Residual radiological opacities correlate with disease outcomes in ICU-treated COVID-19.

Background: Few studies consider both radiological and functional outcomes in COVID-19 survivors treated in the intensive care unit (ICU). We investigated clinical findings and pulmonary abnormalities on chest computed tomography (CT) and compared outcomes of severe versus mild-moderate acute respiratory distress syndrome (ARDS) on long-term follow-up. Methods: This longitudinal cohort study included 118 COVID-19 patients (median age, 58 years; 79% men). Thoracic CT scans were performed 4, 10, and 22 months after hospital discharge. Two independent blinded radiologists analyzed the 10 months scans and scored the radiology findings semi-quantitatively, as no/minor versus widespread opacities [low-radiology opacity grade (ROG) versus high-ROG]. ARDS severity was based on the PaO2/FiO2 ratio. The 6 min walk test (6MWT) was performed after 3 and 9 months, and lung diffusion capacity for carbon monoxide (DLCO) and lung volume measurement after 9 and 15 months. Dynamic spirometry was done at all time points. Residual symptoms and health-related quality-of-life (HRQL) were evaluated using validated questionnaires. Results: At 10 months, most patients (81/118; 69%) were classified as high-ROG, of which 70% had severe ARDS during hospitalisation; 69% of those with mild-moderate ARDS also had high-ROG. Patients with high-ROG had longer ICU stay and lower PaO2/FiO2 during hospitalisation (p < 0.01). At 9 months follow-up, patients with high-ROG had smaller lung volumes as % of predicted values [mean (±CI): 80 (77-84) vs. 93 (88-98) (p < 0.001)], lower DLCO as % of predicted values [74 (70-78) vs. 87 (82-92) (p < 0.001)], lower oxygen saturation during 6MWT (p = 0.02), and a tendency to more severe dyspnoea (p = 0.07), but no difference was found in HRQL compared with no/minor ROG (p = 0.92). A higher opacity score was related to lower DLCO at follow-up (r = -0.48, p < 0.001, Spearman rank test). Severe ARDS patients had slightly more severe fatigue at 9 months compared to mild-moderate, but no differences in dyspnoea or lung function at follow-up. Fibrotic-like changes were found in 93% of patients examined with CT scans at 2 years (55/118; 47%). Severe ARDS could predict widespread opacities (ROG > 25%) in most patients at follow-up at 10 months (AUC 0.74). Conclusion: Residual radiological abnormalities in ICU-treated COVID-19 patients, evaluated for up to 2 years, relate to persisting symptoms and impaired lung function, demanding careful follow-up regardless of ARDS severity at hospitalisation.

Availability of drugs and resistance testing for BPaLM regimen for rifampicin-resistant tuberculosis in Europe.

OBJECTIVES: Multidrug-resistant/Rifampicin-resistant tuberculosis (TB) is a major obstacle to successful TB control. The recommendation by the World Health Organization to use bedaquiline, pretomanid, linezolid and moxifloxacin (BPaL(M)) for 6 months, based on results of three trials with high efficacy and low toxicity, has revolutionized treatment options. METHODS: In this study, representatives of the Tuberculosis Network European Trialsgroup (TBnet) in 44/54 countries of the WHO Europe region document the availability of the medicines and drug susceptibility testing (DST) of the BPaL(M) regimen through a structured questionnaire between September to November 2023. RESULTS: 24/44 (54.5%), 42/44 (95.5%), 43/44 (97.7%), and 43/44 (97.7%) had access to pretomanid, bedaquiline, linezolid, and moxifloxacin, respectively. Overall, 23/44 (52.3%) had access to all the drugs composing the BPaL(M) regimen. 7/44 (15.9%), 28/44 (63.6%), 34/44 (77.3%) and 36/44 (81.8%) had access to DST for pretomanid, bedaquiline, linezolid and moxifloxacin, respectively. DST was available for all medicines composing the BPaL(M) regimen in 6/44 (13.6%) countries. CONCLUSION: Only in about half of the countries participating in the survey clinicians have access to all the BPaL(M) regimen drugs. In less than a fifth of countries, a complete DST is possible. Rapid scale up of DST capacity to prevent unnoticed spread of drug resistance and equal access to new regimens are urgently needed in Europe.

Drug Exposure and Susceptibility of Pyrazinamide Correlate with Treatment Response in Pyrazinamide-Susceptible Patients with Multidrug-Resistant Tuberculosis.

