Objectives The impact of the COVID 19 pandemic on the treatment of patient with aortic valve stenosis is unknown and there is uncertainty on the optimal strategies in managing these patients. Methods This study is supported and endorsed by the Asia Pacific Society of Interventional Cardiology. Due to the inability to have face to face discussions during the pandemic, an online survey was performed by inviting key opinion leaders ( cardiac surgeon/interventional cardiologist/echocardiologist) in the field of transcatheter aortic valve implantation (TAVI) in Asia to participate. The answers to a series of questions pertaining to the impact of COVID-19 on TAVI were collected and analyzed. These led subsequently to an expert consensus recommendations on the conduct of TAVI during the pandemic Results The COVID 19 pandemic had resulted in a 25% (10-80) reduction of case volume and 53% of operators required triaging to manage their patients with severe aortic stenosis. The two most important parameters used to triage were symptoms and valve area. Periprocedural changes included the introduction of teleconsultation, pre-procedure COVD 19 testing, optimization of pre-tests and catheterization laboratory set up. In addition, length of stay was reduced from a mean of 4.4 to 4 days. Conclusion The COVID-19 pandemic has impacted on the delivery of TAVI services to patients in Asia. This expert recommendations on best practices may be a useful to guide to help TAVI teams during this period until a COVID 19 vaccine becomes widely available

We report the successful endovascular repair of a rare case of aortic rupture caused by axillary intra-aortic balloon pump insertion failure. A 38-year-old Jehovah’s Witness female with situs inversus totalis was referred to our hospital for acute decompensated heart failure. We placed an axillary intra-aortic balloon pump for circulatory support. However, an exchange was required due to balloon malfunction (kinked driveline). Unfortunately, the exchange was complicated by an iatrogenic aortic rupture along with large hematoma compressing the trachea. Emergent endovascular repair was performed successfully without any blood transfusion. Postoperative computed tomography showed a successfully repaired aorta and resolving hematoma.

Diastolic dysfunction (DD) is reported to affect up to 35% of the adult general population. The consequence of progressive DD is heart failure with preserved ejection fraction (HFpEF). Coronary microvascular dysfunction (CMD) has been suggested as one of the pathologic mechanisms leading to HFpEF. We investigated whether there was an association between coronary microvascular function and echocardiographic indices of left ventricular diastolic function in patients with chest pain and unobstructed coronary arteries (CPUCA). This retrospective observational study recruited patients referred to cardiology clinics assessment of chest pain who subsequently underwent assessment via CT coronary angiogram (CTA). Coronary microvascular dysfunction was determined by myocardial blood flow reserve (MBFR; <2.0) using myocardial contrast echocardiography. Echocardiographic indices of diastolic function (septal mitral annular e’; septal mitral annular E/e’) were measured from baseline transthoracic echocardiogram. 149 patients (52% men) with a mean age 59.7(9.5) years were recruited. Mean (standard deviation) MBFR was 2.2 (0.51). 37% (55/149) had MBFR<2.0. Median [interquartile range] septal mitral annular e’ velocity and septal mitral annular E/e’ were 7.6 cm/s [6.2, 8.9] and 9.5 [7.5, 10.8] respectively. Univariate regression analysis showed only age was a significant predictor of increasing septal mitral annular E/e’ (=+0.20 95% CI 0.13, +0.28, p<0.001) but not MBFR. Multivariable analysis also showed no association between these septal mitral annular E/e’ and MBFR after adjustment for cardiovascular risk factors. There was no relationship found between echocardiographic indices of left ventricular diastolic function and coronary microvascular function.

Tidal marsh wetlands in the Yellow River Delta provide valuable eco-services to the local population and global ecology. However, this area is suffering from serious degradation under the stresses of social development and climate change. Hydrological connectivity, a new framework in hydrology and ecology, has been proposed as the main factor affecting the ecological processes in coastal wetlands; however, its role in hydrology–soil–vegetation interactions remains unclear. In this study, the researchers parametrically quantified the hydrological connectivity in the tidal marsh wetlands and analyzed its relationship with Phragmites australis, one of the dominant species in this area. Our results showed threshold-like effects on the interaction between hydrological connectivity and P. australis on the plot scale. When biomass is lower than 2.2 kg/m2, the population density and structure size were found to increase with hydrological connectivity. When the biomass is higher than the threshold, the plots disconnected hydrologically because of high water consumption. Compared with soil chemistry, salinity, and water soil content, hydrological connectivity in the surface soil layer is more strongly linked to the plant traits and spatial structure in the tidal marsh wetlands due to the narrow ranges of other variables. Based on the authors’ analysis, the researchers do not recommend dense plantation of P. australis, especially near the freshwater sources in the tidal marsh, because of its high reproduction ability and competitive nature, which may cut the freshwater connectivity off, lowering the richness of plant species and habitat diversity.

