Evaluating the diagnostic and prognostic ability of ischemia modified albumin in COVID-19.

BACKGROUND: Patients with COVID-19 can rapidly deteriorate and develop acute hypoxic respiratory failure. Prominent features of the disease include severe inflammation, endotheliitis, and thrombosis. OBJECTIVES: The aim of the study was to evaluate the diagnostic and prognostic effectiveness of ischemia modified albumin (ΙΜΑ) in a cohort of COVID-19 patients. METHODS: This prospective observational study included adults with SARS-CoV-2 infection confirmed by reverse transcription polymerase chain reaction test, who were hospitalized specifically for COVID-19. The outcomes of interest were progression to severe acute respiratory failure during the index hospitalization defined as partial pressure of oxygen/fraction of inspired oxygen lower or equal to 150, admission to the intensive care unit (ICU) and in-hospital mortality. Admission IMA levels were determined using the commercially available "IMA Assay Kit" method (Abbexa LTD, Cambridge, UK). Adults without SARS-CoV-2 infection were used as controls. RESULTS: 135 COVID-19 patients and 64 controls were included. Admission IMA levels were significantly higher in COVID-19 patients compared to controls [[24.38 (11.94) ng/ml vs. 14.69 (3.52) ng/ml, p < 0.01]. Receiver operating characteristic analysis of admission IMA showed an area under the curve (AUC) of 94% (p < 0.0001) for COVID-19 diagnosis (cut-off value: 17.5 ng/ml; sensitivity: 90.37%; specificity: 87.5%). Admission IMA was also associated with mortality (AUC: 68%, p = 0.01). However, it was not associated with severe acute respiratory failure (AUC: 47%, p = 0.53) or ICU admission (AUC: 58%, p = 0.41). CONCLUSION: Admission IMA was significantly increased in COVID-19 patients and was associated with in-hospital mortality.

Parkin mRNA Expression Levels in Peripheral Blood Mononuclear Cells in Parkin-Related Parkinson's Disease.

INTRODUCTION: Pathogenic variants in parkin (PRKN gene) are the second most prevalent known monogenic cause of Parkinson's disease (PD). How monoallelic or biallelic pathogenic variants in the PRKN gene may affect its transcription in patient-derived biological material has not been systematically studied. METHODS: PRKN mRNA expression levels were measured with real-time polymerase chain reaction (RT-PCR) in peripheral blood mononuclear cells (PBMCs). PBMCs were derived from PRKN-mutated PD patients (PRKN-PD) (n = 12), sporadic PD (sPD) (n = 21) and healthy controls (n = 21). Six of the PRKN-PD patients were heterozygous, four were compound heterozygous, and two were homozygous for PRKN variants. RESULTS: A statistically significant decrease in PRKN expression levels was present, compared to healthy controls and sPD, in heterozygous (P = 0.019 and 0.031 respectively) and biallelic (P < 0.001 for both) PRKN-PD. PRKN expression levels in biallelic PD patients were uniformly very low and were reduced, albeit not significantly, compared to heterozygotes. Based on receiver operating characteristic analysis, low PRKN expression levels were a sensitive and extremely specific indicator for the presence of PRKN pathogenic variants. CONCLUSIONS: Assessment of PRKN mRNA levels in PBMCs may be a useful way to screen for biallelic pathogenic variants in the PRKN gene. Suspicion for certain variants in a heterozygous state may also be raised based on low PRKN mRNA levels. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Intubation Decision Based on Illness Severity and Mortality in COVID-19: An International Study.

