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Active Perception during Angiogenesis: Filopodia speed up Notch selection of tip cells in silico and in vivo
No full textHow do cells make efficient collective decisions during tissue morphogenesis? Humans and other organisms utilize feedback between movement and sensing known as ‘sensorimotor coordination’ or ‘active perception’ to inform behaviour, but active perception has not before been investigated at a cellular level within organs. Here we provide the first proof of concept in silico/in vivo study demonstrating that filopodia (actin-rich, dynamic, finger like cell-membrane protrusions) play an unexpected role in speeding up collective endothelial decisions during the time-constrained process of ‘tip cell’ selection during blood vessel formation (angiogenesis).We first validate simulation predictions in vivo with live imaging of zebrafish intersegmental vessel growth. Further simulation studies then indicate the effect is due to the coupled positive feedback between movement and sensing on filopodia conferring a bistable switch-like property to Notch lateral inhibition, ensuring tip selection is a rapid and robust process. We then employ measures from computational neuroscience to assess whether filopodia function as a primitive (‘basal’) form of active perception and find evidence in support. By viewing cell behaviour through the ‘basal cognitive lens’ we acquire a fresh perspective on the tip cell selection process, revealing a hidden, yet vital time keeping role for filopodia. Finally, we discuss a myriad of new and exciting research directions stemming from our conceptual approach to interpreting cell behaviour
Estimates of Serious Fungal Infection burden in Côte d’Ivoire and Country Health Profile
No full textDue to limited access to more powerful diagnostic tools, there are few data on the burden of fungal infections in Côte d’Ivoire, despite a high HIV and TB burden and many cutaneous diseases. Here we estimate the burden of serious fungal infections in this sub-Saharan country with a health profiling description. National demographics were used and PubMed searches to retrieve all published articles on fungal infections in Côte d’Ivoire and other bordering countries in West Africa. When no data existed, risk populations were used to estimate frequencies of fungal infections, using previously described methodology by LIFE (www.LIFE-Worldwide.org). The population of Côte d’Ivoire is around 25 million; 37% are children (≤14 years), and 9% are >65 years. Tinea capitis in children is common, measured at 13.9% in 2013. Considering the prevalence of HIV infection (2.6% of the population, a total of ~500,000) and a hospital incidence of 12.7% of cryptococcosis, it is estimated that 4,590 patients per year develop cryptococcosis. For pneumocystosis, it is suggested that 2,640 new cases occur each year with the prevalence of 11% of newly diagnosed HIV adults, and 33% of children with HIV/AIDS. Disseminated histoplasmosis is estimated a 1.4% of advanced HIV disease – 513 cases. An estimated 6,568 news cases of chronic pulmonary aspergillosis (CPA) occur after pulmonary tuberculosis (a 5-year prevalence of 6,568 cases (26/100,000)). Allergic bronchopulmonary aspergillosis (ABPA) and severe asthma with fungal sensitisation (SAFS) were estimated in 104/100,000 and 151/100,000 respectively, in 1,152,178 adult asthmatics. Vulvovaginal candidiasis (VVC) is common and recurrent VVC affects ~6% of women in their fertile years - 421,936 women. An unknown number develop candidaemia and invasive aspergillosis. The annual incidence of fungal keratitis is estimated at 3350. No cases of sporotrichosis, mucormycosis and chromoblastomycosis are described, although some cases of mycetoma and Conidiobolus infection have been reported. This study indicates that around to 7.25% (1.8 million) of the population is affected by a serious fungal infection, predominently tinea capitis in children and rVVC in women. These data should be used to inform epidemiological studies, diagnostic needs and therapeutic strategies in Côte d’Ivoire
Brief report: Four-year survival with durvalumab after chemoradiotherapy in Stage III NSCLC – an update from the PACIFIC trial
No full textBackground: In the phase-3, placebo-controlled PACIFIC trial of patients with unresectable, stage III non-small-cell lung cancer (NSCLC) without disease progression after concurrent chemoradiotherapy (CRT), consolidative durvalumab was associated with significant improvements in the primary endpoints of overall survival (OS) (HR, 0.68; 95% CI, 0.53–0.87; P=0.00251; data-cutoff, 22-March-2018) and progression-free survival (PFS; blinded-independent-central-review; RECIST-v1.1) (HR, 0.52; 95% CI, 0.42–65; P<0.0001; 13-February-2017) with manageable safety. We report updated analyses of OS and PFS, approximately 4 years after the last patient was randomized. Methods: Patients with WHO PS 0/1 (any tumor PD-L1 status) were randomized (2:1) to intravenous durvalumab (10 mg/kg), or placebo, every-2-weeks (≤12 months), stratified by age, sex, and smoking history. OS/PFS were analyzed using a stratified log-rank test in the intent-to-treat population. Medians and 4-year OS/PFS rates were estimated by Kaplan-Meier method. Results: Overall, 709/713 randomized patients received durvalumab (n/N=473/476) or placebo (n/N=236/237). As of 20-March-2020 (median follow-up, 34.2 months; range, 0.2–64.9), updated OS (HR, 0.71; 95% CI, 0.57–0.88) and PFS (HR, 0.55; 95% CI, 0.44–0.67) remained consistent with the primary analyses. Median OS for durvalumab was reached (47.5 months; placebo, 29.1 months). Estimated 4-year OS rates were 49.6% versus 36.3% for durvalumab versus placebo, and 4-year PFS rates were 35.3% versus 19.5% respectively. Conclusions: These updated, exploratory analyses demonstrate durable PFS and sustained OS benefit with durvalumab following CRT. An estimated 49.6% of patients randomized to durvalumab remain alive at 4 years (placebo, 36.3%), and 35.3% remain alive and progression free (placebo, 19.5%)
The Thousand-Pulsar-Array programme on MeerKAT II: observing strategy for pulsar monitoring with subarrays
