Progressive changes in pulmonary gas exchange during invasive respiratory support for COVID-19 associated acute respiratory failure: A retrospective study of the association with 90-day mortality.

BACKGROUND: Ratio of arterial pressure of oxygen and fraction of inspired oxygen (P/F ratio) together with the fractional dead space (Vd/Vt) provides a global assessment of pulmonary gas exchange. The aim of this study was to assess the potential value of these variables to prognosticate 90-day survival in patients with COVID-19 associated ARDS admitted to the Intensive Care Unit (ICU) for invasive ventilatory support. METHODS: In this single-center observational, retrospective study, P/F ratios and Vd/Vt were assessed up to 4 weeks after ICU-admission. Measurements from the first 2 weeks were used to evaluate the predictive value of P/F ratio and Vd/Vt for 90-day mortality and reported by the adjusted hazard ratio (HR) and 95% confidence intervals [95%CI] by Cox proportional hazard regression. RESULTS: Almost 20,000 blood gases in 130 patients were analyzed. The overall 90-day mortality was 30% and using the data from the first ICU week, the HR was 0.85 [0.77-0.94] for every 10 mmHg increase in P/F ratio and 1.61 [1.20-2.16] for every 0.1 increase in Vd/Vt. In the second week, the HR for 90-day mortality was 0.82 [0.75-0.89] for every 10 mmHg increase in P/F ratio and 1.97 [1.42-2.73] for every 0.1 increase in Vd/Vt. CONCLUSION: The progressive changes in P/F ratio and Vd/Vt in the first 2 weeks of invasive ventilatory support for COVID-19 ARDS were significant predictors for 90-day mortality.

Acute-Phase Neurofilament Light and Glial Fibrillary Acidic Proteins in Cerebrospinal Fluid Predict Long-Term Outcome After Severe Traumatic Brain Injury.

BACKGROUND: This study investigated trajectory profiles and the association of concentrations of the biomarkers neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) in ventricular cerebrospinal fluid (CSF) with clinical outcome at 1 year and 10-15 years after a severe traumatic brain injury (sTBI). METHODS: This study included patients with sTBI at the Neurointensive Care Unit at Sahlgrenska University Hospital, Gothenburg, Sweden. The injury was regarded as severe if patients had a Glasgow Coma Scale ≤ 8 corresponding to Reaction Level Scale ≥ 4. CSF was collected from a ventricular catheter during a 2-week period. Concentrations of NfL and GFAP in CSF were analyzed with enzyme-linked immunosorbent assay. The Glasgow Outcome Scale (GOS) was used to assess the 1-year and 10-15-year outcomes. After adjustment for age and previous neurological diseases, logistic regression was performed for the outcomes GOS 1 (dead) or GOS 2-5 (alive) and GOS 1-3 (poor) or GOS 4-5 (good) versus the independent continuous variables (NfL and GFAP). RESULTS: Fifty-three patients with sTBI were investigated; forty-seven adults are presented in the article, and six children (aged 7-18 years) are described in Supplement 1. The CSF concentrations of NfL gradually increased over 2 weeks post trauma, whereas GFAP concentrations peaked on days 3-4. Increasing NfL and GFAP CSF concentrations increased the odds of GOS 1-3 outcome 1 year after trauma (odds ratio [OR] 1.73, 95% confidence interval [CI] 1.07-2.80, p = 0.025; and OR 1.61, 95% CI 1.09-2.37, p = 0.016, respectively). Similarly, increasing CSF concentrations of NfL and GFAP increased the odds for GOS 1-3 outcome 10-15 years after trauma (OR 2.04, 95% CI 1.05-3.96, p = 0.035; and OR 1.60, 95% CI 1.02-2.00, p = 0.040). CONCLUSIONS: This study shows that initial high concentrations of NfL and GFAP in CSF are both associated with higher odds for GOS 1-3 outcome 1 year and 10-15 years after an sTBI, implicating its potential usage as a prognostic marker in the future.

Cerebrospinal Fluid Biomarkers of Synaptic Dysfunction are Altered in Parkinson's Disease and Related Disorders.

