Real-World Effectiveness and Safety of Cladribine in Multiple Sclerosis: Longitudinal Data From the Nationwide Registry in Argentina.

OBJECTIVE: The aim was to evaluate patient profiles, effectiveness and safety of cladribine (CLAD) in patients with relapsing-remitting multiple sclerosis in Argentina. METHODS: This was a substudy included in RelevarEM (MS and neuromyelitis optica registry in Argentina, NCT03375177). Patients with MS who received CLAD tablets and were followed up for at least 24 months were included. Clinical evaluations every 3 months collect information about: a) clinical relapses; b) progression of physical disability, evaluated through Expanded Disability Status Scale, and c) new lesions found in the magnetic resonance imaging. Lymphopenia was evaluated during the follow-up and defined as grade 1: absolute lymphocyte count (ALC) 800-999/µL; grade 2: ALC 500-799/µL; grade 3: ALC 200-499/µL and grade 4: ALC <200/µL. RESULTS: A total of 240 patients were included from 19 centers from Argentina. The mean annualized relapse rate during the 12-month pre-CLAD initiation was 1.19 ± 0.56 versus 0.22 ± 0.18 at month 12 and 0.19 ± 0.15 at month 24 ( P < 0.001). A total of 142 (59.2%) fulfilled the criteria of disease activity during the 12 months before treatment initiation, whereas 27 (11.3%) fulfilled it at month 12 and 38 (15.8%) at month 24, P < 0.001. Regarding no evidence of disease activity (NEDA), 202 (84.2%) patients achieved NEDA status at month 12 and 185 (77%) at month 24. The most frequent incidence density of lymphopenia for course 2 observed was also for grade 1, 6.1 (95% confidence interval [CI] = 5.5-7.1). The overall incidence density of lymphopenia grade 4 was 0.1 (95% CI = 0.06-0.19). CONCLUSION: This information will help when choosing the best treatment option for Argentinean patients.

Serotype distribution, clinical characteristics, and antimicrobial resistance of pediatric invasive pneumococcal disease in Colombia during PCV10 mass vaccination (2017-2022).

Introduction: Invasive Pneumococcal Disease (IPD) causes significant morbidity and mortality in children under 5 y. Colombia introduced PCV10 vaccination in 2012, and the Neumocolombia network has been monitoring IPD in pediatric patients since 2008. Materials and methods: This study is a secondary analysis of a prospective cohort involving pediatric patients with IPD admitted to 17 hospitals in Colombia, from January 1st, 2017, to December 31st, 2022. We present data on serotypes (Spn), clinical characteristics, and resistance patterns. Results: We report 530 patients, 215 (40.5%) were younger than 24 months. Among these, 344 cases (64.7%) presented with pneumonia, 95 (17.9%) with primary bacteremia, 53 (10%) with meningitis, 6 (1.1%) had pneumonia and meningitis, and 32 (6%) had other IPD diagnosis. The median hospital stay was 12 days (RIQ 8-14 days), and 268 (50.6%) were admitted to the ICU, of whom 60 (11.3%) died. Serotyping was performed in 298 (56.1%). The most frequent serotypes were Spn19A (51.3%), Spn6C (7.7%), Spn3 (6.7%), Spn6A (3.6%), and Spn14 (3.6%). Of 495 (93%) isolates with known susceptibility, 46 (9.2%) were meningeal (M) and 449 (90.7%) non-meningeal (NM). Among M isolates, 41.3% showed resistance to penicillin, and 21.7% decreased susceptibility to ceftriaxone. For NM isolates, 28.2% had decreased susceptibility to penicilin, and 24.2% decreased susceptibility to ceftriaxone. Spn19A showed the highest resistant to penicillin at 47% and was linked to multiresistance. Conclusion: The prevalence of PCV10-included serotypes decreased, while serotypes 19A and 6C increased, with Spn19A being associated with multiresistance. These findings had played a crucial role in the decision made by Colombia to modify its immunization schedule by switching to PCV13 in July 2022.

Association between Dexmedetomidine Use and Mortality in Patients with COVID-19 Receiving Invasive Mechanical Ventilation: A U.S. National COVID Cohort Collaborative (N3C) Study.

