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Aims: To assess the 'real life' effectiveness of different antiretroviral therapies (ART). Methods: A retrospective multicentre observational study in 150 HIV-1 vertically infected children on the progression to AIDS (study [...]

Unlabelled: Treatment with highly active antiretroviral therapy (HAART) has been shown to modify viral replication dynamics and lead to a significant recovery of CD4+ T-cells. A retrospective multicentre observational study was performed in a non-study population of 151 HIV-1-infected children, categorized into four groups according to therapy: untreated (NT), on monotherapy (MT) with a nucleoside inhibitor, on combination therapy (CT) with two nucleoside inhibitors, and on HAART, protease inhibitor containing regimens, to assess the "real-life" effectiveness of these different therapies on plasma viral load (VL) and CD4+ T-cells. VL was quantified using a standard molecular assay. CD4+ and CD8+ T-cells subsets were determined by flow cytometry. The HAART group showed the highest relative proportion (RP) of increases in 5, 10, 15 and 20% of CD4+ T-cells over baseline, and the earliest fall-off of VL (0.5, 1, 1.5 and 2 log10 copies ml-1). The RP of the fall-off of 0.5, 1, 1.5 and 2 log10 VL below baseline was 3-fold higher in HAART group than in the MT and CT groups. However, no differences were found among the groups of treated children in reaching undetectable VL.Conclusion: A better evolution of VL and CD4+ T-cells was evident in children on HAART, indicating a positive effect on the immune system and clinical status, inhibiting HIV-1 replication and enabling the recovery of CD4+ T-cell counts. [ABSTRACT FROM AUTHOR]

Unlabelled: This study measured cytokine production by mitogen-stimulated peripheral blood mononuclear cells (PBMCs) from 55 human immunodeficiency virus (HIV)-infected children born to HIV-infected mothers, and compared it with vertically exposed but uninfected age-matched children. A significant defect was observed in Th1 cytokine production [interferon-gamma and interleukin-2 (IL-2)] in HIV-infected children compared with controls, but without a concomitant increase in Th2 cytokines. Indeed, IL-5 and IL-10 production was even lower in HIV-infected children than in controls, with the decrease in IL-5 being the best predictive marker of immunodeficiency. In addition, an increased release of tumour necrosis factor-alpha (TNF-alpha) that correlated well with CD4+ levels, and a positive correlation of the TNF-alpha/IL-10 ratio with disease progression was observed. A correlation between AIDS-free status and higher %CD4+ and %CD8+ T-lymphocytes and RANTES (regulated on activation, normal T-cell expressed and secreted) production was also found.Conclusion: A dysfunctional cytokine production of PBMCs was observed in HIV-infected children in both Th1 and Th2 cytokines due to quantitative and qualitative defects induced by HIV-1. An important observation was an increased RANTES production associated with viral isolates of NSI/R5 phenotype and S/L kinetics. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate the relationship between peripheral blood CD4[sup +] T cell subsets and routine viro-immunological markers in vertically HIV-1-infected children undergoing highly active antiretroviral therapy (HAART). CD4[sup +] and CD8[sup +] T cell subsets were examined by three-colour flow cytometry. Plasma viraemia was quantified by a standardized molecular assay. A negative correlation between the %CD4[sup +] T cells and both viral load and the %CD8[sup +] T cells was observed. A strong positive correlation between the %CD4 T cells and naïve, CD38[sup +] and non-activated CD4[sup +] T cell subsets was found, whereas the %CD4 T cells correlated negatively with the numbers of memory, activated and memory-activated CD4[sup +] T cell subsets. Elevated percentages of CD8 T cells were associated with increased memory and CD4[sup +] CD62L-T cell subsets, whereas the naïve and CD4[sup +] HLA-DR[sup ]CD38[sup +] subsets negatively correlated with the CD8%. Co-expression of CD62L on memory CD4[sup +] cells and high expression of HLA-DR (but not of CD38) were associated with high viral load. No association between viral load and naïve CD4[sup +] T cells was observed. Specific CD4[sup +] T cell subsets may be more informative than routine surrogate markers in defining the evolution of HIV infection and immune reconstitution in children. [ABSTRACT FROM AUTHOR]

Background: In the past few decades, researchers have made promising progress, including the development of immune checkpoint inhibitors (ICIs) in the therapy of bladder cancer (BLCA). Existing studies mainly focus on single immune checkpoint inhibitors but lack relevant studies on the gene expression profiles of multiple immune checkpoints. Methods: RNA-sequencing profiling data and clinical information of BLCA patients and normal human bladder samples were acquired from the Cancer Genome Atlas and Gene Expression Omnibus databases and analyzed to identify different expression profiles of immune checkpoint genes (ICGs) after consensus clustering analysis. Based on the 526 intersecting differentially expressed genes, the LASSO Cox regression analysis was utilized to construct the ICG signature. Results: According to the expression of ICGs, BLCA patients were divided into three subtypes with different phenotypic and mechanistic characteristics. Furthermore, the developed ICG signature were independent predictors of outcome in BLCA patients, and was correlated with the immune infiltration, the expression of ICGs and chemotherapeutic effect. Conclusions: This study systematically and comprehensively analyzed the expression profile of immune checkpoint genes, and established the ICG signature to investigate the differences in ICGs expression and tumor immune microenvironment, which will help risk stratification and accelerate precision medicine. Finally, we identified KRT23 as the most critical model gene, and highlighted KRT23 as a potential target to enhance immunotherapy against BLCA. [ABSTRACT FROM AUTHOR]

Neurodevelopmental proteasomopathies constitute a recently defined class of rare Mendelian disorders, arising from genomic alterations in proteasome-related genes. These alterations result in the dysfunction of proteasomes, which are multi-subunit protein complexes essential for maintaining cellular protein homeostasis. The clinical phenotype of these diseases manifests as a syndromic association involving impaired neural development and multisystem abnormalities, notably craniofacial anomalies and malformations of the cardiac outflow tract (OFT). These observations suggest that proteasome loss-offunction variants primarily affect specific embryonic cell types which serve as origins for both craniofacial structures and the conotruncal portion of the heart. In this hypothesis article, we propose that neural crest cells (NCCs), a highly multipotent cell population, which generates craniofacial skeleton, mesenchyme as well as the OFT of the heart, in addition to many other derivatives, would exhibit a distinctive vulnerability to protein homeostasis perturbations. Herein, we introduce the diverse cellular compensatory pathways activated in response to protein homeostasis disruption and explore their potential implications for NCC physiology. Altogether, the paper advocates for investigating proteasome biology within NCCs and their early cranial and cardiac derivatives, offering a rationale for future exploration and laying the initial groundwork for therapeutic considerations. [ABSTRACT FROM AUTHOR]

