Spearmint (Mentha spicata L.) Phytochemical Profile: Impact of Pre/Post-Harvest Processing and Extractive Recovery.

The purpose of this study was to chemically compare samples of Mentha spicata (marketing byproducts, production byproducts, and export material), cultivated in the open field and under greenhouse, using an integrated approach by HPLC/DAD and GC/MS analysis. The presence of phenolic compounds was higher in the marketing byproducts cultivated in the open field. Marketing byproducts also had the highest amount of carvone. For this reason, this byproduct was selected as a candidate for the development of natural ingredients. With the best selected material, the optimization of simultaneous high-intensity ultrasound-assisted extraction processes was proposed for the recovery of the compounds of interest. This extraction was defined by Peleg's equation and polynomial regression analysis. Modeling showed that the factors amplitude, time, and solvent were found to be significant in the recovery process (p < 0.005). The maximum amount of compounds was obtained using 90% amplitude for 5 min and ethanol/water mixture (80:20) for extraction to simultaneously obtain phenolic and terpenoid compounds. This system obtained the highest amount of monoterpenoid and sesquiterpenoid compounds from the essential oil of M. spicata (64.93% vs. 84.55%). Thus, with an efficient and eco-friendly method, it was possible to optimize the extraction of compounds in M. spicata as a starting point for the use of its byproducts.

IL-6-based mortality risk model for hospitalized patients with COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has rapidly become a global pandemic. Because the severity of the disease is highly variable, predictive models to stratify patients according to their mortality risk are needed. OBJECTIVE: Our aim was to develop a model able to predict the risk of fatal outcome in patients with COVID-19 that could be used easily at the time of patients' arrival at the hospital. METHODS: We constructed a prospective cohort with 611 adult patients in whom COVID-19 was diagnosed between March 10 and April 12, 2020, in a tertiary hospital in Madrid, Spain. The analysis included 501 patients who had been discharged or had died by April 20, 2020. The capacity of several biomarkers, measured at the beginning of hospitalization, to predict mortality was assessed individually. Those biomarkers that independently contributed to improve mortality prediction were included in a multivariable risk model. RESULTS: High IL-6 level, C-reactive protein level, lactate dehydrogenase (LDH) level, ferritin level, d-dimer level, neutrophil count, and neutrophil-to-lymphocyte ratio were all predictive of mortality (area under the curve >0.70), as were low albumin level, lymphocyte count, monocyte count, and ratio of peripheral blood oxygen saturation to fraction of inspired oxygen (SpO2/FiO2). A multivariable mortality risk model including the SpO2/FiO2 ratio, neutrophil-to-lymphocyte ratio, LDH level, IL-6 level, and age was developed and showed high accuracy for the prediction of fatal outcome (area under the curve 0.94). The optimal cutoff reliably classified patients (including patients with no initial respiratory distress) as survivors and nonsurvivors with 0.88 sensitivity and 0.89 specificity. CONCLUSION: This mortality risk model allows early risk stratification of hospitalized patients with COVID-19 before the appearance of obvious signs of clinical deterioration, and it can be used as a tool to guide clinical decision making.

Algorithm for antinuclear antibodies in subjects with clinical suspicion of autoimmune diseases.

OBJECTIVES: Antinuclear antibodies (ANA) are fundamental in the diagnosis of systemic autoimmune rheumatic diseases (SARDs). Different assays for ANA screening are available, such as indirect immunofluorescence (IIF) on HEp-2 cells and Multiplex fluorescent immunoassay (MFI). This study aimed to clarify the importance of ANA detected only by IIF in the future development of SARDs and to recommend a laboratory algorithm that integrates the available diagnostic approaches to optimise the diagnosis of ANA IIF+MFI- subjects. METHODS: A total of 9,291 subjects with clinical suspicion of SARDs were evaluated for ANA by IIF and MFI. One hundred and ninety-eight subjects (2.1%) were ANA IIF+MFI-, who were followed up for 2 years. ANA were evaluated using IIF on HEp-2 cells and MFI on the BioPlex 2200. RESULTS: The ANA IIF+MFI- cohort included 106 subjects with SARDs, 26 subject with other autoimmune diseases (not-SARDs) and 66 subjects with minor symptoms or ANA requested in check-ups. Only 94 subjects underwent re-evaluation. After a 2-year follow-up, most re-evaluated subjects (51 patients) became ANA negative for both assays (mainly rheumatoid arthritis, polymyalgia and inflammatory bowel disease patients) and 35 subjects remained ANA IIF+MFI- (principally systemic sclerosis and systemic lupus erythematosus patients). A new algorithm for ANA evaluation was suggested. CONCLUSIONS: According to the proposed algorithm, ANA IIF+MFI- subjects should be screened by an alternative solid-phase assay such as line-immunoassay or ELISA.

