Mitochondrial dysfunction in long COVID: mechanisms, consequences, and potential therapeutic approaches.

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has introduced the medical community to the phenomenon of long COVID, a condition characterized by persistent symptoms following the resolution of the acute phase of infection. Among the myriad of symptoms reported by long COVID sufferers, chronic fatigue, cognitive disturbances, and exercise intolerance are predominant, suggesting systemic alterations beyond the initial viral pathology. Emerging evidence has pointed to mitochondrial dysfunction as a potential underpinning mechanism contributing to the persistence and diversity of long COVID symptoms. This review aims to synthesize current findings related to mitochondrial dysfunction in long COVID, exploring its implications for cellular energy deficits, oxidative stress, immune dysregulation, metabolic disturbances, and endothelial dysfunction. Through a comprehensive analysis of the literature, we highlight the significance of mitochondrial health in the pathophysiology of long COVID, drawing parallels with similar clinical syndromes linked to post-infectious states in other diseases where mitochondrial impairment has been implicated. We discuss potential therapeutic strategies targeting mitochondrial function, including pharmacological interventions, lifestyle modifications, exercise, and dietary approaches, and emphasize the need for further research and collaborative efforts to advance our understanding and management of long COVID. This review underscores the critical role of mitochondrial dysfunction in long COVID and calls for a multidisciplinary approach to address the gaps in our knowledge and treatment options for those affected by this condition.

Gravity sedimentation reveals functionally and morphologically different platelets in human blood.

In contrast to red blood cells, platelets float rather than sediment when a column of blood is placed in the gravitational field. By the analogy of erythrocyte sedimentation (ESR), it can be expressed with the platelet antisedimentation rate (PAR), which quantitates the difference in platelet count between the upper and lower halves of the blood column after 1 h of 1 g sedimentation. Venous blood samples from 21 healthy subjects were analyzed for PAR. After a 1-h sedimentation, the upper and lower fractions of blood samples were analyzed for platelet count, mean platelet volume (MPV), immature platelet fraction (IPF), and high-fluorescence IPF (H-IPF). The mechanisms behind platelet flotation were explored by further partitioning of the blood column, time-dependent measurements of platelet count and comparison with ESR. The structure and function of the platelets were assessed by electron microscopy (EM) and atomic force microscopy (AFM), and platelet aggregometry, respectively. Platelet antisedimentation is driven by density differences and facilitated by a size-exclusion mechanism caused by progressive erythrocyte sedimentation. The area under the curve (AUC) of the whole blood adenosine diphosphate (ADP) aggregation curves showed significant differences between the upper and lower samples (p < .005). AUC in the upper samples of 38% of healthy subjects exceeded the top of the normal range (53-122) suggesting that ascending platelets show an intensified ADP-induced aggregability ex vivo. H-IPF was significantly higher in the upper samples (p < .05). EM and AFM revealed that platelets in the upper samples were larger in volume and contained 1.6 times more alpha granules compared to platelets in the lower samples. Our results indicate that antisedimentation is able to differentiate platelet populations based on their structural and functional properties. Therefore, PAR may be a suitable laboratory parameter in various thromboinflammatory disorders.

It is less known that platelets do not sediment in response to gravitational force but float on the top of the blood column. This phenomenon is called antisedimentation, the rate of which, however, can be different, yet this feature has not been widely studied and used in clinical practice or diagnosis. We tested the idea that antisedimentation of platelets from venous blood samples can be a potential biomarker. We have found that platelet antisedimentation is driven by density differences and facilitated by a size-exclusion mechanism caused by progressive erythrocyte sedimentation and after 1-h upper and lower fractions develop. Interestingly, the aggregation curves showed significant differences between the upper and lower samples, suggesting that the ascending platelets show ex vivo hyperaggregability. Electron and atomic force microscopy revealed that platelets in the upper samples were larger in volume and contained more alpha granules than platelets in the lower samples. Subsequently, antisedimentation can be used to differentiate platelet populations based on their structural and functional properties; thus, it may be a promising biomarker for various thromboinflammatory disorders.