(1) Background/Objectives: Dexmedetomidine is a sedative for patients receiving invasive mechanical ventilation (IMV) that previous single-site studies have found to be associated with improved survival in patients with COVID-19. The reported clinical benefits include dampened inflammatory response, reduced respiratory depression, reduced agitation and delirium, improved preservation of responsiveness and arousability, and improved hypoxic pulmonary vasoconstriction and ventilation-perfusion ratio. Whether improved mortality is evident in large, multi-site COVID-19 data is understudied. (2) Methods: The association between dexmedetomidine use and mortality in patients with COVID-19 receiving IMV was assessed. This retrospective multi-center cohort study utilized patient data in the United States from health systems participating in the National COVID Cohort Collaborative (N3C) from 1 January 2020 to 3 November 2022. The primary outcome was 28-day mortality rate from the initiation of IMV. Propensity score matching adjusted for differences between the group with and without dexmedetomidine use. Adjusted hazard ratios (aHRs) for 28-day mortality were calculated using multivariable Cox proportional hazards models with dexmedetomidine use as a time-varying covariate. (3) Results: Among the 16,357,749 patients screened, 3806 patients across 17 health systems met the study criteria. Mortality was lower with dexmedetomidine use (aHR, 0.81; 95% CI, 0.73-0.90; p < 0.001). On subgroup analysis, mortality was lower with earlier dexmedetomidine use-initiated within the median of 3.5 days from the start of IMV-(aHR, 0.67; 95% CI, 0.60-0.76; p < 0.001) as well as use prior to standard, widespread use of dexamethasone for patients on respiratory support (prior to 30 July 2020) (aHR, 0.54; 95% CI, 0.42-0.69; p < 0.001). In a secondary model that was restricted to 576 patients across six health system sites with available PaO2/FiO2 data, mortality was not lower with dexmedetomidine use (aHR 0.95, 95% CI, 0.72-1.25; p = 0.73); however, on subgroup analysis, mortality was lower with dexmedetomidine use initiated earlier than the median dexmedetomidine start time after IMV (aHR, 0.72; 95% CI, 0.53-0.98; p = 0.04) and use prior to 30 July 2020 (aHR, 0.22; 95% CI, 0.06-0.78; p = 0.02). (4) Conclusions: Dexmedetomidine use was associated with reduced mortality in patients with COVID-19 receiving IMV, particularly when initiated earlier, rather than later, during the course of IMV as well as use prior to the standard, widespread usage of dexamethasone during respiratory support. These particular findings might suggest that the associated mortality benefit with dexmedetomidine use is tied to immunomodulation. However, further research including a large randomized controlled trial is warranted to evaluate the potential mortality benefit of DEX use in COVID-19 and evaluate the physiologic changes influenced by DEX that may enhance survival.

Treatment strategies and responses for attacks of neuromyelitis optica spectrum disorder: A real-world retrospective cohort study.

We aimed to assess the treatment strategies utilized in patients with neuromyelitis optica spectrum disorder (NMOSD) experiencing relapses, including their frequency, types, and response after 6 months based on the Expanded Disability Status Scale (EDSS) score. METHODS: We conducted a retrospective study involving NMOSD patients from the Argentinean MS and NMOSD registry (RelevarEM, NCT03375177). Treatment response at 6 months was categorized as "good" if the EDSS score decreased by ≥1 point after a nadir EDSS score ≤ 3, or by ≥2 points after a nadir EDSS score > 3, "poor" if the EDSS score decrease was slighter, and as "absent" if the EDSS score remained unchanged or worsened. RESULTS: We included 120 NMOSD patients (seropositive N = 75), who experienced 250 NMOSD-related relapses and received 248 treatments. At 6 months, complete recovery was achieved in 70/98 (71.4%) and 15/19 (79%) patients, respectively. Predictors of a "good" response in our regression model were a younger age at disease onset (OR:3.54, CI95% 2.45-5.01, p < 0.0001) and a short delay from onset of relapse to treatment initiation (OR:1.56, CI95% 1.22-2.13, p = 0.004). CONCLUSIONS: Approximately two-thirds of patients experienced complete recovery, and younger age and a short delay to start treatment were independent predictors of a "good" response.