OBJECTIVES: To evaluate the impact of intubation timing, guided by severity criteria, on mortality in critically ill COVID-19 patients, amidst existing uncertainties regarding optimal intubation practices. DESIGN: Prospective, multicenter, observational study conducted from February 1, 2020, to November 1, 2022. SETTING: Ten academic institutions in the United States and Europe. PATIENTS: Adults (≥ 18 yr old) confirmed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and hospitalized specifically for COVID-19, requiring intubation postadmission. Exclusion criteria included patients hospitalized for non-COVID-19 reasons despite a positive SARS-CoV-2 test. INTERVENTIONS: Early invasive mechanical ventilation (EIMV) was defined as intubation in patients with less severe organ dysfunction (Sequential Organ Failure Assessment [SOFA] < 7 or Pa o2 /F io2 ratio > 250), whereas late invasive mechanical ventilation (LIMV) was defined as intubation in patients with SOFA greater than or equal to 7 and Pa o2 /F io2 ratio less than or equal to 250. MEASUREMENTS AND MAIN RESULTS: The primary outcome was mortality within 30 days of hospital admission. Among 4464 patients, 854 (19.1%) required mechanical ventilation (mean age 60 yr, 61.7% male, 19.3% Black). Of those, 621 (72.7%) were categorized in the EIMV group and 233 (27.3%) in the LIMV group. Death within 30 days after admission occurred in 278 patients (42.2%) in the EIMV and 88 patients (46.6%) in the LIMV group ( p = 0.28). An inverse probability-of-treatment weighting analysis revealed a statistically significant association with mortality, with patients in the EIMV group being 32% less likely to die either within 30 days of admission (adjusted hazard ratio [HR] 0.68; 95% CI, 0.52-0.90; p = 0.008) or within 30 days after intubation irrespective of its timing from admission (adjusted HR 0.70; 95% CI, 0.51-0.90; p = 0.006). CONCLUSIONS: In severe COVID-19 cases, an early intubation strategy, guided by specific severity criteria, is associated with a reduced risk of death. These findings underscore the importance of timely intervention based on objective severity assessments.

The Landscape of Monogenic Parkinson's Disease in Populations of Non-European Ancestry: A Narrative Review.

INTRODUCTION: There has been a bias in the existing literature on Parkinson's disease (PD) genetics as most studies involved patients of European ancestry, mostly in Europe and North America. Our target was to review published research data on the genetic profile of PD patients of non-European or mixed ancestry. METHODS: We reviewed articles published during the 2000-2023 period, focusing on the genetic status of PD patients of non-European origin (Indian, East and Central Asian, Latin American, sub-Saharan African and Pacific islands). RESULTS: There were substantial differences regarding monogenic PD forms between patients of European and non-European ancestry. The G2019S Leucine Rich Repeat Kinase 2 (LRRK2) mutation was rather scarce in non-European populations. In contrast, East Asian patients carried different mutations like p.I2020T, which is common in Japan. Parkin (PRKN) variants had a global distribution, being common in early-onset PD in Indians, in East Asians, and in early-onset Mexicans. Furthermore, they were occasionally present in Black African PD patients. PTEN-induced kinase 1 (PINK1) and PD protein 7 (DJ-1) variants were described in Indian, East Asian and Pacific Islands populations. Glucocerebrosidase gene variants (GBA1), which represent an important predisposing factor for PD, were found in East and Southeast Asian and Indian populations. Different GBA1 variants have been reported in Black African populations and Latin Americans. CONCLUSIONS: Existing data reveal a pronounced heterogeneity in the genetic background of PD. A number of common variants in populations of European ancestry appeared to be absent or scarce in patients of diverse ethnic backgrounds. Large-scale studies that include genetic screening in African, Asian or Latin American populations are underway. The outcomes of such efforts will facilitate further clinical studies and will possibly contribute to the identification of either new pathogenic mutations in already described genes or novel PD-related genes.

Double Trouble: Association of Malignant Melanoma with Sporadic and Genetic Forms of Parkinson's Disease and Asymptomatic Carriers of Related Genes: A Brief Report.

