Autophagy modulates endothelial junctions to restrain neutrophil diapedesis during inflammation.

The migration of neutrophils from the blood circulation to sites of infection or injury is a key immune response and requires the breaching of endothelial cells (ECs) that line the inner aspect of blood vessels. Unregulated neutrophil transendothelial cell migration (TEM) is pathogenic, but the molecular basis of its physiological termination remains unknown. Here, we demonstrated that ECs of venules in inflamed tissues exhibited a robust autophagic response that was aligned temporally with the peak of neutrophil trafficking and was strictly localized to EC contacts. Genetic ablation of EC autophagy led to excessive neutrophil TEM and uncontrolled leukocyte migration in murine inflammatory models, while pharmacological induction of autophagy suppressed neutrophil infiltration into tissues. Mechanistically, autophagy regulated the remodeling of EC junctions and expression of key EC adhesion molecules, facilitating their intracellular trafficking and degradation. Collectively, we have identified autophagy as a modulator of EC leukocyte trafficking machinery aimed at terminating physiological inflammation.

Age-related changes in the local milieu of inflamed tissues cause aberrant neutrophil trafficking and subsequent remote organ damage.

Aging is associated with dysregulated immune functions. Here, we investigated the impact of age on neutrophil diapedesis. Using confocal intravital microscopy, we found that in aged mice, neutrophils adhered to vascular endothelium in inflamed tissues but exhibited a high frequency of reverse transendothelial migration (rTEM). This retrograde breaching of the endothelium by neutrophils was governed by enhanced production of the chemokine CXCL1 from mast cells that localized at endothelial cell (EC) junctions. Increased EC expression of the atypical chemokine receptor 1 (ACKR1) supported this pro-inflammatory milieu in aged venules. Accumulation of CXCL1 caused desensitization of the chemokine receptor CXCR2 on neutrophils and loss of neutrophil directional motility within EC junctions. Fluorescent tracking revealed that in aged mice, neutrophils undergoing rTEM re-entered the circulation and disseminated to the lungs where they caused vascular leakage. Thus, neutrophils stemming from a local inflammatory site contribute to remote organ damage, with implication to the dysregulated systemic inflammation associated with aging.

Phase 3 Trial of Concizumab in Hemophilia with Inhibitors.

BACKGROUND: Concizumab is an anti-tissue factor pathway inhibitor monoclonal antibody designed to achieve hemostasis in all hemophilia types, with subcutaneous administration. A previous trial of concizumab (explorer4) established proof of concept in patients with hemophilia A or B with inhibitors. METHODS: We conducted the explorer7 trial to assess the safety and efficacy of concizumab in patients with hemophilia A or B with inhibitors. Patients were randomly assigned in a 1:2 ratio to receive no prophylaxis for at least 24 weeks (group 1) or concizumab prophylaxis for at least 32 weeks (group 2) or were nonrandomly assigned to receive concizumab prophylaxis for at least 24 weeks (groups 3 and 4). After a treatment pause due to nonfatal thromboembolic events in three patients receiving concizumab, including one from the explorer7 trial, concizumab therapy was restarted with a loading dose of 1.0 mg per kilogram of body weight, followed by 0.2 mg per kilogram daily (potentially adjusted on the basis of concizumab plasma concentration as measured at week 4). The primary end-point analysis compared treated spontaneous and traumatic bleeding episodes in group 1 and group 2. Safety, patient-reported outcomes, and pharmacokinetics and pharmacodynamics were also assessed. RESULTS: Of 133 enrolled patients, 19 were randomly assigned to group 1 and 33 to group 2; the remaining 81 were assigned to groups 3 and 4. The estimated mean annualized bleeding rate in group 1 was 11.8 episodes (95% confidence interval [CI], 7.0 to 19.9), as compared with 1.7 episodes (95% CI, 1.0 to 2.9) in group 2 (rate ratio, 0.14 [95% CI, 0.07 to 0.29]; P<0.001). The overall median annualized bleeding rate for patients receiving concizumab (groups 2, 3, and 4) was 0 episodes. No thromboembolic events were reported after concizumab therapy was restarted. The plasma concentrations of concizumab remained stable over time. CONCLUSIONS: Among patients with hemophilia A or B with inhibitors, the annualized bleeding rate was lower with concizumab prophylaxis than with no prophylaxis. (Funded by Novo Nordisk; explorer7 ClinicalTrials.gov number, NCT04083781.).

