Cortical miR-709 links glutamatergic signaling to NREM sleep EEG slow waves in an activity-dependent manner.

MicroRNAs (miRNAs) are key post-transcriptional regulators of gene expression that have been implicated in a plethora of neuronal processes. Nevertheless, their role in regulating brain activity in the context of sleep has so far received little attention. To test their involvement, we deleted mature miRNAs in post-mitotic neurons at two developmental ages, i.e., in early adulthood using conditional Dicer knockout (cKO) mice and in adult mice using an inducible conditional Dicer cKO (icKO) line. In both models, electroencephalographic (EEG) activity was affected and the response to sleep deprivation (SD) altered; while the rapid-eye-movement sleep (REMS) rebound was compromised in both, the increase in EEG delta (1 to 4 Hz) power during non-REMS (NREMS) was smaller in cKO mice and larger in icKO mice compared to controls. We subsequently investigated the effects of SD on the forebrain miRNA transcriptome and found that the expression of 48 miRNAs was affected, and in particular that of the activity-dependent miR-709. In vivo inhibition of miR-709 in the brain increased EEG power during NREMS in the slow-delta (0.75 to 1.75 Hz) range, particularly after periods of prolonged wakefulness. Transcriptome analysis of primary cortical neurons in vitro revealed that miR-709 regulates genes involved in glutamatergic neurotransmission. A subset of these genes was also affected in the cortices of sleep-deprived, miR-709-inhibited mice. Our data implicate miRNAs in the regulation of EEG activity and indicate that miR-709 links neuronal activity during wakefulness to brain synchrony during sleep through the regulation of glutamatergic signaling.

Impact of dementia on 30-, 180-, and 365-day mortality during the first pandemic wave in older adults seen in spanish emergency departments diagnosed with or without COVID-19.

OBJECTIVES: To assess whether dementia is an independent predictor of death after a hospital emergency department (ED) visit by older adults with or without a COVID-19 diagnosis during the first pandemic wave. METHOD: We used data from the EDEN-Covid (Emergency Department and Elderly Needs during Covid) cohort formed by all patients ≥65 years seen in 52 Spanish EDs from March 30 to April 5, 2020. The association of prior history of dementia with mortality at 30, 180 and 365 d was evaluated in the overall sample and according to a COVID-19 or non COVID diagnosis. RESULTS: We included 9,770 patients aged 78.7 ± 8.3 years, 51.1% men, 1513 (15.5%) subjects with prior history of dementia and 3055 (31.3%) with COVID-19 diagnosis. 1399 patients (14.3%) died at 30 d, 2008 (20.6%) at 180 days and 2456 (25.1%) at 365 d. The adjusted Hazard Ratio (aHR) for age, sex, comorbidity, disability and diagnosis for death associated with dementia were 1.16 (95% CI 1.01-1.34) at 30 d; 1.15 at 180 d (95% CI 1.03-1.30) and 1.19 at 365 d (95% CI 1.07-1.32), p < .001. In patients with COVID-19, the aHR were 1.26 (95% CI: 1.04-1.52) at 30 days; 1.29 at 180 d (95% CI: 1.09-1.53) and 1.35 at 365 d (95% CI: 1.15-1.58). CONCLUSION: Dementia in older adults attending Spanish EDs during the first pandemic wave was independently associated with 30-, 180- and 365-day mortality. This impact was lower when adjusted for age, sex, comorbidity and disability, and was greater in patients diagnosed with COVID-19.

Randomised controlled trial of a prognostic assessment and management pathway to reduce the length of hospital stay in normotensive patients with acute pulmonary embolism.

BACKGROUND: The length of hospital stay (LOS) for acute pulmonary embolism (PE) varies considerably. Whether the upfront use of a PE prognostic assessment and management pathway is effective in reducing the LOS remains unknown. METHODS: We conducted a randomised controlled trial of adults hospitalised for acute PE: patients were assigned either to a prognostic assessment and management pathway involving risk stratification followed by predefined criteria for mobilisation and discharge (intervention group) or to usual care (control group). The primary end-point was LOS. The secondary end-points were the cost of prognostic tests and of hospitalisation, and 30-day clinical outcomes. RESULTS: Of 500 patients who underwent randomisation, 498 were included in the modified intention-to-treat analysis. The median LOS was 4.0 days (interquartile range (IQR) 3.7-4.2 days) in the intervention group and 6.1 days (IQR 5.7-6.5 days) in the control group (p<0.001). The mean total cost of prognostic tests was EUR 174.76 in the intervention group, compared with EUR 233.12 in the control group (mean difference EUR -58.37, 95% CI EUR -84.34- to -32.40). The mean total hospitalisation cost per patient was EUR 2085.66 in the intervention group, compared with EUR 3232.97 in the control group (mean difference EUR -1147.31, 95% CI EUR -1414.97- to -879.65). No significant differences were observed in 30-day readmission (4.0% versus 4.8%), all-cause mortality (2.4% versus 2.0%) or PE-related mortality (0.8% versus 1.2%) rates. CONCLUSIONS: The use of a prognostic assessment and management pathway was effective in reducing the LOS for acute PE.