Introduction: Previous epidemiological evidence has established the co-occurrence of malignant melanoma (MM) and Parkinson's disease (PD). Shared molecular mechanisms have been proposed to be implicated in this relationship. The aim of the present study was to assess the prevalence of MM in patients with sporadic and genetic types of PD, as well as in asymptomatic carriers of PD-related genes. Methods: Data regarding past medical history and concomitant disease of 1416 patients with PD (including 20 participants with prodromal disease who phenoconverted to PD), 275 healthy controls (HCs) and 670 asymptomatic carriers of PD-related genes were obtained from the database of the Parkinson's Progression Markers Initiative (PPMI). Focus was placed on information about a medical record of MM. We also retrieved data regarding the genetic status of selected PPMI participants with a positive MM history. Results: In total, 46 patients with PD reported a positive MM history. Concerning the genetic forms of PD, nine of these PD patients (2.47%) carried a Leucine Rich Repeat Kinase 2 (LRRK2) gene mutation (mainly the G2019S), while eight (4.49%) harbored a Glucocerebrosidase (GBA) gene mutation (mainly the N370S). No alpha-synuclein (SNCA) gene mutation was identified in patients with an MM history. The remaining 29 PD patients (3.5%) were genetically undetermined. In total, 18 asymptomatic carriers of PD-related genes had a positive medical history for MM: among them, 10 carried an LRRK2 gene mutation (2.69%) and 10 a GBA gene mutation (3.51%) (2 were dual carriers). MM history was identified for seven HCs (2.5%). Conclusions: We replicated the previously reported association between genetically undetermined PD (GU-PD) and MM. A correlation of LRRK2 mutations with the development of MM could not be verified in either symptomatic PD patients or asymptomatic carriers, implicating distinct pathogenetic mechanisms as compared to GU-PD. Importantly, despite the limited literature evidence on Gaucher disease, this study highlights for the first time the relatively high prevalence of MM among asymptomatic and symptomatic PD GBA mutation carriers, with potential clinical implications.

The Relation of Calculated Plasma Volume Status to Sublingual Microcirculatory Blood Flow and Organ Injury.

BACKGROUND: The calculated plasma volume status (cPVS) was validated as a surrogate of intravascular filling. The aim of this study is to assess the cPVS in relation to sublingual perfusion and organ injury. METHODS: Pre- and postoperative cPVS were obtained by determining the actual and ideal plasma volume levels in surgical patients. The sublingual microcirculation was assessed using SDF imaging, and we determined the De Backer score, the Consensus Proportion of Perfused Vessels (Consensus PPV), and the Consensus PPV (small). Our primary outcome was the assessment of the distribution of cPVS and its association with intraoperative sublingual microcirculation and postoperative complications. RESULTS: The median pre- and postoperative cPVS were -7.25% (IQR -14.29--1.88) and -0.4% (IQR -5.43-6.06), respectively (p < 0.001). The mean intraoperative administered fluid volume was 2.5 ± 2.5 L (1.14 L h-1). No statistically significant correlation was observed between the pre- or postoperative cPVS and sublingual microcirculation variables. Higher preoperative (OR = 1.04, p = 0.098) and postoperative cPVS (OR = 1.057, p = 0.029) were associated with postoperative organ injury and complications (sepsis (30%), anemia (24%), respiratory failure (13%), acute kidney injury (6%), hypotension (6%), stroke (3%)). CONCLUSIONS: The calculated PVS was associated with an increased risk of organ injury and complications in this cohort.

Effects of Vasopressin Receptor Agonists during the Resuscitation of Hemorrhagic Shock: A Systematic Review and Meta-Analysis of Experimental and Clinical Studies.

BACKGROUND: The clinical impact of vasopressin in hemorrhagic shock remains largely unknown. OBJECTIVE: This systematic review and meta-analysis was designed to investigate the effects of vasopressin receptor agonists during the resuscitation of hemorrhagic shock. METHODS: A systematic search of PubMed (MEDLINE), Scopus, and PubMed Central was conducted for relevant articles. Experimental (animal) and clinical studies were included. The primary objective was to investigate the correlation of vasopressin receptor agonist use with mortality and various hemodynamic parameters. RESULTS: Data extraction was possible in thirteen animal studies and two clinical studies. Differences in risk of mortality between patients who received a vasopressin receptor agonist were not statistically significant when compared to those who were not treated with such agents [RR (95% CI): 1.17 (0.67, 2.08); p = 0.562; I2 = 50%]. The available data were insufficient to conduct a meta-analysis assessing the effect of vasopressin receptor agonists on hemodynamics. Drawing safe conclusions from animal studies was challenging, due to significant heterogeneity in terms of species and dosage of vasopressin receptor agonists among studies. CONCLUSIONS: Differences in risk of mortality between patients who received a vasopressin receptor agonist were not statistically significant when compared to those who were not treated with such agents after hemorrhagic shock. More data are needed to deduce certain conclusions.