Senescent endothelial cells promote pathogenic neutrophil trafficking in inflamed tissues.

Cellular senescence is a hallmark of advanced age and a major instigator of numerous inflammatory pathologies. While endothelial cell (EC) senescence is aligned with defective vascular functionality, its impact on fundamental inflammatory responses in vivo at single-cell level remain unclear. To directly investigate the role of EC senescence on dynamics of neutrophil-venular wall interactions, we applied high resolution confocal intravital microscopy to inflamed tissues of an EC-specific progeroid mouse model, characterized by profound indicators of EC senescence. Progerin-expressing ECs supported prolonged neutrophil adhesion and crawling in a cell autonomous manner that additionally mediated neutrophil-dependent microvascular leakage. Transcriptomic and immunofluorescence analysis of inflamed tissues identified elevated levels of EC CXCL1 on progerin-expressing ECs and functional blockade of CXCL1 suppressed the dysregulated neutrophil responses elicited by senescent ECs. Similarly, cultured progerin-expressing human ECs exhibited a senescent phenotype, were pro-inflammatory and prompted increased neutrophil attachment and activation. Collectively, our findings support the concept that senescent ECs drive excessive inflammation and provide new insights into the mode, dynamics, and mechanisms of this response at single-cell level.

Dissecting the polygenic contribution of attention-deficit/hyperactivity disorder and autism spectrum disorder on school performance by their relationship with educational attainment.

Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD) are strongly associated with educational attainment (EA), but little is known about their genetic relationship with school performance and whether these links are explained, in part, by the genetic liability of EA. Here, we aim to dissect the polygenic contribution of ADHD and ASD to school performance, early manifestation of psychopathology and other psychiatric disorders and related traits by their relationship with EA. To do so, we tested the association of polygenic scores for EA, ADHD and ASD with school performance, assessed whether the contribution of the genetic liability of ADHD and ASD to school performance is influenced by the genetic liability of EA, and evaluated the role of EA in the genetic overlap between ADHD and ASD with early manifestation of psychopathology and other psychiatric disorders and related traits in a sample of 4,278 school-age children. The genetic liability for ADHD and ASD dissected by their relationship with EA show differences in their association with school performance and early manifestation of psychopathology, partly mediated by ADHD and ASD symptoms. Genetic variation with concordant effects in ASD and EA contributes to better school performance, while the genetic variation with discordant effects in ADHD or ASD and EA is associated with poor school performance and higher rates of emotional and behavioral problems. Our results strongly support the usage of the genetic load for EA to dissect the genetic and phenotypic heterogeneity of ADHD and ASD, which could help to fill the gap of knowledge of mechanisms underlying educational outcomes.

Follicular CD8+ T Cells Are Elevated in HIV Infection and Induce PD-L1 on B Cells.

Follicular CD8+CXCR5+ T cells are a specialized CD8+ T cell subset with unique follicular-homing capabilities that have been reported to display effector functions in viral immunity, tumor immunity, and autoimmunity. CD8+CXCR5+ T cells exhibit B cell helper functions and express CD40L, ICOS, programmed cell death protein 1 (PD-1), and BCL-6, the transcriptional regulator of CD4+CXCR5+ T follicular helper cells and of germinal center B cells. HIV is known to be sequestered in lymphoid follicles, and CD8+CXCR5+ T cell frequency is a marker for disease severity, given that HIV-infected patients with lower numbers of circulating CD8+CXCR5+ T cells display lower CD4+ T cell counts. Likewise, several groups have reported a direct correlation between the quantity of CD8+CXCR5+ T cells and suppression of HIV viral load. In this study, we observed elevated absolute numbers of CD8+CXCR5+ and CD8+CXCR5+BCL-6+PD-1+ T cells in the blood of HIV-infected participants of the Multicenter AIDS Cohort Study. We further demonstrated in vitro that activated human CD8+CXCR5+ T cells isolated from peripheral blood and tonsil from healthy donors show increased CD40L expression and induce the production of PD ligand 1 (PD-L1)+IgG+ B cells. Moreover, absolute numbers of CD8+CXCR5+ T cells significantly and positively correlated with numbers of PD-L1+ B cells found in blood of HIV-infected individuals. Altogether, these results show that activated CD8+CXCR5+ T cells have the ability to activate B cells and increase the percentage of PD-L1+ and PD-L1+IgG+ B cells, which provides insights into the early events of B cell activation and differentiation and may play a role in disease progression and lymphomagenesis in HIV-infected individuals.

