Field Performance and Diagnostic Accuracy of a Low-Cost Instrument-Free Point-of-Care CD4 Test (Visitect CD4) Performed by Different Health Worker Cadres among Pregnant Women.

Measuring CD4 counts remains an important component of HIV care. The Visitect CD4 is the first instrument-free low-cost point-of-care CD4 test with results interpreted visually after 40 min, providing a result of ≥350 CD4 cells/mm3 The field performance and diagnostic accuracy of the test was assessed among HIV-infected pregnant women in South Africa. A nurse performed testing at the point-of-care using both venous and finger-prick blood, and a counselor and laboratory staff tested venous blood in the clinic laboratory (four Visitect CD4 tests/participant). Performance was compared to the mean CD4 count from duplicate flow cytometry tests on venous blood (FACSCalibur Trucount). In 2017, 156 patients were enrolled, providing a total of 624 Visitect CD4 tests (468 venous and 156 finger-prick samples). Of 624 tests, 28 (4.5%) were inconclusive. Generalized linear mixed modeling showed better performance of the test on venous blood (sensitivity = 81.7%; 95% confidence interval [CI] = 72.3 to 91.1]; specificity = 82.6%, 95% CI = 77.1 to 88.1) than on finger-prick specimens (sensitivity = 60.7%; 95% CI = 45.0 to 76.3; specificity = 89.5%, 95% CI = 83.2 to 95.8; P = 0.001). No difference in performance was detected by cadre of health worker (P = 0.113) or between point-of-care versus laboratory-based testing (P = 0.108). Adequate performance of Visitect CD4 with different operators and at the point of care, with no need of electricity or instrument, shows the potential utility of this device, especially for facilitating decentralization of CD4 testing services in rural areas.

System identification and simulation of soft tissue force feedback in a spine surgical simulator.

Surgical simulators are being introduced as training modalities for surgeons. This paper aims to evaluate dynamic models used to convey force feedback from puncturing the soft tissue during a spine surgical simulation. The force feedback of the tissue is treated as a dynamic system. This is done by performing classical system identification across a bandwidth of frequencies on a tissue analogue and fitting that behaviour to dynamic viscoelastic models. The models that are tested are an inverted linear model, the Maxwell model, the Kelvin-Boltzmann (KB) model, and a higher-order blackbox (HO) model. Several error metrics such as percent variance accounted for (%VAF) are determined to measure solution accuracy. The force feedback models are programmed into a surgical simulator and tested with study participants who rated them based on how well the identified models match the behaviour of the rubber tissue analogue. The highest %VAF is 82.64% when the tissue is modelled as the HO model. Statistically significant differences (p < 0.05) are found between all model ratings from participants except between the HO model and the KB model. However, the HO model has the highest percentage (37.8%) of participants who rank its performance as the closest to the tissue analogue compared to the other force feedback models. The more accurately the dynamic behaviour resembles the tissue analogue, the higher the model was rated by study participants. This study highlights the importance of utilizing dynamic signals to generate dynamic models of soft tissue for spine surgical simulators.

System Identification and Two-Degree-of-Freedom Control of Nonlinear, Viscoelastic Tissues.

OBJECTIVE: This paper presents a force control scheme for brief isotonic holds in an isometrically contracted muscle tissue, with minimal overshoot and settling time to measure its shortening velocity, a key parameter of muscle function. METHODS: A two-degree-of-freedom control configuration, formed by a feedback controller and a feedforward controller, is explored. The feedback controller is a proportional-integral controller and the feedforward controller is designed using the inverse of a control-oriented model of muscle tissue. A generalized linear model and a nonlinear model of muscle tissue are explored using input-output data and system identification techniques. The force control scheme is tested on equine airway smooth muscle and its robustness confirmed with murine flexor digitorum brevis muscle. RESULTS: Performance and repeatability of the force control scheme as well as the number of inputs and level of supervision required from the user were assessed with a series of experiments. The force control scheme was able to fulfill the stated control objectives in most cases, including the requirements for settling time and overshoot. CONCLUSION: The proposed control scheme is shown to enable automation of force control for characterizing muscle mechanics with minimal user input required. SIGNIFICANCE: This paper leverages an inversion-based feedforward controller based on a nonlinear physiological model in a system identification context that is superior to classic linear system identification. The control scheme can be used as a steppingstone for generalized control of nonlinear, viscoelastic materials.

