Long-term impact of COVID-19 hospitalisation among individuals with pre-existing airway diseases in the UK: a multicentre, longitudinal cohort study - PHOSP-COVID.

Background: The long-term outcomes of COVID-19 hospitalisation in individuals with pre-existing airway diseases are unknown. Methods: Adult participants hospitalised for confirmed or clinically suspected COVID-19 and discharged between 5 March 2020 and 31 March 2021 were recruited to the Post-hospitalisation COVID-19 (PHOSP-COVID) study. Participants attended research visits at 5 months and 1 year post discharge. Clinical characteristics, perceived recovery, burden of symptoms and health-related quality of life (HRQoL) of individuals with pre-existing airway disease (i.e., asthma, COPD or bronchiectasis) were compared to the non-airways group. Results: A total of 615 out of 2697 (22.8%) participants had a history of pre-existing airway diseases (72.0% diagnosed with asthma, 22.9% COPD and 5.1% bronchiectasis). At 1 year, the airways group participants were less likely to feel fully recovered (20.4% versus 33.2%, p<0.001), had higher burden of anxiety (29.1% versus 22.0%, p=0.002), depression (31.2% versus 24.7%, p=0.006), higher percentage of impaired mobility using short physical performance battery ≤10 (57.4% versus 45.2%, p<0.001) and 27% had a new disability (assessed by the Washington Group Short Set on Functioning) versus 16.6%, p=0.014. HRQoL assessed using EQ-5D-5L Utility Index was lower in the airways group (mean±SD 0.64±0.27 versus 0.73±0.25, p<0.001). Burden of breathlessness, fatigue and cough measured using a study-specific tool was higher in the airways group. Conclusion: Individuals with pre-existing airway diseases hospitalised due to COVID-19 were less likely to feel fully recovered, had lower physiological performance measurements, more burden of symptoms and reduced HRQoL up to 1 year post-hospital discharge.

Vitamin D and systemic lupus erythematosus: Causality and association with disease activity and therapeutics.

The major role of bioactive vitamin 1,25-dihydroxyvitamin D3 (1,25(OH)2D or calcitriol) is to maintain the levels of calcium and phosphorus to achieve bone and mineral homeostasis. Dietary intake and adequate natural light exposure are the main contributors to normal vitamin D status. In addition to regulating metabolism, vitamin D exerts various immunomodulatory effects that regulate innate and adaptive immunity through immune effector cells such as monocytes, macrophages, T and B lymphocytes, and natural killer cells and nonimmune cells that express vitamin D receptors. Systemic lupus erythematosus (SLE) is an autoimmune disease with an unknown etiology, and the association between vitamin D and SLE remains incompletely understood. Given that the current treatment for SLE relies heavily on corticosteroids and that SLE patients tend to have low vitamin D status, vitamin D supplementation may help to reduce the dosage of corticosteroids and/or attenuate disease severity. In this review, we address the associations between vitamin D and several clinical aspects of SLE. In addition, the underlying immunomodulatory mechanisms accounting for the potential vitamin D-mediated therapeutic effects are discussed. Finally, several confounding factors in data interpretation and the execution of clinical trials and perspectives targeting vitamin D supplementation in patients with SLE are also addressed.

Probabilistic Presurgical Language Functional MRI Atlas of Brain Tumor Patients.