Acute Phase Protein Orosomucoid (Alpha-1-Acid Glycoprotein) Predicts Delayed Cerebral Ischemia and 3-Month Unfavorable Outcome after Aneurysmal Subarachnoid Hemorrhage.

The pathophysiology and consequences of early brain injury (EBI) after aneurysmal subarachnoid hemorrhage (aSAH) remain incompletely understood. This study aims to investigate the role of orosomucoid (ORM) in aSAH, its potential as a marker for assessing the extent of EBI-induced damage, and its correlation with delayed cerebral ischemia (DCI) and functional recovery over a 3-month period. We collected serum specimens 72 h post-aSAH to measure ORM levels. The study included 151 aSAH patients and 105 healthy subjects. The serum ORM levels within the patient cohort significantly exceeded those in the control group (p < 0.001). The ORM value showed significant correlation with the admission WFNS (p < 0.0001) and mFS scores (p < 0.05). Substantially elevated serum ORM levels at 72 h post-aSAH were detected among patients experiencing DCI, as well as those with poor functional outcomes after 3 months (p = 0.009 and p < 0.001). Binary logistic regression analyses revealed that serum ORM at 72 h post-SAH was independently associated with DCI and 3-month functional outcome after adjusting for confounders. The early stage events of aSAH influence the level of ORM. ORM serves as a marker for assessing the extent of damage during EBI and is linked to the occurrence of DCI as well as unfavorable long-term functional outcomes.

Different Kinetics of Serum ADAMTS13, GDF-15, and Neutrophil Gelatinase-Associated Lipocalin in the Early Phase of Aneurysmal Subarachnoid Hemorrhage.

Growth differentiation factor 15 (GDF-15), neutrophil gelatinase-associated lipocalin (NGAL), and ADAMTS13 have previously been implicated in the pathophysiological processes of SAH. In the present study, we aim to examine their role in the early period of SAH and their relationship to primary and secondary outcomes. Serum samples were collected at five time periods after SAH (at 24 h (D1), at 72 h (D3), at 120 h (D5), at 168 h (D7) and at 216 h (D9), post-admission) and) were measured by using MILLIPLEX Map Human Cardiovascular Disease (CVD) Magnetic Bead Panel 2. We included 150 patients with SAH and 30 healthy controls. GDF-15 levels at D1 to D9 were significantly associated with a 3-month unfavorable outcome. Based on the ROC analysis, in patients with a good clinical grade at admission (WFNS I-III), the GDF-15 value measured at time point D3 predicted a 3-month unfavorable outcome (cut-off value: 3.97 ng/mL, AUC:0.833, 95%CI: 0.728-0.938, sensitivity:73.7%, specificity:82.6%, p < 0.001). Univariate binary logistic regression analysis showed that serum NGAL levels at D1-D5 and ADAMTS13 levels at D7-D9 were associated with MVS following SAH. GDF-15 is an early indicator of a poor 3-month functional outcome even in patients with mild clinical conditions at admission.

Cystatin-c May Indicate Subclinical Renal Involvement, While Orosomucoid Is Associated with Fatigue in Patients with Long-COVID Syndrome.

Long-COVID syndrome is associated with high healthcare costs, but its pathophysiology is not yet fully understood. Inflammation, renal impairment or disturbance of the NO system emerge as potential pathogenetic factors. We aimed to investigate the relationship between symptoms of long-COVID syndrome and serum levels of cystatin-c (CYSC), orosomucoid (ORM), l-arginine, symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA). A total of 114 patients suffering from long-COVID syndrome were included in this observational cohort study. We found that serum CYSC was independently associated with the anti-spike immunoglobulin (S-Ig) serum level (OR: 5.377, 95% CI: 1.822-12.361; p = 0.02), while serum ORM (OR: 9.670 (95% CI: 1.34-9.93; p = 0.025) independently predicted fatigue in patients with long-COVID syndrome, both measured at baseline visit. Additionally, the serum CYSC concentrations measured at the baseline visit showed a positive correlation with the serum SDMA levels. The severity of abdominal and muscle pain indicated by patients at the baseline visit showed a negative correlation with the serum level of L-arginine. In summary, serum CYSC may indicate subclinical renal impairment, while serum ORM is associated with fatigue in long-COVID syndrome. The potential role of l-arginine in alleviating pain requires further studies.

