Usability and Feasibility of PIERS on the Move: An mHealth App for Pre-Eclampsia Triage.

BACKGROUND: Pre-eclampsia is one of the leading causes of maternal death and morbidity in low-resource countries due to delays in case identification and a shortage of health workers trained to manage the disorder. Pre-eclampsia Integrated Estimate of RiSk (PIERS) on the Move (PotM) is a low cost, easy-to-use, mobile health (mHealth) platform that has been created to aid health workers in making decisions around the management of hypertensive pregnant women. PotM combines two previously successful innovations into a mHealth app: the miniPIERS risk assessment model and the Phone Oximeter. OBJECTIVE: The aim of this study was to assess the usability of PotM (with mid-level health workers) for iteratively refining the system. METHODS: Development of the PotM user interface involved usability testing with target end-users in South Africa. Users were asked to complete clinical scenario tasks, speaking aloud to give feedback on the interface and then complete a questionnaire. The tool was then evaluated in a pilot clinical evaluation in Tygerberg Hospital, Cape Town. RESULTS: After ethical approval and informed consent, 37 nurses and midwives evaluated the tool. During Study 1, major issues in the functionality of the touch-screen keyboard and date scroll wheels were identified (total errors n=212); during Study 2 major improvements in navigation of the app were suggested (total errors n=144). Overall, users felt the app was usable using the Computer Systems Usability Questionnaire; median (range) values for Study 1 = 2 (1-6) and Study 2 = 1 (1-7). To demonstrate feasibility, PotM was used by one research nurse for the pilot clinical study. In total, more than 500 evaluations were performed on more than 200 patients. The median (interquartile range) time to complete an evaluation was 4 min 55 sec (3 min 25 sec to 6 min 56 sec). CONCLUSIONS: By including target end-users in the design and evaluation of PotM, we have developed an app that can be easily integrated into health care settings in low- and middle-income countries. Usability problems were often related to mobile phone features (eg, scroll wheels, touch screen use). Larger scale evaluation of the clinical impact of this tool is underway

Controlling Level of Unconsciousness by Titrating Propofol with Deep Reinforcement Learning

Reinforcement Learning (RL) can be used to fit a mapping from patient state to a medication regimen. Prior studies have used deterministic and value-based tabular learning to learn a propofol dose from an observed anesthetic state. Deep RL replaces the table with a deep neural network and has been used to learn medication regimens from registry databases. Here we perform the first application of deep RL to closed-loop control of anesthetic dosing in a simulated environment. We use the cross-entropy method to train a deep neural network to map an observed anesthetic state to a probability of infusing a fixed propofol dosage. During testing, we implement a deterministic policy that transforms the probability of infusion to a continuous infusion rate. The model is trained and tested on simulated pharmacokinetic/pharmacodynamic models with randomized parameters to ensure robustness to patient variability. The deep RL agent significantly outperformed a proportional-integral-derivative controller (median absolute performance error 1.7% +/- 0.6 and 3.4% +/- 1.2). Modeling continuous input variables instead of a table affords more robust pattern recognition and utilizes our prior domain knowledge. Deep RL learned a smooth policy with a natural interpretation to data scientists and anesthesia care providers alike.Comment: International Conference on Artificial Intelligence in Medicine 202

Using functional genomics to decipher the complexity of microbial pathogenicity

From the first identification of bacteria as a causative agent of disease, researchers have been developing methods and techniques to understand their pathogenic processes. For decades, this work has been limited to looking at a small number of genetically manipulatable isolates in in vitro assays or animal models of infection. Despite these limitations such work has facilitated the development of successful therapeutic strategies, most notably vaccines that target specific virulence-related features. There are however many antimicrobial resistant pathogens for which vaccination strategies have not worked, as we simply do not know enough about how they cause disease. We are however at the dawn of a new era in the study of microbial pathogenicity, where large collections of bacteria isolated directly from human infections can be sequenced and assayed to identify the bacterial features that affect disease severity in humans. Here, we describe our attempt to perform such a study focussed on the major human pathogen Staphylococcus aureus, which demonstrates the step changes such approaches can make to understanding microbial pathogenicity

