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Objectives COVIDTrach is a UK multicentre prospective cohort study project that aims to evaluate the outcomes of tracheostomy in patients with COVID-19 receiving mechanical ventilation and record the incidence of SARS-CoV-2 infection among healthcare workers involved in the procedure.Design Data on patient demographic, clinical history and outcomes were entered prospectively and updated over time via an online database (REDCap). Clinical variables were compared with outcomes, with logistic regression used to develop a model for mortality. Participants recorded whether any operators tested positive for SARS-CoV-2 within 2 weeks of the procedure.Setting UK National Health Service departments involved in treating patients with COVID-19 receiving mechanical ventilation.Participants The cohort comprised 1605 tracheostomy cases from 126 UK hospitals collected between 6 April and 26 August 2020.Main outcome measures Mortality following tracheostomy, successful wean from mechanical ventilation and length of time from tracheostomy to wean, discharge from hospital, complications from tracheostomy, reported SARS-CoV-2 infection among operators.Results The median time from intubation to tracheostomy was 15 days (IQR 11, 21). 285 (18%) patients died following the procedure. 1229 (93%) of the survivors had been successfully weaned from mechanical ventilation at censoring and 1049 (81%) had been discharged from hospital. Age, inspired oxygen concentration, positive end-expiratory pressure setting, fever, number of days of ventilation before tracheostomy, C reactive protein and the use of anticoagulation and inotropic support independently predicted mortality. Six reports were received of operators testing positive for SARS-CoV-2 within 2 weeks of the procedure.Conclusions Tracheostomy appears to be safe in mechanically ventilated patients with COVID-19 and to operators performing the procedure and we identified clinical parameters that are predictive of mortality.Trial registration number The study is registered with ClinicalTrials.Gov (NCT04572438).

CD161 is a C-type lectin-like receptor expressed on the majority of natural killer (NK) cells; however, the significance of CD161 expression on NK cells has not been comprehensively investigated. Recently, we found that CD161 expression identifies a transcriptional and innate functional phenotype that is shared across various T cell populations. Using mass cytometry and microarray experiments, we demonstrate that this functional phenotype extends to NK cells. CD161 marks NK cells that have retained the ability to respond to innate cytokines during their differentiation, and is lost upon cytomegalovirus-induced maturation in both healthy and human immunodeficiency virus (HIV)-infected patients. These pro-inflammatory NK cells are present in the inflamed lamina propria where they are enriched for integrin CD103 expression. Thus, CD161 expression identifies NK cells that may contribute to inflammatory disease pathogenesis and correlates with an innate responsiveness to cytokines in both T and NK cells.

Abstract The rs6265 single nucleotide polymorphism (SNP) in the gene for brain-derived neurotrophic factor is a common variant that alters therapeutic outcomes for individuals with Parkinson’s disease (PD). We previously investigated the effects of this SNP on the experimental therapeutic approach of neural grafting, demonstrating that young adult parkinsonian rats carrying the variant Met allele exhibited enhanced graft function compared to wild-type rats and also exclusively developed aberrant graft-induced dyskinesias (GID). Aging is the primary risk factor for PD and reduces graft efficacy. Here we investigated whether aging interacts with this SNP to further alter cell transplantation outcomes. We hypothesized that aging would reduce enhancement of graft function associated with this genetic variant and exacerbate GID in all grafted subjects. Unexpectedly, beneficial graft function was maintained in aged rs6265 subjects. However, aging was permissive to GID induction, regardless of genotype, with the greatest incidence and severity found in rs6265-expressing animals.