Adverse Reactions after Booster SARS-CoV-2 Vaccination Have Less Impact on Antibody Response than after Basic Vaccination Scheme.

BACKGROUND: It is known that adverse reactions following SARS-CoV-2 vaccinations show a positive correlation with the subsequent antibody titer. However, it is not clear how the adverse reactions following the booster vaccination are related to the antibody levels that can be measured after a 3rd dose. The primary goal of this study was to investigate whether the adverse reactions following the booster vaccination show a correlation with subsequent antibody levels. METHODS: Adverse reactions occurring within 7 days after the 3rd vaccination were recorded and the anti-SARS-CoV-2 spike protein immunoglobulin (Ig) level in the venous blood was measured on post-vaccination 14th, 60th and 120th days. RESULTS: A total of 218 volunteers were included in the study. MAIN FINDINGS: (i) The adverse reactions that appeared after the booster dose did not show a positive correlation with the subsequent antibody level, except a correlation in the case of fever; (ii) there were more symptomatic patients in the group receiving heterologous booster vaccine, (iii) fever after the 2nd dose was independently associated with a reduction in the likelihood of COVID-19 positivity after the booster dose. CONCLUSION: No adverse reactions, but fever showed a correlation with the antibody level after the booster SARS-CoV-2 vaccine.

Serum Periostin May Help to Identify Patients with Poor Collaterals in the Hyperacute Phase of Ischemic Stroke.

Background: Periostin is a glycoprotein that mediates cell functions in the extracellular matrix and appears to be a promising biomarker in neurological damage, such as ischemic stroke (IS). We aimed to measure serum periostin levels in the hyperacute phase of ischemic stroke to explore its predictive power in identification of patients with poor collaterals (ASPECT < 6). Methods: We prospectively enrolled 122 patients with acute ischemic stroke within the first 6 h after onset. The early ischemic changes were evaluated by calculating ASPECT score on admission using a native CT scan. An unfavorable outcome was defined as the modified Rankin Scale (mRS) > 2 at 90 days follow-up. Blood samples were collected on admission immediately after CT scan and periostin serum concentrations were determined by ELISA. Results: The admission concentration of serum periostin was significantly higher in patients with unfavorable outcome than in patients with favorable outcome (615 ng/L, IQR: 443−1070 vs. 390 ng/L, 260−563, p < 0.001). In a binary logistic regression model, serum periostin level was a significant predictor for ASPECT < 6 status on admission, within 6 h after stroke onset (OR, 5.911; CI, 0.990−0.999; p = 0.015). Conclusion: Admission periostin levels can help to identify patients who are not suitable for neurointervention, especially if advanced neuroimaging is not available.

Biomarker Associations in Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Hemorrhage.

The prognosis for patients with aneurysmal subarachnoid hemorrhage (aSAH) is heavily influenced by the development of delayed cerebral ischemia (DCI), but the adequate and effective therapy of DCI to this day has not been resolved. Multiplex serum biomarker studies may help to understand the pathophysiological processes underlying DCI. Samples were collected from patients with aSAH at two time points: (1) 24 h (Day 1) and (2) 5−7 days after ictus. Serum concentrations of eotaxin, FGF-2, FLT-3L, CX3CL1, Il-1b, IL-4, IP-10, MCP3, and MIP-1b were determined using a customized MILLIPLEX Human Cytokine/Chemokine/Growth Factor Panel A multiplex assay. The functional outcome was defined by the modified Rankin scale (favorable: 0−2, unfavorable: 3−6) measured on the 30th day after aSAH. One-hundred and twelve patients with aSAH were included in this study. The median level of CX3CL1 and MCP-3 measured on Days 5−7 were significantly higher in patients with DCI compared with those without DCI (CX3CL1: with DCI: 110.5 pg/mL, IQR: 82−201 vs. without DCI: 82.6, 58−119, p = 0.036; and MCP-3: with DCI: 22 pg/mL (0−32) vs. without DCI: 0 (0−11), p < 0.001). IP-10, MCP-3, and MIP-1b also showed significant associations with the functional outcome after aSAH. MCP-3 and CX3CL1 may play a role in the pathophysiology of DCI.