BACKGROUND AND PURPOSE: Patients with brain tumors have high intersubject variation in putative language regions, which may limit the utility of straightforward application of healthy-subject brain atlases in clinical scenarios. The purpose of this study was to develop a probabilistic functional brain atlas that consolidates language functional activations of sentence completion and silent word generation language paradigms using a large sample of patients with brain tumors. MATERIALS AND METHODS: The atlas was developed using retrospectively collected fMRI data from patients with brain tumors who underwent their first standard-of-care presurgical language fMRI scan at our institution between July 18, 2015, and May 13, 2022. 317 patients (861 fMRI scans) were used to develop the language functional atlas. An independent presurgical language fMRI dataset of 39 patients with brain tumors from a previous study was used to evaluate our atlas. Family-wise error corrected binary functional activation maps from sentence completion, letter fluency, and category fluency presurgical fMRI were used to create probability overlap maps and pooled probabilistic overlap map in Montreal Neurological Institute standard space. Wilcoxon signed-rank test was used to determine significant difference in the maximum Dice coefficient for our atlas compared to a meta-analysis-based template with respect to expert-delineated primary language area activations. RESULTS: Probabilities of activating left anterior primary language area and left posterior primary language area in temporal lobe were 87.9% and 91.5%, respectively, for sentence completion, 88.5% and 74.2%, respectively, for letter fluency, and 83.6% and 67.6%, respectively, for category fluency. Maximum Dice coefficients for templates derived from our language atlas were significantly higher than the meta-analysis-based template in left anterior primary language area (0.351 and 0.326, respectively, P < .05) and left posterior primary language area in temporal lobe (0.274 and 0.244, respectively, P < .005). CONCLUSIONS: Brain tumor patient-and paradigm-specific probabilistic language atlases were developed. These atlases had superior spatial agreement with fMRI activations in individual patients than the meta-analysis-based template. ABBREVIATIONS: SENT = sentence completion, LETT = letter fluency, CAT = category fluency, PLA = primary language area, aPLA = anterior PLA, pPLAT = posterior PLA in the temporal lobe, pPLAP = posterior PLA in the parietal lobe, SMA = supplementary motor area, DLPFC = dorsolateral prefrontal cortex, BTLA = basal temporal language area.

USP18 induction regulates immunometabolism to attenuate M1 signal-polarized macrophages and enhance IL-4-polarized macrophages in systemic lupus erythematosus.

Effective treatment of systemic lupus erythematosus (SLE) remains an unmet need. Different subsets of macrophages play differential roles in SLE and the modulation of macrophage polarization away from M1 status is beneficial for SLE therapeutics. Given the pathogenic roles of type I interferons (IFN-I) in SLE, this study investigated the effects and mechanisms of a mitochondria localization molecule ubiquitin specific peptidase 18 (USP18) preserving anti-IFN effects and isopeptidase activity on macrophage polarization. After observing USP18 induction in monocytes from SLE patients, we studied mouse bone marrow-derived macrophages and showed that USP18 deficiency increased M1signal (LPS + IFN-γ treatment)-induced macrophage polarization, and the effects involved the induction of glycolysis and mitochondrial respiration and the expression of several glycolysis-associated enzymes and molecules, such as hypoxia-inducible factor-1α. Moreover, the effects on mitochondrial activities, such as mitochondrial DNA release and mitochondrial reactive oxygen species production were observed. In contrast, the overexpression of USP18 inhibited M1signal-mediated and enhanced interleukin-4 (IL-4)-mediated polarization of macrophages and the related cellular events. Moreover, the levels of USP18 mRNA expression showed tendency of correlation with the expression of metabolic enzymes in monocytes from patients with SLE. We thus concluded that by preserving anti-IFN effect and downregulating M1 signaling, promoting USP18 activity may serve as a useful approach for SLE therapeutics.

Comparative analysis of brain language templates with primary language areas detected from presurgical fMRI of brain tumor patients.

INTRODUCTION: Functional brain templates are often used in the analysis of clinical functional MRI (fMRI) studies. However, these templates are mostly built based on anatomy or fMRI of healthy subjects, which have not been fully vetted in clinical cohorts. Our aim was to evaluate language templates by comparing with primary language areas (PLAs) detected from presurgical fMRI of brain tumor patients. METHODS: Four language templates (A-D) based on anatomy, task-based fMRI, resting-state fMRI, and meta-analysis, respectively, were compared with PLAs detected by fMRI with word generation and sentence completion paradigms. For each template, the fraction of PLA activations enclosed by the template (positive inclusion fraction, [PIF]), the fraction of activations within the template but that did not belong to PLAs (false inclusion fraction, [FIF]), and their Dice similarity coefficient (DSC) with PLA activations were calculated. RESULTS: For anterior PLAs, Template A had the greatest PIF (median, 0.95), whereas Template D had both the lowest FIF (median, 0.074), and the highest DSC (median, 0.30), which were all significant compared to other templates. For posterior PLAs, Templates B and D had similar PIF (median, 0.91 and 0.90, respectively) and DSC (both medians, 0.059), which were all significantly higher than that of Template C. Templates B and C had significantly lower FIF (median, 0.061 and 0.054, respectively) compared to Template D. CONCLUSION: This study demonstrated significant differences between language templates in their inclusiveness of and spatial agreement with the PLAs detected in the presurgical fMRI of the patient cohort. These findings may help guide the selection of language templates tailored to their applications in clinical fMRI studies.