Bovine lactoferrin and chimera lactoferrin prevent and destroy Salmonella Typhimurium biofilms in Caco-2 cells.

Salmonellosis is a common foodborne disease caused by Salmonella bacteria. The emergence of multidrug-resistant (MDR) Salmonella serotypes, such as Typhimurium, and Salmonella's ability to form biofilms contribute to their resistance and persistence in host and non-host environments. New strategies are needed to treat or prevent Salmonella infections. This work aimed to determine the effect of the bovine lactoferrin (bLF) and lactoferrin chimera (LFchimera) in preventing or disrupting biofilms formed on abiotic surfaces or Caco-2 cells by S. Typhimurium ATCC 14028 or an MDR strain. The inhibitory activity of planktonic bacteria, prevention of biofilm formation, and destruction of biofilms of S. Typhimurium (ATCC 14028 or MDR strain) on the abiotic surface and Caco-2 cells of bLF and LFchimera were quantified by CFU/mL and visualized by microscopy using Giemsa-stained samples. bLF (75-1000 µM) and LFchimera (1-20 µM) inhibited more than 95% of S. Typhimurium planktonic growth cultures (ATCC 14028 and MDR). In addition, bLF (600, 800, and 1000 µM) and LFchimera (10 and 20 µM) prevented more than 98% of S. Typhimurium adherence and biofilm formation on Caco-2 cells. Finally, bLF (600 and 1000 µM) and LFchimera (10 and 20 µM) destroyed more than 80% of S. Typhimurium biofilms established on abiotic and Caco-2 cells. In conclusion, bLF and LFchimeras have the potential to inhibit and destroy S. Typhimurium biofilms.

A new drying method of thermolabile flexible endoscope channels by laminar and turbulent airflow - a prospective, randomized-controlled, single-center, proof-of-concept trial.

BACKGROUND AND AIMS: International guidelines suggest different possibilities for drying of endoscopes during reprocessing. Clinical results of these available drying methods are not satisfactory. The aim of this study was to compare the drying cycle of a standard endoscope washer-disinfector (EWD) (standard drying method [SD]) with a shortened mandatory drying by the EWD followed by a special drying device using laminar and turbulent air flow (novel drying method [ND]). PATIENTS AND METHODS: Sixty endoscopes (duodenoscopes, colonoscocopes and gastroscopes) from three different manufacturers underwent high-level disinfection and drying depending on the randomization group. Operational time of drying was measured for both groups. Residual fluid in the channels was measured using a laboratory scale. After a 14 day storage period, a sample of the endoscope channels was obtained to determine bacterial contamination. RESULTS: ND had significantly fewer residual water in endoscope channels (SD: 90% vs ND: 0%; p < 0.001) after high-level disinfection and drying, and less bacterial contamination after storage for 14 days (SD: 47% vs ND: 20%; p = 0.028). Time consumed for drying in ND was also significantly shorter (SD: 16min 4sec vs ND: 5min 59sec; p < 0.001). CONCLUSIONS: Drying with a special automatic drying device was superior compared with an EWD's drying program as evidenced by no measurable residual water, reduced microbiological contamination and a more than two-fold decrease in operational time. Thus, drying by laminar and turbulent airflow may represent an attractive alternative to the currently used standard approach in the reprocessing process of flexible endoscopes.

A multicenter study of the risk of major bleeding in patients with and without cirrhosis undergoing percutaneous liver procedures.