Exploring the influence of pyrazinamide exposure and susceptibility on treatment response is crucial for optimizing the management of multidrug-resistant tuberculosis (MDR-TB). This study aimed to investigate the association between pyrazinamide exposure, susceptibility, and response to MDR-TB treatment, as well as find clinical thresholds for pyrazinamide. A prospective multi-center cohort study of participants with MDR-TB using pyrazinamide was conducted in three TB-designated hospitals in China. Univariate and multivariate analyses were applied to investigate the associations. Classification and Regression Tree (CART) analysis was used to identify clinical thresholds, which were further evaluated by multivariate analysis and receiver operating characteristic (ROC) curves. The study included 143 patients with MDR-TB. The exposure/susceptibility ratio of pyrazinamide was associated with two-month culture conversion (adjusted risk ratio (aRR), 1.1; 95% confidence interval (CI), 1.07-1.20), six-month culture conversion (aRR, 1.1; 95% CI, 1.06-1.16), treatment success (aRR, 1.07; 95% CI, 1.03-1.10), as well as culture conversion time (adjusted hazard ratio (aHR) 1.18; 95% CI,1.14-1.23). The threshold for optimal improvement in sputum culture results at the sixth month of treatment was determined to be a pyrazinamide AUC0-24h/MIC ratio of 7.8. In conclusion, the exposure/susceptibility ratio of pyrazinamide is associated with the treatment response of MDR-TB, which may change in different Group A drug-based regimens.

Second-line antituberculosis drug exposure thresholds predictive of adverse events in multidrug-resistant tuberculosis treatment.

OBJECTIVES: This study aimed to investigate the association between drug exposure and adverse events (AEs) during the standardized multidrug-resistant tuberculosis (MDR-TB) treatment, as well as to identify predictive drug exposure thresholds. METHODS: We conducted a prospective, observational multicenter study among participants receiving standardized MDR-TB treatment between 2016 and 2019 in China. AEs were monitored throughout the treatment and their relationships to drug exposure (e.g., the area under the drug concentration-time curve from 0 to 24 h, AUC0-24 h) were analyzed. The thresholds of pharmacokinetic predictors of observed AEs were identified by boosted classification and regression tree (CART) and further evaluated by external validation. RESULTS: Of 197 study participants, 124 (62.9%) had at least one AE, and 15 (7.6%) experienced serious AEs. The association between drug exposure and AEs was observed including bedaquiline, its metabolite M2, moxifloxacin and QTcF prolongation (QTcF >450 ms), linezolid and mitochondrial toxicity, cycloserine and psychiatric AEs. The CART-derived thresholds of AUC0-24 h predictive of the respective AEs were 3.2 mg·h/l (bedaquiline M2); 49.3 mg·h/l (moxifloxacin); 119.3 mg·h/l (linezolid); 718.7 mg·h/l (cycloserine). CONCLUSIONS: This study demonstrated the drug exposure thresholds predictive of AEs for key drugs against MDR-TB treatment. Using the derived thresholds will provide the knowledge base for further randomized clinical trials of dose adjustment to minimize the risk of AEs.

Dysregulations in hemostasis, metabolism, immune response, and angiogenesis in post-acute COVID-19 syndrome with and without postural orthostatic tachycardia syndrome: a multi-omic profiling study.

Post-acute COVID-19 (PACS) are associated with cardiovascular dysfunction, especially postural orthostatic tachycardia syndrome (POTS). Patients with PACS, both in the absence or presence of POTS, exhibit a wide range of persisting symptoms long after the acute infection. Some of these symptoms may stem from alterations in cardiovascular homeostasis, but the exact mechanisms are poorly understood. The aim of this study was to provide a broad molecular characterization of patients with PACS with (PACS + POTS) and without (PACS-POTS) POTS compared to healthy subjects, including a broad proteomic characterization with a focus on plasma cardiometabolic proteins, quantification of cytokines/chemokines and determination of plasma sphingolipid levels. Twenty-one healthy subjects without a prior COVID-19 infection (mean age 43 years, 95% females), 20 non-hospitalized patients with PACS + POTS (mean age 39 years, 95% females) and 22 non-hospitalized patients with PACS-POTS (mean age 44 years, 100% females) were studied. PACS patients were non-hospitalized and recruited ≈18 months after the acute infection. Cardiometabolic proteomic analyses revealed a dysregulation of ≈200 out of 700 analyzed proteins in both PACS groups vs. healthy subjects with the majority (> 90%) being upregulated. There was a large overlap (> 90%) with no major differences between the PACS groups. Gene ontology enrichment analysis revealed alterations in hemostasis/coagulation, metabolism, immune responses, and angiogenesis in PACS vs. healthy controls. Furthermore, 11 out of 33 cytokines/chemokines were significantly upregulated both in PACS + POTS and PACS-POTS vs. healthy controls and none of the cytokines were downregulated. There were no differences in between the PACS groups in the cytokine levels. Lastly, 16 and 19 out of 88 sphingolipids were significantly dysregulated in PACS + POTS and PACS-POTS, respectively, compared to controls with no differences between the groups. Collectively, these observations suggest a clear and distinct dysregulation in the proteome, cytokines/chemokines, and sphingolipid levels in PACS patients compared to healthy subjects without any clear signature associated with POTS. This enhances our understanding and might pave the way for future experimental and clinical investigations to elucidate and/or target resolution of inflammation and micro-clots and restore the hemostasis and immunity in PACS.