Globally, around 11% of neonates are born prematurely, comprising a highly vulnerable population with a myriad of health problems. Premature births are often accompanied by an underdeveloped immune system biased towards a Th2 phenotype and microbiota dysbiosis. Typically, a healthy gut microbiota interacts with the host, driving the proper maturation of the host immunity. However, factors like cesarean section, formula milk feeding, hospitalization in neonatal intensive care units (NICU), and routine antibiotic treatments compromise microbial colonization and increase the risk of developing related diseases. This, along with alterations in the innate immune system, could predispose the neonates to the development of respiratory diseases later in life. Currently, therapeutic strategies are mainly focused on restoring gut microbiota composition using probiotics and prebiotics. Understanding the interactions between the gut microbiota and the immature immune system in premature neonates could help to develop novel therapeutic strategies for treating or preventing gut–lung axis disorders. [ABSTRACT FROM AUTHOR]

Limited molecular data exist on the prevalence and subtype distribution of Blastocystis spp., the most prevalent parasite in human and animal feces worldwide. A total of 44 different subtypes (STs) of Blastocystis are currently recognized based on the sequence of the small subunit ribosomal RNA (SSU-rRNA) gene. This is a molecular study of Blastocystis spp. in hospitalized patients with gastrointestinal symptoms in northern Spain. We analyzed 173 Blastocystis-positive patients with gastrointestinal symptoms by using nested PCR for molecular detection, subtype identification, phylogenetic analyses, and genetic diversity assessment. ST2 (34.1%) and ST3 (34.7%) predominated, followed by ST1 (15.6%) and ST4 (15.6%). Mixed infections with different subtypes were observed in some patients. Sequence analysis revealed for the first time in European humans the allele 88 (a variant of ST1). In other cases, alleles commonly found in animal samples were detected (allele 9 in ST2, allele 34 in ST3, and allele 42 in ST4). Phylogenetic analysis showed high variability in ST1 and ST2, suggesting a polyphyletic origin, while both ST3 and ST4 exhibited higher genetic homogeneity, indicating a possible monophyletic origin and recent transmission to humans. These data confirm Blastocystis spp. subtype diversity and may help in understanding the evolutionary processes and potential zoonotic transmission of this parasite. [ABSTRACT FROM AUTHOR]

Simple Summary: Microsporidia are widespread fungal pathogens that affect several organisms, including humans, and are transmitted by food or water. This study aims to survey the presence of the main human-pathogenic microsporidia in digestive samples of edible marine fish in the Comunidad Valenciana, Spain. For this purpose, 138 farmed fish and 113 wild fish from commercial fishing were simultaneously tested using a specific polymerase chain reaction assay. We detected, for the first time, the presence of the zoonotic species Encephalitozoon intestinalis/hellem in both studied fish groups, together with the presence of microsporidia from the family Enterocytozoonidae. In marine fish, E. intestinalis/hellem suggests a potential risk for public health. However, additional studies in the characterization and epidemiology of these pathogenic microsporidia species in fish are necessary. Microsporidia are widely spread obligate intracellular fungal pathogens from vertebrate and invertebrate organisms, mainly transmitted by contaminated food and water. This study aims to detect the presence of major human-pathogenic microsporidia, i.e., Enterocytozoon bieneusi, Encephalitozoon intestinalis, Encephalitozoon hellem, and Encephalitozoon cuniculi, in the gastrointestinal tract of commercially harvested marine fish from Mediterranean coast of the Comunidad Valenciana, Eastern Spain. A total of 251 fish, 138 farmed fish and 113 wild fish from commercial fishing were tested by SYBR Green real-time PCR, enabling the simultaneous detection of the four targeted species. E. intestinalis/hellem was found in 1.45% of farmed fish and 7.96% of wild fish, while Enterocytozoonidae was detected in 2.90% and 18.58% of farmed and wild fish, respectively. E. cuniculi was not detected in any of the analyzed specimens. To the authors' knowledge, this is the first report of E. intestinalis/hellem in fish, particularly in marine fish. Although the role of fish in these species' epidemiology remains unknown, this finding points out a potential public health risk linked to fish consumption. Further studies are necessary to characterize these microsporidia in fish hosts better and to elucidate their epidemiological role. [ABSTRACT FROM AUTHOR]

Background: High rates of disease progression and HIV drug resistance (HIVDR) among adults taking highly active antiretroviral treatment (HAART) in Sub-Saharan Africa were previously documented. However, children were generally not considered despite their greater risk. Hence, this study was aimed to evaluate HIV-1 disease progression and drug resistance mutation among children on first-line antiretroviral therapy in Ethiopia. Method: A longitudinal study was conducted among 551 HIV-positive children (<15 years old) recruited between 2017 and 2019 at 40 antiretroviral treatment delivery sites in Ethiopia. Disease progression was retrospectively measured over a 12-year (2007–2019) follow-up as the progress towards immunosuppression. Two consecutive viral load (VL) tests were conducted in 6-month intervals to assess virologic failure (VF). For children with VF, HIV-1 genotyping and sequencing was performed for the pol gene region using in-house assay validated at the Chinese Center for Disease Control and Prevention, and the Stanford HIVDB v9.0 algorithm was used for identification of drug resistance mutations. The Kaplan–Meier analysis and Cox proportional hazards regression model were used to estimate the rate and predictors of disease progression, respectively. Results: The disease progression rate was 6.3 per 100 person-years-observation (95% CI = 4.21–8.53). Overall immunosuppression (CD4 count < 200 cells/mm3) during the 12-year follow-up was 11.3% (95% CI = 7.5–15.1). Immunosuppression was significantly increased as of the mean duration of 10.5 (95% CI = 10.1–10.8) years (38.2%) to 67.8% at 12 years (p < 0.001). Overall, 14.5% had resistance to at least one drug, and 6.2% had multi-drug resistance. A resistance of 67.8% was observed among children with VF. Resistance to non-nucleotide reverse transcriptase inhibitors (NNRTI) and nucleotide reverse transcriptase inhibitors (NRTI) drugs were 11.4% and 10.1%, respectively. Mutations responsible for NRTI resistance were M184V (30.1%), K65R (12.1%), and D67N (5.6%). Moreover, NNRTI-associated mutations were K103N (14.8%), Y181C (11.8%), and G190A (7.7%). Children who had a history of opportunistic infection [AHR (95% CI) = 3.4 (1.8–6.2)], vitamin D < 20 ng/mL [AHR (95% CI) = 4.5 (2.1–9.9)], drug resistance [AHR (95% CI) = 2.2 (1.4–3.6)], and VF [AHR (95% CI) = 2.82 (1.21, 3.53)] had a higher hazard of disease progression; whereas, being orphan [AOR (95% CI) = 1.8 (1.2–3.1)], history of drug substitution [(AOR (95% CI) = 4.8 (2.1–6.5), hemoglobin < 12 mg/dL [AOR (95% CI) = 1.2 (1.1–2.1)] had higher odds of developing drug resistance. Conclusions: Immunosuppression was increasing over time and drug resistance was also substantially high. Enhancing routine monitoring of viral load and HIVDR and providing a vitamin-D supplement during clinical management could help improve the immunologic outcome. Limiting HAART substitution is also crucial for children taking HAART in Ethiopia. [ABSTRACT FROM AUTHOR]

