First worldwide use of pulsed-field ablation for ventricular tachycardia ablation via a retrograde approach.

INTRODUCTION: We present the first worldwide use of pulsed-field ablation (PFA) for ventricular tachycardia (VT) ablation via a retrograde approach. METHODS: The patient had previously failed conventional ablation of an intramural circuit underneath the aortic valve. The same VT circuit was inducible during the procedure. The Farawave PFA catheter and Faradrive sheath were used to deliver PFA applications. RESULTS: Post ablation mapping demonstrated scar homogenization. There was no evidence of coronary spasm during PFA applications and no other complications occurred. VT was non-inducible post ablation and the patient has remained free of arrhythmia at follow-up. CONCLUSION: PFA for VT via a retrograde approach is feasible and effective.

All boreal forest successional stages needed to maintain the full suite of soil biodiversity, community composition, and function following wildfire.

Wildfire is a natural disturbance in boreal forest systems that has been predicted to increase in frequency, intensity, and extent due to climate change. Most studies tend to assess the recovery of one component of the community at a time but here we use DNA metabarcoding to simultaneously monitor soil bacteria, fungi, and arthropods along an 85-year chronosequence following wildfire in jack pine-dominated ecosites. We describe soil successional and community assembly processes to better inform sustainable forest management practices. Soil taxa showed different recovery trajectories following wildfire. Bacteria shared a large core community across stand development stages (~ 95-97% of their unique sequences) and appeared to recover relatively quickly by crown closure. By comparison fungi and arthropods shared smaller core communities (64-77% and 68-69%, respectively) and each stage appeared to support unique biodiversity. We show the importance of maintaining a mosaic ecosystem that represents each stand development stage to maintain the full suite of biodiversity in soils following wildfire, especially for fungi and arthropods. These results will provide a useful baseline for comparison when assessing the effects of human disturbance such as harvest or for assessing the effects of more frequent wildfire events due to climate change.

Forest soil biotic communities show few responses to wood ash applications at multiple sites across Canada.

There is interest in utilizing wood ash as an amendment in forestry operations as a mechanism to return nutrients to soils that are removed during harvesting, with the added benefit of diverting this bioenergy waste material from landfill sites. Existing studies have not arrived at a consensus on what the effects of wood ash amendments are on soil biota. We collected forest soil samples from studies in managed forests across Canada that were amended with wood ash to evaluate the effects on arthropod, bacterial and fungal communities using metabarcoding of F230, 16S, 18S and ITS2 sequences as well as enzyme analyses to assess its effects on soil biotic function. Ash amendment did not result in consistent effects across sites, and those effects that were detected were small. Overall, this study suggests that ash amendment applied to managed forest systems in amounts (up to 20 Mg ha-1) applied across the 8 study sties had little to no detectable effects on soil biotic community structure or function. When effects were detected, they were small, and site-specific. These non-results support the application of wood ash to harvested forest sites to replace macronutrients (e.g., calcium) removed by logging operations, thereby diverting it from landfill sites, and potentially increasing stand productivity.

Clinical criteria for COVID-19-associated hyperinflammatory syndrome: a cohort study.