Correlation of drug exposure and bacterial susceptibility with treatment response for Mycobacterium avium complex lung disease: protocol for a prospective observational cohort study.

INTRODUCTION: The burden of Mycobacterium avium complex (MAC) lung disease is increasing globally and treatment outcome is in general poor. Therapeutic drug monitoring has the potential to improve treatment outcome by ensuring adequate drug exposure. However, very limited population-based studies exist for MAC lung disease. This study aims to describe the distribution of drug exposure for key antimycobacterial drugs at population level, and to analyse them in relationship to treatment outcome in patients with MAC lung disease. METHODS AND ANALYSIS: A prospective cohort aiming to include 100 adult patients diagnosed with and treated for MAC lung disease will be conducted in Shanghai Pulmonary Hospital, China. Blood samples will be collected after 1 month MAC treatment for measurement of macrolides, rifamycin, ethambutol, amikacin and/or fluoroquinolones, using a validated liquid-chromatography tandem mass spectrometry method. Respiratory samples will be collected at inclusion and once every 3 months for mycobacterial culture until treatment completion. Minimum inhibitory concentration (MIC) determination will be performed using a commercial broth microdilution plate. In addition to mycobacterial culture, disease severity and clinical improvement will be assessed from the perspective of lung function, radiological presentation and self-reported quality of life. Whole genome sequencing will be performed for any longitudinal isolates with significant change of MIC to explore the emergence of drug resistance-conferring mutations. The relationship between drug exposure and treatment outcome will be analysed and potential confounders will be considered for adjustment in multivariable models. Meanwhile, the associations between drug exposure in relation to MIC and markers of treatment response will be explored using Cox proportional hazards or binary logistic regression models, as appropriate. ETHICS AND DISSEMINATION: This study has been approved by the ethics committee of Shanghai Pulmonary Hospital (No. K22-149Z). Written and oral informed consent will be obtained from all participants. The study results will be submitted to a peer-reviewed journal. TRIAL REGISTERATION NUMBER: NCT05824988.

COVID-19-related stigma among infected people in Sweden; psychometric properties and levels of stigma in two cohorts as measured by a COVID-19 stigma scale.