Using Event-Related Potentials to Evidence the Visual and Semantic Impact: A Pilot Study with N400 Effect and Food Packaging.

Packaging design is pivotal in motivating consumer decisions, as a key communication tool from creation to purchase. Currently, the interpretation and evaluation of packaging's impact are shifting toward non-traditional methods. This pilot study evaluated the packaging perception of York Ham and Turkey Breast products. The event-related potential (ERP) technique, the methodology priming words (positive and negative), and target images (original and modified packaging) were applied. A total of 23 participants were sampled using a 32-channels scalp elastic electrode cap and viewed 200 trials of word-image matching. Participants responded whether the images and adjectives matched or not, using the two groups of images. The results demonstrate an N400 effect in the parietal area. This region was observed to show evidence of cognitive processing related to congruency or incongruency, by contrasting the priming and target of this study. The evaluation positioned the York Ham packaging as the best rated. The findings show a relevant contribution to ERPs and research related to the food packaging perception.

Smartphone-Based Methodology Applied to Electromagnetic Field Exposure Assessment.

This study presents the measurements of exposure to electromagnetic fields, carried out comparatively following standard methods from fixed sites using a broadband meter and using a smartphone on which an App designed for this purpose has been installed. The results of two measurement campaigns carried out on the campus of the University of Alcalá over an area of 1.9 km2 are presented. To characterize the exposure, 20 fixed points were measured in the first case and 860 points along the route made with a bicycle in the last case. The results obtained indicate that there is proportionality between the two methods, making it possible to use the smartphone for comparative measurements. The presented methodology makes it possible to characterize the exposure in the area under study in four times less time than that required with the traditional methodology.

Plastid DNA is a major source of nuclear genome complexity and of RNA genes in the orphan crop moringa.

BACKGROUND: Unlike Transposable Elements (TEs) and gene/genome duplication, the role of the so-called nuclear plastid DNA sequences (NUPTs) in shaping the evolution of genome architecture and function remains poorly studied. We investigate here the functional and evolutionary fate of NUPTs in the orphan crop Moringa oleifera (moringa), featured by the highest fraction of plastid DNA found so far in any plant genome, focusing on (i) any potential biases in their distribution in relation to specific nuclear genomic features, (ii) their contribution to the emergence of new genes and gene regions, and (iii) their impact on the expression of target nuclear genes. RESULTS: In agreement with their potential mutagenic effect, NUPTs are underrepresented among structural genes, although their overall transcription levels and broadness were only lower when involved exonic regions; the occurrence of plastid DNA generally did not result in a broader expression, except among those affected in introns by older NUPTs. In contrast, we found a strong enrichment of NUPTs among specific superfamilies of retrotransposons and several classes of RNA genes, including those participating in the protein biosynthetic machinery (i.e., rRNA and tRNA genes) and a specific class of regulatory RNAs. A significant fraction of NUPT RNA genes was found to be functionally expressed, thus potentially contributing to the nuclear pool. CONCLUSIONS: Our results complete our view of the molecular factors driving the evolution of nuclear genome architecture and function, and support plastid DNA in moringa as a major source of (i) genome complexity and (ii) the nuclear pool of RNA genes.

Selection of disease modifying therapies in multiple sclerosis based on patient's age and disease activity: Data from a nationwide registry.

BACKGROUND: Knowledge of the safety and efficacy of disease-modifying therapies (DMTs) in older patients with Multiple Sclerosis (pwMS) is limited due to their exclusion from clinical trials. Our purpose is to evaluate the choice of DMTs in pwMS older than 50 years old in a real-world setting. METHODS: Cross-sectional study of pwMS from the Argentine MS and NMOSD Registry. We included patients under 35 and above 50 years old prescribed DMTs. Disease activity was categorized as highly active (HA) or not highly active (NHA), and DMTs were classified as low efficacy therapies (LET) or high efficacy therapies (HET). RESULTS: 1460 patients (65% females) were enrolled. The HA group comprised 241 patients, 198 young (82.2%) and 43 older (17.8%). The NHA group included 1219 patients, 893 young (73%) and 326 older (27%). In the NHA group, older patients received LET more frequently than younger patients (66% versus 44%; p < 0.01). In the HA group, older patients received LET in 61% of cases, whereas younger patients received HET in 71% (p = 0.01). CONCLUSION: The study shows the preference of LET in older patients regardless of disease activity. However it does not demonstrate a difference in disability in older patients based on low vs high efficacy DMTs used, probably due to the design of the study. Further longitudinal studies are warranted to address this issue.