Serum Uric Acid as a Putative Biomarker in Prodromal Parkinson's Disease: Longitudinal Data from the PPMI Study.

BACKGROUND: The role of blood uric acid as a biomarker in symptomatic motor PD has been increasingly established in the literature. OBJECTIVE: Our present study assessed the role of serum uric acid as a putative biomarker in a prodromal PD cohort [REM Sleep Behavior disorder (RBD) and Hyposmia] followed longitudinally. METHODS: Longitudinal 5-year serum uric acid measurement data of 39 RBD patients and 26 Hyposmia patients with an abnormal DATSCAN imaging were downloaded from the Parkinson's Progression Markers Initiative database. These cohorts were compared with 423 de novo PD patients and 196 healthy controls enrolled in the same study. RESULTS: After adjusting for age, sex, body mass index, and concomitant disorders (hypertension/gout), baseline and longitudinal serum uric acid levels were higher in the RBD subgroup as compared to the established PD cohort (p = 0.004 and p = 0.001). (Baseline RBD 6.07±1.6 vs. Baseline PD 5.35±1.3 mg/dL and Year-5 RBD 5.7±1.3 vs. Year-5 PD 5.26±1.33). This was also true for longitudinal measurements in the Hyposmic subgroup (p = 0.008) (Baseline Hyposmic 5.7±1.6 vs. PD 5.35±1.3 mg/dL and Year-5 Hyposmic 5.58±1.6 vs. PD 5.26±1.33). CONCLUSION: Our results indicate that serum uric acid levels are higher in prodromal PD subjects with ongoing dopaminergic degeneration compared to those with manifest PD. These data indicate that the well-established decrease in the levels of serum uric acid occurs with the transition from prodromal to clinical PD. Whether the higher levels of serum uric acid observed in prodromal PD may provide protection against conversion to full-blown clinical PD will require further study.

Effects of Etomidate on Postintubation Hypotension, Inflammatory Markers, and Mortality in Critically Ill Patients with COVID-19: An International, Multicenter, Retrospective Study.

OBJECTIVE: To evaluate the association of etomidate with postintubation hypotension, inflammation, and mortality in critically ill patients with COVID-19. DESIGN: International, multicenter, retrospective study. PARTICIPANTS: Critically ill patients hospitalized specifically for COVID-19 from three major academic institutions in the US and Europe. MAIN OUTCOME AND MEASURES: Patients were allocated into the etomidate (ET) group or another induction agent (OA) group. The primary outcome was postintubation hypotension. Secondary outcomes included postintubation inflammatory status, in-hospital mortality, and mortality at 30 days. RESULTS: 171 patients with a median age of 68 (IQR 58-73) years were included (ET, n = 98; OA, n = 73). Etomidate was associated with lower postintubation mean arterial pressure [74.33 (64-85) mm Hg versus 81.84 (69.75-94.25) mm Hg, p = 0.005] compared to other agents. No statistically significant differences were generally observed in inflammatory markers between the two groups at 7- and 14-days after admission to the intensive care unit. In-hospital mortality [77 (79%) versus 41 (56%), p = 0.003] and mortality at 30-days [78 (80%) versus 43 (59%), p = 0.006] were higher in the ET group. In multivariate logistic regression analysis, only etomidate (p = 0.009) and postintubation mean arterial pressure (p < 0.001) had a statistically significant effect on mortality, in contrast to stress-dose steroids (p = 0.301), after adjusting for creatinine (p = 0.695), blood urea nitrogen (p = 0.153), age (p = 0.055), oxygen saturation of hemoglobin (SpO2) (p = 0.941), and fraction of inspired oxygen (FiO2) (p = 0.712). CONCLUSIONS: Administration of a single-bolus dose of etomidate in critically ill patients with COVID-19 is associated with lower postintubation mean arterial pressure and higher in-hospital and 30-day mortality compared to other induction agents.