Incidence, clinical, risk factors and outcomes of Guillain-Barré in Covid-19.

We diagnosed 11 Guillain-Barré syndrome (GBS) cases among 71,904 COVID patients attended at 61 Spanish emergency departments (EDs) during the 2-month pandemic peak. The relative frequency of GBS among ED patients was higher in COVID (0.15‰) than non-COVID (0.02‰) patients (odds ratio [OR] = 6.30, 95% confidence interval [CI] = 3.18-12.5), as was the standardized incidence (9.44 and 0.69 cases/100,000 inhabitant-years, respectively, OR = 13.5, 95% CI = 9.87-18.4). Regarding clinical characteristics, olfactory-gustatory disorders were more frequent in COVID-GBS than non-COVID-GBS (OR = 27.59, 95% CI = 1.296-587) and COVID-non-GBS (OR = 7.875, 95% CI = 1.587-39.09) patients. Although COVID-GBS patients were more frequently admitted to intensive care, mortality was not increased versus control groups. Our results suggest SARS-CoV-2 could be another viral infection causing GBS. ANN NEUROL 2021;89:598-603.

Incidence, Clinical Characteristics, Risk Factors, and Outcomes of Upper Gastrointestinal Bleeding in Patients With COVID-19: Results of the UMC-19-S12.

OBJECTIVE: The authors investigated the incidence, risk factors, clinical characteristics, and outcomes of upper gastrointestinal bleeding (UGB) in patients with coronavirus disease 2019 (COVID-19), who were attending the emergency department (ED), before hospitalization. METHODS: We retrospectively reviewed all COVID-19 patients diagnosed with UGB in 62 Spanish EDs (20% of Spanish EDs, case group) during the first 2 months of the COVID-19 outbreak. We formed 2 control groups: COVID-19 patients without UGB (control group A) and non-COVID-19 patients with UGB (control group B). Fifty-three independent variables and 4 outcomes were compared between cases and controls. RESULTS: We identified 83 UGB in 74,814 patients with COVID-19 who were attending EDs (1.11%, 95% CI=0.88-1.38). This incidence was lower compared with non-COVID-19 patients [2474/1,388,879, 1.78%, 95% confidence interval (CI)=1.71-1.85; odds ratio (OR)=0.62; 95% CI=0.50-0.77]. Clinical characteristics associated with a higher risk of COVID-19 patients presenting with UGB were abdominal pain, vomiting, hematemesis, dyspnea, expectoration, melena, fever, cough, chest pain, and dysgeusia. Compared with non-COVID-19 patients with UGB, COVID-19 patients with UGB more frequently had fever, cough, expectoration, dyspnea, abdominal pain, diarrhea, interstitial lung infiltrates, and ground-glass lung opacities. They underwent fewer endoscopies in the ED (although diagnoses did not differ between cases and control group B) and less endoscopic treatment. After adjustment for age and sex, cases showed a higher in-hospital all-cause mortality than control group B (OR=2.05, 95% CI=1.09-3.86) but not control group A (OR=1.14, 95% CI=0.59-2.19) patients. CONCLUSIONS: The incidence of UGB in COVID-19 patients attending EDs was lower compared with non-COVID-19 patients. Digestive symptoms predominated over respiratory symptoms, and COVID-19 patients with UGB underwent fewer gastroscopies and endoscopic treatments than the general population with UGB. In-hospital mortality in COVID-19 patients with UGB was increased compared with non-COVID patients with UGB, but not compared with the remaining COVID-19 patients.

Pulmonary embolism in patients with COVID-19: incidence, risk factors, clinical characteristics, and outcome.

AIMS: We investigated the incidence, risk factors, clinical characteristics, and outcomes of pulmonary embolism (PE) in patients with COVID-19 attending emergency departments (EDs), before hospitalization. METHODS AND RESULTS: We retrospectively reviewed all COVID-19 patients diagnosed with PE in 62 Spanish EDs (20% of Spanish EDs, case group) during the first COVID-19 outbreak. COVID-19 patients without PE and non-COVID-19 patients with PE were included as control groups. Adjusted comparisons for baseline characteristics, acute episode characteristics, and outcomes were made between cases and randomly selected controls (1:1 ratio). We identified 368 PE in 74 814 patients with COVID-19 attending EDs (4.92‰). The standardized incidence of PE in the COVID-19 population resulted in 310 per 100 000 person-years, significantly higher than that observed in the non-COVID-19 population [35 per 100 000 person-years; odds ratio (OR) 8.95 for PE in the COVID-19 population, 95% confidence interval (CI) 8.51-9.41]. Several characteristics in COVID-19 patients were independently associated with PE, the strongest being D-dimer >1000 ng/mL, and chest pain (direct association) and chronic heart failure (inverse association). COVID-19 patients with PE differed from non-COVID-19 patients with PE in 16 characteristics, most directly related to COVID-19 infection; remarkably, D-dimer >1000 ng/mL, leg swelling/pain, and PE risk factors were significantly less present. PE in COVID-19 patients affected smaller pulmonary arteries than in non-COVID-19 patients, although right ventricular dysfunction was similar in both groups. In-hospital mortality in cases (16.0%) was similar to COVID-19 patients without PE (16.6%; OR 0.96, 95% CI 0.65-1.42; and 11.4% in a subgroup of COVID-19 patients with PE ruled out by scanner, OR 1.48, 95% CI 0.97-2.27), but higher than in non-COVID-19 patients with PE (6.5%; OR 2.74, 95% CI 1.66-4.51). Adjustment for differences in baseline and acute episode characteristics and sensitivity analysis reported very similar associations. CONCLUSIONS: PE in COVID-19 patients at ED presentation is unusual (about 0.5%), but incidence is approximately ninefold higher than in the general (non-COVID-19) population. Moreover, risk factors and leg symptoms are less frequent, D-dimer increase is lower and emboli involve smaller pulmonary arteries. While PE probably does not increase the mortality of COVID-19 patients, mortality is higher in COVID-19 than in non-COVID-19 patients with PE.