Evaluating Quality of Care for Patients with Asthma in the Readmission Penalty Era.

RATIONALE: Asthma poses a significant burden for US patients and health systems, yet inpatient care quality is understudied. National chronic obstructive lung disease (COPD) readmission policies may affect inpatient asthma care through hospital responses to these polices due to imprecise diagnosis and identification of patients with COPD and asthma. OBJECTIVES: Evaluate inpatient care quality care for patients hospitalized with asthma and potential collateral effects of the Medicare COPD Hospital Readmissions Reduction Program (HRRP). METHODS: Retrospective cohort study of patients aged 18-54 years hospitalized for asthma across 924 US hospitals (Premier Healthcare Database). RESULTS: Care quality for patients with asthma was evaluated pre-HRRP implementation (n=20,820; January 2010-September 2014) and post-HRRP implementation (n=26,885; October 2014-December 2018) using adherence to inpatient care guidelines (recommended, non-recommended, and "ideal care" [all recommended with no non-recommended care]). Between 2010-2018, at least 80% of patients received recommended care annually. Recommended care decreased similarly (rate of 0.02%/month) post vs. pre-HRRP (p=0.8). Non-recommended care decreased more rapidly post-HRRP (rate of 0.29%/month) vs. pre-HRRP (rate of 0.17%/month; p<0.001) with changes driven largely by decreased antibiotic prescribing. Ideal care increased more rapidly post-HRRP (rate of 0.25%/month) vs. pre-HRRP (rate of 0.17%/month; p=0.02) with changes driven largely by non-recommended care improvements. CONCLUSIONS: Post-HRRP trends suggest asthma care improved with increased rates of guideline concordance in non-recommended and ideal care. While federal policies (e.g., HRRP) may have had positive collateral effects such as with asthma care, parallel care efforts including antibiotic stewardship likely contributed to these improvements.

Real-World Effectiveness and Safety of Cladribine in Multiple Sclerosis: Longitudinal Data From the Nationwide Registry in Argentina.

OBJECTIVE: The aim was to evaluate patient profiles, effectiveness and safety of cladribine (CLAD) in patients with relapsing-remitting multiple sclerosis in Argentina. METHODS: This was a substudy included in RelevarEM (MS and neuromyelitis optica registry in Argentina, NCT03375177). Patients with MS who received CLAD tablets and were followed up for at least 24 months were included. Clinical evaluations every 3 months collect information about: a) clinical relapses; b) progression of physical disability, evaluated through Expanded Disability Status Scale, and c) new lesions found in the magnetic resonance imaging. Lymphopenia was evaluated during the follow-up and defined as grade 1: absolute lymphocyte count (ALC) 800-999/µL; grade 2: ALC 500-799/µL; grade 3: ALC 200-499/µL and grade 4: ALC <200/µL. RESULTS: A total of 240 patients were included from 19 centers from Argentina. The mean annualized relapse rate during the 12-month pre-CLAD initiation was 1.19 ± 0.56 versus 0.22 ± 0.18 at month 12 and 0.19 ± 0.15 at month 24 (P < 0.001). A total of 142 (59.2%) fulfilled the criteria of disease activity during the 12 months before treatment initiation, whereas 27 (11.3%) fulfilled it at month 12 and 38 (15.8%) at month 24, P < 0.001. Regarding no evidence of disease activity (NEDA), 202 (84.2%) patients achieved NEDA status at month 12 and 185 (77%) at month 24. The most frequent incidence density of lymphopenia for course 2 observed was also for grade 1, 6.1 (95% confidence interval [CI] = 5.5-7.1). The overall incidence density of lymphopenia grade 4 was 0.1 (95% CI = 0.06-0.19). CONCLUSION: This information will help when choosing the best treatment option for Argentinean patients.