BACKGROUND: Epidemics have historically been accompanied by stigma and discrimination. Disease-related stigma has often been shown to have severe consequences for physical, mental and social wellbeing and lead to barriers to diagnosis, treatment and prevention. The aims of this study were to investigate if a HIV-related stigma measure could be adapted and valid and reliable to measure COVID-19-related stigma, and also to investigate levels of self-reported stigma and related factors among people in Sweden with experience of COVID-19 and compare levels of COVID-19-related stigma versus HIV-related stigma among persons living with HIV who had experienced a COVID-19 event. METHODS: Cognitive interviews (n = 11) and cross-sectional surveys were made after the acute phase of the illness using a new 12-item COVID-19 Stigma Scale and the established 12-item HIV Stigma Scale in two cohorts (people who had experienced COVID-19 (n = 166/209, 79%) and people living with HIV who had experienced a COVID-19 event (n = 50/91, 55%). Psychometric analysis of the COVID-19 Stigma Scale was performed by calculating floor and ceiling effects, Cronbach's α and exploratory factor analysis. Levels of COVID-19 stigma between groups were analysed using the Mann-Whitney U test. Levels of COVID-19 and HIV stigma among people living with HIV with a COVID-19 event were compared using the Wilcoxon signed-rank test. RESULTS: The COVID-19 cohort consisted of 88 (53%) men and 78 (47%) women, mean age 51 (19-80); 143 (87%) living in a higher and 22 (13%) in a lower income area. The HIV + COVID-19 cohort consisted of 34 (68%) men and 16 (32%) women, mean age 51 (26-79); 20 (40%) living in a higher and 30 (60%) in a lower income area. The cognitive interviews showed that the stigma items were easy to understand. Factor analysis suggested a four-factor solution accounting for 77% of the total variance. There were no cross loadings, but two items loaded on factors differing from the original scale. All subscales had acceptable internal consistency, showed high floor and no ceiling effects. There was no statistically significant difference between COVID-19 stigma scores between the two cohorts or between genders. People living in lower income areas reported more negative self-image and concerns about public attitudes related to COVID-19 than people in higher income areas (median score 3 vs 3 and 4 vs 3 on a scale from 3-12, Z = -1.980, p = 0.048 and Z = -2.023, p = 0.024, respectively). People from the HIV + COVID-19 cohort reported more HIV than COVID-19 stigma. CONCLUSIONS: The adapted 12-item COVID-19 Stigma Scale may be valid and reliable for measurement of COVID-19-related stigma. However, specific items may need to be rephrased or replaced to better correspond to the COVID-19 context. People who had experienced COVID-19 reported low levels of COVID-19-related stigma in general but people from lower income areas had higher levels of negative self-image and concerns about public attitudes related to COVID-19 than people from areas with higher income, which may call for targeted interventions. Although exhibiting more pronounced HIV stigma levels, people living with HIV who had experienced COVID-19 reported COVID-19-related stigma of the same low magnitude as their peers not living with HIV.

Cardiorespiratory dysautonomia in post-COVID-19 condition: Manifestations, mechanisms and management.

A significant proportion of COVID-19 patients experience debilitating symptoms for months after the acute infection. According to recent estimates, approximately 1 out of 10 COVID-19 convalescents reports persistent health issues more than 3 months after initial recovery. This 'post-COVID-19 condition' may include a large variety of symptoms from almost all domains and organs, and for some patients it may mean prolonged sick-leave, homestay and strongly limited activities of daily life. In this narrative review, we focus on the symptoms and signs of post-COVID-19 condition in adults - particularly those associated with cardiovascular and respiratory systems, such as postural orthostatic tachycardia syndrome or airway disorders - and explore the evidence for chronic autonomic dysfunction as a potential underlying mechanism. The most plausible hypotheses regarding cellular and molecular mechanisms behind the wide spectrum of observed symptoms - such as lingering viruses, persistent inflammation, impairment in oxygen sensing systems and circulating antibodies directed to blood pressure regulatory components - are discussed. In addition, an overview of currently available pharmacological and non-pharmacological treatment options is presented.

Population pharmacokinetics and model-based dosing evaluation of bedaquiline in multidrug-resistant tuberculosis patients.

Aims: Bedaquiline is now recommended to all patients in the treatment of multidrug-resistant tuberculosis (MDR-TB) using standard dosing regimens. As the ability to measure blood drug concentrations is very limited, little is known about drug exposure and treatment outcome. Thus, this study aimed to model the population pharmacokinetics as well as to evaluate the currently recommended dosage. Methodology: A bedaquiline population pharmacokinetic (PK) model was developed based on samples collected from the development cohort before and 1, 2, 3, 4, 5, 6, 8, 12, 18, and 24 h after drug intake on week 2 and week 4 of treatment. In a prospective validation cohort of patients with MDR-TB, treated with bedaquiline-containing standardized regimen, drug exposure was assessed using the developed population PK model and thresholds were identified by relating to 2-month and 6-month sputum culture conversion and final treatment outcome using classification and regression tree analysis. In an exploratory analysis by the probability of target attainment (PTA) analysis, we evaluated the recommended dosage at different MIC levels by Middlebrook 7H11 agar dilution (7H11). Results: Bedaquiline pharmacokinetic data from 55 patients with MDR-TB were best described by a three-compartment model with dual zero-order input. Body weight was a covariate of the clearance and the central volume of distribution, albumin was a covariate of the clearance. In the validation cohort, we enrolled 159 patients with MDR-TB. The 7H11 MIC mode (range) of bedaquiline was 0.06 mg (0.008-0.25 mg/L). The study participants with AUC0-24h/MIC above 175.5 had a higher probability of culture conversion after 2-month treatment (adjusted relative risk, aRR:16.4; 95%CI: 5.3-50.4). Similarly, those with AUC0-24h/MIC above 118.2 had a higher probability of culture conversion after 6-month treatment (aRR:20.1; 95%CI: 2.9-139.4), and those with AUC0-24h/MIC above 74.6 had a higher probability of successful treatment outcome (aRR:9.7; 95%CI: 1.5-64.8). Based on the identified thresholds, simulations showed that the WHO recommended dosage (400 mg once daily for 14 days followed by 200 mg thrice weekly) resulted in PTA >90% for the majority of isolates (94%; MICs ≤0.125 mg/L). Conclusion: We established a population PK model for bedaquiline in patients with MDR-TB in China. Based on the thresholds and MIC distribution derived in a clinical study, the recommended dosage of bedaquiline is sufficient for the treatment of MDR-TB.

