Self-Quenched Fluorophore-DNA Labels for Super-Resolution Fluorescence Microscopy.

Protein labeling through transient and repetitive hybridization of short, fluorophore-labeled DNA oligonucleotides has become widely applied in various optical super-resolution microscopy methods. The main advantages are multitarget imaging and molecular quantification. A challenge is the high background signal originating from the presence of unbound fluorophore-DNA labels in solution. Here, we report the self-quenching of fluorophore dimers conjugated to DNA oligonucleotides as a general concept to reduce the fluorescence background. Upon hybridization, the fluorescence signals of both fluorophores are restored. We expand the toolbox of fluorophores suitable for self-quenching and report their spectra and hybridization equilibria. We apply self-quenched fluorophore-DNA labels to stimulated emission depletion microscopy and single-molecule localization microscopy and report improved imaging performances.

"Living with a question mark": psychosocial experience of Portuguese young adults at risk for hereditary amyloid transthyretin amyloidosis with polyneuropathy.

This study is the first to explore the psychosocial experience of young Portuguese adults at genetic risk for hereditary amyloid transthyretin amyloidosis with polyneuropathy (hATTR-PN). The work focuses on the developmental peculiarities of their experience with the disease. Sixteen semi-structured interviews were conducted with young adults coming for pre-symptomatic testing (PST) at a single genetics outpatient center in Portugal. The data were analyzed qualitatively. The main findings suggest that four themes mark the psychosocial experience of the young adults interviewed. The first refers to the development of psychological representations, namely beliefs, mental representations, and social perceptions about hATTR-PN. The second regards the experienced and anticipated psychosocial impacts, namely, suffering, anxiety, and relief related to the disease. The third is related to using strategies such as performing PST, strategies focused on emotional regulation and the meaning of hATTR-PN, and social strategies to deal with these impacts over time. Finally, the fourth aspect concerns the perceived and expected support for the participants' needs provided by social contexts, that is, family and genetic counseling. In a period of life also marked by qualitatively different characteristics and developmental tasks from other life cycle stages (e.g., identity explorations, instability, and independent decision-making), experience with the disease can add psychosocial challenges to young adults at risk for hATTR-PN. Genetic counseling practices and health policies can be optimized to respond to the psychosocial needs of young adults. Future research should deepen the understanding of the psychosocial experience of individuals and families with late-onset hATTR-PN to improve the clinical response in this population.

A 1:1 flavone cocrystal with cyclic trimeric perfluoro-o-phenyl-enemercury.

The title compound, systematic name tris-(µ2-perfluoro-o-phenyl-ene)(µ2-3-phenyl-4H-chromen-4-one)-triangulo-trimercury, [Hg3(C6F4)3(C15H10O2)], crystallizes in the monoclinic P21/n space group with one flavone (FLA) and one cyclic trimeric perfluoro-o-phenyl-enemercury (TPPM) mol-ecule per asymmetric unit. The FLA mol-ecule is located on one face of the TPPM acceptor and is linked in an asymmetric coordination of its carbonyl oxygen atom with two Hg centers of the TPPM macrocycle. The angular-shaped complexes pack in zigzag chains where they stack via two alternating TPPM-TPPM and FLA-FLA stacking patterns. The distance between the mean planes of the neighboring TPPM macrocycles in the stack is 3.445 (2) Å, and that between the benzo-γ-pyrone moieties of FLA is 3.328 (2) Å. The neighboring stacks are inter-digitated through the shortened F⋯F, CH⋯F and CH⋯π contacts, forming a dense crystal structure.

Metabolic Adaptations and Functional Activity of Macrophages in Homeostasis and Inflammation.