A new MVA ancestor-derived oncolytic vaccinia virus induces immunogenic tumor cell death and robust antitumor immune responses.

Vaccinia viruses (VACVs) are versatile therapeutic agents and different features of various VACV strains allow for a broad range of therapeutic applications. Modified VACV Ankara (MVA) is a particularly altered VACV strain that is highly immunogenic, incapable of replicating in mammalian hosts, and broadly used as a safe vector for vaccination. Alternatively, Western Reserve (WR) or Copenhagen (Cop) are VACV strains that efficiently replicate in cancer cells and, therefore, are used to develop oncolytic viruses. However, the immune evasion capacity of WR or Cop hinders their ability to elicit antitumor immune responses, which is crucial for efficacy in the clinic. Here, we describe a new VACV strain named Immune-Oncolytic VACV Ankara (IOVA), which combines efficient replication in cancer cells with induction of immunogenic tumor cell death (ICD). IOVA was engineered from an MVA ancestor and shows superior cytotoxicity in tumor cells. In addition, the IOVA genome incorporates mutations that lead to massive fusogenesis of tumor cells, which contributes to improved antitumor effects. In syngeneic mouse tumor models, the induction of ICD results in robust antitumor immunity directed against tumor neo-epitopes and eradication of large established tumors. These data present IOVA as an improved immunotherapeutic oncolytic vector.

COVID-19 patient satisfaction and associated factors in telemedicine and hybrid system.

Background: The quality assessment of the home-based isolation and care program (HBIC) relies heavily on patient satisfaction and length of stay. COVID-19 patients who were isolated and received HBIC were monitored through telephone consultations (TC), in-person TC visits, and a self-reporting application. By evaluating patient satisfaction and length of stay in HBIC, healthcare providers could gauge the effectiveness and efficiency of the HBIC program. Methods: A cross-sectional study design enrolled 444 HBIC patients who answered a structured questionnaire. A binary logistic regression model assessed the association between independent variables and patient satisfaction. The length of stay in HBIC was analyzed using Cox regression analysis. The data collection started on April (1-30), 2022, in Addis Ababa, Ethiopia. Results: The median age was 34, and 247 (55.6%) were females. A greater proportion (313, 70.5%) of the participants had high satisfaction. Higher frequency of calls (>3 calls) (AOR = 2.827, 95% CI = 1.798, 4.443, p = 0.000) and those who were symptomatic (AOR = 2.001, 95% CI = 1.289, 3.106, p = 0.002) were found to be significant factors for high user satisfaction. Higher frequency of calls (>3 calls) (AHR = 0.537, 95% CI = 0.415, 0.696, p = 0.000) and more in-person visits (>1 visit) (AHR = 0.495, 95% CI = 0.322, 0.762, p = 0.001) had greater chances to reduce the length of stay in the COVID-19 HBIC. Conclusion: 70.5% of the participants had high satisfaction with the system, and frequent phone call follow-ups on patients' clinical status can significantly improve their satisfaction and length of recovery. An in-person visit is also an invaluable factor in a patient's recovery.

The diagnostic workup of children with the radiologically isolated syndrome differs by age and by sex.

BACKGROUND: Cerebrospinal fluid (CSF) and spinal MRIs are often obtained in children with the radiologically isolated syndrome (RIS) for diagnosis and prognosis. Factors affecting the frequency and timing of these tests are unknown. OBJECTIVE: To determine whether age or sex were associated with (1) having CSF or spinal MRI obtained or (2) the timing of these tests. METHODS: We analyzed children (≤ 18 y) with RIS enrolled in an international longitudinal study. Index scans met 2010/2017 multiple sclerosis (MS) MRI criteria for dissemination in space (DIS). We used Fisher's exact test and multivariable logistic regression (covariates = age, sex, MRI date, MRI indication, 2005 MRI DIS criteria met, and race). RESULTS: We included 103 children with RIS (67% girls, median age = 14.9 y). Children ≥ 12 y were more likely than children < 12 y to have CSF obtained (58% vs. 21%, adjusted odds ratio [AOR] = 4.9, p = 0.03). Pre-2017, girls were more likely than boys to have CSF obtained (n = 70, 79% vs. 52%, AOR = 4.6, p = 0.01), but not more recently (n = 30, 75% vs. 80%, AOR = 0.2, p = 0.1; p = 0.004 for interaction). Spinal MRIs were obtained sooner in children ≥ 12 y (median 11d vs. 159d, p = 0.03). CONCLUSIONS: Younger children with RIS may be at continued risk for misdiagnosis and misclassification of MS risk. Consensus guidelines are needed.

