Accumulation of damaged mitochondria in aging astrocytes due to mitophagy dysfunction: Implications for susceptibility to mitochondrial stress.

Aging disrupts brain function, leading to cognitive decline and neurodegenerative diseases. Senescent astrocytes, a hallmark of aging, contribute to this process through unknown mechanisms. This study investigates how senescence impacts astrocytic mitochondrial dynamics, which are critical for brain health. Our research, conducted using aged mouse brains, represents the first evidence of morphologically damaged mitochondria in astrocytes, along with functional alterations in mitochondrial respiration. In vitro experiments revealed that senescent astrocytes exhibit an increase in mitochondrial fragmentation and impaired mitophagy. Concurrently, there was an upregulation of mitochondrial biogenesis, indicating a compensatory response to mitochondrial damage. Importantly, these senescent astrocytes were more susceptible to mitochondrial stress, a vulnerability reversed by rapamycin treatment. These findings suggest a potential link between senescence, impaired mitochondrial quality control, and increased susceptibility to mitochondrial stress in astrocytes. Overall, our study highlights the importance of addressing mitochondrial dysfunction and senescence-related changes in astrocytes as a promising approach for developing therapies to counter age-related neurodegeneration and improve brain health.

Three-year cardiovascular and non-cardiovascular adverse events in patients with chronic lymphocytic leukemia or small cell lymphocytic lymphoma treated with Bruton tyrosine kinase inhibitors acalabrutinib or ibrutinib: a real-world analysis.

Bruton tyrosine kinase (BTK) inhibitors play an important role in targeted treatment of B-cell lymphoproliferative disorders. However, adverse events may limit the proper course of treatment in many patients. The purpose of this study is to compare the risk of cardiovascular and non-cardiovascular adverse events in patients with chronic lymphocytic leukemia (CLL) or small cell lymphocytic lymphoma (SLL) treated with the first-generation BTK inhibitor ibrutinib versus second-generation acalabrutinib, using real-world data from a collaborative multinational network. We used data from the network (TriNetX), which encompasses more than 100 healthcare organizations worldwide. We queried the database for patients aged ≥ 18 years with chronic lymphocytic leukemia or small-cell lymphomas treated with ibrutinib or acalabrutinib in the past ten years before the analysis. We used propensity score matching to balance the cohorts. The 3-year cumulative incidences and hazard ratios for the following outcomes were calculated: atrial flutter or fibrillation, other arrhythmias, heart failure, ischemic stroke or peripheral embolism, acute coronary syndrome, bleeding, and sepsis. We compared 2,107 patients in each group. Atrial fibrillation or flutter occurred in 150 (7.1%) patients with acalabrutinib and 310 (14.7%) patients with ibrutinib during the 3-year follow-up (hazard ratio, 0.68, 95% CI 0.55-0.84). New-onset hypertension occurred in 342 (16.3%) patients in the acalabrutinib group and 584 (27.7%) patients in the ibrutinib group (hazard ratio 0.81, 95% CI 0.66-0.98). Sepsis was diagnosed in 136 (6.5%) patients in the acalabrutinib group versus 239 (11.3%) patients in the ibrutinib group (hazard ratio 0.77, 95 CI 0.60-0.98). The two groups had no significant differences concerning the other adverse events. In a large retrospective cohort using real-world data from electronic medical registers, patients with CLL or SLL treated with acalabrutinib had a better cardiovascular and non-cardiovascular safety profile than those treated with ibrutinib, with lower risks of atrial flutter or fibrillation, new-onset arterial hypertension, and sepsis.

The microbiome effect on the female reproductive performance.

The female reproductive function is coordinated by the endocrine system driven by the hypothalamic-pituitary-gonadal (HPG) axis. While not directly part of the female reproductive system, the gut microbiome plays a crucial role in overall health, including reproductive health. The gut microbiome communicates bidirectionally with the brain via the gut-brain axis, influencing stress levels, mood, and hormonal balance, which can impact reproductive health and fertility. In addition to that, the vaginal and uterine microbiome are directly involved with the reproductive success of farm animals, including female fertility and offspring development. In this paper, we summarize some of the effects of bacterial contamination in the female reproductive tract and their association with reproductive performance in farm animals.

