Transmission efficiency is a critical factor determining the size of an outbreak of infectious disease. Indeed, the propensity of SARS-CoV-2 to transmit among humans precipitated and continues to ...sustain the COVID-19 pandemic. Nevertheless, the number of new cases among contacts is highly variable and underlying reasons for wide-ranging transmission outcomes remain unclear. Here, we evaluated viral spread in golden Syrian hamsters to define the impact of temporal and environmental conditions on the efficiency of SARS-CoV-2 transmission through the air. Our data show that exposure periods as brief as one hour are sufficient to support robust transmission. However, the timing after infection is critical for transmission success, with the highest frequency of transmission to contacts occurring at times of peak viral load in the donor animals. Relative humidity and temperature had no detectable impact on transmission when exposures were carried out with optimal timing and high inoculation dose. However, contrary to expectation, trends observed with sub-optimal exposure timing and lower inoculation dose suggest improved transmission at high relative humidity or high temperature. In sum, among the conditions tested, our data reveal the timing of exposure to be the strongest determinant of SARS-CoV-2 transmission success and implicate viral load as an important driver of transmission.
Cardiovascular disorders are the major cause of mortality in patients of diabetes mellitus. Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors of nuclear ...hormone receptor superfamily comprising of three subtypes such as PPARα, PPARγ and PPARδ/β. Activation of PPARα reduces triglycerides and involves in regulation of energy homeostasis. Activation of PPARγ causes insulin sensitization and enhances glucose metabolism, whereas activation of PPARδ enhances fatty acid metabolism. Current therapeutic strategies available for the treatment of diabetes do not inhibit the associated secondary cardiovascular complications. Hence, the development of multimodal drugs which can reduce hyperglycemia and concomitantly inhibit the progression of secondary cardiovascular complications may offer valuable therapeutic option. Several basic and clinical studies have exemplified the beneficial effects of PPARα and PPARγ ligands in preventing the cardiovascular risks. The PPARα/γ dual agonists are developed to increase insulin sensitivity and simultaneously prevent diabetic cardiovascular complications. Such compounds are under clinical trials and proposed for treatment of Type II diabetes with secondary cardiovascular complications. However, PPARα/γ dual agonists such as muraglitazar, tesaglitazar and ragaglitazar have been noted to produce several cardiovascular risks and carcinogenicity, which raised number of questions about the clinical applications of dual agonists in diabetes and its associated complications. The ongoing basic studies have elucidated the cardio protective role of PPARδ. Therefore, further studies are on the track to develop PPARα/δ and PPAR γ/δ dual agonists and PPARα/γ/δ pan agonists for the treatment of diabetic cardiovascular complications. The present review critically analyzes the protective and detrimental effect of PPAR agonists in diabetic cardiovascular complications. Moreover, the newly developed PPARα/δ and PPAR γ/δ dual agonists and PPARα/γ/δ pan agonists have also been discussed which may open a new vista in the management of diabetic cardiovascular complications in near future.
The PACIFIC trial demonstrated improved survival in patients with unresectable stage III non-small cell lung cancer (NSCLC) treated with durvalumab following definitive concurrent chemoradiotherapy ...(CRT). This study sought to explore real-world outcomes with durvalumab consolidation therapy at our institution.
We retrospectively identified patients diagnosed with stage III NSCLC at our institution from January 2012 to January 2022. We created two cohorts: one who received durvalumab following definitive CRT and a historical one who did not. Primary outcomes of interest included median progression-free survival (PFS) and overall survival (OS). Additionally, we performed subgroup analysis on the durvalumab cohort to explore the associations between survival and time to durvalumab initiation, PD-L1 expression, and neutrophil-to-lymphocyte ratio (NLR).
We identified 79 patients with locally advanced NSCLC who were not surgical candidates. Patients treated with durvalumab (n=44) had significantly improved survival compared to the historical cohort (n=35) including a median PFS of 17.4 months versus 8.0 months (p=0.0019) and a median OS of 37.0 months versus 17.0 months (log-rank p-value=0.07, Wilcoxon p-value=0.02). Within the durvalumab group, outcomes did not significantly differ between those who initiated therapy before or after 42 days of finishing CRT, between various PD-L1 expression levels, or between high or low NLR.
Patients who received durvalumab as consolidation therapy following definitive CRT demonstrated significantly improved survival compared to a historical cohort who did not receive durvalumab. Furthermore, durvalumab appears to benefit patients regardless of time to initiation, PD-L1 expression, or NLR.
A Silurian shift in fluvial stratigraphic architecture, coincident with the appearance of terrestrial vegetation in the fossil record, is traditionally cited as evidence for exclusively shallow, ...braided planforms in pre‐vegetation rivers. While recent recognition of deep, single‐thread channels in pre‐Silurian strata challenge this paradigm, it is unclear how these rivers maintained stable banks. Here, we reconstruct paleohydraulics and channel planform from fluvial cross‐strata of the 1.2 Ga Stoer Group. These deposits are consistent with deep (4–7 m), low‐sloping rivers (2.7 × 10−4 to 4.5 × 10−5), similar in morphometry to modern single‐thread rivers. We show that reconstructed bank shear stresses approximate the cohesion provided by sand‐mud mixtures with 30%–45% mud—consistent with Stoer floodplain facies composition. These results indicate that sediment cohesion from mud alone could have fostered deep, single‐thread, pre‐vegetation rivers. We suggest that the Silurian stratigraphic shift could mark a kinematic change in channel migration rate rather than a diversification of planform.