Percutaneous liver procedures are frequently performed in patients with abnormal coagulation tests. Current guidelines suggest prophylactic transfusion is not mandatory in all patients with liver disease or cirrhosis, depending on the risk of bleeding. This study aims to describe the incidence and risk of major bleeding after percutaneous liver procedure in patients with and without cirrhosis. This retrospective study includes patients who underwent percutaneous liver biopsy and radiofrequency and microwave ablation of liver lesions at 3 centers in Spain. A transfusion protocol was considered for platelet counts <50,000 and/or international normalized ratio >1.5. The primary outcome was major bleeding. A total of 1797 patients were included in the study, with 316 having cirrhosis (18%) and 1481 without cirrhosis (82%). Among the patients with cirrhosis, 80 were classified as Child A, and percutaneous liver biopsy was the most frequent procedure (86%). Fourteen patients (0.8%) experienced major bleeding, with 0.4% occurring in radiofrequency and microwave ablation and 0.8% in percutaneous liver biopsy. Bleeding occurred in 0.6% of patients with cirrhosis compared to 0.8% in those without ( p = ns). No clinical or procedural variables were associated with bleeding. Twenty-five patients (1.4%) had an international normalized ratio >1.5, and 22 patients (1.2%) had a platelet count <50,000. Only 24% (6/25) of patients with an international normalized ratio >1.5 were transfused with fresh frozen plasma, and 72% (16/22) of those with platelet counts <50,000 received platelet transfusion. Patients with cirrhosis were more frequently transfused (5.9% vs. 1.5%). None of the patients who met the criteria for transfusion experienced major bleeding, regardless of whether they received a transfusion, and none of the patients who had a major bleeding episode met the transfusion criteria. In this cohort, major bleeding after percutaneous liver procedure occurred in <1% of patients, making it a low-risk procedure for patients with and without cirrhosis. Although not uniformly adopted, the current transfusion protocol still led to unnecessary blood product administration.

Cryptic splicing of stathmin-2 and UNC13A mRNAs is a pathological hallmark of TDP-43-associated Alzheimer's disease.

Nuclear clearance and cytoplasmic accumulations of the RNA-binding protein TDP-43 are pathological hallmarks in almost all patients with amyotrophic lateral sclerosis (ALS) and up to 50% of patients with frontotemporal dementia (FTD) and Alzheimer's disease. In Alzheimer's disease, TDP-43 pathology is predominantly observed in the limbic system and correlates with cognitive decline and reduced hippocampal volume. Disruption of nuclear TDP-43 function leads to abnormal RNA splicing and incorporation of erroneous cryptic exons in numerous transcripts including Stathmin-2 (STMN2, also known as SCG10) and UNC13A, recently reported in tissues from patients with ALS and FTD. Here, we identify both STMN2 and UNC13A cryptic exons in Alzheimer's disease patients, that correlate with TDP-43 pathology burden, but not with amyloid-ß or tau deposits. We also demonstrate that processing of the STMN2 pre-mRNA is more sensitive to TDP-43 loss of function than UNC13A. In addition, full-length RNAs encoding STMN2 and UNC13A are suppressed in large RNA-seq datasets generated from Alzheimer's disease post-mortem brain tissue. Collectively, these results open exciting new avenues to use STMN2 and UNC13A as potential therapeutic targets in a broad range of neurodegenerative conditions with TDP-43 proteinopathy including Alzheimer's disease.

The Hypoxic Burden, Clinical Implication of a New Biomarker in the Cardiovascular Management of Sleep Apnea Patients: A Systematic Review.

Background: Obstructive sleep apnea (OSA) is a highly prevalent sleep-disordered breathing. It is associated with adverse co-morbidities, being the most scientific evidence of cardiovascular (CV) disease. Currently, OSA is measured through the apnea-hypopnea index (AHI), the total number of respiratory events per hour of sleep. However, different studies have questioned its utility in OSA management, highlighting the need to search for new parameters that better reflect the heterogeneity of the disease. Hypoxic burden (HB) has emerged as a novel biomarker that informs about the frequency, duration and depth of the desaturation related to the respiratory events. We conducted a systematic review in order to find publications about the heterogeneity of OSA measured by HB and its associations with future disease. Methods: Systematic review was conducted using PubMed and Web of Science. The terms "sleep apne" and "hypoxic burden" were used to look for publications from the date of inception to August 15, 2023. Inclusion criteria: articles in English published in peer-reviewed journals. Exclusion criteria: (1) not available publications; (2) duplicated articles; (3) letters, editorials, and congress communications; (4) articles not including information about HB as a specific biomarker of OSA. Results: 33 studies were included. The results were classified in 2 main sections: (1) HB implication in the CV sphere: HB showed to be a better predictor of CV risk in OSA patients than traditional measures such as AHI with possible clinical management implication in OSA. (2) HB response to OSA treatment: pharmacological and nonpharmacological treatments have demonstrated to be effective in improving hypoxia measured through the HB. Conclusions: HB could be a better and more effective parameter than traditional measurements in terms of diagnosis, risk prediction and therapeutic decisions in patients with OSA. This measure could be incorporated in sleep units and could play a role in OSA management, driving the clinic to a more personalized medicine.