General Anesthesia-Related Drop in Diastolic Blood Pressure May Impact the Long-Term Outcome in Stroke Patients Undergoing Thrombectomy.

Background: Several factors affect the efficacy of endovascular thrombectomy (EVT); however, the anesthesia-related factors have not been fully explored. We aimed to identify independent predictors of outcome by analyzing procedural factors based on a multicentric stroke registry. Methods: Data of consecutive patients with acute ischemic stroke (AIS) were extracted from the prospective STAY ALIVE stroke registry. Demographic, clinical, and periprocedural factors including hemodynamic values were analyzed in patients undergoing thrombectomy with either general anesthesia (GA) or conscious sedation (CS). Independent predictors of outcome both at 30 and 90 days based on the modified Rankin Scale (mRS: 0−2 as favorable outcome) were also explored. Results: A total of 199 patients (GA: 76 (38%) vs. CS: 117 (59%); in addition, six patients were converted from CS to GA) were included. The minimum value of systolic, diastolic, and mean arterial pressure was significantly lower in the GA compared to the CS group, and GA was associated with a longer onset to EVT time and a higher drop in all hemodynamic variables (all, p < 0.001). A higher drop in diastolic blood pressure (DBP) was even independently associated with a poor 90-day outcome (p = 0.024). Conclusion: A GA-related drop in DBP may independently predict a poor long-term outcome in stroke patients undergoing thrombectomy.

Circulating Microvesicles in Convalescent Ischemic Stroke Patients: A Contributor to High-On-Treatment Residual Platelet Reactivity?

INTRODUCTION: Exploration of novel and effective antiplatelet strategies for the secondary prevention of ischemic stroke is utmost. Some platelet derived microparticles (PMVs) in convalescent stroke subjects were found to be predictive for the next vascular event. Patients with high-on-treatment platelet reactivity (HTPR) had a significantly higher risk for ischemic stroke. Here, we aimed to explore associations among circulating microparticles and responsivness to antiplatelet (clopidogrel) therapy. METHODS: A total of 18 patients on clopidogrel therapy due to secondary stroke prevention were rospectively recruited into this study. Twenty age-matched healthy subjects served as controls. Flow cytometric measurements of microparicles (MVs) and data analysis were performed on Beckman-Coulter FC-500 cytometer with CXP software. Besides, platelet aggregometry data were revealed. Both measurements were performed in whole blood and from the lower and upper blood fractions separated after 1-hour gravity sedimentation by the analogy with erythrocyte sedimentation rate. RESULTS: The total number of circulating MVs, and particularly the platelet derived CD42+ and PAC-1+ were significantly higher in post-stroke patients (p < 0.001). The platelet aggregation in the whole blood (area under the curve, AUC) showed a significant negative correlation with the total number of MPs in the lower blood sample after 1-hour gravity sedimentation (r = -0.650, p = 0.005). Next, we analyzed associations among MPs and aggregometry data obtained from clopidogrel responders and non-responders. Both, area under the curve (AUC) and velocity in the whole blood showed opposite correlation with the total number of MVs in the lower blood sample after 1-hour gravity sedimentation. Importantly, a significant negative correlation was observed for the velocity (r = -0.801, p = 0.005), but not for the AUC in responders. Platelet derived CD42+ and PAC-1+ MVs showed positive correlations with neutrophils in the lower blood sample (p = 0.008 and p = 0.006 respectively). CONCLUSIONS: Circulating MVs may allow to monitor the response to antiplatelet therapy in post-stroke patients. In addition, the link between platelet derived MVs and neutrophil granulocytes might become therapeutic targets in the future.

Fever after Vaccination against SARS-CoV-2 with mRNA-Based Vaccine Associated with Higher Antibody Levels during 6 Months Follow-Up.

