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Background: Residual mitral regurgitation (MR) is frequent after transcatheter edge-to-edge repair (TEER). There is controversy regarding the clinical impact of residual MR and its quantitative assessment by transthoracic echocardiography (TTE), which is often challenging with multiple eccentric jets and artifact from the clip. The utility of the velocity time integral (VTI) ratio between the mitral valve (MV) and left ventricular outflow tract (LVOT), (VTIMV/LVOT), a simple Doppler measurement that increases with MR, has not been assessed post TEER. Methods: Baseline characteristics, clinical outcomes, and TTE data from patients who underwent TEER between 2014 and 2021 across three academic centers were retrospectively analyzed. Post-procedure TTEs were evaluated for VTIMV/LVOT in the first three months after TEER. One-year outcomes including all-cause and cardiac mortality, major adverse cardiac events, and MV reintervention were compared between patients with high VTIMV/LVOT (≥2.5) and low (

This work presents the design of a smart activation system for the crack-closure technology of the Hybrid Tendons. Previous research has demonstrated the effectiveness of this technology in providing a self-repairing mechanism for concrete elements. The Hybrid Tendons are made combining a pre-stressed Kevlar inner core restrained by a Shape Memory Polymer sleeve. To trigger the crack-closing action, the Shape memory potential of the outer sleeve needs to be activated via heating. The work focuses on the design and testing of an electric activation system for the Hybrid Tendons using a system of heating wires. Kanthal wires are chosen for this application and integrated in the manufacturing process of the Hybrid Tendons: the wires are wrapped around each tendon and connected to a power supply. An experimental campaign is conducted to assess the system's capability to activate the Hybrid Tendons and deliver the crack-closing action in concrete beams under constant load. Additionally a numerical model is also developed to offer a sound interpretation of the experimental results. The system is ultimately proven successful in activating the Hybrid Tendons embedded in the concrete, effectively delivering the crack-closing action and boosting the flexural response of the structural element.

We have performed shrinkage restraint force measurements on three shape memory polymers of polyethylene terephthalate (PET), polymethyl methacrylate (PMMA) and a blend of the two at a range of temperatures. Observations are made of the change in stress during temperature rise, hold and cooling. All materials show an increase in stress during rise and hold, but on cooling, the three materials behave differently; the PET shows a drop in stress, the PMMA a rise and the blend a much smaller rise. This behaviour correlates with the reversible thermal dimensional change below the shrinkage threshold temperature; the expansion coefficients are negative for PET, positive for PMMA and positive at a lower order of magnitude for the blend. We model the behaviour by supposing that the shrinkage forces are created by prestressed strains effective at long range within a matrix of shorter chains effective at short range. The total stress is the sum of the shrinkage stress and the thermal stress in the matrix. The drops in stress on cooling are modelled using an elastic analysis based on measured elastic moduli and thermal expansion coefficients. For the blend, downward jumps in temperature produce small transient increases in the total stress, leaving it effectively unchanged. This phenomenon and the results of the elastic model for the stress drops imply that the shrinkage stress from the long-range chain network is largely unaffected by the temperature change and so is not entropic.

The mechanisms that govern biological evolution and human cognition are analogous, as both follow the same principles of natural information processing systems. In this article, we describe the following five principles that provide an analogy between biological evolution and human cognition: (a) Randomness as Genesis Principle and (b) Borrowing and Reorganizing Principle, which indicate how natural information processing systems obtain information; (c) Narrow Limits of Change Principle and (d) Information Store Principle, which indicate how information is processed and stored; and (e) Environmental Organizing and Linking Principle, which indicate how stored information is used to generate actions appropriate to an environment. In human cognition, these analogs only apply to cognitive processes associated with biologically secondary knowledge, the knowledge typically taught in educational institutions. Based on these five principles, cognitive load theory researchers have provided diverse prescriptions to optimize instructional activities and materials. We conclude by discussing general instructional implications and future research directions based on this analogy.

Abstract A very general class of axially symmetric metrics in general relativity (GR) that includes rotations is used to discuss the dynamics of rotationally supported galaxies. The exact vacuum solutions of the Einstein equations for this extended Weyl class of metrics allow us to rigorously deduce the following: (i) GR rotational velocity always exceeds the Newtonian velocity (thanks to Lenz’s law in GR). (ii) A non-vanishing intrinsic angular momentum (J) for a galaxy demands the asymptotic constancy of the Weyl (vectorial) length parameter (a)—a behaviour identical to that found for the Kerr metric. (iii) Asymptotic constancy of the same parameter a also demands a plateau in the rotational velocity. Unlike the Kerr metric, the extended Weyl metric can and has been continued within the galaxy, and it has been shown under what conditions Gauß and Ampére laws emerge along with Ludwig’s extended gravito-electromagnetism (GEM) theory with its attendant non-linear rate equations for the velocity field. Better estimates (than that from the Newtonian theory) for the escape velocity of the Sun have been presented.

The aquafeed ingredient inventory is ever changing, from marine to plant based, and recently evolving to incorporate increasing amounts of low trophic, side stream and circular economy based raw materials, each one contributing with variable amounts and qualities of macro- and micronutrients. Meeting the micronutrient requirement of farmed fish for healthy and efficient growth under normal and challenging conditions is of paramount importance. In this study we run a trial based on a 2 × 4 factorial design with three replications for each dietary treatment, where Atlantic salmon smolt were fed one of 8 experimental diets supplemented with either organic or inorganic mineral premixes (copper, iron, manganese, selenium, and zinc) at four dietary inclusion levels. We saw a trend for higher growth rate in the organic mineral groups irrespective of the dietary mineral levels. Mineral digestibility was negatively correlated with increasing mineral supplementation levels for all tested minerals but Se which increased with the increasing supplementation in the inorganic and up to the 2nd inclusion level in the organic mineral groups. Increasing mineral supplementation affected retention efficiency of Zn, Mn, Cu and Fe while mineral source affected only the retention of Se which was higher in the organic mineral groups. Moreover, fish obtained higher EPA and DHA in their body and increased slaughter yield in the organic as compared to the inorganic mineral groups and corroborated that trace mineral inclusion levels play a key role on salmon fillet’s technical quality. More effects from different origin and dietary inclusion levels of trace minerals were seen on fillet yield, fillet technical and nutritional quality, bone strength, skin morphology, organ mineralization and midgut transcriptome.