BACKGROUND: Synaptic dysfunction and degeneration are central contributors to the pathogenesis and progression of parkinsonian disorders. Therefore, identification and validation of biomarkers reflecting pathological synaptic alterations are greatly needed and could be used in prognostic assessment and to monitor treatment effects. OBJECTIVE: To explore candidate biomarkers of synaptic dysfunction in Parkinson's disease (PD) and related disorders. METHODS: Mass spectrometry was used to quantify 15 synaptic proteins in two clinical cerebrospinal fluid (CSF) cohorts, including PD (n1  = 51, n2  = 101), corticobasal degeneration (CBD) (n1  = 11, n2  = 3), progressive supranuclear palsy (PSP) (n1  = 22, n2  = 21), multiple system atrophy (MSA) (n1  = 31, n2  = 26), and healthy control (HC) (n1  = 48, n2  = 30) participants, as well as Alzheimer's disease (AD) (n2  = 23) patients in the second cohort. RESULTS: Across both cohorts, lower levels of the neuronal pentraxins (NPTX; 1, 2, and receptor) were found in PD, MSA, and PSP, compared with HC. In MSA and PSP, lower neurogranin, AP2B1, and complexin-2 levels compared with HC were observed. In AD, levels of 14-3-3 zeta/delta, beta- and gamma-synuclein were higher compared with the parkinsonian disorders. Lower pentraxin levels in PD correlated with Mini-Mental State Exam scores and specific cognitive deficits (NPTX2; rho = 0.25-0.32, P < 0.05) and reduced dopaminergic pre-synaptic integrity as measured by DaTSCAN (NPTX2; rho = 0.29, P = 0.023). Additionally, lower levels were associated with the progression of postural imbalance and gait difficulty symptoms (All NPTX; ß-estimate = -0.025 to -0.038, P < 0.05) and cognitive decline (NPTX2; ß-estimate = 0.32, P = 0.021). CONCLUSIONS: These novel findings show different alterations of synaptic proteins in parkinsonian disorders compared with AD and HC. The neuronal pentraxins may serve as prognostic CSF biomarkers for both cognitive and motor symptom progression in PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Presence of neural surface and onconeural autoantibodies in cerebrospinal fluid and serum in neurological diseases presents a potential risk for misdiagnosis.

BACKGROUND AND PURPOSE: Autoantibodies have been found to contribute to pathology and are used in the diagnosis of some neurological diseases. We examined the prevalence of autoantibodies in patients with various neurological diseases and whether patients who had autoantibodies differed in age, sex, or disability from those who did not. METHODS: We examined the prevalence of neural surface and onconeural autoantibodies in cerebrospinal fluid (CSF) and serum from patients with multiple sclerosis (n = 64), Parkinson disease plus atypical parkinsonism (n = 150), amyotrophic lateral sclerosis (n = 43), or autoimmune encephalitis (positive control; n = 7) and a healthy control group (n = 37). A total of 12 onconeural autoantibodies and six neural surface autoantibodies were tested in all participants. RESULTS: Autoantibodies were present in all cohorts. The prevalence of autoantibodies was high (>80%) in the autoimmune encephalitis cohort but low (<20%) in all other cohorts. When comparing patients within cohorts who were positive for autoantibodies to patients who were not, there was no difference in age, sex, and disability. This was apart from the multiple sclerosis and Parkinson disease plus atypical parkinsonism cohorts, where those with positivity for autoantibodies in the CSF were significantly older. CONCLUSIONS: The presence of the autoantibodies examined does not appear to have a substantial clinical impact within the diseases examined in this study. The presence of autoantibodies in all cohorts presents a risk for misdiagnosis when the method is used incorrectly on patients with atypical clinical presentation.

SCRN1: A cerebrospinal fluid biomarker correlating with tau in Alzheimer's disease.

