The effect of treatment on pathogen virulence.

The optimal virulence of a pathogen is determined by a trade-off between maximizing the rate of transmission and maximizing the duration of infectivity. Treatment measures such as curative therapy and case isolation exert selective pressure by reducing the duration of infectivity, reducing the value of duration-increasing strategies to the pathogen and favoring pathogen strategies that maximize the rate of transmission. We extend the trade-off models of previous authors, and represents the reproduction number of the pathogen as a function of the transmissibility, host contact rate, disease-induced mortality, recovery rate, and treatment rate, each of which may be influenced by the virulence. We find that when virulence is subject to a transmissibility-mortality trade-off, treatment can lead to an increase in optimal virulence, but that in other scenarios (such as the activity-recovery trade-off) treatment decreases the optimal virulence. Paradoxically, when levels of treatment rise with pathogen virulence, increasing control efforts may raise predicted levels of optimal virulence. Thus we show that conflict can arise between the epidemiological benefits of treatment and the evolutionary risks of heightened virulence

Pain Experiences and Their Relation to Opioid Misuse Risk and Emotion Dysregulation

Pain is a complex, multidimensional experience but often is measured as a unidimensional experience. This study aimed to separately assess the sensory and affective components of pain and identify their relations to important pain-related outcomes, particularly in terms of opioid misuse risk and emotion dysregulation among patients with chronic pain receiving treatment in Appalachia. Two hundred and twelve patients presenting to a multidisciplinary pain center completed the Difficulties in Emotion Regulation Scale (DERS-18), Screener and Opioid Assessment for Patients with Pain—Revised (SOAPP-R), and short-form McGill Pain Questionnaire (SF-MPQ). The sensory experience of pain was unrelated to emotion dysregulation (r = 0.06, p = 0.57) and weakly related to opioid misuse risk (r = 0.182, p \u3c 0.05). In contrast, the affective experience of pain was moderately related to emotion dysregulation (r = 0.217, p \u3c 0.05) and strongly related to opioid misuse risk (r = 0.37, p \u3c 0.01). In addition, emotion dysregulation predicted variance in opioid misuse risk above and beyond the affective and sensory experiences of pain ((b = 0.693, p \u3c 0.001). The results suggest patients with a strong affective experience versus sensory experience of pain and challenges with emotion regulation may require a more comprehensive intervention to address these underlying components in order to reduce their risk of misusing opioid medications

Epirubicin With Cyclophosphamide Followed by Docetaxel With Trastuzumab and Bevacizumab as Neoadjuvant Therapy for HER2-Positive Locally Advanced Breast Cancer or as Adjuvant Therapy for HER2-Positive Pathologic Stage III Breast Cancer: A Phase II Trial of the NSABP Foundation Research Group, FB-5

Background The purpose of this study was to determine the cardiac safety and clinical activity of trastuzumab and bevacizumab with docetaxel after epirubicin with cyclophosphamide (EC) in patients with HER2-positive locally advanced breast cancer (LABC) or pathologic stage 3 breast cancer (PS3BC). Patients and Methods Patients received every 3 week treatment with 4 cycles of EC (90/600 mg/m2) followed by 4 cycles of docetaxel (100 mg/m2). Targeted therapy with standard-dose trastuzumab with bevacizumab 15 mg/kg was given for a total of 1 year. Coprimary end points were (1) rate of cardiac events (CEs) in all patients defined as clinical congestive heart failure with a significant decrease in left ventricular ejection fraction or cardiac deaths; and (2) pathologic complete response (pCR) in breast and nodes in the neoadjuvant cohort. An independent cardiac review panel determined whether criteria for a CE were met. Results A total of 105 patients were accrued, 76 with LABC treated with neoadjuvant therapy and 29 with PS3BC treated with adjuvant therapy. Median follow-up was 59.2 months. Among 99 evaluable patients for cardiac safety, 4 (4%; 95% confidence interval [CI], 1.1%-10.0%) met CE criteria. The pCR percentage in LABC patients was 46% (95% CI, 34%-59%). Five-year recurrence-free survival (RFS) and overall survival (OS) for all patients was 79.9% and 90.8%, respectively. Conclusion The regimen met predefined criteria for activity of interest with an acceptable rate of CEs. Although the pCR percentage was comparable with chemotherapy regimens with trastuzumab alone the high RFS and OS are of interest in these high-risk populations