Pulmonary MRI of hyperpolarized xenon-129 (hp129Xe) dissolved in the lung parenchyma and vascular phase is gaining increasing attention for clinical assessment of gas exchange in multiple diseases. These conditions can involve thickening of barrier tissues due to fibrotic scarring or reduced capillary blood flow leading to diminished gas-blood exchange hence, the ratios between hp129Xe signals arising from the lung membrane (M), the red blood cells (RBC), and the gas phase hold significant diagnostic value. However, comparing hp129Xe signal ratios quantitatively across different studies may pose challenges due to varied experimental conditions and opted pulse sequence protocols.A solution to this problem arises from materials science applications of hp129Xe where xenon dissolved in porous materials or polymers can display chemical shifts similar to the M and RBC shift in lungs. This work explored the generation of MR spectral profiles with respect to chemical shift and signal intensity ratios that closely resemble spectral profiles observed in human lungs in health and disease. At ambient temperatures, reticulated open cell polyurethane foam treated with olive oil as a fatty phase produced dissolved phase 129Xe chemical shifts of 215 ppm and 196 ppm, respectively, that emulate typical RBC and M signals. The uptake kinetics into the non-toxic materials was sufficiently similar to pulmonary signal uptake to enable hp129Xe MRI with dissolved phase ratios that closely resembled clinical data.A phantom assembly was devised to allow for gas handling protocols that matched clinical protocols. The current iteration of the developed phantom enables rapid testing of basic experimental protocols and can be used for training purposes without regulatory approval and governance. Furthermore, the introduced concept shows a pathway for the development of a quantitative universal phantom standard for dissolved phase pulmonary hp129Xe MRI. A robust phantom standard will require materials with longer shelf lifetime than the oil-foam system used in this study and would benefit from a hierarchical porous network with more defined microstructure similar to that found in lungs.

Commercial human MR scanners are optimised for proton imaging, containing sophisticated prescan algorithms with setting parameters such as RF transmit gain and power. These are not optimal for X-nuclear application and are challenging to apply to hyperpolarised experiments, where the non-renewable magnetisation signal changes during the experiment. We hypothesised that, despite the complex and inherently nonlinear electrodynamic physics underlying coil loading and spatial variation, simple linear regression would be sufficient to accurately predict X-nuclear transmit gain based on concomitantly acquired data from the proton body coil. We collected data across 156 scan visits at two sites as part of ongoing studies investigating sodium, hyperpolarised carbon, and hyperpolarised xenon. We demonstrate that simple linear regression is able to accurately predict sodium, carbon, or xenon transmit gain as a function of position and proton gain, with variation that is less than the intrasubject variability. In conclusion, sites running multinuclear studies may be able to remove the time-consuming need to separately acquire X-nuclear reference power calibration, inferring it from the proton instead.

Abstract Functional lung imaging modalities such as hyperpolarized gas MRI ventilation enable visualization and quantification of regional lung ventilation; however, these techniques require specialized equipment and exogenous contrast, limiting clinical adoption. Physiologically-informed techniques to map proton (1H)-MRI ventilation have been proposed. These approaches have demonstrated moderate correlation with hyperpolarized gas MRI. Recently, deep learning (DL) has been used for image synthesis applications, including functional lung image synthesis. Here, we propose a 3D multi-channel convolutional neural network that employs physiologically-informed ventilation mapping and multi-inflation structural 1H-MRI to synthesize 3D ventilation surrogates (PhysVENeT). The dataset comprised paired inspiratory and expiratory 1H-MRI scans and corresponding hyperpolarized gas MRI scans from 170 participants with various pulmonary pathologies. We performed fivefold cross-validation on 150 of these participants and used 20 participants with a previously unseen pathology (post COVID-19) for external validation. Synthetic ventilation surrogates were evaluated using voxel-wise correlation and structural similarity metrics; the proposed PhysVENeT framework significantly outperformed conventional 1H-MRI ventilation mapping and other DL approaches which did not utilize structural imaging and ventilation mapping. PhysVENeT can accurately reflect ventilation defects and exhibits minimal overfitting on external validation data compared to DL approaches that do not integrate physiologically-informed mapping.