A site-wise reliability analysis of the ABCD diffusion fractional anisotropy and cortical thickness: impact of scanner platforms.

The Adolescent Brain and Cognitive Development (ABCD) project is the largest study of adolescent brain development. ABCD longitudinally tracks 11,868 participants aged 9-10 years from 21 sites using standardized protocols for multi-site MRI data collection and analysis. While the multi-site and multi-scanner study design enhances the robustness and generalizability of analysis results, it may also introduce non-biological variances including scanner-related variations, subject motion, and deviations from protocols. ABCD imaging data were collected biennially within a period of ongoing maturation in cortical thickness and integrity of cerebral white matter. These changes can bias the classical test-retest methodologies, such as intraclass correlation coefficients (ICC). We developed a site-wise adaptive ICC (AICC) to evaluate the reliability of imaging-derived phenotypes while accounting for ongoing brain development. AICC iteratively estimates the population-level age-related brain development trajectory using a weighted mixed model and updates age-corrected site-wise reliability until convergence. We evaluated the test-retest reliability of regional fractional anisotropy (FA) measures from diffusion tensor imaging and cortical thickness (CT) from structural MRI data for each site. The mean AICC for 20 FA tracts across sites was 0.61±0.19, lower than the mean AICC for CT in 34 regions across sites, 0.76±0.12. Remarkably, sites using Siemens scanners consistently showed significantly higher AICC values compared to those using GE/Philips scanners for both FA (AICC=0.71±0.12 vs 0.46±0.17, p<0.001) and CT (AICC=0.80±0.10 vs 0.69±0.11, p<0.001). These findings demonstrate site-and-scanner related variations in data quality and underscore the necessity for meticulous data curation in subsequent association analyses.

Radiation enhancement using focussed ultrasound-stimulated microbubbles for head and neck cancer: A phase 1 clinical trial.

BACKGROUND AND PURPOSE: Preclinical research demonstrated that the exposure of microbubbles (intravascular gas microspheres) to focussed ultrasound within the targeted tumour upregulates pro-apoptotic pathways and enhances radiation-induced tumour cell death. This study aimed to assess the safety and efficacy of magnetic resonance (MR)-guided focussed ultrasound-stimulated microbubbles (MRgFUS-MB) for head and neck cancers (HN). MATERIALS AND METHODS: This prospective phase 1 clinical trial included patients with newly diagnosed or recurrent HN cancer (except nasopharynx malignancies) for whom locoregional radiotherapy with radical- or palliative-intent as deemed appropriate. Patients with contraindications for microbubble administration or contrast-enhanced MR were excluded. MR-coupled focussed ultrasound sonicated intravenously administered microbubbles within the MR-guided target volume. Patients receiving 5-10 and 33-35 radiation fractions were planned for 2 and 3 MRgFUS-MB treatments, respectively. Primary endpoint was toxicity per CTCAEv5.0. Secondary endpoint was tumour response at 3 months per RECIST 1.1 criteria. RESULTS: Twelve patients were enrolled between Jun/2020 and Nov/2023, but 1 withdrew consent. Eleven patients were included in safety analysis. Median follow-up was 7 months (range, 0.3-38). Most patients had oropharyngeal cancer (55 %) and received 20-30 Gy/5-10 fractions (63 %). No systemic toxicity or MRgFUS-MB-related adverse events occurred. The most severe acute adverse events were radiation-related grade 3 toxicities in 6 patients (55 %; dermatitis in 3, mucositis in 1, dysphagia in 6). No radiation necrosis or grade 4/5 toxicities were reported. 8 patients were included in the 3-month tumour response assessment: 4 had partial response (50 %), 3 had complete response (37.5 %), and 1 had progressive disease (12.5 %). CONCLUSIONS: MRgFUS-MB treatment was safe and associated with high rates of tumour response at 3 months.