Congenital right coronary artery-superior vena cava (RCA-SVC) fistula is rare and typically does not manifest any symptoms until the fifth decade of life. The present case demonstrates a 48-year-old woman who developed Sinus node dysfunction of unknown cause after Percutaneous coil embolization of the RCA-SVC fistula requiring permanent pacemaker. (Level of Difficulty: Intermediate.)

The interleaving effect indicates that students learn better from multiple areas that are interleaved rather than blocked. Two experiments tested the hypothesis that the effect is because interleaving facilitates comparisons between areas and is a variation of the variability effect that increases intrinsic cognitive load. Experiment 1 used an interleaved design with two obviously different topics and found no interleaving effect. Experiment 2 used a similar design but used topics that were more difficult to discriminate between, resulting in a clear advantage for the interleaved group associated with an increase in cognitive load. These results support the hypothesis that the interleaving and variability effects are closely related.

Abstract Molecular biomarkers of ionizing radiation (IR) exposure are a promising new tool in various disciplines: they can give necessary information for adaptive treatment planning in cancer radiotherapy, enable risk projection for radiation-induced survivorship diseases, or facilitate triage and intervention in radiation hazard events. However, radiation biomarker discovery has not yet resolved the most basic features of personalized medicine: age and sex. To overcome this critical bias in biomarker identification, we quantitated age and sex effects and assessed their relevance in the radiation response across the blood proteome. We used high-throughput mass spectrometry on blood plasma collected 24 h after 0.5 Gy total body irradiation (15 MV nominal photon energy) from male and female C57BL/6 N mice at juvenile (7-weeks-old) or adult (18-weeks-old) age. We also assessed sex and strain effects using juvenile male and female BALB/c nude mice. We showed that age and sex created significant effects in the proteomic response regarding both extent and functional quality of IR-induced responses. Furthermore, we found that age and sex effects appeared non-linear and were often end-point specific. Overall, age contributed more to differences in the proteomic response than sex, most notably in immune responses, oxidative stress, and apoptotic cell death. Interestingly, sex effects were pronounced for DNA damage and repair pathways and associated cellular outcome (pro-survival vs. pro-apoptotic). Only one protein (AHSP) was identified as a potential general biomarker candidate across age and sex, while GMNN, REG3B, and SNCA indicated some response similarity across age. This low yield advocated that unisex or uniage biomarker screening approaches are not feasible. In conclusion, age- and sex-specific screening approaches should be implemented as standard protocol to ensure robustness and diagnostic power of biomarker candidates. Bias-free molecular biomarkers are a necessary progression towards personalized medicine and integral for advanced adaptive cancer radiotherapy and risk assessment.

Abstract Background The aquaculture sector now accounts for almost 50% of all fish for human consumption and is anticipated to provide 62% by 2030. Innovative strategies are being sought to improve fish feeds and feed additives to enhance fish performance, welfare, and the environmental sustainability of the aquaculture industry. There is still a lack of knowledge surrounding the importance and functionality of the teleost gut microbiome in fish nutrition. In vitro gut model systems might prove a valuable tool to study the effect of feed, and additives, on the host’s microbial communities. Several in vitro gut models targeted at monogastric vertebrates are now in operation. Here, we report the development of an Atlantic salmon gut model, SalmoSim, to simulate three gut compartments (stomach, pyloric caecum, and midgut) and associated microbial communities. Results The gut model was established in a series of linked bioreactors seeded with biological material derived from farmed adult marine-phase salmon. We first aimed to achieve a stable microbiome composition representative of founding microbial communities derived from Atlantic salmon. Then, in biological triplicate, the response of the in vitro system to two distinct dietary formulations (fishmeal and fishmeal free) was compared to a parallel in vivo trial over 40 days. Metabarcoding based on 16S rDNA sequencing qPCR, ammoniacal nitrogen, and volatile fatty acid measurements were undertaken to survey the microbial community dynamics and function. SalmoSim microbiomes were indistinguishable (p = 0.230) from their founding inocula at 20 days and the most abundant genera (e.g., Psycrobacter, Staphylococcus, Pseudomonas) proliferated within SalmoSim (OTUs accounting for 98% of all reads shared with founding communities). Real salmon and SalmoSim responded similarly to the introduction of novel feed, with majority of the taxa (96% Salmon, 97% SalmoSim) unaffected, while a subset of taxa (e.g., a small fraction of Psychrobacter) was differentially affected across both systems. Consistent with a low impact of the novel feed on microbial fermentative activity, volatile fatty acid profiles were not significantly different in SalmoSim pre- and post-feed switch. Conclusion By establishing stable and representative salmon gut communities, this study represents an important step in the development of an in vitro gut system as a tool for the improvement of fish nutrition and welfare. The steps of the system development described in this paper can be used as guidelines to develop various other systems representing other fish species. These systems, including SalmoSim, aim to be utilised as a prescreening tool for new feed ingredients and additives, as well as being used to study antimicrobial resistance and transfer and fundamental ecological processes that underpin microbiome dynamics and assembly. Video abstract