Plain Language Summary
The earliest appearance of rooted plant fossils coincides with widespread evidence of meandering rivers in the geologic record. This correlation has led researchers to suggest that meandering rivers only existed on our planet since terrestrial plants colonized the continents, and that pre‐vegetation rivers were predominantly characterized by shallow and multi‐thread channels. While there is growing evidence of deep, single‐thread rivers predating the rise of land plants, it is currently unclear how these rivers maintained stable banks. Here, we combine observations of 1.2‐billion‐year‐old river sediments in NW Scotland with mechanistic theories of river dune formation to constrain the geometry of pre‐vegetation rivers. We show that our field observations are consistent with deposition by deep, low‐sloping, and single‐thread rivers, whose reconstructed geometry is similar to modern‐day meandering, rather than braided, rivers. We also demonstrate that the mud fraction of the floodplain sediment could have provided sufficient cohesion to resist erosional forces in deep, low‐sloping rivers. Together, our results indicate that single‐thread rivers could have been prevalent before the rise of land plants, and that mud can provide sufficient bank strength for the development of deep rivers.
Key Points
Quantitative paleohydraulic tools indicate that deep, low‐sloping rivers were characteristic of 1.2 Ga Stoer Group
Paleohydraulic data plot in the single‐thread river planform regime in mechanistic frameworks for discriminating channel planform
Field observations and theory indicate that the mud in bank sediments can provide sufficient cohesion to maintain deep flows
Due to its high homologous temperature (0.4
-
0.8
T
m
), isothermal aging of Sn3.0Ag0.5Cu solder alloy causes microstructural changes that significantly affect its observed macroscopic creep ...behavior. In order to characterize such changes in mechanical behavior of the macroscale solder joint, a stereological description of the microstructural changes due to aging is needed. The microstructure of the as-reflowed solder joint mainly consists of primary Sn dendrites surrounded by a eutectic microconstituent consisting of Sn, Ag
3
Sn, and Cu
6
Sn
5
phases. Upon aging, the microstructure evolves with the growth of the Ag
3
Sn precipitates within the eutectic microconstituent and change in relative volume fractions of dendritic and eutectic regions. In this study, microstructural changes that occur in Ag
3
Sn precipitate during aging at temperatures of 25°C, 75°C, and 125°C are monitored for various aging times ranging from 1 to 90 days by employing areal and lineal analysis stereological techniques. The Ag
3
Sn precipitates are treated as oblate spheroids in shape and their size distributions for all microstructures are determined on the basis of Saltykov–DeHoff analysis. The various microstructures are characterized in terms of Sn dendrite cell size and Ag
3
Sn particle size. The importance of the developed stereological model for microstructurally adaptive creep modeling is finally discussed.
Background Patients with congenital heart disease (CHD) are at risk for the development of low cardiac output and other physiologic derangements, which could be detected early through continuous ...stroke volume (SV) measurement. Unfortunately, existing SV measurement methods are limited in the clinic because of their invasiveness (eg, thermodilution), location (eg, cardiac magnetic resonance imaging), or unreliability (eg, bioimpedance). Multimodal wearable sensing, leveraging the seismocardiogram, a sternal vibration signal associated with cardiomechanical activity, offers a means to monitoring SV conveniently, affordably, and continuously. However, it has not been evaluated in a population with significant anatomical and physiological differences (ie, children with CHD) or compared against a true gold standard (ie, cardiac magnetic resonance). Here, we present the feasibility of wearable estimation of SV in a diverse CHD population (N=45 patients). Methods and Results We used our chest-worn wearable biosensor to measure baseline ECG and seismocardiogram signals from patients with CHD before and after their routine cardiovascular magnetic resonance imaging, and derived features from the measured signals, predominantly systolic time intervals, to estimate SV using ridge regression. Wearable signal features achieved acceptable SV estimation (28% error with respect to cardiovascular magnetic resonance imaging) in a held-out test set, per cardiac output measurement guidelines, with a root-mean-square error of 11.48 mL and
of 0.76. Additionally, we observed that using a combination of electrical and cardiomechanical features surpassed the performance of either modality alone. Conclusions A convenient wearable biosensor that estimates SV enables remote monitoring of cardiac function and may potentially help identify decompensation in patients with CHD.
