Abstract
Background
The incidence of pneumonic tularemia is very low; therefore, it is not feasible to conduct clinical efficacy testing of tularemia medical countermeasures (MCMs) in humans. The US ...Food and Drug Administration’s Animal Model Qualification Program under the Drug Development Tools Program is a regulatory pathway for animal models used in MCM efficacy testing and approval under the Animal Rule. The National Institute of Allergy and Infectious Diseases and Biomedical Advanced Research and Development Authority worked together to qualify the cynomolgus macaque model of pneumonic tularemia.
Methods
Using the model parameters and end points defined in the qualified model, efficacy of the antibiotics doxycycline and ciprofloxacin was evaluated in separate studies. Antibiotic administration, aimed to model approved human dosing, was initiated at time points of 24 hours or 48 hours after onset of fever as an indicator of disease.
Results
Upon aerosol exposure (target dose of 1000 colony-forming units) to Francisella tularensis SchuS4, 80% of vehicle-treated macaques succumbed or were euthanized. Ciprofloxacin treatment led to 10 of 10 animals surviving irrespective of treatment time. Doxycycline administered at 48 hours post-fever led to 10 of 10 animals surviving, while 9/10 animals survived in the group treated with doxycycline 24 hours after fever. Selected surviving animals in both the placebo and doxycycline 48-hour group showed residual live bacteria in peripheral tissues, while there were no bacteria in tissues from ciprofloxacin-treated macaques.
Conclusions
Both doxycycline and ciprofloxacin were efficacious in treatment of pneumonic tularemia, although clearance of bacteria may be different between the 2 drugs.
This article conceptualizes and presents a research agenda for the emerging area of transformative service research, which lies at the intersection of service research and transformative consumer ...research and focuses on well-being outcomes related to service and services. A conceptual framework provides a big-picture view of how the interaction between service entities (e.g., individual service employees, service processes or offerings, organizations) and consumer entities (e.g., individuals, collectives such as families or communities, the ecosystem) influences the well-being outcomes of both. Research questions derived from the framework in the context of financial services, health care, and social services help catalyze new research in the transformative service research domain.
Attributes and predictors of long COVID Sudre, Carole H; Murray, Benjamin; Varsavsky, Thomas ...
Nature Medicine,
04/2021, Volume:
27, Issue:
4
Journal Article, Magazine Article
Peer reviewed
Open access
Reports of long-lasting coronavirus disease 2019 (COVID-19) symptoms, the so-called 'long COVID', are rising but little is known about prevalence, risk factors or whether it is possible to predict a ...protracted course early in the disease. We analyzed data from 4,182 incident cases of COVID-19 in which individuals self-reported their symptoms prospectively in the COVID Symptom Study app
. A total of 558 (13.3%) participants reported symptoms lasting ≥28 days, 189 (4.5%) for ≥8 weeks and 95 (2.3%) for ≥12 weeks. Long COVID was characterized by symptoms of fatigue, headache, dyspnea and anosmia and was more likely with increasing age and body mass index and female sex. Experiencing more than five symptoms during the first week of illness was associated with long COVID (odds ratio = 3.53 (2.76-4.50)). A simple model to distinguish between short COVID and long COVID at 7 days (total sample size, n = 2,149) showed an area under the curve of the receiver operating characteristic curve of 76%, with replication in an independent sample of 2,472 individuals who were positive for severe acute respiratory syndrome coronavirus 2. This model could be used to identify individuals at risk of long COVID for trials of prevention or treatment and to plan education and rehabilitation services.
