Bivariate stochastic modeling of functional response with natural mortality

A correction due to Abbott (1925) is the standard method of dealing with control mortality in insect bioassay to estimate the mortality of an insect conditional on control mortality not having occurred. In this article a bivariate stochastic process for overall mortality is developed in which natural mortality and predation are jointly modeled to take account of the competing-risks associated with prey loss. The total mortality estimate from this model is essentially identical with that from more classical modeling. However, when predation loss is estimated in the absence of control mortality the results are somewhat different, with the estimate from the bivariate model being lower than that from using Abbott’s formula in conjunction with the classical model. It is argued that overdispersion in observed mortality data corresponds to correlated outcomes (death or survival) for the prey initially present, while Abbott’s correction relies implicitly on independence

Bridging Time Scales in Cellular Decision Making with a Stochastic Bistable Switch

Cellular transformations which involve a significant phenotypical change of the cell's state use bistable biochemical switches as underlying decision systems. In this work, we aim at linking cellular decisions taking place on a time scale of years to decades with the biochemical dynamics in signal transduction and gene regulation, occuring on a time scale of minutes to hours. We show that a stochastic bistable switch forms a viable biochemical mechanism to implement decision processes on long time scales. As a case study, the mechanism is applied to model the initiation of follicle growth in mammalian ovaries, where the physiological time scale of follicle pool depletion is on the order of the organism's lifespan. We construct a simple mathematical model for this process based on experimental evidence for the involved genetic mechanisms. Despite the underlying stochasticity, the proposed mechanism turns out to yield reliable behavior in large populations of cells subject to the considered decision process. Our model explains how the physiological time constant may emerge from the intrinsic stochasticity of the underlying gene regulatory network. Apart from ovarian follicles, the proposed mechanism may also be of relevance for other physiological systems where cells take binary decisions over a long time scale.Comment: 14 pages, 4 figure

Community first responders and responder schemes in the United Kingdom: systematic scoping review

Background: Community First Responder (CFR) schemes support lay people to respond to medical emergencies, working closely with ambulance services. They operate widely in the UK. There has been no previous review of UK literature on these schemes. This is the first systematic scoping review of UK literature on CFR schemes, which identifies the reasons for becoming a CFR, requirements for training and feedback and confusion between the CFR role and that of ambulance service staff. This study also reveals gaps in the evidence base for CFR schemes. Methods: We conducted a systematic scoping review of the published literature, in the English language from 2000 onwards using specific search terms in six databases. Narrative synthesis was used to analyse article content. Results: Nine articles remained from the initial search of 15,969 articles after removing duplicates, title and abstract and then full text review. People were motivated to become CFRs through an altruistic desire to help others. They generally felt rewarded by their work but recognised that the help they provided was limited by their training compared with ambulance staff. There were concerns about the possible emotional impact on CFRs responding to incidents. CFRs felt that better feedback would enhance their learning. Ongoing training and support were viewed as essential to enable CFRs to progress. They perceived that public recognition of the CFR role was low, patients sometimes confusing them with ambulance staff. Relationships with the ambulance service were sometimes ambivalent due to confusion over roles. There was support for local autonomy of CFR schemes but with greater sharing of best practice. Discussion: Most studies dated from 2005 and were descriptive rather than analytical. In the UK and Australia CFRs are usually lay volunteers equipped with basic skills for responding to medical emergencies, whereas in the US they include other emergency staff as well as lay people. Conclusion: Opportunities for future research include exploring experiences and perceptions of patients who have been treated by CFRs and other stakeholders, while also evaluating the effectiveness and costs of CFR schemes

Climacteric Lowers Plasma Levels of Platelet-Derived Microparticles: A Pilot Study in Pre-versus Postmenopausal Women

Background: Climacteric increases the risk of thrombotic events by alteration of plasmatic coagulation. Up to now, less is known about changes in platelet-(PMP) and endothelial cell-derived microparticles (EMP). Methods: In this prospective study, plasma levels of microparticles (MP) were compared in 21 premenopausal and 19 postmenopausal women. Results: No altered numbers of total MP or EMP were measured within the study groups. However, the plasma values of CD61-exposing MP from platelets/megakaryocytes were higher in premenopausal women (5,364 x 10(6)/l, range 4,384-17,167) as compared to postmenopausal women (3,808 x 10(6)/l, range 2,009-8,850; p = 0.020). This differentiation was also significant for the subgroup of premenopausal women without hormonal contraceptives (5,364 x 10(6)/l, range 4,223-15,916; p = 0.047; n = 15). Furthermore, in premenopausal women, higher plasma levels of PMP exposing CD62P were also present as compared to postmenopausal women (288 x 10(6)/l, range 139-462, vs. 121 x 10(6)/l, range 74-284; p = 0.024). This difference was also true for CD63+ PMP levels (281 x 10(6)/l, range 182-551, vs. 137 x 10(6)/l, range 64-432; p = 0.015). Conclusion: Climacteric lowers the level of PMP but has no impact on the number of EMP in women. These data suggest that PMP and EMP do not play a significant role in enhancing the risk of thrombotic events in healthy, postmenopausal women. Copyright (C) 2012 S. Karger AG, Base