INTRODUCTION: Secernin-1 (SCRN1) is a neuronal protein that co-localizes with neurofibrillary tangles in Alzheimer's disease (AD), but not with tau inclusions in corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), or Pick's disease. METHODS: We measured SCRN1 concentration in cerebrospinal fluid (CSF) using a novel mass spectrometric parallel reaction monitoring method in three clinical cohorts comprising patients with neurochemically characterized AD (n = 25) and controls (n = 28), clinically diagnosed Parkinson's disease (PD; n = 38), multiple system atrophy (MSA; n = 31), PSP (n = 20), CBD (n = 8), healthy controls (n = 37), and neuropathology-confirmed AD (n = 47). RESULTS: CSF SCRN1 was significantly increased in AD (P < 0.01, fold change = 1.4) compared to controls (receiver operating characteristic area under the curve = 0.78) but not in CBD, PSP, PD, or MSA. CSF SCRN1 positively correlated with CSF total tau (R = 0.78, P = 1.1 × 10-13 ), phosphorylated tau181 (R = 0.64, P = 3.2 × 10-8 ), and Braak stage and negatively correlated with Mini-Mental State Examination score. DISCUSSION: CSF SCRN1 is a candidate biomarker of AD, reflecting tau pathology. HIGHLIGHTS: We developed a parallel reaction monitoring assay to measure secernin-1 (SCRN1) in cerebrospinal fluid (CSF). CSF SCRN1 was increased in Alzheimer's disease compared to healthy controls. CSF SCRN1 remained unchanged in Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, or corticobasal degeneration compared to controls. CSF SCRN1 correlated strongly with CSF phosphorylated tau and total tau. CSF SCRN1 increased across Braak stages and negatively correlated with Mini-Mental State Examination score.

Cardiac dysfunction and mortality in critically ill patients with COVID-19: A Swedish multicentre observational study.

BACKGROUND: The prevalence and importance of cardiac dysfunction in critically ill patients with COVID-19 in Sweden is not yet established. The aim of the study was to assess the prevalence of cardiac dysfunction and elevated pulmonary artery pressure (PAP), and its influence on mortality in patients with COVID-19 in intensive care in Sweden. METHODS: This was a multicentre observational study performed in five intensive care units (ICUs) in Sweden. Patients admitted to participating ICU with COVID-19 were examined with echocardiography within 72 h from admission and again after 4 to 7 days. Cardiac dysfunction was defined as left ventricular (LV) dysfunction (ejection fraction <50% and/or regional hypokinesia) or right ventricular (RV) dysfunction (defined as TAPSE <17 mm or visually assessed moderate/severe RV dysfunction). RESULTS: We included 132 patients, of whom 127 (96%) were intubated. Cardiac dysfunction was found in 42 (32%) patients. Most patients had cardiac dysfunction at the first assessment (n = 35) while a few developed cardiac dysfunction later (n = 7) and some changed type of dysfunction (n = 3). LV dysfunction was found in 21 and RV dysfunction in 19 patients, while 5 patients had combined dysfunction. Elevated PAP was found in 34 patients (26%) and was more common in patients with RV dysfunction. RV dysfunction and elevated PAP were independently associated with an increased risk of death (OR 3.98, p = .013 and OR 3.88, p = .007, respectively). CONCLUSIONS: Cardiac dysfunction occurs commonly in critically ill patients with COVID-19 in Sweden. RV dysfunction and elevated PAP are associated with an increased risk of death.

Impact of norepinephrine on right ventricular afterload and function in septic shock-a strain echocardiography study.

BACKGROUND: In this observational study, the effects of norepinephrine-induced changes in mean arterial pressure (MAP) on right ventricular (RV) systolic function, afterload and pulmonary haemodynamics were studied in septic shock patients. We hypothesised that RV systolic function improves at higher doses of norepinephrine/MAP levels. METHODS: Eleven patients with septic shock requiring norepinephrine after fluid resuscitation were included <24 hours after ICU arrival. Study enrolment and insertion of a pulmonary artery catheter was performed after written informed consent from the next of kin. Norepinephrine infusion was titrated to target mean arterial pressures (MAP) of 60, 75 and 90 mmHg in a random sequential order. At each target MAP, strain-and conventional echocardiographic-and pulmonary haemodynamic variables were measured. RV afterload was assessed as effective pulmonary arterial elastance, (Epa ) and pulmonary vascular resistance index, (PVRI). RV free wall peak strain was the primary end-point. RESULTS: At highest compared to lowest norepinephrine dose/MAP level, RV free wall peak strain increased from -19% to -25% (32%, P = .003), accompanied by increased tricuspid annular plane systolic excursion (22%, P = .01). At the highest norepinephrine dose/MAP, RV end-diastolic area index (16%, P < .001), central venous pressure (38%, P < .001), stroke volume index (7%, P = .001), mean pulmonary artery pressure (19%, P < .001) and RV stroke work index (15%, P = .045) increased, with no effects on PVRI or Epa . Cardiac index did not change, assessed by thermodilution (P = .079) and echocardiography (P = .054). CONCLUSIONS: Higher doses of norepinephrine to a target MAP of 90 mm Hg improved RV systolic function while RV afterload was not affected.