In recent years, the role of cellular metabolism in immunity has come into the focus of many studies. These processes form a basis for the maintenance of tissue integrity and homeostasis, as well as represent an integral part of the immune response, in particular, inflammation. Metabolic adaptations not only ensure energy supply for immune response, but also affect the functions of immune cells by controlling transcriptional and post-transcriptional programs. Studying the immune cell metabolism facilitates the search for new treatment approaches, especially for metabolic disorders. Macrophages, innate immune cells, are characterized by a high functional plasticity and play a key role in homeostasis and inflammation. Depending on the phenotype and origin, they can either perform various regulatory functions or promote inflammation state, thus exacerbating the pathological condition. Furthermore, their adaptations to the tissue-specific microenvironment influence the intensity and type of immune response. The review examines the effect of metabolic reprogramming in macrophages on the functional activity of these cells and their polarization. The role of immunometabolic adaptations of myeloid cells in tissue homeostasis and in various pathological processes in the context of inflammatory and metabolic diseases is specifically discussed. Finally, modulation of the macrophage metabolism-related mechanisms reviewed as a potential therapeutic approach.

Reverse Genetics Applied to Immunobiology of Tumor Necrosis Factor, a Multifunctional Cytokine.

Tumor necrosis factor (TNF) is one of many cytokines - protein molecules responsible for communication between the cells of immune system. TNF was discovered and given its grand name because of its striking antitumor effects in experimental systems, but its main physiological functions in the context of whole organism turned out to be completely unrelated to protection against tumors. This short review discusses "man-made" mouse models generated by early genome-editing technologies, which enabled us to establish true functions of TNF in health and certain diseases as well as to unravel potential strategies for improving therapy of TNF-dependent diseases.

Microglia and Dendritic Cells as a Source of IL-6 in a Mouse Model of Multiple Sclerosis.

Multiple sclerosis (MS) is a complex autoimmune disease of central nervous system (CNS) characterized by the myelin sheath destruction and compromised nerve signal transmission. Understanding molecular mechanisms driving MS development is critical due to its early onset, chronic course, and therapeutic approaches based only on symptomatic treatment. Cytokines are known to play a pivotal role in the MS pathogenesis with interleukin-6 (IL-6) being one of the key mediators. This study investigates contribution of IL-6 produced by microglia and dendritic cells to the development of experimental autoimmune encephalomyelitis (EAE), a widely used mouse model of MS. Mice with conditional inactivation of IL-6 in the CX3CR1+ cells, including microglia, or CD11c+ dendritic cells, displayed less severe symptoms as compared to their wild-type counterparts. Mice with microglial IL-6 deletion exhibited an elevated proportion of regulatory T cells and reduced percentage of pathogenic IFNγ-producing CD4+ T cells, accompanied by the decrease in pro-inflammatory monocytes in the CNS at the peak of EAE. At the same time, deletion of IL-6 from microglia resulted in the increase of CCR6+ T cells and GM-CSF-producing T cells. Conversely, mice with IL-6 deficiency in the dendritic cells showed not only the previously described increase in the proportion of regulatory T cells and decrease in the proportion of TH17 cells, but also reduction in the production of GM-CSF and IFNγ in the secondary lymphoid organs. In summary, IL-6 functions during EAE depend on both the source and localization of immune response: the microglial IL-6 exerts both pathogenic and protective functions specifically in the CNS, whereas the dendritic cell-derived IL-6, in addition to being critically involved in the balance of regulatory T cells and TH17 cells, may stimulate production of cytokines associated with pathogenic functions of T cells.

Comparison of Continuous Intracortical and Scalp Electroencephalography in Comatose Patients with Acute Brain Injury.