Association between mean arterial pressure and sublingual microcirculation during major non-cardiac surgery: Post hoc analysis of a prospective cohort.

OBJECTIVE: To test the hypothesis that there is an association between mean arterial pressure (MAP) and sublingual perfusion during major surgery, and perhaps an identifiable harm threshold. METHODS: This post hoc analysis of a prospective cohort included patients who had elective major non-cardiac surgery with a duration of ≥2 h under general anesthesia. We assessed sublingual microcirculation every 30 min using SDF+ imaging and determined the De Backer score, Consensus Proportion of Perfused Vessels (Consensus PPV), and the Consensus PPV (small). Our primary outcome was the relationship between MAP and sublingual perfusion which was evaluated with linear mixed effects modeling. RESULTS: A total of 100 patients were included, with MAP ranging between 65 mmHg and 120 mmHg during anesthesia and surgery. Over a range of intraoperative MAPs between 65 and 120 mmHg, there were no meaningful associations between blood pressure and various measures of sublingual perfusion. There were also no meaningful changes in microcirculatory flow over 4.5 h of surgery. CONCLUSIONS: In patients having elective major non-cardiac surgery with general anesthesia, sublingual microcirculation is well maintained when MAP ranges between 65 and 120 mmHg. It remains possible that sublingual perfusion will be a useful marker of tissue perfusion when MAP is lower than 65 mmHg.

a-Synuclein and lipids in erythrocytes of Gaucher disease carriers and patients before and after enzyme replacement therapy.

It is well established that patients with Gaucher disease, as well as carriers of the disease have an increased risk for developing Parkinson's disease. A plethora of evidence suggests that disturbed α-Synuclein homeostasis is the link between Gaucher disease and Parkinson's disease. The pathogenic mechanism linking these entities is still a topic of debate and both gain- and loss-of-function theories have been put forward, which however are not mutually exclusive. In the present study we expanded our previous studies to include not only Gaucher disease patients but also Gaucher disease carriers and Gaucher disease patients following Enzyme Replacement Therapy. In these groups we investigated α-Synuclein in red blood cell membranes in association with lipid abnormalities described in Gaucher disease. These included glucosylceramide and its species, glucosylsphingosine, glucosylcholesterol and plasmalogens. Increased oligomerization of α-Synuclein in red blood cell membranes was observed not only in Gaucher disease patients but also in carriers of the disease. There were no qualitative differences in the lipids identified in the groups studied. However, significant quantitative differences compared to controls were observed in Gaucher disease patients but not in Gaucher disease carriers. Enzyme Replacement Therapy reversed the biochemical defects and normalized α-Synuclein homeostasis, providing for the first time evidence in human subjects that such homeostatic dysregulation is reversible. Further studies investigating α-Synuclein status during the differentiation of erythroid progenitors could provide new data on the pathogenic mechanism of α-Synuclein oligomerization in this system.

The use of mean circulatory filling pressure analogue for monitoring hemodynamic coherence: A post-hoc analysis of the SPARSE data and proof-of-concept study.

BACKGROUND: Dissociation between macrocirculation and microcirculation is often observed in surgical patients. OBJECTIVE: To test the hypothesis that the analogue of mean circulatory filling pressure (Pmca) can monitor hemodynamic coherence during major non-cardiac surgery. METHODS: In this post-hoc analysis and proof-of-concept study, we used the central venous pressure (CVP), mean arterial pressure (MAP), and cardiac output (CO) to calculate Pmca. Efficiency of the heart (Eh), arterial resistance (Rart), effective arterial elastance (Ea), venous compartment resistance (Rven), oxygen delivery (DO2), and oxygen extraction ratio (O2ER) were also calculated. Sublingual microcirculation was assessed using SDF + imaging, and the De Backer score, Consensus Proportion of Perfused Vessels (Consensus PPV), and Consensus PPV (small) were determined. RESULTS: Thirteen patients were included, with a median age of 66 years. Median Pmca was 16 (14.9-18) mmHg and was positively associated with CO [p < 0.001; a 1 mmHg increase in Pmca increases CO by 0.73 L  min-1 (p < 0.001)], Eh (p < 0.001), Rart (p = 0.01), Ea (p = 0.03), Rven (p = 0.005), DO2 (p = 0.03), and O2ER (p = 0.02). A significant correlation was observed between Pmca and Consensus PPV (p = 0.02), but not with De Backer Score (p = 0.34) or Consensus PPV (small) (p = 0.1). CONCLUSION: Significant associations exist between Pmca and several hemodynamic and metabolic variables including Consensus PPV. Adequately powered studies should determine whether Pmca can provide real-time information on hemodynamic coherence.

