From inflammation to degeneration – Enlarged perivascular spaces and glymphatic clearance in neuropsychiatric long-COVID syndrome

Neuropsychiatric symptoms, such as executive dysfunction, fatigue and depression, are highly prevalent and severely incapacitating among Long- and Post-COVID patients (Schou et al., 2021), to the point where some are unable to resume their jobs and even their daily lives. While the prognosis of these patients remains elusive, cognition worsens over time in many of them (Lu et al., 2020). Perivascular inflammation in the brain, as a consequence of the blood-brain barrier damage caused by SARS-CoV-2 (Yang et al., 2020), is one of the mechanisms of ongoing systemic and intracerebral inflammation proposed to contribute to these long-lasting symptoms. We thus investigated two surrogate measurements of glymphatics, enlarged perivascular spaces in T1-w magnetic resonance imaging and three-dimensional propagation of cardiorespiratory pulsations in ultrafast magnetic resonance encephalography (Barghoorn et al., 2021), in 60 neuropsychiatric long-COVID patients, 30 healthy COVID-19 survivors and 30 never-infected healthy controls. We provide evidence of EPVS burden being associated with cognitive impairment and cardiorespiratory pulsations slightly varying among these groups. We hypothesize glymphatic clearance dysfunction might be a way for post-COVID to transition into a neurodegenerative disorder.

Healthcare outcomes in patients with HIV infection at a tertiary hospital during the COVID-19 pandemic Resultados en la atención a pacientes con infección por VIH en un hospital terciario durante la pandemia COVID-19

Background The COVID-19 pandemic has affected the care of patients with other diseases. Difficulty in access to healthcare during these months has been especially relevant for persons with HIV infection (PWH). This study therefore sought to ascertain the clinical outcomes and effectiveness of the measures implemented among PWH in a region with one of the highest incidence rates in Europe. Methods Retrospective, observational, pre-post intervention study to compare the outcomes of PWH attended at a high-complexity healthcare hospital from March to October 2020 and during the same months across the period 2016–2019. The intervention consisted of home drug deliveries and preferential use of non face-to-face consultations. The effectiveness of the measures implemented was determined by reference to the number of emergency visits, hospitalisations, mortality rate, and percentage of PWH with viral load >50 copies, before and after the two pandemic waves. Results A total of 2760 PWH were attended from January 2016 to October 2020. During the pandemic, there was a monthly mean of 106.87 telephone consultations and 2075 home deliveries of medical drugs dispensed to ambulatory patients. No statistically significant differences were found between the rate of admission of patients with COVID-HIV co-infection and that of the remaining patients (1172.76 admissions/100,000 population vs. 1424.29, p = 0.401) or in mortality (11.54% vs. 12.96%, p = 0.939). The percentage of PWH with viral load >50 copies was similar before and after the pandemic (1.20% pre-pandemic vs. 0.51% in 2020, p = 0.078). Conclusion Our results show that the strategies implemented during the first 8 months of the pandemic prevented any deterioration in the control and follow-up parameters routinely used on PWH. Furthermore, they contribute to the debate about how telemedicine and telepharmacy can fit into future healthcare models.