Performance characteristics of an instrument-free point-of-care CD4 test (VISITECT®CD4) for use in resource-limited settings.

OBJECTIVE: CD4+ T lymphocyte count remains the most common biomarker of immune status and disease progression in human immunodeficiency virus (HIV)-positive individuals. VISITECT®CD4 is an instrument-free, low-cost point-of-care CD4 test with a cut-off of 350 CD4 cells/µL. This study aimed to evaluate VISITECT®CD4 test's diagnostic accuracy. METHODS: Two hundred HIV-positive patients attending a tertiary HIV centre in South India were recruited. Patients provided venous blood for reference and VISITECT®CD4 tests. An additional finger-prick blood sample was obtained for VISITECT®CD4. VISITECT®CD4's diagnostic performance in identifying individuals with CD4 counts ≤350 cells/µL was assessed by calculating sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) taking flow cytometry as the reference. RESULTS: The overall agreement between VISITECT®CD4 and flow cytometry was 89.5% using venous blood and 81.5% using finger-prick blood. VISITECT®CD4 showed better performance using venous blood [sensitivity: 96.6% (95% confidence interval: 92.1%-98.9%), specificity: 70.9% (57.1%-82.4%), PPV: 89.7% (83.9%-94.0%) and NPV: 88.6% (75.4%-96.2%)] than using finger-prick blood [sensitivity: 84.8% (77.9%-90.2%), specificity: 72.7% (59.0%-83.9%), PPV: 89.1% (82.7%-93.8%) and NPV: 64.5% (51.3%-76.3%)]. CONCLUSION: VISITECT®CD4 performed well using venous blood, demonstrating its potential utility in decentralization of CD4 testing services in resource-constrained settings.

Frequency and clinical spectrum of in-flight medical incidents during domestic and international flights.

Most medical practitioners are not specifically trained to diagnose or manage in-flight medical incidents, yet there may occur a moral obligation to do so when least expected. We felt that knowledge of the frequency of emergency versus non-serious medical incidents, in addition to the clinical spectrum of incidents most often encountered, would be of interest to medical practitioners and, in particular, critical care physicians, who happen to find themselves asked to assist with such events. To this end we collaborated with the Department of Medical Services of a major Australian airline to define the incidence, severity, and type of all in-flight medical events encountered over the course of a year's flights. We audited in-flight medical data collected over a continuous 12-month period, which covered 131,890 international and domestic flight sectors transporting more than 27 million passengers. There was an average of 296 medical events per month (3555 in total) making the per-flight incidence of a medical event approximately 1:40 (2.7%). Of these in-flight incidents, 915 (26%) were graded as emergencies, with the commonest descriptors of such incidents being either loss of consciousness (37%) or a suspected cardiovascular event (12%). Six of these 915 emergencies proved fatal. Twenty-one flights were diverted due to medical incidents (<0.016% of all flights), with 52% of these attributed to suspected cardiac events. In this series, medical in-flight events were recorded in approximately one in 40 flights, whereas medical emergencies occurred in approximately one in 150 flights.

Better living through conifer removal: A demographic analysis of sage-grouse vital rates.

Sagebrush (Artemisia spp.) obligate wildlife species such as the imperiled greater sage-grouse (Centrocercus urophasianus) face numerous threats including altered ecosystem processes that have led to conifer expansion into shrub-steppe. Conifer removal is accelerating despite a lack of empirical evidence on grouse population response. Using a before-after-control-impact design at the landscape scale, we evaluated effects of conifer removal on two important demographic parameters, annual survival of females and nest survival, by monitoring 219 female sage-grouse and 225 nests in the northern Great Basin from 2010 to 2014. Estimates from the best treatment models showed positive trends in the treatment area relative to the control area resulting in an increase of 6.6% annual female survival and 18.8% nest survival relative to the control area by 2014. Using stochastic simulations of our estimates and published demographics, we estimated a 25% increase in the population growth rate in the treatment area relative to the control area. This is the first study to link sage-grouse demographics with conifer removal and supports recommendations to actively manage conifer expansion for sage-grouse conservation. Sage-grouse have become a primary catalyst for conservation funding to address conifer expansion in the West, and these findings have important implications for other ecosystem services being generated on the wings of species conservation.

Conditional overexpression of active transforming growth factor beta1 in vivo accelerates metastases of transgenic mammary tumors.

