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.

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.

Artificial intelligence-based screening for amblyopia and its risk factors: comparison with four classic stereovision tests.

Introduction: The development of costs-effective and sensitive screening solutions to prevent amblyopia and identify its risk factors (strabismus, refractive problems or mixed) is a significant priority of pediatric ophthalmology. The main objective of our study was to compare the classification performance of various vision screening tests, including classic, stereoacuity-based tests (Lang II, TNO, Stereo Fly, and Frisby), and non-stereoacuity-based, low-density static, dynamic, and noisy anaglyphic random dot stereograms. We determined whether the combination of non-stereoacuity-based tests integrated in the simplest artificial intelligence (AI) model could be an alternative method for vision screening. Methods: Our study, conducted in Spain and Hungary, is a non-experimental, cross-sectional diagnostic test assessment focused on pediatric eye conditions. Using convenience sampling, we enrolled 423 children aged 3.6-14 years, diagnosed with amblyopia, strabismus, or refractive errors, and compared them to age-matched emmetropic controls. Comprehensive pediatric ophthalmologic examinations ascertained diagnoses. Participants used filter glasses for stereovision tests and red-green goggles for an AI-based test over their prescribed glasses. Sensitivity, specificity, and the area under the ROC curve (AUC) were our metrics, with sensitivity being the primary endpoint. AUCs were analyzed using DeLong's method, and binary classifications (pathologic vs. normal) were evaluated using McNemar's matched pair and Fisher's nonparametric tests. Results: Four non-overlapping groups were studied: (1) amblyopia (n = 46), (2) amblyogenic (n = 55), (3) non-amblyogenic (n = 128), and (4) emmetropic (n = 194), and a fifth group that was a combination of the amblyopia and amblyogenic groups. Based on AUCs, the AI combination of non-stereoacuity-based tests showed significantly better performance 0.908, 95% CI: (0.829-0.958) for detecting amblyopia and its risk factors than most classical tests: Lang II: 0.704, (0.648-0.755), Stereo Fly: 0.780, (0.714-0.837), Frisby: 0.754 (0.688-0.812), p < 0.02, n = 91, DeLong's method). At the optimum ROC point, McNemar's test indicated significantly higher sensitivity in accord with AUCs. Moreover, the AI solution had significantly higher sensitivity than TNO (p = 0.046, N = 134, Fisher's test), as well, while the specificity did not differ. Discussion: The combination of multiple tests utilizing anaglyphic random dot stereograms with varying parameters (density, noise, dynamism) in AI leads to the most advanced and sensitive screening test for identifying amblyopia and amblyogenic conditions compared to all the other tests studied.

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.

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.

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.

Cannabidiol in low back pain: scientific rationale for clinical trials in low back pain.

INTRODUCTION: The pooled worldwide prevalence of low-back pain-related presentations in primary care varies between 6.8% and 28.4% in the high-income countries rendering it a major healthcare/economy problem. To best manage this complex bio-psycho-social condition a 360-degree approach is needed, as the psycho-social components are often more important than the scant pathophysiology. Pattern analysis of cannabis users suggested that attempts to alleviate musculo-skeletal pain is often seen as a major drive to use cannabinoids. AREAS COVERED: Unlike NSAIDs/opioids, cannabidiol might directly affect more than one modality of pain signaling/perception. The 2019 guideline of the National Institute for Clinical Excellence recommended further studies with cannabidiol in pain medicine because of its excellent safety profile and presumed therapeutic potential. Therefore, we have researched relevant databases for pharmaco-physiological papers published between 2000 and 2021 to collate evidence in a narrative fashion to determine the clinical rationale for this cannabinoid in low-back pain. EXPERT OPINION: Observational research reported good results with CBD in pain and fear reduction, which are both key factors in low-back pain. Given the paucity of high-quality evidence, further research is needed to determine the efficacy/non-inferiority of CBD in primary/emergency care setting, using multimodal assessment of various patient-reported outcomes.

Corona vaccine review / Koronavírusvakcina-vademecum.