BACKGROUND: A subset of patients with COVID-19 develops a hyperinflammatory syndrome that has similarities with other hyperinflammatory disorders. However, clinical criteria specifically to define COVID-19-associated hyperinflammatory syndrome (cHIS) have not been established. We aimed to develop and validate diagnostic criteria for cHIS in a cohort of inpatients with COVID-19. METHODS: We searched for clinical research articles published between Jan 1, 1990, and Aug 20, 2020, on features and diagnostic criteria for secondary haemophagocytic lymphohistiocytosis, macrophage activation syndrome, macrophage activation-like syndrome of sepsis, cytokine release syndrome, and COVID-19. We compared published clinical data for COVID-19 with clinical features of other hyperinflammatory or cytokine storm syndromes. Based on a framework of conserved clinical characteristics, we developed a six-criterion additive scale for cHIS: fever, macrophage activation (hyperferritinaemia), haematological dysfunction (neutrophil to lymphocyte ratio), hepatic injury (lactate dehydrogenase or asparate aminotransferase), coagulopathy (D-dimer), and cytokinaemia (C-reactive protein, interleukin-6, or triglycerides). We then validated the association of the cHIS scale with in-hospital mortality and need for mechanical ventilation in consecutive patients in the Intermountain Prospective Observational COVID-19 (IPOC) registry who were admitted to hospital with PCR-confirmed COVID-19. We used a multistate model to estimate the temporal implications of cHIS. FINDINGS: We included 299 patients admitted to hospital with COVID-19 between March 13 and May 5, 2020, in analyses. Unadjusted discrimination of the maximum daily cHIS score was 0·81 (95% CI 0·74-0·88) for in-hospital mortality and 0·92 (0·88-0·96) for mechanical ventilation; these results remained significant in multivariable analysis (odds ratio 1·6 [95% CI 1·2-2·1], p=0·0020, for mortality and 4·3 [3·0-6·0], p<0·0001, for mechanical ventilation). 161 (54%) of 299 patients met two or more cHIS criteria during their hospital admission; these patients had higher risk of mortality than patients with a score of less than 2 (24 [15%] of 138 vs one [1%] of 161) and for mechanical ventilation (73 [45%] vs three [2%]). In the multistate model, using daily cHIS score as a time-dependent variable, the cHIS hazard ratio for worsening from low to moderate oxygen requirement was 1·4 (95% CI 1·2-1·6), from moderate oxygen to high-flow oxygen 2·2 (1·1-4·4), and to mechanical ventilation 4·0 (1·9-8·2). INTERPRETATION: We proposed and validated criteria for hyperinflammation in COVID-19. This hyperinflammatory state, cHIS, is commonly associated with progression to mechanical ventilation and death. External validation is needed. The cHIS scale might be helpful in defining target populations for trials and immunomodulatory therapies. FUNDING: Intermountain Research and Medical Foundation.

Synergistic drug combinations and machine learning for drug repurposing in chordoma.

Chordoma is a devastating rare cancer that affects one in a million people. With a mean-survival of just 6 years and no approved medicines, the primary treatments are surgery and radiation. In order to speed new medicines to chordoma patients, a drug repurposing strategy represents an attractive approach. Drugs that have already advanced through human clinical safety trials have the potential to be approved more quickly than de novo discovered medicines on new targets. We have taken two strategies to enable this: (1) generated and validated machine learning models of chordoma inhibition and screened compounds of interest in vitro. (2) Tested combinations of approved kinase inhibitors already being individually evaluated for chordoma. Several published studies of compounds screened against chordoma cell lines were used to generate Bayesian Machine learning models which were then used to score compounds selected from the NIH NCATS industry-provided assets. Out of these compounds, the mTOR inhibitor AZD2014, was the most potent against chordoma cell lines (IC50 0.35 µM U-CH1 and 0.61 µM U-CH2). Several studies have shown the importance of the mTOR signaling pathway in chordoma and suggest it as a promising avenue for targeted therapy. Additionally, two currently FDA approved drugs, afatinib and palbociclib (EGFR and CDK4/6 inhibitors, respectively) demonstrated synergy in vitro (CI50 = 0.43) while AZD2014 and afatanib also showed synergy (CI50 = 0.41) against a chordoma cell in vitro. These findings may be of interest clinically, and this in vitro- and in silico approach could also be applied to other rare cancers.

Variations in terrestrial arthropod DNA metabarcoding methods recovers robust beta diversity but variable richness and site indicators.

Terrestrial arthropod fauna have been suggested as a key indicator of ecological integrity in forest systems. Because phenotypic identification is expert-limited, a shift towards DNA metabarcoding could improve scalability and democratize the use of forest floor arthropods for biomonitoring applications. The objective of this study was to establish the level of field sampling and DNA extraction replication needed for arthropod biodiversity assessments from soil. Processing 15 individually collected soil samples recovered significantly higher median richness (488-614 sequence variants) than pooling the same number of samples (165-191 sequence variants) prior to DNA extraction, and we found no significant richness differences when using 1 or 3 pooled DNA extractions. Beta diversity was robust to changes in methodological regimes. Though our ability to identify taxa to species rank was limited, we were able to use arthropod COI metabarcodes from forest soil to assess richness, distinguish among sites, and recover site indicators based on unnamed exact sequence variants. Our results highlight the need to continue DNA barcoding local taxa during COI metabarcoding studies to help build reference databases. All together, these sampling considerations support the use of soil arthropod COI metabarcoding as a scalable method for biomonitoring.

