

The rarity of reports in the literature of brief and spatially limited observations of drizzle at temperatures below -20°C suggest that riming and other temperature-dependent cloud microphysical processes such as heterogeneous ice nucleation and ice crystal depositional growth prevent drizzle persistence in cold environments. In this study, we report on a persistent drizzle event observed by ground-based remote-sensing measurements at McMurdo Station, Antarctica. The temperatures in the drizzle-producing cloud were below -25°C and the drizzle persisted for a period exceeding 7.5 hours. Using ground-based, satellite, and reanalysis data we conclude that drizzle was likely present in parts of a widespread cloud field, which stretched more than ~1000 km along the Ross Ice Shelf coast. Parameter space sensitivity tests using two-moment bulk microphysics in large-eddy simulations constrained by the observations suggest that activated ice freezing nuclei (IFN) and accumulation-mode aerosol number concentrations aloft during this persistent drizzle period were likely on the order of 0.2 L-1 and 20 cm-3, respectively. In such constrained simulations, the drizzle moisture flux through cloud base exceeds that of ice. The simulations also indicate that drizzle can lead to the formation of multiple peaks in cloud water content profiles. This study suggests that persistent drizzle at these low temperatures may be common at the low aerosol concentrations typical of the Antarctic and Southern Ocean atmospheres.

Application of Urinary Volatile Organic Compounds (VOCs) for the Diagnosis of Prostate Cancer.

BACKGROUND: Prostate cancer (PCa) screening using serum prostate-specific antigen (PSA) testing has caused unnecessary biopsies and overdiagnosis owing to its low accuracy and reliability. Therefore, there is an increased interest in identifying better PCa biomarkers. Studies showed that trained dogs can discriminate patients with PCa from unaffected men by sniffing urine. We hypothesized that urinary volatile organic compounds (VOCs) may be the source of that odor and could be used to develop urinary VOC PCa diagnosis models. PATIENTS AND METHODS: Urine samples from 55 and 53 biopsy proven PCa-positive and -negative patients respectively were initially obtained for diagnostic model development. Urinary metabolites were analyzed by gas chromatography-mass spectrometry. A PCa diagnosis model was developed and validated using innovative statistical machine-learning techniques. A second set of samples (53 PCa-positive and 22 PCa-negative patients) were used to evaluate the previously developed PCa diagnosis model. RESULTS: The analysis resulted in 254 and 282 VOCs for their significant association (P < .05) with either PCa-positive or -negative samples respectively. Regularized logistic regression analysis and the Firth method were then applied to predict PCa prevalence, resulting in a final model that contains 11 VOCs. Under cross-validation, the area under the receiver operating characteristic curve (AUC) for the final model was 0.92 (sensitivity, 0.96; specificity, 0.80). Further evaluation of the developed model using a testing cohort yielded an AUC of 0.86. As a comparison, the PSA-based diagnosis model only rendered an AUC of 0.54. CONCLUSION: The study describes the development of a urinary VOC-based model for PCa detection.

Simulation of mesoscale cellular convection in marine stratocumulus.: Part I: Drizzling conditions.

This study uses eddy-permitting simulations to investigate the mechanisms that promote mesoscale variability of moisture in drizzling stratocumulus-topped marine boundary layers. Simulations show that precipitation tends to increase horizontal scales. Analysis of terms in the prognostic equation for total water mixing ratio variance indicates that moisture stratification plays a leading role in setting horizontal scales. This result is supported by simulations in which horizontal mean thermodynamic profiles are strongly nudged to their initial well-mixed state, which limits cloud scales. It is found that the spatial variability of sub-cloud moist cold pools surprisingly tends to respond to, rather than determine, the mesoscale variability, which may distinguish them from dry cold pools associated with deeper convection. Simulations also indicate that moisture stratification increases cloud scales specifically by increasing latent heating within updrafts, which increases updraft buoyancy and favors greater horizontal scales.

Dual targeting of HSP70 does not induce the heat shock response and synergistically reduces cell viability in muscle invasive bladder cancer.

Muscle invasive bladder cancer (MIBC) is a common malignancy and major cause of morbidity worldwide. Over the last decade mortality rates for MIBC have not decreased as compared to other cancers indicating a need for novel strategies. The molecular chaperones HSP70 and HSP90 fold and maintain the 3-dimensional structures of numerous client proteins that signal for cancer cell growth and survival. Inhibition of HSP70 or HSP90 results in client protein degradation and associated oncogenic signaling. Here we targeted HSP70 and HSP90 with small molecule inhibitors that trap or block each chaperone in a low client-affinity "open" conformation. HSP70 inhibitors, VER155008 (VER) and MAL3-101 (MAL), along with HSP90 inhibitor, STA-9090 (STA), were tested alone and in combination for their ability to reduce cell viability and alter protein levels in 4 MIBC cell lines. When combined, VER+MAL synergistically reduced cell viability in each MIBC cell line while not inducing expression of heat shock proteins (HSPs). STA+MAL also synergistically reduced cell viability in each cell line but induced expression of cytoprotective HSPs indicating the merits of targeting HSP70 with VER+MAL. Additionally, we observed that STA induced the expression of the stress-related transcription factor HSF2 while reducing levels of the co-chaperone TTI1.