ABSTRACT Alpha mannose-oligosaccharide (MOS) prebiotics are widely deployed in animal agriculture as immunomodulators as well as to enhance growth and gut health. Their mode of action is thought to be mediated through their impact on host microbial communities and their associated metabolism. Bio-Mos is a commercially available prebiotic currently used in the agri-feed industry, but studies show contrasting results of its effect on fish performance and feed efficiency. Thus, detailed studies are needed to investigate the effect of MOS supplements on the fish microbiome to enhance our understanding of the link between MOS and gut health. To assess Bio-Mos for potential use as a prebiotic growth promoter in salmonid aquaculture, we have modified an established Atlantic salmon in vitro gut model, SalmoSim, to evaluate its impact on the host microbial communities. The microbial communities obtained from ceca compartments from four adult farmed salmon were inoculated in biological triplicate reactors in SalmoSim. Prebiotic treatment was supplemented for 20 days, followed by a 6-day washout period. Inclusion of Bio-Mos in the media resulted in a significant increase in formate (P = 0.001), propionate (P = 0.037) and 3-methyl butanoic acid (P = 0.024) levels, correlated with increased abundances of several, principally, anaerobic microbial genera (Fusobacterium, Agarivorans, Pseudoalteromonas). DNA metabarcoding with the 16S rDNA marker confirmed a significant shift in microbial community composition in response to Bio-Mos supplementation with observed increase in lactic acid producing Carnobacterium. In conjunction with previous in vivo studies linking enhanced volatile fatty acid production alongside MOS supplementation to host growth and performance, our data suggest that Bio-Mos may be of value in salmonid production. Furthermore, our data highlights the potential role of in vitro gut models to complementin vivo trials of microbiome modulators. IMPORTANCE In this paper we report the results of the impact of a prebiotic (alpha-MOS supplementation) on microbial communities, using an in vitro simulator of the gut microbial environment of the Atlantic salmon. Our data suggest that Bio-Mos may be of value in salmonid production as it enhances volatile fatty acid production by the microbiota from salmon pyloric ceca and correlates with a significant shift in microbial community composition with observed increase in lactic acid producing Carnobacterium. In conjunction with previous in vivo studies linking enhanced volatile fatty acid production alongside MOS supplementation to host growth and performance, our data suggest that Bio-Mos may be of value in salmonid production. Furthermore, our data highlights the potential role of in vitro gut models to augment in vivo trials of microbiome modulators.

Functional crosslinked hydrogels were prepared from 2-hydroxyethyl methacrylate (HEMA) and acrylic acid (AA). The acid monomer was incorporated both via copolymerization and chain extension of a branching, reversible addition–fragmentation chain-transfer agent incorporated into the crosslinked polymer gel. The hydrogels were intolerant to high levels of acidic copolymerization as the acrylic acid weakened the ethylene glycol dimethacrylate (EGDMA) crosslinked network. Hydrogels made from HEMA, EGDMA and a branching RAFT agent provide the network with loose-chain end functionality that can be retained for subsequent chain extension. Traditional methods of surface functionalization have the downside of potentially creating a high volume of homopolymerization in the solution. Branching RAFT comonomers act as versatile anchor sites by which additional polymerization chain extension reactions can be carried out. Acrylic acid grafted onto HEMA–EGDMA hydrogels showed higher mechanical strength than the equivalent statistical copolymer networks and was shown to have functionality as an electrostatic binder of cationic flocculants.

Background In TAILOR‐PCI, genotype‐guided selection of P2Y12 inhibitors after percutaneous coronary intervention did not significantly reduce the risk of ischemic events at 12 months. The Age, Body Mass Index, Chronic Kidney Disease, Diabetes, and Genotyping (ABCD‐GENE) score identifies patients with high platelet reactivity on clopidogrel at increased risk of ischemic events. The aim of this study was to investigate the value of the ABCD‐GENE score for tailoring P2Y12 inhibitor selection after percutaneous coronary intervention. Methods and Results In a post hoc analysis of the TAILOR‐PCI, outcomes were analyzed by ABCD‐GENE score and allocation to genotype‐guided or conventional P2Y12 inhibitor selection. Primary (death, myocardial infarction, or stroke) and secondary (cardiovascular death, myocardial infarction, stroke, stent thrombosis, or severe recurrent ischemia) outcomes were assessed. Among 3883 patients discharged on clopidogrel in the genotype‐guided and conventional therapy groups, 15.8% and 84.2% had high (≥10 points) or low (

Abstract Background Transcatheter aortic valve replacement (TAVR) is a reliable method of treating patients with severe aortic stenosis, but is associated with postprocedure conduction defects. Objective The purpose of this study was to compare clinical outcomes in patients who developed advanced conduction defects post‐TAVR to those who did not. Methods We conducted a retrospective chart review of 243 patients who underwent balloon‐expandable TAVR with the Edwards Sapien valve to determine the incidence of advanced conduction defects in our cohort. We compared clinical outcomes including overall mortality, improvement in symptomatology, and improvement in left ventricular ejection fraction. Results Among the 243 patients included in the study, 9.1% (22/243) required permanent pacemaker (PPM); 19.8% (48/243) developed left bundle branch block (LBBB), and 71.2% (173/243) did not develop any permanent advanced conduction defects. Overall 1‐year mortality was similar across all three groups. There was significant improvement in New York Heart Association functional capacity of all groups post‐TAVR, but this was much less in the PPM group (45.5% vs 68.8%, P = .04). Postprocedure from TAVR, patients with LBBB or PM were less likely to have improvement in their ejection fraction (net loss of −0.7% for LBBB and −5.7% for PPM compared to a net gain of 2.3% for no‐LBBB/PM (P = .02). Conclusion Patients who develop LBBB or require PM post‐TAVR with Edwards Sapien valves are less likely to improve New York Heart Association functional capacity and more likely to have no improvement or deterioration of their pre‐TAVR left ventricular ejection fraction.

