Dating Violence and Emotional Dependence in University Students.

The aim of this study was to analyse the relationship between dating violence and emotional dependence in young university students in Ecuador by identifying differences based on sex. Using purposive non-probabilistic sampling, 3203 students were selected, of which 35.7% were men and 64.3% were women aged 16 to 48 (M = 21.50; SD = 2.82). Two psychological scales were applied: Questionnaire on Violence in Couples (CUVINO) and Questionnaire on Emotional Dependence (EDQ). According to the results obtained, based on sex, it was found that dating violence is a severe problem that both men and women experience. With regard to emotional dependence, women scored higher than men. In addition, emotional dependence was linked to dating violence. The implications of the results obtained for further research and for prevention and intervention programmes are presented, and the strengths and limitations of this study are detailed.

Role of affinity in plasma cell development in the germinal center light zone.

Protective immune responses to many pathogens depend on the development of high-affinity antibody-producing plasma cells (PC) in germinal centers (GCs). Transgenic models suggest that there is a stringent affinity-based barrier to PC development. Whether a similar high-affinity barrier regulates PC development under physiologic circumstances and the nature of the PC fate decision has not been defined precisely. Here, we use a fate-mapping approach to examine the relationship between GC B cells selected to undergo additional rounds of affinity maturation, GC pre-PC, and PC. The data show that initial PC selection overlaps with GC B cell selection, but that the PC compartment accumulates a less diverse and higher affinity collection of antibodies over time. Thus, whereas the GC continues to diversify over time, affinity-based pre-PC selection sieves the GC to enable the accumulation of a more restricted group of high-affinity antibody-secreting PC.

Continually recruited naïve T cells contribute to the follicular helper and regulatory T cell pools in germinal centers.

Follicular helper T cells (TFH) mediate B cell selection and clonal expansion in germinal centers (GCs), and follicular regulatory T cells (TFR) prevent the emergence of self-reactive B cells and help to extinguish the reaction. Here we show that GC reactions continually recruit T cells from both the naïve conventional and naive thymic regulatory T cell (Treg) repertoires. In the early GC, newly recruited T cells develop into TFH, whereas cells entering during the contraction phase develop into TFR cells that contribute to GC dissolution. The TFR fate decision is associated with decreased antigen availability and is modulated by slow antigen delivery or mRNA vaccination. Thus, invasion of ongoing GCs by newly developing TFH and TFR helps remodel the GC based on antigen availability.

X-ray radiation dose and associated factors in neonates from the newborn unit of Hospital Universitario San Ignacio, Bogotá, Colombia / Dosis de radiación por radiografías y factores asociados en neonatos de la Unidad de Recién Nacidos del Hospital Universitario San Ignacio, Bogotá, Colombia.

Introduction: Radiographs are still widely used, underestimating the risks. This situation is frequent in neonatal care units, generating radiation doses than in adults. Objective: To quantify the received radiation doses when performing radiographs on neonates and the possible factors associated with higher doses. Materials and methods: We performed an observational study of 160 neonates from the newborn unit of the Hospital Universitario San Ignacio, Bogotá, Colombia. We considered the input dose of each radiograph as the dependent variable. Patients were characterized and a multivariate analysis with multiple linear regression was performed to identify associated factors. Results: We analyzed 160 newborns and 492 radiographs. The most frequent findings were male patients (n=87, 54.4%), cesarean delivery (n=122, 76.3%), and radiograph indication for respiratory distress (n=123, 24.9%). One-point eight percent of the patients (n=9) did not have radiograph indication. The most frequently taken radiograph was chest (322, 65.4%). Most radiographs were taken with a computerized equipment (n=352, 71.5%), compared to a digital one (n=140, 28.4%). The median input dose with computerized equipment was 0.112 mGy (0.022, 0.134 mGy), and with the digital equipment was 0.020 mGy (0.019, 0.022 mGy). Conclusions: The general and specific absorbed radiation doses were measured in neonates with a computerized and a digital equipment. We identified higher doses with the computerized equipment. In addition, it was recognized the correlation between computerized radiography equipment with lower corrected gestational ages as the main factor for dose increase.

