Molecular docking, molecular dynamics simulations and binding free energy studies of interactions between Mycobacterium tuberculosis Pks13, PknG and bioactive constituents of extremophilic bacteria.

Mycobacterial pathogens present a significant challenge to disease control efforts globally due to their inherent resistance to multiple antibiotics. The rise of drug-resistant strains of Mycobacterium tuberculosis has prompted an urgent need for innovative therapeutic solutions. One promising way to discover new tuberculosis drugs is by utilizing natural products from the vast biochemical space. Multidisciplinary methods can used to harness the bioactivity of these natural products. This study aimed to evaluate the antimycobacterial efficacy of functional crude extracts from bacteria isolated from gold mine tailings in South Africa. Bacterial strains were identified using 16S rRNA sequencing. The crude extracts obtained from the bacteria were tested against Mycobacterium tuberculosis H37Rv, Mycobacterium smegmatis mc2155, and Mycobacterium aurum A+. Untargeted HPLC-qTOF and molecular networking were used to identify the functional constituents present in extracts that exhibited inhibitory activity. A virtual screening workflow (VSW) was used to filter compounds that were strong binders to Mycobacterium tuberculosis Pks13 and PknG. The ligands returned from the VSW were subjected to optimization using density functional theory (DFT) at M06-2X/6-311++ (d,p) level of theory and basis set implemented in Gaussian16 Rev.C01. The optimized ligands were re-docked against Mycobacterium tuberculosis Pks13 and PknG. Molecular dynamics simulation and molecular mechanics generalized born surface area were used to evaluate the stability of the protein-ligand complexes formed by the identified hits. The hit that showed promising binding characteristics was virtually modified through multiple synthetic routes using reaction-driven enumeration. Three bacterial isolates showed significant activity against the two strains of Mycobacterium, while only two, Bacillus subtilis and Bacillus licheniformis, exhibited activity against both Mycobacterium tuberculosis H37Rv, Mycobacterium smegmatis mc2155, and Mycobacterium aurum A+. The tentatively identified compounds from the bacterial crude extracts belonged to various classes of natural compounds associated with antimicrobial activity. Two compounds, cyclo-(L-Pro-4-OH-L-Leu) and vazabitide A, showed strong binding against PknG and Pks13, with pre-MD MM-GBSA values of - 42.8 kcal/mol and - 47.6 kcal/mol, respectively. The DFT-optimized compounds exhibited the same docking scores as the ligands optimized using the OPSL-4 force field. After modifying vazabitide A, its affinity to the Pks13 binding site increased to - 85.8 kcal/mol, as revealed by the post-MD MM-GBSA analysis. This study highlights the potential of bacteria isolates from gold mine tailings as a source of new scaffolds for designing and optimizing anti-Mycobacterium agents. These agents synthesized in-silico can be further tested in-vitro to evaluate their efficacy.

Transcarotid versus transaxillary access for transcatheter aortic valve replacement with a self-expanding valve: A propensity-matched analysis.

Transaxillary access has been the most frequently used nonfemoral access route for transcatheter aortic valve replacement (TAVR) with a self-expanding valve. Use of transcarotid TAVR is increasing; however, comparative data on these methods are limited. We compared outcomes following transcarotid or transaxillary TAVR with a self-expanding, supra-annular valve. Methods: The Transcatheter Valve Therapy Registry was queried for TAVR procedures using transaxillary and transcarotid access between July 2015 and June 2021. Patients received a self-expanding Evolut R, PRO, or PRO + valve (Medtronic) and had 1-year follow-up. Thirty-day and 1-year outcomes were compared in transcarotid and transaxillary groups after 1:2 propensity score-matching. Multivariable regression models were fitted to identify predictors of key end points. Results: The propensity score-matched cohort included 576 patients receiving transcarotid and 1142 receiving transaxillary access. Median procedure time (99 vs 118 minutes; P < .001) and hospital stay (2 vs 3 days; P < .001) were shorter with transcarotid versus transaxillary access. At 30 days, patients with transcarotid access had similar mortality (Kaplan-Meier estimates 3.7% vs 4.3%, P = .57) but significantly lower stroke (3.1% vs 5.9%; P = .017) and mortality or stroke (6.0% vs 8.9%; P = .033) compared with patients receiving transaxillary access. Similar differences were observed at 1 year. Transaxillary access was associated with increased risk of 30-day stroke (hazard ratio, 2.14; 95% confidence interval, 1.27-3.58) by multivariable regression analysis. Conclusions: Transcarotid versus transaxillary access for TAVR using a self-expanding valve is associated with procedural benefits and significantly lower stroke and mortality or stroke at 30 days. In patients with unsuitable femoral anatomy, transcarotid access may be the preferred delivery route for self-expanding valves.

Rare disease variant curation from literature: assessing gaps with creatine transport deficiency in focus.

BACKGROUND: Approximately 4-8% of the world suffers from a rare disease. Rare diseases are often difficult to diagnose, and many do not have approved therapies. Genetic sequencing has the potential to shorten the current diagnostic process, increase mechanistic understanding, and facilitate research on therapeutic approaches but is limited by the difficulty of novel variant pathogenicity interpretation and the communication of known causative variants. It is unknown how many published rare disease variants are currently accessible in the public domain. RESULTS: This study investigated the translation of knowledge of variants reported in published manuscripts to publicly accessible variant databases. Variants, symptoms, biochemical assay results, and protein function from literature on the SLC6A8 gene associated with X-linked Creatine Transporter Deficiency (CTD) were curated and reported as a highly annotated dataset of variants with clinical context and functional details. Variants were harmonized, their availability in existing variant databases was analyzed and pathogenicity assignments were compared with impact algorithm predictions. 24% of the pathogenic variants found in PubMed articles were not captured in any database used in this analysis while only 65% of the published variants received an accurate pathogenicity prediction from at least one impact prediction algorithm. CONCLUSIONS: Despite being published in the literature, pathogenicity data on patient variants may remain inaccessible for genetic diagnosis, therapeutic target identification, mechanistic understanding, or hypothesis generation. Clinical and functional details presented in the literature are important to make pathogenicity assessments. Impact predictions remain imperfect but are improving, especially for single nucleotide exonic variants, however such predictions are less accurate or unavailable for intronic and multi-nucleotide variants. Developing text mining workflows that use natural language processing for identifying diseases, genes and variants, along with impact prediction algorithms and integrating with details on clinical phenotypes and functional assessments might be a promising approach to scale literature mining of variants and assigning correct pathogenicity. The curated variants list created by this effort includes context details to improve any such efforts on variant curation for rare diseases.

Tandem LC-MS Identification of Antitubercular Compounds in Zones of Growth Inhibition Produced by South African Filamentous Actinobacteria.

Novel antitubercular compounds are urgently needed to combat drug-resistant Mycobacterium tuberculosis (Mtb). Filamentous actinobacteria have historically been an excellent source of antitubercular drugs. Despite this, drug discovery from these microorganisms has fallen out of favour due to the continual rediscovery of known compounds. To increase the chance of discovering novel antibiotics, biodiverse and rare strains should be prioritised. Subsequently, active samples need to be dereplicated as early as possible to focus efforts on truly novel compounds. In this study, 42 South African filamentous actinobacteria were screened for antimycobacterial activity using the agar overlay method against the Mtb indicator Mycolicibacterium aurum under six different nutrient growth conditions. Known compounds were subsequently identified through extraction and high-resolution mass spectrometric analysis of the zones of growth inhibition produced by active strains. This allowed the dereplication of 15 hits from six strains that were found to be producing puromycin, actinomycin D and valinomycin. The remaining active strains were grown in liquid cultures, extracted and submitted for screening against Mtb in vitro. Actinomadura napierensis B60T was the most active sample and was selected for bioassay-guided purification. This resulted in the identification of tetromadurin, a known compound, but which we show for the first time to have potent antitubercular activity, with the MIC90s within the range of 73.7-151.6 nM against M. tuberculosis H37RvTin vitro under different test conditions. This shows that South African actinobacteria are a good source of novel antitubercular compounds and warrant further screening. It is also revealed that active hits can be dereplicated by HPLC-MS/MS analysis of the zones of growth inhibition produced by the agar overlay technique.