Effect of a novel Low-Concentration Hydrogen Peroxide Bleaching Gel Containing Nano-Sized Sodium Trimetaphosphate and fluoride.

OBJECTIVES: To evaluate in vitro the effects of nano-sized sodium trimetaphosphate (TMPnano) and sodium fluoride (F) added to a 17.5% hydrogen peroxide (H2O2) bleaching gel on the color change, enamel mechanical and morphological properties, and H2O2 transamelodentinal diffusion. MATERIALS AND METHODS: Bovine enamel/dentin discs (n = 180) were divided according to the bleaching gel: 17.5% H2O2 (17.5% HP); 17.5% H2O2 + 0.1% F (HP/F); 17.5% H2O2 + 1% TMPnano (HP/TMPnano); 17.5% H2O2 + 0.1% F + 1% TMPnano (HP/F/TMPnano) and 35% H2O2 (35% HP). The gels were applied for 40 min on three sessions, each session spaced 7 days apart. The total color change (ΔE*ab) according to the Commission Internationale de l'Eclairage (CIE) L*a*b* color change measured by CIEDE2000 (ΔE00), whitening index (ΔWID), surface hardness (SH), surface roughness (Ra), cross-sectional hardness (ΔKHN), and transamelodentinal diffusion were assessed. Enamel surfaces were examined using Scanning Electron Microscopy (SEM) and Energy Dispersive X-ray (EDS) analysis. The data were analyzed using ANOVA, followed by the Student-Newman-Keuls test (p < 0.05). RESULTS: ΔE*ab, ΔE00, and ΔWID values were comparable among the gels that produced a bleaching effect post-treatment (p < 0.001). The HP/F/TMPnano group exhibited lower mineral loss (SH and ΔKHN), Ra, and H2O2 diffusion compared to the 17.5% HP and 35% HP groups, which had the highest values (p < 0.001). SEM/EDS analysis revealed surface changes in all bleached groups, though these changes were less pronounced with F/TMPnano. CONCLUSIONS: The 17.5% HP gel containing F/TMPnano maintains the bleaching effect while reducing enamel demineralization, roughness, H2O2 diffusion, and enamel morphological changes. CLINICAL RELEVANCE: Low-Concentration H2O2 bleaching gel containing F/TMPnano can be used as a novel approach to enhance safety and maintain the performance of aesthetic effects.

Enrichment of Rare Variants of Hemophagocytic Lymphohistiocytosis Genes in Systemic Juvenile Idiopathic Arthritis.

OBJECTIVE: Our objective was to evaluate whether there is an enrichment of rare variants in familial hemophagocytic lymphohistiocytosis (HLH)-associated genes among patients with systemic juvenile idiopathic arthritis (sJIA) with or without macrophage activation syndrome (MAS). METHODS: Targeted sequencing of HLH genes (LYST, PRF1, RAB27A, STX11, STXBP2, UNC13D) was performed in patients with sJIA from an established cohort. Sequence data from control participants were obtained in silico (database of Genotypes and Phenotypes: phs000280.v8.p2). Rare variant association testing (RVT) was performed with sequence kernel association test package. Significance was defined as P < 0.05 after 100,000 permutations. RESULTS: Sequencing data from 524 sJIA cases were jointly called and harmonized with exome-derived target data from 3,000 controls. Quality control operations produced a set of 480 cases and 2,924 ancestrally matched control participants. RVT of cases and controls revealed a significant association with rare protein-altering variants (minor allele frequency [MAF] < 0.01) of STXBP2 (P = 0.020) and ultrarare variants (MAF < 0.001) of STXBP2 (P = 0.006) and UNC13D (P = 0.046). A subanalysis of 32 cases with known MAS and 90 without revealed a significant difference in the distribution of rare UNC13D variants (P = 0.0047) between the groups. Additionally, patients with sJIA more often carried two or more HLH variants than did controls (P = 0.007), driven largely by digenic combinations involving LYST. CONCLUSION: We identified an enrichment of rare HLH variants in patients with sJIA compared with controls, driven by STXBP2 and UNC13D. Biallelic variation in HLH genes was associated with sJIA, driven by LYST. Only UNC13D displayed enrichment in patients with MAS. This suggests that HLH variants may contribute to the pathophysiology of sJIA, even without MAS.