Speckle tracking-vs conventional echocardiography for the detection of myocardial injury-A study on patients with subarachnoid haemorrhage.

BACKGROUND: Myocardial injury with regional wall motion abnormalities (RWMA) is common in subarachnoid haemorrhage (SAH). We hypothesized that the diagnostic performance of left ventricular (LV) global and regional longitudinal strain (GLS and RLS, respectively), assessed with speckle tracking echocardiography is superior to standard echocardiography for the detection of myocardial injury in SAH. METHODS: Seventy-one unselected patients with verified SAH were included. Echocardiography was performed within 48 hours after admission. hsTnT was followed daily up to 3 days post-admission. RWMA, LV ejection fraction (LVEF), GLS and RLS were analysed by two experienced echocardiographists, blinded to the information on plasma hsTnT. A reduced GLS was defined as >-15%. Two cut-off levels were used for the definition of RLS, ie when segmental strain was >-15% (liberal) or >-11% (conservative) in ≥2 adjacent segments. Myocardial injury was defined as a peak hsTnT ≥90 ng/L. RESULTS: The incidence of myocardial injury was 25%. The hsTnT (median, 25% and 75% percentile) in patients with (a) reduced LV ejection fraction (LVEF <50%, n = 10) was 502 (175-718), (b) RWMA (n = 12) was 648 (337-750), (c) reduced GLS (n = 12) was 502 (132-750) and (d) reduced RLS (n = 42) was 40 (10-216), respectively. The specificity/sensitivity for LVEF, RWMA, GLS and RLS to detect myocardial injury 98%/50%, 100%/67%, 96%/56% and 54%/94%, respectively. The intra- and inter-observer variability for assessment of RLS was high. CONCLUSION: The diagnostic performance of GLS by strain imaging is not superior to standard echocardiography for the detection of myocardial injury in SAH. RLS could not reliably detect regional myocardial injury.

General anesthesia and positive pressure ventilation suppress left and right ventricular myocardial shortening in patients without myocardial disease - a strain echocardiography study.

BACKGROUND: Myocardial deformation imaging using speckle-tracking echocardiography to assess global longitudinal strain (GLS) is today considered a more sensitive measure of left ventricular (LV) systolic function than ejection fraction. General anesthesia and positive pressure ventilation (PPV) are known to change the right ventricular (RV) and LV loading conditions. However, little is known about the effects of anesthesia and PPV on RV free wall and LV GLS. We studied the influence of general anesthesia and PPV on RV and LV longitudinal strain in patients without myocardial disease. METHODS: Twenty-one patients scheduled for non-cardiac surgery were included. The baseline examination was performed on the un-premedicated patients within 60 min of anesthesia. The second examination was performed 10-15 min after induction of anesthesia (propofol, remifentanil), intubation and start of PPV. The examinations included apical four-, two- and three-chamber projections, mitral and aortic Doppler flow velocities and tissue Doppler velocities of tricuspid and mitral annulus. LV end-systolic elastance (Ees) and aortic elastance were determined (Ea). RESULTS: General anesthesia and PPV reduced the mean arterial blood pressure (- 29%, p <  0.0019), stroke volume index (- 13%, p <  0.001) and cardiac index (- 23%, p <  0.001). RV end-diastolic area index and LV end-diastolic volume index decreased significantly, while systemic vascular resistance was not significantly affected. Ees decreased significantly with the induction of anaesthesia (- 23%, p = 0.002), while there was a trend for a decrease in Ea (p = 0.053). The ventriculo-arterial coupling, Ea/Ees, was not significantly affected by the anesthetics and PPV. The LV GLS decreased from - 19.1 ± 2.3% to - 17.3 ± 2.9% (p <  0.001) and RV free wall strain decreased from - 26.5 ± 3.9% to - 24.1 ± 4.2% (p = 0.001). One patient (5%) had at baseline a LV GLS > - 16% compared with 6 patients (28%) during general anesthesia and PPV. Three patients (14%) had a RV free wall strain > - 24% compared to 8 patients (38%) during general anesthesia and PPV. CONCLUSIONS: General anesthesia and PPV reduces systolic LV and RV function to levels considered indicating dysfunction in a substantial proportion of patients without myocardial disease.