Radiation enhancement using focussed ultrasound-stimulated microbubbles for breast cancer: A Phase 1 clinical trial.

BACKGROUND: Preclinical studies have demonstrated that tumour cell death can be enhanced 10- to 40-fold when radiotherapy is combined with focussed ultrasound-stimulated microbubble (FUS-MB) treatment. The acoustic exposure of microbubbles (intravascular gas microspheres) within the target volume causes bubble cavitation, which induces perturbation of tumour vasculature and activates endothelial cell apoptotic pathways responsible for the ablative effect of stereotactic body radiotherapy. Subsequent irradiation of a microbubble-sensitised tumour causes rapid increased tumour death. The study here presents the mature safety and efficacy outcomes of magnetic resonance (MR)-guided FUS-MB (MRgFUS-MB) treatment, a radioenhancement therapy for breast cancer. METHODS AND FINDINGS: This prospective, single-center, single-arm Phase 1 clinical trial included patients with stages I-IV breast cancer with in situ tumours for whom breast or chest wall radiotherapy was deemed adequate by a multidisciplinary team (clinicaltrials.gov identifier: NCT04431674). Patients were excluded if they had contraindications for contrast-enhanced MR or microbubble administration. Patients underwent 2 to 3 MRgFUS-MB treatments throughout radiotherapy. An MR-coupled focussed ultrasound device operating at 800 kHz and 570 kPa peak negative pressure was used to sonicate intravenously administrated microbubbles within the MR-guided target volume. The primary outcome was acute toxicity per Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Secondary outcomes were tumour response at 3 months and local control (LC). A total of 21 female patients presenting with 23 primary breast tumours were enrolled and allocated to intervention between August/2020 and November/2022. Three patients subsequently withdrew consent and, therefore, 18 patients with 20 tumours were included in the safety and LC analyses. Two patients died due to progressive metastatic disease before 3 months following treatment completion and were excluded from the tumour response analysis. The prescribed radiation doses were 20 Gy/5 fractions (40%, n = 8/20), 30 to 35 Gy/5 fractions (35%, n = 7/20), 30 to 40 Gy/10 fractions (15%, n = 3/20), and 66 Gy/33 fractions (10%, n = 2/20). The median follow-up was 9 months (range, 0.3 to 29). Radiation dermatitis was the most common acute toxicity (Grade 1 in 16/20, Grade 2 in 1/20, and Grade 3 in 2/20). One patient developed grade 1 allergic reaction possibly related to microbubbles administration. At 3 months, 18 tumours were evaluated for response: 9 exhibited complete response (50%, n = 9/18), 6 partial response (33%, n = 6/18), 2 stable disease (11%, n = 2/18), and 1 progressive disease (6%, n = 1/18). Further follow-up of responses indicated that the 6-, 12-, and 24-month LC rates were 94% (95% confidence interval [CI] [84%, 100%]), 88% (95% CI [75%, 100%]), and 76% (95% CI [54%, 100%]), respectively. The study's limitations include variable tumour sizes and dose fractionation regimens and the anticipated small sample size typical for a Phase 1 clinical trial. CONCLUSIONS: MRgFUS-MB is an innovative radioenhancement therapy associated with a safe profile, potentially promising responses, and durable LC. These results warrant validation in Phase 2 clinical trials. TRIAL REGISTRATION: clinicaltrials.gov, identifier NCT04431674.

Long COVID and cardiovascular disease: a prospective cohort study.

BACKGROUND: Pre-existing cardiovascular disease (CVD) or cardiovascular risk factors have been associated with an increased risk of complications following hospitalisation with COVID-19, but their impact on the rate of recovery following discharge is not known. OBJECTIVES: To determine whether the rate of patient-perceived recovery following hospitalisation with COVID-19 was affected by the presence of CVD or cardiovascular risk factors. METHODS: In a multicentre prospective cohort study, patients were recruited following discharge from the hospital with COVID-19 undertaking two comprehensive assessments at 5 months and 12 months. Patients were stratified by the presence of either CVD or cardiovascular risk factors prior to hospitalisation with COVID-19 and compared with controls with neither. Full recovery was determined by the response to a patient-perceived evaluation of full recovery from COVID-19 in the context of physical, physiological and cognitive determinants of health. RESULTS: From a total population of 2545 patients (38.8% women), 472 (18.5%) and 1355 (53.2%) had CVD or cardiovascular risk factors, respectively. Compared with controls (n=718), patients with CVD and cardiovascular risk factors were older and more likely to have had severe COVID-19. Full recovery was significantly lower at 12 months in patients with CVD (adjusted OR (aOR) 0.62, 95% CI 0.43 to 0.89) and cardiovascular risk factors (aOR 0.66, 95% CI 0.50 to 0.86). CONCLUSION: Patients with CVD or cardiovascular risk factors had a delayed recovery at 12 months following hospitalisation with COVID-19. Targeted interventions to reduce the impact of COVID-19 in patients with cardiovascular disease remain an unmet need. TRAIL REGISTRATION NUMBER: ISRCTN10980107.