Leaf stomatal density is known to covary with leaf vein density. However, the functional underpinning of this relation, and how it scales to whole-plant water transport anatomy, is still unresolved. We hypothesized that the balance of water exchange between the vapour phase (in stomata) and liquid phase (in vessels) depends on the consistent scaling between the summed stomatal areas and xylem cross-sectional areas, both at the whole-plant and single-leaf level. This predicted size-covariation should be driven by the covariation of numbers of stomata and terminal vessels. We examined the relationships of stomatal traits and xylem anatomical traits from the entire plant to individual leaves across seedlings of 53 European woody angiosperm species. There was strong and convergent scaling between total stomatal area and stem xylem area per plant and between leaf total stomatal area and midvein xylem area per leaf across all the species, irrespective of variation in leaf habit, growth-form or relative growth rate (RGR). Moreover, strong scaling was found between stomatal number and terminal vessel number while not in their respective average areas. Our findings have broad implications for integrating xylem architecture and stomatal distribution, and deepen our understanding of the design rules of plants’ water transport network.

Today’s available therapies to treat patients infected with human immunodeficiency virus (HIV) aim at preventing viral replication and transmission but fail to eliminate the virus. Although transplantation of an allogeneic CCR5Δ32 homozygous stem cell grafts provided a cure for three patients, this approach is not considered a general therapeutic strategy because of potential severe side effects. Conversely, genome editing to disrupt the CCR5 locus that encodes the major HIV coreceptor was shown to confer resistance to R5-tropic HIV strains on the cellular level. Here, we present a clinically relevant and highly efficient approach to produce HIV-1 resistant CD4+ T cells. After transferring mRNA coding for CCR5-targeting TALEN into CD4+ T cells by electroporation, up to 89% of CCR5 alleles were disrupted. Genotyping confirmed genetic stability of the edited cell product and off-target analyses established absence of relevant mutagenic events. When challenging these edited T cells with R5-tropic HIV, we observed protection in a dose-dependent manner. Functional assessments revealed no significant differences between edited and control CD4+ T cells in terms of proliferation capacity and their ability to secrete cytokines upon exogenous stimuli. Overall, we successfully engineered HIV-resistant CD4+ T cells under clinically relevant conditions, paving the way for clinical translation.

Severe recurrent mitral regurgitation (MR) within 1 year of mitral valve repair is usually attributed to a technical issue with the original repair procedure. However, when artificial chordae are employed to correct mitral valve prolapse, ventricular remodeling (i.e. decreased ventricular size) can lead to recurrent prolapse and valve dysfunction. To highlight this phenomena, we present 2 patients who experienced early failure after undergoing mitral valve repair with artificial chordae.

After its first description in Wuhan (China), SARS-CoV-2 the agent of coronavirus disease 2019 (COVID-19) rapidly spread worldwide. Previous studies suggested that pets could be susceptible to SARS-CoV-2. Here, we investigated the putative infection of SARS-CoV-2 in 22 cats and 11 dogs from owners previously infected or suspected of being infected by SARS-CoV-2. For each animal, rectal, nasopharyngeal swabs and serum were taken. Swabs were submitted to RT-qPCR assays targeting 2 genes of SARS-CoV-2. All dogs were tested SARS-CoV-2 negative. One cat was tested positive by RT-qPCR on rectal swab. Nasopharyngeal swabs from this animal were tested negative. This cat showed mild respiratory and digestive signs. Serological analysis confirm the presence of antibodies against the SARS-CoV-2 in the two serum samples taken 10 days apart. Genome sequence analysis revealed that the cat SARS-CoV-2 belongs to the phylogenetic clade A2a like most of the French human SARS-CoV-2. This study reports for the first time the natural infection of a cat in France (near Paris) probably through their owners. There is currently no evidence that cats can spread COVID-19 and owners should not abandon their pets or compromise their welfare.