Queues with Lévy input and hysteretic control

We consider a (doubly) reflected Lévy process where the Lévy exponent is controlled by a hysteretic policy consisting of two stages. In each stage there is typically a different service speed, drift parameter, or arrival rate. We determine the steady-state performance, both for systems with finite and infinite capacity. Thereby, we unify and extend many existing results in the literature, focusing on the special cases of M/G/1 queues and Brownian motion. © The Author(s) 2009

Proteomic Signatures of Human Oral Epithelial Cells in HIV-Infected Subjects

The oral epithelium, the most abundant structural tissue lining the oral mucosa, is an important line of defense against infectious microorganisms. HIV infected subjects on highly active antiretroviral therapy (HAART) are susceptible to comorbid viral, bacterial and fungal infections in the oral cavity. To provide an assessment of the molecular alterations of oral epithelia potentially associated with susceptibility to comorbid infections in such subjects, we performed various proteomic studies on over twenty HIV infected and healthy subjects. In a discovery phase two Dimensional Difference Gel Electrophoresis (2-D DIGE) analyses of human oral gingival epithelial cell (HOEC) lysates were carried out; this identified 61 differentially expressed proteins between HIV-infected on HAART subjects and healthy controls. Down regulated proteins in HIV-infected subjects include proteins associated with maintenance of protein folding and pro- and anti-inflammatory responses (e.g., heat-shock proteins, Cryab, Calr, IL-1RA, and Galectin-3-binding protein) as well as proteins involved in redox homeostasis and detoxification (e.g., Gstp1, Prdx1, and Ero1). Up regulated proteins include: protein disulfide isomerases, proteins whose expression is negatively regulated by Hsp90 (e.g., Ndrg1), and proteins that maintain cellular integrity (e.g., Vimentin). In a verification phase, proteins identified in the protein profiling experiments and those inferred from Ingenuity Pathway Analysis were analyzed using Western blotting analysis on separate HOEC lysate samples, confirming many of the discovery findings. Additionally in HIV-infected patient samples Heat Shock Factor 1 is down regulated, which explains the reduced heat shock responses, while activation of the MAPK signal transduction cascade is observed. Overall, HAART therapy provides an incomplete immune recovery of the oral epithelial cells of the oral cavity for HIV-infected subjects, and the toxic side effects of HAART and/or HIV chronicity silence expression of multiple proteins that in healthy subjects function to provide robust innate immune responses and combat cellular stress. © 2011 Yohannes et al

Utility of prehospital electrocardiogram interpretation in ST-segment elevation myocardial infarction utilizing computer interpretation and transmission for interventional cardiologist consultation

Objectives: We examined the appropriateness of prehospital cardiac catheter laboratory activation (CCL-A) in ST-segment elevation myocardial infarction (STEMI) utilizing the University of Glasgow algorithm (UGA) and remote interventional cardiologist consultation. Background: The incremental benefit of prehospital electrocardiogram (PH-ECG) transmission on the diagnostic accuracy and appropriateness of CCL-A has been examined in a small number of studies with conflicting results. Methods: We identified consecutive PH-ECG transmissions between June 2, 2010 and October 6, 2016. Blinded adjudication of ECGs, appropriateness of CCL-A, and index diagnoses were performed using the fourth universal definition of MI. The primary outcome was the appropriate CCL-A rate. Secondary outcomes included rates of false-positive CCL-A, inappropriate CCL-A, and inappropriate CCL nonactivation. Results: Among 1088 PH-ECG transmissions, there were 565 (52%) CCL-As and 523 (48%) CCL nonactivations. The appropriate CCL-A rate was 97% (550 of 565 CCL-As), of which 4.9% (n = 27) were false-positive. The inappropriate CCL-A rate was 2.7% (15 of 565 CCL-As) and the inappropriate CCL nonactivation rate was 3.6% (19 of 523 CCL nonactivations). Reasons for appropriate CCL nonactivation (n = 504) included nondiagnostic ST-segment elevation (n = 128, 25%), bundle branch block (n = 132, 26%), repolarization abnormality (n = 61, 12%), artefact (n = 72, 14%), no ischemic symptoms (n = 32, 6.3%), severe comorbidities (n = 26, 5.2%), transient ST-segment elevation (n = 20, 4.0%), and others. Conclusions: PH-ECG interpretation utilizing UGA with interventional cardiologist consultation accurately identified STEMI with low rates of inappropriate and false-positive CCL-As, whereas using UGA alone would have almost doubled CCL-As. The benefits of cardiologist consultation were identifying “masquerading” STEMI and avoiding unnecessary CCL-As

