Stretch‐Induced Increase in Cardiac Contractility Is Independent of Myocyte Ca\u3csup\u3e2+\u3c/sup\u3e While Block of Stretch Channels by Streptomycin Improves Contractility After Ischemic Stunning

Stretching the cardiac left ventricle (LV) enhances contractility but its effect on myoplasmic [Ca2+] is controversial. We measured LV pressure (LVP) and [Ca2+] as a function of intra-LV stretch in guinea pig intact hearts before and after 15 min global stunning ± perfusion with streptomycin (STM), a stretch activated channel blocker. LV wall [Ca2+] was measured by indo-1 fluorescence and LVP by a saline-filled latex balloon inflated in 50 μL steps to stretch the LV. We implemented a mathematical model to interpret crossbridge dynamics and myofilament Ca2+ responsiveness from the instantaneous relationship between [Ca2+] and LVP ± stretching. We found that: (1) stretch enhanced LVP but not [Ca2+] before and after stunning in either control (CON) and STM groups, (2) after stunning [Ca2+] increased in both groups although higher in STM versus CON (56% vs. 39%), (3) STM-enhanced LVP after stunning compared to CON (98% vs. 76% of prestunning values), and (4) stretch-induced effects on LVP were independent of [Ca2+] before or after stunning in both groups. Mathematical modeling suggested: (1) cooperativity in cross-bridge kinetics and myofilament Ca2+ handling is reduced after stunning in the unstretched heart, (2) stunning results in depressed myofilament Ca2+ sensitivity in the presence of attached cross-bridges regardless of stretch, and (3) the initial mechanism responsible for increased contractility during stretch may be enhanced formation of cross-bridges. Thus stretch-induced enhancement of contractility is not due to increased [Ca2+], whereas enhanced contractility after stunning in STM versus CON hearts results from improved Ca2+ handling and/or enhanced actinomyosin cross-bridge cycling

Data-Driven Threat Analysis for Ensuring Security in Cloud Enabled Systems

Cloud computing offers many benefits including business flexibility, scalability and cost savings but despite these benefits, there exist threats that require adequate attention for secure service delivery. Threats in a cloud-based system need to be considered from a holistic perspective that accounts for data, application, infrastructure and service, which can pose potential risks. Data certainly plays a critical role within the whole ecosystem and organisations should take account of and protect data from any potential threats. Due to the variation of data types, status, and location, understanding the potential security concerns in cloud-based infrastructures is more complex than in a traditional system. The existing threat modeling approaches lack the ability to analyse and prioritise data-related threats. The main contribution of the paper is a novel data-driven threat analysis (d-TM) approach for the cloud-based systems. The main motivation of d-TM is the integration of data from three levels of abstractions, i.e., management, control, and business and three phases, i.e., storage, process and transmittance, within each level. The d-TM provides a systematic flow of attack surface analysis from the user agent to the cloud service provider based on the threat layers in cloud computing. Finally, a cloud-based use case scenario was used to demonstrate the applicability of the proposed approach. The result shows that d-TM revealed four critical threats out of the seven threats based on the identified assets. The threats targeted management and business data in general, while targeting data in process and transit more specifically

In search of the right literature search engine(s)