Optoacoustic Cooling of Traveling Hypersound Waves.

We experimentally demonstrate optoacoustic cooling via stimulated Brillouin-Mandelstam scattering in a 50 cm long tapered photonic crystal fiber. For a 7.38 GHz acoustic mode, a cooling rate of 219 K from room temperature has been achieved. As anti-Stokes and Stokes Brillouin processes naturally break the symmetry of phonon cooling and heating, resolved sideband schemes are not necessary. The experiments pave the way to explore the classical to quantum transition for macroscopic objects and could enable new quantum technologies in terms of storage and repeater schemes.

Disease and treatment burden of patients with haemophilia entering the explorer6 non-interventional study.

OBJECTIVES: We aimed to characterise baseline disease and treatment burden in a large population with haemophilia A/B, both with (HAwI/HBwI) and without (HA/HB) inhibitors. METHODS: The prospective, non-interventional explorer6 study included patients ≥12 years old with severe HA, severe/moderate HB or HAwI/HBwI of any severity, treated according to local standard of care (excluding previous/current exposure to concizumab or emicizumab). Baseline characteristics and historical clinical data were collected and patient-reported outcomes, including treatment burden, were assessed. RESULTS: The explorer6 study enrolled 231 patients with haemophilia (84 HAwI/HBwI) from 33 countries. At baseline, patients with HA/HB treated with prophylaxis had the lowest median annualised bleeding rates (ABRs; 2.0), irrespective of haemophilia type; of these patients, 27.5% (HA) and 31.4% (HB) had target joints. Patients with HAwI/HBwI treated episodically reported the highest treatment burden. Of these patients, 28.5% (HAwI) and 25.1% (HBwI) performed sports activities in the month before screening. CONCLUSION: Despite receiving routine clinical care, historical and baseline information from patients enrolled in explorer6 showed that patients with HA/HB treated episodically and patients with HAwI/HBwI had higher ABRs, higher treatment burden and participated in sports less than those with HA/HB treated with prophylaxis. Emerging treatments could be beneficial in addressing these unmet medical needs.

Circadian rhythmicity in schizophrenia male patients with and without substance use disorder comorbidity.

Circadian rhythmicity is associated to clinical variables that play an important role in both schizophrenia (SZ) and substance use disorders (SUD), although the characteristics of the coexistence of these two diagnoses (SZ +) remain mostly unknown. Hence, we studied a sample of 165 male patients divided in three groups each of 55, according to their diagnoses (SZ + , SZ, and SUD), as well as a healthy control (HC; n = 90) group. Alongside with sociodemographic and clinical variables, circadian rhythms were registered through a sleep-wake data structured interview, a circadian typology questionnaire, and distal skin temperature (DST) using the Thermochron iButton every 2 min during 48 h. Analyses showed that SZ + and SZ patients presented a longer sleep (delay in wake-up time) and mostly an intermediate circadian typology, while SUD patients slept less hours, displaying a morning typology. The DST showed the highest daily activation and stability for the SUD group, even when compared with the HC group. The presence of schizophrenia (SZ + and SZ) was related to a DST pattern with a reduced amplitude determined by a wakefulness impairment, which was more pronounced for SZ patients whose sleep period was adequate. The assessment of circadian rhythms in under treatment male patients with SZ should be focused on the diurnal period as a possible marker of either treatment adherence or patient's recovery, irrespective of the presence of a comorbid SUD. Further research with additional objective measures may provide knowledge transferable to therapeutic strategies and could be useful to establish possible endophenotypes in the future.

Validation in Spanish and English of the Transgender Inclusive Behavior Scale.