Predictors of Tumor Dynamics Over a 6-Week Course of Concurrent Chemoradiotherapy for Glioblastoma and the Effect on Survival.

PURPOSE: We present the final analyses of tumor dynamics and their prognostic significance during a 6-week course of concurrent chemoradiotherapy for glioblastoma in the Glioblastoma Longitudinal Imaging Observational study. METHODS AND MATERIALS: This is a prospective serial magnetic resonance imaging study in 129 patients with glioblastoma who had magnetic resonance imaging obtained at radiation therapy (RT) planning (F0), fraction 10 (F10), fraction 20 (F20), and 1-month post-RT. Tumor dynamics assessed included gross tumor volume relative to F0 (Vrel) and tumor migration distance (dmigration). Covariables evaluated included: corpus callosum involvement, extent of surgery, O6-methylguanine-DNA-methyltransferase methylation, and isocitrate dehydrogenase mutation status. RESULTS: The median Vrel were 0.85 (range, 0.25-2.29) at F10, 0.79 (range, 0.09-2.22) at F20, and 0.78 (range, 0.13-4.27) at 1 month after completion of RT. The median dmigration were 4.7 mm (range, 1.1-20.4 mm) at F10, 4.7 mm (range, 0.8-20.7 mm) at F20, and 6.1 mm (range, 0.0-45.5 mm) at 1 month after completion of RT. Compared with patients who had corpus callosum involvement (n = 26), those without corpus callosum involvement (n = 103) had significant Vrel reduction at F20 (P = .03) and smaller dmigration at F20 (P = .007). Compared with patients who had biopsy alone (n = 19) and subtotal resection (n = 71), those who had gross total resection (n = 38) had significant Vrel reduction at F10 (P = .001) and F20 (P = .001) and a smaller dmigration at F10 (P = .03) and F20 (P = .002). O6-Methylguanine-DNA-methyltransferase methylation and isocitrate dehydrogenase mutation status were not significantly associated with tumor dynamics. The median progression-free survival and overall survival (OS) were 8.5 months (95% CI, 6.9-9.9) and 20.4 months (95% CI, 17.6-25.2). In multivariable analyses, patients with Vrel ≥ 1.33 at F10 had worse OS (hazard ratio [HR], 4.6; 95% CI, 1.8-11.4; P = .001), and patients with dmigration ≥ 5 mm at 1-month post-RT had worse progression-free survival (HR, 1.76; 95% CI, 1.08-2.87) and OS (HR, 2.2; 95% CI, 1.2-4.0; P = .007). CONCLUSIONS: Corpus callosum involvement and extent of surgery are independent predictors of tumor dynamics during RT and can enable patient selection for adaptive RT strategies. Significant tumor enlargement at F10 and tumor migration 1-month post-RT were associated with poorer OS.

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.

Predicting suicidality in late-life depression by 3D convolutional neural network and cross-sample entropy analysis of resting-state fMRI.