To address the role of transforming growth factor (TGF) beta in the progression of established tumors while avoiding the confounding inhibitory effects of TGF-beta on early transformation, we generated doxycycline (DOX)-inducible triple transgenic mice in which active TGF-beta1 expression could be conditionally regulated in mouse mammary tumor cells transformed by the polyomavirus middle T antigen. DOX-mediated induction of TGF-beta1 for as little as 2 weeks increased lung metastases >10-fold without a detectable effect on primary tumor cell proliferation or tumor size. DOX-induced active TGF-beta1 protein and nuclear Smad2 were restricted to cancer cells, suggesting a causal association between autocrine TGF-beta and increased metastases. Antisense-mediated inhibition of TGF-beta1 in polyomavirus middle T antigen-expressing tumor cells also reduced basal cell motility, survival, anchorage-independent growth, tumorigenicity, and metastases. Therefore, induction and/or activation of TGF-beta in hosts with established TGF-beta-responsive cancers can rapidly accelerate metastatic progression.

Early changes in protein expression detected by mass spectrometry predict tumor response to molecular therapeutics.

Biomarkers that predict therapeutic response are essential for the development of anticancer therapies. We have used matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) to directly analyze protein profiles in mouse mammary tumor virus/HER2 transgenic mouse frozen tumor sections after treatment with the erbB receptor inhibitors OSI-774 and Herceptin. Inhibition of tumor cell proliferation and induction of apoptosis and tumor reduction were predicted by a >80% reduction in thymosin beta4 and ubiquitin levels that were detectable after 16 hours of a single drug dose before any evidence of in situ cellular activity. These effects were time- and dose-dependent, and their spatial distribution in the tumor correlated with that of the small-molecule inhibitor OSI-774. In addition, they predicted for therapeutic synergy of OSI-774 and Herceptin as well as for drug resistance. These results suggest that drug-induced early proteomic changes as measured by MALDI-MS can be used to predict the therapeutic response to established and novel therapies.

When language affects cognition and when it does not: an analysis of grammatical gender and classification.

The focus of this work was on the relation between grammatical gender and categorization. In one set of studies, monolingual English-, Spanish-, French-, and German-speaking children and adults assigned male and female voices to inanimate objects. Results from Spanish and French speakers indicated effects of grammatical gender on classification; results from German speakers did not. A connectionist model simulated the contradicting findings. The connectionist networks were also used to investigate which aspect of grammatical gender was responsible for the different pattern of findings. The predictions from the connectionist simulations were supported by the results from an artificial language-learning task. The results from this work demonstrate how connectionist networks can be used to identify the differences between languages that affect categorization.

Toddlers' attention to intentions-in-action in learning novel action words.

Toddlers' ability to use cues such as eye gaze and gestures to infer the meaning of novel action words was examined. In Experiment 1, 21- and 27-month-olds were taught labels for pairs of videotaped actions that were either similar or dissimilar in appearance. Similar actions differed mainly in the presence of behavioral cues related to the agents' intentions (e.g., extended arms). Only the older children were able to learn the labels for the similar actions. In Experiment 2, 3 new pairs of labels (2 similar, 1 dissimilar) were taught to children in the same age range. Eye gaze and gestures were the main features distinguishing the similar events. The same developmental effect was observed, with only the older children showing learning of both types of verbs and the younger children being impeded by the appearance of the actions. The results show that by the middle of the 2nd year, children begin to consider intentions-in-action when acquiring the meaning of novel action verbs.

Inhibition of mammalian target of rapamycin is required for optimal antitumor effect of HER2 inhibitors against HER2-overexpressing cancer cells.