Clinical differences between early-onset and mid-and-late-onset Parkinson's disease: Data analysis of the Hellenic Biobank of Parkinson's disease.

BACKGROUND: Age at onset is one of the most critical factors contributing to the clinical heterogeneity of Parkinson's disease (PD), and available evidence is rather conflicting. OBJECTIVE: The aim of this study is to investigate the clinical differences between early-onset PD (EOPD) and mid-and-late-onset PD (MLOPD) in the Greek population, based on the existing data of the Hellenic Biobank of PD (HBPD). METHODS: HBPD contains information of PD cases from two centers in Greece during 2006-2017. Patients with the A53T mutation in the SNCA gene or mutations in the GBA1 gene were excluded. Associations between clinical characteristics (motor and non-motor symptoms, side of onset, first symptom, motor complications) and MLOPD versus EOPD were explored with a single logistic regression model adjusting for gender, family history of PD, disease and dopaminergic therapy duration, disease severity (UPDRS III), levodopa equivalent daily dose, as well as each of the other clinical characteristics. RESULTS: 675 patients (129 EOPD, 546 MLOPD) were included. EOPD was more frequently associated with dystonia (OR 0.19, 95% CI 0.08-0.50, p < 0.01) and motor complications (0.23, 0.07-0.76, 0.02), compared to MLOPD. Bilateral onset (9.38, 1.05-84.04, 0.045) and autonomic dysfunction (2.31, 1.04-5.11, 0.04) were more frequently associated with MLOPD. CONCLUSIONS: EOPD and MLOPD display distinct clinical profiles, regarding motor and non-motor symptoms, side of onset and motor complications in the Greek population. These differences may reflect diverse pathophysiological backgrounds, potentially attributed to genetic or age-related epigenetic influences.

Blood Biomarkers and Metabolomic Profiling for the Early Diagnosis of Vancomycin-Associated Acute Kidney Injury: A Systematic Review and Meta-Analysis of Experimental Studies.

BACKGROUND: several blood-based biomarkers have been proposed for predicting vancomycin-associated kidney injury (VIKI). However, no systematic analysis has compared their prognostic value. OBJECTIVE: this systematic review and meta-analysis was designed to investigate the role of blood biomarkers and metabolomic profiling as diagnostic and prognostic predictors in pre-clinical studies of VIKI. METHODS: a systematic search of PubMed was conducted for relevant articles from January 2000 to May 2022. Animal studies that administered vancomycin and studied VIKI were eligible for inclusion. Clinical studies, reviews, and non-English literature were excluded. The primary outcome was to investigate the relationship between the extent of VIKI as measured by blood biomarkers and metabolomic profiling. Risk of bias was assessed with the CAMARADES checklist the SYRCLE's risk of bias tool. Standard meta-analysis methods (random-effects models) were used. RESULTS: there were four studies for the same species, dosage, duration of vancomycin administration and measurement only for serum creatine and blood urea nitrogen in rats. A statistically significant increase was observed between serum creatinine in the vancomycin group compared to controls (pooled p = 0.037; Standardized Mean Difference: 2.93; 95% CI: 0.17 to 5.69; I2 = 92.11%). Serum BUN levels were not significantly different between control and vancomycin groups (pooled p = 0.11; SMD: 3.05; 95% CI: 0.69 to 6.8; I2 = 94.84%). We did not identify experimental studies using metabolomic analyses in animals with VIKI. CONCLUSIONS: a total of four studies in rodents only described outcomes of kidney injury as defined by blood biomarkers. Blood biomarkers represented included serum creatinine and BUN. Novel blood biomarkers have not been explored.