Background The objective of the PERSONAL‐CovidBP (Personalised Electronic Record Supported Optimisation When Alone for Patients With Hypertension: Pilot Study for Remote Medical Management of Hypertension During the COVID‐19 Pandemic) trial was to assess the efficacy and safety of smartphone‐enabled remote precision dosing of amlodipine to control blood pressure (BP) in participants with primary hypertension during the COVID‐19 pandemic. Methods and Results This was an open‐label, remote, dose titration trial using daily home self‐monitoring of BP, drug dose, and side effects with linked smartphone app and telemonitoring. Participants aged ≥18 years with uncontrolled hypertension (5–7 day baseline mean ≥135 mm Hg systolic BP or ≥85 mm Hg diastolic BP) received personalized amlodipine dose titration using novel (1, 2, 3, 4, 6, 7, 8, 9 mg) and standard (5 and 10 mg) doses daily over 14 weeks. The primary outcome of the trial was mean change in systolic BP from baseline to end of treatment. A total of 205 participants were enrolled and mean BP fell from 142/87 (systolic BP/diastolic BP) to 131/81 mm Hg (a reduction of 11 (95% CI, 10–12)/7 (95% CI, 6–7) mm Hg, P

Mainstreaming nature-based solutions in cities has grown in scale and magnitude in recent times but is still considered to be the main challenge for transitioning our cities and their communities to be more climate resilient and liveable: environmentally, economically, and socially. Furthermore, taking nature-based solutions to the next level, and scaling them out to all urban contexts to achieve a greater impact, is proving to be slow and often conflicts with other transitioning initiatives such as energy generation, mobility and transport initiatives, and infilling to combat sprawl. So, the task is neither easy nor straightforward; there are many barriers to this novel transition, especially when it comes to collaborative approaches to implementing nature-based solutions with diverse urban communities and within city authorities themselves. This paper reports on a new process that is systematically co-produced and captured as a framework for planning nature-based solutions that emerged during the Connecting Nature project. The Connecting Nature Framework is a three-stage, iterative process that involves seven key activity areas for mainstreaming nature-based solutions: technical solutions, governance, financing and business models, nature-based enterprises, co-production, reflexive monitoring, and impact assessment. The tested and applied framework is designed to address and overcome barriers to the implementation of nature-based solutions in cities via a co-created, iterative, and reflective approach. The planning process guided by the proposed framework has already yielded promising results with some of the cities of the project, though further usage and its adoption by other cities is needed to explore its potential in different contexts especially in the Global South. The paper concludes with suggestions on how this may be realised.

Abstract Background Hypogonadism in older men is often considered as late onset hypogonadism. However, this clinical condition results from primary testicular failure which could be of genetic origin with Klinefelter syndrome being the most common chromosomal abnormality associated with it. Case presentation We report a heterogeneous group of cases who were diagnosed with hypergonadotropic hypogonadism in their adulthood and were found to have rare chromosomal aberrations. All were elderly men (in their 70 s and 80 s) for whom the diagnosis was made during the evaluation of incidental symptoms suggestive of endocrinopathy. The first had hyponatremia; the other two had gynaecomastia and features of hypogonadism noted during admission for various acute medical problems. With respect to their genetic results; the first had a male karyotype with balanced reciprocal translocation between the long arm of chromosome 4 and the short arm of chromosome 7. The second case had a male karotype with one normal X chromosome and an isochrome for the short arm of the Y chromosome. The third case was an XX male with unbalanced translocation between the X & Y chromosomes with retention of the SRY locus. Conclusion Hypergonadotrophic hypogonadism in the elderly, may be due to chromosomal aberrations, resulting in heterogeneous and diverse clinical phenotypes. Vigilance must be exercised when seeing cases with subtle clinical findings. This report suggests that in selected cases of adult hypergonadotropic hypogonadism, chromosomal analysis may be indicated.