Strain echocardiography identifies impaired longitudinal systolic function in patients with septic shock and preserved ejection fraction.

BACKGROUND: Myocardial dysfunction is recognized in sepsis. We hypothesized that mechanical left (LV) and right (RV) ventricular function analysed using 2-dimensional speckle-tracking echocardiography in a cohort of early severe sepsis or septic shock patients, would be different to that of a group of critically ill, non-septic patients. METHODS: Critically ill adult patients with early, severe sepsis/septic shock (n = 48) and major trauma patients with no sepsis (n = 24) were included retrospectively, as well as healthy controls (n = 16). Standard echocardiographic examinations, including right (RV) left (LV) volumes and mitral, aortic and pulmonary vein Doppler flow profiles, were retrospectively identified and the studies were then reanalysed for assessment of myocardial strain using speckle-tracking echocardiography. Endocardial tracing of the LV was performed in apical four-chamber (4-Ch), two-chamber (2-Ch), apical long-axis (3-Ch) and apical views of RV determining the longitudinal LV and RV free wall strain in each subject. RESULTS: In septic patients, heart rate was significantly higher (p = 0.009) and systolic (p < 0.001) and mean arterial pressures (p < 0.001), as well as systemic vascular resistance (p < 0.001) were significantly lower when compared to the non-septic trauma group. Ninety-three per cent of the septic patients and 50% of the trauma patients were treated with norepinephrine (p < 0.001). LV ejection fraction (LVEF) was lower in the septic patients (p = 0.019). In septic patients with preserved LVEF (>50%, n = 34), seventeen patients (50%) had a depressed LV global longitudinal function, defined as a LV global strain > -15%, compared to two patients (8.7%) in the non-septic group (p = 0.0014). In septic patients with preserved LVEF, LV global and RV free wall strain were 14% (p = 0.014) and 17% lower (p = 0.008), respectively, compared to the non-septic group with preserved LVEF. There were no significant differences between groups with respect to LV end-diastolic or end-systolic volumes, stroke volume, or cardiac output. There were no signs of diastolic dysfunction from the mitral or pulmonary vein Doppler profiles in the septic patients. CONCLUSIONS: LV and RV systolic function is impaired in critically ill patients with early septic shock and preserved LVEF, as detected by Speckle-tracking 2D echocardiography. Strain imaging may be useful in the early detection of myocardial dysfunction in sepsis.

High levels of neurofilament light and YKL-40 in cerebrospinal fluid are related to poor outcome in ALS.

Amyotrophic lateral sclerosis (ALS) is a neurological disease without effective treatment. No pathognomonic test can diagnose ALS in sporadic cases. Routine investigation in suspected cases includes neurological examination, imaging of the brain and spine and electromyography supported by blood and cerebrospinal fluid (CSF) analyses. The ALS diagnosis is made by clinical judgement and results from examinations. We aimed to study if the CSF biomarkers neurofilament light protein (NFL), glial fibrillary acidic protein (GFAP), YKL-40, soluble amyloid precursor protein (sAPP) α and ß, and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) were associated with ALS diagnosis and could predict disease progression. Eighty-one patients with suspected ALS were included after referral to the neurological clinic at Sahlgrenska University Hospital. Fifty-nine patients were diagnosed having ALS, while 22 patients were given alternative diagnoses and labeled ALS mimics. Finally, 25 age-matched neurologically intact individuals were used as controls. ALS patients had significantly higher CSF levels of NFL than controls and mimics. Levels of YKL-40 and GFAP were significantly higher in ALS patients compared with controls. No difference was found between study groups when comparing levels of sAPPα, sAPPß and sTREM2. Further, elevated levels of NFL and YKL-40 were associated with an increased hazard of death and the annual decline in ALSFRS-R. We also found that patients with elevated levels of both NFL and YKL-40 had a particularly poor prognosis. The results demonstrate the usefulness of CSF biomarkers in the diagnosis and prognostication of ALS.

Radiological appearance and lung function six months after invasive ventilation in ICU for COVID-19 pneumonia: An observational follow-up study.