The Transgender Inclusive Behavior Scale (TIBS) seeks to measure transgender-inclusive behavior, specifically actions and language use that support transgender people. The TIBS was developed in the United States. This study aimed to develop a Spanish version of the TIBS and confirm the structure of the English version to explore the psychometric properties and evaluate the construct validity in new contexts. We examined predictors of transgender-inclusive behavior by conducting a comparative analysis between participants from Spain and the United Kingdom. The study involved 1,110 university students, with 545 participants hailing from Spain (375 women, 162 men, and 8 non-binary individuals) and 565 participants from the United Kingdom (368 women, 178 men, and 19 non-binary individuals). Exploratory and confirmatory factor analysis were conducted to investigate and validate the factorial structure of the TIBS. The factor analysis results for the 15 items on the scale confirmed a three-dimensional structure in both languages. The scale score reliability was excellent with a Cronbach's alpha (α) = .95 in the British sample and with an α = .89 in the Spanish sample. Being a woman, being lesbian, gay, bisexual, trans, queer, intersex, and/or asexual, and being non-religious were the strongest predictors of inclusive behaviors towards transgender people in both countries. The correlations found indicated that people with lower sexual risk behaviors, and lower sexist, homophobic, and transphobic attitudes also presented higher inclusive behaviors towards trans people. These findings support the development of community strategies to increase the social inclusion of transgender people. The TIBS is a useful measure to track their success.

Evaluation of the implementation of a community health worker-led COVID-19 contact tracing intervention in Chiapas, Mexico, from March 2020 to December 2021.

BACKGROUND: Mexico is one of the countries with the greatest excess death due to COVID-19. Chiapas, the poorest state in the country, has been particularly affected. Faced with an exacerbated shortage of health professionals, medical supplies, and infrastructure to respond to the pandemic, the non-governmental organization Compañeros En Salud (CES) implemented a COVID-19 infection prevention and control program to limit the impact of the pandemic in the region. We evaluated CES's implementation of a community health worker (CHW)-led contact tracing intervention in eight rural communities in Chiapas. METHODS: Our retrospective observational study used operational data collected during the contract tracing intervention from March 2020 to December 2021. We evaluated three outcomes: contact tracing coverage, defined as the proportion of named contacts that were located by CHWs, successful completion of contact tracing, and incidence of suspected COVID-19 among contacts. We described how these outcomes changed over time as the intervention evolved. In addition, we assessed associations between these three main outcomes and demographic characteristics of contacts and intervention period (pre vs. post March 2021) using univariate and multivariate logistic regression. RESULTS: From a roster of 2,177 named contacts, 1,187 (54.5%) received at least one home visit by a CHW and 560 (25.7%) had successful completion of contact tracing according to intervention guidelines. Of 560 contacts with complete contact tracing, 93 (16.6%) became suspected COVID-19 cases. We observed significant associations between sex and coverage (p = 0.006), sex and complete contact tracing (p = 0.049), community of residence and both coverage and complete contact tracing (p < 0.001), and intervention period and both coverage and complete contact tracing (p < 0.001). CONCLUSIONS: Our analysis highlights the promises and the challenges of implementing CHW-led COVID-19 contact tracing programs. To optimize implementation, we recommend using digital tools for data collection with a human-centered design, conducting regular data quality assessments, providing CHWs with sufficient technical knowledge of the data collection system, supervising CHWs to ensure contact tracing guidelines are followed, involving communities in the design and implementation of the intervention, and addressing community member needs and concerns surrounding stigmatization arising from lack of privacy.

Inherited human ezrin deficiency impairs adaptive immunity.

BACKGROUND: Inborn errors of immunity (IEI) are a group of monogenic diseases that confer susceptibility to infection, autoimmunity, and cancer. Despite the life-threatening consequences of some IEI, their genetic cause remains unknown in many patients. OBJECTIVE: We investigated a patient with an IEI of unknown genetic etiology. METHODS: Whole-exome sequencing identified a homozygous missense mutation of the gene encoding ezrin (EZR), substituting a threonine for an alanine at position 129. RESULTS: Ezrin is one of the subunits of the ezrin, radixin, and moesin (ERM) complex. The ERM complex links the plasma membrane to the cytoskeleton and is crucial for the assembly of an efficient immune response. The A129T mutation abolishes basal phosphorylation and decreases calcium signaling, leading to complete loss of function. Consistent with the pleiotropic function of ezrin in myriad immune cells, multidimensional immunophenotyping by mass and flow cytometry revealed that in addition to hypogammaglobulinemia, the patient had low frequencies of switched memory B cells, CD4+ and CD8+ T cells, MAIT, γδ T cells, and centralnaive CD4+ cells. CONCLUSIONS: Autosomal-recessive human ezrin deficiency is a newly recognized genetic cause of B-cell deficiency affecting cellular and humoral immunity.

