Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease.

One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood1. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain-gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials.

Mendelian Randomization Study With Clinical Follow-Up Links Metabolites to Risk and Severity of Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) exhibits phenotypic heterogeneity and variable response to therapy. The metabolome has been implicated in the pathogenesis of PAH, but previous works have lacked power to implicate specific metabolites. Mendelian randomization (MR) is a method for causal inference between exposures and outcomes. METHODS AND RESULTS: Using genome-wide association study summary statistics, we implemented MR analysis to test for potential causal relationships between serum concentration of 575 metabolites and PAH. Five metabolites were causally associated with the risk of PAH after multiple testing correction. Next, we measured serum concentration of candidate metabolites in an independent clinical cohort of 449 patients with PAH to check whether metabolite concentrations are correlated with markers of disease severity. Of the 5 candidates nominated by our MR work, serine was negatively associated and homostachydrine was positively associated with clinical severity of PAH via direct measurement in this independent clinical cohort. Finally we used conditional and orthogonal approaches to explore the biology underlying our lead metabolites. Rare variant burden testing was carried out using whole exome sequencing data from 578 PAH cases and 361 675 controls. Multivariable MR is an extension of MR that uses a single set of instrumental single-nucleotide polymorphisms to measure multiple exposures; multivariable MR is used to determine interdependence between the effects of different exposures on a single outcome. Rare variant analysis demonstrated that loss-of-function mutations within activating transcription factor 4, a transcription factor responsible for upregulation of serine synthesis under conditions of serine starvation, are associated with higher risk for PAH. Homostachydrine is a xenobiotic metabolite that is structurally related to l-proline betaine, which has previously been linked to modulation of inflammation and tissue remodeling in PAH. Our multivariable MR analysis suggests that the effect of l-proline betaine is actually mediated indirectly via homostachydrine. CONCLUSIONS: Our data present a method for study of the metabolome in the context of PAH, and suggests several candidates for further evaluation and translational research.

Dermatological patients with itch report more stress, stigmatization experience, anxiety and depression compared to patients without itch: Results from a European multi-centre study.

BACKGROUND: Itch as the most common symptom in dermatology has been shown to be related to psychological factors such as stress, anxiety and depression. Moreover, associations were found between perceived stigmatization and itch. However, studies investigating the differences between patients with dermatoses with and without itch regarding perceived stress, stigmatization, anxiety and depression are missing. Therefore, one of the aims of the second study of the European Society for Dermatology and Psychiatry (ESDaP study II) was to investigate these relationships in a large cohort of patients with different itchy dermatoses. RESULTS: 3399 patients with 14 different itchy dermatoses were recruited at 22 centres in 17 European countries. They filled in questionnaires to assess perceived stigmatization, stress, signs of clinically relevant anxiety or depression, itch-related quality of life, the overall health status, itch duration, frequency and intensity. The most significant association between the severity of itching and the perception of stress was observed among individuals with rosacea (correlation coefficient r = 0.314). Similarly, the strongest links between itch intensity and experiences of stigmatization, anxiety, and depression were found in patients with seborrheic dermatitis (correlation coefficients r = 0.317, r = 0.356, and r = 0.400, respectively). Utilizing a stepwise linear regression analysis, it was determined that within the entire patient cohort, 9.3% of the variation in itch intensity could be accounted for by factors including gender, levels of anxiety, depression, and perceived stigmatization. Females and individuals with elevated anxiety, depression, and perceived stigmatization scores reported more pronounced itch intensities compared to those with contrary attributes. CONCLUSION: This study underscores the connection between experiencing itch and its intensity and the psychological strain it places on individuals. Consequently, psychological interventions should encompass both addressing the itch itself and the interconnected psychological factors. In specific cases, it becomes imperative for dermatologists to direct individuals towards suitable healthcare resources to undergo further psychological assessment.

Toxoplasmosis epidemic in a population of urbanised allied rock-wallabies (Petrogale assimilis) on Magnetic Island (Yunbenun), North Queensland.

