Dynamic exchange of myosin VI on endocytic structures.

The actin-based molecular motor myosin VI functions in the endocytic uptake pathway, both during the early stages of clathrin-mediated uptake and in later transport to/from early endosomes. This study uses fluorescence recovery after photobleaching (FRAP) to examine the turnover rate of myosin VI during endocytosis. The results demonstrate that myosin VI turns over dynamically on endocytic structures with a characteristic half-life common to both the large insert isoform of myosin VI on clathrin-coated structures and the no-insert isoform on early endosomes. This half-life is shared by the myosin VI-binding partner Dab2 and is identical for full-length myosin VI and the cargo-binding tail region. The 4-fold slower half-life of an artificially dimerized construct of myosin VI on clathrin-coated structures suggests that wild type myosin VI does not function as a stable dimer, but either as a monomer or in a monomer/dimer equilibrium. Taken together, these FRAP results offer insight into both the basic turnover dynamics and the monomer/dimer nature of myosin VI

Post-operative determinants of chronic pain after primary knee replacement surgery:Analysis of data on 258,386 patients from the National Joint Registry for England, Wales, Northern Ireland and the Isle of Man (NJR)

Objective: To identify post-operative risk factors for the development of chronic pain after knee replacement. Design: Primary knee replacements in persons aged ≥18 years between April 2008 and December 2016 from the National Joint Registry, linked with English Hospital Episode Statistics data, and Patient Reported Outcome Measures. The outcome was chronic pain 6-months after surgery (Oxford Knee pain score). Logistic regression modelling identified risk factors for chronic pain outcome. Results: 258,386 patients; 56.7% women; average age 70.1 years (SD ​± ​8.8 years). 43,702 (16.9%) were identified as having chronic pain 6-months post-surgery. Within 3 months of surgery complications were uncommon: intra-operative complications 1224 (0.5%); ≥1 medical complication 6073 (2.4%)); 32,930 (12.7%) hospital readmissions; 3848 (1.5%) re-operation; 835 (0.3%) revision. Post-surgical risk factors of chronic pain were: mechanical complication of prosthesis odds ratio (OR) 1.56 (95% Confidence Interval 1.35, 1.80); surgical site infection OR 1.13 (0.99, 1.29); readmission OR 1.47 (1.42, 1.52); re-operation OR 1.39 (1.27, 1.51); revision OR 1.92 (1.64, 2.25); length of stay e.g. 6+ vs. <2 days OR 1.48 (1.35, 1.63), blood transfusion OR 0.47 (0.26, 0.86) and myocardial infarction OR 0.69 (0.49, 0.97). Discriminatory ability of the model was only fair (c-statistic 0.71) indicating that post-surgical predictors explain a limited amount of variability in chronic pain. Conclusions: We identified a number of post-operative factors relating to the operation and early recovery that are associated with chronic pain following primary knee replacement. The model had weak discriminatory ability indicating that there remains considerable unexplained variability in chronic pain outcome

Burned area and carbon emissions across northwestern boreal North America from 2001-2019

Fire is the dominant disturbance agent in Alaskan and Canadian boreal ecosystems and releases large amounts of carbon into the atmosphere. Burned area and carbon emissions have been increasing with climate change, which have the potential to alter the carbon balance and shift the region from a historic sink to a source. It is therefore critically important to track the spatiotemporal changes in burned area and fire carbon emissions over time. Here we developed a new burned-area detection algorithm between 2001-2019 across Alaska and Canada at 500 m (meters) resolution that utilizes finer-scale 30 m Landsat imagery to account for land cover unsuitable for burning. This method strictly balances omission and commission errors at 500 m to derive accurate landscape- and regional-scale burned-area estimates. Using this new burned-area product, we developed statistical models to predict burn depth and carbon combustion for the same period within the NASA Arctic-Boreal Vulnerability Experiment (ABoVE) core and extended domain. Statistical models were constrained using a database of field observations across the domain and were related to a variety of response variables including remotely sensed indicators of fire severity, fire weather indices, local climate, soils, and topographic indicators. The burn depth and aboveground combustion models performed best, with poorer performance for belowground combustion. We estimate 2.37×106 ha (2.37 Mha) burned annually between 2001-2019 over the ABoVE domain (2.87 Mha across all of Alaska and Canada), emitting 79.3 ± 27.96 Tg (±1 standard deviation) of carbon (C) per year, with a mean combustion rate of 3.13 ± 1.17 kg C m-2. Mean combustion and burn depth displayed a general gradient of higher severity in the northwestern portion of the domain to lower severity in the south and east. We also found larger-fire years and later-season burning were generally associated with greater mean combustion. Our estimates are generally consistent with previous efforts to quantify burned area, fire carbon emissions, and their drivers in regions within boreal North America; however, we generally estimate higher burned area and carbon emissions due to our use of Landsat imagery, greater availability of field observations, and improvements in modeling. The burned area and combustion datasets described here (the ABoVE Fire Emissions Database, or ABoVE-FED) can be used for local- to continental-scale applications of boreal fire science