Efficacies and ADME properties of redox active methylene blue and phenoxazine analogues for use in new antimalarial triple drug combinations with amino-artemisinins.

Efforts to develop new artemisinin triple combination therapies effective against artemisinin-tolerant strains of Plasmodium falciparum based on rational combinations comprising artemisone or other amino-artemisinins, a redox active drug and a third drug with a different mode of action have now been extended to evaluation of three potential redox partners. These are the diethyl analogue AD01 of methylene blue (MB), the benzo [α]phenoxazine PhX6, and the thiosemicarbazone DpNEt. IC50 values in vitro against CQ-sensitive and resistant P. falciparum strains ranged from 11.9 nM for AD01-41.8 nM for PhX6. PhX6 possessed the most favourable pharmacokinetic (PK) profile: intrinsic clearance rate CLint was 21.47 ± 1.76 mL/min/kg, bioavailability was 60% and half-life was 7.96 h. AD01 presented weaker, but manageable pharmacokinetic properties with a rapid CLint of 74.41 ± 6.68 mL/min/kg leading to a half-life of 2.51 ± 0.07 h and bioavailability of 15%. DpNEt exhibited a half-life of 1.12 h and bioavailability of 8%, data which discourage its further examination, despite a low CLint of 10.20 mL/min/kg and a high Cmax of 6.32 µM. Efficacies of AD01 and PhX6 were enhanced synergistically when each was paired with artemisone against asexual blood stages of P. falciparum NF54 in vitro. The favourable pharmacokinetics of PhX6 indicate this is the best partner among the compounds examined thus far for artemisone. Future work will focus on extending the drug combination studies to artemiside in vitro, and conducting efficacy studies in vivo for artemisone with each of PhX6 and the related benzo[α]phenoxazine SSJ-183.

The evaluation of ADME and pharmacokinetic properties of decoquinate derivatives for the treatment of malaria.

The emergence of Plasmodium falciparum (Pf) parasite strains tolerant of the artemisinin component and resistant to the other drug component in artemisinin combination therapies (ACTs) used for treatment now markedly complicates malaria control. Thus, development of new combination therapies are urgently required. For the non-artemisinin component, the quinolone ester decoquinate (DQ) that possesses potent activities against blood stage Pf and acts on a distinct target, namely the Pf cytochrome bc 1 complex, was first considered. However, DQ has poor drug properties including high lipophilicity and exceedingly poor aqueous solubility (0.06 µg/ml), rendering it difficult to administer. Thus, DQ was chemically modified to provide the secondary amide derivative RMB005 and the quinoline O-carbamate derivatives RMB059 and RMB060. The last possesses sub-nanomolar activities against multidrug resistant blood stages of Pf, and P. berghei sporozoite liver stages. Here we present the results of ADME analyses in vitro and pharmacokinetic analyses using C57BL/6 mice. The amide RMB005 had a maximum mean whole blood concentration of 0.49 ± 0.02 µM following oral administration; however, the area under the curve (AUC), elimination half-life (t1/2) and bioavailability (BA) were not significantly better than those of DQ. Surprisingly, the quinoline O-carbamates which can be recrystallized without decomposition were rapidly converted into DQ in human plasma and blood samples. The maximum concentrations of DQ reached after oral administration of RMB059 and RMB060 were 0.23 ± 0.05 and 0.11 ± 0.01 µM, the DQ elimination half-lives were 4.79 ± 1.66 and 4.66 ± 1.16 h, and the DQ clearance were 19.40 ± 3.14 and 21.50 ± 3.38 respectively. Under these assay conditions, the BA of DQ could not be calculated Overall although RMB059 and -060 are labile in physiological medium with respect to the DQ parent, the potential to apply these as prodrugs is apparent from the current data coupled with their ease of preparation.

Discovery of Novel Cyclic Ethers with Synergistic Antiplasmodial Activity in Combination with Valinomycin.