Abstract Background Children with orofacial clefts are highly susceptible to malnutrition, with severe malnutrition restricting their eligibility to receive safe surgery. Ready-to-use therapeutic foods (RUTF) are an effective treatment for malnutrition; however, the effectiveness has not been demonstrated in this patient population prior to surgery. We studied the effectiveness of short-term RUTF use in transitioning children with malnutrition, who were initially ineligible for surgery, into surgical candidates. Methods A cohort of patients from Ghana, Honduras, Malawi, Madagascar, Nicaragua, and Venezuela enrolled in a nutrition program were followed by Operation Smile from June 2017 to January 2020. Age, weight, and length/height were tracked at each visit. Patients were included until they were sufficiently nourished (Z > = -1) with a secondary outcome of receiving surgery. The study was part of a collaborative program between Operation Smile (NGO), Birdsong Peanuts (peanut shellers and distributors), and MANA Nutrition (RUTF producer). Results A total of 556 patients were recruited between June 2017 and January 2020. At baseline 28.2% (n = 157) of patients were diagnosed with severe, 21.0% (n = 117) moderate, and 50.7% (n = 282) mild malnutrition. 324 (58.3%) presented for at least one return visit. Of those, 207 (63.7%) reached optimal nutrition status. By visit two, the mean z-score increased from -2.5 (moderate) to -1.7 (mild) (p

Abstract Aims In people at risk of heart failure (HF) enrolled in the Heart ‘OMics’ in AGEing (HOMAGE) trial, spironolactone reduced circulating markers of collagen synthesis, natriuretic peptides, and blood pressure and improved cardiac structure and function. In the present report, we explored factors associated with dyskalaemia. Methods and results The HOMAGE trial was an open‐label study comparing spironolactone (up to 50 mg/day) versus standard care in people at risk for HF. After randomization, serum potassium was assessed at 1 and 9 months and was defined as low when ≤3.5 mmol/L (hypokalaemia) and high when ≥5.5 mmol/L (hyperkalaemia). Multivariable logistic regression models were constructed to identify clinical predictors of dyskalaemia. A total of 513 participants (median age 74 years, 75% men, median estimated glomerular filtration rate 71 mL/min/1.73 m2) had serum potassium available and were included in this analysis. At randomization, 88 had potassium 5.0 mmol/L. During follow‐up, on at least one occasion, a serum potassium 5.0 mmol/L was observed in 38 (8%) and >5.5 mmol/L in 5 (1.0%) participants. The median (percentile25−75) increase in serum potassium with spironolactone during the study was 0.23 (0.16; 0.29) mmol/L. Because of the low incidence of dyskalaemia, for regression analysis, hypokalaemia and hyperkalaemia thresholds were set at 5.0 mmol/L, respectively. The occurrence of a serum potassium > 5.0 mmol/L during follow‐up was positively associated with the presence of diabetes mellitus {odds ratio [OR]: 1.21 [95% confidence interval (CI) 2.14; 3.79]} and randomization to spironolactone (OR: 2.83 [95% CI 1.49; 5.37]). Conversely, the occurrence of a potassium concentration

This paper presents the development and evaluation of a Subtidal Seagrass Detector (the Detector). Deep learning models were used to detect most forms of seagrass occurring in a diversity of habitats across the northeast Australian seascape from underwater images and classify them based on how much the cover of seagrass was present. Images were collected by scientists and trained contributors undertaking routine monitoring using drop-cameras mounted over a 50 x 50 cm quadrat. The Detector is composed of three separate models able to perform the specific tasks of: detecting the presence of seagrass (Model #1); classify the seagrass present into three broad cover classes (low, medium, high) (Model #2); and classify the substrate or image complexity (simple of complex) (Model #3). We were able to successfully train the three models to achieve high level accuracies with 97%, 80.7% and 97.9%, respectively. With the ability to further refine and train these models with newly acquired images from different locations and from different sources (e.g. Automated Underwater Vehicles), we are confident that our ability to detect seagrass will improve over time. With this Detector we will be able rapidly assess a large number of images collected by a diversity of contributors, and the data will provide invaluable insights about the extent and condition of subtidal seagrass, particularly in data-poor areas.