Introducción: Las radiografías continúan usándose ampliamente, subestimando los riesgos. Esto sucede, especialmente, en las unidades de cuidado neonatal, lo que implica que los neonatos reciben una dosis de radiación ionizante mayor que los adultos. Objetivo: Cuantificar las dosis de radiación recibidas al tomar radiografías y evaluar los posibles factores asociados con el aumento de la dosis. Materiales y métodos: Se llevó a cabo un estudio observacional de 160 neonatos de la Unidad de Recién Nacidos del Hospital Universitario San Ignacio, Bogotá, Colombia. Se consideró como variable dependiente la dosis de entrada en piel por cada radiografía. Se hizo la caracterización de los pacientes, seguida de un análisis multivariado con regresión lineal múltiple para identificar factores asociados. Resultados: Se analizaron 160 pacientes y 492 radiografías en total. Entre los hallazgos más frecuentes, se encuentran: pacientes de sexo masculino (n=87; 54,4 %), nacimiento por cesárea (n=122; 76,3 %) e indicación de toma de radiografías por dificultad respiratoria (n=123; 24,9 %). El 1,8 % (n=9) de los pacientes no tenían una indicación para la toma de la radiografía. La radiografía más frecuente fue la de tórax (n=322; 65,4 %). La mayoría de las radiografías se tomaron con el equipo computarizado (n=352; 71,5 %) y no con el digital (n=140, 28,4 %). La mediana de la dosis de entrada en piel con el equipo computarizado fue de 0,112 mGy (0,022; 0,134 mGy) y, con el equipo digital, de 0,020 mGy (0,019, 0,022 mGy). Conclusiones: Se cuantificaron las dosis de radiación absorbida en neonatos, general y específica, con el equipo computarizado y el digital. Se identificaron mayores dosis con el equipo computarizado. Se reconoció la interacción entre el equipo computarizado con menores edades gestacionales corregidas como principal factor para el aumento de la dosis. Además, se reconoció la relación entre el equipo computarizado y una menor edad gestacional corregida, como principal factor para una mayor dosis.

Impact of a TLR9 agonist and broadly neutralizing antibodies on HIV-1 persistence: the randomized phase 2a TITAN trial.

Inducing antiretroviral therapy (ART)-free virological control is a critical step toward a human immunodeficiency virus type 1 (HIV-1) cure. In this phase 2a, placebo-controlled, double-blinded trial, 43 people (85% males) with HIV-1 on ART were randomized to (1) placebo/placebo, (2) lefitolimod (TLR9 agonist)/placebo, (3) placebo/broadly neutralizing anti-HIV-1 antibodies (bNAbs) or (4) lefitolimod/bNAb. ART interruption (ATI) started at week 3. Lefitolimod was administered once weekly for the first 8 weeks, and bNAbs were administered twice, 1 d before and 3 weeks after ATI. The primary endpoint was time to loss of virologic control after ATI. The median delay in time to loss of virologic control compared to the placebo/placebo group was 0.5 weeks (P = 0.49), 12.5 weeks (P = 0.003) and 9.5 weeks (P = 0.004) in the lefitolimod/placebo, placebo/bNAb and lefitolimod/bNAb groups, respectively. Among secondary endpoints, viral doubling time was slower for bNAb groups compared to non-bNAb groups, and the interventions were overall safe. We observed no added benefit of lefitolimod. Despite subtherapeutic plasma bNAb levels, 36% (4/11) in the placebo/bNAb group compared to 0% (0/10) in the placebo/placebo group maintained virologic control after the 25-week ATI. Although immunotherapy with lefitolimod did not lead to ART-free HIV-1 control, bNAbs may be important components in future HIV-1 curative strategies. ClinicalTrials.gov identifier: NCT03837756 .

Epigenetic memory of coronavirus infection in innate immune cells and their progenitors.

Inflammation can trigger lasting phenotypes in immune and non-immune cells. Whether and how human infections and associated inflammation can form innate immune memory in hematopoietic stem and progenitor cells (HSPC) has remained unclear. We found that circulating HSPC, enriched from peripheral blood, captured the diversity of bone marrow HSPC, enabling investigation of their epigenomic reprogramming following coronavirus disease 2019 (COVID-19). Alterations in innate immune phenotypes and epigenetic programs of HSPC persisted for months to 1 year following severe COVID-19 and were associated with distinct transcription factor (TF) activities, altered regulation of inflammatory programs, and durable increases in myelopoiesis. HSPC epigenomic alterations were conveyed, through differentiation, to progeny innate immune cells. Early activity of IL-6 contributed to these persistent phenotypes in human COVID-19 and a mouse coronavirus infection model. Epigenetic reprogramming of HSPC may underlie altered immune function following infection and be broadly relevant, especially for millions of COVID-19 survivors.

Poly(ß-amino ester)s-Based Delivery Systems for Targeted Transdermal Vaccination.