BACKGROUND: Predicting suicide is a pressing issue among older adults; however, predicting its risk is difficult. Capitalizing on the recent development of machine learning, considerable progress has been made in predicting complex behavior such as suicide. As depression remained the strongest risk for suicide, we aimed to apply deep learning algorithms to identify suicidality in a group with late-life depression (LLD). METHODS: We enrolled 83 patients with LLD, 35 of which were non-suicidal and 48 were suicidal, including 26 with only suicidal ideation and 22 with past suicide attempts, for resting-state functional magnetic resonance imaging (MRI). Cross-sample entropy (CSE) analysis was conducted to examine the complexity of MRI signals among brain regions. Three-dimensional (3D) convolutional neural networks (CNNs) were used, and the classification accuracy in each brain region was averaged to predict suicidality after sixfold cross-validation. RESULTS: We found brain regions with a mean accuracy above 75% to predict suicidality located mostly in default mode, fronto-parietal, and cingulo-opercular resting-state networks. The models with right amygdala and left caudate provided the most reliable accuracy in all cross-validation folds, indicating their neurobiological importance in late-life suicide. CONCLUSION: Combining CSE analysis and the 3D CNN, several brain regions were found to be associated with suicidality.

Plasma steroid concentrations reflect acute disease severity and normalise during recovery in people hospitalised with COVID-19.

OBJECTIVE: Endocrine systems are disrupted in acute illness, and symptoms reported following coronavirus disease 2019 (COVID-19) are similar to those found with clinical hormone deficiencies. We hypothesised that people with severe acute COVID-19 and with post-COVID symptoms have glucocorticoid and sex hormone deficiencies. DESIGN/PATIENTS: Samples were obtained for analysis from two UK multicentre cohorts during hospitalisation with COVID-19 (International Severe Acute Respiratory Infection Consortium/World Health Organisation [WHO] Clinical Characterization Protocol for Severe Emerging Infections in the UK study), and at follow-up 5 months after hospitalisation (Post-hospitalisation COVID-19 study). MEASUREMENTS: Plasma steroids were quantified by liquid chromatography-mass spectrometry. Steroid concentrations were compared against disease severity (WHO ordinal scale) and validated symptom scores. Data are presented as geometric mean (SD). RESULTS: In the acute cohort (n = 239, 66.5% male), plasma cortisol concentration increased with disease severity (cortisol 753.3 [1.6] vs. 429.2 [1.7] nmol/L in fatal vs. least severe, p < .001). In males, testosterone concentrations decreased with severity (testosterone 1.2 [2.2] vs. 6.9 [1.9] nmol/L in fatal vs. least severe, p < .001). In the follow-up cohort (n = 198, 62.1% male, 68.9% ongoing symptoms, 165 [121-192] days postdischarge), plasma cortisol concentrations (275.6 [1.5] nmol/L) did not differ with in-hospital severity, perception of recovery, or patient-reported symptoms. Male testosterone concentrations (12.6 [1.5] nmol/L) were not related to in-hospital severity, perception of recovery or symptom scores. CONCLUSIONS: Circulating glucocorticoids in patients hospitalised with COVID-19 reflect acute illness, with a marked rise in cortisol and fall in male testosterone. These findings are not observed 5 months from discharge. The lack of association between hormone concentrations and common post-COVID symptoms suggests steroid insufficiency does not play a causal role in this condition.

Post-acute COVID-19 neuropsychiatric symptoms are not associated with ongoing nervous system injury.

A proportion of patients infected with severe acute respiratory syndrome coronavirus 2 experience a range of neuropsychiatric symptoms months after infection, including cognitive deficits, depression and anxiety. The mechanisms underpinning such symptoms remain elusive. Recent research has demonstrated that nervous system injury can occur during COVID-19. Whether ongoing neural injury in the months after COVID-19 accounts for the ongoing or emergent neuropsychiatric symptoms is unclear. Within a large prospective cohort study of adult survivors who were hospitalized for severe acute respiratory syndrome coronavirus 2 infection, we analysed plasma markers of nervous system injury and astrocytic activation, measured 6 months post-infection: neurofilament light, glial fibrillary acidic protein and total tau protein. We assessed whether these markers were associated with the severity of the acute COVID-19 illness and with post-acute neuropsychiatric symptoms (as measured by the Patient Health Questionnaire for depression, the General Anxiety Disorder assessment for anxiety, the Montreal Cognitive Assessment for objective cognitive deficit and the cognitive items of the Patient Symptom Questionnaire for subjective cognitive deficit) at 6 months and 1 year post-hospital discharge from COVID-19. No robust associations were found between markers of nervous system injury and severity of acute COVID-19 (except for an association of small effect size between duration of admission and neurofilament light) nor with post-acute neuropsychiatric symptoms. These results suggest that ongoing neuropsychiatric symptoms are not due to ongoing neural injury.