No full textThe Thousand Pulsar Array (TPA) project currently monitors about 500 pulsars with the sensitive MeerKAT radio telescope by using subarrays to observe multiple sources simultaneously. Here we define the adopted observing strategy, which guarantees that each target is observed long enough to obtain a high fidelity pulse profile, thereby reaching a sufficient precision of a simple pulse shape parameter. This precision is estimated from the contribution of the system noise of the telescope, and the pulse-to-pulse variability of each pulsar, which we quantify under some simplifying assumptions. We test the assumptions and choice of model parameters using data from the MeerKAT 64-dish array, Lovell and Parkes telescopes. We demonstrate that the observing times derived from our method produce high fidelity pulse profiles that meet the needs of the TPA in studying pulse shape variability and pulsar timing. Our method can also be used to compare strategies for observing large numbers of pulsars with telescopes capable of forming multiple subarray configurations. We find that using two 32-dish MeerKAT subarrays is the most efficient strategy for the TPA project. We also find that the ability to observe in different array configurations will become increasingly important for large observing programmes using the Square Kilometre Array telescope
Development of an open-source thermally stabilized quartz crystal microbalance instrument for biomolecule-substrate binding assays on gold and graphene
No full textThe interaction of biomolecules, such as proteins, with biomaterial surfaces is key to disease diagnostic andtherapeutic development applications. There is a significant need for rapid, low-cost, field-serviceableinstruments to monitor such interactions, where open-source tools can help to improve the accessibility todisease screening instruments especially in low- and middle-income countries. We have developed andevaluated a low-cost integrated quartz crystal microbalance (QCM) instrument for biomolecular analysisbased on an open-source QCM device. The custom QCM instrument was equipped with a custom-madeelectronically controlled isothermal chamber with a closed-loop control routine. A thermal coefficient of5.6 ppm/°C was obtained from a series of evaluations of the implemented control. Additionally, a customdesigneddata acquisition system and a mathematical processing and analysis tool is implemented. Thequartz crystal detection chips used here incorporate gold and reduced graphene oxide (rGO) coated surfaces.We demonstrate the system capability to monitor and record the biomolecular interaction between a typicalprotein bovine serum albumin (BSA) and these two substrates. This instrument was compared to acommercial QCM, demonstrating good correspondence between the computed mass adsorption densityresponses using the Sauerbrey model. For both Au and rGO surfaces, the custom QCM significantlyoutperforms the commercial system in limit of detection, sensitivity and linear range. The instrumentpresented here has the potential to serve as a ubiquitous bioelectronic tool for point-of-care diseasescreening and rapid therapeutics development
Unraveling the influence of residence time distribution on the performance of reactive distillation – process optimization and experimental validation
No full textThis work is the first to explore the influence and illustrate the impact of the stage average residence time distribution (SARTD) in the reaction section on the performance of reactive distillation (RD) systems, providing guidance for the design of the internals and industrial applications of RD processes. The experimental validation and process optimization were performed using the ethyl levulinate production as case study. Kinetics of the esterification reaction between levulinic acid (LA) and ethanol was explored using an ionexchange resin as catalyst, and then fitted by a pseudo-homogeneous model, providing basic data for subsequent RD pilot-scale experiment and process simulations. The RD experimentwas firstly successfully carried out for two catalyst-loading conditions (uniform or non uniform per stage) to illustrate the impact of SARDT on the RD performance. The experimental results show that the conversion of LA increases by about 10% after catalyst loading redistribution. A genetic algorithm (GA) with global convergence and fast convergence speed was used to realize the optimization of SARTD instead of using arbitrary settings. The objective function to be minimized was the reboiler duty per unit product (RDP). The optimization results show that the conversion of LA increases by 3.06% (percentagepoints) and RDP decreases by 10.09% if the SARTD is optimally redistributed. Based on this, it can be predicted that the total catalyst-loading can be reduced by reasonable catalyst redistribution in the industrial applications of RD. In addition, a new method for optimal design of SARTD is proposed, paving the way for optimizing other RD processes
Qualitative evaluation of a community-based cancer awareness initiative: Views of those delivering and managing the intervention
No full textAim: Many people delay presenting to health services with cancer symptoms due to lack of awareness, particularly in areas of high socioeconomic deprivation. A three-year community-based intervention was launched in Northwest England to improve public awareness of cancer symptoms. In this study, we aimed to evaluate this intervention by exploring the views of those involved in its management and delivery.Methods: Ten semi-structured interviews were conducted with volunteers as well as members of the project management and steering group. Interviews were analysed qualitatively using thematic analysis. Results: Participants felt they succeeded in raising awareness, influencing behaviour, connecting with local communities and engaging with vulnerable people. Participants perceived some weaknesses in the delivery of the intervention, including limited engagement of stakeholders, particularly general practitioners (GPs), and socially excluded groups. Conclusions: Future public health interventions should pay particular attention to engagement of socially excluded individuals who do not interact with community events or groups, and to the engagement of stakeholders in early planning stages of the intervention. This should involve a specific GP engagement plan.<br/