A mortality event involving 23 allied rock-wallabies (Petrogale assimilis) displaying neurological signs and sudden death occurred in late April to May 2021 in a suburban residential area directly adjacent to Magnetic Island National Park, on Magnetic Island (Yunbenun), North Queensland, Australia. Three allied rock-wallabies were submitted for necropsy, and in all three cases, the cause of death was disseminated toxoplasmosis. This mortality event was unusual because only a small, localised population of native wallabies inhabiting a periurban area on a tropical island in the Great Barrier Reef World Heritage Area were affected. A disease investigation determined the outbreak was likely linked to the presence of free-ranging feral and domesticated cats inhabiting the area. There were no significant deaths of other wallabies or wildlife in the same or other parts of Magnetic Island (Yunbenun) at the time of the outbreak. This is the first reported case of toxoplasmosis in allied rock-wallabies (Petrogale assimilis), and this investigation highlights the importance of protecting native wildlife species from an infectious and potentially fatal parasitic disease.

Metabolic-associated fatty liver disease and hepatocellular carcinoma: a prospective study of characteristics and response to therapy.

BACKGROUND AND AIM: The rising incidence of hepatocellular carcinoma (HCC) in Australia is related to increasing rates of metabolic-associated fatty liver disease (MAFLD). This study aimed to prospectively characterize the metabolic profile, lifestyle, biometric features, and response to treatment of HCC patients in an Australian population. METHOD: Multicenter prospective cohort analysis of newly diagnosed HCC patients at six multidisciplinary team meetings over a 2-year period. RESULTS: Three hundred and thirteen (313) newly diagnosed HCC patients with MAFLD (n = 77), MAFLD plus other liver disease (n = 57) (the "mixed" group), and non-MAFLD (n = 179) were included in the study. Alcohol-associated liver disease (ALD) (43%) and MAFLD (43%) were the most common underlying liver diseases. MAFLD-HCC patients were older (73 years vs 67 years vs 63 years), more likely to be female (40% vs 14% vs 20%), less likely to have cirrhosis (69% vs 88% vs 85%), showed higher ECOG, and were less likely to be identified by screening (29% vs 53% vs 45%). Metabolic syndrome was more prevalent in the MAFLD and mixed groups. The severity of underlying liver disease and HCC characteristics were the same across groups. While the MAFLD population self-reported more sedentary lifestyles, reported dietary patterns were no different across the groups. Dyslipidemia was associated with tumor size, and those taking statins had a lower recurrence rate. CONCLUSION: Equal to ALD, MAFLD is now the most common underlying liver disease seen in HCC patients in Australia. Future HCC prevention screening and treatment strategies need to take this important group of patients into consideration.

Systematic pulmonary embolism follow-up increases diagnostic rates of chronic thromboembolic pulmonary hypertension and identifies less severe disease: results from the ASPIRE Registry.

BACKGROUND: Diagnostic rates and risk factors for the subsequent development of chronic thromboembolic pulmonary hypertension (CTEPH) following pulmonary embolism (PE) are not well defined. METHODS: Over a 10-year period (2010-2020), consecutive patients attending a PE follow-up clinic in Sheffield, UK (population 554 600) and all patients diagnosed with CTEPH at a pulmonary hypertension (PH) referral centre in Sheffield (referral population estimated 15-20 million) were included. RESULTS: Of 1956 patients attending the Sheffield PE clinic 3 months following a diagnosis of acute PE, 41 were diagnosed with CTEPH with a cumulative incidence of 2.10%, with 1.89% diagnosed within 2 years. Of 809 patients presenting with pulmonary hypertension (PH) and diagnosed with CTEPH, 32 were Sheffield residents and 777 were non-Sheffield residents. Patients diagnosed with CTEPH at the PE follow-up clinic had shorter symptom duration (p<0.01), better exercise capacity (p<0.05) and less severe pulmonary haemodynamics (p<0.01) compared with patients referred with suspected PH. Patients with no major transient risk factors present at the time of acute PE had a significantly higher risk of CTEPH compared with patients with major transient risk factors (OR 3.6, 95% CI 1.11-11.91; p=0.03). The presence of three computed tomography (CT) features of PH in combination with two or more out of four features of chronic thromboembolic pulmonary disease at the index PE was found in 19% of patients who developed CTEPH and in 0% of patients who did not. Diagnostic rates and pulmonary endarterectomy (PEA) rates were higher at 13.2 and 3.6 per million per year, respectively, for Sheffield residents compared with 3.9-5.2 and 1.7-2.3 per million per year, respectively, for non-Sheffield residents. CONCLUSIONS: In the real-world setting a dedicated PE follow-up pathway identifies patients with less severe CTEPH and increases population-based CTEPH diagnostic and PEA rates. At the time of acute PE diagnosis the absence of major transient risk factors, CT features of PH and chronic thromboembolism are risk factors for a subsequent diagnosis of CTEPH.