Genetic Analysis of Genome-Scale Recombination Rate Evolution in House Mice

The rate of meiotic recombination varies markedly between species and among individuals. Classical genetic experiments demonstrated a heritable component to population variation in recombination rate, and specific sequence variants that contribute to recombination rate differences between individuals have recently been identified. Despite these advances, the genetic basis of species divergence in recombination rate remains unexplored. Using a cytological assay that allows direct in situ imaging of recombination events in spermatocytes, we report a large (∼30%) difference in global recombination rate between males of two closely related house mouse subspecies (Mus musculus musculus and M. m. castaneus). To characterize the genetic basis of this recombination rate divergence, we generated an F2 panel of inter-subspecific hybrid males (n = 276) from an intercross between wild-derived inbred strains CAST/EiJ (M. m. castaneus) and PWD/PhJ (M. m. musculus). We uncover considerable heritable variation for recombination rate among males from this mapping population. Much of the F2 variance for recombination rate and a substantial portion of the difference in recombination rate between the parental strains is explained by eight moderate- to large-effect quantitative trait loci, including two transgressive loci on the X chromosome. In contrast to the rapid evolution observed in males, female CAST/EiJ and PWD/PhJ animals show minimal divergence in recombination rate (∼5%). The existence of loci on the X chromosome suggests a genetic mechanism to explain this male-biased evolution. Our results provide an initial map of the genetic changes underlying subspecies differences in genome-scale recombination rate and underscore the power of the house mouse system for understanding the evolution of this trait

Predator Dispersal Determines the Effect of Connectivity on Prey Diversity

Linking local communities to a metacommunity can positively affect diversity by enabling immigration of dispersal-limited species and maintenance of sink populations. However, connectivity can also negatively affect diversity by allowing the spread of strong competitors or predators. In a microcosm experiment with five ciliate species as prey and a copepod as an efficient generalist predator, we analysed the effect of connectivity on prey species richness in metacommunities that were either unconnected, connected for the prey, or connected for both prey and predator. Presence and absence of predator dispersal was cross-classified with low and high connectivity. The effect of connectivity on local and regional richness strongly depended on whether corridors were open for the predator. Local richness was initially positively affected by connectivity through rescue of species from stochastic extinctions. With predator dispersal, however, this positive effect soon turned negative as the predator spread over the metacommunity. Regional richness was unaffected by connectivity when local communities were connected only for the prey, while predator dispersal resulted in a pronounced decrease of regional richness. The level of connectivity influenced the speed of richness decline, with regional species extinctions being delayed for one week in weakly connected metacommunities. While connectivity enabled rescue of prey species from stochastic extinctions, deterministic extinctions due to predation were not overcome through reimmigration from predator-free refuges. Prey reimmigrating into these sink habitats appeared to be directly converted into increased predator abundance. Connectivity thus had a positive effect on the predator, even when the predator was not dispersing itself. Our study illustrates that dispersal of a species with strong negative effects on other community members shapes the dispersal-diversity relationship. When connections enable the spread of a generalist predator, positive effects of connectivity on prey species richness are outweighed by regional extinctions through predation

Impact of resilience enhancing programs on youth surviving the Beslan school siege

The objective of this study was to evaluate a resilience-enhancing program for youth (mean age = 13.32 years) from Beslan, North Ossetia, in the Russian Federation. The program, offered in the summer of 2006, combined recreation, sport, and psychosocial rehabilitation activities for 94 participants, 46 of who were taken hostage in the 2004 school tragedy and experienced those events first hand. Self-reported resilience, as measured by the CD-RISC, was compared within subjects at the study baseline and at two follow-up assessments: immediately after the program and 6 months later. We also compared changes in resilience levels across groups that differed in their traumatic experiences. The results indicate a significant intra-participant mean increase in resilience at both follow-up assessments, and greater self-reported improvements in resilience processes for participants who experienced more trauma events

Quantitative modeling of the physiology of ascites in portal hypertension

Although the factors involved in cirrhotic ascites have been studied for a century, a number of observations are not understood, including the action of diuretics in the treatment of ascites and the ability of the plasma-ascitic albumin gradient to diagnose portal hypertension. This communication presents an explanation of ascites based solely on pathophysiological alterations within the peritoneal cavity. A quantitative model is described based on experimental vascular and intraperitoneal pressures, lymph flow, and peritoneal space compliance. The model's predictions accurately mimic clinical observations in ascites, including the magnitude and time course of changes observed following paracentesis or diuretic therapy