Real-world hearing aid usage patterns and smartphone connectivity
No full textData for monitoring individual hearing aid usage has historically been limited to retrospective questionnaires or data logged intrinsically in the hearing aid cumulatively over time (e.g. days or more). This limits the investigation of longitudinal interactions between hearing aid use and environmental or behavioral factors. Recently it has become possible to analyze remotely logged hearing aid data from in-market and smartphone compatible hearing aids. This can provide access to novel insights about individual hearing aid usage patterns and their association to environmental factors. Here, we use remotely logged longitudinal data from 64 hearing aid users to establish basic norms regarding smartphone connectivity (i.e., comparing remotely logged data with cumulative true hearing aid on-time) and to assess whether such data can provide representative information about ecological usage patterns. The remotely logged data consists of minute-by-minute timestamped logs of cumulative hearing aid on-time and characteristics of the momentary acoustic environment. Using K-means clustering, we demonstrate that hourly hearing aid usage patterns (i.e., usage as minutes/hour) across participants are separated by four clusters that account for almost 50% of the day-to-day variation. The clusters indicate that hearing aids are worn either sparsely throughout the day; early morning to afternoon; from noon to late evening; or across the day from morning to late evening. Using linear mixed-effects regression modeling, we document significant associations between daily signal-to-noise, sound intensity, and sound diversity with hearing aid usage. Participants encounter louder, noisier, and more diverse sound environments the longer the hearing aids are worn. Finally, we find that remote logging via smartphones underestimates the daily hearing aid usage with a pooled median of 1.25 hours, suggesting an overall connectivity of 85%. The 1.25 hour difference is constant across days varying in total hearing aid on-time, and across participants varying in average daily hearing aid-on-time, and it does not depend on the identified patterns of daily hearing aid usage. In sum, remote data logging with hearing aids has high representativeness and face-validity, and can offer ecologically true information about individual usage patterns and the interaction between usage and everyday contexts
Identifying targets for interventions to increase uptake and use of hearing protection in noisy recreational settings
No full textInterventions to increase hearing protection behaviours within noisy recreational settings are limited by the lack of an underpinning evidence base. The aim of the present study was to identify targets for interventions in a population exposed to recreational noise, including those who had used hearing protection (ever-performers) versus those who had not (never-performers). A cross-sectional survey was administered to 185 UK adults who had been involved in noisy recreational activities. Participants had an average age of 36.79 years, a majority were women (68.1%), from a white ethic background (87.6%), and with non-manual occupations (75.7%). Using chi-square, MANOVA and ANOVA we looked for differences in sociodemographic variables and variables from the capabilities, opportunities and motivations model of behaviour change (COM-B) between ever- and never-performers. Ever-performers were more likely to be younger (p<.050), men (p<.050), and in a manual occupation (p<.050) compared to never-performers. Although the two groups felt capable and reported similar opportunities to use hearing protection, never-performers lacked automatic motivation (p<.001) and reflective motivation (p<.001) compared to ever-performers. For the first time, the present study identifies potential groups at whom hearing protection interventions might be targeted and what those interventions may contain. Further work is required to develop interventions targeted at older people, women and those in non-manual occupations. Lack of motivation is a key concern and further work that uses specific theoretical frameworks such as the PRIME (Plans, Responses, Impulses, Motives, and Evaluations) theory of motivation, may shed light on the kinds of interventions that are needed to boost hearing protection use effectively
Druggable molecular alterations in bile duct cancer: potential and current therapeutic applications in clinical trials
No full textIntroduction: Cholangiocarcinomas (CCA) are rare tumors that are associated with a variety of molecular alterations. Many of these alterations are now actionable using drugs currently in development, and CCA may be a perfect example of application of a precision oncology approach. However, development of drugs in CCA faces the challenge of targeting rare alterations in a rare disease.Areas covered: In this review, we present the current data on targeted therapies in development for CCA, focusing on IDH1, FGFR2, BRAF and HER2 alterations. We also discuss rationale for targeting other alterations, currently without specific development in CCA. We searched pubmed and google scholar in February 2021 for relevant articles and presentation in recent congress regarding the literature on molecular alterations, drugs in cholangiocarcinomas and biliary tract cancers.Expert opinion: Despite a strong rationale and promising early results, applying a precision oncology approach in CCA for everyday patients is still exposed to significant challenges: obtaining the molecular portrait of these tumors due to difficulties with biopsy access, complexities of drug development in subgroups of these relatively rare tumors, and sub-optimal access to drugs outside clinical trials