Improving Prognostication in Pulmonary Hypertension Using AI-quantified Fibrosis and Radiologic Severity Scoring at Baseline CT.

Background There is clinical need to better quantify lung disease severity in pulmonary hypertension (PH), particularly in idiopathic pulmonary arterial hypertension (IPAH) and PH associated with lung disease (PH-LD). Purpose To quantify fibrosis on CT pulmonary angiograms using an artificial intelligence (AI) model and to assess whether this approach can be used in combination with radiologic scoring to predict survival. Materials and Methods This retrospective multicenter study included adult patients with IPAH or PH-LD who underwent incidental CT imaging between February 2007 and January 2019. Patients were divided into training and test cohorts based on the institution of imaging. The test cohort included imaging examinations performed in 37 external hospitals. Fibrosis was quantified using an established AI model and radiologically scored by radiologists. Multivariable Cox regression adjusted for age, sex, World Health Organization functional class, pulmonary vascular resistance, and diffusing capacity of the lungs for carbon monoxide was performed. The performance of predictive models with or without AI-quantified fibrosis was assessed using the concordance index (C index). Results The training and test cohorts included 275 (median age, 68 years [IQR, 60-75 years]; 128 women) and 246 (median age, 65 years [IQR, 51-72 years]; 142 women) patients, respectively. Multivariable analysis showed that AI-quantified percentage of fibrosis was associated with an increased risk of patient mortality in the training cohort (hazard ratio, 1.01 [95% CI: 1.00, 1.02]; P = .04). This finding was validated in the external test cohort (C index, 0.76). The model combining AI-quantified fibrosis and radiologic scoring showed improved performance for predicting patient mortality compared with a model including radiologic scoring alone (C index, 0.67 vs 0.61; P < .001). Conclusion Percentage of lung fibrosis quantified on CT pulmonary angiograms by an AI model was associated with increased risk of mortality and showed improved performance for predicting patient survival when used in combination with radiologic severity scoring compared with radiologic scoring alone. © RSNA, 2024 Supplemental material is available for this article.

X-ray self-emission imaging with spherically bent Bragg crystals on the Z-machine.

An x-ray imaging scheme using spherically bent crystals was implemented on the Z-machine to image x rays emitted by the hot, dense plasma generated by a Magnetized Liner Inertial Fusion (MagLIF) target. This diagnostic relies on a spherically bent crystal to capture x-ray emission over a narrow spectral range (<15 eV), which is established by a limiting aperture placed on the Rowland circle. The spherical crystal optic provides the necessary high-throughput and large field-of-view required to produce a bright image over the entire, one-cm length of the emitting column of a plasma. The average spatial resolution was measured and determined to be 18 µm for the highest resolution configuration. With this resolution, the radial size of the stagnation column can be accurately determined and radial structures, such as bifurcations in the column, are clearly resolved. The success of the spherical-crystal imager has motivated the implementation of a new, two-crystal configuration for identifying sources of spectral line emission using a differential imaging technique.

Unsupervised machine learning to investigate trajectory patterns of COVID-19 symptoms and physical activity measured via the MyHeart Counts App and smart devices.