Abstract Purpose To assess the anthropometric dimensions of the coracoid process and the glenoid articular surface and to determine possible implications with the different commercially available Latarjet fixation techniques. Methods In a total of 101 skeletal scapulae the glenoid length (GL), the glenoid width (GW), the coracoid length (CL), the coracoid width (CW) and the coracoid thickness (CTh) were measured. In order to assess the ability of the transferred coracoid to restore the glenoid anatomy we created a hypothetical model of 10%, 15%, 20%, 25% and 30% glenoid bone loss. We analyzed four common surgical fixation techniques for the Latarjet procedure (4.5 mm screws, 3.75 mm screws, 3.5 mm screws, and 2.8 mm button). The distances from the superior-inferior and medio-lateral limits of the coracoid using the four different fixation methods were calculated. We hypothesized that the “safe distance” between the implant and the coracoid osteotomy should be at least equal to the diameter of the implant. Results The intra and inter-observer reliability tests were almost perfect for all measurements. The mean GH was 36.8 ± 2.5 mm, the GW 26.4 ± 2.2 mm, the CL 23.9 ± 3 mm, the CW 13.6 ± 2.mm, and the mean CTh was 8.7 ± 1.3 mm. The CL was

PurposeWe report short-term patency outcomes of a proof of concept study conducted to determine the efficacy of drug-eluting stent (DES) for the treatment of arteriovenous fistula (AVF) stenosis in hemodialysis patients.Materials and Methods : This is a single-center, retrospective observational study involving 10 patients with AVF dysfunction treated with DESs between January 2017 and December 2017. The primary outcome was AVF patency confirmed by sonographic and clinical assessment at 1 month and 6 to 9 months after treatment.Results : A total of 12 DESs were deployed in 10 patients with dysfunctional AVF (radiocephalic: 7, brachiocephalic: 3). During the early follow up (mean: 28.6 days), primary access circuit and DES patency was 100%, with an average volume flow rate of 886.4 mL/min. Nine patients were available for short-term follow up (mean: 202.4 days; 1 unrelated death), with a mean volume flow rate of 1,048.9 mL/min. The primary DES patency was 7/9 (77.8%), and 3 patients required angioplasty at other parts of the circuit (primary access circuit patency: 4/9 [44.4%]). The assisted primary access circuit patency was 77.8%. In 2 patients, the ultrasound revealed that the DESs were thrombosed without any antecedent stenosis; they were salvaged with angioplasty. Both patients previously underwent 2 DESs implanted and recently stopped dual antiplatelet therapy. B-mode sonographic assessment at all timepoints showed minimal intimal ingrowth on the stent struts.Conclusion : This study demonstrates acceptable short-term patency for DESs in the treatment of AVF stenosis. Dual antiplatelet therapy is probably mandatory in the short term.

In the early 1980s, John Swaim was the president of the NMSA Board of Trustees. John Lounsbury, then editor of The Middle School Journal, collaborated with John Swaim and the Board of Trustees to commission the writing of the original document, This We Believe. In the spring of 2020 [Author] contacted John Swaim to tell the story of how This We Believe was conceived. They collaborated using an interview format. The most recent version of The Successful Middle School: This we believe (Bishop & Harrison, 2021) was also recorded with input from leaders in middle level education providing preservice and inservice teachers with tools and inspiration on the best way to respond to the needs of young adolescents. John’s story provides a backdrop for professors to use with preservice teachers to honor and acknowledge the work of those who have come before us, and highlights the power and value of collaboration in support of middle level education.

Objectives Consumer-grade smart devices are now commonly used by the public to measure waking activity and sleep. However, the ability of these devices to accurately measure sleep in clinical populations warrants more examination. The aim of the present study was to assess the accuracy of three consumer-grade sleep monitors compared with gold standard polysomnography (PSG).Design A prospective cohort study was performed.Setting Adults undergoing PSG for investigation of a suspected sleep disorder.Participants 54 sleep-clinic patients were assessed using three consumer-grade sleep monitors (Jawbone UP3, ResMed S+ and Beddit) in addition to PSG.Outcomes Jawbone UP3, ResMed S+ and Beddit were compared with gold standard in-laboratory PSG on four major sleep parameters—total sleep time (TST), sleep onset latency (SOL), wake after sleep onset (WASO) and sleep efficiency (SE).Results The accelerometer Jawbone UP3 was found to overestimate TST by 28 min (limits of agreement, LOA=−100.23 to 157.37), with reasonable agreement compared with gold standard for TST, WASO and SE. The doppler radar ResMed S+ device underestimated TST by 34 min (LOA=−257.06 to 188.34) and had poor absolute agreement compared with PSG for TST, SOL and SE. The mattress device, Beddit underestimated TST by 53 min (LOA=−238.79 to 132) on average and poor reliability compared with PSG for all measures except TST. High device synchronisation failure occurred, with 20% of recordings incomplete due to Bluetooth drop out and recording loss.Conclusion Poor to moderate agreement was found between PSG and each of the tested devices, however, Jawbone UP3 had relatively better absolute agreement than other devices in sleep measurements compared with PSG. Consumer grade devices assessed do not have strong enough agreement with gold standard measurement to replace clinical evaluation and PSG sleep testing. The models tested here have been superseded and newer models may have increase accuracy and thus potentially powerful patient engagement tools for long-term sleep measurement.