Nucleic acid vaccines have become a transformative technology to fight emerging infectious diseases and cancer. Delivery of such via the transdermal route could boost their efficacy given the complex immune cell reservoir present in the skin that is capable of engendering robust immune responses. We have generated a novel library of vectors derived from poly(ß-amino ester)s (PBAEs) including oligopeptide-termini and a natural ligand, mannose, for targeted transfection of antigen presenting cells (APCs) such as Langerhans cells and macrophages in the dermal milieu. Our results reaffirmed terminal decoration of PBAEs with oligopeptide chains as a powerful tool to induce cell-specific transfection, identifying an outstanding candidate with a ten-fold increased transfection efficiency over commercial controls in vitro. The inclusion of mannose in the PBAE backbone rendered an additive effect and increased transfection levels, achieving superior gene expression in human monocyte-derived dendritic cells and other accessory antigen presenting cells. Moreover, top performing candidates were capable of mediating surface gene transfer when deposited as polyelectrolyte films onto transdermal devices such as microneedles, offering alternatives to conventional hypodermic administration. We predict that the use of highly efficient delivery vectors derived from PBAEs could advance clinical translation of nucleic acid vaccination over protein- and peptide-based strategies.

LOCUS (LOng Covid-Understanding Symptoms, events and use of services in Portugal): A three-component study protocol.

Approximately 10% of patients experience symptoms of Post COVID-19 Condition (PCC) after a SARS-CoV-2 infection. Akin acute COVID-19, PCC may impact a multitude of organs and systems, such as the cardiovascular, respiratory, musculoskeletal, and neurological systems. The frequency and associated risk factors of PCC are still unclear among both community and hospital settings in individuals with a history of COVID-19. The LOCUS study was designed to clarify the PCC's burden and associated risk factors. LOCUS is a multi-component study that encompasses three complementary building blocks. The "Cardiovascular and respiratory events following COVID-19" component is set to estimate the incidence of cardiovascular and respiratory events after COVID-19 in eight Portuguese hospitals via electronic health records consultation. The "Physical and mental symptoms following COVID-19" component aims to address the community prevalence of self-reported PCC symptoms through a questionnaire-based approach. Finally, the "Treating and living with Post COVID-19 Condition" component will employ semi-structured interviews and focus groups to characterise reported experiences of using or working in healthcare and community services for the treatment of PCC symptoms. This multi-component study represents an innovative approach to exploring the health consequences of PCC. Its results are expected to provide a key contribution to the optimisation of healthcare services design.

CD4 binding site immunogens elicit heterologous anti-HIV-1 neutralizing antibodies in transgenic and wild-type animals.

Passive transfer of broadly neutralizing anti-HIV-1 antibodies (bNAbs) protects against infection, and therefore, eliciting bNAbs by vaccination is a major goal of HIV-1 vaccine efforts. bNAbs that target the CD4 binding site (CD4bs) on HIV-1 Env are among the most broadly active, but to date, responses elicited against this epitope in vaccinated animals have lacked potency and breadth. We hypothesized that CD4bs bNAbs resembling the antibody IOMA might be easier to elicit than other CD4bs antibodies that exhibit higher somatic mutation rates, a difficult-to-achieve mechanism to accommodate Env's N276gp120 N-glycan, and rare five-residue light chain complementarity-determining region 3. As an initial test of this idea, we developed IOMA germline-targeting Env immunogens and evaluated a sequential immunization regimen in transgenic mice expressing germline-reverted IOMA. These mice developed CD4bs epitope-specific responses with heterologous neutralization, and cloned antibodies overcame neutralization roadblocks, including accommodating the N276gp120 glycan, with some neutralizing selected HIV-1 strains more potently than IOMA. The immunization regimen also elicited CD4bs-specific responses in mice containing polyclonal antibody repertoires as well as rabbits and rhesus macaques. Thus, germline targeting of IOMA-class antibody precursors represents a potential vaccine strategy to induce CD4bs bNAbs.

Root canal microbiota as an augmented reservoir of antimicrobial resistance genes in type 2 diabetes mellitus patients.