Previous studies have associated COVID-19 symptoms severity with levels of physical activity. We therefore investigated longitudinal trajectories of COVID-19 symptoms in a cohort of healthcare workers (HCWs) with non-hospitalised COVID-19 and their real-world physical activity. 121 HCWs with a history of COVID-19 infection who had symptoms monitored through at least two research clinic visits, and via smartphone were examined. HCWs with a compatible smartphone were provided with an Apple Watch Series 4 and were asked to install the MyHeart Counts Study App to collect COVID-19 symptom data and multiple physical activity parameters. Unsupervised classification analysis of symptoms identified two trajectory patterns of long and short symptom duration. The prevalence for longitudinal persistence of any COVID-19 symptom was 36% with fatigue and loss of smell being the two most prevalent individual symptom trajectories (24.8% and 21.5%, respectively). 8 physical activity features obtained via the MyHeart Counts App identified two groups of trajectories for high and low activity. Of these 8 parameters only 'distance moved walking or running' was associated with COVID-19 symptom trajectories. We report a high prevalence of long-term symptoms of COVID-19 in a non-hospitalised cohort of HCWs, a method to identify physical activity trends, and investigate their association. These data highlight the importance of tracking symptoms from onset to recovery even in non-hospitalised COVID-19 individuals. The increasing ease in collecting real-world physical activity data non-invasively from wearable devices provides opportunity to investigate the association of physical activity to symptoms of COVID-19 and other cardio-respiratory diseases.

Understanding primary care transformation and implications for ageing populations and health inequalities: a systematic scoping review of new models of primary health care in OECD countries and China.

BACKGROUND: Many countries have introduced reforms with the aim of primary care transformation (PCT). Common objectives include meeting service delivery challenges associated with ageing populations and health inequalities. To date, there has been little research comparing PCT internationally. Our aim was to examine PCT and new models of primary care by conducting a systematic scoping review of international literature in order to describe major policy changes including key 'components', impacts of new models of care, and barriers and facilitators to PCT implementation. METHODS: We undertook a systematic scoping review of international literature on PCT in OECD countries and China (published protocol: https://osf.io/2afym ). Ovid [MEDLINE/Embase/Global Health], CINAHL Plus, and Global Index Medicus were searched (01/01/10 to 28/08/21). Two reviewers independently screened the titles and abstracts with data extraction by a single reviewer. A narrative synthesis of findings followed. RESULTS: A total of 107 studies from 15 countries were included. The most frequently employed component of PCT was the expansion of multidisciplinary teams (MDT) (46% of studies). The most frequently measured outcome was GP views (27%), with < 20% measuring patient views or satisfaction. Only three studies evaluated the effects of PCT on ageing populations and 34 (32%) on health inequalities with ambiguous results. For the latter, PCT involving increased primary care access showed positive impacts whilst no benefits were reported for other components. Analysis of 41 studies citing barriers or facilitators to PCT implementation identified leadership, change, resources, and targets as key themes. CONCLUSIONS: Countries identified in this review have used a range of approaches to PCT with marked heterogeneity in methods of evaluation and mixed findings on impacts. Only a minority of studies described the impacts of PCT on ageing populations, health inequalities, or from the patient perspective. The facilitators and barriers identified may be useful in planning and evaluating future developments in PCT.

Establishing minimally important differences for cardiac MRI end-points in pulmonary arterial hypertension.

BACKGROUND: Cardiac magnetic resonance (CMR) is the gold standard technique to assess biventricular volumes and function, and is increasingly being considered as an end-point in clinical studies. Currently, with the exception of right ventricular (RV) stroke volume and RV end-diastolic volume, there is only limited data on minimally important differences (MIDs) reported for CMR metrics. Our study aimed to identify MIDs for CMR metrics based on US Food and Drug Administration recommendations for a clinical outcome measure that should reflect how a patient "feels, functions or survives". METHODS: Consecutive treatment-naïve patients with pulmonary arterial hypertension (PAH) between 2010 and 2022 who had two CMR scans (at baseline prior to treatment and 12 months following treatment) were identified from the ASPIRE registry. All patients were followed up for 1 additional year after the second scan. For both scans, cardiac measurements were obtained from a validated fully automated segmentation tool. The MID in CMR metrics was determined using two distribution-based (0.5sd and minimal detectable change) and two anchor-based (change difference and generalised linear model regression) methods benchmarked to how a patient "feels" (emPHasis-10 quality of life questionnaire), "functions" (incremental shuttle walk test) or "survives" for 1-year mortality to changes in CMR measurements. RESULTS: 254 patients with PAH were included (mean±sd age 53±16 years, 79% female and 66% categorised as intermediate risk based on the 2022 European Society of Cardiology/European Respiratory Society risk score). We identified a 5% absolute increase in RV ejection fraction and a 17 mL decrease in RV end-diastolic or end-systolic volumes as the MIDs for improvement. Conversely, a 5% decrease in RV ejection fraction and a 10 mL increase in RV volumes were associated with worsening. CONCLUSIONS: This study establishes clinically relevant CMR MIDs for how a patient "feels, functions or survives" in response to PAH treatment. These findings provide further support for the use of CMR as a clinically relevant clinical outcome measure and will aid trial size calculations for studies using CMR.