Introduction: Autoinflammatory diseases (AIDs) constitute several disorders that are characterized by the presence of recurrent episodes of unprovoked inflammation due to dysregulated innate immune system in the absence of autoantibodies or infections. Most of them have a strong genetic background, with mutations in single genes involved in inflammation referred to monogenic AIDs. In this article, we will review the cardiac manifestations in various monogenic AIDs. Areas covered: Various cardiac manifestations can be seen in various monogenic AIDs, including pericarditis, valvular diseases, coronary diseases, cardiomyopathies, and pulmonary hypertension, especially in Familial Mediterranean fever (FMF). Expert commentary: Monogenic AIDs can manifest a variety of cardiac lesions, the most common of which is pericardial effusion, which may be local pericardial inflammation secondary to systemic inflammatory responses. While, the pathogenesis and incidence are still unclear. More research is still needed to explore the relationship between monogenic AIDs and cardiac damage for better understanding these diseases. [ABSTRACT FROM AUTHOR]

Background: Chronic active Epstein-Barr virus infection (CAEBV) is a systemic EBV-positive lymphoproliferative disorder (EBV-LPD) considered to be associated with a genetic immunological abnormality, although its cause is still unclear. EBV is usually detected in T cells or NK cells in CAEBV patients with only a few cases involving B cells described in East Asia, which may be due to differences in genetic and environmental factors. Case description: A 16-year-old boy who seemed to be diagnosed as CAEBV of B cell type was studied. The patient had IM-like symptoms persisting for more than 3 months, high levels of EBV DNA in the PB, and positive EBER in situ hybridization in B cells. In addition, to exclude underlying genetic disorders, we performed next-generation sequencing (NGS) and whole-exome sequencing (WES), which identified the missense mutation in PIK3CD (E1021K), ADA (S85L) and CD3D (Q140K) in the patient while no same genetic mutation was detected in his parents and sister. However, there is no diagnosis of CAEBV of B cell type in the most recent World Health Organization classification of tumors of hematopoietic and lymphoid tissues, therefore we finally diagnosed this patient as EBV-B-LPD. Conclusions: This study shows a rare case of a patient meeting the definition of CAEBV B-cell disease in East Asia. Meanwhile, the case indicates that the missense mutation and the disease are related. [ABSTRACT FROM AUTHOR]

The presence of mucocutaneous manifestations has clinical significance, as it may be a part of the initial presentation or activation stage of both autoimmune and autoinflammatory rheumatic diseases. The cutaneous signs may display a particular morphological and topographic distribution according to taxonomy, whereas heterogeneity is likely observed among the individuals. The review aims to cluster and systematically approach the mucocutaneous manifestations met in autoimmune and autoinflammatory rheumatic diseases of childhood. The search strategy involved a comprehensive inquiry on Web of Science, PubMed, MEDLINE, and Embase databases using relevant search terms such as "dermatologic, cutaneous, mucocutaneous, skin, rash" for each disease and category. The awareness of the distinctive mucocutaneous manifestations and their correlation with rheumatic diseases provides a convenient definition, well‐timed control of the underlying condition, and prevention of cosmetic issues. In the management of rheumatic diseases, planning the pertinent differential diagnosis and determining the requirement of histopathological assessment are essential with a multidisciplinary approach to rheumatology, dermatology, and allergy‐immunology specialties. [ABSTRACT FROM AUTHOR]

Simple Summary: It is well known that mammals can harbor various pathogens that can affect humans (known as zoonotic pathogens) including viruses, bacteria, fungi and parasites. Microsporidia are a group of pathogens related to fungi and parasites of several animals that can cause diarrhea or systemic infection in humans. Due to the limited knowledge about microsporidia infection in hedgehogs worldwide, this study aimed to analyze the presence and identity of microsporidia in a group of North African hedgehogs from the Canary Islands (Spain). Enterocytozoon bieneusi and Encephalitozoon cuniculi, two zoonotic species of microsporidia, were identified. These results suggest that microsporidia species with zoonotic risk circulate in the archipelago. Microsporidia are unicellular eukaryotic obligate intracellular parasites with a wide range of hosts reported worldwide; however, little is known about the epidemiological data on microsporidia infection in animals from the Canary Islands. Since data on microsporidia infection in hedgehog species are scarce, the aim of this study was to analyze the presence and identity of microsporidia in a group of North African hedgehogs (Atelerix algirus) using microscopic and molecular methods. From December 2020 to September 2021, a total of 36 fecal samples were collected from naturally deceased hedgehogs from Tenerife and Gran Canaria. All samples showed spore-compatible structures (100%; 36/36) under microscopic analysis, of which 61.1% (22/36) were amplified via the nested-polymerase chain reaction (PCR) targeting the partial sequence of the 16S rRNA gene, the internal transcribed spacer (ITS) region, and the partial sequence of the 5.8S rRNA gene. After Sanger sequencing and ITS analysis, Enterocytozoon bieneusi was detected in 47.2% (17/36) of the samples, identifying two novel genotypes (AAE1 and AAE2), followed by the detection of an undetermined species in 8.3% (3/36) and Encephalitozoon cuniculi genotype I in 5.6% (2/36) of the samples. This study constitutes the first report of microsporidia species in Atelerix algirus worldwide, highlighting the high prevalence of zoonotic species. [ABSTRACT FROM AUTHOR]