B-Cell Targeted Therapies in Patients with Multiple Sclerosis and Incidence of Headache: A Systematic Review and Meta-Analysis.

BACKGROUND: Multiple Sclerosis treatment with B-cell targeted therapies may be associated with an increased incidence of headache. We aimed to find and compare the association of B-cell targeted therapies with the incidence of headache in patients with Multiple Sclerosis. METHODS: In a systematic based approach, the following databases were searched from inception until the 6th of June 2020: Pubmed/MEDLINE, ClinicalTrials.gov, EU Clinical Trials Register. Only randomized clinical trials (RCTs) enrolling patients with Multiple Sclerosis comparing B-cell targeted therapies (Rituximab, Ocrelizumab, Ofatumumab, Ublituximab or Cladribine) with placebo were selected for the systematic review and further meta-analysis. PRISMA guidelines were followed at all stages of the systematic review. The primary outcome was an all-cause headache of B-cell targeting therapy in patients with Multiple Sclerosis. RESULTS: Nine RCTs were included. Compared with placebo, treatment with B-cell targeting therapies revealed a trend in headache risk, but it was not statistically significant (Relative Risk 1.12 [95% Confidence Interval 0.96-1.30]; p = 0.15; I2 = 9.32%). Surprisingly, in a sub-group analysis, Cladribine was statistically significant for an increase in headache risk (RR 1.20 [95% CI 1.006-1.42]; p = 0.042; I2 = 0%; 3 studies with 2107 participants). CONCLUSIONS: Even though a trend is shown, B-cell targeted therapies do not correlate with an increased incidence of headache as an adverse effect. Sub-analyses revealed a significant association between Cladribine alone and an increased incidence of headache. Whereas a purinergic signaling cascade is proposed as a mechanism of action, further research is needed to unravel the underlying pathogenetic mechanism of headache induction and establish headache prevention strategies.

Treating Spontaneous Intracranial Hypotension with an Anesthetic Modality: The Role of the Epidural Blood Patch.

Background: Spontaneous intracranial hypotension (SIH) is a rare syndrome characterized by heterogeneity of presentation and prognosis, which can occasionally result in serious complications, such as the formation of subdural hematomas (SDHs). This case series aims to emphasize that SIH remains a diagnostic and therapeutic challenge; it can present with a broad clinical spectrum of symptoms, can lead to SDH and, if conservative treatment fails, an epidural blood patch (EBP) is a viable treatment option. Although the exact etiology of SIH is not known, it is believed to be due to cerebrospinal fluid (CSF) leak or a low CSF pressure. Case Series: Three patients (two males and one female) with ages ranging between 38 and 53 years old who presented with complaints of not only an orthostatic headache, but also a variety of symptoms of SIH, including the formation of two SDHs in one of them, were included in this series. These patients did not respond to conservative management and, subsequently, given the clinical and radiological evidence of SIH, were referred to the Anesthesiology Department for an EBP. Diagnostic workup was facilitated by imaging modalities, including magnetic resonance imaging (MRI) of the brain and spinal cord, prior to the EBP. All three patients were subjected to an EBP with an 18-gauge epidural needle. A total of between 30 and 43 mL of autologous blood was collected from the patients and was injected into the epidural space under strict aseptic conditions. Two lumbar (L1-L2, L2-L3) EBPs and one thoracic (T11-T12) EBP were performed on the three patients, respectively. All patients reported complete resolution of symptoms following the EBPs, while MRI improved substantially. Conclusions: This report describes three cases of SIH with CSF leak originating from the cervical, the thoracic and the lumbar level. The EBP restored CSF pressure and relieved the patients' persistent symptoms. MRI helps in revealing indirect signs of a low volume of CSF, though it may not be possible to locate the actual site of the leak. In conclusion, EBP is a well-accepted and beneficial treatment modality for SIH when conventional measures fail.