BACKGROUND: The effect of post-vaccination adverse events on immunogenicity is unknown. We aimed to explore relationship between post-vaccination adverse reactions and antibody levels during 6-month follow-up. METHODS: Blood was serially drawn from healthcare workers after the second dose of BNT162b2 mRNA vaccine (Day 12, 30, 60, 90, 120, 150, and 180) and anti-SARS-CoV-2 spike IgG (S-IgG) levels were measured. Following each vaccine dose, volunteers completed a questionnaire regarding adverse reactions (symptomatic vs. asymptomatic groups). RESULTS: A total of 395 subjects received the second dose of the vaccine. The main results were as follows: (i) fever after the 2nd dose was independently associated with the median S-IgG level at all follow-up time points; (ii) significantly higher S-IgG levels were observed in the symptomatic group of patients without prior COVID-19 infection throughout the entire follow-up period; (iii) prior COVID-19 positivity resulted in higher S-IgG levels only in the asymptomatic group from Day 90 of the follow-up period; (iv) both prior COVID-19 disease with asymptomatic status and symptomatic status without prior COVID-19 infection resulted in similar S-IgG antibody levels; (v) significantly lower serum S-IgG levels were observed in smokers. CONCLUSION: Fever may play an important role in the post-vaccination immune response in the long term.

Serum Level of Anti-Nucleocapsid, but Not Anti-Spike Antibody, Is Associated with Improvement of Long COVID Symptoms.

BACKGROUND: Long COVID is a condition characterized by long-term sequelae persisting after the typical convalescence period of COVID-19. Previous reports have suggested the role of an unsatisfactory immune response and impaired viral clearance in the pathogenesis of long COVID syndrome. We focused on potential associations between post-vaccination changes of antibody titers and the severity of long COVID symptoms and factors influencing the state of remission observed in patients with long COVID after vaccination. METHODS: The severity of long COVID symptoms and serum anti-SARS-CoV-2 spike (S-Ig) and nucleocapsid (NC-Ig) levels were assessed in 107 post-COVID subjects at two time points: at baseline, and 17-24 weeks later. Besides, vaccination status was also assessed. Symptoms were evaluated based on the Chalder fatigue scale (CFQ-11) and visual analogue scale (VAS). RESULTS: Serum level of S-Ig and NC-Ig at baseline were significantly higher in the patients with non-severe fatigue than those with severe fatigue, and this difference remained significant at follow-up in the case of NC-Ig. NC-Ig level above median was as an independent predictor for complete remission at follow-up. The difference in NC-Ig levels in subgroup analyses (severe fatigue vs. non-severe fatigue; complete remission vs. incomplete remission or progression) was found to be significant only in patients who received vaccination. CONCLUSIONS: The immune response against the SARS-CoV-2 nucleocapsid may play a more important role than the spike in the course of long-term COVID syndrome.

Clinical Frailty Scale (CFS) indicated frailty is associated with increased in-hospital and 30-day mortality in COVID-19 patients: a systematic review and meta-analysis.

BACKGROUND: The concept of frailty provides an age-independent, easy-to-use tool for risk stratification. We aimed to summarize the evidence on the efficacy of frailty tools in risk assessment in COVID-19 patients. METHODS: The protocol was registered (CRD42021241544). Studies reporting on frailty in COVID-19 patients were eligible. The main outcomes were mortality, length of hospital stay (LOH) and intensive care unit (ICU) admission in frail and non-frail COVID-19 patients. Frailty was also compared in survivors and non-survivors. Five databases were searched up to 24th September 2021. The QUIPS tool was used for the risk of bias assessment. Odds ratios (OR) and weighted mean differences (WMD) were calculated with 95% confidence intervals (CI) using a random effect model. Heterogeneity was assessed using the I2 and χ2 tests. RESULTS: From 3640 records identified, 54 were included in the qualitative and 42 in the quantitative synthesis. Clinical Frailty Scale (CFS) was used in 46 studies, the Hospital Frailty Risk Score (HFRS) by 4, the Multidimensional Prognostic Index (MPI) by 3 and three studies used other scores. We found that patients with frailty (CFS 4-9 or HFRS ≥ 5) have a higher risk of mortality (CFS: OR: 3.12; CI 2.56-3.81; HFRS OR: 1.98; CI 1.89-2.07). Patients with frailty (CFS 4-9) were less likely to be admitted to ICU (OR 0.28, CI 0.12-0.64). Quantitative synthesis for LOH was not feasible. Most studies carried a high risk of bias. CONCLUSIONS: As determined by CFS, frailty is strongly associated with mortality; hence, frailty-based patient management should be included in international COVID-19 treatment guidelines. Future studies investigating the role of frailty assessment on deciding ICU admission are strongly warranted.