The 22q11.2 deletion syndrome is a multisystemic disorder characterized by a marked variability of phenotypic features, making the diagnosis challenging for clinicians. The wide spectrum of clinical manifestations includes congenital heart defects—most frequently conotruncal cardiac anomalies—thymic hypoplasia and predominating cellular immune deficiency, laryngeal developmental defects, midline anomalies with cleft palate and velar insufficiency, structural airway defects, facial dysmorphism, parathyroid and thyroid gland hormonal dysfunctions, speech delay, developmental delay, and neurocognitive and psychiatric disorders. Significant progress has been made in understanding the complex molecular genetic etiology of 22q11.2 deletion syndrome underpinning the heterogeneity of clinical manifestations. The deletion is caused by chromosomal rearrangements in meiosis and is mediated by non-allelic homologous recombination events between low copy repeats or segmental duplications in the 22q11.2 region. A range of genetic modifiers and environmental factors, as well as the impact of hemizygosity on the remaining allele, contribute to the intricate genotype-phenotype relationships. This comprehensive review has been aimed at highlighting the molecular genetic background of 22q11.2 deletion syndrome in correlation with a clinical multidisciplinary approach. [ABSTRACT FROM AUTHOR]

Purpose of Review: This review focuses on immunologic findings, relationships among immunologic findings and associated conditions of autoimmunity and atopy, and management of immunologic disease in chromosome 22q11.2 deletion syndrome (22q11.2DS, historically known as DiGeorge syndrome). Recent Findings: The implementation of assessment of T cell receptor excision circles (TRECs) in newborn screening has led to increased detection of 22q11.2 deletion syndrome. While not yet applied in clinical practice, cell-free DNA screening for 22q11.2DS also has the potential to improve early detection, which may benefit prompt evaluation and management. Multiple studies have further elucidated phenotypic features and potential biomarkers associated with immunologic outcomes, including the development of autoimmune disease and atopy. Summary: The clinical presentation of 22q11.2DS is highly variable particularly with respect to immunologic manifestations. Time to recovery of immune system abnormalities is not well-defined in current literature. An understanding of the underlying causes of immunologic changes found in 22q11.2DS, and the progression and evolution of immunologic changes over the lifespan have expanded over time and with improved survival. An included case highlights the variability of presentation and potential severity of T cell lymphopenia in partial DiGeorge syndrome and demonstrates successful spontaneous immune reconstitution in partial DiGeorge syndrome despite initial severe T cell lymphopenia. [ABSTRACT FROM AUTHOR]

Microsporidia are fungi-related eukaryotic intracellular parasites that opportunistically infect immunocompromised individuals such as those infected by the human immunodeficiency virus (HIV). Among them, Enterocytozoon bieneusi and Encephalitozoon spp. are the most clinically relevant species. We investigated the occurrence and genetic diversity of microsporidial and protist infections in mostly immunocompetent HIV-positive patients in Madrid, Spain. A structured questionnaire was used to retrieve data on factors potentially associated with an increased risk of infection, including sexual attitudes and sex-risk behaviour. Faecal samples (n = 96) from 81 HIV-positive patients were collected and analysed by molecular (PCR and Sanger sequencing) methods. Two microsporidial pathogens were detected: Ent. bieneusi (2.5%, 95% CI: 0.3–8.6) and Enc.intestinalis (4.9%, 95% CI: 1.4–12.2). The two Ent. bieneusi isolates were identified as zoonotic genotype A. Among protists, Entamoeba dispar was the species most prevalently found (33.3%, 95% CI: 23.2–44.7), followed by Blastocystis spp. (19.8%, 95% CI: 11.7–30.1), Giardia duodenalis (13.6%, 95% CI: 7.0–23.0), and Cryptosporidium spp. and Entamoeba histolytica (2.5%, 95% CI: 0.3–8.6 each). Cyclospora cayetanensis and Cystoisospora belli were not detected. Subtypes ST1 (70.6%, 12/17) and ST3 (29.4%, 5/17) were identified within Blastocystis sp., sub-assemblages AII and BIII (50%, 1/2 each) within G. duodenalis, and Cry. parvum and canine-adapted Cry. canis (50%, 1/2 each) within Cryptosporidium spp. Microsporidial and protist parasites were frequent in well-controlled, mostly immunocompetent HIV-positive patients and should be included in diagnostic algorithms when diarrhoea is present. Lay Summary: Opportunistic microsporidial and protist intestinal infections were relatively common in well-controlled HIV-positive patients in Madrid, Spain. These agents should be suspected and appropriately diagnosed in HIV-positive patients presenting with diarrhoea regardless of their immunological status. [ABSTRACT FROM AUTHOR]

The Chromosome 22q11.2 deletion syndrome (22q11.2DS) results in an inborn error of immunity due to defective thymic organogenesis. Immunological abnormalities in 22q11.2DS patients are thymic hypoplasia, reduced output of T lymphocytes by the thymus, immunodeficiency and increased incidence of autoimmunity. While the precise mechanism responsible for increased incidence of autoimmunity is not completely understood, a previous study suggested a defect in regulatory T cells (Treg) cell lineage commitment during T cell development in thymus. Here, we aimed to analyze this defect in more detail. Since Treg development in human is still ill-defined, we first analyzed where Treg lineage commitment occurs. We performed systematic epigenetic analyses of the Treg specific demethylation region (TSDR) of the FOXP3 gene in sorted thymocytes at different developmental stages. We defined CD3+CD4+CD8+ FOXP3+CD25+ as the T cell developmental stage in human where TSDR demethylation first occurs. Using this knowledge, we analyzed the intrathymic defect in Treg development in 22q11.2DS patients by combination of TSDR, CD3, CD4, CD8 locus epigenetics and multicolor flow cytometry. Our data showed no significant differences in Treg cell frequencies nor in their basic phenotype. Collectively, these data suggest that although 22q11.2DS patients present with reduced thymic size and T cell output, the frequencies and the phenotype of Treg cell at each developmental stage are surprisingly well preserved. [ABSTRACT FROM AUTHOR]