Allergic contact dermatitis to Tinosorb S, Scutellaria baicalensis, and other emerging allergens in cosmetics.

Patch tests are highly recommended in eczema patients with eyelid involvement. Sunscreen constitutes a potential cause of eyelid or facial allergic contact dermatitis, and should be considered in patients with refractory eczema on these locations. We report a patient sensitized to several emerging allergens such as bis-ethylhexyloxyphenol methoxyphenyl triazine (Tinosorb S), Scutellaria baicalensis extract, and propylene glycol with an eyelid dermatitis. Patch tests to the combined ingredients propylene carbonate, cyclopentasiloxane, and disteardimonium hectorite; and talc, Cl 77 491, and dimethicone/methicone copolymer were also positive. We highlight the importance of systematically patch testing with the cosmetics brought in by our patients, as well as with the individual ingredients whenever positive. The identification of emerging allergies to new compounds in cosmetics mainly depends on this practice.

The Weight of IgA Anti-ß2glycoprotein I in the Antiphospholipid Syndrome Pathogenesis: Closing the Gap of Seronegative Antiphospholipid Syndrome.

The specific value of IgA Anti-ß2glycoprotein I antibodies (aB2GP1) in the diagnosis and management of antiphospholipid syndrome (APS) is still controversial and a matter of active debate. The relevance of the IgA aB2GP1 isotype in the pathophysiology of APS has been increasingly studied in the last years. There is well know that subjects with multiple positive APS tests are at increased risk of thrombosis and/or miscarriage. However, these antibodies are not included in the 2006 APS classification criteria. Since 2010 the task force of the Galveston International Congress on APS recommends testing IgA aB2GP1 isotype in patients with APS clinical criteria in the absence of criteria antibodies. In this review, we summarize the molecular and clinical "state of the art" of the IgA aB2GP in the context of APS. We also discuss some of the characteristics that may help to evaluate the real value of the IgA aB2GP1 determination in basic research and clinical practice. The scientific community should be aware of the importance of clarifying the role of IgA aB2GP1 in the APS diagnosis.

Human rotavirus strains circulating in Venezuela after vaccine introduction: predominance of G2P[4] and reemergence of G1P[8].

BACKGROUND: Rotavirus (RV) is the most common cause of severe childhood diarrhea worldwide. Despite Venezuela was among the first developing countries to introduce RV vaccines into their national immunization schedules, RV is still contributing to the burden of diarrhea. Concerns exist about the selective pressure that RV vaccines could exert on the predominant types and/or emergence of new strains. RESULTS: To assess the impact of RV vaccines on the genotype distribution 1 year after the vaccination was implemented, a total of 912 fecal specimens, collected from children with acute gastroenteritis in Caracas from February 2007 to April 2008, were screened, of which 169 (18.5%) were confirmed to be RV positive by PAGE. Rotavirus-associated diarrhea occurred all year-round, although prevailed during the coolest and driest months among unvaccinated children under 24 months old. Of 165 RV strains genotyped for G (VP7) and P (VP4) by seminested multiplex RT-PCR, 77 (46.7%) were G2P[4] and 63 (38.2%) G1P[8]. G9P[8], G3P[8] and G2P[6] were found in a lower proportion (7.3%). Remarkable was also the detection of <5% of uncommon combinations (G8P[14], G8P[4], G1P[4] and G4P[4]) and 3.6% of mixed infections. A changing pattern of G/P-type distribution was observed during the season studied, with complete predominance of G2P[4] from February to June 2007 followed by its gradual decline and the reemergence of G1P[8], predominant since January 2008. Phylogenetic analysis of VP7 and VP4 genes revealed a high similarity among G2P[4] and global strains belonging to G2-II and P[4]-V lineages. The amino acid substitution 96D → N, related with reemergence of the G2 genotype elsewhere, was observed. The G1P[8] strains from Caracas were grouped into the lineages G1-I and P[8]-III, along with geographically remote G1P[8] rotaviruses, but they were rather distant from Rotarix® vaccine and pre-vaccine strains. Unique amino acid substitutions observed on neutralization domains of the VP7 sequence from Venezuelan post-vaccine G1P[8] could have conditioned their re-emergence and a more efficient dissemination into susceptible population. CONCLUSIONS: The results suggest that natural fluctuations of genotypes in combination with forces driving the genetic evolution could determine the spread of novel strains, whose long-term effect on the efficacy of available vaccines should be determined.