BACKGROUND: Depth electroencephalography (dEEG) is a recent invasive monitoring technique used in patients with acute brain injury. This study aimed to describe in detail the clinical manifestations of nonconvulsive seizures (NCSzs) with and without a surface EEG correlate, analyze their long-standing effects, and provide data that contribute to understanding the significance of certain scalp EEG patterns observed in critically ill patients. METHODS: We prospectively enrolled a cohort of 33 adults with severe acute brain injury admitted to the neurological intensive care unit. All of them underwent multimodal invasive monitoring, including dEEG. All patients were scanned on a 3T magnetic resonance imaging scanner at 6 months after hospital discharge, and mesial temporal atrophy (MTA) was calculated using a visual scale. RESULTS: In 21 (65.6%) of 32 study participants, highly epileptiform intracortical patterns were observed. A total of 11 (34.3%) patients had electrographic or electroclinical seizures in the dEEG, of whom 8 had both spontaneous and stimulus-induced (SI) seizures, and 3 patients had only spontaneous intracortical seizures. An unequivocal ictal scalp correlate was observed in only 3 (27.2%) of the 11 study participants. SI-NCSzs occurred during nursing care, medical procedures, and family visits. Subtle clinical manifestations, such as restlessness, purposeless stereotyped movements of the upper limbs, ventilation disturbances, jerks, head movements, hyperextension posturing, chewing, and oroalimentary automatisms, occurred during intracortical electroclinical seizures. MTA was detected in 18 (81.8%) of the 22 patients. There were no statistically significant differences between patients with MTA with and without seizures or status epilepticus. CONCLUSIONS: Most NCSzs in critically ill comatose patients remain undetectable on scalp EEG. SI-NCSzs frequently occur during nursing care, medical procedures, and family visits. Semiology of NCSzs included ictal minor signs and subtle symptoms, such as breathing pattern changes manifested as patient-ventilator dyssynchrony.

Identification of a Novel Indel Variant in the DARS2 Gene in Russian Patients with Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation.

BACKGROUND: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation is an inherited disease caused by pathogenic biallelic variants in the gene DARS2, which encodes mitochondrial aspartyl-tRNA synthetase. This disease is characterized by slowly progressive spastic gait, cerebellar symptoms, and leukoencephalopathy with brainstem and spinal cord involvement. CASE PRESENTATION: Peripheral blood samples were collected from four patients from four unrelated families to extract genomic DNA. All patients underwent partial exon analysis of the DARS2 gene using Sanger sequencing, which detected the c.228-21_228-20delinsC variant in a heterozygous state. Further DNA from three patients was analyzed using a next-generation sequencing-based custom AmpliSeq™ panel for 59 genes associated with leukodystrophies, and one of the patients underwent whole genome sequencing. We identified a novel pathogenic variant c.1675-1256_*115delinsGCAACATTTCGGCAACATTCCAACC in the DARS2 gene. Three patients (patients 1, 2, and 4) had slowly progressive cerebellar ataxia, and two patients (patients 1 and 2) had spasticity. In addition, two patients (patients 2 and 4) showed signs of axonal neuropathy, such as decreased tendon reflexes and loss of distal sensitivity. Three patients (patients 1, 2, and 3) also had learning difficulties. It should be noted the persistent presence of characteristic changes in brain MRI in all patients, which emphasizes its importance as the main diagnostic tool for suspicion and subsequent confirmation of LBSL. Conclusions: We found a novel indel variant in the DARS2 gene in four patients with LBSL and described their clinical and genetic characteristics. These results expand the mutational spectrum of LBSL and aim to improve the laboratory diagnosis of this form of leukodystrophy.

Treatment of atopic dermatitis with upadacitinib: adcare single center experience.

Introduction: The role of upadacitinib in the management of moderate to severe atopic dermatitis seems promising, but more data on its efficacy and safety are needed. This study endeavors to assess the practical impact and safety of upadacitinib in patients with moderate to severe atopic dermatitis. The study aims to evaluate the efficacy and safety of upadacitinib in the treatment of moderate to severe atopic dermatitis, focusing on analyzing patient responses to the treatment. Methods: In this study, adult patients diagnosed with moderate to severe atopic dermatitis received upadacitinib at daily doses of 15 mg or 30 mg, as prescribed by their attending physicians. The therapeutic efficacy of upadacitinib was meticulously assessed using established clinical metrics. Simultaneously, a comprehensive safety assessment was conducted through monthly monitoring, including the evaluation of potential effects of upadacitinib intake on hepatic function, lipid profile, and hematopoiesis using the pertinent laboratory tests. Results: Sixteen participants were enrolled in the study. At 1month follow-up, there was a significant reduction in the mean Eczema Area and Severity Index (EASI) score to 18.8 points, which further increased to 24 points at the 4-month mark. Additionally, 9 participants (56%) demonstrated an EASI-50 response after 1 month of treatment, with this response increasing to 9 participants (90%) after 4 months. Furthermore, enhanced therapeutic responses were observed at 4 months, with 6 patients (38%) achieving an EASI-75 response at 1month and 8 patients (80%) achieving this milestone at the 4-month follow-up. This study highlights the potential of upadacitinib as an effective treatment option for moderate to severe atopic dermatitis. While it demonstrates improved symptom management, close monitoring for potential adverse events, particularly infections and the known risks of Janus kinase inhibitors, is essential. Further research is essential to determine the long-term safety and efficacy of upadacitinib.