With drug resistance threatening our first line antimalarial treatments, novel chemotherapeutics need to be developed. Ionophores have garnered interest as novel antimalarials due to their theorized ability to target unique systems found in the Plasmodium-infected erythrocyte. In this study, during the bioassay-guided fractionation of the crude extract of Streptomyces strain PR3, a group of cyclodepsipeptides, including valinomycin, and a novel class of cyclic ethers were identified and elucidated. Further study revealed that the ethers were cyclic polypropylene glycol (cPPG) oligomers that had leached into the bacterial culture from an extraction resin. Molecular dynamics analysis suggests that these ethers are able to bind cations such as K+, NH4+ and Na+. Combination studies using the fixed ratio isobologram method revealed that the cPPGs synergistically improved the antiplasmodial activity of valinomycin and reduced its cytotoxicity in vitro. The IC50 of valinomycin against P. falciparum NF54 improved by 4-5-fold when valinomycin was combined with the cPPGs. Precisely, it was improved from 3.75 ± 0.77 ng/mL to 0.90 ± 0.2 ng/mL and 0.75 ± 0.08 ng/mL when dosed in the fixed ratios of 3:2 and 2:3 of valinomycin to cPPGs, respectively. Each fixed ratio combination displayed cytotoxicity (IC50) against the Chinese Hamster Ovary cell line of 57-65 µg/mL, which was lower than that of valinomycin (12.4 µg/mL). These results indicate that combinations with these novel ethers may be useful in repurposing valinomycin into a suitable and effective antimalarial.

The Critical Importance of Spatial and Temporal Scales in Designing and Interpreting Immune Cell Migration Assays.

Intravital microscopy and other direct-imaging techniques have allowed for a characterisation of leukocyte migration that has revolutionised the field of immunology, resulting in an unprecedented understanding of the mechanisms of immune response and adaptive immunity. However, there is an assumption within the field that modern imaging techniques permit imaging parameters where the resulting cell track accurately captures a cell's motion. This notion is almost entirely untested, and the relationship between what could be observed at a given scale and the underlying cell behaviour is undefined. Insufficient spatial and temporal resolutions within migration assays can result in misrepresentation of important physiologic processes or cause subtle changes in critical cell behaviour to be missed. In this review, we contextualise how scale can affect the perceived migratory behaviour of cells, summarise the limited approaches to mitigate this effect, and establish the need for a widely implemented framework to account for scale and correct observations of cell motion. We then extend the concept of scale to new approaches that seek to bridge the current "black box" between single-cell behaviour and systemic response.

Anomaly Detection and Automatic Labeling for Solar Cell Quality Inspection Based on Generative Adversarial Network.

Quality inspection applications in industry are required to move towards a zero-defect manufacturing scenario, with non-destructive inspection and traceability of 100% of produced parts. Developing robust fault detection and classification models from the start-up of the lines is challenging due to the difficulty in getting enough representative samples of the faulty patterns and the need to manually label them. This work presents a methodology to develop a robust inspection system, targeting these peculiarities, in the context of solar cell manufacturing. The methodology is divided into two phases: In the first phase, an anomaly detection model based on a Generative Adversarial Network (GAN) is employed. This model enables the detection and localization of anomalous patterns within the solar cells from the beginning, using only non-defective samples for training and without any manual labeling involved. In a second stage, as defective samples arise, the detected anomalies will be used as automatically generated annotations for the supervised training of a Fully Convolutional Network that is capable of detecting multiple types of faults. The experimental results using 1873 Electroluminescence (EL) images of monocrystalline cells show that (a) the anomaly detection scheme can be used to start detecting features with very little available data, (b) the anomaly detection may serve as automatic labeling in order to train a supervised model, and (c) segmentation and classification results of supervised models trained with automatic labels are comparable to the ones obtained from the models trained with manual labels.

Toward New Transmission-Blocking Combination Therapies: Pharmacokinetics of 10-Amino-Artemisinins and 11-Aza-Artemisinin and Comparison with Dihydroartemisinin and Artemether.