Incidence, Clinical Characteristics, Risk Factors and Outcomes of Acute Coronary Syndrome in Patients With COVID-19: Results of the UMC-19-S1010.

BACKGROUND: There is a lack of knowledge about the real incidence of acute coronary syndrome (ACS) in patients with COVID-19, their clinical characteristics, and their prognoses. OBJECTIVE: We investigated the incidence, clinical characteristics, risk factors, and outcomes of ACS in patients with COVID-19 in the emergency department. METHODS: We retrospectively reviewed all COVID-19 patients diagnosed with ACS in 62 Spanish emergency departments between March and April 2020 (the first wave of COVID-19). We formed 2 control groups: COVID-19 patients without ACS (control A) and non-COVID-19 patients with ACS (control B). Unadjusted comparisons between cases and control subjects were performed regarding 58 characteristics and outcomes. RESULTS: We identified 110 patients with ACS in 74,814 patients with COVID-19 attending the ED (1.48% [95% confidence interval {CI} 1.21-1.78%]). This incidence was lower than that observed in non-COVID-19 patients (3.64% [95% CI 3.54-3.74%]; odds ratio [OR] 0.40 [95% CI 0.33-0.49]). The clinical characteristics of patients with COVID-19 associated with a higher risk of presenting ACS were: previous coronary artery disease, age ≥60 years, hypertension, chest pain, raised troponin, and hypoxemia. The need for hospitalization and admission to intensive care and in-hospital mortality were higher in cases than in control group A (adjusted OR [aOR] 6.36 [95% CI 1.84-22.1], aOR 4.63 [95% CI 1.88-11.4], and aOR 2.46 [95% CI 1.15-5.25]). When comparing cases with control group B, the aOR of admission to intensive care was 0.41 (95% CI 0.21-0.80), while the aOR for in-hospital mortality was 5.94 (95% CI 2.84-12.4). CONCLUSIONS: The incidence of ACS in patients with COVID-19 attending the emergency department was low, around 1.48%, but could be increased in some circumstances. Patients with COVID-19 with ACS had a worse prognosis than control subjects with higher in-hospital mortality.

A case-control, multicentre study of consecutive patients with COVID-19 and acute (myo)pericarditis: incidence, risk factors, clinical characteristics and outcomes.

OBJECTIVE: To estimate incidence, risk factors, clinical characteristics and outcomes of acute (myo)pericarditis (AMP) in patients with COVID-19. METHODS: Case-control, retrospective review, consecutive case inclusion performed in 62 Spanish EDs. All COVID-19 patients with AMP (cases) were compared in clinical characteristics and outcomes with COVID-19 without AMP (control group A) and non-COVID patients with AMP (control group B). We estimated unadjusted standardised incidence (SI, not adjusted by population's age/sex) of AMP in COVID-19 and non-COVID populations (per 100 000/year). RESULTS: We identified 67 AMP in COVID-19 patients (SI=56.5, OR with respect to non-COVID patients=4.43, 95% CI=3.98 to 4.94). Remarkably, COVID-19 cases presented with chest pain less frequently than non-COVID patients and had less typical ECG changes, higher NT-proBNP (N-terminal prohormone of brain natriuretic peptide), more left and right ventricular dysfunction in echocardiography and more need of inotropic/vasopressor drugs. Admission to intensive care was higher than control group A (OR=3.22, 95% CI=1.43 to 7.23), and in-hospital mortality was higher than control group B (OR=7.75, 95% CI=2.77 to 21.7). CONCLUSION: AMP is unusual as a form of COVID-19 presentation (about 1‰ cases), but SI is more than fourfold higher than non-COVID population, and it is less symptomatic, more severe and has higher in-hospital mortality; therefore, rapid recognition, echocardiographic assessment of myopericardial inflammation/dysfunction and treatment with vasoactive drugs when needed are recommended in AMP in patients with COVID-19.