Late Outcomes of Patients With Prehospital ST-Segment Elevation and Appropriate Cardiac Catheterization Laboratory Nonactivation

BACKGROUND: Patients with suspected ST-segment–elevation myocardial infarction (STEMI) and cardiac catheterization laboratory nonactivation (CCL-NA) or cancellation have reportedly similar crude and higher adjusted risks of death compared with those with CCL activation, though reasons for these poor outcomes are not clear. We determined late clinical outcomes among patients with prehospital ECG STEMI criteria who had CCL-NA compared with those who had CCL activation. METHODS AND RESULTS: We identified consecutive prehospital ECG transmissions between June 2, 2010 to October 6, 2016. Diagnoses according to the Fourth Universal Definition of myocardial infarction (MI), particularly rates of myocardial injury, were adjudicated. The primary outcome was all-cause death. Secondary outcomes included cardiovascular death/MI/stroke and noncardiovascular death. To explore competing risks, cause-specific hazard ratios (HRs) were obtained. Among 1033 included ECG transmissions, there were 569 (55%) CCL activations and 464 (45%) CCL-NAs (1.8% were inappropriate CCL-NAs). In the CCL activation group, adjudicated index diagnoses included MI (n=534, 94%, of which 99.6% were STEMI and 0.4% non-STEMI), acute myocardial injury (n=15, 2.6%), and chronic myocardial injury (n=6, 1.1%). In the CCL-NA group, diagnoses included MI (n=173, 37%, of which 61% were non-STEMI and 39% STEMI), chronic myocardial injury (n=107, 23%), and acute myocardial injury (n=47, 10%). At 2 years, the risk of all-cause death was higher in patients who had CCL-NA compared with CCL activation (23% versus 7.9%, adjusted risk ratio, 1.58, 95% CI, 1.24–2.00), primarily because of an excess in noncardiovascular deaths (adjusted HR, 3.56, 95% CI, 2.07–6.13). There was no significant difference in the adjusted risk for cardiovascular death/MI/stroke between the 2 groups (HR, 1.23, 95% CI, 0.87–1.73). CONCLUSIONS: CCL-NA was not primarily attributable to missed STEMI, but attributable to “masquerading” with high rates of non-STEMI and myocardial injury. These patients had worse late outcomes than patients who had CCL activation, mainly because of higher rates of noncardiovascular deaths

The troublesome ticks research protocol: Developing a comprehensive, multidiscipline research plan for investigating human tick-associated disease in Australia

In Australia, there is a paucity of data about the extent and impact of zoonotic tick-related illnesses. Even less is understood about a multifaceted illness referred to as Debilitating Symptom Complexes Attributed to Ticks (DSCATT). Here, we describe a research plan for investigating the aetiology, pathophysiology, and clinical outcomes of human tick-associated disease in Australia. Our approach focuses on the transmission of potential pathogens and the immunological responses of the patient after a tick bite. The protocol is strengthened by prospective data collection, the recruitment of two external matched control groups, and sophisticated integrative data analysis which, collectively, will allow the robust demonstration of associations between a tick bite and the development of clinical and pathological abnormalities. Various laboratory analyses are performed including metagenomics to investigate the potential transmission of bacteria, protozoa and/or viruses during tick bite. In addition, multi-omics technology is applied to investigate links between host immune responses and potential infectious and non-infectious disease causations. Psychometric profiling is also used to investigate whether psychological attributes influence symptom development. This research will fill important knowledge gaps about tick-borne diseases. Ultimately, we hope the results will promote improved diagnostic outcomes, and inform the safe management and treatment of patients bitten by ticks in Australia

A Validated Model of Serum Anti-Müllerian Hormone from Conception to Menopause

Background Anti-Müllerian hormone (AMH) is a product of growing ovarian follicles. The concentration of AMH in blood may also reflect the non-growing follicle (NGF) population, i.e. the ovarian reserve, and be of value in predicting reproductive lifespan. A full description of AMH production up to the menopause has not been previously reported. Methodology/Principal Findings By searching the published literature for AMH concentrations in healthy pre-menopausal females, and using our own data (combined ) we have generated and robustly validated the first model of AMH concentration from conception to menopause. This model shows that 34% of the variation in AMH is due to age alone. We have shown that AMH peaks at age 24.5 years, followed by a decline to the menopause. We have also shown that there is a neonatal peak and a potential pre-pubertal peak. Our model allows us to generate normative data at all ages. Conclusions/Significance These data highlight key inflection points in ovarian follicle dynamics. This first validated model of circulating AMH in healthy females describes a transition period in early adulthood, after which AMH reflects the progressive loss of the NGF pool. The existence of a neonatal increase in gonadal activity is confirmed for females. An improved understanding of the relationship between circulating AMH and age will lead to more accurate assessment of ovarian reserve for the individual woman.Publisher PDFPeer reviewe