Background: About 1.3 million pregnant women lived with HIV and were eligible to receive antiretroviral therapy (ART) worldwide in 2021. The World Health Organization recommends protease inhibitors (PI)-based regimen as second or third-line during pregnancy. With remaining pregnant women exposed to PIs, there is still an interest to assess whether this treatment affects perinatal outcomes. Adverse perinatal outcomes after prenatal exposure to PI-based ART remain conflicting: some studies report an increased risk of preterm birth (PTB) and low-birth-weight (LBW), while others do not find these results. We assessed adverse perinatal outcomes associated with prenatal exposure to PI-based compared with non-nucleoside reverse transcriptase (NNRTI)-based ART. Methods: We performed a systematic review searching PubMed, Reprotox, Clinical Trial Registry (clinicaltrials.gov) and abstracts of HIV conferences between 01/01/2002 and 29/10/2021. We used Oxford and Newcastle-Ottawa scales to assess the methodological quality. Studied perinatal outcomes were spontaneous abortion, stillbirth, congenital abnormalities, PTB (< 37 weeks of gestation), very preterm birth (VPTB, < 32 weeks of gestation), LBW (< 2500 grs), very low-birth-weight (VLBW, < 1500 g), small for gestational age (SGA) and very small for gestational age (VSGA). The association between prenatal exposure to PI-based compared to NNRTI-based ART was measured for each adverse perinatal outcome using random-effect meta-analysis to estimate pooled relative risks (RR) and their corresponding 95% confidence intervals (CI). Pre-specified analyses were stratified according to country income and study quality assessment, and summarized when homogeneous. Results: Out of the 49,171 citations identified, our systematic review included 32 published studies, assessing 45,427 pregnant women. There was no significant association between prenatal exposure to PIs compared to NNRTIs for VPTB, LBW, SGA, stillbirth, and congenital abnormalities. However, it was inconclusive for PTB, and PI-based ART is significantly associated with an increased risk of VSGA (sRR 1.41 [1.08-1.84]; I2 = 0%) compared to NNRTIs. Conclusions: We did not report any significant association between prenatal exposure to PIs vs NNRTIs-based regimens for most of the adverse perinatal outcomes, except for VSGA significantly increased (+ 41%). The evaluation of antiretroviral exposure on pregnancy outcomes remains crucial to fully assess the benefice-risk balance, when prescribing ART in women of reproductive potential with HIV. PROSPERO number: CRD42022306896. [ABSTRACT FROM AUTHOR]

Mice modeling the hemizygous deletion of chromosome 22q11.2 (22qMc) have been utilized to address various clinical phenotypes associated with the disease, including cardiac malformations, altered neural circuitry, and behavioral deficits. Yet, the status of the T cell compartment, an important clinical concern among 22q11.2 deletion syndrome (22qDS) patients, has not been addressed. While infancy and early childhood in 22qDS are associated with deficient T cell numbers and thymic hypoplasia, which can be severe in a small subset of patients, studies suggest normalization of the T cell counts by adulthood. We found that adult 22qMc do not exhibit thymic hypoplasia or altered thymic T cell development. Our findings that immune cell counts and inflammatory T cell activation are unaffected in 22qMc lend support to the hypothesis that human 22qDS immunodeficiencies are secondary to thymic hypoplasia, rather than intrinsic effects due to the deletion. Furthermore, the 22q11.2 deletion does not impact the differentiation capacity of T cells, nor their activity and response during inflammatory activation. Thus, 22qMc reflects the T cell compartment in adult 22qDS patients, and our findings suggest that 22qMc may serve as a novel model to address experimental and translational aspects of immunity in 22qDS. [ABSTRACT FROM AUTHOR]

Microglia are the resident immune cells of the central nervous system (CNS) and play a major role in the regulation of brain homeostasis. To maintain their cellular protein homeostasis, microglia express standard proteasomes and immunoproteasomes (IP), a proteasome isoform that preserves protein homeostasis also in non-immune cells under challenging conditions. The impact of IP on microglia function in innate immunity of the CNS is however not well described. Here, we establish that IP impairment leads to proteotoxic stress and triggers the unfolded and integrated stress responses in mouse and human microglia models. Using proteomic analysis, we demonstrate that IP deficiency in microglia results in profound alterations of the ubiquitin-modified proteome among which proteins involved in the regulation of stress and immune responses. In line with this, molecular analysis revealed chronic activation of NF-kB signaling in IP-deficient microglia without further stimulus. In addition, we show that IP impairment alters microglial function based on markers for phagocytosis and motility. At the molecular level IP impairment activates interferon signaling promoted by the activation of the cytosolic stress response protein kinase R. The presented data highlight the importance of IP function for the proteostatic potential as well as for precision proteolysis to control stress and immune signaling in microglia function. [ABSTRACT FROM AUTHOR]

Child vaccination reduces infant mortality rates. HIV-infected children present higher risk of diseases than non-infected. We report the protection coverage rates for 6 vaccine-preventable diseases in a paediatric population from the Democratic Republic of the Congo (DRC) and the impact of HIV infection, providing the first data on the validity of dried blood samples (DBS) to monitor the immune protection. During 2016–2018 DBS from 143 children/adolescents were collected in Kinshasa (DRC), being 52 HIV-infected. Forty-two had a paired plasma sample. Protective IgG was quantified (VirClia-IgG,VIRCELL) to obtain the optimal cut-off in IgG detection in DBS. ROC curves were generated with R software and statistical analyses with Stata. Protective IgG levels varied across pathogens, not reaching herd immunity. HIV-infected presented lower vaccine protection than uninfected for all analyzed pathogens, except rubella, with statistically significant differences for measles (30.8% vs. 53.8%; p = 0.008) and tetanus (3.8% vs. 22%; p = 0.0034). New cut-offs were calculated when using DBS to improve test performance. We reinforce the necessity to increase pediatric vaccination coverage in Kinshasa, especially in HIV seropositive, with less capacity to maintain adequate antibody levels. DBS were useful to monitor vaccination coverage in seroprevalence studies in resource-limited settings, after optimizing the cut-off value for each pathogen. [ABSTRACT FROM AUTHOR]