Population Pharmacokinetics and Dose Evaluation of Cycloserine among Patients with Multidrug-Resistant Tuberculosis under Standardized Treatment Regimens.

Although cycloserine is a recommended drug for the treatment of multidrug-resistant tuberculosis (MDR-TB) according to World Health Organization (WHO), few studies have reported on pharmacokinetics (PK) and/or pharmacodynamics (PD) data of cycloserine in patients with standardized MDR-TB treatment. This study aimed to estimate the population PK parameters for cycloserine and to identify clinically relevant PK/PD thresholds, as well as to evaluate the current recommended dosage. Data from a large cohort with full PK curves was used to develop a population PK model. This model was used to estimate drug exposure in patients with MDR-TB from a multicentre prospective study in China. The classification and regression tree was used to identify the clinically relevant PK/PD thresholds. Probability of target attainment was analyzed to evaluate the currently recommended dosing strategy. Cycloserine was best described by a two-compartment disposition model. A percentage of time concentration above MICs (T>MIC) of 30% and a ratio of area under drug concentration-time curve (AUC0-24h) over MIC of 36 were the valid predictors for 6-month sputum culture conversion and final treatment outcome. Simulations showed that with WHO-recommended doses (500 mg and 750 mg for patients weighing <45 kg and ≥45 kg), the probability of target attainment exceeded 90% at MIC ≤16 mg/L in MGIT for both T>MIC of 30% and AUC0-24h/MIC of 36. New clinically relevant PK/PD thresholds for cycloserine were identified in patients with standardized MDR-TB treatment. WHO-recommended doses were considered adequate for the MGIT MIC distribution in our cohort of Chinese patients with MDR-TB.

Stress native T1 and native T2 mapping compared to myocardial perfusion reserve in long-term follow-up of severe Covid-19.

Severe Covid-19 may cause a cascade of cardiovascular complications beyond viral pneumonia. The severe inflammation may affect the microcirculation which can be assessed by cardiovascular magnetic resonance (CMR) imaging using quantitative perfusion mapping and calculation of myocardial perfusion reserve (MPR). Furthermore, native T1 and T2 mapping have previously been shown to identify changes in myocardial perfusion by the change in native T1 and T2 during adenosine stress. However, the relationship between native T1, native T2, ΔT1 and ΔT2 with myocardial perfusion and MPR during long-term follow-up in severe Covid-19 is currently unknown. Therefore, patients with severe Covid-19 (n = 37, median age 57 years, 24% females) underwent 1.5 T CMR median 292 days following discharge. Quantitative myocardial perfusion (ml/min/g), and native T1 and T2 maps were acquired during adenosine stress, and rest, respectively. Both native T1 (R2 = 0.35, p < 0.001) and native T2 (R2 = 0.28, p < 0.001) correlated with myocardial perfusion. However, there was no correlation with ΔT1 or ΔT2 with MPR, respectively (p > 0.05 for both). Native T1 and native T2 correlate with myocardial perfusion during adenosine stress, reflecting the coronary circulation in patients during long-term follow-up of severe Covid-19. Neither ΔT1 nor ΔT2 can be used to assess MPR in patients with severe Covid-19.

Hyperbaric oxygen therapy for long COVID (HOT-LoCO), an interim safety report from a randomised controlled trial.