*Background*
Collecting scientific publications related to a specific topic is crucial for different phases of research, health care and ‘effective text mining’. Available bio-literature search engines vary in their ability to scan different sections of articles, for the user-provided search terms and/or phrases. Since a thorough scientific analysis of all major bibliographic tools has not been done, their selection has often remained subjective. We have considered most of the existing bio-literature search engines (http://www.shodhaka.com/startbioinfo/LitSearch.html) and performed an extensive analysis of 18 literature search engines, over a period of about 3 years. Eight different topics were taken and about 50 searches were performed using the selected search engines. The relevance of retrieved citations was carefully assessed after every search, to estimate the citation retrieval efficiency. Different other features of the search tools were also compared using a semi-quantitative method.
*Results*
The study provides the first tangible comparative account of relative retrieval efficiency, input and output features, resource coverage and a few other utilities of the bio-literature search tools. The results show that using a single search tool can lead to loss of up to 75% relevant citations in some cases. Hence, use of multiple search tools is recommended. But, it would also not be practical to use all or too many search engines. The detailed observations made in the study can assist researchers and health professionals in making a more objective selection among the search engines. A corollary study revealed relative advantages and disadvantages of the full-text scanning tools.
*Conclusion*
While many studies have attempted to compare literature search engines, important questions remained unanswered till date. Following are some of those questions, along with answers provided by the current study:
a)	Which tools should be used to get the maximum number of relevant citations with a reasonable effort? ANSWER: _Using PubMed, Scopus, Google Scholar and HighWire Press individually, and then compiling the hits into a union list is the best option. Citation-Compiler (http://www.shodhaka.com/compiler) can help to compile the results from each of the recommended tool._
b)	What is the approximate percentage of relevant citations expected to be lost if only one search engine is used? ANSWER: _About 39% of the total relevant citations were lost in searches across 4 topics; 49% hits were lost while using PubMed or HighWire Press, while 37% and 20% loss was noticed while using Google Scholar and Scopus, respectively._ 
c)	Which full text search engines can be recommended in general? ANSWER: _HighWire Press and Google Scholar._
d)	Among the mostly used search engines, which one can be recommended for best precision? ANSWER: _EBIMed._
e)	Among the mostly used search engines, which one can be recommended for best recall? ANSWER: _Depending on the type of query used, best recall could be obtained by HighWire Press or Scopus.

Mapping an atlas of tissue-specific drosophila melanogaster metabolomes by high resolution mass spectrometry

Metabolomics can provide exciting insights into organismal function, but most work on simple models has focussed on the whole organism metabolome, so missing the contributions of individual tissues. Comprehensive metabolite profiles for ten tissues from adult Drosophila melanogaster were obtained here by two chromatographic methods, a hydrophilic interaction (HILIC) method for polar metabolites and a lipid profiling method also based on HILIC, in combination with an Orbitrap Exactive instrument. Two hundred and forty two polar metabolites were putatively identified in the various tissues, and 251 lipids were observed in positive ion mode and 61 in negative ion mode. Although many metabolites were detected in all tissues, every tissue showed characteristically abundant metabolites which could be rationalised against specific tissue functions. For example, the cuticle contained high levels of glutathione, reflecting a role in oxidative defence; the alimentary canal (like vertebrate gut) had high levels of acylcarnitines for fatty acid metabolism, and the head contained high levels of ether lipids. The male accessory gland uniquely contained decarboxylated S-adenosylmethionine. These data thus both provide valuable insights into tissue function, and a reference baseline, compatible with the FlyAtlas.org transcriptomic resource, for further metabolomic analysis of this important model organism, for example in the modelling of human inborn errors of metabolism, aging or metabolic imbalances such as diabetes

Factors of interrupting chemotherapy in patients with Advanced Non-Small-Cell Lung Cancer

<p>Abstract</p> <p>Background</p> <p>Little is known about prognosis of metastatic patients after receiving a first-line treatment and failure. Our group already showed in pre-treated patients enrolled in phase I clinical trials that a performance status (PS) > 2 and an LDH > 600 UI/L were independent prognostic factors. In this prospective study, which included 45 patients, we identified clinical and biological variables as outcome predictors in metastatic Non-Small Cell lung cancer after first line chemotherapy were identified.</p> <p>Findings</p> <p>Forty-five patients that were previously treated for metastatic disease from 12/2000 to 11/2005 in the comprehensive cancer centre (Centre Léon Bérard). Clinical assessment and blood parameters were recorded and considered. Patient prognostic factors for overall survival (OS) with a 0.05-significance level in univariate analysis were entered in a multivariate Cox model for further analysis.</p> <p>Patients' median age was 58.5 years (range: 37 - 76). Sixty two percent of the patients were PS = 0 or 1. After inclusion, nine patients received second-line (22.5%), and two received third-line chemotherapy (5%). Univariate analysis showed that the factors associated with reduced OS were: PS > 2, weight loss >10%, more than one line of chemotherapy treatment and abnormal blood parameters (hemoglobin (Hb), platelet and neutrophils counts). Multiple regression analysis confirmed that PS > 2 and abnormal hemoglobin were independent predictors for low overall survival. According to the presence of none (33%), 1 (37%) and 2 (30%) prognostic factors, median OS were 12, 5 and 2 months respectively.</p> <p>Conclusion</p> <p>From this prospective study, both PS and anemia were found as independent determinants of survival, we found that both PS and anemia were independent determinants of survival. The combination of poor PS and anemia is an effective strategy to predict survival in the case of patients with metastatic NSCLC receiving further treatment after the first line.</p