The effect of exposure to RF-EMF from the laboratory simulator of 5G NR base station on physiological parameters and cognitive abilities of male wistar rats of different ages.

In this article, the impact of radiofrequency electromagnetic field (RF-EMF) exposure from a simulated base station for the 5G New Radio (5G NR) telecommunication on rats was studied. The base station affects all age groups of the population, thus, for the first time, the experiment was conducted on male Wistar rats of three different ages (juvenile, adult, and presenile). The base station exposure parameters were chosen according to ICNIRP recommendations for limiting the exposure to radiofrequency electromagnetic field: frequency 2.4 GHz with an average specific absorption rate of 0.0076 W/kg and 0.0059 W/kg over the whole body of experimental animals. Throughout the experiment, body weight was examined weekly, and the dynamics of body weight gain was monitored. Rectal and skin surface temperature on the right hind limb was monitored weekly. Testing in the Morris water maze was performed during the last, Week 5, of RF-EMF exposure. After euthanasia, organ weights were determined in experimental and control animals. None of the investigated parameters did show any statistically significant differences between exposed and control animals of the same age. The data obtained can be used to assess the possible consequences of chronic exposure to RF-EMF from 5G NR base stations.

Cannabidivarin and cannabigerol induce unfolded protein response and angiogenesis dysregulation in placental trophoblast HTR-8/SVneo cells.

Cannabidivarin (CBDV) and cannabigerol (CBG) are minor phytocannabinoids from Cannabis sativa, whose health benefits have been reported. However, studies about the impact of these cannabinoids on fundamental cellular processes in placentation are scarce. Placental development involves physiological endoplasmic reticulum (ER) stress, however when exacerbated it can lead to altered angiogenesis and pregnancy disorders, such as intrauterine growth restriction and preeclampsia. In this work, the effects of CBDV and CBG (1-10 µM) on placental extravillous trophoblasts were studied, using the in vitro model HTR-8/SVneo cells. Both cannabinoids induced anti-proliferative effects and reactive oxygen/nitrogen species generation, which was dependent on transient receptor potential vanilloid 1 (TRPV1) activation. Moreover, CBDV and CBG significantly upregulated, in a TRPV-1 dependent manner, the gene expression of HSPA5/Glucose-regulated protein 78 (GRP78/BiP), a critical chaperone involved in ER stress and unfolded protein response (UPR) activation. Nevertheless, the UPR pathways were differentially activated. Both cannabinoids were able to recruit the IRE branch, while only CBDV enhanced the expression of downstream effectors of the PERK pathway, namely p-eIF2α, ATF4 and CHOP. It also augmented the activity of the apoptotic initiator caspases-8 and -9, though the effector caspases-3/-7 were not activated. TRB3 expression was increased by CBDV, which may hinder apoptosis termination. Moreover, both compounds upregulated the mRNA levels of the angiogenic factors VEGFA, PGF and sFLT1, and disrupted the endothelial-like behavior of HTR-8/SVneo cells, by reducing tube formation. Thus, CBDV and CBG treatment interferes with EVTs functions and may have a negative impact in placentation and in pregnancy outcome.

Gastroschisis and septo-optic-pituitary dysplasia: Is there an association?