Background Continued donor organ shortage and improved outcomes with current left ventricular assist device (LVAD) technology have increased the number of patients supported with ...bridge-to-transplantation (BTT) therapy. Using the United Network of Organ Sharing (UNOS) database, we assessed the impact on survival in patients supported with BTT while on the heart transplant waiting list. Methods The UNOS database was queried from January 2005 to June 2012 to identify patients listed for heart transplantation as UNOS status 1A or 1B. Patients implanted with a pulsatile-flow device or an LVAD other than the HeartMate II (HM II; Thoratec Inc, Pleasanton, CA) were excluded. Patients were divided into LVAD and non-LVAD groups based on status at the time of listing. Patients were propensity matched (LVAD –non-LVAD = 1:2) for age, sex, weight, presence of diabetes, creatinine levels, mean pulmonary artery pressure, and UNOS status. Kaplan-Meier curves were analyzed for survival. Results A total of 8,688 patients were analyzed, with 1,504 (17%) in the LVAD group. Average age (52.6 ± 11.8 versus 51.3 ± 12.9 years; p = 0.0002) and weight (86.6 ± 18.6 versus 80.8 ± 18.2 kg; p < 0.0001) at time of listing were higher in the LVAD group. There were more men (79% versus 74%; p < 0.0001) and more patients with diabetes (30% versus 27%; p = 0.03) in the LVAD group. Of all patients, 6,943 patients (80%) underwent transplantation, 862 (10%) died, and 883 (10%) remained on the waiting list. After propensity matching, survival to transplantation was significantly better in the LVAD group than in the non-LVAD group at both 1 year (91% versus 77%) and 2 years (85% versus 68%). Conclusions Patients supported with an HM II LVAD as BTT therapy were older with increased comorbidities; they demonstrated an improved survival while listed for heart transplantation. The use of LVADs as a BTT strategy can potentially improve patient survival while waiting for transplantation and allow better allocation of donor hearts.
Social valuation of ecosystem services and public policy alternatives is one of the greatest challenges facing ecological economists today. Frameworks for valuing nature increasingly include ...shared/social values as a distinct category of values. However, the nature of shared/social values, as well as their relationship to other values, has not yet been clearly established and empirical evidence about the importance of shared/social values for valuation of ecosystem services is lacking. To help address these theoretical and empirical limitations, this paper outlines a framework of shared/social values across five dimensions: value concept, provider, intention, scale, and elicitation process. Along these dimensions we identify seven main, non-mutually exclusive types of shared values: transcendental, cultural/societal, communal, group, deliberated and other-regarding values, and value to society. Using a case study of a recent controversial policy on forest ownership in England, we conceptualise the dynamic interplay between shared/social and individual values. The way in which social value is assessed in neoclassical economics is discussed and critiqued, followed by consideration of the relation between shared/social values and Total Economic Value, and a review of deliberative and non-monetary methods for assessing shared/social values. We conclude with a discussion of the importance of shared/social values for decision-making.
Display omitted
•Individualist valuation approaches obscure and underplay collective meanings and significance ascribed to natural environments•There is a lack of theoretical and empirical clarity on what constitutes shared and social values and how they can be assessed•We provide a theoretical framework to discriminate dimensions of shared/social values and an overview of valuation methods•A shared values approach to valuation can enhance legitimacy, effectiveness and transparency of evidence and help manage risks
In vitro fertilization involving frozen embryo transfer and donor oocytes increases preeclampsia risk. These in vitro fertilization protocols typically yield pregnancies without a corpus luteum (CL), ...which secretes vasoactive hormones. We investigated whether in vitro fertilization pregnancies without a CL disrupt maternal circulatory adaptations and increase preeclampsia risk. Women with 0 (n=26), 1 (n=23), or >1 (n=22) CL were serially evaluated before, during, and after pregnancy. Because increasing arterial compliance is a major physiological adaptation in pregnancy, we assessed carotid-femoral pulse wave velocity and transit time. In a parallel prospective cohort study, obstetric outcomes for singleton livebirths achieved with autologous oocytes were compared between groups by CL number (n=683). The expected decline in carotid-femoral pulse wave velocity and rise in carotid-femoral transit time during the first trimester were attenuated in the 0-CL compared with combined single/multiple-CL cohorts, which were similar (group-time interactionP=0.06 and 0.03, respectively). The blunted changes of carotid-femoral pulse wave velocity and carotid-femoral transit time from prepregnancy in the 0-CL cohort were most striking at 10 to 12 weeks of gestation (P=0.01 and 0.006, respectively, versus 1 and >1 CL). Zero CL was predictive of preeclampsia (adjusted odds ratio, 2.73; 95% CI, 1.14–6.49) and preeclampsia with severe features (6.45; 95% CI, 1.94–25.09) compared with 1 CL. Programmed frozen embryo transfer cycles (0 CL) were associated with higher rates of preeclampsia (12.8% versus 3.9%; P=0.02) and preeclampsia with severe features (9.6% versus 0.8%; P=0.002) compared with modified natural frozen embryo transfer cycles (1 CL). In common in vitro fertilization protocols, absence of the CL perturbed the maternal circulation in early pregnancy and increased the incidence of preeclampsia.