An island in a sea of sand: a first checklist of the herpetofauna of the Serra da Neve inselberg, southwestern Angola.

The Serra da Neve inselberg in Namibe Province, southwestern Angola is the second highest peak of Angola with an elevation of 2489 m. It remains one of the least explored regions in the country, despite several endemic species having been recently described from this inselberg. Here we provide an inventory of the amphibian and reptile species ocurring in Serra da Neve and compare its fauna with that of the surrounding habitats at lower elevations. We also examine the phylogenetic affinities of the inselberg taxa. A total of 59 herpetological taxa were recorded for the Serra da Neve inselberg and its immediate surroundings. These include 11 species of amphibians, belonging to nine genera and seven different families, and 48 species of reptiles, belonging to 32 genera and 12 families. Of these, one amphibian and seven reptiles from seven different genera are strictly endemic, making the inselberg the richest region in southwestern Africa with respect to strict endemics, with one endemic reptile taxa per 127 km2. Not surprisingly, most of the recorded taxa belong to clades that are endemic, or at least strongly associated, with southern Africa, but two are representatives of central African clades, and another two are more closely related to eastern African highland taxa. We also provide comments on the threats to the conservation of this endemic-rich inselberg.

New discoveries in the genetics and genomics of systemic juvenile idiopathic arthritis.

INTRODUCTION: Systemic juvenile idiopathic arthritis (sJIA) is a severe inflammatory condition with onset in childhood. It is sporadic, but elements of its stereotypical innate immune responses are likely genetically encoded by both common variants with small effect sizes and rare variants with larger effects. AREAS COVERED: Genomic investigations have defined the unique genetic architecture of sJIA. Identification of the class II HLA locus as the strongest sJIA risk factor for the first time brought attention to T lymphocytes and adaptive immune mechanisms in sJIA. The importance of the human leukocyte antigen (HLA) locus was reinforced by recognition that HLA-DRB1*15 alleles are strongly associated with development of drug reactions and sJIA-associated lung disease (sJIA-LD). At the IL1RN locus, genetic variation relates to both risk of sJIA and may also predict non-response to anakinra. Finally, rare genetic variants may have critical roles in disease complications, such as homozygous LACC1 mutations in families with an sJIA-like illness, and hemophagocytic lymphohistiocytosis (HLH) gene variants in some children with macrophage activation syndrome (MAS). EXPERT OPINION: Genetic and genomic analysis of sJIA holds great promise for both basic discovery of the course and complications of sJIA, and may help guide personalized medicine and therapeutic decision-making.

Lack of country-wide systematic herpetology collections in Portugal jeopardizes future research and conservation.

Natural History Collections (NHCs) represent the world's largest repositories of long-term biodiversity datasets. Specimen collection and voucher deposition has been the backbone of NHCs since their inception, but recent decades have seen a drastic decline in rates of growth via active collecting. Amphibians and reptiles are amongst the most threatened zoological groups on the planet and are historically underrepresented in most worldwide NHCs. As part of an ongoing project to review the Portuguese zoological collections in the country's NHCs, herpetological data from its three major museums and smaller collections was gathered and used to examine the coverage and representation of the different taxa extant in Portugal. These collections are not taxonomically, geographically, or temporally complete. Approximately 90% of the Portuguese herpetological taxa are represented in the country's NHCs, and around half of the taxa are represented by less than 50 specimens. Geographically, the collections cover less than 30% of the country's territory and almost all of the occurring taxa have less than 10% of their known distribution represented in the collections. A discussion on the implications for science of such incomplete collections and a review of the current status of Portuguese NHCs is presented.

Enrichment of Rare Variants of Hemophagocytic Lymphohistiocytosis Genes in Systemic Juvenile Idiopathic Arthritis.