Health economic evaluation of Human Papillomavirus vaccines in women from Venezuela by a lifetime Markov cohort model.

BACKGROUND: Cervical cancer (CC) and genital warts (GW) are a significant public health issue in Venezuela. Our objective was to assess the cost-effectiveness of the two available vaccines, bivalent and quadrivalent, against Human Papillomavirus (HPV) in Venezuelan girls in order to inform decision-makers. METHODS: A previously published Markov cohort model, informed by the best available evidence, was adapted to the Venezuelan context to evaluate the effects of vaccination on health and healthcare costs from the perspective of the healthcare payer in an 11-year-old girls cohort of 264,489. Costs and quality-adjusted life years (QALYs) were discounted at 5%. Eight scenarios were analyzed to depict the cost-effectiveness under alternative vaccine prices, exchange rates and dosing schemes. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: Compared to screening only, the bivalent and quadrivalent vaccines were cost-saving in all scenarios, avoiding 2,310 and 2,143 deaths, 4,781 and 4,431 CCs up to 18,459 GW for the quadrivalent vaccine and gaining 4,486 and 4,395 discounted QALYs respectively. For both vaccines, the main determinants of variations in the incremental costs-effectiveness ratio after running deterministic and probabilistic sensitivity analyses were transition probabilities, vaccine and cancer-treatment costs and HPV 16 and 18 distribution in CC cases. When comparing vaccines, none of them was consistently more cost-effective than the other. In sensitivity analyses, for these comparisons, the main determinants were GW incidence, the level of cross-protection and, for some scenarios, vaccines costs. CONCLUSIONS: Immunization with the bivalent or quadrivalent HPV vaccines showed to be cost-saving or cost-effective in Venezuela, falling below the threshold of one Gross Domestic Product (GDP) per capita (104,404 VEF) per QALY gained. Deterministic and probabilistic sensitivity analyses confirmed the robustness of these results.

Diversity of floral regulatory genes of japonica rice cultivated at northern latitudes.

BACKGROUND: Rice is considered a short day plant. Originally from tropical regions rice has been progressively adapted to temperate climates and long day conditions in part by modulating its sensitivity to day length. Heading date 3a (Hd3a) and RICE FLOWERING LOCUS T 1 (RFT1) that code for florigens, are known as major regulatory genes of floral transition in rice. Both Hd3a and RFT1 are regulated by Early heading date 1 (Ehd1) and Days to heading on chromosome 2 (DTH2) while Heading date 1 (Hd1) also governs Hd3a expression. To investigate the mechanism of rice adaptation to temperate climates we have analyzed the natural variation of these five genes in a collection of japonica rice representing the genetic diversity of long day cultivated rice. RESULTS: We have investigated polymorphisms of Hd3a, RFT1, Ehd1, Hd1 and DTH2 in a collection of 57 japonica varieties. Hd3a and RFT1 were highly conserved, displaying one major allele. Expression analysis suggested that RFT1 rather than Hd3a could be the pivotal gene controlling flowering under long day conditions. While few alleles were found in the Ehd1 promoter and DTH2 coding region, a high degree of variation in Hd1, including non-functional alleles, was observed. Correlation analysis between gene expression levels and flowering periods suggested the occurrence of other factors, additionally to Ehd1, affecting RFT1 regulation in long day adapted cultivars. CONCLUSIONS: During domestication, rice expansion was accompanied by changes in the regulatory mechanism of flowering. The existence of non-functional Hd1 alleles and the lack of correlation of their presence with flowering times in plants grown under long day conditions, indicate a minor role of this branch in this process and the existence of an alternative regulatory pathway in northern latitudes. Expression analysis data and a high degree of conservation of RFT1 suggested that this gene could be the main factor regulating flowering among japonica cultivars adapted to northern areas. In the absence of inhibition exerted by Hd1 through repression of Hd3a expression, the role of Ehd1 as a regulator of RFT1 and Hd3a appears to be reinforced. Data also indicated the occurrence of additional regulatory factors controlling flowering.