Association of Preoperative Basal Inflammatory State, Measured by Plasma suPAR Levels, with Intraoperative Sublingual Microvascular Perfusion in Patients Undergoing Major Non-Cardiac Surgery.

It remains unknown whether chronic systemic inflammation is associated with impaired microvascular perfusion during surgery. We evaluated the association between the preoperative basal inflammatory state, measured by plasma soluble urokinase-type plasminogen activator receptor (suPAR) levels, and intraoperative sublingual microcirculatory variables in patients undergoing major non-cardiac surgery. Plasma suPAR levels were determined in 100 non-cardiac surgery patients using the suPARnostic® quick triage lateral flow assay. We assessed sublingual microcirculation before surgical incision and every 30 min during surgery using Sidestream Darkfield (SDF+) imaging and determined the De Backer score, the Consensus Proportion of Perfused Vessels (Consensus PPV), and the Consensus PPV (small). Elevated suPAR levels were associated with lower intraoperative De Backer score, Consensus PPV, and Consensus PPV (small). For each ng mL−1 increase in suPAR, De Backer score, Consensus PPV, and Consensus PPV (small) decreased by 0.7 mm−1, 2.5%, and 2.8%, respectively, compared to baseline. In contrast, CRP was not significantly correlated with De Backer score (r = −0.034, p = 0.36), Consensus PPV (r = −0.014, p = 0.72) or Consensus PPV Small (r = −0.037, p = 0.32). Postoperative De Backer score did not change significantly from baseline (5.95 ± 3.21 vs. 5.89 ± 3.36, p = 0.404), while postoperative Consensus PPV (83.49 ± 11.5 vs. 81.15 ± 11.8, p < 0.001) and Consensus PPV (small) (80.87 ± 13.4 vs. 78.72 ± 13, p < 0.001) decreased significantly from baseline. In conclusion, elevated preoperative suPAR levels were associated with intraoperative impairment of sublingual microvascular perfusion in patients undergoing elective major non-cardiac surgery.

Assessment of Dynamic Changes in Stressed Volume and Venous Return during Hyperdynamic Septic Shock.

The present work investigated the dynamic changes in stressed volume (Vs) and other determinants of venous return using a porcine model of hyperdynamic septic shock. Septicemia was induced in 10 anesthetized swine, and fluid challenges were started after the diagnosis of sepsis-induced arterial hypotension and/or tissue hypoperfusion. Norepinephrine infusion targeting a mean arterial pressure (MAP) of 65 mmHg was started after three consecutive fluid challenges. After septic shock was confirmed, norepinephrine infusion was discontinued, and the animals were left untreated until cardiac arrest occurred. Baseline Vs decreased by 7% for each mmHg decrease in MAP during progression of septic shock. Mean circulatory filling pressure (Pmcf) analogue (Pmca), right atrial pressure, resistance to venous return, and efficiency of the heart decreased with time (p < 0.001 for all). Fluid challenges did not improve hemodynamics, but noradrenaline increased Vs from 107 mL to 257 mL (140%) and MAP from 45 mmHg to 66 mmHg (47%). Baseline Pmca and post-cardiac arrest Pmcf did not differ significantly (14.3 ± 1.23 mmHg vs. 14.75 ± 1.5 mmHg, p = 0.24), but the difference between pre-arrest Pmca and post-cardiac arrest Pmcf was statistically significant (9.5 ± 0.57 mmHg vs. 14.75 ± 1.5 mmHg, p < 0.001). In conclusion, the baseline Vs decreased by 7% for each mmHg decrease in MAP during progression of hyperdynamic septic shock. Significant changes were also observed in other determinants of venous return. A new physiological intravascular volume existing at zero transmural distending pressure was identified, termed as the rest volume (Vr).

Asymptomatic carriers of the p.A53T SNCA mutation: Data from the PPMI study.

We assessed non motor characteristics of 12 asymptomatic p.A53T mutation carriers (A53T-AC) compared with 36 healthy controls (HC) enrolled in the Parkinson's Progression Markers Initiative (PPMI) study. Olfaction score was lower and anxiety was marginally more prevalent in A53T- AC. These findings suggest distinct prodromal features in this group of subjects.