BACKGROUND: Antimicrobial resistance is a global public health problem. Root canal microbiota associated with apical periodontitis represents a well-known reservoir of antimicrobial resistance genes (ARGs). However, the effect of type 2 diabetes mellitus (T2DM) in this reservoir is unknown. This study aimed to establish if root canal microbiota associated with apical periodontitis in T2DM patients is an augmented reservoir by identifying the prevalence of nine common ARGs and comparing it with the prevalence in nondiabetic patients. METHODOLOGY: This cross-sectional study included two groups: A T2DM group conformed of 20 patients with at least ten years of living with T2DM and a control group of 30 nondiabetic participants. Premolar or molar teeth with pulp necrosis and apical periodontitis were included. A sample was collected from each root canal before endodontic treatment. DNA was extracted, and ARGs were identified by polymerase chain reaction. RESULTS: tetW and tetM genes were the most frequent (93.3 and 91.6%, respectively), while ermA was the least frequent (8.3%) in the total population. The distribution of the ARGs was similar in both groups, but a significant difference (p<0.005) was present in ermB, ermC, cfxA, and tetQ genes, being more frequent in the T2DM group. A total of eighty percent of the T2DM patients presented a minimum of four ARGs, while 76.6% of the control group presented a maximum of three. CONCLUSIONS: Root canal microbiota associated with apical periodontitis in T2DM patients carries more ARGs. Therefore, this pathological niche could be considered an augmented reservoir.

Continuous germinal center invasion contributes to the diversity of the immune response.

Antibody responses are characterized by increasing affinity and diversity over time. Affinity maturation occurs in germinal centers by a mechanism that involves repeated cycles of somatic mutation and selection. How antibody responses diversify while also undergoing affinity maturation is not as well understood. Here, we examined germinal center (GC) dynamics by tracking B cell entry, division, somatic mutation, and specificity. Our experiments show that naive B cells continuously enter GCs where they compete for T cell help and undergo clonal expansion. Consistent with late entry, invaders carry fewer mutations but can contribute up to 30% or more of the cells in late-stage germinal centers. Notably, cells entering the germinal center at later stages of the reaction diversify the immune response by expressing receptors that show low affinity to the immunogen. Paradoxically, the affinity threshold for late GC entry is lowered in the presence of high-affinity antibodies.

Antibody feedback regulates immune memory after SARS-CoV-2 mRNA vaccination.

Feedback inhibition of humoral immunity by antibodies was first documented in 19091. Subsequent studies showed that, depending on the context, antibodies can enhance or inhibit immune responses2,3. However, little is known about how pre-existing antibodies influence the development of memory B cells. Here we examined the memory B cell response in individuals who received two high-affinity anti-SARS-CoV-2 monoclonal antibodies and subsequently two doses of an mRNA vaccine4-8. We found that the recipients of the monoclonal antibodies produced antigen-binding and neutralizing titres that were only fractionally lower compared than in control individuals. However, the memory B cells of the individuals who received the monoclonal antibodies differed from those of control individuals in that they predominantly expressed low-affinity IgM antibodies that carried small numbers of somatic mutations and showed altered receptor binding domain (RBD) target specificity, consistent with epitope masking. Moreover, only 1 out of 77 anti-RBD memory antibodies tested neutralized the virus. The mechanism underlying these findings was examined in experiments in mice that showed that germinal centres formed in the presence of the same antibodies were dominated by low-affinity B cells. Our results indicate that pre-existing high-affinity antibodies bias germinal centre and memory B cell selection through two distinct mechanisms: (1) by lowering the activation threshold for B cells, thereby permitting abundant lower-affinity clones to participate in the immune response; and (2) through direct masking of their cognate epitopes. This may in part explain the shifting target profile of memory antibodies elicited by booster vaccinations9.

Early intervention with 3BNC117 and romidepsin at antiretroviral treatment initiation in people with HIV-1: a phase 1b/2a, randomized trial.