Project OPUS: Development and evaluation of an electronic platform for pain management education of medical undergraduates in resource-limited settings

Introduction Pain is a very frequent symptom that is reported by patients when they present to health professionals but remains undertreated or untreated, particularly in low-resource settings including Nigeria. Lack of training in pain management remains the most significant obstacle to pain treatment alongside an inadequate emphasis on pain education in undergraduate medical curricula, negatively impacting on subsequent care of patients. This study aimed to determine the effect of a 12-week structured e-Learning course on the knowledge of pain management among Nigerian undergraduate medical students. Methods Prospective, multisite, pre-post study conducted across five medical colleges in Nigeria. Structured modules covering aspects of pain management were delivered on an e-Learning platform. Pre- and post-test self-assessments were carried out in the 12-week duration of the study. User experience questionnaires and qualitative interviews were conducted via instant messaging to evaluate user experiences of the platform. User experience data was analysed using the UEQ Data Analysis Tool and Framework Analysis. Results A total of 216 of 659 eligible students completed all sections of the e-Learning course. Participant mean age was 23.52 years, with a slight female predominance (55.3%). Across all participants, an increase in median pre- and post-test scores occurred, from 40 to 60 (Z = 11.3, p<0.001, effect size = 1.3), suggestive of increased knowledge acquisition relating to pain management. Participants suggested e-Learning is a valuable approach to delivering pain education alongside identifying factors to address in future iterations. Conclusion e-Learning approaches to pain management education can enhance traditional learning methods and may increase students’ knowledge. Future iterations of e-Learning approaches will need to consider facilitating the download of data and content for the platform to increase user uptake and engagement. The platform was piloted as an optional adjunct to existing curricula. Future efforts to advocate and support integration of e-Learning for pain education should be two-fold; both to include pain education in the curricula of medical colleges across Nigeria and the use of e-Learning approaches to enhance teaching where feasible. Methods: Prospective, multisite, pre-post study conducted across five medical colleges in Nigeria. Structured modules covering aspects of pain management were delivered on an e-Learning platform. Pre- and post-test self-assessments were carried out in the 12-week duration of the study. User experience questionnaires and qualitative interviews were conducted via instant messaging to evaluate user experiences of the platform. User experience data was analysed using the UEQ Data Analysis Tool and Framework Analysis. Results: A total of 216 of 659 eligible students completed all sections of the e-Learning course. Participant mean age was 23.52 years, with a slight female predominance (55.3%). Across all participants, an increase in median pre- and post-test scores occurred, from 40 to 60 (Z=11.3, p<0.001, effect size=1.3), suggestive of increased knowledge acquisition relating to pain management. Participants suggested e-Learning is a valuable approach to delivering pain education alongside identifying factors to address in future iterations. Conclusion: e-Learning approaches to pain management education can enhance traditional learning methods and may increase students’ knowledge. Future iterations of e-Learning approaches will need to consider facilitating the download of data and content for the platform to increase user uptake and engagement. The platform was piloted as an optional adjunct to existing curricula. Future efforts to advocate and support integration of e-Learning for pain education should be two-fold; both to include pain education in the curricula of medical colleges across Nigeria and the use of e-Learning approaches to enhance teaching where feasible

Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma

Background: Uveal melanoma is a disease that is distinct from cutaneous melanoma, with a low tumor mutational burden and a 1-year overall survival of approximately 50% in patients with metastatic uveal melanoma. Data showing a proven overall survival benefit with a systemic treatment are lacking. Tebentafusp is a bispecific protein consisting of an affinity-enhanced T-cell receptor fused to an anti-CD3 effector that can redirect T cells to target glycoprotein 100-positive cells. Methods: In this open-label, phase 3 trial, we randomly assigned previously untreated HLA-A*02:01-positive patients with metastatic uveal melanoma in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with single-agent pembrolizumab, ipilimumab, or dacarbazine (control group), stratified according to the lactate dehydrogenase level. The primary end point was overall survival. Results: A total of 378 patients were randomly assigned to either the tebentafusp group (252 patients) or the control group (126 patients). Overall survival at 1 year was 73% in the tebentafusp group and 59% in the control group (hazard ratio for death, 0.51; 95% confidence interval [CI], 0.37 to 0.71; P<0.001) in the intention-to-treat population. Progression-free survival was also significantly higher in the tebentafusp group than in the control group (31% vs. 19% at 6 months; hazard ratio for disease progression or death, 0.73; 95% CI, 0.58 to 0.94; P = 0.01). The most common treatment-related adverse events in the tebentafusp group were cytokine-mediated events (due to T-cell activation) and skin-related events (due to glycoprotein 100-positive melanocytes), including rash (83%), pyrexia (76%), and pruritus (69%). These adverse events decreased in incidence and severity after the first three or four doses and infrequently led to discontinuation of the trial treatment (2%). No treatment-related deaths were reported. Conclusions: Treatment with tebentafusp resulted in longer overall survival than the control therapy among previously untreated patients with metastatic uveal melanoma. (Funded by Immunocore; ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.). Copyright © 2021 Massachusetts Medical Society

Patterns and Risk Factors of Helminthiasis and Anemia in a Rural and a Peri-urban Community in Zanzibar, in the Context of Helminth Control Programs

In many parts of the developing world, parasitic worms and anemia are of considerable public health and economic importance. We studied the patterns and risk factors of parasitic worm infections in a rural and a peri-urban community on Zanzibar Island, Tanzania, in the context of national deworming programs. We invited 658 individuals aged between 5 and 100 years and examined their stool and urine for the presence of parasitic worm eggs. Additionally, we obtained a finger-prick blood sample to estimate the level of anemia and to assess for specific immune reactions against parasitic worm infections. We found that, despite large-scale deworming efforts in Zanzibar over the past 15 years, three-quarter of the rural participants and half of the peri-urban residents were infected with parasitic worms. Every second participant was anemic. Risk factors for a parasitic worm infection were age, sex, consumption of raw vegetables or salad, recent travel history, and socio-economic status. For a sustainable control of parasitic worm infections and prevention of anemia, access to safe and efficacious drugs, complemented with health education and improvements in water supply and adequate sanitation are necessary

A quantitative systems pharmacology approach, incorporating a novel liver model, for predicting pharmacokinetic drug-drug interactions

All pharmaceutical companies are required to assess pharmacokinetic drug-drug interactions (DDIs) of new chemical entities (NCEs) and mathematical prediction helps to select the best NCE candidate with regard to adverse effects resulting from a DDI before any costly clinical studies. Most current models assume that the liver is a homogeneous organ where the majority of the metabolism occurs. However, the circulatory system of the liver has a complex hierarchical geometry which distributes xenobiotics throughout the organ. Nevertheless, the lobule (liver unit), located at the end of each branch, is composed of many sinusoids where the blood flow can vary and therefore creates heterogeneity (e.g. drug concentration, enzyme level). A liver model was constructed by describing the geometry of a lobule, where the blood velocity increases toward the central vein, and by modeling the exchange mechanisms between the blood and hepatocytes. Moreover, the three major DDI mechanisms of metabolic enzymes; competitive inhibition, mechanism based inhibition and induction, were accounted for with an undefined number of drugs and/or enzymes. The liver model was incorporated into a physiological-based pharmacokinetic (PBPK) model and simulations produced, that in turn were compared to ten clinical results. The liver model generated a hierarchy of 5 sinusoidal levels and estimated a blood volume of 283 mL and a cell density of 193 × 106 cells/g in the liver. The overall PBPK model predicted the pharmacokinetics of midazolam and the magnitude of the clinical DDI with perpetrator drug(s) including spatial and temporal enzyme levels changes. The model presented herein may reduce costs and the use of laboratory animals and give the opportunity to explore different clinical scenarios, which reduce the risk of adverse events, prior to costly human clinical studies