Plain language summaryPulmonary arterial hypertension (PAH) is a disease of the vessels of the lung that causes their narrowing and stiffening. As a result, the heart pumping blood into these diseased lung vessels has to work harder and eventually gets worn out. PAH can affect patients' ability to function in daily activities and impact their quality of life. It also reduces their life expectancy dramatically. Patients are, therefore, often monitored and undergo several investigations to adapt treatment according to their situation. These investigations include a survey of how a patient feels (the emPHasis-10 questionnaire), functions (walking test) and how well the heart is coping with the disease (MRI of the heart). Until now, it is unclear how changes on MRI of the heart reflect changes in how a patient feels and functions. Our study identified patients that had the emPHasis-10 questionnaire, walking test and MRI of the heart at both the time of PAH diagnosis and one year later. This allowed us to compare how the changes in the different tests relate to each other. And because previous research identified thresholds for important changes in the emPHasis-10 questionnaire and the walking tests, we were able to use these tests as a benchmark for changes in the MRI of the heart. Our study identified thresholds for change on heart MRI that might indicate whether a patient has improved or worsened. This finding might have implications for how patients are monitored in clinical practice and future research on PAH treatments.

Neurocognitive basis of model-based decision making and its metacontrol in childhood.

Human behavior is supported by both goal-directed (model-based) and habitual (model-free) decision-making, each differing in its flexibility, accuracy, and computational cost. The arbitration between habitual and goal-directed systems is thought to be regulated by a process known as metacontrol. However, how these systems emerge and develop remains poorly understood. Recently, we found that while children between 5 and 11 years displayed robust signatures of model-based decision-making, which increased during this developmental period, there were substantial individual differences in the display of metacontrol. Here, we inspect the neurocognitive basis of model-based decision-making and metacontrol in childhood and focus this investigation on executive functions, fluid reasoning, and brain structure. A total of 69 participants between the ages of 6-13 completed a two-step decision-making task and an extensive behavioral test battery. A subset of 44 participants also completed a structural magnetic resonance imaging scan. We find that individual differences in metacontrol are specifically associated with performance on an inhibition task and individual differences in thickness of dorsolateral prefrontal, temporal, and superior-parietal cortices. These brain regions likely reflect the involvement of cognitive processes crucial to metacontrol, such as cognitive control and contextual processing.

HTS driven by fluorescence lifetime detection of FRET identifies activators and inhibitors of cardiac myosin.

Small molecules that bind to allosteric sites on target proteins to alter protein function are highly sought in drug discovery. High-throughput screening (HTS) assays are needed to facilitate the direct discovery of allosterically active compounds. We have developed technology for high-throughput time-resolved fluorescence lifetime detection of fluorescence resonance energy transfer (FRET), which enables the detection of allosteric modulators by monitoring changes in protein structure. We tested this approach at the industrial scale by adapting an allosteric FRET sensor of cardiac myosin to high-throughput screening (HTS), based on technology provided by Photonic Pharma and the University of Minnesota, and then used the sensor to screen 1.6 million compounds in the HTS facility at Bristol Myers Squibb. The results identified allosteric activators and inhibitors of cardiac myosin that do not compete with ATP binding, demonstrating high potential for FLT-based drug discovery.

Demonstration of improved laser preheat with a cryogenically cooled magnetized liner inertial fusion platform.