AIM: There are several case reports describing patients with both optic nerve hypoplasia/septo-optic-pituitary dysplasia (ONH/SOD) and gastroschisis (GS). Our aim was to investigate whether ONH/SOD is associated with GS. METHODS: A retrospective population-based study was undertaken using the Population Research Data Repository at the Manitoba Center for Health Policy in Manitoba, Canada to investigate if any patient with ONH/SOD also had GS. In addition, Winnipeg's Surgical Database of Outcomes and Management (WiSDOM), a hospital-based paediatric surgical database, was searched to ascertain if any of the patients with GS also have ONH/SOD. RESULTS: Cases were 124 patients with ONH/SOD diagnosed during 1990-2019. None had GS. The surgical database had 188 patients from Manitoba with GS during 1991-2019. None had ONH/SOD. CONCLUSION: There does not appear to be an association between ONH/SOD and GS in our cohorts of patients with these two disorders.

Field Testing the Family Behavior Support Mobile Application (FBSApp) During a Global Pandemic.

We developed and tested an evidence-based mobile application designed to support families in using functional assessment-based intervention strategies with their young children with disabilities and challenging behaviors in home settings. Five families participated in the study. We utilized a multiple-probe across participants design to examine the effects of the FBSApp on parents' use of intervention strategies and childrens' use of challenging behaviors and replacement behaviors. We adapted our procedures to include individualized coaching to provide meaningful and effective support after the onset of the COVID-19 pandemic. A functional relation was not identified between access to FBSApp and caregiver use of strategies; however, the addition of coaching did lead to increased strategy use for two of four caregivers. A functional relation was identified between the use of the FBSApp plus coaching and CB. Families reported the app and coaching procedures favorably. We found that responsive, family-centered research CAN be conducted in spite of significant history events, and that mobile apps and virtual meeting platforms can be an accessible and efficient method for supporting families. The use of single case design allowed for flexible, yet methodologically sound procedures. More work is needed examining effective and efficient virtual supports for families.

Leucoverdazyls as Novel Potent Inhibitors of Enterovirus Replication.

Enteroviruses (EV) are important pathogens causing human disease with various clinical manifestations. To date, treatment of enteroviral infections is mainly supportive since no vaccination or antiviral drugs are approved for their prevention or treatment. Here, we describe the antiviral properties and mechanisms of action of leucoverdazyls-novel heterocyclic compounds with antioxidant potential. The lead compound, 1a, demonstrated low cytotoxicity along with high antioxidant and virus-inhibiting activity. A viral strain resistant to 1a was selected, and the development of resistance was shown to be accompanied by mutation of virus-specific non-structural protein 2C. This resistant virus had lower fitness when grown in cell culture. Taken together, our results demonstrate high antiviral potential of leucoverdazyls as novel inhibitors of enterovirus replication and support previous evidence of an important role of 2C proteins in EV replication.

Are There Differences Among Evidence-Based Psychotherapies for Treating Different DSM-5 PTSD Symptom Clusters? A Systematic Review and Meta-analysis of Controlled Clinical Trials.

ABSTRACT: Posttraumatic stress disorder (PTSD) is a heterogeneous disease defined by four Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) symptom clusters: reexperiencing, avoidance, negative alterations in cognitions and mood, and hyperarousal. There are effective evidence-based psychotherapies (EBPs) for PTSD. However, given the variety of PTSD clinical presentations, we conducted the first meta-analysis investigating whether DSM-5 PTSD symptom clusters show different responses to EBPs. We systematically reviewed the literature for controlled clinical trials in five databases, performed a meta-analysis, and evaluated the methodological quality of the studies. We screened 633 studies and included seven. Three showed high risk, two showed some concerns, and one showed a low risk of bias. The symptom clusters do not seem to respond differently to EBPs (SMD cluster B: -0.40; 95% confidence interval [CI], -0.87 to 0.08; cluster C: -0.49; 95% CI, -0.90 to -0.08; cluster D: -0.44; 95% CI, -0.94 to 0.05; cluster E: -0.54; 95% CI, -1.07 to -0.0), even when analyzed by the therapeutic focuses. The findings dovetail nicely with the network theory of PTSD symptom, as although it is a heterogeneous disorder, the EBPs seem to promote a kind of cascade of symptom improvement.

Measuring local genetic variation in permethrin-resistant head lice (Phthiraptera: Pediculidae) from Buenos Aires, Argentina.