To contribute in knowledge for the development of safe, efficient and sustainable functional salmon diets, we ran a feeding trial applying a 23 full factorial design to investigate combined effects, on Atlantic salmon smoltification and post transfer performance, of variable supplementation levels of essential amino acid (Lys, Met, Thr and Arg), essential trace mineral (Zn, Fe and Se) and vitamins (E, C and astaxanthin as provitamin A) premixes in low fishmeal diets, using crystalline amino acids, organic trace minerals and synthetic vitamins, respectively. The nutrient levels used in our study were chosen to meet the known requirements of fish reflecting the variation in commercial feeds. Fish performance, nutrient digestibility, skin, and intestinal health were evaluated in Atlantic salmon parr-smolt, the latter by means of qPCR, global transcriptomics, and immunohistochemistry. The results revealed the potential for significant improvement of salmon post smoltification growth by simultaneous dietary level increase of Met, Lys, Thr and Arg (5% higher body weight increase). Significantly negative effect on fish post transfer growth and survival (22.5 % lower body weight growth and 2.6 times higher mortality) was observed in the high dietary vitamin supplementation treatments which was not present in the simultaneous high trace mineral and vitamin supplementation treatments (8% higher body weight increase and 2.8 times lower mortality in the high trace mineral supplementation treatments). In the high trace mineral supplemented dietary treatments was also observed improved FCR (8.5 %) and a further improvement in performance was seen in the treatments with simultaneous high essential amino acid and trace mineral supplementation levels (12.6 % higher body growth increase). Redox-sensitive gene and extracellular matrix components’ gene transcription effects and compensatory mechanisms on protein and energy metabolism, immune modulation, skin repair systems and erythropoiesis were observed by transcriptomic and histological analyses in response to the variable dietary essential nutrient levels.

Abstract Background Immune checkpoint blockade (ICB) promotes adaptive immunity and tumor regression in some cancer patients. However, in patients with immunologically “cold” tumors, tumor-resident innate immune cell activation may be required to prime an adaptive immune response and so exploit the full potential of ICB. Whilst Toll-like receptor (TLR) agonists have been used topically to successfully treat some superficial skin tumors, systemic TLR agonists have not been well-tolerated. Methods The response of human immune cells to TLR7 and 8 agonism was measured in primary human immune cell assays. MEDI9197 (3M-052) was designed as a novel lipophilic TLR7/8 agonist that is retained at the injection site, limiting systemic exposure. Retention of the TLR7/8 agonist at the site of injection was demonstrated using quantitative whole-body autoradiography, HPLC-UV, and MALDI mass spectrometry imaging. Pharmacodynamic changes on T cells from TLR7/8 agonist treated B16-OVA tumors was assessed by histology, quantitative real time PCR, and flow cytometry. Combination activity of TLR7/8 agonism with immunotherapies was assessed in vitro by human DC-T cell MLR assay, and in vivo using multiple syngeneic mouse tumor models. Results Targeting both TLR7 and 8 triggers an innate and adaptive immune response in primary human immune cells, exemplified by secretion of IFNα, IL-12 and IFNγ. In contrast, a STING or a TLR9 agonist primarily induces release of IFNα. We demonstrate that the TLR7/8 agonist, MEDI9197, is retained at the sight of injection with limited systemic exposure. This localized TLR7/8 agonism leads to Th1 polarization, enrichment and activation of natural killer (NK) and CD8+ T cells, and inhibition of tumor growth in multiple syngeneic models. The anti-tumor activity of this TLR7/8 agonist is enhanced when combined with T cell-targeted immunotherapies in pre-clinical models. Conclusion Localized TLR7/8 agonism can enhance recruitment and activation of immune cells in tumors and polarize anti-tumor immunity towards a Th1 response. Moreover, we demonstrate that the anti-tumor effects of this TLR7/8 agonist can be enhanced through combination with checkpoint inhibitors and co-stimulatory agonists.

Developing a robust drought monitoring tool is vital to mitigate the adverse impacts of drought. A drought monitoring system that integrates multiple agrometeorological variables into a single drought indicator is lacking in areas such as Ethiopia, which is extremely susceptible to this natural hazard. The overarching goal of this study is to develop a combined drought indicator (CDI-E) to monitor the spatial and temporal extents of historic agricultural drought events in Ethiopia. The CDI-E was developed by combining four satellite-based agrometeorological input parameters – the Standardized Precipitation Index (SPI), Land Surface Temperature (LST) anomaly, Standardized Normalized Difference Vegetation Index (stdNDVI) and Soil Moisture (SM) anomaly – for the period from 2001 to 2015. The method used to combine these indices is based on a quantitative approach that assigns a weight to each input parameter using Principal Component Analysis (PCA). The CDI-E results were evaluated using satellite-based gridded rainfall (3-month SPI) and crop yield data for 36 intra-country crop growing zones for a 15-year period (2001 to 2015). The evaluation was carried out for the main rainfall season, Kiremt (June-September), and the short rainfall season, Belg (February-May). The results showed that moderate to severe droughts were detected by the CDI-E across the food insecure regions reported by FEWS NET during Kiremt and Belg rainfall seasons. Relatively higher correlation coefficient values (r > 0.65) were obtained when CDI-E was compared with the 3-month SPI across the majority of Ethiopia. The spatial correlation analyses of CDI-E and cereal crop yields showed relatively good correlations (r > 0.5) in some of the crop growing zones in the northern, eastern and southwestern parts of the country. The CDI-E generally mapped the spatial and temporal patterns of historic drought and non-drought years and hence the CDI-E could potentially be used to develop an agricultural drought monitoring and early warning system in Ethiopia. Moreover, decision makers and donors may potentially use CDI-E to more accurately monitor crop yields across the food-insecure regions in Ethiopia.

Abstract Background There is overwhelming evidence to support the promotion of physical activity in adults in terms of benefits to well-being, physical and mental health. Physical activity guidelines suggest that adults should accumulate at least 150 min of moderate to vigorous physical activity per week. In Ireland, the majority of adults do not achieve these guidelines, with costs to health and economy. ‘Move for Life’ (MFL) employs behavioural change techniques delivered by an instructor and peer mentor, using a train-the-trainer (cascade) model. This study will conduct a feasibility cluster randomised controlled trial of the MFL intervention for modifying physical activity behaviours in inactive adults aged 45 years and older. Methods The trial is set in eight Local Sports Partnership (LSP) hubs that have structured physical activity programmes. The hubs are the units of randomisation (clusters), and individuals are the units of analysis (participants). Eligible participants will contact one of the hubs, with each hub running four physical activity programmes. Each programme requires between 12–15 inactive adults, resulting in 48–60 participants per hub. Allowing for 20% dropout rate, an additional 96 people will be recruited giving a maximum sample of 576. The hub will be randomised: true control, usual programme or MFL intervention. The true control group will be given information about physical activity but will not be included in a programme for the duration of the trial; the intervention will involve the instructor training one (or more) of the participants to be a peer mentor using an educational toolkit; and usual care groups will have physical activity classes delivered as normal. Baseline data will collect physical activity measures and follow-up measurements will be obtained at 3 and 6 months. All participants will be asked to wear a device for measuring activity on the thigh (activPAL) for 7 days before commencing the programme and at 3 and 6 months. The primary objective of the study is to investigate if it is feasible to deliver the intervention and collect data on moderate to vigorous physical activity (MVPA) on all participants, thereby providing valuable information to guide sample size calculation for a future, more definitive trial. Trial registration number ISRCTN11235176