As artemisinin combination therapies (ACTs) are compromised by resistance, we are evaluating triple combination therapies (TACTs) comprising an amino-artemisinin, a redox drug, and a third drug with a different mode of action. Thus, here we briefly review efficacy data on artemisone, artemiside, other amino-artemisinins, and 11-aza-artemisinin and conduct absorption, distribution, and metabolism and excretion (ADME) profiling in vitro and pharmacokinetic (PK) profiling in vivo via intravenous (i.v.) and oral (p.o.) administration to mice. The sulfamide derivative has a notably long murine microsomal half-life (t1/2 > 150 min), low intrinsic liver clearance and total plasma clearance rates (CLint 189.4, CLtot 32.2 ml/min/kg), and high relative bioavailability (F = 59%). Kinetics are somewhat similar for 11-aza-artemisinin (t1/2 > 150 min, CLint = 576.9, CLtot = 75.0 ml/min/kg), although bioavailability is lower (F = 14%). In contrast, artemether is rapidly metabolized to dihydroartemisinin (DHA) (t1/2 = 17.4 min) and eliminated (CLint = 855.0, CLtot = 119.7 ml/min/kg) and has low oral bioavailability (F) of 2%. While artemisone displays low t1/2 of <10 min and high CLint of 302.1, it displays a low CLtot of 42.3 ml/min/kg and moderate bioavailability (F) of 32%. Its active metabolite M1 displays a much-improved t1/2 of >150 min and a reduced CLint of 37.4 ml/min/kg. Artemiside has t1/2 of 12.4 min, CLint of 673.9, and CLtot of 129.7 ml/kg/min, likely a reflection of its surprisingly rapid metabolism to artemisone, reported here for the first time. DHA is not formed from any amino-artemisinin. Overall, the efficacy and PK data strongly support the development of selected amino-artemisinins as components of new TACTs.

Referral for Imaging in Physical Therapist Practice: Key Recommendations for Successful Implementation.

In recent years, the use of diagnostic imaging in physical therapist practice in the United States has gained considerable interest. In several countries around the world and in the US military, patient direct referral for diagnostic imaging has been considered normative practice for decades. US physical therapy program accreditation standards now stipulate that diagnostic imaging content must be included in physical therapist educational curricula. The American Physical Therapy Association has made efforts to pursue practice authority for imaging referral. A recent review of state practice acts and other statutory language concluded that many states have no prohibitions against physical therapists referring for imaging studies. Additionally, physical therapists can now pursue certification as musculoskeletal sonographers. In light of these advances, and with a growing number of physical therapists serving patients who have not yet seen another health care provider, it may be helpful for those who have been actively involved in the use of imaging in physical therapist practice to provide their collective recommendations to serve as a guideline to those interested in incorporating this practice privilege. The purpose of this perspective article is to provide an overview of the key elements necessary for effective implementation of referral for imaging in physical therapist practice while emphasizing the cornerstone of effective communication.

Wearable Technology May Assist in Retraining Foot Strike Patterns in Previously Injured Military Service Members: A Prospective Case Series.

A rearfoot strike (RFS) pattern with increased average vertical loading rates (AVLR) while running has been associated with injury. This study evaluated the ability of an instrumented sock, which provides real-time foot strike and cadence audio biofeedback, to transition previously injured military service members from a RFS to a non-rearfoot strike (NRFS) running pattern. Nineteen RFS runners (10 males, 9 females) were instructed to wear the instrumented socks to facilitate a change in foot strike while completing an independent walk-to-run progression and lower extremity exercise program. Kinetic data were collected during treadmill running while foot strike was determined using video analysis at initial (T1), post-intervention (T2), and follow-up (T3) data collections. Nearly all runners (18/19) transitioned to a NRFS pattern following intervention (8 ± 2.4 weeks after the initial visit). Most participants (16/18) maintained the transition at follow-up (5 ± 0.8 weeks after the post-intervention visit). AVLR of the involved and uninvolved limb decreased 29% from initial [54.7 ± 13.2 bodyweights per sec (BW/s) and 55.1 ± 12.7 BW/s] to post-intervention (38.7 ± 10.1 BW/s and 38.9 ± 10.0 BW/s), respectively. This effect persisted 5-weeks later at follow-up, representing an overall 30% reduction on the involved limb and 24% reduction on the uninvolved limb. Cadence increased from the initial to the post-intervention time-point (p = 0.045); however, this effect did not persist at follow-up (p = 0.08). With technology provided feedback from instrumented socks, approximately 90% of participants transitioned to a NRFS pattern, decreased AVLR, reduced stance time and maintained these running adaptations 5-weeks later.