The cosmopolitan ectoparasite human head louse, Pediculus humanus capitis (De Geer)(Phthiraptera:Pediculidae), affects mostly school-aged children, with infestations reported every year mainly due to louse resistance to pyrethroids. One of the main resistance mechanisms of pyrethroids is the target site insensitivity (kdr), which is caused by single-nucleotide point mutations (SNPs) located in the voltage-sensitive sodium channel gene. In this study, we analyzed individual head lice toxicologically via the description of their susceptibility profile to permethrin and genetically through the genotypification of their kdr alleles as well as nuclear microsatellite loci. Lice were collected from 4 schools in the city of Buenos Aires, Argentina. The resistance ratios varied from 33.3% to 71.4%, with a frequency of the T917I kdr mutation of 87.31% and with 83.6% of the head lice being homozygous resistant to pyrethroids. Microsatellite data indicated that all the louse school populations had genotype proportions that deviated from Hardy-Weinberg expectations, with FIS > 0 reflecting a deficit of heterozygotes. Bottleneck analysis suggested that all louse school populations underwent a recent reduction in population sizes, while 3 of the 4 schools had gene flow values around 1, indicating ongoing gene flow among those schools. Our study suggests that school louse populations in the city of Buenos Aires may form a metapopulation, where each school represents a small population that undergoes extinction and recolonization processes under strong permethrin selection. This is the first multilevel analysis integrating toxicological, kdr-genotyping, and microsatellite data in human louse populations.

Association between EEG metrics and continuous cerebrovascular autoregulation assessment: a scoping review.

OBJECTIVE: Cerebrovascular autoregulation is defined as the capacity of cerebral blood vessels to maintain stable cerebral blood flow despite changing blood pressure. It is assessed using the pressure reactivity index (the correlation coefficient between mean arterial blood pressure and intracranial pressure). The objective of this scoping review is to describe the existing evidence concerning the association of EEG and cerebrovascular autoregulation in order to identify key concepts and detect gaps in the current knowledge. METHODS: Embase, MEDLINE, SCOPUS, and Web of Science were searched considering articles between their inception up to September 2023. Inclusion criteria were human (paediatric and adult) and animal studies describing correlations between continuous EEG and cerebrovascular autoregulation assessments. RESULTS: Ten studies describing 481 human subjects (67% adult, 59% critically ill) were identified. Seven studies assessed qualitative (e.g. seizures, epileptiform potentials) and five evaluated quantitative (e.g. bispectral index, alpha-delta ratio) EEG metrics. Cerebrovascular autoregulation was evaluated based on intracranial pressure, transcranial Doppler, or near infrared spectroscopy. Specific combinations of cerebrovascular autoregulation and EEG metrics were evaluated by a maximum of two studies. Seizures, highly malignant patterns or burst suppression, alpha peak frequency, and bispectral index were associated with cerebrovascular autoregulation. The other metrics showed either no or inconsistent associations. CONCLUSION: There is a paucity of studies evaluating the link between EEG and cerebrovascular autoregulation. The studies identified included a variety of EEG and cerebrovascular autoregulation acquisition methods, age groups, and diseases allowing for few overarching conclusions. However, the preliminary evidence for the presence of an association between EEG metrics and cerebrovascular autoregulation prompts further in-depth investigations.

Prophylactic tranexamic acid in Cesarean delivery: an updated meta-analysis with a trial sequential analysis.