In the present study one hundred and sixteen partial G gene sequences of Avian metapneumovirus (aMPV) subtype B, obtained during routine diagnostics in different European Countries in the last few years (2014-2019), were analysed by sequence and phylogenetic analyses in order to draw an updated picture of the molecular characteristics of circulating strains. Nucleotide sequences were compared with other sequences of European and extra-European aMPV-Bs collected prior to that period or retrieved from GenBank. Phylogenetic relationships among the aMPV-B strains, reconstructed using the Maximum Likelihood method implemented in MEGA X, demonstrated that aMPV-B has evolved in Europe from its first appearance, frequently displaying a clear relation with the geographic area of detection. The 40% of aMPV-B viruses analysed were classified as vaccine-derived strains, being phylogenetically related, and showing high nucleotide identity with live commercial vaccine strains licensed in Europe. The remaining 60% were classified as field strains since they clustered separately and showed a low nucleotide identity with vaccines and vaccine-derived strains. The phylogenetic tree showed that the virus has continued to evolve from its first appearance in the ’80s since more recently detected strains belonged to clades phylogenetically distant from the older strains. Unlike vaccine-derived strains, field strains tended to cluster according to their geographic origin and irrespective of the host species where the viruses had been detected. In conclusion, the molecular characterization of aMPV-B and the differentiation between vaccines and field strains through G gene sequence analysis can be a useful tool towards correct diagnosis and should be routinely applied in order to better address the control strategies.

Soil water stable isotopes are widely used across disciplines (e.g. hydrology, ecology, soil science, and biogeochemistry). However, the full potential of stables isotopes as a tool for characterizing the origin, flow path, transport processes and residence times of water in different eco-, hydro-, and geological compartments has not yet been exploited. This is mainly due to the large variety of different methods for pore water extraction. While recent work has shown that matric potential affects the equilibrium fractionation, little work has examined how different water retention characteristics might affect the sampled water isotopic composition. Here, we present a simple laboratory experiment with two well-studied standard soils differing in their physico-chemical properties (e.g., clayey loam and silty sand). Samples were sieved, oven-dried and spiked with water of known isotopic composition to full saturation. For investigating the effect of water retention characteristics on the extracted water isotopic composition, we used pressure extractors to sample isotopically labelled soil water along the pF curve. After pressure extraction, we further extracted the soil samples via cryogenic vacuum extraction. The null hypothesis guiding our work was that water held at different tensions shows the same isotopic composition. Our results showed that the sampled soil water differed isotopically from the introduced isotopic label over time and sequentially along the pF curve. Our and previous studies suggest caution in interpreting isotope results of extracted soil water and a need to better characterize processes that govern isotope fractionation with respect to soil water retention characteristics. In the future, knowledge about soil water retention characteristics could be applied to predict soil water fractionation effects under natural and non-stationary conditions.

Aims: Opioid misuse and overuse has contributed to a widespread overdose crisis and many patients and physicians are considering medical cannabis to support opioid tapering and chronic pain control. Using a five-step modified Delphi process, we aimed to develop consensus-based recommendations on: 1) when and how to safely initiate and titrate cannabinoids in the presence of opioids, 2) when and how to safely taper opioids in the presence of cannabinoids, and 3) how to monitor patients and evaluate outcomes when treating with opioids and cannabinoids. Results: In patients with chronic pain taking opioids not reaching treatment goals, there was consensus that cannabinoids may be considered for patients experiencing or displaying opioid-related complications, despite psychological or physical interventions. There was consensus observed to initiate with a CBD-predominant oral extract in the daytime and consider adding THC. When adding THC, start with 0.5–3 mg, and increase by 1–2 mg once or twice weekly up to 30–40 mg/day. Initiate opioid tapering when the patient reports a minor/major improvement in function, seeks less as-needed medication to control pain, and/or the cannabis dose has been optimized. The opioid tapering schedule may be 5%–10% of the morphine equivalent dose (MED) every 1 to 4 weeks. Clinical success could be defined by an improvement in function/quality of life, a ≥ 30% reduction in pain intensity, a ≥ 25% reduction in opioid dose, a reduction in opioid dose to < 90 mg MED, and/or reduction in opioid-related adverse events. Conclusions: This five-stage modified Delphi process led to the development of consensus-based recommendations surrounding the safe introduction and titration of cannabinoids in concert with tapering opioids.

Less invasive techniques for cardiothoracic surgical procedures are designed to limit surgical trauma, but technical requirements and preoperative planning are more demanding than those for conventional sternotomy. Patient selection, interdisciplinary collaboration, and surgical skills are key factors for procedural success. Aortic valve replacement is frequently performed through an upper hemisternotomy, but the right anterior minithoracotomy represents an even less traumatic, technical advancement. Preoperative assessment of the ascending aorta in relation to the sternum is mandatory to select patients and the intercostal access site. This description of the surgical technique focuses on the specific procedural details including the obligatory planning with computed tomography, and our cannulation strategy. We also sought to define the anatomical ascending aorto-sternal relationship, as it is of utmost importance in preoperative computed tomographic planning.