The current COVID-19 pandemic highlights the critical importance of ubiquitous respiratory health monitoring. The two fundamental elements of monitoring respiration are respiration rate (the ...frequency of breathing) and tidal volume (TV, the volume of air breathed by the lungs in each breath). Wearable sensing systems have been demonstrated to provide accurate measurement of respiration rate, but TV remains challenging to measure accurately with wearable and unobtrusive technology. In this work, we leveraged electrocardiogram (ECG) and seismocardiogram (SCG) measurements obtained with a custom wearable sensing patch to derive an estimate of TV from healthy human participants. Specifically, we fused both ECG-derived and SCG-derived respiratory signals (EDR and SDR) and trained a machine learning model with gas rebreathing as the ground truth to estimate TV. The respiration cycle modulates ECG and SCG signals in multiple different ways that are synergistic. Thus, here we extract EDRs and SDRs using a multitude of different demodulation techniques. The extracted features are used to train a subject independent machine learning model to accurately estimate TV. By fusing the extracted EDRs and SDRs, we were able to estimate the TV with a root-mean-square error (RMSE) of 181.45 mL and Pearson correlation coefficient (r) of 0.61, with a global subject-independent model. We further show that SDRs are better TV estimators than EDRs. Among SDRs, amplitude modulated (AM) SCG features are the most correlated to TV. We demonstrated that fusing EDRs and SDRs can result in moderately accurate estimation of TV using a subject-independent model. Additionally, we highlight the most informative features for estimating TV. This work presents a significant step towards achieving continuous, calibration free, and unobtrusive TV estimation, which could advance the state of the art in wearable respiratory monitoring.
We consider a two-hop cellular system in which the mobile nodes help the base station by relaying information to the dead spots. While two-hop cellular schemes have been analyzed previously, the ...distribution of the node locations has not been explicitly taken into account. In this paper, we model the base station locations deterministically and the mobile stations by a point process on the plane. The node with the best channel to the destination that received information in the first hop acts as a relay to the destination (selection cooperation), and we obtain the success probability of this two-hop scheme, accounting for the interference from all other cells. We use tools from stochastic geometry and point process theory to analyze this two-hop opportunistic relaying scheme. Besides the results obtained, a main contribution of the paper is to introduce a mathematical framework that can be used to analyze arbitrary relaying schemes.
In contrast to other cancers, survival rates for pancreatic ductal adenocarcinoma (PDAC) patients have improved but minimally over the past thirty years. The aim of this study was to perform a ...meta-analysis of clinical trials published since 1986 to determine trends in median overall survival in primarily metastatic PDAC.
All Phase 2-4 clinical trials published during or after 1986 investigating first-line systemic chemotherapy in metastatic PDAC were included in the meta-analysis. Publications obtained through PubMed and www.ClinicalTrials.gov were cross-referenced to identify additional trials. Trials enrolling fewer than 50% of study participants with metastatic disease were excluded.
Of 19,488 patients enrolled in 151 clinical trials, 84% had metastatic disease and 16% had locally advanced pancreatic cancer. In clinical trials published from 1986 to 2016, the weighted median overall survival (wMOS) increased by 3.0 months. The median wMOS was higher in combination therapy (7.31 months, IQR 5.4 to 8.5) compared to non-gemcitabine, single-agent therapy (4.76 months, IQR 3.5 to 6.0), gemcitabine monotherapy (6.48 months, IQR 5.9 to 7.2), and gemcitabine plus single-agent therapy (7.09 months, IQR 6.3 to 8.2). Of all regimens used in more than one study arm, FOLFIRINOX had the highest wMOS (10.9 months).
Regardless of treatment regimen, survival rates in PDAC have minimally improved over time. Of drugs used in two or more study arms, only FOLFIRINOX has a wMOS greater than ten months. Emphasis should, therefore, be placed on identification of novel targets that promote early diagnosis and intervention.
The authors on this manuscript are in parts, supported by grants from the National Institutes of Health (EDRN U01 CA200466, SPORE P50 CA127297, R01 CA183459, R21 AA026428 and R01 CA 195586).
The purposes of this study were to provide a case-based overview of various immune-mediated side effects detected by 18F-Fluorodeoxyglucose (F-18 FDG) positron emission tomography-computed tomography ...(PET-CT) in the patients receiving ipilimumab immunotherapy for treatment of malignant melanoma, and discuss the importance of recognizing immune-mediated side effects in the use of F-18 FDG PET-CT for monitoring therapeutic effects of ipilimumab on metastatic melanoma.
This is a retrospective case series study of the patients diagnosed with melanoma who were subjected to immunomodulating therapy with ipilimumab. F-18 FDG PET-CT findings were reviewed, and the patients with immune-mediated side effects were selected for further analysis, in conjunction with review of clinical progress notes, the results of laboratory tests, and findings of other imaging tests.
Four patients with immune-mediated side effects were identified among the patients being treated with ipilimumab and subjected to F-18 FDG PET-CT for monitoring therapeutic effects. These immune mediated side effects include new findings of abnormal increased FDG uptake associated with immune-mediated pancreatitis and hypophysitis, as well as immune-mediated thyroiditis and colitis reported previously.
Various immune-mediated side effects were detected by F-18 FDG PET-CT in the patients subjected to immunomodulating therapy with ipilimumab. It is essential for the interpreting provider to recognize and differentiate abnormal FDG uptake associated with immune-mediated side effects from hypermetabolic malignant lesions when using F-18 FDG PET-CT for monitoring therapeutic effects of ipilimumab on melanoma lesions.
PDF