Shape memory polymer (SMP) products have been developed for application as crack closure devices in concrete. They have been made from PET in the form of both fibres and hollow tubes. Here, manufacturing methods using die-drawing and mandrel-drawing to induce shape memory are reported. The fibre-based devices are incorporated into concrete and, upon triggering, exert shrinkage restraint forces that close cracks in the concrete. The evolution of shrinkage restraint force in the fibres as manufactured was measured as a function of temperature, showing stresses in excess of 35 MPa. Tendons consisting of fibre bundles are incorporated into concreate beams subjected to controlled cracking. When activated, the tendons reduce the crack widths by 80%. The same fibres are used to produce another class of device known as knotted fibres, which have knotted ends that act as anchor points when they incorporated directly into concrete. Upon activation within the cracked concrete, these devices are shown to completely close cracks. The tubes are used to enclose and restrain prestressed Kevlar fibres. When the tubes are triggered, they shrink and release the prestress force in the Kevlar, which is transferred to the surrounding concrete in the form of a compressive force, thereby closing cracks. The Kevlar fibres also provide substantial reinforcement after activation. The devices are shown to be able to partially and fully close cracks that have been opened to 0.3 mm and achieve post-activation flexural strengths comparable to those of conventional reinforced and prestressed structural elements. Finally, a preliminary life cycle assessment study was used to assess the carbon footprint a nominal unit of concrete made with SMPs fibres compared to conventional concrete.

Lateral patellofemoral osteoarthritis is a relatively common condition in young, active patients. Partial lateral patellar facetectomy is a relatively minimally invasive option to restore knee function and return to sport when conservative treatments are insufficient. We describe the arthroscopic technique of partial lateral patellar facetectomy , which has been historically performed as an open procedure. We describe preoperative planning, arthroscopic portals, landmarks, intra-articular evaluation of bone resection, and surgical difficulties. The goal of the preoperative planning was a target bone resection of 10 to 15 mm including osteophytes and the lateral facet of the patella. Arthroscopic anterolateral and anterior superolateral portals were used to achieve the desired resection. An arthroscopic technique allows a direct view of the osteoarthritic bone for removal and permits intraoperative dynamic evaluation, which allows the surgeon to finetune the bone resection and obtain optimal patellar tracking. Avoiding arthrotomy could reduce morbidity and allows a rapid postoperative rehabilitation.

The Trillat procedure is a surgical treatment for recurrent anterior shoulder instability in the setting of significant or irreparable rotator cuff tears in elderly patients. The procedure comprises an inferior closing wedge partial osteotomy of the coracoid process with fixation to the glenoid neck. This results in a lowered and medialized coracoid process that acts as a bone block and the conjoint tendon is brought closer to the glenohumeral joint, thus closing the subcoracoid space, which blocks humeral dislocation. We describe an arthroscopic step-by-step guided Trillat technique that is simple, efficient, and reproducible, while minimizing risk in the extra-articular subcoracoid space. Our technique does not require the release of the pectoralis minor tendon from the coracoid process, which reduces the risk of damaging the brachial plexus. We use a tight-rope fixation construct that allows progressive transfer of the coracoid process, limiting fracture risk and the risk of overtightening of the subscapularis muscle. Because there is a trend for more complex procedures being performed arthroscopically, it is important to develop and simplify operative techniques, aiding surgeons in achieving reproducible and reliable patient outcomes.

Since patients with medullary thyroid cancer (MTC) often have metastatic disease at the time of diagnosis, the development of efficient systemic treatment options for MTC is important. Vandetanib and cabozantinib are two tyrosine kinase inhibitors (TKIs) that were recently approved by FDA and EMA for systemic treatment of metastatic MTC. Additionally, since MTC is of a neuroendocrine tumour type, treatment with radiolabelled somatostatin analogues (e.g. 177Lu-octreotate) is a valid option for patients with MTC. The aim of this study was to investigate the potentially increased therapeutic effect of combining radiation therapy with these TKIs for treatment of MTC in a mouse model. Nude mice carrying patient-derived MTC tumours (GOT2) were treated with external beam radiotherapy (EBRT) and/or one of the two TKIs vandetanib or cabozantinib. The tumour volume was determined and compared with that of mock-treated controls. The treatment doses were chosen to give a moderate effect as monotherapy to be able to detect any increased therapeutic effect from the combination therapy. At the end of follow-up, tumours were processed for immunohistochemical (IHC) analyses. The animals in the combination therapy groups showed the largest reduction in tumour volume and the longest time to tumour progression. Two weeks after start of treatment, the tumour volume for these mice was reduced by about 70-75% compared with controls. Furthermore, also EBRT and TKI monotherapy resulted in a clear anti-tumour effect with a reduced tumour growth compared with controls. The results show that an increased therapeutic effect could be achieved when irradiation is combined with TKIs for treatment of MTC. Future studies should evaluate the potential of using 177Lu-octreotate therapy in combination with TKIs in patients.