PURPOSE: A significant fraction of HER2-overexpressing breast cancers exhibit resistance to the HER2 antibody trastuzumab. Hyperactivity of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway confers trastuzumab resistance, and mammalian target of rapamycin (mTOR) is a major downstream effector of PI3K/AKT. Therefore, we examined whether mTOR inhibitors synergize with trastuzumab. EXPERIMENTAL DESIGN: Immunocompetent mice bearing HER2(+) mammary tumors were treated with trastuzumab, the mTOR inhibitor rapamycin, or the combination. Mice were imaged for tumor cell death using an optical Annexin-V probe and with [(18)F]FDG positron emission tomography. The signaling and growth effects of the mTOR inhibitor RAD001 on HER2(+) cells treated with trastuzumab or lapatinib were evaluated. RESULTS: Treatment of mice with trastuzumab plus rapamycin was more effective than single-agent treatments, inducing complete regression of 26 of 26 tumors. The combination induced tumor cell death (Annexin-V binding) and inhibited FDG uptake. Rapamycin inhibited mTOR and tumor cell proliferation as determined by phosphorylated S6 and Ki-67 immunohistochemistry, respectively. In culture, the combination of RAD001 plus trastuzumab inhibited cell growth more effectively than either drug alone. Trastuzumab partially decreased PI3K but not mTOR activity. Knockdown of TSC2 resulted in HER2-independent activation of mTOR and dampened the response to trastuzumab and lapatinib. Treatment with the HER2 inhibitor lapatinib decreased phosphorylated S6 and growth in TSC2-expressing cells but not in TSC2-knockdown cells. CONCLUSIONS: Inhibition of PI3K and mTOR are required for the growth-inhibitory effect of HER2 antagonists. These findings collectively support the combined use of trastuzumab and mTOR inhibitors for the treatment of HER2(+) breast cancer.

A Method for the 12-Hour Evaluation of Analgesic Efficacy in Outpatients with Postoperative Oral Surgery Pain: Three Studies of Diflunisal.

We have developed a method for measuring the efficacy of a single dose of an analgesic for 12 hours after administration to outpatients with postoperative oral surgery pain. Using a self-rating record, patients evaluate their pain and its relief for 12 hours after medication. We have used this method successfully in a series of three studies to compare diflunisal, a new nonsteroidal antiinflammatory analgesic, with placebo and aspirin 650 mg, acetaminophen 600 mg, propoxyphene napsylate 100 mg, or a combination of acetaminophen with either codeine 60 mg or propoxyphene 100 mg. Diflunisal evinced an unusually long duration of analgesic effect. In each study, all doses of diflunisal were significantly superior to placebo through the end of the 12-hour observation period, while the standards were superior for periods ranging from 2 to 7 hours. In terms of peak analgesia, diflunisal 1,000 mg was comparable to the acetaminophen-codeine combination and was significantly superior to all the other analgesic standards.

A 12-Hour Evaluation of the Analgesic Efficacy of Diflunisal, Acetaminophen, an Acetaminophen-Codeine Combination, and Placebo in Postoperative Pain.

The analgesic efficacy of single 500 and 1,000 mg doses of diflunisal, a new nonsteroidal antiinflammatory analgesic, was compared in a double-blind study with acetaminophen 600 mg, the combination of acetaminophen 600 mg with codeine 60 mg, and placebo in 132 inpatients with postoperative pain. Using a self-rating record, patients rated their pain and its relief hourly for up to 12 hours after medication. Diflunisal 500 and 1,000 mg were significantly superior to placebo for every measure of total and peak analgesia, and a significant analgesic effect persisted for 8 hours. Acetaminophen alone and the acetaminophen-codeine combination were significantly superior to placebo for most measures of analgesia, and their effects were significant for 4 and 5 hours respectively. Differences among the active medications were not statistically significant for measures of total or peak analgesia.

A 12-Hour Evaluation of the Analgesic Efficacy of Diflunisal, Zomepirac Sodium, Aspirin, and Placebo in Postoperative Oral Surgery Pain.

One hundred ninety-nine outpatients with pain following oral surgery were randomly assigned, on a double-blind basis, a single oral dose of diflunisal (500 or 1,000 mg), zomepirac sodium 100 mg, aspirin 650 mg, or placebo. Using a self-rating record, subjects rated their pain and its relief hourly for 12 hours after medication. Measures of total and peak analgesia were derived from these patients' subjective reports. Diflunisal (500 and 1,000 mg) and zomepirac were significantly superior to aspirin and placebo for every measure of total and peak analgesia. Based upon the first 4 hours of observation, aspirin was superior to placebo for every measure of analgesia. Diflunisal 500 and 1,000 mg were comparable to zomepirac in peak analgesia and significantly superior to zomepirac for all measures of total analgesia. The onset of analgesia was comparable for 1,000 mg diflunisal, zomepirac, and aspirin, but more rapid for these treatments than for 500 mg diflunisal. The duration of analgesia was 12 hours for diflunisal, 9 hours for zomepirac, and 3 hours for aspirin.