Modulation of drug-linker design to enhance in vivo potency of homogeneous antibody-drug conjugates.

Antibody-drug conjugates (ADCs) are a promising class of anticancer agents which have undergone substantial development over the past decade and are now achieving clinical success. The development of novel site-specific conjugation technologies enables the systematic study of architectural features within the antibody conjugated drug linker that may affect overall therapeutic indices. Here we describe the results of a systematic study investigating the impact of drug-linker design on the in vivo properties of a series of homogeneous ADCs with a conserved site of conjugation, a monodisperse drug loading, a lysosomal release functionality and monomethyl auristatin E as a cytotoxic payload. The ADCs, which differed only in the relative position of certain drug-linker elements within the reagent, were first evaluated in vitro using anti-proliferation assays and in vivo using mouse pharmacokinetics (PK). Regardless of the position of a discrete polymer unit, the ADCs showed comparable in vitro potencies, but the in vivo PK properties varied widely. The best performing drug-linker design was further used to prepare ADCs with different drug loadings of 4, 6 and 8 drugs per antibody and compared to Adcetris® in a Karpas-299 mouse xenograft model. The most efficacious ADC showed complete tumor regression and 10/10 tumor free survivors at a single 0.5mg/kg dose. This study revealed drug-linker design as a critical parameter in ADC development, with the potential to enhance ADC in vivo potency for producing more efficacious ADCs.

Reconciling Harvest Intensity and Plant Diversity in Boreal Ecosystems: Does Intensification Influence Understory Plant Diversity?

Overall demand for forest products in the boreal forest is increasing to supply growing bio-energy demands in addition to traditional forest products. As a result, there is a need to refine current forest policies to reconcile production and ecosystem function within the context of ecologically sustainable management. This study assessed understory plants' richness, evenness, and diversity in six harvested boreal black spruce-dominated stands situated on loam, sand, and peat site types 15 years after the application of four harvest treatments of increasing biomass removals. Treatments included uncut, stem-only harvest, full-tree harvest, and full-tree harvest + blading of O horizon. Following canopy removal, species richness and diversity (Shannon's and Simpson's indices) increased on all soil types. The more than doubling of slash loading on the stem-only treatment plots compared to the full-tree plots led to significantly lower species diversity on loam sites; however, the reverse was observed on peat sites where the slash provided warmer, drier microsites facilitating the establishment of a broader array of species. Preexisting ericaceous shrub and sphagnum components continued to dominate on the peat sites. Compositional shifts were most evident for the full-tree + bladed treatment on all soil types, with increases in herbaceous cover including ruderal species. The results suggest that the intensification of harvesting on plant diversity varies with soil type, and these differential results should be considered in the refinement of forest biomass-harvesting guidelines to ensure ecological sustainability and biodiversity conservation over a broad suite of soil types.

Effects of oral lactate consumption on metabolism and exercise performance.

Study of lactate metabolism has revealed that orally consumed lactate is used as an energy substrate either directly by oxidation or by conversion to glucose. Disposal of lactate by oxidation or gluconeogenesis consumes protons and can fortify blood bicarbonate levels temporarily and increase pH. These characteristics have led to investigations of lactate consumption as an energy substrate and as a buffering agent. Evidence has revealed no effects of lactate consumption on time to exhaustion during low- to moderate-intensity exercise, suggesting that it is ineffective as an energy supplement. Lactate ingestion has been shown to increase blood pH and bicarbonate levels and increase time to exhaustion in short, high-intensity work bouts. Future work should focus on determining optimal doses of lactate, temporal relationships between doses and exercise, and the efficacy of lactate as an ergogenic in different types of high-intensity exercise.

Actually achieving marine sustainability demands a radical re-think in approach, not 'more of the same'.

The UK is committed to meeting a series of 'high-level marine objectives' which are required to satisfy national obligations and to meet international commitments for the marine environment. There are more than 16 such international high-level policy driven obligations and commitments, together with more than 18 European and more than 12 of national origin. In the UK, there is an assumption that the current and planned monitoring will provide evidence to demonstrate achievement against these high-level objectives.