Intro: The Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) proposed “Biotypes,” subgroups of psychosis cases with neuro-cognitive homology. Neural activity unbound to stimulus processing (nonspecific or intrinsic activity) was important for differentiating Biotypes, with Biotype-2 characterized by high nonspecific neural activity. A precise estimate of intrinsic activity (IA) was not included in the initial Biotypes characterization. This report hypothesizes intrinsic activity is a critical differentiating feature for psychosis Biotypes. Method: Participants were recruited at B-SNIP sites and included probands with psychosis (schizophrenia, schizoaffective disorder, bipolar I disorder), their first-degree biological relatives, and healthy persons (N = 1338). Probands were also sub-grouped by psychosis Biotype. 10-sec inter-stimulus intervals during an auditory paired-stimuli task were used to quantify intrinsic activity from 64 EEG sensors. Single-trial power and connectivity measures at empirically derived frequency bands were quantified. Multivariate discriminant and correlational analyses were used to summarize variables that efficiently and maximally differentiated groups by conventional diagnoses and Biotypes and to determine their relationship to clinical and social functioning. Results: Biotype-1 consistently exhibited low IA, and Biotype 2 exhibited high IA relative to healthy persons across power frequency bands (delta/theta, alpha, beta, gamma) and alpha band connectivity estimates. DSM groups did not differ from healthy persons on any IA measure. Discussion: Psychosis Biotypes, but not DSM syndromes, were differentiated by intrinsic activity; Biotype-2 was uniquely characterized by an accentuation of this measure. Neurobiologically defined psychosis subgroups may facilitate the use of intrinsic activity in translation models aimed at developing effective treatments for psychosis-relevant deviations in neural modulation.

Sheet specimens of a PLLA-based polymer have been extended at a temperature near to the glass transition in both uniaxial and planar tension, with stress relaxation observed for some time after reaching the final strain. Both axial and transverse stresses were recorded in the planar experiments. In all cases during loading, yielding at small strain was followed by a drop in true stress and then strain hardening. This was followed by stress relaxation at constant strain, during which stress dropped to reach an effectively constant level. Stresses were modelled as steady state and transient components. Steady-state components were identified with the long-term stress in stress relaxation and associated with an elastic component of the model. Transient stresses were modelled using Eyring mechanisms. The greater part of the stress during strain hardening was associated with dissipative Eyring processes. The model was successful in predicting stresses in both uniaxial and planar extension over a limited range of strain rate.

In Canada, more than 80% of energy in the residential sector is used for space heating and domestic hot water (DHW) production. This study aimed to model and compare the performance of four different systems, using solar energy as a renewable energy source for DHW production. A novel microchannel (MC) solar thermal collector and a microchannel-based hybrid photovoltaic/thermal collector (PVT) were fabricated (utilizing a microchannel heat exchanger in both cases), mathematical models were created, and performance was simulated in TRNSYS software. A water-to-water heat pump (HP) was integrated with these two collector-based solar systems, namely MCPVT-HP and MCST-HP, to improve the total solar fraction. System performance was then compared with that of a conventional solar-thermal-collector-based system and that of a PV-resistance (PV-R) system, using a monocrystalline PV collector. The heat pump was added to the systems to improve the systems’ efficiency and provide the required DHW temperatures when solar irradiance was insufficient. Comparisons were performed based on the temperature of the preheated water storage tank, the PV panel efficiency, overall system efficiency, and the achieved solar fraction. The microchannel PVT-heat pump (MCPVT-HP) system has the highest annual solar fraction among all the compared systems, at 76.7%. It was observed that this system had 10% to 35% higher solar fraction than the conventional single-tank solar-thermal-collector-based system during the wintertime in a cold climate. The performance of the two proposed MC-based systems is less sensitive than the two conventional systems to collector tilt angle in the range of 45 degrees to 90 degrees. If roof space is limited, the MCPVT-HP system is the best choice, as the MCPVT collector can perform effectively when mounted vertically on the facades of high-rise residential and commercial buildings. A comparison among five Canadian cities was also performed, and we found that direct beam radiation has a great effect on overall system solar faction.

Abstract Background Angiosarcoma involving the lung can represent either primary or metastatic malignancy. Due to the rarity of this condition, knowledge surrounding the natural history and clinical presentation is scarce. The aim of this scoping review is to summarize the existing literature on pulmonary angiosarcoma, particularly as it pertains to the clinical presentation and ancillary tests used for diagnosis in addition to histopathology. Methods We will conduct a systematic search using Ovid MEDLINE and EMBASE electronic databases. Two investigators will independently screen identified titles and abstracts to select articles reporting on pulmonary angiosarcoma. The data will be summarized in a narrative fashion and organized according to aspects of epidemiology, risk factors, clinical presentation, diagnostic methods, and treatment. Discussion Scoping reviews are increasingly used to synthesize the evidence on a particular topic, to identify gaps in the literature, and to determine if future systematic reviews are feasible. In order to improve the care of patients with angiosarcoma, earlier recognition and diagnosis is required. This review will be valuable for highlighting the range of clinical presentations and the role of imaging and other diagnostic tools in the diagnosis of metastatic and primary pulmonary angiosarcoma. Systematic review registration PROSPERO registration: CRD42017059052

Abstract Salmonella Typhimurium causes a self-limiting gastroenteritis that may lead to systemic disease. Bacteria invade the small intestine, crossing the intestinal epithelium from where they are transported to the mesenteric lymph nodes (MLNs) within migrating immune cells. MLNs are an important site at which the innate and adaptive immune responses converge but their architecture and function is severely disrupted during S. Typhimurium infection. To further understand host-pathogen interactions at this site, we used mass spectrometry imaging (MSI) to analyse MLN tissue from a murine model of S. Typhimurium infection. A molecule, identified as palmitoylcarnitine (PalC), was of particular interest due to its high abundance at loci of S. Typhimurium infection and MLN disruption. High levels of PalC localised to sites within the MLNs where B and T cells were absent and where the perimeter of CD169+ sub capsular sinus macrophages was disrupted. MLN cells cultured ex vivo and treated with PalC had reduced CD4+CD25+ T cells and an increased number of B220+CD19+ B cells. The reduction in CD4+CD25+ T cells was likely due to apoptosis driven by increased caspase-3/7 activity. These data indicate that PalC significantly alters the host response in the MLNs, acting as a decisive factor in infection outcome.