Cognitive protection and brain entropy changes from omega-3 polyunsaturated fatty acids supplement in late-life depression: A 52-week randomized controlled trial.

BACKGROUND: Late-life depression (LLD) is associated with risk of dementia, yet intervention of LLD provides an opportunity to attenuate subsequent cognitive decline. Omega-3 polyunsaturated fatty acids (PUFAs) supplement is a potential intervention due to their beneficial effect in depressive symptoms and cognitive function. To explore the underlying neural mechanism, we used resting-state functional MRI (rs-fMRI) before and after omega-3 PUFAs supplement in older adults with LLD. METHODS: A 52-week double-blind randomized controlled trial was conducted. We used multi-scale sample entropy to analyze rs-fMRI data. Comprehensive cognitive tests and inflammatory markers were collected to correlate with brain entropy changes. RESULTS: A total of 20 patients completed the trial with 11 under omega-3 PUFAs and nine under placebo. While no significant global cognitive improvement was observed, a marginal enhancement in processing speed was noted in the omega-3 PUFAs group. Importantly, participants receiving omega-3 PUFAs exhibited decreased brain entropy in left posterior cingulate gyrus (PCG), multiple visual areas, the orbital part of the right middle frontal gyrus, and the left Rolandic operculum. The brain entropy changes of the PCG in the omega-3 PUFAs group correlated with improvement of language function and attenuation of interleukin-6 levels. LIMITATIONS: Sample size is small with only marginal clinical effect. CONCLUSION: These findings suggest that omega-3 PUFAs supplement may mitigate cognitive decline in LLD through anti-inflammatory mechanisms and modulation of brain entropy. Larger clinical trials are warranted to validate the potential therapeutic implications of omega-3 PUFAs for deterring cognitive decline in patients with late-life depression.

Intraoperative language mapping guided by real-time visualization of gamma band modulation electrocorticograms: Case report and proof of concept.

Background: Electrocorticography (ECoG) language mapping is often performed extraoperatively, frequently involves offline processing, and relationships with direct cortical stimulation (DCS) remain variable. We sought to determine the feasibility and preliminary utility of an intraoperative language mapping approach guided by real-time visualization of electrocorticograms. Methods: A patient with astrocytoma underwent awake craniotomy with intraoperative language mapping, utilizing a dual iPad stimulus presentation system coupled to a real-time neural signal processing platform capable of both ECoG recording and delivery of DCS. Gamma band modulations in response to 4 language tasks at each electrode were visualized in real-time. Next, DCS was conducted for each neighboring electrode pair during language tasks. Results: All language tasks resulted in strongest heat map activation at an electrode pair in the anterior to mid superior temporal gyrus. Consistent speech arrest during DCS was observed for Object and Action naming tasks at these same electrodes, indicating good correspondence with ECoG heat map recordings. This region corresponded well with posterior language representation via preoperative functional MRI. Conclusions: Intraoperative real-time visualization of language task-based ECoG gamma band modulation is feasible and may help identify targets for DCS. If validated, this may improve the efficiency and accuracy of intraoperative language mapping.

Immune mechanisms of granuloma formation in sarcoidosis and tuberculosis.

Sarcoidosis is a complex immune-mediated disease characterized by clusters of immune cells called granulomas. Despite major steps in understanding the cause of this disease, many questions remain. In this Review, we perform a mechanistic interrogation of the immune activities that contribute to granuloma formation in sarcoidosis and compare these processes with its closest mimic, tuberculosis, highlighting shared and divergent immune activities. We examine how Mycobacterium tuberculosis is sensed by the immune system; how the granuloma is initiated, formed, and perpetuated in tuberculosis compared with sarcoidosis; and the role of major innate and adaptive immune cells in shaping these processes. Finally, we draw these findings together around several recent high-resolution studies of the granuloma in situ that utilized the latest advances in single-cell technology combined with spatial methods to analyze plausible disease mechanisms. We conclude with an overall view of granuloma formation in sarcoidosis.

USP18 enhances dengue virus replication by regulating mitochondrial DNA release.