BACKGROUND: Respiratory functional sequelae in COVID-19 patients admitted to the intensive care unit for invasive ventilation are sparsely reported. The aim of this study was to investigate the radiological lung appearance, lung function and their association at 6 months after hospital discharge. It was hypothesized that the degree of pathological morphology on CT scans would correlate with lung function at the time of follow-up. METHODS AND FINDINGS: In this single-centre prospective observational study, 86 from 154 patients admitted to ICU due to COVID-19 between March 2020 and May 2021 were followed up at 6 months post discharge with computed tomography (CT) of the chest and pulmonary function tests (PFTs). The PFT results were expressed as z-scores calculated as the difference between the measured and predicted values divided by the standard deviation obtained from a reference population. Correlations were evaluated by Spearman's rho including the 95% confidence interval. Pathological changes on CT were found in 78/85 participants with fibrous parenchymal bands being the most prevalent finding (91%) followed by traction bronchiectasis (64%) and ground glass opacities (41%). Sixty-five participants performed PFTs, and a restrictive pattern was the most prevalent abnormality (34%). Diffusing capacity of the lung for carbon monoxide (DLCO) was reduced in 66% of participants. The CT severity score weakly correlated with forced vital capacity (FVC) z-score (0.295, p = 0.006), DLCO z-score (-0.231, p = 0.032) and alveolar volume (VA) z-score (0.253, p = 0.019). CONCLUSIONS: Most patients showed persistent radiological abnormalities on CT and reduced lung volumes, impaired diffusion capacity and patterns of restrictive lung function at 6 months post discharge from the ICU. The correlations between abnormalities on CT and lung function tests were weak. Further, studies with a long-term follow-up of lung function in this group of patients are needed.

Fractional spinal anesthesia and systemic hemodynamics in frail elderly hip fracture patients.

Background: Systemic haemodynamic effects of intrathecal anaesthesia in an aging and frail population has not been well investigated. We examined the systemic haemodynamics of fractional spinal anaesthesia following intermittent microdosing of a local anaesthetic and an opioid. Methods: We included 15 patients aged over 65 with significant comorbidities, planned for hip fracture repair. Patients received a spinal catheter and cardiac output monitoring using the LiDCOplus system. All measurements were performed prior to start of surgery. Invasive mean arterial pressure (MAP), cardiac index (CI), systemic vascular resistance index (SVRI), heart rate and stroke volume index (SVI) were registered. Two doses of bupivacaine 2.25 mg and fentanyl 15 µg were administered with 25-minute intervals. Hypotension was defined as a fall in MAP by >30% or a MAP <65 mmHg. Results: The incidence of hypotension was 30%. Hypotensive patients (n=5) were treated with low doses of norepinephrine (0.01-0.12 µg/kg/min). MAP showed a maximum reduction of 17% at 10 minutes following the first dose. CI, systemic vascular resistance index and stroke volume index decreased by 10%, 6%, and 7%, respectively, while heart rate was unchanged over time. After the second dose, none of the systemic haemodynamic variables were affected. Conclusions: Fractional spinal anaesthesia administered prior to surgery induced a minor to moderate fall in MAP, mainly caused by a reduction in cardiac output, induced by systemic venodilation, causing a fall in venous return. Our results are contrary to the widely held belief that hypotension is mainly the result of a reduction of systemic vascular resistance.

α-Synuclein seed amplification assay as a diagnostic tool for parkinsonian disorders.

INTRODUCTION: Synucleinopathies such as Parkinson's disease (PD) and multiple system atrophy (MSA) can be challenging to diagnose due to the symptom overlap with, for example, atypical parkinsonisms like progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Seed amplification assays (SAA), developed for the detection of α-synuclein (αSyn) aggregates in CSF, have been successful when used as a biomarker evaluation for synucleinopathies. In this study, we investigated the potential of this assay to not only detect αSyn seeds in CSF, but also discriminate between movement disorders. METHODS: The αSyn-SAA was tested in a Scandinavian cohort composed of 129 CSF samples from patients with PD (n = 55), MSA (n = 27), CBD (n = 7), and PSP (n = 16), as well as healthy controls (HC, n = 24). RESULTS: The αSyn seed amplification assay (αSyn-SAA) was able to correctly identify all PD samples as positive (sensitivity of 100%) while also discriminating the PD group from HC (70.8% specificity, p < 0.0001) and tauopathies [CBD (71% specificity) and PSP (75% specificity), p < 0.0001)]. The αSyn-SAA was also able to identify almost all MSA samples as positive for αSyn aggregation (sensitivity of 92.6%). In general, this assay is able to discriminate between the synucleinopathies and tauopathies analyzed herein (p < 0.0001) despite the overlapping symptoms in these diseases. CONCLUSION: These findings suggest the αSyn-SAA is a useful diagnostic tool for differentiating between different parkinsonian disorders, although further optimization may be needed.