BACKGROUND: With ~ 50 million individuals suffering from post-COVID condition (PCC), low health related quality of life (HRQoL) is a vast problem. Common symptoms of PCC, that persists 3 months from the onset of COVID-19 are fatigue, shortness of breath and cognitive dysfunction. No effective treatment options have been widely adopted in clinical practice. Hyperbaric oxygen (HBO2) is a candidate drug. METHODS: The objective of this interim analysis is to describe our cohort and evaluate the safety of HBO2 for post covid condition. In an ongoing randomised, placebo-controlled, double blind, clinical trial, 20 previously healthy subjects with PCC were assigned to HBO2 or placebo. Primary endpoints are physical domains in RAND-36; Physical functioning (PF) and Role Physical (RP) at 13 weeks. Secondary endpoints include objective physical tests. Safety endpoints are occurrence, frequency, and seriousness of Adverse Events (AEs). An independent data safety monitoring board (DSMB) reviewed unblinded data. The trial complies with Good Clinical Practice. Safety endpoints are evaluated descriptively. Comparisons against norm data was done using t-test. RESULTS: Twenty subjects were randomised, they had very low HRQoL compared to norm data. Mean (SD) PF 31.75 (19.55) (95% Confidence interval; 22.60-40.90) vs 83.5 (23.9) p < 0.001 in Rand-36 PF and mean 0.00 (0.00) in RP. Very low physical performance compared to norm data. 6MWT 442 (180) (95% CI 358-525) vs 662 (18) meters p < 0.001. 31 AEs occurred in 60% of subjects. In 20 AEs, there were at least a possible relationship with the study drug, most commonly cough and chest pain/discomfort. CONCLUSIONS: An (unexpectedly) high frequency of AEs was observed but the DSMB assessed HBO2 to have a favourable safety profile. Our data may help other researchers in designing trials. Trial Registration ClinicalTrials.gov: NCT04842448. Registered 13 April 2021, https://clinicaltrials.gov/ct2/show/NCT04842448 . EudraCT: 2021-000764-30. Registered 21 May 2021, https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-000764-30/SE.

European Working Group on SARS-CoV-2: Current Understanding, Unknowns, and Recommendations on the Neurological Complications of COVID-19.

Background: The emergence of COVID-19 was rapidly followed by infection and the deaths of millions of people across the globe. With much of the research and scientific advancement rightly focused on reducing the burden of severe and critical acute COVID-19 infection, the long-term effects endured by those who survived the acute infection has been previously overlooked. Now, an appreciation for the post-COVID-19 condition, including its neurological manifestations, is growing, although there remain many unknowns regarding the etiology and risk factors of the condition, as well as how to effectively diagnose and treat it. Methods: Here, drawing upon the experiences and expertise of the clinicians and academics of the European working group on COVID-19, we have reviewed the current literature to provide a comprehensive overview of the neurological sequalae of the post-COVID-19 condition. Results: In this review, we provide a summary of the neurological symptoms associated with the post-COVID-19 condition, before discussing the possible mechanisms which may underly and manifest these symptoms. Following this, we explore the risk factors for developing neurological symptoms as a result of COVID-19 and the post-COVID-19 condition, as well as how COVID-19 infection may itself be a risk factor for the development of neurological disease in the future. Lastly, we evaluate how the post-COVID condition could be accurately diagnosed and effectively treated, including examples of the current guidelines, clinical outcomes, and tools that have been developed to aid in this process, as well as addressing the protection provided by COVID-19 vaccines against the post-COVID-19 condition. Conclusions: Overall, this review provides a comprehensive overview of the neurological sequalae of the post-COVID-19 condition. Impact statement With our understanding of the neurological complications of the post-COVID-19 condition currently lacking sufficient depth, this review aimed at highlighting the current knowns and unknowns of the post-COVID-19 condition. In this review, we draw upon the experiences and expertise of the clinicians and academics of the European working group on COVID-19, as well as explore the current published literature, to evaluate a range of topics associated with the neurological complications of the post-COVID-19 condition. As a result, we have provided a comprehensive review of the topic. The European Working Group on SARS-CoV-2 Many essential questions surrounding COVID-19 remain unanswered, including its neurological complications and associated sequalae. In this review, we aim at identifying the current gaps in our understanding of post-COVID-19 neurological sequalae and suggest how future studies should be undertaken to fill these gaps. This review will draw upon the current biological and mechanistic understanding of COVID-19 and post-COVID-19 complications to discuss the clinically relevant aspects associated with the neurological manifestations of post-COVID-19 syndrome. From our discussions, the following questions were considered highly relevant for contemplation.

Post COVID-19 condition diagnosis: A population-based cohort study of occurrence, associated factors, and healthcare use by severity of acute infection.