The most critical question for climate research is no longer about the problem, but about how to facilitate the transformative changes necessary to avoid catastrophic climate-induced change. ...Addressing this question, however, will require massive upscaling of research that can rapidly enhance learning about transformations. Ten essentials for guiding action-oriented transformation and energy research are therefore presented, framed in relation to second-order science. They include: (1) Focus on transformations to low-carbon, resilient living; (2) Focus on solution processes; (3) Focus on ‘how to’ practical knowledge; (4) Approach research as occurring from within the system being intervened; (5) Work with normative aspects; (6) Seek to transcend current thinking; (7) Take a multi-faceted approach to understand and shape change; (8) Acknowledge the value of alternative roles of researchers; (9) Encourage second-order experimentation; and (10) Be reflexive. Joint application of the essentials would create highly adaptive, reflexive, collaborative and impact-oriented research able to enhance capacity to respond to the climate challenge. At present, however, the practice of such approaches is limited and constrained by dominance of other approaches. For wider transformations to low carbon living and energy systems to occur, transformations will therefore also be needed in the way in which knowledge is produced and used.
Previous analyses of relations, divergence times, and diversification patterns among extant mammalian families have relied on supertree methods and local molecular clocks. We constructed a molecular ...supermatrix for mammalian families and analyzed these data with likelihood-based methods and relaxed molecular clocks. Phylogenetic analyses resulted in a robust phylogeny with better resolution than phylogenies from supertree methods. Relaxed clock analyses support the long-fuse model of diversification and highlight the importance of including multiple fossil calibrations that are spread across the tree. Molecular time trees and diversification analyses suggest important roles for the Cretaceous Terrestrial Revolution and Cretaceous-Paleogene (KPg) mass extinction in opening up ecospace that promoted interordinal and intraordinal diversification, respectively. By contrast, diversification analyses provide no support for the hypothesis concerning the delayed rise of present-day mammals during the Eocene Period.
The developmental programs that generate a broad repertoire of regulatory T cells (T
cells) able to respond to both self antigens and non-self antigens remain unclear. Here we found that mature T
...cells were generated through two distinct developmental programs involving CD25
T
cell progenitors (CD25
T
P cells) and Foxp3
T
cell progenitors (Foxp3
T
P cells). CD25
T
P cells showed higher rates of apoptosis and interacted with thymic self antigens with higher affinity than did Foxp3
T
P cells, and had a T cell antigen receptor repertoire and transcriptome distinct from that of Foxp3
T
P cells. The development of both CD25
T
P cells and Foxp3
T
P cells was controlled by distinct signaling pathways and enhancers. Transcriptomics and histocytometric data suggested that CD25
T
P cells and Foxp3
T
P cells arose by coopting negative-selection programs and positive-selection programs, respectively. T
cells derived from CD25
T
P cells, but not those derived from Foxp3
T
P cells, prevented experimental autoimmune encephalitis. Our findings indicate that T
cells arise through two distinct developmental programs that are both required for a comprehensive T
cell repertoire capable of establishing immunotolerance.
Pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease with a 5-year survival rate of 4%. A key hallmark of PDAC is extensive stromal involvement, which makes capturing precise ...tumor-specific molecular information difficult. Here we have overcome this problem by applying blind source separation to a diverse collection of PDAC gene expression microarray data, including data from primary tumor, metastatic and normal samples. By digitally separating tumor, stromal and normal gene expression, we have identified and validated two tumor subtypes, including a 'basal-like' subtype that has worse outcome and is molecularly similar to basal tumors in bladder and breast cancers. Furthermore, we define 'normal' and 'activated' stromal subtypes, which are independently prognostic. Our results provide new insights into the molecular composition of PDAC, which may be used to tailor therapies or provide decision support in a clinical setting where the choice and timing of therapies are critical.
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