Sex difference in circulating soluble form of ACE2 protein in moderate and severe COVID-19 and healthy controls.

Introduction: Membrane-bound angiotensin-converting enzyme-2 (ACE2) in epithelial cells is the main receptor for SARS-CoV-2. The extracellular portion of ACE2 may be shedded to plasma in which process ADAM17 (a disintegrin and metalloproteinase 17) is important. Results on the relationship between circulating levels of the soluble form of ACE2 (sACE2) and disease severity are inconclusive. This study investigates if sACE2 concentration correlates with COVID-19 severity, and whether this is affected by sex. Materials and methods: Soluble form of ACE2 was analyzed in three groups: 104 patients (23 women and 81 men) with severe COVID-19 admitted to an intensive care unit (ICU), patients with moderate COVID-19 who required hospital care (n = 19, 4 women and 15 men), and age and sex matched healthy controls (n = 20, 4 women and 16 men). Blood samples were collected at hospital admission between 18 March 2020, and 3 May 2021, and at follow-up between 27 October 2020, and 19 October 2021. Circulating sACE2 (µg/L) was measured in EDTA plasma with a sensitive enzyme-linked immunosorbent assay. Additionally, CRP, ferritin, and lymphocyte count were analyzed during hospital stay. Results: In total, 23 patients (22%) died in the ICU. When comparing healthy controls [mean age 58.1 (SD 11.4) years] and patients with moderate COVID-19 [mean age 61.0 (SD 13.2) years] with patients in the ICU [mean age 63.6 (SD 11.6) years], we found that sACE2 concentration decreased (70% reduction) with disease severity in men (p = 0.002) but increased 3.7-fold with severity in women (p = 0.043), suggesting a sex-related difference in how COVID-19 severity is related to sACE2 concentration. Moreover, we identified a relationship between inflammatory biomarkers and sACE2 concentration during the intensive care treatment, such that higher CRP and higher ferritin concentration correlated with lower sACE2 concentration in men. Conclusion: The decrease in sACE2 concentration, selectively in men, in severe COVID-19 is of pathophysiological interest since men are affected more severely by the disease compared to women. Additionally, the inflammatory biomarkers, CRP and ferritin, correlated inversely with sACE2 concentration, suggesting a role in severe disease. Our findings imply that sACE2 is a possible biomarker of disease severity in a sex-specific manner.

Cardiac involvement in critically ill and mechanically ventilated patients with COVID-19 - a prospective, observational echocardiographic study.

INTRODUCTION: In this prospective, observational study, we have evaluated right (RV) and left (LV) ventricular function with echocardiography and correlated it to the levels of biomarkers, hs-TNT, NT-pro-BNP, D-dimer and fibrinogen. In a subgroup, we have evaluated the effect of inhaled milrinone on RV afterload and function. METHODS: Thirty-one ICU patients with COVID-19 in need of mechanical ventilation and norepinephrine infusion were prospectively included. Hemodynamic and respiratory variables were measured at the time of the echocardiographic examination and biomarkers were obtained on arrival at the ICU and then followed up routinely. Eight patients received inhaled aerosolized milrinone at a dose of 2.5 mg/hour. RESULTS: The most common echocardiographic pattern was RV dilation with or without systolic dysfunction, which was found in 62% of patients. Pulmonary acceleration time was abnormal in 55% and indices of RV systolic function, such as fractional area of change, RV strain, were abnormal in 30% and 31% of patients respectively. A cardiac index of < 2.5 l/min*m2 was seen in 58% of the patients. Left ventricular ejection fraction and global left ventricular strain were impaired in 10% and 16% respectively. The correlation between echocardiographic variables and cardiac biomarkers was poor. RV afterload correlated well to the levels of D-dimer. Milrinone inhalation did not improve RV function or afterload. CONCLUSION: RV dysfunction was the most common finding. The poor correlation to cardiac biomarkers argues against extensive myocardial involvement. The lack of improvement in RV function after milrinone inhalation suggests that the most likely cause of RV dysfunction is increased RV afterload caused by pulmonary thrombosis/embolism.