Objective: To evaluate whether there is an enrichment of rare variants in familial hemophagocytic lymphohistiocytosis (HLH) genes and systemic juvenile idiopathic arthritis (sJIA) with or without macrophage activation syndrome (MAS). Methods: Targeted sequencing of HLH genes (LYST, PRF1, RAB27A, STX11, STXBP2, UNC13D) was performed in sJIA subjects from an established cohort. Sequence data from control subjects were obtained in silico (dbGaP:phs000280.v8.p2). Rare variant association testing (RVT) was performed with sequence kernel association test (SKAT) package. Significance was defined as p<0.05 after 100,000 permutations. Results: Sequencing data from 524 sJIA cases were jointly called and harmonized with exome-derived target data from 3000 controls. Quality control operations produced a set of 481 cases and 2924 ancestrally-matched control subjects. RVT of sJIA cases and controls revealed a significant association with rare protein-altering variants (minor allele frequency [MAF]<0.01) of STXBP2 (p=0.020), and ultra-rare variants (MAF<0.001) of STXBP2 (p=0.007) and UNC13D (p=0.045). A subanalysis of 32 cases with known MAS and 90 without revealed significant association of rare UNC13D variants (p=0.0047). Additionally, sJIA patients more often carried ≥2 HLH variants than did controls (p=0.007), driven largely by digenic combinations involving LYST. Conclusion: We identified an enrichment of rare HLH variants in sJIA patients compared with healthy controls, driven by STXBP2 and UNC13D. Biallelic variation in HLH genes was associated with sJIA, driven by LYST. Only UNC13D displayed enrichment in patients with MAS. This suggests that HLH variants may contribute to the pathophysiology of sJIA, even without MAS.

Immune reconstitution inflammatory syndrome-associated lymphoma: A retrospective Brazilian cohort.

After initiating combined antiretroviral therapy (cART), individuals with human immunodeficiency virus (HIV) may develop Hodgkin/non-Hodgkin lymphoma due to immune reconstitution inflammatory syndrome (IRIS). This retrospective cohort study evaluated the incidence, clinical features and prognosis of IRIS-associated lymphomas in Brazilian patients. Incidence in 2000-2019 was 9.8% (27/276 patients with HIV and lymphoma; viral load drop >1 log). Time between HIV diagnosis and cART initiation was <1 year in 70.3% of cases. Time between cART initiation and lymphoma diagnosis was <3 months in 11 cases and 3-6 months in 16 cases. Overall and progression-free survival rates were similar between cases of non-IRIS-associated lymphoma and IRIS-associated lymphoma.

Influenza A virus propagation requires the activation of the unfolded protein response and the accumulation of insoluble protein aggregates.

Influenza A virus (IAV) employs multiple strategies to manipulate cellular mechanisms and support proper virion formation and propagation. In this study, we performed a detailed analysis of the interplay between IAV and the host cells' proteostasis throughout the entire infectious cycle. We reveal that IAV infection activates the inositol requiring enzyme 1 (IRE1) branch of the unfolded protein response, and that this activation is important for an efficient infection. We further observed the accumulation of virus-induced insoluble protein aggregates, containing both viral and host proteins, associated with a dysregulation of the host cell RNA metabolism. Our data indicate that this accumulation is important for IAV propagation and favors the final steps of the infection cycle, more specifically the virion assembly. These findings reveal additional mechanisms by which IAV disrupts host proteostasis and uncovers new cellular targets that can be explored for the development of host-directed antiviral strategies.

Cystoid Macular Edema: A Rare Adverse Reaction to Rituximab.

Membranous glomerulonephritis is the leading cause of nephrotic syndrome in non-diabetic Caucasian adults. For patients at risk of progressing to end-stage renal disease, immunosuppression, particularly rituximab, is the recommended treatment. While extremely rare, cases of cystoid macular edema associated with rituximab have been documented in the literature. In this report, we present the case of a 54-year-old male with membranous glomerulonephritis at a high risk of progressing to end-stage renal disease who experienced cystoid macular edema hours after receiving rituximab infusion. Following the discontinuation of the medication, the patient spontaneously recovered visual acuity without the need for any targeted therapy.