BACKGROUND: The occurrence and healthcare use trajectory of post COVID-19 condition (PCC) is poorly understood. Our aim was to investigate these aspects in SARS-CoV-2-positive individuals with and without a PCC diagnosis. METHODS: We conducted a population-based cohort study of adults in Stockholm, Sweden, with a verified infection from 1 March 2020 to 31 July 2021, stratified by the severity of the acute infection. The outcome was a PCC diagnosis registered any time 90-360 days after a positive test. We performed Cox regression models to assess baseline characteristics associated with the PCC diagnosis. Individuals diagnosed with PCC were then propensity-score matched to individuals without a diagnosis to assess healthcare use beyond the acute infection. RESULTS: Among 204,805 SARS-CoV-2-positive individuals, the proportion receiving a PCC diagnosis was 1% among individuals not hospitalized for their COVID-19 infection, 6% among hospitalized, and 32% among intensive care unit (ICU)-treated individuals. The most common new-onset symptom diagnosis codes among individuals with a PCC diagnosis were fatigue (29%) among nonhospitalized and dyspnea among both hospitalized (25%) and ICU-treated (41%) individuals. Female sex was associated with a PCC diagnosis among nonhospitalized and hospitalized individuals, with interactions between age and sex. Previous mental health disorders and asthma were associated with a PCC diagnosis among nonhospitalized and hospitalized individuals. Among individuals with a PCC diagnosis, the monthly proportion with outpatient care was substantially elevated up to 1 year after acute infection compared to before, with substantial proportions of this care attributed to PCC-related care. CONCLUSION: The differential association of age, sex, comorbidities, and healthcare use with the severity of the acute infection indicates different trajectories and phenotypes of PCC, with incomplete resolution 1 year after infection.

Enhanced External Counterpulsation for Management of Postacute Sequelae of SARS-CoV-2 Associated Microvascular Angina and Fatigue: An Interventional Pilot Study.

Background: Postacute sequelae of SARS-CoV-2 infection (PASC) are a novel clinical syndrome characterized in part by endothelial dysfunction. Enhanced external counterpulsation (EECP) produces pulsatile shear stress, which has been associated with improvements in systemic endothelial function. Objective: To explore the effects of EECP on symptom burden, physical capacity, mental health, and health-related quality of life (HRQoL) in patients with PASC-associated angina and microvascular dysfunction (MVD). Methods: An interventional pilot study was performed, including 10 patients (male = 5, mean age 50.3 years) recruited from a tertiary specialized PASC clinic. Patients with angina and MVD, defined as index of microcirculatory resistance (IMR) ≥25 and/or diagnosed through stress perfusion cardiac magnetic resonance imaging, were included. Patients underwent one modified EECP course (15 one-hour sessions over five weeks). Symptom burden, six-minute walk test, and validated generic self-reported instruments for measuring psychological distress and HRQoL were assessed before and one month after treatment. Results: At baseline, most commonly reported PASC symptoms were angina (100%), fatigue (80%), and dyspnea (80%). Other symptoms included palpitations (50%), concentration impairment (50%), muscle pain (30%), and brain fog (30%). Mean IMR was 63.6. After EECP, 6MWD increased (mean 29.5 m, median 21 m) and angina and fatigue improved. Mean depression scores showed reduced symptoms (-0.8). Mean HRQoL scores improved in seven out of eight subscales (+0.2 to 10.5). Conclusions: Patients with PASC-associated angina and evidence of MVD experienced subjective and objective benefits from EECP. The treatment was well-tolerated. These findings warrant controlled studies in a larger cohort.

A protein signature associated with active tuberculosis identified by plasma profiling and network-based analysis.

Annually, approximately 10 million people are diagnosed with active tuberculosis (TB), and 1.4 million die of the disease. If left untreated, each person with active TB will infect 10-15 new individuals. The lack of non-sputum-based diagnostic tests leads to delayed diagnoses of active pulmonary TB cases, contributing to continued disease transmission. In this exploratory study, we aimed to identify biomarkers associated with active TB. We assessed the plasma levels of 92 proteins associated with inflammation in individuals with active TB (n = 20), latent TB (n = 14), or healthy controls (n = 10). Using co-expression network analysis, we identified one module of proteins with strong association with active TB. We removed proteins from the module that had low abundance or were associated with non-TB diseases in published transcriptomic datasets, resulting in a 12-protein plasma signature that was highly enriched in individuals with pulmonary and extrapulmonary TB and was further associated with disease severity.