Dengue virus (DENV) infection remains a challenging health threat worldwide. Ubiquitin-specific protease 18 (USP18), which preserves the anti-interferon (IFN) effect, is an ideal target through which DENV mediates its own immune evasion. However, much of the function and mechanism of USP18 in regulating DENV replication remains incompletely understood. In addition, whether USP18 regulates DENV replication merely by causing IFN hyporesponsiveness is not clear. In the present study, by using several different approaches to block IFN signaling, including IFN neutralizing antibodies (Abs), anti-IFN receptor Abs, Janus kinase inhibitors and IFN alpha and beta receptor subunit 1 (IFNAR1)knockout cells, we showed that USP18 may regulate DENV replication in IFN-associated and IFN-unassociated manners. Localized in mitochondria, USP18 regulated the release of mitochondrial DNA (mtDNA) to the cytosol to affect viral replication, and mechanisms such as mitochondrial reactive oxygen species (mtROS) production, changes in mitochondrial membrane potential, mobilization of calcium into mitochondria, 8-oxoguanine DNA glycosylase 1 (OGG1) expression, oxidation and fragmentation of mtDNA, and opening of the mitochondrial permeability transition pore (mPTP) were involved in USP18-regulated mtDNA release to the cytosol. We therefore identify mitochondrial machineries that are regulated by USP18 to affect DENV replication and its association with IFN effects.

Single cell spatial analysis reveals inflammatory foci of immature neutrophil and CD8 T cells in COVID-19 lungs.

Single cell spatial interrogation of the immune-structural interactions in COVID -19 lungs is challenging, mainly because of the marked cellular infiltrate and architecturally distorted microstructure. To address this, we develop a suite of mathematical tools to search for statistically significant co-locations amongst immune and structural cells identified using 37-plex imaging mass cytometry. This unbiased method reveals a cellular map interleaved with an inflammatory network of immature neutrophils, cytotoxic CD8 T cells, megakaryocytes and monocytes co-located with regenerating alveolar progenitors and endothelium. Of note, a highly active cluster of immature neutrophils and CD8 T cells, is found spatially linked with alveolar progenitor cells, and temporally with the diffuse alveolar damage stage. These findings offer further insights into how immune cells interact in the lungs of severe COVID-19 disease. We provide our pipeline [Spatial Omics Oxford Pipeline (SpOOx)] and visual-analytical tool, Multi-Dimensional Viewer (MDV) software, as a resource for spatial analysis.

A randomised phase 2a study to investigate the effects of blocking interleukin-33 with tozorakimab in patients hospitalised with COVID-19: ACCORD-2.

Background: Increased serum interleukin (IL)-33 predicts poor outcomes in patients hospitalised with coronavirus disease 2019 (COVID-19). We examined the efficacy and safety of tozorakimab, a monoclonal antibody that neutralises IL-33, in improving outcomes in ACCORD-2 (EudraCT: 2020-001736-95). Methods: ACCORD-2 was an open-label, phase 2a study in adults hospitalised with COVID-19. Patients were randomised 1:1 to tozorakimab 300 mg plus standard of care (SoC) or SoC alone. The primary end-point was time to clinical response (sustained clinical improvement of ≥2 points on the World Health Organization ordinal scale, discharge from hospital or fit for discharge) by day 29. Other end-points included death or respiratory failure, mortality and intensive care unit admission by day 29, and safety. Serum IL-33/soluble stimulated-2 (sST2) complex levels were measured by high-sensitivity immunoassay. Results: Efficacy analyses included 97 patients (tozorakimab+SoC, n=53; SoC, n=44). Median time to clinical response did not differ between the tozorakimab and SoC arms (8.0 and 9.5 days, respectively; HR 0.96, 80% CI 0.70-1.31; one-sided p=0.33). Tozorakimab was well tolerated and the OR for risk of death or respiratory failure with treatment versus SoC was 0.55 (80% CI 0.27-1.12; p=0.26), while the OR was 0.31 (80% CI 0.09-1.06) in patents with high baseline serum IL-33/sST2 complex levels. Conclusions: Overall, ACCORD-2 results suggest that tozorakimab could be a novel therapy for patients hospitalised with COVID-19, warranting further investigation in confirmatory phase 3 studies.