Healthcare outcomes in patients with HIV infection at a tertiary hospital during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has affected the care of patients with other diseases. Difficulty in access to healthcare during these months has been especially relevant for persons with HIV infection (PWH). This study therefore sought to ascertain the clinical outcomes and effectiveness of the measures implemented among PWH in a region with one of the highest incidence rates in Europe. METHODS: Retrospective, observational, pre-post intervention study to compare the outcomes of PWH attended at a high-complexity healthcare hospital from March to October 2020 and during the same months across the period 2016-2019. The intervention consisted of home drug deliveries and preferential use of non face-to-face consultations. The effectiveness of the measures implemented was determined by reference to the number of emergency visits, hospitalisations, mortality rate, and percentage of PWH with viral load >50copies, before and after the two pandemic waves. RESULTS: A total of 2760 PWH were attended from January 2016 to October 2020. During the pandemic, there was a monthly mean of 106.87 telephone consultations and 2075 home deliveries of medical drugs dispensed to ambulatory patients. No statistically significant differences were found between the rate of admission of patients with COVID-HIV co-infection and that of the remaining patients (1172.76 admissions/100,000 population vs. 1424.29, p=0.401) or in mortality (11.54% vs. 12.96%, p=0.939). The percentage of PWH with viral load >50copies was similar before and after the pandemic (1.20% pre-pandemic vs. 0.51% in 2020, p=0.078). CONCLUSION: Our results show that the strategies implemented during the first 8 months of the pandemic prevented any deterioration in the control and follow-up parameters routinely used on PWH. Furthermore, they contribute to the debate about how telemedicine and telepharmacy can fit into future healthcare models.

The Effectiveness of a Four-Week Digital Physiotherapy Intervention to Improve Functional Capacity and Adherence to Intervention in Patients with Long COVID-19.

Long COVID-19 has been defined as the condition occurring in individuals with a history of probable or confirmed SARS-CoV-2 infection, with related symptoms lasting at least 2 months and not explainable by an alternative diagnosis. The practice of digital physiotherapy presents itself as a promising complementary treatment method to standard physiotherapy, playing a key role in the recovery of function in subjects who have passed the disease and who maintain some symptomatology over time. The aims of this research are to explore the effect of a digital physiotherapy intervention on functional recovery in patients diagnosed with Long COVID-19 and to identify the level of adherence to the treatment carried out. A quasi-experimental pre-post study assessed initially and at the end of the 4-week intervention the functional capacity (1-min STS and SPPB) and the adherence (software) of a total of 32 participants. After the 4-week digital physiotherapy practice intervention with an individualised and customise exercise programme, a statistically significant improvement was observed (p < 0.05) with a small to medium effect size, high adherence rates and values above the minimal clinically important difference (MCID). We consider our intervention feasible, safe and consistent with our objectives. However, further randomised clinical trials and studies with larger samples are needed to draw extrapolable conclusions. Trial registration NCT04742946.

sFlt-1 Is an Independent Predictor of Adverse Maternal Outcomes in Women With SARS-CoV-2 Infection and Hypertensive Disorders of Pregnancy.

Background: Preeclampsia (PE) and COVID-19 share a common vascular-endothelial physiopathological pathway that may aggravate or worsen women's outcomes when both coexist. This study aims to evaluate the association of sFlt-1 levels and adverse maternal outcomes among positive SARS-CoV-2 pregnant women with and without hypertensive disorders of pregnancy (HDP). Methods: We performed a multicenter retrospective cohort study of pregnant women with confirmed SARS-CoV-2 infection that required hospital admission. The exposed cohort comprised women with a diagnosis of an HDP. The primary outcome was a composite definition of adverse maternal outcome. The association between predictors and the main and secondary outcomes was assessed using an elastic-net regression which comprised a Lasso and Ridge regression method for automatic variable selection and penalization of non-statistically significant coefficients using a 10-fold cross-validation where the best model if automatically chosen by the lowest Akaike information criterion (AIC) and Bayesian information criteria (BIC). Results: Among 148 pregnant women with COVID-19, the best predictive model comprised sFlt-1 MoMs [odds ratio (OR): 5.13; 95% CI: 2.19-12.05], and HDP (OR: 32.76; 95% CI: 5.24-205). sFlt-1 MoMs were independently associated with an increased probability of an adverse maternal outcome despite adjusting for HDP. Conclusions: Our study shows that sFlt-1 is an independent predictor of adverse outcomes in women with SARS-CoV-2 despite hypertension status.

Building an i2b2-Based Population Repository for COVID-19 Research.

Reuse of Electronic Health Records (EHRs) for specific diseases such as COVID-19 requires data to be recorded and persisted according to international standards. Since the beginning of the COVID-19 pandemic, Hospital Universitario 12 de Octubre (H12O) evolved its EHRs: it identified, modeled and standardized the concepts related to this new disease in an agile, flexible and staged way. Thus, data from more than 200,000 COVID-19 cases were extracted, transformed, and loaded into an i2b2 repository. This effort allowed H12O to share data with worldwide networks such as the TriNetX platform and the 4CE Consortium.

Making EHRs Trustable: A Quality Analysis of EHR-Derived Datasets for COVID-19 Research.

One approach to verifying the quality of research data obtained from EHRs is auditing how complete and correct the data are in comparison with those collected by manual and controlled methods. This study analyzed data quality of an EHR-derived dataset for COVID-19 research, obtained during the pandemic at Hospital Universitario 12 de Octubre. Data were extracted from EHRs and a manually collected research database, and then transformed into the ISARIC-WHO COVID-19 CRF model. Subsequently, a data analysis was performed, comparing both sources through this convergence model. More concepts and records were obtained from EHRs, and PPV (95% CI) was above 85% in most sections. In future studies, a more detailed analysis of data quality will be carried out.

Plasma Total Antioxidant Capacity and Carbonylated Proteins Are Increased in Pregnant Women with Severe COVID-19.

Oxidative stress (OS) induced by SARS-CoV-2 infection may play an important role in COVID-19 complications. However, information on oxidative damage in pregnant women with COVID-19 is limited. OBJECTIVE: We aimed to compare lipid and protein oxidative damage and total antioxidant capacity (TAC) between pregnant women with severe and non-severe COVID-19. METHODS: We studied a consecutive prospective cohort of patients admitted to the obstetrics emergency department. All women positive for SARS-CoV-2 infection by reverse transcription-polymerase chain reaction (RT-qPCR) were included. Clinical data were collected and blood samples were obtained at hospital admission. Plasma OS markers, malondialdehyde (MDA), carbonylated proteins (CP), and TAC; angiogenic markers, fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF); and renin-angiotensin system (RAS) markers, angiotensin-converting enzyme 2 (ACE-2) and angiotensin-II (ANG-II) were measured. Correlation between OS, angiogenic, and RAS was evaluated. RESULTS: In total, 57 pregnant women with COVID-19 were included, 17 (28.9%) of which had severe COVID-19; there were 3 (5.30%) maternal deaths. Pregnant women with severe COVID-19 had higher levels of carbonylated proteins (5782 pmol vs. 6651 pmol; p = 0.024) and total antioxidant capacity (40.1 pmol vs. 56.1 pmol; p = 0.001) than women with non-severe COVID-19. TAC was negatively correlated with ANG-II (p < 0.0001) and MDA levels (p < 0.0001) and positively with the sFlt-1/PlGF ratio (p = 0.027). CONCLUSIONS: In pregnant women, severe COVID-19 is associated with an increase in protein oxidative damage and total antioxidant capacity as a possible counterregulatory mechanism.

Plasma Total Antioxidant Capacity and Carbonylated Proteins Are Increased in Pregnant Women with Severe COVID-19

Oxidative stress (OS) induced by SARS-CoV-2 infection may play an important role in COVID-19 complications. However, information on oxidative damage in pregnant women with COVID-19 is limited. Objective: We aimed to compare lipid and protein oxidative damage and total antioxidant capacity (TAC) between pregnant women with severe and non-severe COVID-19. Methods: We studied a consecutive prospective cohort of patients admitted to the obstetrics emergency department. All women positive for SARS-CoV-2 infection by reverse transcription-polymerase chain reaction (RT-qPCR) were included. Clinical data were collected and blood samples were obtained at hospital admission. Plasma OS markers, malondialdehyde (MDA), carbonylated proteins (CP), and TAC;angiogenic markers, fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF);and renin-angiotensin system (RAS) markers, angiotensin-converting enzyme 2 (ACE-2) and angiotensin-II (ANG-II) were measured. Correlation between OS, angiogenic, and RAS was evaluated. Results: In total, 57 pregnant women with COVID-19 were included, 17 (28.9%) of which had severe COVID-19;there were 3 (5.30%) maternal deaths. Pregnant women with severe COVID-19 had higher levels of carbonylated proteins (5782 pmol vs. 6651 pmol;p = 0.024) and total antioxidant capacity (40.1 pmol vs. 56.1 pmol;p = 0.001) than women with non-severe COVID-19. TAC was negatively correlated with ANG-II (p < 0.0001) and MDA levels (p < 0.0001) and positively with the sFlt-1/PlGF ratio (p = 0.027). Conclusions: In pregnant women, severe COVID-19 is associated with an increase in protein oxidative damage and total antioxidant capacity as a possible counterregulatory mechanism.

Maternal Death by COVID-19 Associated with Elevated Troponin T Levels.

Cardiomyocyte injury and troponin T elevation has been reported within COVID-19 patients and are associated with a worse prognosis. Limited data report this association among COVID-19 pregnant patients. OBJECTIVE: We aimed to analyze the association between troponin T levels in severe COVID-19 pregnant women and risk of viral sepsis, intensive care unit (ICU) admission, or maternal death. METHODS: We performed a prospective cohort of all obstetrics emergency admissions from a Mexican National Institute. All pregnant women diagnosed by reverse transcription-polymerase chain reaction (RT-qPCR) for SARS-CoV-2 infection between October 2020 and May 2021 were included. Clinical data were collected, and routine blood samples were obtained at hospital admission. Seric troponin T was measured at admission. RESULTS: From 87 included patients, 31 (35.63%) had severe COVID-19 pneumonia, and 6 (6.89%) maternal deaths. ROC showed a significant relationship between troponin T and maternal death (AUC 0.979, CI 0.500-1.000). At a cutoff point of 7 ng/mL the detection rate for severe pneumonia was 83.3% (95%CI: 0.500-0.100) at 10% false-positive rate. CONCLUSION: COVID-19 pregnant women with elevated levels of troponin T present a higher risk of death and severe pneumonia.

Changing Attitudes towards Occupational Medicine with Blended Learning Methods Is Possible among Medical Students in Spain: A Longitudinal Study.

Medical students generally express a low interest in Occupational Medicine. We aimed to assess the attitudes and changes in attitudes of students towards this area after completing a course on Occupational Medicine in two Medical Universities in Spain (Zaragoza and Castilla-La Mancha). The teaching method included blended learning as a model that used online virtual patient platforms (CASUS) and/or EMUTOM, as well as traditional methods such as face-to-face teaching. A total of 526 students (98 of whom attended the University of Castilla-La Mancha) participated during three academic years (2015-2016, 2016-2017 and 2017-2018). The validation of the questionnaire was carried out using reliability, exploratory and confirmatory factor analysis. For the analysis of internal consistency and discrimination, Cronbach's alpha was used. The adequacy of the factor analysis was measured by means of KMO, and a correlation matrix was examined by means of Bartlett's test of sphericity. To identify differences between students before and after completing the course, the Mann-Whitney U-test for independent samples was used. Our results show that despite a negative or neutral attitude towards Occupational Medicine, the acquisition of competences and skills in this area and their training were recognized as fundamental for their future professional performance as doctors in any specialty.

Antimalarials exert a cardioprotective effect in lupus patients: Insights from the Spanish Society of Rheumatology Lupus Register (RELESSER) analysis of factors associated with heart failure.

BACKGROUND/OBJECTIVES: Factors associated with chronic heart failure (CHF) in patients with systemic lupus erythematosus (SLE) have received little attention. Recent data on the use of hydroxychloroquine in the treatment of SARS-CoV-2 infection have cast doubt on its cardiac safety. The factors associated with CHF, including therapy with antimalarials, were analyzed in a large multicenter SLE cohort. METHODS: Cross-sectional study including all patients with SLE (ACR-1997 criteria) included in the Spanish Society of Rheumatology Lupus Register (RELESSER), based on historically gathered data. Patients with CHF prior to diagnosis of SLE were excluded. A multivariable analysis exploring factors associated with CHF was conducted. RESULTS: The study population comprised 117 patients with SLE (ACR-97 criteria) and CHF and 3,506 SLE controls. Ninety percent were women. Patients with CHF were older and presented greater SLE severity, organ damage, and mortality than those without CHF. The multivariable model revealed the factors associated with CHF to be ischemic heart disease (7.96 [4.01-15.48], p < 0.0001), cardiac arrhythmia (7.38 [4.00-13.42], p < 0.0001), pulmonary hypertension (3.71 [1.84-7.25], p < 0.0002), valvulopathy (6.33 [3.41-11.62], p < 0.0001), non-cardiovascular damage (1.29 [1.16-1.44], p < 0.000) and calcium/vitamin D treatment (5.29 [2.07-16.86], p = 0.0015). Female sex (0.46 [0.25-0.88], p = 0.0147) and antimalarials (0.28 [0.17-0.45], p < 0.000) proved to be protective factors. CONCLUSIONS: Patients with SLE and CHF experience more severe SLE. Treatment with antimalarials appears to confer a cardioprotective effect.

FACE MASK CONTAMINATION DURING COVID-19 PANDEMIA. A STUDY ON PATIENTS RECEIVING INTRAVITREAL INJECTIONS.

PURPOSE: To investigate the bacterial growth in the surgical face masks used by patients who received intravitreal injections and study the effect of povidone-iodine on the periocular area (PA) of masks. METHODS: Forty patients who attended for intravitreal injections were divided in those with less (<4 hours) and more (>4 hours) than 4 hours of mask use. Each group was divided depending on the application or not of povidone-iodine in the PA of the mask. Bacterial load was studied on PA and mouth area samples. RESULTS: The bacterial load in the PA was higher in the >4 hours group compared with the <4 hours group (13.2 vs. 48.75 colony-forming units/µL; P = 0.03). The contamination in the PA significantly decreased after applying povidone-iodine in the >4 hours group (P = 0.01). The use or not of povidone-iodine was strongly correlated to a positive culture (OR = 9.0, P = 0.00. CI 1.63-49.44). CONCLUSION: Surgical face masks worn for more than 4 hours present higher contamination in the PA than those with less use. Bacterial load in the PA is reduced with povidone-iodine on masks used for more than 4 hours. This contamination should be considered in the asepsis protocol of intravitreal injections.

Novel Ratio Soluble Fms-like Tyrosine Kinase-1/Angiotensin-II (sFlt-1/ANG-II) in Pregnant Women Is Associated with Critical Illness in COVID-19.

BACKGROUND: In healthy pregnancies, components of the Renin-Angiotensin system (RAS) are present in the placental villi and contribute to invasion, migration, and angiogenesis. At the same time, soluble fms-like tyrosine kinase 1 (sFlt-1) production is induced after binding of ANG-II to its receptor (AT-1R) in response to hypoxia. As RAS plays an essential role in the pathogenesis of COVID-19, we hypothesized that angiogenic marker (sFlt-1) and RAS components (ANG-II and ACE-2) may be related to adverse outcomes in pregnant women with COVID-19; Methods: Prospective cohort study. Primary outcome was severe pneumonia. Secondary outcomes were ICU admission, intubation, sepsis, and death. Spearman's Rho test was used to analyze the correlation between sFlt-1 and ANG-II levels. The sFlt-1/ANG-II ratio was determined and the association with each adverse outcome was explored by logistic regression analysis and the prediction was assessed using receiver-operating-curve (ROC); Results: Among 80 pregnant women with COVID-19, the sFlt-1/ANG-II ratio was associated with an increased probability of severe pneumonia (odds ratio [OR]: 1.31; p = 0.003), ICU admission (OR: 1.05; p = 0.007); intubation (OR: 1.09; p = 0.008); sepsis (OR: 1.04; p = 0.008); and death (OR: 1.04; p = 0.018); Conclusion: sFlt-1/ANG-II ratio is a good predictor of adverse events such as pneumonia, ICU admission, intubation, sepsis, and death in pregnant women with COVID-19.

Use of EHRs in a Tertiary Hospital During COVID-19 Pandemic: A Multi-Purpose Approach Based on Standards.

This work aims to describe how EHRs have been used to meet the needs of healthcare providers and researchers in a 1,300-beds tertiary Hospital during COVID-19 pandemic. For this purpose, essential clinical concepts were identified and standardized with LOINC and SNOMED CT. After that, these concepts were implemented in EHR systems and based on them, data tools, such as clinical alerts, dynamic patient lists and a clinical follow-up dashboard, were developed for healthcare support. In addition, these data were incorporated into standardized repositories and COVID-19 databases to improve clinical research on this new disease. In conclusion, standardized EHRs allowed implementation of useful multi- purpose data resources in a major Hospital in the course of the pandemic.

Resilience and psychological distress in pregnant women during quarantine due to the COVID-19 outbreak in Spain: a multicentre cross-sectional online survey.

PURPOSE: To examine the prevalence of depressive and anxiety symptoms and the corresponding risk factors among pregnant women during the confinement due to the COVID-19 outbreak in Spain. MATERIALS AND METHODS: Between 15 April and 14 May 2020, a multicentre cross-sectional survey was performed to study depression, anxiety and resilience in a sample of Spanish pregnant women during the lockdown set up by the Government in response to COVID-19 pandemic outbreak. We designed an anonymous online self-administered questionnaire (https://bit.ly/34RRpq1) that included the Spanish validated versions of the Edinburgh Postpartum Depression Scale (EPDS), the State-Trait Anxiety Inventory (STAI) and the Connor-Davidson Resilience 10-items Scale (CD-RISC-10). RESULTS: A total of 514 pregnant women completed the survey. 72.8% had been confined < 40 days and 27.2% between 41 and 60 days. 182 (35.4%) participants scored over 10, with 21.3% scoring over 13 (75th Percentile) in depressive symptoms rates. We found high trait and anxiety scores, with 223 (43.4%) and 227 (44.2%) pregnant women scoring over the trait and state mean scores. Neither depression, anxiety or resilience levels showed any significant correlation with the length of confinement. We found low CD-RISC-10 scores. CONCLUSIONS: We found a high prevalence of depression and anxiety symptoms during the quarantine, although we did not find an increased prevalence of psychological distress according to length of home confinement. Resilience correlated negatively with depression and anxiety.

Telerehabilitation Intervention in Patients with COVID-19 after Hospital Discharge to Improve Functional Capacity and Quality of Life. Study Protocol for a Multicenter Randomized Clinical Trial.

COVID-19 can cause important sequels in the respiratory system and frequently presents loss of strength, dyspnea, polyneuropathies and multi-organic affectation. Physiotherapy interventions acquire a fundamental role in the recovery of the functions and the quality of life. Regarding the recovery phases after hospital discharge, the current evidence available is very preliminary. Telerehabilitation is presented as a promising complementary treatment method to standard physiotherapy. The main objective of this research is to evaluate the effectiveness of a personalized telerehabilitation intervention after discharge from hospital for the improvement of functional capacity and quality of life compared to a program of health education and/or care in a rehabilitation center. As secondary objectives, to identify the satisfaction and perception of patients with the telerehabilitation intervention and the presence of barriers to its implementation, as well as to evaluate the cost-effectiveness from the perspective of the health system. This study protocol will be carried out through a single blind multicenter randomized clinical trial in the south of Spain. We hypothesize that the implementation of a telerehabilitation program presents results not inferior to those obtained with the current standard intervention. If the hypothesis is confirmed, it would be an opportunity to define new policies and interventions to address this disease and its consequences. Trial registration NCT04742946.