Proteostasis, a portmanteau of the words protein and homeostasis, refers to the ability of eukaryotic cells to maintain a stable proteome by acting on protein synthesis, quality control and/or degradation. Over the last two decades, an increasing number of disorders caused by proteostasis perturbations have been identified. Depending on their molecular etiology, such diseases may be classified into ribosomopathies, proteinopathies and proteasomopathies. Strikingly, most—if not all—of these syndromes exhibit an autoinflammatory component, implying a direct cause-and-effect relationship between proteostasis disruption and the initiation of innate immune responses. In this review, we provide a comprehensive overview of the molecular pathogenesis of these disorders and summarize current knowledge of the various mechanisms by which impaired proteostasis promotes autoinflammation. We particularly focus our discussion on the notion of how cells sense and integrate proteostasis perturbations as danger signals in the context of autoinflammatory diseases to provide insights into the complex and multiple facets of sterile inflammation. [ABSTRACT FROM AUTHOR]

Objective: Autoinflammatory type I interferonopathies, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/proteasome‐associated autoinflammatory syndrome (CANDLE/PRAAS), stimulator of interferon genes (STING)–associated vasculopathy with onset in infancy (SAVI), and Aicardi‐Goutières syndrome (AGS) are rare and clinically complex immunodysregulatory diseases. With emerging knowledge of genetic causes and targeted treatments, a Task Force was charged with the development of "points to consider" to improve diagnosis, treatment, and long‐term monitoring of patients with these rare diseases. Methods: Members of a Task Force consisting of rheumatologists, neurologists, an immunologist, geneticists, patient advocates, and an allied health care professional formulated research questions for a systematic literature review. Then, based on literature, Delphi questionnaires, and consensus methodology, "points to consider" to guide patient management were developed. Results: The Task Force devised consensus and evidence‐based guidance of 4 overarching principles and 17 points to consider regarding the diagnosis, treatment, and long‐term monitoring of patients with the autoinflammatory interferonopathies, CANDLE/PRAAS, SAVI, and AGS. Conclusion: These points to consider represent state‐of‐the‐art knowledge to guide diagnostic evaluation, treatment, and management of patients with CANDLE/PRAAS, SAVI, and AGS and aim to standardize and improve care, quality of life, and disease outcomes. [ABSTRACT FROM AUTHOR]

Oral fungal infections are a worldwide healthcare problem. Although Candida albicans is still the most common yeast involved in the infections of oral cavity, non-Candida albicans Candida species (NCACs) have been highly related to these infections, particularly in older, immunosuppressed or patients with long exposure to antimicrobial drugs. The goal of this work was to perform a quick epidemiological and mycological study on the oral samples collected from a laboratory of a hospital in Slovakia, for 60 days. The samples' identification was performed by Germ-tube formation test, CHROMID® Candida, Auxacolor 2, ID 32C automated method, and the antifungal susceptibility testing determined by E-test®. Results confirm that comparing with bacteria, yeasts still occur in the lower number, but there is a high rate of antifungal resistance (81.6%)—to, at least one drug—among the collected samples, particularly to azoles and 5′-FC, which is clinically noteworthy. [ABSTRACT FROM AUTHOR]

Objective We investigated the effect of antenatal steroid therapy(AST) on white blood cell (WBC) and neutrophil counts and the inflammatory markers C-reactive protein(CRP), interleukin 6(IL-6), interleukin 10(IL-10), and beta-2 microglobulin(ß2M) in preterm infants. Materials Method Neonates born at ≤34 weeks of gestation and admitted at hospital between May and November 2018 were included. The neonates were divided into three groups based on AST dose administered: 24 mg betamethasone (full course), 12 mg betamethasone (incomplete course), and no AST. 170 infants were analyzed. Results Of these, 45.2% (n = 77) received a full course of AST, 38.8% (n = 66) received an incomplete course of AST, and 15.8% (n = 27) did not receive AST. WBC, CRP, IL-6, IL-10, and ß2M levels were similar between the three groups, whereas neutrophil count was significantly lower in full course AST group. Conclusion Consistent with the literature data, AST was associated with reduced neutrophil count but did not affect the other inflammatory markers studied. [ABSTRACT FROM AUTHOR]

Background: Mucocutaneous diseases (MCD) have been commonly described among human immunodeficiency virus (HIV) infected patients before the combined antiretroviral therapy (cART) era. There is limited data on the frequency and type of MCD in the cART era in African children and adolescents. This study aimed to describe the prevalence and spectrum of MCD in South African children and adolescents seropositive for HIV on cART. Methods: A cross‐sectional study of 310 participants aged 0–19 years attending a public sector ART clinic at King Edward VIII Hospital, Durban, South Africa, was conducted. Demographic, clinical, and laboratory information was obtained from the participants and hospital records. Participants were examined. Data were collated and analyzed with SPSS version 23. Results: MCD were observed in 77.4% of HIV‐infected children. The prevalence was higher among males and adolescents above 16 years old (83.9%). Infectious skin disorders (44.7%) were less common than noninfectious dermatoses (55.3%). More common disorders encountered included generalized pruritus (32.6%), fungal infections (20.9%), and inflammatory (20.4%) and pigmentary (20.4%) skin disorders. Tinea capitis and pedis were the most prevalent fungal infections, while oral candidiasis (0.2%) was the least. Inflammatory skin disorders and dyschromia appeared to be more common than in the pre‐cART era. Conclusions: While MCD are still common in HIV‐infected children and adolescents in the cART era, the pattern and types of disorders have changed to a predominance of non‐infectious dermatoses. [ABSTRACT FROM AUTHOR]

Objective. The purpose of the present study is to screen the hub genes associated with sepsis, comprehensively understand the occurrence and progress mechanism of sepsis, and provide new targets for clinical diagnosis and treatment of sepsis. Methods. The microarray data of GSE9692 and GSE95233 were downloaded from the Gene Expression Omnibus (GEO) database. The dataset GSE9692 contained 29 children with sepsis and 16 healthy children, while the dataset GSE95233 included 102 septic subjects and 22 healthy volunteers. Differentially expressed genes (DEGs) were screened by GEO2R online analysis. The DAVID database was applied to conduct functional enrichment analysis of the DEGs. The STRING database was adopted to acquire protein-protein interaction (PPI) networks. Results. We identified 286 DEGs (217 upregulated DEGs and 69 downregulated DEGs) in the dataset GSE9692 and 357 DEGs (236 upregulated DEGs and 121 downregulated DEGs) in the dataset GSE95233. After the intersection of DEGs of the two datasets, a total of 98 co-DEGs were obtained. DEGs associated with sepsis were involved in inflammatory responses such as T cell activation, leukocyte cell-cell adhesion, leukocyte-mediated immunity, cytokine production, immune effector process, lymphocyte-mediated immunity, defense response to fungus, and lymphocyte-mediated immunity. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis suggested that sepsis was connected to bacterial and viral infections. Through PPI network analysis, we screened the most important hub genes, including ITK, CD247, MMP9, CD3D, MMP8, KLRK1, and GZMK. Conclusions. In conclusion, the present study revealed an unbalanced immune response at the transcriptome level of sepsis and identified genes for potential biomarkers of sepsis, such as ITK, CD247, MMP9, CD3D, MMP8, KLRK1, and GZMK. [ABSTRACT FROM AUTHOR]