We report on progress implementing and testing cryogenically cooled platforms for Magnetized Liner Inertial Fusion (MagLIF) experiments. Two cryogenically cooled experimental platforms were developed: an integrated platform fielded on the Z pulsed power generator that combines magnetization, laser preheat, and pulsed-power-driven fuel compression and a laser-only platform in a separate chamber that enables measurements of the laser preheat energy using shadowgraphy measurements. The laser-only experiments suggest that ∼89% ± 10% of the incident energy is coupled to the fuel in cooled targets across the energy range tested, significantly higher than previous warm experiments that achieved at most 67% coupling and in line with simulation predictions. The laser preheat configuration was applied to a cryogenically cooled integrated experiment that used a novel cryostat configuration that cooled the MagLIF liner from both ends. The integrated experiment, z3576, coupled 2.32 ± 0.25 kJ preheat energy to the fuel, the highest to-date, demonstrated excellent temperature control and nominal current delivery, and produced one of the highest pressure stagnations as determined by a Bayesian analysis of the data.

Non-invasive detection of severe PH in lung disease using magnetic resonance imaging.

Introduction: Severe pulmonary hypertension (mean pulmonary artery pressure ≥35 mmHg) in chronic lung disease (PH-CLD) is associated with high mortality and morbidity. Data suggesting potential response to vasodilator therapy in patients with PH-CLD is emerging. The current diagnostic strategy utilises transthoracic Echocardiography (TTE), which can be technically challenging in some patients with advanced CLD. The aim of this study was to evaluate the diagnostic role of MRI models to diagnose severe PH in CLD. Methods: 167 patients with CLD referred for suspected PH who underwent baseline cardiac MRI, pulmonary function tests and right heart catheterisation were identified. In a derivation cohort (n = 67) a bi-logistic regression model was developed to identify severe PH and compared to a previously published multiparameter model (Whitfield model), which is based on interventricular septal angle, ventricular mass index and diastolic pulmonary artery area. The model was evaluated in a test cohort. Results: The CLD-PH MRI model [= (-13.104) + (13.059 * VMI)-(0.237 * PA RAC) + (0.083 * Systolic Septal Angle)], had high accuracy in the test cohort (area under the ROC curve (0.91) (p < 0.0001), sensitivity 92.3%, specificity 70.2%, PPV 77.4%, and NPV 89.2%. The Whitfield model also had high accuracy in the test cohort (area under the ROC curve (0.92) (p < 0.0001), sensitivity 80.8%, specificity 87.2%, PPV 87.5%, and NPV 80.4%. Conclusion: The CLD-PH MRI model and Whitfield model have high accuracy to detect severe PH in CLD, and have strong prognostic value.

Machine learned interatomic potential for dispersion strengthened plasma facing components.

Tungsten (W) is a material of choice for the divertor material due to its high melting temperature, thermal conductivity, and sputtering threshold. However, W has a very high brittle-to-ductile transition temperature, and at fusion reactor temperatures (≥1000 K), it may undergo recrystallization and grain growth. Dispersion-strengthening W with zirconium carbide (ZrC) can improve ductility and limit grain growth, but much of the effects of the dispersoids on microstructural evolution and thermomechanical properties at high temperatures are still unknown. We present a machine learned Spectral Neighbor Analysis Potential for W-ZrC that can now be used to study these materials. In order to construct a potential suitable for large-scale atomistic simulations at fusion reactor temperatures, it is necessary to train on ab initio data generated for a diverse set of structures, chemical environments, and temperatures. Further accuracy and stability tests of the potential were achieved using objective functions for both material properties and high temperature stability. Validation of lattice parameters, surface energies, bulk moduli, and thermal expansion is confirmed on the optimized potential. Tensile tests of W/ZrC bicrystals show that although the W(110)-ZrC(111) C-terminated bicrystal has the highest ultimate tensile strength (UTS) at room temperature, observed strength decreases with increasing temperature. At 2500 K, the terminating C layer diffuses into the W, resulting in a weaker W-Zr interface. Meanwhile, the W(110)-ZrC(111) Zr-terminated bicrystal has the highest UTS at 2500 K.

Longitudinal Lung Function Assessment of Patients Hospitalized With COVID-19 Using 1H and 129Xe Lung MRI.