Association of metabolic syndrome components and NAFLD with quality of life: Insights from a cross-sectional study.

AIM: Metabolic syndrome (MetS) is associated with higher cardiovascular and metabolic risks, as well as with psychosocial disorders. Data regarding quality of life (QoL) in patients with MetS, point towards a significative association between MetS and a worse QoL. It remains unclear whether MetS components and non-alcoholic fatty liver disease (NAFLD) are associated with QoL in these individuals. We aimed to evaluate the association between QoL of patients with MetS and prespecified metabolic parameters (anthropometric, lipidic and glucose profiles), the risk of hepatic steatosis and fibrosis, and hepatic elastography parameters. METHODS: Cross-sectional study including patients from microDHNA cohort. This cohort includes patients diagnosed with MetS, 18 to 75 years old, followed in our tertiary center. The evaluation included anamnesis, physical examination, a QoL questionnaire (Short-Form Health Survey, SF-36), blood sampling and hepatic elastography. We used ordered logistic regression models adjusted to sex, age and body mass index to evaluate the associations between the QoL domains evaluated by SF-36 and the prespecified parameters. RESULTS: We included a total of 65 participants with MetS, with 54% being female and the mean age 61.9 ± 9.6 years old. A worse metabolic profile, specifically higher waist circumference, lower HDL, higher triglycerides, and more severe hepatic steatosis, were associated with worse QoL scores in several domains. We found no significant association of hepatic fibrosis with QoL. CONCLUSION: Our data suggests that there is a link between a worse metabolic profile (specifically poorer lipidic profile and presence of hepatic steatosis) and a worse QoL in patients with MetS.

A comprehensive review on PFAS including survey results from the EFLM Member Societies.

OBJECTIVES: Per- and polyfluoroalkyl substances (PFASs) are a large class of synthetic chemicals widely used for their unique properties. Without PFAS, many medical device and in vitro diagnostic technologies would not be able to perform their intended purposes. Potential health risks associated with exposure to PFAS influence their use in IVD applications. This paper aims to assess the current situation concerning PFAS, including regulations and legislations for their use. It is important to know what happens to (PFAS) at the end of their lives in medical laboratories. METHODS: A survey was conducted in March 2023 to collect information on the potential emission and end-of-life of PFAS-containing medical technologies in the medical laboratories of the EFLM member societies. A series of questions were presented to the EFLM national societies and the results were documented. RESULTS: Eight respondents participated in the survey, representing EFLM member societies in seven different countries including hospital laboratories, university laboratories, and private laboratories. CONCLUSIONS: PFAS uses in MD and IVD are influenced by several factors, including evolving regulations, advances in technology, safety and efficacy of these substances. Advancements in analytical techniques may lead to more sensitive and precise methods for detecting and quantifying PFAS in biological samples, which can be essential for IVD applications related to biomarker analysis and disease diagnosis. Collaboration among regulatory agencies, industry, research institutions, hospitals, and laboratories on a global scale can aid in establishing harmonized guidelines and standards for the use of PFAS, ensuring consistency and safety within their applications.

Corrigendum: Increase in pediatric recurrent fever evaluations during the first year of the COVID-19 pandemic in North America.

[This corrects the article DOI: 10.3389/fped.2023.1240242.].

Validity, sensitivity and specificity of a measure of medication adherence instrument among patients taking oral anticoagulants.

Although self-report instruments are currently considered a valuable tool for measuring adherence, due to their low cost and ease of implementation, there are still important factors that impact measurement accuracy, such as social desirability and memory bias. Thus, the Global Assessment of Medication Adherence Instrument (GEMA) was developed to provide an accurate measure of this construct. The aim of this study was to evaluate the properties of the measurement of the Global Evaluation of Medication Adherence Instrument (GEMA) among patients with chronic diseases. A methodological study was conducted in the public hospital of the state of São Paulo, Brazil. The adherence to anticoagulants as well as the international normalized ratio (INR) was assessed on 127 patients. Besides GEMA, two other instruments were used to assess adherence: the Morisky Medication Adherence Scale-8 (MMAS-8) and the Measurement of Adhesion to Treatments (MAT). The GEMA presented a satisfactory level of specificity (0.76) to identify adherents among those with a stable INR, low sensitivity (0.43) for the identification of non-adherents among those with an unstable INR, and a Positive Predictive Value of 0.70. Positive and weak to moderate correlations were observed between the proportion of doses assessed with GEMA and the scores on the MMAS-8 (r = .26 and r = .22, respectively) and the MAT (r = .22 and r = .30, respectively). The GEMA presented good practicality, acceptability, and evidence of specificity regarding the stability of the INR. The validity of the construct was partially supported by the relationship with self-reported measures of adherence.