In the past 25 years, the prevalence of Parkinson's disease (PD) has nearly doubled. Age remains the primary risk factor for PD and as the global aging population increases this trend is predicted to continue. Even when treated with levodopa, the gold standard dopamine (DA) replacement therapy, individuals with PD frequently develop therapeutic side effects. Levodopa-induced dyskinesia (LID), a common side effect of long-term levodopa use, represents a significant unmet clinical need in the treatment of PD. Previously, in young adult (3-month-old) male parkinsonian rats, we demonstrated that the silencing of CaV1.3 (Cacan1d) L-type voltage-gated calcium channels via striatal delivery of rAAV-CaV1.3-shRNA provides uniform protection against the induction of LID, and significant reduction of established severe LID. With the goal of more closely replicating a clinical demographic, the current study examined the effects of CaV1.3-targeted gene therapy on LID escalation in male and female parkinsonian rats of advanced age (18-month-old at study completion). We tested the hypothesis that silencing aberrant CaV1.3 channel activity in the parkinsonian striatum would prevent moderate to severe dyskinesia with levodopa dose escalation. To test this hypothesis, 15-month-old male and female F344 rats were rendered unilaterally parkinsonian and primed with low-dose (3–4 mg/kg) levodopa. Following the establishment of stable, mild dyskinesias, rats received an intrastriatal injection of either the Cacna1d-specific rAAV-CaV1.3-shRNA vector (CAV-shRNA), or the scramble control rAAV-SCR-shRNA vector (SCR-shRNA). Daily (M-Fr) low-dose levodopa was maintained for 4 weeks during the vector transduction and gene silencing window followed by escalation to 6 mg/kg, then to 12 mg/kg levodopa. SCR-shRNA-shRNA rats showed stable LID expression with low-dose levodopa and the predicted escalation of LID severity with increased levodopa doses. Conversely, complex behavioral responses were observed in aged rats receiving CAV-shRNA, with approximately half of the male and female subjects—therapeutic ‘Responders’—demonstrating protection against LID escalation, while the remaining half—therapeutic ‘Non-Responders’—showed LID escalation similar to SCR-shRNA rats. Post-mortem histological analyses revealed individual variability in the detection of Cacna1d regulation in the DA-depleted striatum of aged rats. However, taken together, male and female therapeutic ‘Responder’ rats receiving CAV-shRNA had significantly less striatal Cacna1d in their vector-injected striatum relative to contralateral striatum than those with SCR-shRNA. The current data suggest that mRNA-level silencing of striatal CaV1.3 channels maintains potency in a clinically relevant in vivo scenario by preventing dose-dependent dyskinesia escalation in rats of advanced age. As compared to the uniform response previously reported in young male rats, there was notable variability between individual aged rats, particularly females, in the current study. Future investigations are needed to derive the sex-specific and age-related mechanisms which underlie variable responses to gene therapy and to elucidate factors which determine the therapeutic efficacy of treatment for PD.

Abstract Background Plastic and reconstructive surgery (PRS) remains highly relevant to the unmet need for surgery in Malawi. Better understanding the current PRS landscape and its barriers may help address some of these challenges. This scoping review aimed to describe: (1) the scope and focus of the PRS literature being produced in Malawi and (2) the challenges, deficits, and barriers to providing accessible, high-quality PRS in Malawi. Methods This scoping review was conducted on four databases (SCOPUS, PubMed, Web of Science, EMBASE) from inception through September 1, 2020 following the PRISMA-ScR guidelines. Results The database search retrieved 3852 articles, of which 31 were included that examined the burden of PRS-related conditions in Malawi. Of these 31 articles, 25 primarily discussed burn-related care. Burns injuries have a high mortality rate; between 27 and 75% in the studies. The literature revealed that there are only two burn units nationally with one PRS specialist in each unit, compounded by a lack of interest in PRS specialization by Malawian medical students. Congenital anomalies were the only other PRS-related condition examined and reported in the literature, accounting for 23% of all pediatric surgeries in tertiary facilities. Conclusions There is a need to increase the country's capacity to handle burn reconstruction and other PRS-related conditions to reduce overall morbidity and mortality. Additional publicly funded research at the district and community level is warranted to determine the true burden of PRS disease in Malawi to derive health system strengthening and workforce capacity building strategies.