L-arginine, asymmetric and symmetric dimethylarginine for early outcome prediction in unselected cardiac arrest victims: a prospective cohort study.

Early prediction of the mortality, neurological outcome is clinically essential after successful cardiopulmonary resuscitation. To find a prognostic marker among unselected cardiac arrest survivors, we aimed to evaluate the alterations of the L-arginine pathway molecules in the early post-resuscitation care. We prospectively enrolled adult patients after successfully resuscitated in- or out-of-hospital cardiac arrest. Blood samples were drawn within 6, 24, and 72 post-cardiac arrest hours to measure asymmetric and symmetric dimethylarginine (ADMA and SDMA) and L-arginine plasma concentrations. We recorded Sequential Organ Failure Assessment, Simplified Acute Physiology Score, and Cerebral Performance Category scores. Endpoints were 72 h, intensive care unit, and 30-day mortality. Among 54 enrolled patients [median age: 67 (61-78) years, 48% male], the initial ADMA levels were significantly elevated in those who died within 72 h [0.88 (0.64-0.97) µmol/L vs. 0.55 (0.45-0.69) µmol/L, p = 0.001]. Based on receiver operator characteristic analysis (AUC = 0.723; p = 0.005) of initial ADMA for poor neurological outcome, the best cutoff was determined as > 0.65 µmol/L (sensitivity = 66.7%; specificity = 81.5%), while for 72 h mortality (AUC = 0.789; p = 0.001) as > 0.81 µmol/L (sensitivity = 71.0%; specificity = 87.5%). Based on multivariate analysis, initial ADMA (OR = 1.8 per 0.1 µmol/L increment; p = 0.002) was an independent predictor for 72 h mortality. Increased initial ADMA predicts 72 h mortality and poor neurological outcome among unselected cardiac arrest victims.

Plasma Fibrinogen Independently Predicts Hypofibrinolysis in Severe COVID-19.

High rates of thrombosis are present in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Deeper insight into the prothrombotic state is essential to provide the best thromboprophylaxis care. Here, we aimed to explore associations among platelet indices, conventional hemostasis parameters, and viscoelastometry data. This pilot study included patients with severe COVID-19 (n = 21) and age-matched controls (n = 21). Each patient received 100 mg aspirin therapy at the time of blood sampling. Total platelet count, high immature platelet fraction (H-IPF), fibrinogen, D-dimer, Activated Partial Thromboplastin Time, von Willebrand factor antigen and von Willebrand factor ristocetin cofactor activity, plasminogen, and alpha2-antiplasmin were measured. To monitor the aspirin therapy, a platelet function test from hirudin anticoagulated whole blood was performed using the ASPI test by Multiplate analyser. High on-aspirin platelet reactivity (n = 8) was defined with an AUC > 40 cut-off value by ASPI tests. In addition, in vitro viscoelastometric tests were carried out using a ClotPro analyser in COVID-associated thromboembolic events (n = 8) (p = 0.071) nor the survival rate (p = 0.854) showed associations with high on-aspirin platelet reactivity status. The platelet count (p = 0.03), all subjects. COVID-19 patients presented with higher levels of inflammatory markers, compared with the controls, along with evidence of hypercoagulability by ClotPro. H-IPF (%) was significantly higher among non-survivors (n = 18) compared to survivors (p = 0.011), and a negative correlation (p = 0.002) was found between H-IPF and plasminogen level in the total population. The platelet count was significantly higher among patients with high on-aspirin platelet reactivity (p = 0.03). Neither the ECA-A10 (p = 0.008), and ECA-MCF (p = 0.016) were significantly higher, while the tPA-CFT (p < 0.001) was significantly lower among patients with high on-aspirin platelet reactivity. However, only fibrinogen proved to be an independent predictor of hypofibrinolysis in severe COVID-19 patients. In conclusion, a faster developing, more solid clot formation was observed in aspirin 'non-responder' COVID-19 patients. Therefore, an individually tailored thromboprophylaxis is needed to prevent thrombotic complications, particularly in the hypofibrinolytic cluster.