Misfolded α-Synuclein in Autosomal Dominant Alzheimer's Disease.

We analyzed Lewy body (LB) pathology in 18 autosomal dominant Alzheimer's disease (ADAD) brains via immunohistochemistry. Real-time quaking induced conversion was used to detect misfolded α-synuclein (α-syn) in 18 living ADAD cerebrospinal fluid (CSF) samples. Concomitant LB pathology was present in 44% ADAD brains. Only 6% CSF samples were positive for misfolded α-syn. In an additional AD sample, all patients with confirmed LB presented misfolded α-syn in postmortem CSF regardless of the LB staging. In conclusion, misfolded α-syn in CSF was scarce in symptomatic living ADAD individuals, in contrast to postmortem brain tissue. These results suggest late appearance of LB pathology in ADAD.

MOG Antibodies Restricted to CSF in Children With Inflammatory CNS Disorders.

OBJECTIVES: To assess the clinical significance of myelin oligodendrocyte glycoprotein antibodies (MOG-abs) restricted to CSF in children with inflammatory CNS disorders. METHODS: Patients included 760 children (younger than 18 years) from 3 multicenter prospective cohort studies: (A) acquired demyelinating syndromes, including acute disseminated encephalomyelitis (ADEM); (B) non-ADEM encephalitis; and (C) noninflammatory neurologic disorders. For all cases, paired serum/CSF samples were systematically examined using brain immunohistochemistry and live cell-based assays. RESULTS: A total of 109 patients (14%) had MOG-abs in serum or CSF: 79 from cohort A, 30 from B, and none from C. Of these, 63 (58%) had antibodies in both samples, 37 (34%) only in serum, and 9 (8%) only in CSF. Children with MOG-abs only in CSF were older than those with MOG-abs only in serum or in both samples (median 12 vs 6 vs 5 years, p = 0.0002) and were more likely to have CSF oligoclonal bands (86% vs 12% vs 7%, p = 0.0001) and be diagnosed with multiple sclerosis (6/9 [67%] vs 0/37 [0%] vs 1/63 [2%], p < 0.0001). DISCUSSION: Detection of MOG-abs in serum or CSF is associated with CNS inflammatory disorders. Children with MOG-abs restricted to CSF are more likely to have CSF oligoclonal bands and multiple sclerosis than those with MOG-abs detectable in serum.

Corrigendum: Immune dysregulation is an important factor in the underlying complications in Influenza infection. ApoH, IL-8 and IL-15 as markers of prognosis.

[This corrects the article DOI: 10.3389/fimmu.2024.1443096.].

Immune dysregulation is an important factor in the underlying complications in Influenza infection. ApoH, IL-8 and IL-15 as markers of prognosis.