Optimised Anaesthesia to Reduce Post Operative Cognitive Decline (POCD) in Older Patients Undergoing Elective Surgery, a Randomised Controlled Trial

Background The study determined the one year incidence of post operative cognitive decline (POCD) and evaluated the effectiveness of an intra-operative anaesthetic intervention in reducing post-operative cognitive impairment in older adults (over 60 years of age) undergoing elective orthopaedic or abdominal surgery. Methods and Trial Design The design was a prospective cohort study with a nested randomised, controlled intervention trial, using intra-operative BiSpectral index and cerebral oxygen saturation monitoring to enable optimisation of anaesthesia depth and cerebral oxygen saturation in older adults undergoing surgery. Results In the 52 week prospective cohort study (192 surgical patients and 138 controls), mild (?2 = 17.9 p<0.0001), moderate (?2 = 7.8 p = 0.005) and severe (?2 = 5.1 p = 0.02) POCD were all significantly higher after 52 weeks in the surgical patients than among the age matched controls. In the nested RCT, 81 patients were randomized, 73 contributing to the data analysis (34 intervention, 39 control). In the intervention group mild POCD was significantly reduced at 1, 12 and 52 weeks (Fisher’s Exact Test p = 0.018, ?2 = 5.1 p = 0.02 and ?2 = 5.9 p = 0.015), and moderate POCD was reduced at 1 and 52 weeks (?2 = 4.4 p = 0·037 and ?2 = 5.4 p = 0.02). In addition there was significant improvement in reaction time at all time-points (Vigilance Reaction Time MWU Z = ?2.1 p = 0.03, MWU Z = ?2.7 p = 0.004, MWU Z = ?3.0 p = 0.005), in MMSE at one and 52 weeks (MWU Z = ?2.9 p = 0.003, MWU Z = ?3.3 p = 0.001), and in executive function at 12 and 52 weeks (Trail Making MWU Z = ?2.4 p = .0.018, MWU Z = ?2.4 p = 0.019). Conclusion POCD is common and persistent in older adults following surgery. The results of the nested RCT indicate the potential benefits of intra-operative monitoring of anaesthetic depth and cerebral oxygenation as a pragmatic intervention to reduce post-operative cognitive impairment

Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWAS for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally-diverse individuals (European, African, Asian and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n=109,122 individuals. We identified 59 sentinel variants (p-value OBFC1indicated the independent signals colocalized with cell-type specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated our TL polygenic trait scores (PTS) were associated with increased risk of cancer-related phenotypes

25th RCOphth Congress, President's Session paper:25 years of progress in medical retina

The quarter century since the foundation of the Royal College of Ophthalmologists has coincided with immense change in the subspecialty of medical retina, which has moved from being the province of a few dedicated enthusiasts to being an integral, core part of ophthalmology in every eye department. In age-related macular degeneration, there has been a move away from targeted, destructive laser therapy, dependent on fluorescein angiography to intravitreal injection therapy of anti-growth factor agents, largely guided by optical coherence tomography. As a result of these changes, ophthalmologists have witnessed a marked improvement in visual outcomes for their patients with wet age-related macular degeneration (AMD), while at the same time developing and enacting entirely novel ways of delivering care. In the field of diabetic retinopathy, this period also saw advances in laser technology and a move away from highly destructive laser photocoagulation treatment to gentler retinal laser treatments. The introduction of intravitreal therapies, both steroids and anti-growth factor agents, has further advanced the treatment of diabetic macular oedema. This era has also seen in the United Kingdom the introduction of a coordinated national diabetic retinopathy screening programme, which offers an increasing hope that the burden of blindness from diabetic eye disease can be lessened. Exciting future advances in retinal imaging, genetics, and pharmacology will allow us to further improve outcomes for our patients and for ophthalmologists specialising in medical retina, the future looks very exciting but increasingly busy

Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways

The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (&gt;250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice