Background More than 20% of hospitalized patients with coronavirus disease 2019 (COVID-19) develop acute respiratory distress syndrome (ARDS) requiring intensive care unit (ICU) admission. The long-term respiratory sequelae in ICU survivors remain unclear. Research question what are the major long-term pulmonary sequelae in critical COVID-19 survivors? Study Design and Methods Consecutive patients with COVID-19 requiring ICU admission were recruited and evaluated 3 months after hospitalization discharge. The follow-up comprised symptom and quality of life, anxiety and depression questionnaires, pulmonary function tests, exercise test (6-minute walking test (6MWT)) and chest computed tomography (CT). Results 125 ICU patients with ARDS secondary to COVID-19 were recruited between March and June 2020. At the 3-month follow-up, 62 patients were available for pulmonary evaluation. The most frequent symptoms were dyspnea (46.7%), and cough (34.4%). Eighty-two percent of patients showed a lung diffusing capacity of less than 80%. The median (IQR) distance in the 6MWT was 400 (362;440) meters. CT scans were abnormal in 70.2% of patients, showing reticular lesions in 49.1% and fibrotic patterns in 21.1%. Patients with more severe alterations on chest CT had worse pulmonary function and presented more degrees of desaturation in the 6MWT. Factors associated with the severity of lung damage on chest CT were age and length of invasive mechanical ventilation during the ICU stay. Interpretation Pulmonary structural abnormalities and functional impairment are highly prevalent in surviving ICU patients with ARDS secondary to COVID-19 3 months after hospital discharge. Pulmonary evaluation should be considered for all critical COVID-19 survivors 3 months post discharge.

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Question We evaluated whether the time between first respiratory support and intubation of patients receiving invasive mechanical ventilation (IMV) due to COVID-19 was associated with mortality or pulmonary sequelae. Materials and methods Prospective cohort of critical COVID-19 patients on IMV. Patients were classified as early intubation if they were intubated within the first 48 h from the first respiratory support or delayed intubation if they were intubated later. Surviving patients were evaluated after hospital discharge. Results We included 205 patients (140 with early IMV and 65 with delayed IMV). The median [p25;p75] age was 63 [56.0; 70.0] years, and 74.1% were male. The survival analysis showed a significant increase in the risk of mortality in the delayed group with an adjusted hazard ratio (HR) of 2.45 (95% CI 1.29–4.65). The continuous predictor time to IMV showed a nonlinear association with the risk of in-hospital mortality. A multivariate mortality model showed that delay of IMV was a factor associated with mortality (HR of 2.40; 95% CI 1.42–4.1). During follow-up, patients in the delayed group showed a worse DLCO (mean difference of − 10.77 (95% CI − 18.40 to − 3.15), with a greater number of affected lobes (+ 1.51 [95% CI 0.89–2.13]) and a greater TSS (+ 4.35 [95% CI 2.41–6.27]) in the chest CT scan. Conclusions Among critically ill patients with COVID-19 who required IMV, the delay in intubation from the first respiratory support was associated with an increase in hospital mortality and worse pulmonary sequelae during follow-up.

The long-term clinical management and evolution of a cohort of critical COVID-19 survivors have not been described in detail. We report a prospective observational study of COVID-19 patients admitted to the ICU between March and August 2020. The follow-up in a post-COVID consultation comprised symptoms, pulmonary function tests, the 6-minute walking test (6MWT), and chest computed tomography (CT). Additionally, questionnaires to evaluate the prevalence of post-COVID-19 syndrome were administered at 1 year. A total of 181 patients were admitted to the ICU during the study period. They were middle-aged (median [IQR] of 61 [52;67]) and male (66.9%), with a median ICU stay of 9 (5–24.2) days. 20% died in the hospital, and 39 were not able to be included. A cohort of 105 patients initiated the follow-up. At 1 year, 32.2% persisted with respiratory alterations and needed to continue the follow-up. Ten percent still had moderate/severe lung diffusion (DLCO) involvement (<60%), and 53.7% had a fibrotic pattern on CT. Moreover, patients had a mean (SD) number of symptoms of 5.7 ± 4.6, and 61.3% met the criteria for post-COVID syndrome at 1 year. During the follow-up, 46 patients were discharged, and 16 were transferred to other consultations. Other conditions, such as emphysema (21.6%), COPD (8.2%), severe neurocognitive disorders (4.1%), and lung cancer (1%) were identified. A high use of health care resources is observed in the first year. In conclusion, one-third of critically ill COVID-19 patients need to continue follow-up beyond 1 year, due to abnormalities on DLCO, chest CT, or persistent symptoms.

OBJECTIVES: To evaluate the sleep and circadian rest-activity pattern of critical COVID-19 survivors 3 months after hospital discharge. DESIGN: Observational, prospective study. SETTING: Single-center study. PATIENTS: One hundred seventy-two consecutive COVID-19 survivors admitted to the ICU with acute respiratory distress syndrome. INTERVENTIONS: Seven days of actigraphy for sleep and circadian rest-activity pattern assessment; validated questionnaires; respiratory tests at the 3-month follow-up. MEASUREMENTS AND MAIN RESULTS: The cohort included 172 patients, mostly males (67.4%) with a median (25th–75th percentile) age of 61.0 years (52.8–67.0 yr). The median number of days at the ICU was 11.0 (6.00–24.0), and 51.7% of the patients received invasive mechanical ventilation (IMV). According to the Pittsburgh Sleep Quality Index (PSQI), 60.5% presented poor sleep quality 3 months after hospital discharge, which was further confirmed by actigraphy. Female sex was associated with an increased score in the PSQI ( p < 0.05) and IMV during ICU stay was able to predict a higher fragmentation of the rest-activity rhythm at the 3-month follow-up ( p < 0.001). Furthermore, compromised mental health measured by the Hospital Anxiety and Depression Scale was associated with poor sleep quality ( p < 0.001). CONCLUSIONS: Our findings highlight the importance of considering sleep and circadian health after hospital discharge. Within this context, IMV during the ICU stay could aid in predicting an increased fragmentation of the rest-activity rhythm at the 3-month follow-up. Furthermore, compromised mental health could be a marker for sleep disruption at the post-COVID period.

Huntington’s disease (HD) is a neurological disorder characterized by motor disturbances. HD pathology is most prominent in the striatum, the central hub of the basal ganglia. The cerebral cortex is the main striatal afferent, and progressive cortico-striatal disconnection characterizes HD. We mapped striatal network dysfunction in HD mice to ultimately modulate the activity of a specific cortico-striatal circuit to ameliorate motor symptoms and recover synaptic plasticity. Multimodal MRI in vivo indicates cortico-striatal and thalamo-striatal functional network deficits and reduced glutamate/glutamine ratio in the striatum of HD mice. Moreover, optogenetically-induced glutamate release from M2 cortex terminals in the dorsolateral striatum (DLS) was undetectable in HD mice and striatal neurons show blunted electrophysiological responses. Remarkably, repeated M2-DLS optogenetic stimulation normalized motor behavior in HD mice and evoked a sustained increase of synaptic plasticity. Overall, these results reveal that selective stimulation of the M2-DLS pathway can become an effective therapeutic strategy in HD.

BackgroundThe pathophysiology of COVID-19-related critical illness is not completely understood. Here, we analyzed the microRNA (miRNA) profile of bronchial aspirate (BAS) samples from COVID-19 and non-COVID-19 patients admitted to the ICU to identify prognostic biomarkers of fatal outcomes and to define molecular pathways involved in the disease and adverse events.MethodsTwo patient populations were included (n = 89): (i) a study population composed of critically ill COVID-19 and non-COVID-19 patients; (ii) a prospective study cohort composed of COVID-19 survivors and non-survivors among patients assisted by invasive mechanical ventilation (IMV). BAS samples were obtained by bronchoaspiration during the ICU stay. The miRNA profile was analyzed using RT-qPCR. Detailed biomarker and bioinformatics analyses were performed.ResultsThe deregulation in five miRNA ratios (miR-122-5p/miR-199a-5p, miR-125a-5p/miR-133a-3p, miR-155-5p/miR-486-5p, miR-214-3p/miR-222-3p, and miR-221-3p/miR-27a-3p) was observed when COVID-19 and non-COVID-19 patients were compared. In addition, five miRNA ratios segregated between ICU survivors and nonsurvivors (miR-1-3p/miR-124-3p, miR-125b-5p/miR-34a-5p, miR-126-3p/miR-16-5p, miR-199a-5p/miR-9-5p, and miR-221-3p/miR-491-5p). Through multivariable analysis, we constructed a miRNA ratio-based prediction model for ICU mortality that optimized the best combination of miRNA ratios (miR-125b-5p/miR-34a-5p, miR-199a-5p/miR-9-5p, and miR-221-3p/miR-491-5p). The model (AUC 0.85) and the miR-199a-5p/miR-9-5p ratio (AUC 0.80) showed an optimal discrimination value and outperformed the best clinical predictor for ICU mortality (days from first symptoms to IMV initiation, AUC 0.73). The survival analysis confirmed the usefulness of the miRNA ratio model and the individual ratio to identify patients at high risk of fatal outcomes following IMV initiation. Functional enrichment analyses identified pathological mechanisms implicated in fibrosis, coagulation, viral infections, immune responses and inflammation.ConclusionsCOVID-19 induces a specific miRNA signature in BAS from critically ill patients. In addition, specific miRNA ratios in BAS samples hold individual and collective potential to improve risk-based patient stratification following IMV initiation in COVID-19-related critical illness. The biological role of the host miRNA profiles may allow a better understanding of the different pathological axes of the disease.

The objective was to describe the clinical characteristics and outcomes of hospitalized COVID-19 patients during the two different epidemic periods. Prospective, observational, cohort study of hospitalized COVID-19. A total of 421 consecutive patients were included, 188 during the first period (March-May 2020) and 233 in the second wave (July-December 2020). Clinical, epidemiological, prognostic and therapeutic data were compared. Patients of the first outbreak were older and more comorbid, presented worse PaO2/FiO2 ratio and an increased creatinine and D-dimer levels at hospital admission. The hospital stay was shorter (14.5[8;29] vs 8[6;14] days, p<0.001), ICU admissions (31.9% vs 13.3%, p<0.001) and the number of patients who required mechanical ventilation (OR = 0.12 [0.05–10.26]; p<0.001) were reduced. There were no significant differences in hospital and 30-day after discharge mortality (adjusted HR = 1.56; p = 0.1056) or hospital readmissions. New treatments and clinical strategies appear to improve hospital length, ICU admissions and the requirement for mechanical ventilation. However, we did not observe differences in mortality or readmissions.