Attempts to reduce the human immunodeficiency virus type 1 (HIV-1) reservoir and induce antiretroviral therapy (ART)-free virologic control have largely been unsuccessful. In this phase 1b/2a, open-label, randomized controlled trial using a four-group factorial design, we investigated whether early intervention in newly diagnosed people with HIV-1 with a monoclonal anti-HIV-1 antibody with a CD4-binding site, 3BNC117, followed by a histone deacetylase inhibitor, romidepsin, shortly after ART initiation altered the course of HIV-1 infection ( NCT03041012 ). The trial was undertaken in five hospitals in Denmark and two hospitals in the United Kingdom. The coprimary endpoints were analysis of initial virus decay kinetics and changes in the frequency of CD4+ T cells containing intact HIV-1 provirus from baseline to day 365. Secondary endpoints included changes in the frequency of infected CD4+ T cells and virus-specific CD8+ T cell immunity from baseline to day 365, pre-ART plasma HIV-1 3BNC117 sensitivity, safety and tolerability, and time to loss of virologic control during a 12-week analytical ART interruption that started at day 400. In 55 newly diagnosed people (5 females and 50 males) with HIV-1 who received random allocation treatment, we found that early 3BNC117 treatment with or without romidepsin enhanced plasma HIV-1 RNA decay rates compared to ART only. Furthermore, 3BNC117 treatment accelerated clearance of infected cells compared to ART only. All groups had significant reductions in the frequency of CD4+ T cells containing intact HIV-1 provirus. At day 365, early 3BNC117 + romidepsin was associated with enhanced HIV-1 Gag-specific CD8+ T cell immunity compared to ART only. The observed virological and immunological effects of 3BNC117 were most pronounced in individuals whose pre-ART plasma HIV-1 envelope sequences were antibody sensitive. The results were not disaggregated by sex. Adverse events were mild to moderate and similar between the groups. During a 12-week analytical ART interruption among 20 participants, 3BNC117-treated individuals harboring sensitive viruses were significantly more likely to maintain ART-free virologic control than other participants. We conclude that 3BNC117 at ART initiation enhanced elimination of plasma viruses and infected cells, enhanced HIV-1-specific CD8+ immunity and was associated with sustained ART-free virologic control among persons with 3BNC117-sensitive virus. These findings strongly support interventions administered at the time of ART initiation as a strategy to limit long-term HIV-1 persistence.

Administration of broadly neutralizing anti-HIV-1 antibodies at ART initiation maintains long-term CD8+ T cell immunity.

In simian-human immunodeficiency virus (SHIV)-infected non-human primates, broadly neutralizing antibodies (bNAbs) against the virus appear to stimulate T cell immunity. To determine whether this phenomenon also occurs in humans we measured HIV-1-specific cellular immunity longitudinally in individuals with HIV-1 starting antiviral therapy (ART) with or without adjunctive bNAb 3BNC117 treatment. Using the activation-induced marker (AIM) assay and interferon-γ release, we observe that frequencies of Pol- and Gag-specific CD8+ T cells, as well as Gag-induced interferon-γ responses, are significantly higher among individuals that received adjunctive 3BNC117 compared to ART-alone at 3 and 12 months after starting ART. The observed changes in cellular immunity were directly correlated to pre-treatment 3BNC117-sensitivity. Notably, increased HIV-1-specific immunity is associated with partial or complete ART-free virologic control during treatment interruption for up to 4 years. Our findings suggest that bNAb treatment at the time of ART initiation maintains HIV-1-specific CD8+ T cell responses that are associated with ART-free virologic control.

Distinct gene expression by expanded clones of quiescent memory CD4+ T cells harboring intact latent HIV-1 proviruses.

Antiretroviral therapy controls, but does not cure, HIV-1 infection due to a reservoir of rare CD4+ T cells harboring latent proviruses. Little is known about the transcriptional program of latent cells. Here, we report a strategy to enrich clones of latent cells carrying intact, replication-competent HIV-1 proviruses from blood based on their expression of unique T cell receptors. Latent cell enrichment enabled single-cell transcriptomic analysis of 1,050 CD4+ T cells belonging to expanded clones harboring intact HIV-1 proviruses from 6 different individuals. The analysis reveals that most of these cells are T effector memory cells that are enriched for expression of HLA-DR, HLA-DP, CD74, CCL5, granzymes A and K, cystatin F, LYAR, and DUSP2. We conclude that expanded clones of latent cells carrying intact HIV-1 proviruses persist preferentially in a distinct CD4+ T cell population, opening possibilities for eradication.

Memory B cell responses to Omicron subvariants after SARS-CoV-2 mRNA breakthrough infection in humans.

Individuals who receive a third mRNA vaccine dose show enhanced protection against severe COVID-19, but little is known about the impact of breakthrough infections on memory responses. Here, we examine the memory antibodies that develop after a third or fourth antigenic exposure by Delta or Omicron BA.1 infection, respectively. A third exposure to antigen by Delta breakthrough increases the number of memory B cells that produce antibodies with comparable potency and breadth to a third mRNA vaccine dose. A fourth antigenic exposure with Omicron BA.1 infection increased variant-specific plasma antibody and memory B cell responses. However, the fourth exposure did not increase the overall frequency of memory B cells or their general potency or breadth compared to a third mRNA vaccine dose. In conclusion, a third antigenic exposure by Delta infection elicits strain-specific memory responses and increases in the overall potency and breadth of the memory B cells. In contrast, the effects of a fourth antigenic exposure with Omicron BA.1 are limited to increased strain-specific memory with little effect on the potency or breadth of memory B cell antibodies. The results suggest that the effect of strain-specific boosting on memory B cell compartment may be limited.