PURPOSE: Postpartum hemorrhage (PPH) is a leading cause of maternal mortality worldwide. Although several studies on the prophylactic use of tranexamic acid (TXA) in parturients undergoing Cesarean delivery have been published, conflicting results raise questions regarding its use. Thus, we aimed to investigate the safety and efficacy of PPH prophylaxis with TXA. SOURCE: We searched PubMed®, Embase, Cochrane Central, and ClinicalTrials.gov for randomized controlled trials (RCTs) comparing prophylactic TXA with placebo or no treatment in parturients undergoing Cesarean delivery. Our main outcomes were PPH, any blood transfusion, need for additional uterotonics, and adverse events. We performed a trial sequential analysis (TSA) of all outcomes to investigate the reliability and conclusiveness of findings. PRINCIPAL FINDINGS: We included 38 RCTs including 22,940 parturients, 11,535 (50%) of whom were randomized to receive prophylactic TXA. Patients treated with TXA had significantly fewer cases of PPH (risk ratio [RR], 0.51; 95% confidence interval [CI], 0.38 to 0.69; P < 0.001); less blood transfusion (RR, 0.43; 95% CI, 0.30 to 0.61; P < 0.001), and less use of additional uterotonics (RR, 0.52; 95% CI, 0.40 to 0.68; P < 0.001). No significant differences were found between the groups in terms of adverse effects and thromboembolic events. CONCLUSION: Prophylactic TXA administration for parturients undergoing Cesarean delivery significantly reduced blood loss, without increasing adverse events, supporting its use as a safe and effective strategy for reducing PPH in this population. STUDY REGISTRATION: PROSPERO (CRD42023422188); first submitted 27 April 2023.

RéSUMé: OBJECTIF: L'hémorragie du post-partum (HPP) est l'une des principales causes de mortalité maternelle dans le monde. Bien que plusieurs études sur l'utilisation prophylactique d'acide tranexamique (TXA) chez les personnes parturientes ayant accouché par césarienne aient été publiées, des résultats contradictoires soulèvent des questions quant à son utilisation. Ainsi, nous avons cherché à étudier l'innocuité et l'efficacité de la prophylaxie à base de TXA pour l'HPP. SOURCES: Nous avons fait une recherche sur PubMed®, Embase, Cochrane Central et ClinicalTrials.gov pour en tirer les études randomisées contrôlées (ERC) comparant le TXA prophylactique à un placebo ou à l'absence de traitement chez les personnes parturientes accouchant par césarienne. Nos principaux critères d'évaluation étaient l'HPP, toute transfusion sanguine, la nécessité d'un utérotonique supplémentaire et les événements indésirables. Nous avons effectué une analyse séquentielle des études pour tous les résultats afin d'examiner la fiabilité et le caractère concluant des conclusions. CONSTATATIONS PRINCIPALES: Nous avons inclus 38 ERC comprenant 22 940 personnes parturientes, dont 11 535 (50 %) ont été randomisées pour recevoir du TXA prophylactique. La patientèle traitée par TXA présentait significativement moins de cas d'HPP (risque relatif [RR], 0,51; intervalle de confiance [IC] à 95 %, 0,38 à 0,69; P < 0,001); moins de transfusion sanguine (RR, 0,43; IC 95 %, 0,30 à 0,61; P < 0,001) et moins d'utilisation d'utérotoniques supplémentaires (RR, 0,52; IC 95 %, 0,40 à 0,68; P < 0,001). Aucune différence significative n'a été constatée entre les groupes en termes d'effets indésirables et d'événements thromboemboliques. CONCLUSION: L'administration prophylactique de TXA pour les personnes parturientes accouchant par césarienne a considérablement réduit les pertes de sang sans augmenter les événements indésirables, ce qui soutient son utilisation comme stratégie sécuritaire et efficace pour réduire l'HPP dans cette population. ENREGISTREMENT DE L'éTUDE: PROSPERO (CRD42023422188); première soumission le 27 avril 2023.

Systematic computer-aided disulfide design as a general strategy to stabilize prefusion class I fusion proteins.

Numerous enveloped viruses, such as coronaviruses, influenza, and respiratory syncytial virus (RSV), utilize class I fusion proteins for cell entry. During this process, the proteins transition from a prefusion to a postfusion state, undergoing substantial and irreversible conformational changes. The prefusion conformation has repeatedly shown significant potential in vaccine development. However, the instability of this state poses challenges for its practical application in vaccines. While non-native disulfides have been effective in maintaining the prefusion structure, identifying stabilizing disulfide bonds remains an intricated task. Here, we present a general computational approach to systematically identify prefusion-stabilizing disulfides. Our method assesses the geometric constraints of disulfide bonds and introduces a ranking system to estimate their potential in stabilizing the prefusion conformation. We found, for the RSV F protein, that disulfides restricting the initial stages of the conformational switch can offer higher stability to the prefusion state than those preventing unfolding at a later stage. The implementation of our algorithm on the RSV F protein led to the discovery of prefusion-stabilizing disulfides, providing evidence that supports our hypothesis. Furthermore, the evaluation of our top design as a vaccine candidate in a cotton rat model demonstrated robust protection against RSV infection, highlighting the potential of our approach for vaccine development.