Background: Preterm infants are highly vulnerable to infectious disease. While many factors are likely to contribute to this enhanced susceptibility, the immature nature of the preterm immune system is postulated as one key factor. Methods: In our study, we used high-dimensional flow cytometry and cytokine assays to characterise the immune profiles in 25 preterm (range: 30.4-34.1 weeks gestational age) and 25 term infant (range: 37-40 weeks gestational age) cord blood samples. Results: We found that preterm infants exhibit reduced frequencies of monocytes, CD56bright NK cells, CD8+ T-cells, γδ T-cells and an increased frequency of intermediate monocytes, CD4+ T-cells, central memory CD4+ and CD8+ T-cells, Tregs and transitional B-cells compared to term infants. Pro-inflammatory cytokines IL-1β, IL-6 and IL-17A were lower in preterm infants in addition to chemokines IL-8, eotaxin, MIP-1α and MIP-1β. However, IL-15 and MCP-1 were higher in preterm infants. Conclusion: Overall, we identify key differences in pro-inflammatory immune profiles between preterm and term infants. These findings may help to explain why preterm infants are more susceptible to infectious disease during early life and facilitate the development of targeted interventions to protect this highly vulnerable group. [ABSTRACT FROM AUTHOR]

Purpose: Chromosome 22q11.2 deletion syndrome is a common inborn error of immunity. The early consequences of thymic hypoplasia are low T cell numbers. Later in life, atopy, autoimmunity, inflammation, and evolving hypogammaglobulinemia can occur and the causes of these features are not understood. This study utilized an unbiased discovery approach to define alterations in histone modifications. Our goal was to identify durable chromatin changes that could influence cell behavior. Methods: CD4 T cells and CD19 B cells underwent ChIP-seq analysis using antibodies to H3K4me3, H3K27ac, and H4ac. RNA effects were defined in CD4 T cells by RNA-seq. Serum cytokines were examined by Luminex. Results: Histone marks of transcriptional activation at CD4 T cell promoters and enhancers were globally increased. The promoter activation signature had elements related to T cell activation and inflammation, concordant with effects seen in the transcriptome. B cells, in contrast, had a minimally altered epigenetic landscape in 22q11.2. Both cell types had an "edge" effect with markedly altered chromatin adjacent to the deletion. Conclusions: People with 22q11.2 deletion have altered CD4 T cell chromatin and a transcriptome concordant with the changes in the epigenome. These effects support a disease model where qualitative changes to T cells occur in addition to quantitative defects that have been well characterized. This study offers unique insight into qualitative differences in the T cells in 22q11.2 deletion, an aspect that has received limited attention. [ABSTRACT FROM AUTHOR]

Some enteric parasites causing zoonotic diseases in livestock have been poorly studied or even neglected. This is the case in stramenopile Blastocystis sp. and the microsporidia Enterocytozoon bieneusi in Spain. This transversal molecular epidemiological survey aims to estimate the prevalence and molecular diversity of Blastocystis sp. and E. bieneusi in cattle faecal samples (n = 336) in the province of Álava, Northern Spain. Initial detection of Blastocystis and E. bieneusi was carried out by polymerase chain reaction (PCR) and Sanger sequencing of the small subunit (ssu) rRNA gene and internal transcribed spacer (ITS) region, respectively. Intra-host Blastocystis subtype diversity was further investigated by next generation amplicon sequencing (NGS) of the ssu rRNA gene in those samples that tested positive by conventional PCR. Amplicons compatible with Blastocystis sp. and E. bieneusi were observed in 32.1% (108/336, 95% CI: 27.2-37.4%) and 0.6% (2/336, 95% CI: 0.0-1.4%) of the cattle faecal samples examined, respectively. Sanger sequencing produced ambiguous/unreadable sequence data for most of the Blastocystis isolates sequenced. NGS allowed the identification of 10 Blastocystis subtypes including ST1, ST3, ST5, ST10, ST14, ST21, ST23, ST24, ST25, and ST26. All Blastocystis-positive isolates involved mixed infections of 2-8 STs in a total of 31 different combinations. The two E. bieneusi sequences were confirmed as potentially zoonotic genotype BEB4. Our data demonstrate that Blastocystis mixed subtype infections are extremely frequent in cattle in the study area. NGS was particularly suited to discern underrepresented subtypes or mixed subtype infections that were undetectable or unreadable by Sanger sequencing. The presence of zoonotic Blastocystis ST1, ST3, and ST5, and E. bieneusi BEB4 suggest cross-species transmission and a potential risk of human infection/colonization. [ABSTRACT FROM AUTHOR]

Although most causes of death and morbidity in premature infants are related to immune maladaptation, the premature immune system remains poorly understood. We provide a comprehensive single-cell depiction of the neonatal immune system at birth across the spectrum of viable gestational age (GA), ranging from 25 weeks to term. A mass cytometry immunoassay interrogated all major immune cell subsets, including signaling activity and responsiveness to stimulation. An elastic net model described the relationship between GA and immunome (R=0.85, p=8.75e-14), and unsupervised clustering highlighted previously unrecognized GA-dependent immune dynamics, including decreasing basal MAP-kinase/NFκB signaling in antigen presenting cells; increasing responsiveness of cytotoxic lymphocytes to interferon-α; and decreasing frequency of regulatory and invariant T cells, including NKT-like cells and CD8+CD161+ T cells. Knowledge gained from the analysis of the neonatal immune landscape across GA provides a mechanistic framework to understand the unique susceptibility of preterm infants to both hyper-inflammatory diseases and infections. [ABSTRACT FROM AUTHOR]