BACKGROUND: Microvascular abnormalities and impaired gas transfer have been observed in patients with COVID-19. The progression of pulmonary changes in these patients remains unclear. RESEARCH QUESTION: Do patients hospitalized with COVID-19 without evidence of architectural distortion on structural imaging exhibit longitudinal improvements in lung function measured by using 1H and 129Xe MRI between 6 and 52 weeks following hospitalization? STUDY DESIGN AND METHODS: Patients who were hospitalized with COVID-19 pneumonia underwent a pulmonary 1H and 129Xe MRI protocol at 6, 12, 25, and 51 weeks following hospital admission in a prospective cohort study between November 2020 and February 2022. The imaging protocol was as follows: 1H ultra-short echo time, contrast-enhanced lung perfusion, 129Xe ventilation, 129Xe diffusion-weighted, and 129Xe spectroscopic imaging of gas exchange. RESULTS: Nine patients were recruited (age 57 ± 14 [median ± interquartile range] years; six of nine patients were male). Patients underwent MRI at 6 (n = 9), 12 (n = 9), 25 (n = 6), and 51 (n = 8) weeks following hospital admission. Patients with signs of interstitial lung damage were excluded. At 6 weeks, patients exhibited impaired 129Xe gas transfer (RBC to membrane fraction), but lung microstructure was not increased (apparent diffusion coefficient and mean acinar airway dimensions). Minor ventilation abnormalities present in four patients were largely resolved in the 6- to 25-week period. At 12 weeks, all patients with lung perfusion data (n = 6) showed an increase in both pulmonary blood volume and flow compared with 6 weeks, although this was not statistically significant. At 12 weeks, significant improvements in 129Xe gas transfer were observed compared with 6-week examinations; however, 129Xe gas transfer remained abnormally low at weeks 12, 25, and 51. INTERPRETATION: 129Xe gas transfer was impaired up to 1 year following hospitalization in patients who were hospitalized with COVID-19 pneumonia, without evidence of architectural distortion on structural imaging, whereas lung ventilation was normal at 52 weeks.

Correlates of substance use in a large naturalistic cohort of young people with early and emerging psychosis.

BACKGROUND: Substance use remains a barrier to recovery for young people accessing early intervention services for psychosis. While correlates of use have been explored in populations experiencing a first episode of psychosis (FEP), sample sizes have been small and less research assesses cohorts at ultrahigh risk of psychosis (UHR). METHODS: This study uses data from a naturalistic cohort including UHR and FEP participants (N = 1252) to elucidate clinical correlates of use in the past 3 months of any illicit substance, amphetamine-type stimulants (ATS), cannabis, and tobacco. Moreover, network analysis based on use of these substances and additionally alcohol, cocaine, hallucinogens, sedatives, inhalants, and opioids was completed. RESULTS: Young people with FEP used substances at significantly higher rates than those at UHR. High concurrence of use was seen between substances. In the FEP group, participants who had used any illicit substance, ATS, and/or tobacco had increased positive symptoms and decreased negative symptoms. Young people with FEP who used cannabis had increased positive symptoms. In the UHR group, participants who had used any illicit substance, ATS, and/or cannabis in the past 3 months showed decreased negative symptoms compared to those who had not. CONCLUSION: A distinct clinical picture of more florid positive symptoms and alleviated negative symptoms seen in those who use substances in the FEP group appears muted in the UHR cohort. Treating young people at UHR in early intervention services represents the earliest opportunity to address substance use early to improve outcomes.

Transcriptomic response and immunological responses to chimpanzee adenovirus- and MVA viral-vectored vaccines for RSV in healthy adults.

Cohorts of healthy younger adults (18-50yrs) and healthy older adults (60-75yrs) were immunized intramuscularly or intranasally with an adenovirus-vectored RSV vaccine (PanAd3-RSV) as a prime dose and boosted with PanAd3-RSV or a poxvirus-vectored vaccine (MVA-RSV) encoding the same insert. Whole blood gene expression was measured at baseline, 3- and 7-days post vaccination. Intramuscular prime vaccination with PanAd3-RSV induced differential expression of 643 genes (DEGs, FDR < 0.05). Intranasal prime vaccination with PanAd3-RSV did not induce any differentially expressed genes (DEGs) in blood samples at 3 days post vaccination. Intranasally primed participants showed greater numbers of DEGS on boosting than intramuscularly primed participants. The most highly enriched biological processes related to DEGs after both prime and boost vaccination were type-1 interferon related pathways, lymphocytic and humoral immune responses.