Nuclear translocation of the membrane oxoeicosanoid/androgen receptor, OXER1: Possible mechanisms involved.

OXER1, the receptor for the arachidonic acid metabolite 5-οxo-eicosatetraenoic acid (5-oxo-ETE), has been reported to also bind and mediate the membrane-initiated actions of androgens. Indeed, androgens antagonize the 5-oxo-ETE effects through OXER1, affecting a number of signaling pathways and inhibiting cancer cell proliferation and migration. OXER1, being a GPCR, was classically described to be localized in the plasma membrane. However, for numerous GPCRs, there is now strong evidence that they can be also found in other cellular compartments, including the nucleus. The aim of the present work was to investigate OXER1's possible localization in the nucleus and identify the mechanism(s) involved. For this purpose, we verified OXER1's nuclear presence by immunofluorescence and western blot, in whole cells and nuclei of two different prostate cancer cell lines (DU-145 and LNCaP) and in CHO cells transfected with a GFP labelled OXER1, both in untreated and OXER1 ligands' treated cells. Mutated, OXER1-tGFP expressing, CHO cells were used to verify that OXER1 agonist (5-oxo-ETE) binding is necessary for OXER1 nuclear translocation. NLS sequences were in silico identified, and a specific inhibitor, as well as, specific importins' siRNAs were also utilized to explore the mechanism involved. Moreover, we examined the role of palmitoylation in OXER1 nuclear translocation by in silico identifying possible palmitoylation sites and using a palmitoylation inhibitor. Our results clearly show that OXER1 can be localized in the nucleus, in an agonist-dependent manner, that is inhibited by androgens. We also provide evidence for two possible mechanisms for its nuclear trafficking, that involve receptor palmitoylation and importin-mediated cytoplasmic-nuclear transport. In our knowledge, it is the first time that a membrane androgen receptor is identified into the nucleus, suggesting an alternative, more direct, mode of action, involving nuclear mechanisms. Therefore, our findings provide new insights on androgen-mediated actions and androgen-lipid interactions, and reveal new possible therapeutic targets, not only for cancer, but also for other pathological conditions in which OXER1 may have an important role.

Evaluation of the influenza-like illness case definition and the acute respiratory infection case definition in the diagnosis of influenza and COVID-19 in healthcare personnel.

BACKGROUND: To evaluate the influenza-like illness (ILI) and acute respiratory infection (ARI) case definitions in the diagnosis of COVID-19 and influenza in healthcare personnel (HCP). METHODS: We followed a cohort of 5752 HCP from November 2022 to May 2023. Symptomatic HCP were tested for SARS-CoV-2 and influenza by real-time PCR and/or rapid antigen detection test. ILI was defined as the sudden onset of ≥1 systemic symptom and ≥1 respiratory symptom. ARI was defined as the sudden onset of ≥1 respiratory symptom. Patients with respiratory symptoms were grouped either as ILI or as ARI based on the presence of fever, malaise, headache and/or myalgia. RESULTS: Overall, 466 ILI cases and 383 ARI cases occurred. HCP with ILI had an adjusted odds ratio (aOR) of 22.05 [95% confidence interval (CI): 6.23-78.04] to be diagnosed with influenza. HCP with ARI had an aOR of 2.70 (95% CI: 1.88-3.88) to be diagnosed with COVID-19. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of ILI for influenza were 96.6%, 49.9%, 18.2%, and 99.2%, respectively. The sensitivity, specificity, PPV, and NPV of ARI for COVID-19 were 51.7%, 73.6%, 84.9%, and 34.8%, respectively. ILI and ARI had an overall correct classification rate of 89.6% and 74.1%, respectively. CONCLUSION: Our findings support the use of both ILI and ARI case definitions in the diagnosis of influenza and COVID-19 in HCP.

An Overview on the Synthesis of Lamellarins and Related Compounds with Biological Interest.