Introduction: Influenza virus infection can cause a range of clinical symptoms, including respiratory failure (RF) and even death. The mechanisms responsible for the most severe forms of the disease are not yet well understood. The objective is to assess the initial immune response upon admission and its potential impact on infection progression. Methods: We conducted a prospective observational study of patients with influenza virus infection who required admission to a tertiary hospital in the 2017/18 and 2018/19 flu seasons. Immune markers, surrogate markers of neutrophil activation, and blood levels of DNase I and Apolipoprotein-H (ApoH) were determined in the first serum sample available during hospital care. Patients were followed until hospital discharge or death. Initially, 792 patients were included. From this group, 107 patients with poor evolution were selected, and a random control group was matched by day of admission. Results: Patients with poor outcomes had significantly reduced ApoH levels, a soluble protein that regulate both complement and coagulation pathways. In multivariate analysis, low plasma levels of ApoH (OR:5.43; 2.21-13.4), high levels of C- reactive protein (OR:2.73: 1.28-5.4), hyperferritinemia (OR:2.83; 1.28-5.4) and smoking (OR:3.41; 1.04-11.16), were significantly associated with a worse prognosis. RF was independently associated with low levels of ApoH (OR: 5.12; 2.02-1.94), while high levels of IL15 behaved as a protective factor (OR:0.30; 0.12-0.71). Discussion: Therefore, in hospitalized influenza patients, a dysregulated early immune response is associated with a worse outcome. Adequate plasma levels of ApoH are protective against severe influenza and RF and High levels of IL15 protect against RF.

Impact of demographics and comorbid conditions on plasma biomarkers concentrations and their diagnostic accuracy in a memory clinic cohort.

Plasma biomarkers have emerged as promising tools for identifying amyloid beta (Aß) pathology. Before implementation in routine clinical practice, confounding factors modifying their concentration beyond neurodegenerative diseases should be identified. We studied the association of a comprehensive list of demographics, comorbidities, medication and laboratory parameters with plasma p-tau181, glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) on a prospective memory clinic cohort and studied their impact on diagnostic accuracy for discriminating CSF/amyloid PET-defined Aß status. Three hundred sixty patients (mean age 66.5 years, 55% females, 53% Aß positive) were included. Sex, age and Aß status-adjusted models showed that only estimated glomerular filtration rate (eGFR, standardized ß -0.115 [-0.192 to -0.035], p = 0.005) was associated with p-tau181 levels, although with a much smaller effect than Aß status (0.685 [0.607-0.763], p < 0.001). Age, sex, body mass index (BMI), Charlson comorbidity index (CCI) and eGFR significantly modified GFAP concentration. Age, blood volume (BV) and eGFR were associated with NfL levels. p-tau181 predicted Aß status with 87% sensitivity and specificity with no relevant increase in diagnostic performance by adding any of the confounding factors. Using two cut-offs, plasma p-tau181 could have spared 62% of amyloid-PET/CSF testing. Excluding patients with chronic kidney disease did not change the proposed cut-offs nor the diagnostic performance. In conclusion, in a memory clinic cohort, age, sex, eGFR, BMI, BV and CCI slightly modified plasma p-tau181, GFAP and NfL concentrations but their impact on the diagnostic accuracy of plasma biomarkers for Aß status discrimination was minimal.

Cognitive profile, neuroimaging and fluid biomarkers in post-acute COVID-19 syndrome.

We aimed to characterize the cognitive profile of post-acute COVID-19 syndrome (PACS) patients with cognitive complaints, exploring the influence of biological and psychological factors. Participants with confirmed SARS-CoV-2 infection and cognitive complaints ≥ 8 weeks post-acute phase were included. A comprehensive neuropsychological battery (NPS) and health questionnaires were administered at inclusion and at 1, 3 and 6 months. Blood samples were collected at each visit, MRI scan at baseline and at 6 months, and, optionally, cerebrospinal fluid. Cognitive features were analyzed in relation to clinical, neuroimaging, and biochemical markers at inclusion and follow-up. Forty-nine participants, with a mean time from symptom onset of 10.4 months, showed attention-executive function (69%) and verbal memory (39%) impairment. Apathy (64%), moderate-severe anxiety (57%), and severe fatigue (35%) were prevalent. Visual memory (8%) correlated with total gray matter (GM) and subcortical GM volume. Neuronal damage and inflammation markers were within normal limits. Over time, cognitive test scores, depression, apathy, anxiety scores, MRI indexes, and fluid biomarkers remained stable, although fewer participants (50% vs. 75.5%; p = 0.012) exhibited abnormal cognitive evaluations at follow-up. Altered attention/executive and verbal memory, common in PACS, persisted in most subjects without association with structural abnormalities, elevated cytokines, or neuronal damage markers.