YouthBuild Providence Sustainability Learning Center Design

Renee integrated coarse stucco and horizontal corrugated metal in white and black as a pattern signifying the major spaces. Over the entry and in the main construction space, she played with pattern in the curtain walls by replacing some glass panels with metal panels that are orange, the YouthBuild school color. The orange color is very prominent in the main entry and the construction facility, emphasizing the importance of construction to the YouthBuild philosophy

Coinfections by noninteracting pathogens are not independent and require new tests of interaction.

If pathogen species, strains, or clones do not interact, intuition suggests the proportion of coinfected hosts should be the product of the individual prevalences. Independence consequently underpins the wide range of methods for detecting pathogen interactions from cross-sectional survey data. However, the very simplest of epidemiological models challenge the underlying assumption of statistical independence. Even if pathogens do not interact, death of coinfected hosts causes net prevalences of individual pathogens to decrease simultaneously. The induced positive correlation between prevalences means the proportion of coinfected hosts is expected to be higher than multiplication would suggest. By modelling the dynamics of multiple noninteracting pathogens causing chronic infections, we develop a pair of novel tests of interaction that properly account for nonindependence between pathogens causing lifelong infection. Our tests allow us to reinterpret data from previous studies including pathogens of humans, plants, and animals. Our work demonstrates how methods to identify interactions between pathogens can be updated using simple epidemic models

Dimerization of functional pyrroloindolizines for the synthesis of complex myrmicarin alkaloids

The union of functionalized pyrroloindolizines for the synthesis of heterodimeric products relevant to myrmicarin alkaloids is described. Design and synthesis of tricyclic substrates and new methods for their union enable the investigation of late-stage cyclopentannulation strategies. The rapid assembly of dimeric structures using unique modes of pyrroloindolizine reactivity presents a concise approach to the dimeric myrmicarins and relevant derivatives.National Institutes of Health (U.S.) (NIH-NIGMS (GM074825))Alfred P. Sloan Foundation (Research Fellowship)Henry & Camille Dreyfus Foundation (Teacher-Scholar)Novartis (Firm) (Graduate Fellowship

Bimodal dynamics of granular organelles in primary renin-expressing cells revealed using TIRF microscopy

Renin is the initiator and rate-limiting factor in the renin-angiotensin blood pressure regulation system. Although renin is not exclusively produced in the kidney, in nonmurine species the synthesis and secretion of the active circulatory enzyme is confined almost exclusively to the dense core granules of juxtaglomerular (JG) cells, where prorenin is processed and stored for release via a regulated pathway. Despite its importance, the structural organization and regulation of granules within these cells is not well understood, in part due to the difficulty in culturing primary JG cells in vitro and the lack of appropriate cell lines. We have streamlined the isolation and culture of primary renin-expressing cells suitable for high-speed, high-resolution live imaging using a Percoll gradient-based procedure to purify cells from RenGFP+ transgenic mice. Fibronectin-coated glass coverslips proved optimal for the adhesion of renin-expressing cells and facilitated live cell imaging at the plasma membrane of primary renin cells using total internal reflection fluorescence microscopy (TIRFM). To obtain quantitative data on intracellular function, we stained mixed granule and lysosome populations with Lysotracker Red and stimulated cells using 100 nM isoproterenol. Analysis of membrane-proximal acidic granular organelle dynamics and behavior within renin-expressing cells revealed the existence of two populations of granular organelles with distinct functional responses following isoproterenol stimulation. The application of high-resolution techniques for imaging JG and other specialized kidney cells provides new opportunities for investigating renal cell biology

Empirical Evidence for the Effect of Airline Travel on Inter-Regional Influenza Spread in the United States