Abbreviations Full term COVID-19 coronavirus disease 2019 SARS-CoV-2 Severe acute respiratory syndrome corona virus 2

Rationale, aims and objectives: The diversity of safety signals (e.g., case reports, animal studies and observational studies) makes the assessment of the (un-)safety of a drug a formidable challenge. While frequentist viewpoints to uncertain inference struggle in aggregating these signals, the more flexible Bayesian approaches seem better suited for this quest. Artificial Intelligence (AI) offers great promise to these approaches for information retrieval, decision support and leaning probabilities from data. E-Synthesis is a Bayesian framework for drug safety assessments build on philosophical principles and considerations. It aims to aggregate all the available information, in order to provide a Bayesian probability of a drug causing an adverse reaction. We delineate and assess ways in which AI can support E-Synthesis. Results: We find that AI can help with information retrieval, usability (graphical decision making aids), learning Bayes factors from historical data, assessing quality of information and determining conditional probabilities for the so-called “indicators” of causation for E-Synthesis. Conclusions: Properly applied, AI can help the transition of philosophical principles and considerations concerning evidence aggregation for drug safety to a tool that can be used in practise.

Viral vectors have a great potential for gene delivery, but manufacturing at pharmaceutical scale is a big challenge for the industry. The baculovirus-insect cells system is one of the most scalable platforms to produce clinical grade recombinant Adeno-Associated Virus (rAAV) vectors, however, the standard procedure to generate recombinant baculovirus based on Tn7 transposition is time consuming and still suffers technical constraints. Indeed, we recently shown that baculoviral sequences adjacent to the AAV ITRs are preferentially encapsidated into the rAAV vector particles. This observation raised concern about safety for clinical applications due to the presence of bacterial and antibiotic resistance coding sequences with Tn7-mediated system for the construction of recombinant baculoviruses. Here, we investigated a faster and safer method to generate baculovirus reagents based on homologous recombination (HR) for its use in rAAV manufacturing compared to the Tn7-based system. First, we confirmed the functionality of inserted cassette and the absence of undesirable genes into HR-derived baculoviral genomes. Strikingly, we found that the exogenous cassette shown an increased stability over passages when using HR system. Finally, we tested these materials to produce rAAV vectors. The baculoviruses originated from either system lead to high rAAV vector genome yields, with the advantage for the HR method being that the rAAV lots are exempted of undesirable gentamycin and kanamycin genes derived sequences which provides an additional level of safety for the manufacturing of rAAV vectors. Overall, this study highlights the importance of the upstream process and starting biologic materials to generate safer rAAV biotherapeutic products.

Treating twenty-five cases of chronic resistant otitis externa with fluticasone propionate (Flixonase®): a case series Utilising Flixonase® in treatment of chronic otitis externaKey points:Chronic cases of otitis externa, resistant to conventional treatments are notoriously difficult to treat, with resolution in these cases challenging.Guidelines suggest the use of corticosteroid in chronic otitis externa, however, there is no specific advice on which corticosteroid to utilise.Our case-series demonstrates the potential benefit of fluticasone propionate in patients who have previously failed a multitude of conventional management options.Despite the limitations of our study, our experience highlights a gap in the literature and suggest fluticasone propionate as an exciting and potentially important tool in the arsenal of the otolaryngologist.

We describe the case of a 59-year old female affected by aortic extensive endocarditis with communication between aortic annulus and right cavities, treated with double pericardial patch reconstruction and rapid-deployment aortic valve prosthesis implantation.

The FastDesign protocol in the molecular modeling program Rosetta iterates between sequence optimization and structure refinement to stabilize de novo designed protein structures and complexes. FastDesign has been used previously to design novel protein folds and assemblies with important applications in research and medicine. To promote sampling of alternative conformations and sequences, FastDesign includes stages where the energy landscape is smoothened by reducing repulsive forces. Here, we discover that this process disfavors larger amino acids in the protein core because the protein compresses in the early stages of refinement. By testing alternative ramping strategies for the repulsive weight, we arrive at a scheme that produces lower energy designs with more native-like sequence composition in the protein core. We further validate the protocol by designing and experimentally characterizing over 4000 proteins and show that the new protocol produces higher stability proteins.