Lamellarins are natural products with a [3,4]-fused pyrrolocoumarin skeleton possessing interesting biological properties. More than 70 members have been isolated from diverse marine organisms, such as sponges, ascidians, mollusks, and tunicates. There is a continuous interest in the synthesis of these compounds. In this review, the synthetic strategies for the synthesis of the title compounds are presented along with their biological properties. Three routes are followed for the synthesis of lamellarins. Initially, pyrrole derivatives are the starting or intermediate compounds, and then they are fused to isoquinoline or a coumarin moiety. Second, isoquinoline is the starting compound fused to an indole moiety. In the last route, coumarins are the starting compounds, which are fused to a pyrrole moiety and an isoquinoline scaffold. The synthesis of isolamellarins, azacoumestans, isoazacoumestans, and analogues is also described. The above synthesis is achieved via metal-catalyzed cross-coupling, [3 + 2] cycloaddition, substitution, and lactonization reactions. The title compounds exhibit cytotoxic, multidrug resistance (MDR), topoisomerase I-targeted antitumor, anti-HIV, antiproliferative, anti-neurodegenerative disease, and anti-inflammatory activities.

Characteristics of trans and non-binary children and adolescents who attended a tertiary hospital. / Características de niños, niñas y adolescentes trans y no binarios atendidos en un hospital de tercer nivel.

Introduction. The trans population in Argentina represents 0.43%. Our objective was to describe the characteristics of trans and non-binary children and adolescents. Population and methods. A cross-sectional study was designed. The population was all trans or nonbinary persons under 24 years of age seen by an interdisciplinary team in a tertiary university hospital from January 2019 to May 2023. The sample was obtained from the database of patients seen by reviewing electronic medical records (EMR). Results. The EMRs of 107 individuals were analyzed; the average age at first consultation was 15.3 years, and the age of self-perceived transgender identity was 11.1 years. Seventy-two percent perceived themselves as having a trans male identity; in 89.7%, their gender expression was by their self-perception, and 46.3% had a bisexual sexual orientation. Seventy-six percent acknowledged having family support; 87.3%, school support; and 92.5%, peer support. 44.8% had a hormonal strategy, 14.1% had surgery, 57.1% had mental health intervention, and 29.1% received psychiatric medication. Only three patients (2.8%) detransitioned their gender identity. Conclusion. Most individuals were trans men and perceived good support from their environments. Almost half received a hormonal strategy; less than a quarter received a surgical intervention; more than half received a mental health intervention. The detransition was infrequent.

Introducción. La población trans en Argentina representa el 0,43 %. Nuestro objetivo fue describir las características de niñas, niños y adolescentes trans y no binarios. Población y métodos. Se diseñó un estudio de corte transversal. La población fueron todas las personas menores de 24 años trans o no binarias atendidas por un equipo interdisciplinario en un hospital universitario de tercer nivel desde enero de 2019 hasta mayo de 2023. La muestra se obtuvo de la base de datos de pacientes atendidos a través de la revisión de las historias clínicas electrónicas (HCE). Resultados. Se analizaron las HCE de 107 personas; el promedio de la primera consulta fue 15,3 años y la edad de autopercepción de identidad de género trans, 11,1 años. El 72 % se percibió con una identidad varón trans; en el 89,7 %, su expresión de género fue acorde a su autopercepción y el 46,3 % tuvo una orientación sexual bisexual. El 76 % reconoció tener contención familiar; el 87,3 %, contención escolar; y el 92,5 %, contención de sus pares. El 44,8 % realizó una estrategia hormonal; el 14,1 %, intervención quirúrgica; el 57,1 %, intervención con salud mental; y el 29,1 % recibió medicación psiquiátrica. Solo 3 pacientes (2,8 %) detransicionaron su identidad de género. Conclusión. La mayoría de las personas eran varones trans y percibieron una buena contención de sus entornos. Casi la mitad recibió una estrategia hormonal; menos de un cuarto, una intervención quirúrgica; más de la mitad, una intervención con salud mental. La detransición fue infrecuente.