Occurrence of area postrema syndrome during follow-up: phenotype and influence over NMOSD activity in LATAM in real-world settings.

INTRODUCTION: We aimed to assess the frequency, duration, and severity of area postrema syndrome (APS) during follow-up in neuromyelitis optica spectrum disorder (NMOSD) patients, as well as its association with inflammatory activity and prognostic factors of APS severity in a real-world setting. METHODS: We conducted a retrospective study on a cohort of Latin American (LATAM) NMOSD patients who had experienced APS during their follow-up. Patients from Mexico, Peru, Brazil, Colombia, Panama, Chile and Argentina patients who met 2015 NMOSD criteria were included. We evaluated data on symptom type (nausea, vomiting and/or hiccups), frequency, duration, severity (measured by APS severity scale), association with other NMOSD core relapses, and acute treatments (symptomatic and immunotherapy or plasmapheresis). Logistic regression was conducted to evaluate factors associated with APS severity (vs. mild-moderate). RESULTS: Out of 631 NMOSD patients, 116 (18.3%) developed APS during their follow-up. The most common APS phenotype was severe. Inflammatory activity (i.e., relapses) significantly decreased after the onset of APS. Half of the patients experienced isolated APS with a median duration of 10 days, and the most frequently used acute treatment was IV steroids. All three symptoms were present in 44.6% of the patients. APS symptoms resolved following immunotherapy. Logistic regression did not identify independent factors associated with the severity of APS. CONCLUSIONS: Our findings indicate that 18.3% of NMOSD patients developed APS during the follow-up period, with most patients fulfilling criteria for severe APS. The inflammatory activity decreased after the onset of APS compared to the previous year.

Burden of treatment and quality of life in relapsing remitting multiple sclerosis patients under early high efficacy therapy in Argentina: Data from the Argentinean registry.

The objective of this study was to describe and compare the burden of treatment (BOT) and the quality of life (QoL) in early high efficacy therapy (HET) vs. escalation therapy in relapsing remitting multiple sclerosis (RRMS) patients included in RelevarEM, the Argentinean registry of MS (RelevarEM, NCT 03,375,177). METHODS: cross sectional study conducted between September and December 2022. Participating patients were adults, RRMS patients who initiated (during the last three years) their treatment with a HET (natalizumab, ocrelizumab, alemtuzumab, cladribine) or with escalation treatment (beta interferon, glatiramer acetate, teriflunomide, dimethyl fumarate or fingolimod). Clinical and demographic aspect were collected. QoL and BOT was measured with the validated to Spanish MusiQol and BOT questionnaire. Propensity score (PS)-based nearest-neighbor matching was applied to homogenize groups. Comparisons were be done using a linear regression analysis model stratified by matched pairs, with BOT and QoL assessments as main outcomes. RESULTS: 269 patients were included in the analysis, mean age 33.7 ± 5.7 years, 193 (71.7 %) were female. A total of 136 patients were on early HET while 133 were on escalation therapy. In the entire group the mean total BOT score (±SD) was 48.5 ± 15.3 while in the group of patients receiving early HET we observed that the mean BOT score (±SD) was 43.5 ± 12.2 vs. 54.3 ± 13.3 in escalation treatment (p < 0.0001). Regarding the score QoL (±SD), in the entire sample we observed a global score of 77.4 ± 11.2. When we stratified groups, in HET (±SD) it was 81.3 ± 14 vs. 74.1 ± 18.3 in escalation therapy (p = 0.0003). CONCLUSION: in this multicenter study that included 269 patients from Argentina we observed in early HET a significantly lower BOT and higher QoL than patients receiving escalation therapy.

COVID-19 waves in an urban setting 2020-2022: an electronic medical record analysis.