Nicotine Overrides DNA Damage-Induced G1/S Restriction in Lung Cells

As an addictive substance, nicotine has been suggested to facilitate pro-survival activities (such as anchorage-independent growth or angiogenesis) and the establishment of drug resistance to anticancer therapy. Tobacco smoking consists of a variety of carcinogens [such as benzopyrene (BP) and nitrosamine derivatives] that are able to cause DNA double strand breaks. However, the effect of nicotine on DNA damage-induced checkpoint response induced by genotoxins remains unknown. In this study, we investigated the events occurred during G1 arrest induced by γ-radiation or BP in nicotine-treated murine or human lung epithelial cells. DNA synthesis was rapidly inhibited after exposure to γ-radiation or BP treatment, accompanied with the activation of DNA damage checkpoint. When these cells were co-treated with nicotine, the growth restriction was compromised, manifested by upregulation of cyclin D and A, and attenuation of Chk2 phosphorylation. Knockdown of cyclin D or Chk2 by the siRNAs blocked nicotine-mediated effect on DNA damage checkpoint activation. However, nicotine treatment appeared to play no role in nocodazole-induced mitotic checkpoint activation. Overall, our study presented a novel observation, in which nicotine is able to override DNA damage checkpoint activated by tobacco-related carcinogen BP or γ-irradiation. The results not only indicates the potentially important role of nicotine in facilitating the establishment of genetic instability to promote lung tumorigenesis, but also warrants a dismal prognosis for cancer patients who are smokers, heavily exposed second-hand smokers or nicotine users

Platelet-activating factor receptor (PAF-R)-dependent pathways control tumour growth and tumour response to chemotherapy

<p>Abstract</p> <p>Background</p> <p>Phagocytosis of apoptotic cells by macrophages induces a suppressor phenotype. Previous data from our group suggested that this occurs via Platelet-activating factor receptor (PAF-R)-mediated pathways. In the present study, we investigated the impact of apoptotic cell inoculation or induction by a chemotherapeutic agent (dacarbazine, DTIC) on tumour growth, microenvironmental parameters and survival, and the effect of treatment with a PAF-R antagonist (WEB2170). These studies were performed in murine tumours: Ehrlich Ascitis Tumour (EAT) and B16F10 melanoma.</p> <p>Methods</p> <p>Tumour growth was assessed by direct counting of EAT cells in the ascitis or by measuring the volume of the solid tumour. Parameters of the tumour microenvironment, such as the frequency of cells expressing cyclo-oxygenase-2 (COX-2), caspase-3 and galectin-3, and microvascular density, were determined by immunohistochemistry. Levels of vascular endothelium growth factor (VEGF) and prostaglandin E2 (PGE2) were determined by ELISA, and levels of nitric oxide (NO) by Griess reaction. PAF-R expression was analysed by immunohistochemistry and flow cytometry.</p> <p>Results</p> <p>Inoculation of apoptotic cells before EAT implantation stimulated tumour growth. This effect was reversed by <it>in vivo </it>pre-treatment with WEB2170. This treatment also reduced tumour growth and modified the microenvironment by reducing PGE2, VEGF and NO production. In B16F10 melanoma, WEB2170 alone or in association with DTIC significantly reduced tumour volume. Survival of the tumour-bearing mice was not affected by WEB2170 treatment but was significantly improved by the combination of DTIC with WEB2170. Tumour microenvironment elements were among the targets of the combination therapy since the relative frequency of COX-2 and galectin-3 positive cells and the microvascular density within the tumour mass were significantly reduced by treatment with WEB2170 or DTIC alone or in combination. Antibodies to PAF-R stained the cells from inside the tumour, but not the tumour cells grown <it>in vitro</it>. At the tissue level, a few cells (probably macrophages) stained positively with antibodies to PAF-R.</p> <p>Conclusions</p> <p>We suggest that PAF-R-dependent pathways are activated during experimental tumour growth, modifying the microenvironment and the phenotype of the tumour macrophages in such a way as to favour tumour growth. Combination therapy with a PAF-R antagonist and a chemotherapeutic drug may represent a new and promising strategy for the treatment of some tumours.</p