A Novel Ventilator Design for COVID-19 and Resource-Limited Settings.

There has existed a severe ventilator deficit in much of the world for many years, due in part to the high cost and complexity of traditional ICU ventilators. This was highlighted and exacerbated by the emergence of the COVID-19 pandemic, during which the increase in ventilator production rapidly overran the global supply chains for components. In response, we propose a new approach to ventilator design that meets the performance requirements for COVID-19 patients, while using components that minimise interference with the existing ventilator supply chains. The majority of current ventilator designs use proportional valves and flow sensors, which remain in short supply over a year into the pandemic. In the proposed design, the core components are on-off valves. Unlike proportional valves, on-off valves are widely available, but accurate control of ventilation using on-off valves is not straightforward. Our proposed solution combines four on-off valves, a two-litre reservoir, an oxygen sensor and two pressure sensors. Benchtop testing of a prototype was performed with a commercially available flow analyser and test lungs. We investigated the accuracy and precision of the prototype using both compressed gas supplies and a portable oxygen concentrator, and demonstrated the long-term durability over 15 days. The precision and accuracy of ventilation parameters were within the ranges specified in international guidelines in all tests. A numerical model of the system was developed and validated against experimental data. The model was used to determine usable ranges of valve flow coefficients to increase supply chain flexibility. This new design provides the performance necessary for the majority of patients that require ventilation. Applications include COVID-19 as well as pneumonia, influenza, and tuberculosis, which remain major causes of mortality in low and middle income countries. The robustness, energy efficiency, ease of maintenance, price and availability of on-off valves are all advantageous over proportional valves. As a result, the proposed ventilator design will cost significantly less to manufacture and maintain than current market designs and has the potential to increase global ventilator availability.

Three-Year Outcomes With a Contemporary Self-Expanding Transcatheter Valve From the Evolut PRO US Clinical Study.

BACKGROUND: Paravalvular regurgitation (PVR) following transcatheter aortic valve replacement (TAVR) is associated with increased morbidity and mortality. PVR continues to plague TAVR jeopardizing long-term results. New device iterations, such as the self-expandable Evolut PRO valve, aim to decrease PVR while maintaining optimal hemodynamics. This study sought to evaluate clinical and hemodynamic performance of the Evolut PRO system at 3 years. METHODS: The Evolut PRO US Clinical Study included 60 patients at high or extreme surgical risk undergoing TAVR with the Evolut PRO valve at 8 centers in the United States. Clinical outcomes were evaluated using Valve Academic Research Consortium (VARC)-2 criteria and included all-cause mortality, cardiovascular mortality, disabling stroke and valve complications. An independent core laboratory centrally assessed all echocardiographic measures. RESULTS: At 3 years, all-cause mortality was 25.8% (cardiovascular mortality 16.5%) and the disabling stroke rate was 10.7%. There were no cases of repeat valve intervention, endocarditis or coronary obstruction. Valve thrombosis was identified in 1 patient 2 years post-procedure and was treated medically. Hemodynamics at 3 years included a mean gradient of 7.2 ± 4.5 mm Hg, an effective orifice area of 2.0 ± 0.5 cm2, and 88.2% of patients had no or trace PVR. The remaining patients had mild PVR. Most of the surviving patients (80.6%) had New York Heart Association class I symptoms at 3 years. CONCLUSION: Outcomes at 3-years following TAVR with a contemporary self-expanding prosthesis are favorable, with no signal of valve deterioration, excellent hemodynamics including very low prevalence of PVR.