Background: Global and national surveillance efforts have tracked COVID-19 incidence and clinical outcomes, but few studies have compared comorbid conditions and clinical outcomes across each wave of the pandemic. We analyzed data from the COVID-19 registry of a large urban healthcare system to determine the associations between presenting comorbidities and clinical outcomes during the pandemic. Methods: We analyzed registry data for all inpatients and outpatients with COVID-19 from March 2020 through September 2022 (N = 44,499). Clinical outcomes were death, hospitalization, and intensive care unit (ICU) admission. Demographic and clinical outcomes data were analyzed overall and for each wave. Unadjusted and multivariable logistic regressions were performed to explore the associations between age, sex, race, ethnicity, comorbidities, and mortality. Results: Waves 2 and 3 (Alpha and Delta variants) were associated with greater hospitalizations, ICU admissions, and mortality than other variants. Chronic pulmonary disease was the most common comorbid condition across all age groups and waves. Mortality rates were higher in older patients but decreased across all age groups in later waves. In every wave, mortality was associated with renal disease, congestive heart failure, cerebrovascular disease, diabetes, and chronic pulmonary disease. Multivariable analysis found that liver disease and renal disease were significantly associated with mortality, hospitalization, and ICU admission, and diabetes was significantly associated with hospitalization and ICU admission. Conclusion: The COVID-19 registry is a valuable resource to identify risk factors for clinical outcomes. Our findings may inform risk stratification and care planning for patients with COVID-19 based on age and comorbid conditions.

Biological basis of extensive pleiotropy between blood traits and cancer risk.

BACKGROUND: The immune system has a central role in preventing carcinogenesis. Alteration of systemic immune cell levels may increase cancer risk. However, the extent to which common genetic variation influences blood traits and cancer risk remains largely undetermined. Here, we identify pleiotropic variants and predict their underlying molecular and cellular alterations. METHODS: Multivariate Cox regression was used to evaluate associations between blood traits and cancer diagnosis in cases in the UK Biobank. Shared genetic variants were identified from the summary statistics of the genome-wide association studies of 27 blood traits and 27 cancer types and subtypes, applying the conditional/conjunctional false-discovery rate approach. Analysis of genomic positions, expression quantitative trait loci, enhancers, regulatory marks, functionally defined gene sets, and bulk- and single-cell expression profiles predicted the biological impact of pleiotropic variants. Plasma small RNAs were sequenced to assess association with cancer diagnosis. RESULTS: The study identified 4093 common genetic variants, involving 1248 gene loci, that contributed to blood-cancer pleiotropism. Genomic hotspots of pleiotropism include chromosomal regions 5p15-TERT and 6p21-HLA. Genes whose products are involved in regulating telomere length are found to be enriched in pleiotropic variants. Pleiotropic gene candidates are frequently linked to transcriptional programs that regulate hematopoiesis and define progenitor cell states of immune system development. Perturbation of the myeloid lineage is indicated by pleiotropic associations with defined master regulators and cell alterations. Eosinophil count is inversely associated with cancer risk. A high frequency of pleiotropic associations is also centered on the regulation of small noncoding Y-RNAs. Predicted pleiotropic Y-RNAs show specific regulatory marks and are overabundant in the normal tissue and blood of cancer patients. Analysis of plasma small RNAs in women who developed breast cancer indicates there is an overabundance of Y-RNA preceding neoplasm diagnosis. CONCLUSIONS: This study reveals extensive pleiotropism between blood traits and cancer risk. Pleiotropism is linked to factors and processes involved in hematopoietic development and immune system function, including components of the major histocompatibility complexes, and regulators of telomere length and myeloid lineage. Deregulation of Y-RNAs is also associated with pleiotropism. Overexpression of these elements might indicate increased cancer risk.

Clinical impact of gender and age at onset on disease trajectory in primary progressive multiple sclerosis patients.