Cerebral and Systemic Stress Parameters in Correlation with Jugulo-Arterial CO2 Gap as a Marker of Cerebral Perfusion during Carotid Endarterectomy.

Intraoperative stress is common to patients undergoing carotid endarterectomy (CEA); thus, impaired oxygen and metabolic balance may appear. In this study, we aimed to identify new markers of intraoperative cerebral ischemia, with predictive value on postoperative complications during CEA, performed in regional anesthesia. A total of 54 patients with significant carotid stenosis were recruited and submitted to CEA. Jugular and arterial blood samples were taken four times during operation, to measure the jugulo-arterial carbon dioxide partial pressure difference (P(j-a)CO2), and cortisol, S100B, L-arginine, and lactate levels. A positive correlation was found between preoperative cortisol levels and all S100B concentrations. In addition, they are positively correlated with P(j-a)CO2 values. Conversely, postoperative cortisol inversely correlates with P(j-a)CO2 and postoperative S100B values. A negative correlation was observed between maximum systolic and pulse pressures and P(j-a)CO2 after carotid clamp and before the release of clamp. Our data suggest that preoperative cortisol, S100B, L-arginine reflect patients' frailty, while these parameters postoperatively are influenced by intraoperative stress and injury. As a novelty, P(j-a)CO2 might be an emerging indicator of cerebral blood flow during CEA.

Severe Fatigue and Memory Impairment Are Associated with Lower Serum Level of Anti-SARS-CoV-2 Antibodies in Patients with Post-COVID Symptoms.

BACKGROUND: Post-COVID manifestation is defined as persistent symptoms or long-term complications beyond 4 weeks from disease onset. Fatigue and memory impairment are common post-COVID symptoms. We aimed to explore associations between the timeline and severity of post-COVID fatigue and anti-SARS-CoV-2 antibodies. METHODS: Fatigue and memory impairment were assessed in a total of 101 post-COVID subjects using the Chalder fatigue scale (CFQ-11) and a visual analogue scale. Using the bimodal scoring system generated from CFQ-11, a score ≥4 was defined as severe fatigue. Serum anti-SARS-CoV-2 spike (anti-S-Ig) and nucleocapsid (anti-NC-Ig) antibodies were examined at two time points: 4-12 weeks after onset of symptoms, and beyond 12 weeks. RESULTS: The serum level of anti-S-Ig was significantly higher in patients with non-severe fatigue compared to those with severe fatigue at 4-12 weeks (p = 0.006) and beyond 12 weeks (p = 0.016). The serum level of anti-NC-Ig remained high in patients with non-severe fatigue at both time points. In contrast, anti-NC-Ig decreased significantly in severe fatigue cases regardless of the elapsed time (4-12 weeks: p = 0.024; beyond 12 weeks: p = 0.005). The incidence of memory impairment was significantly correlated with lower anti-S-Ig levels (-0.359, p < 0.001). CONCLUSION: The systemic immune response reflected by antibodies to SARS-CoV-2 is strongly correlated with the severity of post-COVID fatigue.