Effects of environmental features and sport hunting on caribou migration in northwestern Alaska.

BACKGROUND: Ungulate movements are influenced by a variety of biotic and abiotic factors, which may affect connectivity between key resource areas and seasonal ranges. In northwestern Alaska, one important question regarding human impacts on ungulate movement involves caribou (Rangifer tarandus) response to autumn hunting and related aircraft activity. While concerns have been voiced by local hunters about the influence of transporter aircraft and non-local sport hunters, there has been little quantitative analysis of the effects of hunter activity on caribou movement. We utilized a novel spatial dataset of commercial aircraft landing locations and sport hunter camps in and around Noatak National Preserve to analyze resource selection of caribou in autumn for non-local hunting activity and environmental features. We combined step selection functions with randomized shortest paths to investigate whether terrain ruggedness, river width, land cover, and hunting activity (in the form of aircraft landings and sport hunter camps) facilitated or impeded caribou movement. By varying a parameter in the randomized shortest path models, we also explored the tradeoff between exploration and exploitation in movement behavior exhibited by traveling caribou. RESULTS: We found that caribou avoided rugged terrain and areas with more river, forest, and tall shrubs while selecting for areas dominated by tussock tundra and dwarf shrubs. Migration of caribou through Noatak does not appear to be inhibited by sport hunting activity, though this does not preclude the possibility of temporary effects altering availability of caribou for individual hunters. Caribou exhibited exploratory movement, following predictions of a random walk model. This behavior may facilitate the location of remaining patches of high-quality forage prior to the onset of winter, especially during mild autumns. CONCLUSIONS: Understanding animal movement behavior is fundamental to protecting critical areas of connectivity and to informing management decisions. Our study identifies migratory connectivity and hotspots of potential conflict among user groups, enabling development of policies that balance human access with species conservation.

Imaging for spine tumors and new applications.

OBJECTIVES: Discuss intramedullary, intradural/extramedullary, and extradural spinal tumors including imaging characteristics with emphasis on MR and advances in treatment. METHODS: Literature and institutional review. RESULTS: Spinal tumors: intramedullary, intradural/extramedullary, and extradural, comprise a wide range of histological tumors with an even wider range of clinical symptoms and prognostic features. They are relatively rare and if left untreated, can cause serious neurological deficits and disability. An accurate diagnosis is therefore crucial in determining prognosis and directing therapy. Magnetic resonance imaging (MRI) has revolutionized the diagnosis of intraspinal tumors, allowing for early detection and improved anatomical localization. Magnetic resonance has also become an integral part in staging of both primary and metastatic neoplasms of the spine for guiding therapy and is an excellent modality for follow-up. Advances in MRI (perfusion and molecular imaging) may help refine and describe these neoplasms for accurate treatment and prognosis in the future. Surveillance protocols and role of magnetic resonance are not well established. CONCLUSIONS: Magnetic resonance plays an integral role in evaluation of spinal tumors with increasing role in staging and treatment.

On averaging aspect ratios and distortion parameters over ice crystal population ensembles for estimating effective scattering asymmetry parameters.

The use of ensemble-average values of aspect ratio and distortion parameter of hexagonal ice prisms for the estimation of ensemble-average scattering asymmetry parameters is evaluated. Using crystal aspect ratios greater than unity generally leads to ensemble-average values of aspect ratio that are inconsistent with the ensemble-average asymmetry parameters. When a definition of aspect ratio is used that limits the aspect ratio to below unity (α≤1) for both hexagonal plates and columns, the effective asymmetry parameters calculated using ensemble-average aspect ratios are generally consistent with ensemble-average asymmetry parameters, especially if aspect ratios are geometrically averaged. Ensemble-average distortion parameters generally also yield effective asymmetry parameters that are largely consistent with ensemble-average asymmetry parameters. In the case of mixtures of plates and columns, it is recommended to geometrically average the α≤1 aspect ratios and to subsequently calculate the effective asymmetry parameter using a column or plate geometry when the contribution by columns to a given mixture's total projected area is greater or lower than 50%, respectively. In addition, we show that ensemble-average aspect ratios, distortion parameters and asymmetry parameters can generally be retrieved accurately from simulated multi-directional polarization measurements based on mixtures of varying columns and plates. However, such retrievals tend to be somewhat biased toward yielding column-like aspect ratios. Furthermore, generally large retrieval errors can occur for mixtures with approximately equal contributions of columns and plates and for ensembles with strong contributions of thin plates.