New Insights into Endogenous Retrovirus-K Transcripts in Amyotrophic Lateral Sclerosis.

Retroviral reverse transcriptase activity and the increased expression of human endogenous retroviruses (HERVs) are associated with amyotrophic lateral sclerosis (ALS). We were interested in confirming HERVK overexpression in the ALS brain, its use as an accessory diagnostic marker for ALS, and its potential interplay with neuroinflammation. Using qPCR to analyze HERVK expression in peripheral blood mononuclear cells (PBMCs) and in postmortem brain samples from ALS patients, no significant differences were observed between patients and control subjects. By contrast, we report alterations in the expression patterns of specific HERVK copies, especially in the brainstem. Out of 27 HERVK copies sampled, the relative expression of 17 loci was >1.2-fold changed in samples from ALS patients. In particular, the relative expression of two HERVK copies (Chr3-3 and Chr3-5) was significantly different in brainstem samples from ALS patients compared with controls. Further qPCR analysis of inflammation markers in brain samples revealed a significant increase in NLRP3 levels, while TNFA, IL6, and GZMB showed slight decreases. We cannot confirm global HERVK overexpression in ALS, but we can report the ALS-specific overexpression of selected HERVK copies in the ALS brain. Our data are compatible with the requirement for better patient stratification and support the potential importance of particular HERVK copies in ALS.

Analysis of the pH levels in energy and pre-workout beverages and frequency of consumption: a cross-sectional study.

BACKGROUND: Erosive tooth wear is an increasingly common pathology in the youth population. It refers to the chronic, localized, painless loss of dental hard tissues caused by non-bacterial acids, often originating from external sources like acidic beverages. Energy drink consumption is on the rise, frequently preceding physical exercise to enhance perceived energy levels. However, there are other types of beverages that also provide energy, such as pre-workout drinks, classified as sports drinks. The main objective of this research study has been conducted with the purpose of analyzing the pH of energy drinks and pre-workout beverages, and studying the frequency of consumption of such beverages in amateur athletes who practice sports. METHODS: A total of 67 beverages were examined, comprising 43 energy drinks and 24 sports supplementation beverages, also known as pre-workout or pre-training beverages. The participants were given a survey to complete. They were asked to respond whether they consumed any type of pre-workout or energy drink, and they were also asked about the timing of consumption. RESULTS: The findings indicated an average pH of 3.3 among the studied beverages, indicating a pH below the critical threshold. Out of the 113 participants, 51% reported taking some form of supplementation. CONCLUSIONS: Consequently, it was concluded that most of the analyzed beverages recorded pH values low enough to classify them as erosive, posing a threat to enamel surface. When analyzing the frequency of consumption of energy drinks and pre-workout beverages in amateur athletes, we observed that most participants aged 29 years or younger took supplements 3 to 5 times a week, while the older age groups more frequently took supplements 1 to 2 times a week.

School Nursing Practice in Education Settings in Spain.

School nurses and pediatric nurses play vital roles in providing healthcare for children and adolescents in educational and healthcare settings. School nurses operate within educational institutions, serving as caregivers and facilitating communication between the school, families, and the healthcare system. These professionals closely collaborate with pediatric nurses. The primary objective of this study was to examine the state of school nursing in Spain. The research comprised 27 nurses, including 18 school nurses and 9 pediatric nurses, chosen through theoretical sampling. These nurses participated in in-depth interviews as part of the data collection process. Grounded theory, following Charmaz's process, was employed for data analysis. The findings underscore the nurses' call for their mandated presence and regulation in all Spanish educational institutions to address contemporary health challenges and ensure inclusive education.