Fatty Acid-Binding Protein 3 and CXC-Chemokine Ligand 16 are Associated with Unfavorable Outcome in Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) is associated with activation of the inflammatory cascade contributing to unfavorable outcome and secondary complications, such as delayed cerebral ischemia (DCI). Both fatty acid-binding protein 3 (FABP3) and CXC-chemokine ligand 16 (CXCL-16) have been linked to vascular inflammation and cellular death. The authors aimed to assess the 30-day prognostic value of serum levels of FABP3 and CXCL-16 and explore their associations with DCI in aSAH patients. METHODS: A total of 60 patients with aSAH were prospectively enrolled. Sampling for markers was done at 24 hours after the index event. FABP3 and CXCL-16 serum concentrations were determined by MilliPlex multiplex immunoassay method. The primary endpoint was unfavorable outcome at Day 30 based on the modified Rankin Scale. RESULTS: Both FABP3 and CXCL-16 levels were significantly elevated in patients with unfavorable outcome compared to those with favorable outcome after aSAH (FABP3: 2133 pg/mL, IQR: 1053-4567 vs. 3773, 3295-13116; p<0.003 and CXCL-16: 384 pg/mL, 313-502 vs. 498, 456-62, p<0.001). The area under the curve (AUC) for serum CXCL-16 levels as a predictor of unfavorable outcome at Day 30 was 0.747 (95% CI =0.622-0.871; p<0.001). Based on binary logistic regression analysis, serum CXCL-16 with a cut-off level >446.7 ng/L independently predicted Day 30 unfavorable outcome with a sensitivity of 81% and a specificity of 62%. Neither CXCL-16 nor FABP3 showed a significant correlation with DCI. CONCLUSION: Early FABP3 and CXCL-16 levels are significantly associated with poor 30-day outcome in patients with aSAH.

Novel Predictors of Future Vascular Events in Post-stroke Patients-A Pilot Study.

Introduction: A modified platelet function test (mPFT) was recently found to be superior compared to impedance aggregometry for selection of post-stroke patients with high on-treatment platelet reactivity (HTPR). We aimed to explore some peripheral blood cell characteristics as predictors of recurrent ischemic episodes. The predictive value of mPFT was also assessed in a cohort followed up to 36 months regarding recurrent ischemic vascular events. Methods: As a novelty, not only whole blood (WB), but after 1-h gravity sedimentation the separated upper (UB) and lower half blood (LB) samples were analyzed including neutrophil antisedimentation rate (NAR) in 52 post-stroke patients taking clopidogrel. Area under the curve (AUC, AUCupper and AUClower, respectively) was separately measured by Multiplate in the WB, UB and LB samples to characterize ex vivo platelet aggregation in the presence of ADP. Next, the occurrence of vascular events (stroke, acute coronary syndrome, ACS) were evaluated during 36-month follow-up. Results: A total of 11 vascular events (stroke n = 5, ACS n = 6) occurred during the follow-up period. The AUCupper was significantly higher in patients with recurrent stroke compared to those with uneventful follow-up (p = 0.03). The AUCupper with a cut-off value ≥70 based on the mPFT, was able to predict all stroke events (p = 0.01), while the total vascular events were independently predicted by NAR with a sensitivity of 82% and specificity of 88%. Conclusions: A combination of NAR reflecting the inflammatory state and AUCupper indicating HTPR may provide a better prediction of recurrent ischemic events suggesting a better selection of patients at risk, thus providing an individually tailored vascular therapy.

Capability of stroke scales to detect large vessel occlusion in acute ischemic stroke - a pilot study.

BACKGROUND AND PURPOSE: Rapid changes of stroke management in recent years facilitate the need for accurate and easy-to-use screening methods for early detection of large vessel occlusion (LVO) in acute ischemic stroke (AIS). Our aim was to evaluate the ability of various stroke scales to discriminate an LVO in AIS. METHODS: We have performed a cross-sectional, observational study based on a registry of consecutive patients with first ever AIS admitted up to 4.5 hours after symptom onset to a comprehensive stroke centre. The diagnostic capability of 14 stroke scales were investigated using receiver operating characteristic (ROC) analysis. RESULTS: Area under the curve (AUC) values of NIHSS, modified NIHSS, shortened NIHSS-EMS, sNIHSS-8, sNIHSS-5 and Rapid Arterial Occlusion Evaluation (RACE) scales were among the highest (>0.800 respectively). A total of 6 scales had cut-off values providing at least 80% specificity and 50% sensitivity, and 5 scales had cut-off values with at least 70% specificity and 75% sensitivity. CONCLUSION: Certain stroke scales may be suitable for discriminating an LVO in AIS. The NIHSS and modified NIHSS are primarily suitable for use in hospital settings. However, sNIHSS-EMS, sNIHSS-8, sNIHSS-5, RACE and 3-Item Stroke Scale (3I-SS) are easier to perform and interpret, hence their use may be more advantageous in the prehospital setting. Prospective (prehospital) validation of these scales could be the scope of future studies.