Investigating the 2023 MOGAD Criteria in Children and Adults With MOG-Antibody Positivity Within and Outside Attacks.

BACKGROUND AND OBJECTIVES: The 2023 criteria for myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) perform well in adults but have not been assessed in children. METHODS: This prospective observational nationwide study includes children and adults with demyelinating syndromes or encephalitis, whose serum or CSF was found MOG-immunoglobulin G (IgG) positive at Institut d'Investigacions Biomèdiques August Pi i Sunyer-Hospital Clínic of Barcelona (Spain). Exclusion criteria were lack of clinical information and follow-up <1 year, and serum unavailable for antibody testing. The primary outcome was to assess the accuracy of the 2023 MOGAD criteria, using as gold standard the most plausible diagnosis after a follow-up >1 year. MOGAD criteria were retrospectively applied assessing core syndromes, supportive clinical-radiological features, and MOG-IgG titers. Patients tested ≤3 months of a disease attack (acute phase) or afterward (remission) were considered separately. The positive predictive value (PPV) of the criteria (true-positive [patients classified as MOGAD and MOGAD diagnosis last follow-up] divided by total positive [all patients classified as MOGAD]), and its 95% CI, was calculated with the Wilson procedure. RESULTS: A total of 257 patients (133 children) were included in the study (median age 15 years [interquartile range 6-38], 54% female). Among 202 patients assessed during a disease attack, 158 (78%) had high MOG-IgG serum titers, 36 (18%) low titers, and 8 (4%) antibodies only in CSF. No differences were identified between patients with high and low titers, but those with low titers were more likely to have an alternative diagnosis at last follow-up (2/36 [6%] vs 0/158, p = 0.012). Supportive features were present in 230 of 257 (89%) patients, regardless of age, MOG-IgG titers, and core syndromes except for optic neuritis in adults whose assessment with orbital MRI was not systematic. Overall, 240 of 257 (94%) patients were well classified by the MOGAD criteria (e.g., 236 eventually having MOGAD and 4 alternative diagnoses), and 17 were wrongly classified (e.g., 11 eventually having MOGAD and 6 alternative diagnoses). Although the criteria classified better during disease attacks than during remissions (187 [96%] vs 49 [89%] serum MOG-IgG-positive patients were well-classified, p = 0.038), the PPV was high in both settings (99% [95% CI 97-100] vs 98% [95% CI 89-100]). DISCUSSION: The 2023 MOGAD criteria correctly identified most children and adults with MOGAD. The highest accuracy occurred when they were applied during disease attacks. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that the 2023 MOGAD criteria accurately identify adults and children with MOGAD.

Algorithm to improve the diagnosis of paraneoplastic neurological syndromes associated with SOX1 antibodies.

SOX1 antibodies (SOX1-abs) are associated with paraneoplastic neurological syndromes (PNS) and small cell lung cancer (SCLC). In many clinical laboratories SOX1-abs are determined by commercial line blots without confirmation by cell-based assay (CBA) with HEK293 cells expressing SOX1. However, the diagnostic yield of commercial line blots is low and the accessibility to the CBA, that is not commercially available, limited. Here, we evaluated if the addition of the band intensity data of the line blot and the immunoreactivity in a tissue-based assay (TBA) improve the diagnostic performance of the line blot. We examined serum of 34 consecutive patients with adequate clinical information that tested positive for SOX1-abs in a commercial line blot. Samples were also assessed by TBA and CBA. SOX1-abs were confirmed by CBA in 17 (50%) patients, all (100%) had lung cancer (SCLC in 16) and 15/17 (88%) had a PNS. In the remaining 17 patients the CBA was negative and none had PNS associated with lung cancer. TBA was assessable in 30/34 patients and SOX1-abs reactivity was detected in 15/17 (88%) with positive and in 0/13 (0%) with negative CBA. Only 2 (13%) of the 15 TBA-negative patients were CBA-positive. The frequency of TBA-negative but CBA-positive increased from 10% (1/10) when the band intensity of the line blot was weak to 20% (1/5) in patients with a moderate or strong intensity band. Confirmation by CBA should be mandatory for samples (56% in this series) not assessable (4/34; 12%) or negative in the TBA (15/34; 44%).