Socio-Demographic Health Determinants Are Associated with Poor Prognosis in Spanish Patients Hospitalized with COVID-19.

INTRODUCTION: Social vulnerability is a known determinant of health in respiratory diseases. Our aim was to identify whether there are socio-demographic factors among COVID-19 patients hospitalized in Spain and their potential impact on health outcomes during the hospitalization. METHODS: A multicentric retrospective case series study based on administrative databases that included all COVID-19 cases admitted in 19 Spanish hospitals from 1 March to 15 April 2020. Socio-demographic data were collected. Outcomes were critical care admission and in-hospital mortality. RESULTS: We included 10,110 COVID-19 patients admitted to 18 Spanish hospitals (median age 68 (IQR 54-80) years old; 44.5% female; 14.8% were not born in Spain). Among these, 779 (7.7%) cases were admitted to critical care units and 1678 (16.6%) patients died during the hospitalization. Age, male gender, being immigrant, and low hospital saturation were independently associated with being admitted to an intensive care unit. Age, male gender, being immigrant, percentile of average per capita income, and hospital experience were independently associated with in-hospital mortality. CONCLUSIONS: Social determinants such as residence in low-income areas and being born in Latin American countries were associated with increased odds of being admitted to an intensive care unit and of in-hospital mortality. There was considerable variation in outcomes between different Spanish centers.

Incidence, clinical characteristics, risk factors and outcomes of meningoencephalitis in patients with COVID-19.

We investigated the incidence, clinical characteristics, risk factors, and outcome of meningoencephalitis (ME) in patients with COVID-19 attending emergency departments (ED), before hospitalization. We retrospectively reviewed all COVID patients diagnosed with ME in 61 Spanish EDs (20% of Spanish EDs, COVID-ME) during the COVID pandemic. We formed two control groups: non-COVID patients with ME (non-COVID-ME) and COVID patients without ME (COVID-non-ME). Unadjusted comparisons between cases and controls were performed regarding 57 baseline and clinical characteristics and 4 outcomes. Cerebrospinal fluid (CSF) biochemical and serologic findings of COVID-ME and non-COVID-ME were also investigated. We identified 29 ME in 71,904 patients with COVID-19 attending EDs (0.40‰, 95%CI=0.27-0.58). This incidence was higher than that observed in non-COVID patients (150/1,358,134, 0.11‰, 95%CI=0.09-0.13; OR=3.65, 95%CI=2.45-5.44). With respect to non-COVID-ME, COVID-ME more frequently had dyspnea and chest X-ray abnormalities, and neck stiffness was less frequent (OR=0.3, 95%CI=0.1-0.9). In 69.0% of COVID-ME, CSF cells were predominantly lymphocytes, and SARS-CoV-2 antigen was detected by RT-PCR in 1 patient. The clinical characteristics associated with a higher risk of presenting ME in COVID patients were vomiting (OR=3.7, 95%CI=1.4-10.2), headache (OR=24.7, 95%CI=10.2-60.1), and altered mental status (OR=12.9, 95%CI=6.6-25.0). COVID-ME patients had a higher in-hospital mortality than non-COVID-ME patients (OR=2.26; 95%CI=1.04-4.48), and a higher need for hospitalization (OR=8.02; 95%CI=1.19-66.7) and intensive care admission (OR=5.89; 95%CI=3.12-11.14) than COVID-non-ME patients. ME is an unusual form of COVID presentation (<0.5‰ cases), but is more than 4-fold more frequent than in non-COVID patients attending the ED. As the majority of these MEs had lymphocytic predominance and in one patient SARS-CoV-2 antigen was detected in CSF, SARS-CoV-2 could be the cause of most of the cases observed. COVID-ME patients had a higher unadjusted in-hospital mortality than non-COVID-ME patients.

Effect of a Diagnostic Strategy Using an Elevated and Age-Adjusted D-Dimer Threshold on Thromboembolic Events in Emergency Department Patients With Suspected Pulmonary Embolism: A Randomized Clinical Trial.