BACKGROUND AND OBJECTIVES: Primary-progressive multiple sclerosis (PPMS) is characterized by gradual neurological deterioration without relapses. This study aimed to investigate the clinical impact of gender and age at disease onset on disease progression and disability accumulation in patients with this disease phenotype. METHODS: Secondary data from the RelevarEM registry, a longitudinal database in Argentina, were analyzed. The cohort comprised patients with PPMS who met inclusion criteria. Statistical analysis with multilevel Bayesian robust regression modeling was conducted to assess the associations between gender, age at onset, and Expanded Disability Status Scale (EDSS) score trajectories. RESULTS: We identified 125 patients with a confirmed diagnosis of PPMS encompassing a total of 464 observations. We found no significant differences in EDSS scores after 10 years of disease progression between genders (-0.08; credible interval (CI): -0.60, 0.42). A 20-year difference in age at onset did not show significant differences in EDSS score after 10 years of disease progression (0.281; CI: -0.251, 0.814). Finally, we also did not find any clinically relevant difference between gender EDSS score with a difference of 20 years in age at onset (-0.021; CI: -0.371, 0.319). CONCLUSION: Biological plausibility of gender and age effects does not correlate with clinical impact measured by EDSS score.

Impact of Lipids and Vascular Damage on Early Atherosclerosis in Adolescents with Parental Premature Coronary Artery Disease.

AIM: To assess the relationship of cardiovascular risk factors (CRFs) with carotid intima media thickness (IMT) in adolescents with a parental history of premature coronary artery disease (PCAD). METHODS: This cross-sectional study included 50 healthy adolescents, aged 14-18 years, both sexes, with a parental history of PCAD, that were compared to 50 controls without this history. Questionnaires regarding information of CRFs were applied. Blood chemistry analyses, included lipid profile, lipoprotein (a), low density lipoprotein (LDL) susceptibility to oxidation, and inflammatory cytokine levels. The IMT was evaluated by ultrasound. RESULTS: The mean age of all participants was 15.9 years. Anthropometric measurements, blood pressure, and lipid profile were similar in both groups. However, the parental history of PCAD group exhibited lower high density lipoprotein cholesterol concentrations, shorter LDL particle oxidation time, and higher lipoprotein (a) levels compared to the control group. IMT was significantly higher in adolescents with a parental history of PCAD compared to controls, (0.53 ± 0.04 mm vs 0.47 ± 0.02 mm, p = 0.001). Among adolescents with a parental history of PCAD, those with ≥ 3 CRFs had significantly higher IMT values (0.56 mm) than those with < 3 CRFs (0.52 mm) and controls (0.48 mm). Multivariable analyses identified that systolic blood pressure and parental history of PCAD explained 26.8% and 16.1% of the variation in IMT. Furthermore, body mass index, LDL-C, ApoB-100, triglycerides and lipoprotein (a) interact with blood pressure levels to explain the IMT values. CONCLUSION: Adolescents with a parental history of PCAD had higher IMT values than the control group, primary explained by systolic blood pressure and the parental inheritance. Adolescents with parental history of PCAD and ≥ 3 CRFs exhibited the highest IMT values. Notably, lipids and systolic blood pressure jointly contribute to explain IMT in these adolescents.

Comparison between Platelet Lysate, Platelet Lysate Serum, and Fetal Bovine Serum as Supplements for Cell Culture, Expansion, and Cryopreservation.

As cell culture supplements, human platelet lysate (PL) and human platelet lysate serum (PLS) are alternatives to fetal bovine serum (FBS) due to FBS-related issues such as ethical concerns, variability between batches, and the possible introduction of xenogenic contaminants. This study compared the composition and efficacy of PL, PLS, and FBS as supplements in the culture and cryopreservation of human dermal fibroblasts, Wharton's jelly-derived mesenchymal stem cells (WJ-MCS), and adipose tissue (AdMSC). Biochemical components, some growth factors, and cytokines present in each of them were analyzed; in addition, the cells were cultured in media supplemented with 5% PL, 5% PLS, and 10% FBS and exposed to different freezing and thawing solutions with the supplements under study. Biochemical parameters were found to be similar in PL and PLS compared to FBS, with some differences in fibrinogen and calcium concentration. Growth factors and cytokines were higher in PL and PLS compared to FBS. Cell proliferation and morphology showed no significant differences between the three culture media. Regarding the cryopreservation and thawing of cells, better results were obtained with PLS and FBS. In conclusion, PL and PLS are an excellent choice to replace the standard supplement of animal origin (FBS) in the media used for the culture and cryopreservation of fibroblasts, WJ-MSC, and AdMSC.