Hyperbaric oxygen for treatment of long COVID-19 syndrome (HOT-LoCO): protocol for a randomised, placebo-controlled, double-blind, phase II clinical trial.

INTRODUCTION: Long COVID-19, where symptoms persist 12 weeks after the initial SARS-CoV-2-infection, is a substantial problem for individuals and society in the surge of the pandemic. Common symptoms are fatigue, postexertional malaise and cognitive dysfunction. There is currently no effective treatment and the underlying mechanisms are unknown, although several hypotheses exist, with chronic inflammation as a common denominator. In prospective studies, hyperbaric oxygen therapy (HBOT) has been suggested to be effective for the treatment of similar syndromes such as chronic fatigue syndrome and fibromyalgia. A case series has suggested positive effects of HBOT in long COVID-19. This randomised, placebo-controlled clinical trial will explore HBOT as a potential treatment for long COVID-19. The primary objective is to evaluate if HBOT improves health-related quality of life (HRQoL) for patients with long COVID-19 compared with placebo/sham. The main secondary objective is to evaluate whether HBOT improves endothelial function, objective physical performance and short-term HRQoL. METHODS AND ANALYSIS: A randomised, placebo-controlled, double-blind, phase II clinical trial in 80 previously healthy subjects debilitated due to long COVID-19, with low HRQoL. Clinical data, HRQoL questionnaires, blood samples, objective tests and activity metre data will be collected at baseline. Subjects will be randomised to a maximum of 10 treatments with hyperbaric oxygen or sham treatment over 6 weeks. Assessments for safety and efficacy will be performed at 6, 13, 26 and 52 weeks, with the primary endpoint (physical domains in RAND 36-Item Health Survey) and main secondary endpoints defined at 13 weeks after baseline. Data will be reviewed by an independent data safety monitoring board. ETHICS AND DISSEMINATION: The trial is approved by the Swedish National Institutional Review Board (2021-02634) and the Swedish Medical Products Agency (5.1-2020-36673). Positive, negative and inconclusive results will be published in peer-reviewed scientific journals with open access. TRIAL REGISTRATION NUMBER: NCT04842448.

Corrigendum to "Mass spectrometry for therapeutic drug monitoring of anti-tuberculosis drugs" [Clin. Mass Spectrom. 14(Part A) (2019) 34-45].

[This corrects the article DOI: 10.1016/j.clinms.2018.10.002.].

Drug exposure and susceptibility of second-line drugs correlate with treatment response in patients with multidrug-resistant tuberculosis: a multicentre prospective cohort study in China.

BACKGROUND: Understanding the impact of drug exposure and susceptibility on treatment response of multidrug-resistant tuberculosis (MDR-TB) will help to optimise treatment. This study aimed to investigate the association between drug exposure, susceptibility and response to MDR-TB treatment. METHODS: Drug exposure and susceptibility for second-line drugs were measured for patients with MDR-TB. Multivariate analysis was applied to investigate the impact of drug exposure and susceptibility on sputum culture conversion and treatment outcome. Probability of target attainment was evaluated. Random Forest and CART (Classification and Regression Tree) analysis was used to identify key predictors and their clinical targets among patients on World Health Organization-recommended regimens. RESULTS: Drug exposure and corresponding susceptibility were available for 197 patients with MDR-TB. The probability of target attainment was highly variable, ranging from 0% for ethambutol to 97% for linezolid, while patients with fluoroquinolones above targets had a higher probability of 2-month culture conversion (56.3% versus 28.6%; adjusted OR 2.91, 95% CI 1.42-5.94) and favourable outcome (88.8% versus 68.8%; adjusted OR 2.89, 95% CI 1.16-7.17). Higher exposure values of fluoroquinolones, linezolid and pyrazinamide were associated with earlier sputum culture conversion. CART analysis selected moxifloxacin area under the drug concentration-time curve/minimum inhibitory concentration (AUC0-24h/MIC) of 231 and linezolid AUC0-24h/MIC of 287 as best predictors for 6-month culture conversion in patients receiving identical Group A-based regimens. These associations were confirmed in multivariate analysis. CONCLUSIONS: Our findings indicate that target attainment of TB drugs is associated with response to treatment. The CART-derived thresholds may serve as targets for early dose adjustment in a future randomised controlled study to improve MDR-TB treatment outcome.