Importance: Uncontrolled studies suggest that pulmonary embolism (PE) can be safely ruled out using the YEARS rule, a diagnostic strategy that uses varying D-dimer thresholds. Objective: To prospectively validate the safety of a strategy that combines the YEARS rule with the pulmonary embolism rule-out criteria (PERC) rule and an age-adjusted D-dimer threshold. Design, Settings, and Participants: A cluster-randomized, crossover, noninferiority trial in 18 emergency departments (EDs) in France and Spain. Patients (N = 1414) who had a low clinical risk of PE not excluded by the PERC rule or a subjective clinical intermediate risk of PE were included from October 2019 to June 2020, and followed up until October 2020. Interventions: Each center was randomized for the sequence of intervention periods. In the intervention period (726 patients), PE was excluded without chest imaging in patients with no YEARS criteria and a D-dimer level less than 1000 ng/mL and in patients with 1 or more YEARS criteria and a D-dimer level less than the age-adjusted threshold (500 ng/mL if age <50 years or age in years × 10 in patients ≥50 years). In the control period (688 patients), PE was excluded without chest imaging if the D-dimer level was less than the age-adjusted threshold. Main Outcomes and Measures: The primary end point was venous thromboembolism (VTE) at 3 months. The noninferiority margin was set at 1.35%. There were 8 secondary end points, including chest imaging, ED length of stay, hospital admission, nonindicated anticoagulation treatment, all-cause death, and all-cause readmission at 3 months. Results: Of the 1414 included patients (mean age, 55 years; 58% female), 1217 (86%) were analyzed in the per-protocol analysis. PE was diagnosed in the ED in 100 patients (7.1%). At 3 months, VTE was diagnosed in 1 patient in the intervention group (0.15% [95% CI, 0.0% to 0.86%]) vs 5 patients in the control group (0.80% [95% CI, 0.26% to 1.86%]) (adjusted difference, -0.64% [1-sided 97.5% CI, -∞ to 0.21%], within the noninferiority margin). Of the 6 analyzed secondary end points, only 2 showed a statistically significant difference in the intervention group compared with the control group: chest imaging (30.4% vs 40.0%; adjusted difference, -8.7% [95% CI, -13.8% to -3.5%]) and ED median length of stay (6 hours [IQR, 4 to 8 hours] vs 6 hours [IQR, 5 to 9 hours]; adjusted difference, -1.6 hours [95% CI, -2.3 to -0.9]). Conclusions and Relevance: Among ED patients with suspected PE, the use of the YEARS rule combined with the age-adjusted D-dimer threshold in PERC-positive patients, compared with a conventional diagnostic strategy, did not result in an inferior rate of thromboembolic events. Trial Registration: ClinicalTrials.gov Identifier: NCT04032769.

Effect of a Pulmonary Embolism Diagnostic Strategy on Clinical Outcomes in Patients Hospitalized for COPD Exacerbation: A Randomized Clinical Trial.

Importance: Active search for pulmonary embolism (PE) may improve outcomes in patients hospitalized for exacerbations of chronic obstructive pulmonary disease (COPD). Objective: To compare usual care plus an active strategy for diagnosing PE with usual care alone in patients hospitalized for COPD exacerbation. Design, Setting, and Participants: Randomized clinical trial conducted across 18 hospitals in Spain. A total of 746 patients were randomized from September 2014 to July 2020 (final follow-up was November 2020). Interventions: Usual care plus an active strategy for diagnosing PE (D-dimer testing and, if positive, computed tomography pulmonary angiogram) (n = 370) vs usual care (n = 367). Main Outcomes and Measures: The primary outcome was a composite of nonfatal symptomatic venous thromboembolism (VTE), readmission for COPD, or death within 90 days after randomization. There were 4 secondary outcomes, including nonfatal new or recurrent VTE, readmission for COPD, and death from any cause within 90 days. Adverse events were also collected. Results: Among the 746 patients who were randomized, 737 (98.8%) completed the trial (mean age, 70 years; 195 [26%] women). The primary outcome occurred in 110 patients (29.7%) in the intervention group and 107 patients (29.2%) in the control group (absolute risk difference, 0.5% [95% CI, -6.2% to 7.3%]; relative risk, 1.02 [95% CI, 0.82-1.28]; P = .86). Nonfatal new or recurrent VTE was not significantly different in the 2 groups (0.5% vs 2.5%; risk difference, -2.0% [95% CI, -4.3% to 0.1%]). By day 90, a total of 94 patients (25.4%) in the intervention group and 84 (22.9%) in the control group had been readmitted for exacerbation of COPD (risk difference, 2.5% [95% CI, -3.9% to 8.9%]). Death from any cause occurred in 23 patients (6.2%) in the intervention group and 29 (7.9%) in the control group (risk difference, -1.7% [95% CI, -5.7% to 2.3%]). Major bleeding occurred in 3 patients (0.8%) in the intervention group and 3 patients (0.8%) in the control group (risk difference, 0% [95% CI, -1.9% to 1.8%]; P = .99). Conclusions and Relevance: Among patients hospitalized for an exacerbation of COPD, the addition of an active strategy for the diagnosis of PE to usual care, compared with usual care alone, did not significantly improve a composite health outcome. The study may not have had adequate power to assess individual components of the composite outcome. Trial Registration: ClinicalTrials.gov Identifier: NCT02238639.

Alteration of cytokines in saliva of children with caries and obesity.

Caries and obesity are multifactorial diseases with inflammatory components, whose processes involve cells and molecules, such as cytokines. Therefore, the objective of this work was to compare the concentrations of IL-6, IL-8, IL-15, and IL-18 in the salivary samples of children with caries and obesity. The study was carried out with 80 children: 43 with a normal weight and 37 with obesity. The diagnosis of caries was carried out using the ICDAS system. Salivary samples were used to measure the cytokine levels via the ELISA technique. Our results show that children with obesity and dental cavities have high levels of IL-6 and IL-15. Similarly, obese children have elevated levels of these two cytokines, while children with cavitated carious lesions presented alterations in their concentrations of IL-6 and IL-8. In conclusion, our data suggest that IL-6 has a significant effect on both obesity and caries, although IL-8 is more related to caries, and IL-15 is more related to obesity.