Background The high morbidity and mortality of premature neonates remain significant problem in Indonesia with respiratory distress syndrome (RDS) as one of the most common problem. Vitamin D plays an important role in lung maturity. Vitamin D deficiency causes epithelial cell inflammation, leading to a higher risk of RDS. Previous studies suggest that T regulatory cells (Treg) in inflammatory diseases, such as RDS in neonates, are possibly linked to vitamin D deficiency. Objective To determine the role of vitamin D on RDS and Treg cells in very premature or very low birth weight neonates. Methods A prospective cohort study conducted on premature neonates in Neonatology Division, Department of Child Health, Dr. Cipto Mangunkusumo Hospital, Jakarta, Indonesia. Umbilical cord blood samples were collected to evaluate total vitamin D 25-OH levels and Treg cells. Subjects with RDS were evaluated until the end of the observation period. Results The mean umbilical cord vitamin D level was 15.79 (SD 6.9) ng/mL, and 53% of the subjects were found to be deficient. As much as 65.1% of neonates had RDS. The mean Treg level was 11.38 (SD 2.45)%. No significant correlation was observed between vitamin D level and the occurrence of RDS (RR 0.87; 95%CI 0.56 to 1.34; P=0.53); vitamin D level and the dysregulation of Treg cells (RR 1.30; 95%CI 0.76 to 2.21; P=0.31) as well as between Treg dysregulation and RDS (RR 1.11; 95%CI 0.70 to 1.75; P=0.64). However, we found that RDS group had a lower gestational age and higher presentation of dysregulation Treg. Conclusion In very premature or very low birth weight neonates, no association between occurence of RDS and vitamin D deficiency as well as Treg cell dysregulation. [ABSTRACT FROM AUTHOR]

Purpose: To determine immunological and virological failure and associated factors among children infected with human immunodeficiency virus receiving antiretroviral treatments at Hawassa University Hospital, Southern Ethiopia.Methods: A hospital-based cross-sectional study was conducted among 273 HIV-infected children from July 1 to December 1, 2019. Data were collected using a structured questionnaire and review of patient records. Blood samples for viral load and CD4 count were collected. Data were analyzed using SPSS version 20. Significance group comparison was done by the Kaplan-Meier log-rank test. The Cox proportional hazard model was used to select significant factors of the variability between groups.Results: A total of 273 children, between the age ranges of 1 to 14 years, were included. Of these, 139 (50.9%) and 134 (49.1%) were males and females, respectively. Children from the rural area were almost five times more vulnerable for virological and immunological failure than those children from the urban area (AOR = 4.912, (1.276-8.815), P = 0.032). The overall viral load suppression was 196 (71.8%) with a good adherence of 226 (82.9%). Nonsuppressed HIV viral load was found to be 77 (28.2%) which had two times more viral load copies (AOR = 2.01, (1.21-2.66), P = 0.001) when compared to those who had suppressed viral load copies. The proportions of children who had immunological nonresponse were 45.6% (21 out of 46), 30.4% (14 out of 46), and 23.9% (11 out of 46) among children with baseline CD4 of <200, 201-500, and >500 cells/μl, respectively. Unimproved outcomes among females were noted for immunological and virological failure in this study (AOR = 1.901, (1.038-3.481), P = 0.038).Conclusion: In conclusion, the highly active antiretroviral treatment appeared highly effective in terms of immunological and virological long-term outcomes. However, viral suppression (71.8%) in our study was far apart from the UNAIDS target of 90% in 2020. For that reason, strengthening adherence counseling and early initiation of HAART is important. [ABSTRACT FROM AUTHOR]

The immune system plays a major role in recognizing and eliminating malignant cells, and this has been exploited in the development of immunotherapies aimed at either activating or reactivating the anti-tumor activity of a patient's immune system. A wide range of therapeutic approaches involving T lymphocytes, such as programmed cell death protein ligand-1 (PDL-1) inhibitors, cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) blockers, and CD19-targeted T-cell therapy through chimeric antigen receptor (CAR)-T cells or CD19/CD3 bi-specific T-cell engagers, have been introduced to the field of oncology, leading to significant improvements in overall survival of adult cancer patients. During the past few years, the availability and approval of T-cell based immunotherapies have become a reality also for the treatment of childhood cancers. However, the distribution, ratio of regulatory to effector cells and the quality of T-cell responses early in life are distinct from those during adolescence and adulthood, raising the possibility that these differences impact the efficacy of immunotherapy. Herein we provide a brief overview of the properties of conventional T cell subsets during early life. Focusing on the most common cancer type during childhood, acute lymphoblastic leukemia (ALL), we describe how current conventional therapies used against ALL influence the T-cell compartment of small children. We describe early life T-cell responses in relation to immunotherapies engaging T-cell anticancer reactivity and present our opinion that it is not only immaturity of the adaptive immune system, but also the impact of an immunosuppressive environment that may prove disadvantageous in the setting of immunotherapies targeting pediatric cancer cells. [ABSTRACT FROM AUTHOR]

Background: Preterm birth affects almost 9-11% of newborns and is one of the leading causes of childhood neurodevelopmental disabilities; the underlying molecular networks are poorly defined. In neurons, retrotransposons LINE-1 (L1) are an active source of genomic mosaicism that is deregulated in several neurological disorders; early life experience has been shown to regulate L1 activity in mice.Methods: Very preterm infants were randomized to receive standard care or early intervention. L1 methylation was measured at birth and at hospital discharge. At 12 and 36 months, infants' neurodevelopment was evaluated with the Griffiths Scales. L1 methylation and CNVs were measured in mouse brain areas at embryonic and postnatal stages.Results: Here we report that L1 promoter is hypomethylated in preterm infants at birth and that an early intervention program, based on enhanced maternal care and positive multisensory stimulation, restores L1 methylation levels comparable to healthy newborns and ameliorates neurodevelopment in childhood. We further show that L1 activity is fine-tuned in the perinatal mouse brain, suggesting a sensitive and vulnerable window for the L1 epigenetic setting.Conclusions: Our results open the field on the inspection of L1 activity as a novel molecular and predictive approach to infants' prematurity-related neurodevelopmental outcomes.Trial Registration: ClinicalTrial.gov ( NCT02983513 ). Registered on 6 December 2016, retrospectively registered. [ABSTRACT FROM AUTHOR]