Comparison of chest X-ray interpretation by Emergency Department clinicians and radiologists in suspected COVID-19 infection: a retrospective cohort study.

OBJECTIVES: We describe the inter-rater agreement between Emergency Department (ED) clinicians and reporting radiologists in the interpretation of chest X-rays (CXRs) in patients presenting to ED with suspected COVID-19. METHODS: We undertook a retrospective cohort study of patients with suspected COVID-19. We compared ED clinicians' and radiologists' interpretation of the CXRs according to British Society of Thoracic Imaging (BSTI) guidelines, using the area under the receiver operator curve (ROC area). RESULTS: CXRs of 152 cases with suspected COVID-19 infection were included. Sensitivity and specificity for 'classic' COVID-19 CXR findings reported by ED clinician was 84 and 83%, respectively, with a ROC area of 0.84 (95%CI 0.77 to 0.90). Accuracy improved with ED clinicians' experience, with ROC areas of 0.73 (95%CI 0.45 to 1.00), 0.81 (95%CI 0.73 to 0.89), 1.00 (95%CI 1.00 to 1.00) and 0.90 (95%CI 0.70 to 1.00) for foundation year doctors, senior house officers, higher speciality trainees and ED consultants, respectively (p < 0.001). CONCLUSIONS: ED clinicians demonstrated moderate inter-rater agreement with reporting radiologists according to the BSTI COVID-19 classifications. The improvement in accuracy with ED clinician experience suggests training of junior ED clinicians in the interpretation of COVID-19 related CXRs might be beneficial. Large-scale survey studies might be useful in the further evaluation of this topic. ADVANCES IN KNOWLEDGE: This is the first study to examine inter-rater agreement between ED clinicians and radiologists in regards to COVID-19 CXR interpretation.Further service configurations such as 24-hr hot reporting of CXRs can be guided by these data, as well as an ongoing, nationwide follow-up study.

Rise of the Robots: Is Artificial Intelligence a Friend or Foe to Nursing Practice?

Much like other aspects of health care, nursing has become increasingly saturated with technology over the past several decades. Existing technology has advanced nursing in many ways and contributed to patient safety but at the cost of decreasing nurse-patient interaction. As health care technology progresses to the inclusion of artificial intelligence (AI), the future impact on nursing and direct patient care remains largely unknown, unexplored, and difficult to predict. This article aims to explore the relevance of nursing in a technologically advanced postmodern health care system. The relevance of nursing in the future is solidified by the unique nature of nursing that includes the embodiment of human caring and emotional intelligence. Nurses' abilities to intervene before patient deterioration, care for patients holistically, and manage various aspects of care will be heightened by the adoption of AI. Nurses should embrace AI technology, as we predict that it will decrease nurse workload and cognitive overload and allow for increased patient-nurse interaction. Current and future nurses should take the lead on determining how it augments nursing practice.

Biomolecules as Flame Retardant Additives for Polymers: A Review.

Biological molecules can be obtained from natural sources or from commercial waste streams and can serve as effective feedstocks for a wide range of polymer products. From foams to epoxies and composites to bulk plastics, biomolecules show processability, thermal stability, and mechanical adaptations to fulfill current material requirements. This paper summarizes the known bio-sourced (or bio-derived), environmentally safe, thermo-oxidative, and flame retardant (BEST-FR) additives from animal tissues, plant fibers, food waste, and other natural resources. The flammability, flame retardance, and-where available-effects on polymer matrix's mechanical properties of these materials will be presented. Their method of incorporation into the matrix, and the matrices for which the BEST-FR should be applicable will also be made known if reported. Lastly, a review on terminology and testing methodology is provided with comments on future developments in the field.

Preclinical Activity of HER2-Selective Tyrosine Kinase Inhibitor Tucatinib as a Single Agent or in Combination with Trastuzumab or Docetaxel in Solid Tumor Models.