Frequency of five unusual presentations in patients with COVID-19: results of the UMC-19-S1.

Despite SARS-CoV-19 infection has a stereotypical clinical picture, isolated cases with unusual manifestations have been reported, some of them being well-known to be triggered by viral infections. However, the real frequency in COVID-19 is unknown. Analysing data of 63 822 COVID patients attending 50 Spanish emergency department (ED) during the COVID outbreak, before hospitalisation, we report frequencies of (myo)pericarditis (0.71‰), meningoencephalitis (0.25‰), Guillain-Barré syndrome (0.13‰), acute pancreatitis (0.71‰) and spontaneous pneumothorax (0.57‰). Compared with general ED population, COVID patients developed more frequently Guillain-Barré syndrome (odds ratio (OR) 4.55, 95% confidence interval (CI) 2.09-9.90), spontaneous pneumothorax (OR 1.98, 95% CI 1.40-2.79) and (myo)pericarditis (OR 1.45, 95% CI 1.07-1.97), but less frequently pancreatitis (OR 0.44, 95% CI 0.33-0.60).

Electroencephalogram paroxysmal θ characterizes cataplexy in mice and children.

Astute control of brain activity states is critical for adaptive behaviours and survival. In mammals and birds, electroencephalographic recordings reveal alternating states of wakefulness, slow wave sleep and paradoxical sleep (or rapid eye movement sleep). This control is profoundly impaired in narcolepsy with cataplexy, a disease resulting from the loss of orexin/hypocretin neurotransmitter signalling in the brain. Narcolepsy with cataplexy is characterized by irresistible bouts of sleep during the day, sleep fragmentation during the night and episodes of cataplexy, a sudden loss of muscle tone while awake and experiencing emotions. The neural mechanisms underlying cataplexy are unknown, but commonly thought to involve those of rapid eye movement-sleep atonia, and cataplexy typically is considered as a rapid eye movement sleep disorder. Here we reassess cataplexy in hypocretin (Hcrt, also known as orexin) gene knockout mice. Using a novel video/electroencephalogram double-blind scoring method, we show that cataplexy is not a state per se, as believed previously, but a dynamic, multi-phased process involving a reproducible progression of states. A knockout-specific state and a stereotypical paroxysmal event were introduced to account for signals and electroencephalogram spectral characteristics not seen in wild-type littermates. Cataplexy almost invariably started with a brief phase of wake-like electroencephalogram, followed by a phase featuring high-amplitude irregular theta oscillations, defining an activity profile distinct from paradoxical sleep, referred to as cataplexy-associated state and in the course of which 1.5-2 s high-amplitude, highly regular, hypersynchronous paroxysmal theta bursts (∼7 Hz) occurred. In contrast to cataplexy onset, exit from cataplexy did not show a predictable sequence of activities. Altogether, these data contradict the hypothesis that cataplexy is a state similar to paradoxical sleep, even if long cataplexies may evolve into paradoxical sleep. Although not exclusive to overt cataplexy, cataplexy-associated state and hypersynchronous paroxysmal theta activities are highly enriched during cataplexy in hypocretin/orexin knockout mice. Their occurrence in an independent narcolepsy mouse model, the orexin/ataxin 3 transgenic mouse, undergoing loss of orexin neurons, was confirmed. Importantly, we document for the first time similar paroxysmal theta hypersynchronies (∼4 Hz) during cataplexy in narcoleptic children. Lastly, we show by deep recordings in mice that the cataplexy-associated state and hypersynchronous paroxysmal theta activities are independent of hippocampal theta and involve the frontal cortex. Cataplexy hypersynchronous paroxysmal theta bursts may represent medial prefrontal activity, associated in humans and rodents with reward-driven motor impulse, planning and conflict monitoring.

Model integration of circadian- and sleep-wake-driven contributions to rhythmic gene expression reveals distinct regulatory principles.

Analyses of gene-expression dynamics in research on circadian rhythms and sleep homeostasis often describe these two processes using separate models. Rhythmically expressed genes are, however, likely to be influenced by both processes. We implemented a driven, damped harmonic oscillator model to estimate the contribution of circadian- and sleep-wake-driven influences on gene expression. The model reliably captured a wide range of dynamics in cortex, liver, and blood transcriptomes taken from mice and humans under various experimental conditions. Sleep-wake-driven factors outweighed circadian factors in driving gene expression in the cortex, whereas the opposite was observed in the liver and blood. Because of tissue- and gene-specific responses, sleep deprivation led to a long-lasting intra- and inter-tissue desynchronization. The model showed that recovery sleep contributed to these long-lasting changes. The results demonstrate that the analyses of the daily rhythms in gene expression must take the complex interactions between circadian and sleep-wake influences into account. A record of this paper's transparent peer review process is included in the supplemental information.

Interpreting the Function of the IL-23/IL-17 Axis through Bioinformatics.