Influence of bleaching gels formulated with nano-sized sodium trimetaphosphate and fluoride on the physicochemical, mechanical, and morphological properties of dental enamel.

OBJECTIVES: To evaluate in vitro the effects of sodium fluoride (F) and nano-sized sodium trimetaphosphate (TMPnano) added to a 35% hydrogen peroxide (H2O2) bleaching gel on the color alteration, enamel mechanical and morphological properties, and H2O2 transamelodentinal diffusion. MATERIALS AND METHODS: Bovine enamel/dentin discs (n = 180) were divided according to the bleaching gel: 35% H2O2 (HP); 35% H2O2 + 0.1% F (HP/F); 35% H2O2 + 1% TMPnano (HP/TMPnano); 35% H2O2 + 0.1% F + 1% TMPnano (HP/F/TMPnano) and 35% H2O2 + 2% calcium gluconate (HP/Ca). The gels were applied 3 times by 40 min; once each 7-day. The Commission Internationale de l'Eclairage (CIE) L*a*b* total color alteration (ΔE), color alteration by CIEDE2000 (ΔE00), whitening index (ΔWID), surface (SH) and cross-sectional hardness (ΔKHN), surface roughness (Ra), and transamelodentinal diffusion were determined. Enamel surfaces were evaluated by Scanning Electron Microscopy (SEM) and X-ray Dispersive Energy (EDX). Data were submitted to ANOVA, followed by the Student-Newman-Keuls test (p <0.05). RESULTS: ΔE, ΔE00, and ΔWID were similar among the gels that promoted a bleaching effect after treatment (p <0.001). Mineral loss (SH and ΔKHN), Ra, and H2O2 diffusion were lower for HP/F/TMPnano; the HP and HP/Ca groups presented the highest values (p <0.001). For SEM/EDX, surface changes were observed in all bleached groups, but less intense with TMPnano. CONCLUSIONS: Gels containing F/TMPnano do not interfere with the bleaching effect and reduce enamel demineralization, roughness, H2O2 diffusion, and morphological changes. CLINICAL RELEVANCE: Whitening gels containing F/TMPnano can be used as a new strategy to increase safety and maintain clinical performance.

Increase in pediatric recurrent fever evaluations during the first year of the COVID-19 pandemic in North America.

The impact of the COVID-19 pandemic on new diagnoses of recurrent fevers and autoinflammatory diseases is largely unknown. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) PFAPA/AID Working Group aimed to investigate the impact of the COVID-19 pandemic on the number of pediatric patients evaluated for recurrent fevers and autoinflammatory diseases in North America. The absolute number of new outpatient visits and the proportion of these visits attributed to recurrent fever diagnoses during the pre-pandemic period (1 March 2019-29 February 2020) and the first year of the COVID-19 pandemic (1 March 2020-28 February 2021) were examined. Data were collected from 27 sites in the United States and Canada. Our results showed an increase in the absolute number of new visits for recurrent fever evaluations in 21 of 27 sites during the COVID-19 pandemic compared to the pre-pandemic period. The increase was observed across different geographic regions in North America. Additionally, the proportion of new visits to these centers for recurrent fever in relation to all new patient evaluations was significantly higher during the first year of the pandemic, increasing from 7.8% before the pandemic to 10.9% during the pandemic year (p < 0.001). Our findings showed that the first year of the COVID-19 pandemic was associated with a higher number of evaluations by pediatric subspecialists for recurrent fevers. Further research is needed to understand the reasons behind these findings and to explore non-infectious triggers for recurrent fevers in children.