BACKGROUND: The influence of air travel on influenza spread has been the subject of numerous investigations using simulation, but very little empirical evidence has been provided. Understanding the role of airline travel in large-scale influenza spread is especially important given the mounting threat of an influenza pandemic. Several recent simulation studies have concluded that air travel restrictions may not have a significant impact on the course of a pandemic. Here, we assess, with empirical data, the role of airline volume on the yearly inter-regional spread of influenza in the United States. METHODS AND FINDINGS: We measured rate of inter-regional spread and timing of influenza in the United States for nine seasons, from 1996 to 2005 using weekly influenza and pneumonia mortality from the Centers for Disease Control and Prevention. Seasonality was characterized by band-pass filtering. We found that domestic airline travel volume in November (mostly surrounding the Thanksgiving holiday) predicts the rate of influenza spread (r (2) = 0.60; p = 0.014). We also found that international airline travel influences the timing of influenza mortality (r (2) = 0.59; p = 0.016). The flight ban in the US after the terrorist attack on September 11, 2001, and the subsequent depression of the air travel market, provided a natural experiment for the evaluation of flight restrictions; the decrease in air travel was associated with a delayed and prolonged influenza season. CONCLUSIONS: We provide the first empirical evidence for the role of airline travel in long-range dissemination of influenza. Our results suggest an important influence of international air travel on the timing of influenza introduction, as well as an influence of domestic air travel on the rate of inter-regional influenza spread in the US. Pandemic preparedness strategies should account for a possible benefit of airline travel restrictions on influenza spread

Effects of Web-Based Self-Reporting: College Students’ Self-Efficacy Regarding Fruit and Vegetable Intake

This study evaluated the effect of an online diet-tracking tool on college students’ self-efficacy regarding fruit and vegetable intake. A convenience sample of students completed online self-efficacy surveys before and after a six-week intervention in which they tracked dietary intake with an online tool. Group one (n=22 fall, n=43 spring) accessed a tracking tool without nutrition tips; group two (n=20 fall, n=33 spring) accessed the tool and weekly nutrition tips. The control group (n=36 fall, n=60 spring) had access to neither. Each semester there were significant changes in self-efficacy from pre- to post-test for men and for women when experimental groups were combined (p<0.05 for all); however, these changes were inconsistent. Qualitative data showed that participants responded well to the simplicity of the tool, the immediacy of feedback, and the customized database containing foods available on campus. Future models should improve user engagement by increasing convenience, potentially by automation

Biomarkers of coagulation, endothelial function, and fibrinolysis in critically ill patients with COVID-19: A single-center prospective longitudinal study

Background: Immunothrombosis and coagulopathy in the lung microvasculature may lead to lung injury and disease progression in coronavirus disease 2019 (COVID-19). We aim to identify biomarkers of coagulation, endothelial function, and fibrinolysis that are associated with disease severity and may have prognostic potential. Methods: We performed a single-center prospective study of 14 adult COVID-19(+) intensive care unit patients who were age- and sex-matched to 14 COVID-19(−) intensive care unit patients, and healthy controls. Daily blood draws, clinical data, and patient characteristics were collected. Baseline values for 10 biomarkers of interest were compared between the three groups, and visualized using Fisher\u27s linear discriminant function. Linear repeated-measures mixed models were used to screen biomarkers for associations with mortality. Selected biomarkers were further explored and entered into an unsupervised longitudinal clustering machine learning algorithm to identify trends and targets that may be used for future predictive modelling efforts. Results: Elevated D-dimer was the strongest contributor in distinguishing COVID-19 status; however, D-dimer was not associated with survival. Variable selection identified clot lysis time, and antigen levels of soluble thrombomodulin (sTM), plasminogen activator inhibitor-1 (PAI-1), and plasminogen as biomarkers associated with death. Longitudinal multivariate k-means clustering on these biomarkers alone identified two clusters of COVID-19(+) patients: low (30%) and high (100%) mortality groups. Biomarker trajectories that characterized the high mortality cluster were higher clot lysis times (inhibited fibrinolysis), higher sTM and PAI-1 levels, and lower plasminogen levels. Conclusions: Longitudinal trajectories of clot lysis time, sTM, PAI-1, and plasminogen may have predictive ability for mortality in COVID-19