INTRODUCTION/OBJECTIVE: Bioinformatic analysis is a valuable tool that allows us to collect, archive, analyze, and disseminate biological data for further interpretation. Analysis of the IL-23/IL-17A axis and its receptors will provide us with essential information about their functions, interactions, and relationships with various diseases. This review aims to identify the central genes co-expressed in the IL-23/IL-17A axis and their receptors and to understand their ontology and modifying factors. METHODS: We used several databases, including COXPRESdb to obtain the co-expressed genes, ShinyGO and ToppGene platforms to explore gene functional enrichment, and the NetworkAnalyst 3.0 platform for gene expression profiling. RESULTS: We found that genes encoding IL-23/IL-17A axis proteins and their receptors mainly respond to microbial components, participate in the inflammatory response, and are primarily associated with inflammatory and autoimmune diseases. In addition, we observed an association of the IL-23/IL-17 axis with Behcet's disease, Graft-versus-host disease, and Hodgkin's disease, although there is no direct evidence of their interaction. CONCLUSION: The IL-23/IL-17A axis is associated with several inflammatory and autoimmune pathologies. Therefore, we suggest further research to confirm its role in these pathologies and, if possible, use it as a therapeutic target.

Calcium trafficking and gastrointestinal physiology following an acute lipopolysaccharide challenge in pigs.

The influence of systemic immune activation on whole-body calcium (Ca) trafficking and gastrointestinal tract (GIT) physiology is not clear. Thus, the study objectives were to characterize the effects of lipopolysaccharide (LPS) on Ca pools and GIT dynamics to increase understanding of immune-induced hypocalcemia, ileus, and stomach hemorrhaging. Twelve crossbred pigs [44 ±â€…3 kg body weight (BW)] were randomly assigned to 1 of 2 intramuscular treatments: (1) control (CON; 2 mL saline; n = 6) or (2) LPS (40 µg LPS/kg BW; n = 6). Pigs were housed in metabolism stalls to collect total urine and feces for 6 h after treatment administration, at which point they were euthanized, and various tissues, organs, fluids, and digesta were weighed, and analyzed for Ca content. Data were analyzed with the MIXED procedure in SAS 9.4. Rectal temperature and respiration rate increased in LPS relative to CON pigs (1.4 °C and 32%, respectively; P ≤ 0.05). Inflammatory biomarkers such as circulating alkaline phosphatase, aspartate aminotransferase, and total bilirubin increased in LPS compared with CON pigs whereas albumin decreased (P ≤ 0.02). Plasma glucose and urea nitrogen decreased and increased, respectively, after LPS (43% and 80%, respectively; P < 0.01). Pigs administered LPS had reduced circulating ionized calcium (iCa) compared to CON (15%; P < 0.01). Considering estimations of total blood volume, LPS caused an iCa deficit of 23 mg relative to CON (P < 0.01). Adipose tissue and urine from LPS pigs had reduced Ca compared to CON (39% and 77%, respectively; P ≤ 0.05). There did not appear to be increased Ca efflux into GIT contents and no detectable increases in other organ or tissue Ca concentrations were identified. Thus, while LPS caused hypocalcemia, we were unable to determine where circulating Ca was trafficked. LPS administration markedly altered GIT dynamics including stomach hemorrhaging, diarrhea (increased fecal output and moisture), and reduced small intestine and fecal pH (P ≤ 0.06). Taken together, changes in GIT physiology suggested dyshomeostasis and alimentary pathology. Future research is required to fully elucidate the etiology of immune activation-induced hypocalcemia and GIT pathophysiology.

Lipopolysaccharide (LPS) activates the immune system and this is accompanied with hypocalcemia and altered gastrointestinal tract (GIT) physiology. The study objectives were to characterize whole-body calcium (Ca) trafficking and evaluate GIT dynamics during LPS-induced immune activation. Ca concentrations were analyzed after intramuscular LPS injection. Administering LPS caused marked alterations in metabolic and inflammatory biomarkers and GIT dynamics, characterized by increased lower GIT motility and stomach hemorrhaging. Circulating Ca and adipose tissue and urine Ca output were decreased after LPS. Ca concentrations in other tissues and GIT contents were not detectably different. Thus, we were unable to account for about 110 mg Ca following LPS. Where and how circulating Ca is partitioned during immune activation remains unclear.

Effects of SNAPPS in clinical reasoning teaching: a systematic review with meta-analysis of randomized controlled trials.

INTRODUCTION: Clinical reasoning is crucial in medical practice, yet its teaching faces challenges due to varied clinical experiences, limited time, and absence from competency frameworks. Despite efforts, effective teaching methodologies remain elusive. Strategies like the One Minute Preceptor (OMP) and SNAPPS are proposed as solutions, particularly in workplace settings. SNAPPS, introduced in 2003, offers a structured approach but lacks comprehensive evidence of its effectiveness. Methodological shortcomings hinder discerning its specific effects. Therefore, a systematic review is proposed to evaluate SNAPPS' impact on clinical reasoning teaching. CONTENT: We searched PubMed, EMBASE, and CINAHL for randomized controlled trials (RCTs) comparing SNAPPS against other methods. Data selection and extraction were performed in duplicate. Bias and certainty of evidence were evaluated using Cochrane RoB-2 and GRADE approach. SUMMARY: We identified five RCTs performed on medical students and residents. Two compared SNAPPS with an active control such as One Minute Preceptor or training with feedback. None reported the effects of SNAPPS in workplace settings (Kirkpatrick Level 3) or patients (Kirkpatrick Level 4). Low to moderate certainty of evidence suggests that SNAPPS increases the total presentation length by increasing discussion length. Low to moderate certainty of evidence may increase the number of differential diagnoses and the expression of uncertainties. Low certainty of evidence suggests that SNAPPS may increase the odds of trainees initiating a management plan and seeking clarification. OUTLOOK: Evidence from this systematic review suggests that SNAPPS has some advantages in terms of clinical reasoning, self-directed learning outcomes, and cost-effectiveness. Furthermore, it appears more beneficial when used by residents than medical students. However, future research should explore outcomes outside SNAPPS-related outcomes, such as workplace or patient-related outcomes.

Investigating intestinal mast cell dynamics during acute heat stress in growing pigs.

Objectives were to examine the temporal pattern of intestinal mast cell dynamics and the effects of a mast cell stabilizer (ketotifen [Ket]) during acute heat stress (HS) in growing pigs. Crossbred barrows (n = 42; 32.3 ±â€…1.9 kg body weight [BW]) were randomly assigned to 1 of 7 environmental-therapeutic treatments: (1) thermoneutral (TN) control (TNCon; n = 6), (2) 2 h HS control (2 h HSCon; n = 6), (3) 2 h HS + Ket (2 h HSKet; n = 6); (4) 6 h HSCon (n = 6), (5) 6 h HSKet (n = 6), (6) 12 h HSCon (n = 6), or (7) 12 h HSKet (n = 6). Following 5 d of acclimation to individual pens, pigs were enrolled in two experimental periods (P). During P1 (3 d), pigs were housed in TN conditions (21.5 ±â€…0.8 °C) for the collection of baseline measurements. During P2, TNCon pigs remained in TN conditions for 12 h, while HS pigs were exposed to constant HS (38.1 ±â€…0.2 °C) for either 2, 6, or 12 h. Pigs were euthanized at the end of P2, and blood and tissue samples were collected. Regardless of time or therapeutic treatment, pigs exposed to HS had increased rectal temperature, skin temperature, and respiration rate compared to their TNCon counterparts (1.9 °C, 6.9° C, and 119 breaths/min; P < 0.01). As expected, feed intake and BW gain markedly decreased in HS pigs relative to their TNCon counterparts (P < 0.01). Irrespective of therapeutic treatment, circulating corticotropin-releasing factor decreased from 2 to 12 h of HS relative to TNCon pigs (P < 0.01). Blood cortisol increased at 2 h of HS (2-fold; P = 0.04) and returned to baseline by 6 h. Plasma histamine (a proxy of mast cell activation) remained similar across thermal treatments and was not affected by Ket administration (P > 0.54). Independent of Ket or time, HS increased mast cell numbers in the jejunum (94%; P < 0.01); however, no effects of HS on mast cell numbers were detected in the ileum or colon. Jejunum and ileum myeloperoxidase area remained similar among treatments (P > 0.58) but it tended to increase (12%; P = 0.08) in the colon in HSCon relative to TNCon pigs. Circulating lymphocytes and basophils decreased in HSKet relative to TN and HSCon pigs (P ≤ 0.06). Blood monocytes and eosinophils were reduced in HS pigs relative to their TNCon counterparts (P < 0.01). In summary, HS increased jejunum mast cell numbers and altered leukocyte dynamics and proinflammatory biomarkers. However, Ket administration had no effects on mast cell dynamics measured herein.

Heat stress (HS) affects various physiological, metabolic, and endocrine parameters, ostensibly due to reduced intestinal barrier integrity and the ensuing immune response. Evidence indicates that generalized "stress" may be a critical component of HS-induced leaky gut, a mechanism likely mediated by mast cells. Mast cell activation has been extensively associated with various stress-related intestinal inflammatory conditions; however, its contribution to intestinal barrier dysfunction during HS remains unclear. Thus, this study was designed to evaluate mast cell dynamics during an acute HS challenge and to assess the effects a mast cell stabilizer on biomarkers of intestinal inflammation. Herein, HS induced a rapid increase in circulating cortisol, increased jejunum mast cell numbers, and altered metabolism, leukocyte dynamics, and proinflammatory biomarkers. Contrary to our hypothesis, HS did not alter circulating histamine (a biomarker of mast cell activation), and mast cell stabilization did not affect mast cell numbers nor altered histamine concentrations. Altogether, our observations support a connection between HS and intestinal mast cell infiltration that may contribute to the pathophysiology of intestinal dysfunction during a heat load.