Abstract When standing waves are present in a rectangular waveguide, the resistive losses in the walls are not uniformly distributed. This affects the measurement of the attenuation constant. Here the phenomenon for the TE10 mode in air‐filled waveguide, where the deviation from the normal travelling wave attenuation constant is only about ±1% over the conventional bandwidth, is discussed. However, the paper also shows that nearer the cut‐off frequency for the waveguide, the deviation could be as high as ±100%.

The signalling pathways that maintain primed human pluripotent stem cells (hPSCs) have been well characterised, revealing a critical role for TGFβ/Activin/Nodal signalling. In contrast, the signalling requirements of naïve human pluripotency have not been fully established. Here, we demonstrate that TGFβ signalling is required to maintain naïve hPSCs. The downstream effector proteins – SMAD2/3 – bind common sites in naïve and primed hPSCs, including shared pluripotency genes. In naïve hPSCs, SMAD2/3 additionally bind to active regulatory regions near to naïve pluripotency genes. Inhibiting TGFβ signalling in naïve hPSCs causes the downregulation of SMAD2/3-target genes and pluripotency exit. Single-cell analyses reveal that naïve and primed hPSCs follow different transcriptional trajectories after inhibition of TGFβ signalling. Primed hPSCs differentiate into neuroectoderm cells, whereas naïve hPSCs transition into trophectoderm. These results establish that there is a continuum for TGFβ pathway function in human pluripotency spanning a developmental window from naïve to primed states.

Abstract The crust and upper mantle structure of the Greater and Lesser Antilles Arc provides insights into key subduction zone processes in a unique region of slow convergence of old slow‐spreading oceanic lithosphere. We use ambient noise tomography gathered from island broadband seismic stations and the temporary ocean bottom seismometer network installed as part of the Volatile Recycling in the Lesser Antilles experiment to map crustal and upper mantle shear‐wave velocity of the eastern Greater Antilles and the Lesser Antilles Arc. Taking the depth to the 2.0 km/s contour as a proxy, we find sediment thickness up to 15 km in the south in the Grenada and Tobago basins and thinner sediments near the arc and to the north. We observe thicker crust, based on the depth to the 4.0 km/s velocity contour, beneath the arc platforms with the greatest crustal thickness of around 30 km, likely related to crustal addition from arc volcanism through time. There are distinct low velocity zones (4.2–4.4 km/s) in the mantle wedge (30–50 km depth), beneath the Mona Passage, Guadeloupe‐Martinique, and the Grenadines. The Mona passage mantle anomaly may be related to ongoing extension there, while the Guadeloupe‐Martinique and Grenadine anomalies are likely related to fluid flux, upwelling, and/or partial melt related to nearby slab features. The location of the Guadeloupe‐Martinique anomaly is slightly to the south of the obliquely subducted fracture zones. This feature could be explained by either three‐dimensional mantle flow, a gap in the slab, variable slab hydration, and/or melt dynamics including ponding and interactions with the upper plate.

Seagrass meadows are at increasing risk of thermal stress and recent work has shown that water temperature around seagrass meadows could be used as an indicator for seagrass condition. Satellite thermal data have not been linked to the thermal properties of seagrass meadows. This work assessed the covariation between 20 in situ average daily temperature logger measurement sites in tropical seagrass meadows and satellite derived daytime SST (sea surface temperature) from the daytime MODIS and Landsat sensors along the Great Barrier Reef coast in Australia. Statistically significant (R2 = 0.787–0.939) positive covariations were found between in situ seagrass logger temperatures and MODIS SST temperature and Landsat sensor temperatures at all sites along the reef. The MODIS SST were consistently higher than in situ temperature at the majority of the sites, possibly due to the sensor’s larger pixel size and location offset from field sites. Landsat thermal data were lower than field-measured SST, due to differences in measurement scales and times. When refined significantly and tested over larger areas, this approach could be used to monitor seagrass health over large (106 km2) areas in a similar manner to using satellite SST for predicting thermal stress for corals.