Összefoglaló. A SARS-CoV-2 okozta megbetegedés (COVID-19) a cikk megírásáig a világon több mint 82 millió embert érintett, a halálos áldozatok száma 1,8 millió (2,2%). Hazánkban eddig 300 000 feletti esetszámot regisztráltak, a cikk megjelenésének idején már várhatóan több mint 10 000 halottal (3%). Habár a megbetegedésnek oki gyógyszeres terápiája egyelore nincs, egyes antivirális szerek és a rekonvaleszcens plazma alkalmazása a tapasztalatok szerint csökkentik a vírusterhelést, és ezzel hozzájárulnak a beteg gyógyulásához. Az eddig példa nélküli epidemiológiai rendelkezések nem tudták megállítani, csak lelassítani a betegség terjedését, ezért a megelozés tunik az egyetlen, a közeljövoben tömegek számára is elérheto megoldásnak. A jelen cikk nem egy virológiai vagy biotechnológiai szakmunka, sokkal inkább egy összefoglaló házi- és általános orvosok számára, amely ismerteti a jelenleg engedélyezett, illetve a közeljövoben forgalomba kerülo védooltások elonyeit és hátrányait a COVID-19 tágabb kontextusában. Írásunkban bemutatjuk a leggyakoribb álhíreket, rémhíreket is, valamint ezek cáfolatát is annak érdekében, hogy kollégáink felkészültebben tudják betegeiket informálni, valamint segíteni a vakcináció fontosságával kapcsolatos döntéshozatalt. Egy járvány megfékezésének legkézenfekvobb módja a társadalmi szintu védettség megvalósítása. A nyájimmunitás kialakulása nélkül nagy valószínuséggel e jelenlegi pandémia sem állítható meg. Amennyiben egyéni és társadalmi szinten is vissza szeretnénk térni a vírus elotti életünkhöz, újra élvezve az akadálytalan áru- és kereskedelmi forgalom jelentette elonyöket, akkor a tömeges oltás tunik a leghatékonyabb eszköznek ennek eléréséhez. A fertozo betegségek számának és mortalitásának a 20. században tapasztalt jelentos csökkenése egyértelmuen a társadalmi szintu átoltottságnak, valamint a higiénés körülmények javulásának köszönheto. Az oltás ugyan önkéntes, de felvételének kérdése pandémiás helyzetben valószínuleg nemcsak egyéni döntés, de társadalmi felelosségvállalás kérdése is. Orv Hetil. 2021; 162(8): 283-292. Summary. Out of more than 82 million people worldwide, 1.8 million (2.2%) succumbed to SARS-CoV-2 disease (COVID-19). In 2020, more than 300 000 cases were registered in Hungary, and by the time of publication of this article, the death toll would probably exceed 10 000 (3%). Currently no causative drug therapy is available, however, observational evidence suggests that certain antivirals and the use of convalescent plasma may change the disease course. The unprecedented, strict epidemiological provisions managed to slow down the spread of the disease though they could not stop it. It seems that prevention remains the only readily available option to beat COVID-19. This is not a virology or biotechnology paper, but an unbiased review for general practitioners, aiming to summarize the advantages/disadvantages of the (emergency) authorized and soon-to-be-launched vaccines in the wider context of COVID-19. We also intended to address and debunk the most common misconceptions, aiming to help both doctors and patients to make a fact-based, informed decision about vaccination. Herd immunity is paramount to combat COVID pandemic. Without population-level vaccination, we are unlikely to regain the quality of life, the freedom of travel and the unrestricted economy/commerce we enjoyed before. It is obvious that the significant reduction in morbity/mortality of infectious diseases in the 20th century was achieved through advancements in vaccinology and improved hygiene. Albeit voluntary, vaccination in a pandemic situation is probably not only an individual decision, but social responsibility as well. Orv Hetil. 2021; 162(8): 283-292.

The role of vitamin E acetate (VEA) and its derivatives in the vaping associated lung injury: systematic review of evidence.

Small scale observational evidence suggested that Vitamin E (VE) might play beneficial role in human and animal respiratory conditions of various origin by stabilizing surfactant functions. The intra-aleveolar VE level is directly proportionate to the lung's response to inflammation. Electronic cigarette or vaping associated lung injury was a dominantly respiratory syndrome in the United States with seemingly strong association between potential Vitamin E acetate inhalation exposure and the onset of symptoms. This systematic review intended to assess if there was previous evidence of any potential respiratory/gastrointestinal toxicity associated with Vitamin E acetate or any of its derivatives. A systematic review was constructed and prospectively registered at PROSPERO to search important clinical databases between 2000 and 2020 for full text human articles investigating the effect of VEA or any of its derivatives administered via any route (oral/parenteral/aerosolised) in adults with any respiratory conditions. Out of 363 records investigating the effect of VEA and/or its derivatives/isomers in (any) lung injury (inflammatory, oxidative, infective, asthma/COPD) seven articles qualified. The papers reported various surrogate outcomes (APACHEII score, spirometry, etc) with equivocal results. There was one case report of harmful exposure to both Vitamin E (intramuscular) and Vitamin E acetate (topical). The present review found evidence of neither harm nor any significant clinical improvement associated with the administration of VEA or any derivatives via any route in adult inflammatory lung conditions however, the articles were of low-level evidence. Further studies are needed to correct flaws in research to explore the role of Vitamin E in pulmonology.