HER2 is a transmembrane tyrosine kinase receptor that mediates cell growth, differentiation, and survival. HER2 is overexpressed in approximately 20% of breast cancers and in subsets of gastric, colorectal, and esophageal cancers. Both antibody and small-molecule drugs that target HER2 and block its tyrosine kinase activity are effective in treating HER2-driven cancers. In this article, we describe the preclinical properties of tucatinib, an orally available, reversible HER2-targeted small-molecule tyrosine kinase inhibitor. In both biochemical and cell signaling experiments, tucatinib inhibits HER2 kinase activity with single-digit nanomolar potency and provides exceptional selectivity for HER2 compared with the related receptor tyrosine kinase EGFR, with a >1,000-fold enhancement in potency for HER2 in cell signaling assays. Tucatinib potently inhibits signal transduction downstream of HER2 and HER3 through the MAPK and PI3K/AKT pathways and is selectively cytotoxic in HER2-amplified breast cancer cell lines in vitro. In vivo, tucatinib is active in multiple HER2+ tumor models as a single agent and shows enhanced antitumor activity in combination with trastuzumab or docetaxel, resulting in improved rates of partial and complete tumor regression. These preclinical data, taken together with the phase-I tucatinib clinical trial results demonstrating preliminary safety and activity, establish the unique pharmacologic properties of tucatinib and underscore the rationale for investigating its utility in HER2+ cancers. GRAPHICAL ABSTRACT: http://mct.aacrjournals.org/content/molcanther/19/4/976/F1.large.jpg.

Post-intravitreal injection endophthalmitis secondary to Turicella otitidis: a case report.

BACKGROUND: Endophthalmitis is a rare but potentially devastating complication of intravitreal injection. The causative organism plays an important role in prognosis following endophthalmitis. Here we present the first reported case of Turicella otitidis endophthalmitis, which is notable for a delayed presentation. CASE PRESENTATION: A 71 year old male who was receiving intravitreal aflibercept injections for neovascular age-related macular degeneration presented 4 weeks after his most recent intravitreal injection and was found to have endophthalmitis. Polymerase chain reaction (PCR) testing of aqueous fluid was positive for Turicella otitidis. The endophthalmitis responded well to treatment with intravitreal antibiotics. CONCLUSIONS: Coryneform bacteria are a rare cause of endophthalmitis, and this is the first reported case of endophthalmitis caused by the corynebacterium species Turicella otitidis. As in this case, post-intravitreal injection endophthalmitis may have a bacterial etiology even with delayed presentation. The relatively indolent disease course and excellent response to intravitreal antibiotics is consistent with previous ophthalmic reports regarding other corynebacteria, as well as with otolaryngology and hematology oncology reports addressing Turicella otitidis specifically. This case supports the growing body of evidence for pathogenicity of Turicella otitidis and demonstrates the utility of PCR for diagnosis in small volume aqueous specimens.

An Integrated Pipeline for Combining in vitro Data and Mathematical Models Using a Bayesian Parameter Inference Approach to Characterize Spatio-temporal Chemokine Gradient Formation.

All protective and pathogenic immune and inflammatory responses rely heavily on leukocyte migration and localization. Chemokines are secreted chemoattractants that orchestrate the positioning and migration of leukocytes through concentration gradients. The mechanisms underlying chemokine gradient establishment and control include physical as well as biological phenomena. Mathematical models offer the potential to both understand this complexity and suggest interventions to modulate immune function. Constructing models that have powerful predictive capability relies on experimental data to estimate model parameters accurately, but even with a reductionist approach most experiments include multiple cell types, competing interdependent processes and considerable uncertainty. Therefore, we propose the use of reduced modeling and experimental frameworks in complement, to minimize the number of parameters to be estimated. We present a Bayesian optimization framework that accounts for advection and diffusion of a chemokine surrogate and the chemokine CCL19, transport processes that are known to contribute to the establishment of spatio-temporal chemokine gradients. Three examples are provided that demonstrate the estimation of the governing parameters as well as the underlying uncertainty. This study demonstrates how a synergistic approach between experimental and computational modeling benefits from the Bayesian approach to provide a robust analysis of chemokine transport. It provides a building block for a larger research effort to gain holistic insight and generate novel and testable hypotheses in chemokine biology and leukocyte trafficking.