Detection of plasma anti-lipopolysaccharide (LPS)antibodies against enterohemorrhagic Escherichia coli(EHEC) in asymptomatic kindergarten teachers fromBuenos Aires province

Resumen En Argentina, el síndrome urémico hemolítico causado por Escherichia coli enterohemorrágica (EHEC) tiene la más alta incidencia del mundo. Las infecciones por EHEC tienen un comportamiento endemoepidémico y causan del 20 al 30% de los síndromes de diarrea sanguinolenta en niños menores de 5 años. En el período 2016-2020, se notificaron 272 nuevos casos por año al Sistema de Vigilancia de Salud Nacional. Múltiples factores son responsables de la alta incidencia de SUH en Argentina, incluyendo la transmisión persona-persona. Con el objetivo de detectar posibles portadores asintomáticos de EHEC, realizamos un estudio preliminar de la frecuencia de anticuerpos antilipopolisacáridos contra los serotipos de EHEC más prevalentes en Argentina. El estudio se realizó con muestras de plasma obtenidas de 61 maestras y maestros de jardines de infantes de 26 instituciones del distrito de José C. Paz, localizado en el área suburbana de la provincia de Buenos Aires, Argentina. El 51% de las muestras presentaron anticuerpos contra los serotipos de lipopolisacáridos O157, O145, O121 y O103; el 6,4% de las muestras positivas tuvieron el isotipo IgM (n=2), el 61,3% el isotipo IgG (n=19) y el 32,3% los isotipos IgM e IgG (n=10). Dado que los anticuerpos antilipopolisacáridos presentan usualmente una duración corta, la detección de IgM específica podría indicar una infección reciente. Además, el alto porcentaje de muestras positivas hallado podría indicar una exposición frecuente a las cepas de EHEC en la cohorte estudiada. Asimismo, la gran población de adultos portadores asintomáticos de estas cepas patógenas podría contribuir al comportamiento endémico, a través de la transmisión persona-persona. El perfeccionamiento de programas educacionales continuos en jardines de infantes podría constituir una medida importante para reducir los casos de síndrome urémico hemolítico, no solo en Argentina, sino también en el mundo.

Abstract In Argentina, hemolytic uremic syndrome (HUS) caused by EHEC has the highest incidence in the world. EHEC infection has an endemo-epidemic behavior, causing 20-30% of acute bloody diarrhea syndrome in children under 5 years old. In the period 2016-2020, 272 new cases per year were notified to the National Health Surveillance System. Multiple factors are responsible for HUS incidence in Argentina including person-to-person transmission. In order to detect possible EHEC carriers, we carried out a preliminary study of the frequency of kindergarten teachers with anti-LPS antibodies against the most prevalent EHEC serotypes in Argentina. We analyzed 61 kindergarten teachers from 26 institutions from José C. Paz district, located in the suburban area of Buenos Aires province, Argentina. Fifty-one percent of the plasma samples had antibodies against O157, O145, O121 and O103 LPS: 6.4% of the positive samples had IgM isotype (n=2), 61.3% IgG isotype (n=19) and 32.3% IgM and IgG (n=10). Given that antibodies against LPS antigens are usually short-lived specific IgM detection may indicate a recent infection. In addition, the high percentage of positive samples may indicate a frequent exposure to EHEC strains in the cohort studied, as well as the existence of a large non-symptomatic population of adults carrying pathogenic strains that could contribute to the endemic behavior through person-to-person transmission. The improvement of continuous educational programs in kindergarten institutions could be a mandatory measure to reduce HUS cases not only in Argentina but also globally.