Introduction The use of a noninvasive pelvic circumferential compression device (PCCD) to achieve pelvic stabilization by both decreasing pelvic volume and limiting inter-fragmentary motion has become commonplace, and is a well-established component of Advanced Trauma Life Support (ATLS) protocol in the treatment of pelvic ring injuries. The purpose of this study was to evaluate the following: 1) how consistently a PCCD was placed on patients who arrived at our hospital with unstable pelvic ring injuries; 2) if they were placed in a timely manner; and 3) if hemodynamic instability influenced their use. Methods We performed an institutional review board-approved retrospective study on 112 consecutive unstable pelvic ring injuries, managed over a two-year period at our Level I trauma center. Our hospital electronic medical records were used to review EMT, physician, nurses’, operative notes and radiographic images, to obtain information on the injury and PCCD application. The injuries were classified by an orthopaedic trauma surgeon and a senior orthopaedic resident. Proper application of a pelvic binder using a sheet is demonstrated. Results Only 47% of unstable pelvic fractures received PCCD placement, despite being the standard of care according to ATLS. Lateral compression mechanism pelvic injuries received PCCDs in 33% of cases, while anterior posterior compression (APC) and vertical shear (VS) injuries had applications in 63% of cases. Most of these PCCD devices were applied after imaging (72%). Hemodynamic instability did not influence PCCD application. Conclusion PCCD placement was missed in many (37%) of APC and VS mechanism injuries, where their application could have been critical to providing stability. Furthermore, to provide rapid stability, pelvic circumferential compression devices should be applied after secondary examination, rather than after receiving imaging results. Better education on timing and technique of PCCD placement at our institution is required to improve treatment of pelvic ring injuries.

Patients with medullary thyroid cancer (MTC) are often diagnosed with spread tumour disease and the development of better systemic treatment options for these patients is important. Treatment with the radiolabelled somatostatin analogue 177Lu-octreotate is already a promising option but can be optimised. For example, combination treatment with another substance could increase the effect on tumour tissue. Gemcitabine is a nucleoside analogue that has been shown to sensitise tumour cells to radiation. The aim of this study was to investigate potentially additive or synergistic effects of combining radiation with gemcitabine for treatment of MTC. Nude mice transplanted with patient-derived MTC tumours (GOT2) were divided into groups and treated with radiation and/or gemcitabine. Radiation treatment was given as 177Lu-octreotate or external beam radiotherapy (EBRT). The volume of treated and untreated tumours was followed. The absorbed dose and amount of gemcitabine were chosen to give moderate tumour volume reduction when given as monotherapy to enable detection of increased effects from combination treatment. After follow-up, the mice were killed and tumours were immunohistochemically (IHC) analysed. Overall, the animals that received a combination of EBRT and gemcitabine showed the largest reduction in tumour volume. Monotherapy with EBRT or gemcitabine also resulted in a clear detrimental effect on tumour volume, while the animals that received 177Lu-octreotate monotherapy showed similar response as the untreated animals. The GOT2 tumour was confirmed in the IHC analyses by markers for MTC. The IHC analyses also revealed that the proliferative activity of tumour cells was similar in all tumours, but indicated that fibrotic tissue was more common after EBRT and/or gemcitabine treatment. The results indicate that an additive, or even synergistic, effect may be achieved by combining radiation with gemcitabine for treatment of MTC. Future studies should be performed to evaluate the full potential of combining 177Lu-octreotate with gemcitabine in patients.

Hepatic artery stenosis after liver transplant is often treated with endovascular stent placement. Our institution has adopted use of drug-eluting stents, particularly in small-caliber arteries. We aimed to compare patency rates of drug-eluting stents vs. traditional bare-metal stents. This was a single-institution, retrospective study of liver transplant hepatic artery stenosis treated with stents. Primary patency was defined as time from stent placement to resistive index on Doppler ultrasonography (p = 0.41). Primary patency for small-caliber arteries (3.5–4.5 mm) with drug-eluting stents was 93%, 75%, 75%, and 75%; bare-metal stents: 60%, 60%, 50%, and 38% (p = 0.19). Overall survival was 100%, 100%, 94%, and 91%. Graft survival was 100%, 98%, 96%, and 90%. Stenting for hepatic artery stenosis was safe and effective. While not statistically significant, patency improved with drug-eluting stents compared with bare-metal stents, especially in arteries < 4.5 mm in diameter. Drug-eluting stents can be considered for liver transplant hepatic artery stenosis, particularly in small-caliber arteries.

Total knee arthroplasty (TKA) is an effective treatment for severe osteoarthritis. Despite good survival rates, up to 20% of TKA patients remain dissatisfied. Recently, promising new technologies have been developed in knee arthroplasty, and could improve the functional outcomes. The aim of this paper was to present some new technologies in TKA, their current concepts, their advantages, and limitations. The patient-specific instrumentations can allow an improvement of implant positioning and limb alignment, but no difference is found for functional outcomes. The customized implants are conceived to reproduce the native knee anatomy and to reproduce its biomechanics. The sensors have to aim to give objective data on ligaments balancing during TKA. Few studies are published on the results at mid-term of these two devices currently. The accelerometers are smart tools developed to improve the TKA alignment. Their benefits remain yet controversial. The robotic-assisted systems allow an accurate and reproducible bone preparation due to a robotic interface, with a 3D surgical planning, based on preoperative 3D imaging or not. This promising system, nevertheless, has some limits. The new technologies in TKA are very attractive and have constantly evolved. Nevertheless, some limitations persist and could be improved by artificial intelligence and predictive modeling.