Development and evaluation of a TaqMan® real-time PCR assay for species-specific detection of Ehrlichia canis.

The aim of this work was to develop a real-time PCR assay with a TaqMan® probe that detects a species-specific part of the 16S rDNA gene of Ehrlichia canis. Canine blood samples (n = 207), collected and tested by a conventional PCR assay within a study conducted by De Salvo et al., were simultaneously analyzed with the novel designed real-time PCR, and the results of both assays were compared. The agreement between the two methods was 97.6 % with a kappa value of 0.92186. Hereby, the standard error was 0.034416 and the 95 % confidence interval from 0.8544 to 0.98931. While the conventional PCR assay showed false negative results (2.42 %; 5/207), the real-time PCR assays showed a specificity of 100 %. The results of the current study showed that the developed assay presents sensitivity and specificity for the detection of E. canis in blood samples, adding a new tool for the diagnosis of this pathogen.

Knowledge, Attitudes, and Perceptions of Maternity Care Providers on the Implementation of Calcium Supplementation during Pregnancy in Three Public Hospitals in Argentina: A Qualitative Study.

The aim of this study was to explore maternity care providers' knowledge, attitudes, and perceptions about the use of calcium supplements during pregnancy for the prevention of preeclampsia in three hospitals from Metropolitan Buenos Aires, Argentina. We conducted semi-structured interviews and followed a thematic analysis framework. Maternity care providers' knowledge, attitudes, and practices regarding calcium supplementation during pregnancy are linked to barriers to the potential implementation of calcium supplementation. Free provision of calcium supplements by the government, coupled with training that reinforces the scientific evidence supporting their use to prevent preeclampsia, along with documented recommendations from credible sources, would be crucial to ensure that health providers adopt the use of calcium supplements in antenatal care. Future studies should assess pregnant women and policymakers' perceptions about calcium supplementation during pregnancy, as well as local infrastructure to provide access to free-of-charge calcium supplements in antenatal care settings. Economic evaluation with local information could inform policymakers and advocate for the implementation of strategies to reduce preeclampsia.

Evaluation of postoperative delirium in geriatric patients given acetaminophen with and without melatonin: A retrospective cohort study.

OBJECTIVE: Postoperative delirium has many consequences and should be prevented when possible. Non-opioid pain treatments have known delirium prevention benefits, while melatonin has promising prevention data in non-surgical populations. The incidence of postoperative delirium was retrospectively compared in patients prescribed acetaminophen with and without melatonin following orthopedic surgery. METHODS: Retrospective data was analyzed in adults ≥65-years-old who were hospitalized within one health system following an orthopedic procedure. Patients receiving at least acetaminophen 1000 mg/day with and without melatonin 1 mg/day for at least 48 hours perioperatively were included. Patients were excluded if they had prior delirium, an intensive care unit placement >24 hours, or other risk factors for developing delirium to reduce confounders. The primary outcome was delirium incidence or positive CAM-ICU score. Key secondary endpoints included hospital length of stay and 30-day hospital readmission. RESULTS: Two hundred patients were assessed, and 134 patients were included in the analysis (ie, 66 acetaminophen plus melatonin, 68 acetaminophen alone). There was a lower rate of delirium when comparing the combination vs acetaminophen alone (5% vs 25%; P = 0.001). There were no differences in 30-day readmission. Patients taking the combination had a longer length of stay than acetaminophen alone (5 vs 4 days; P = 0.04). CONCLUSION: Geriatric patients taking acetaminophen plus melatonin after orthopedic surgery had a significantly lower risk of delirium than patients receiving acetaminophen alone. Using combination melatonin and acetaminophen before orthopedic surgery is a promising delirium prevention strategy and should be considered in future prospective trials.

[Recommendations about immunizations in patients with inborn errors of immunity]. / Recomendaciones para la inmunización de pacientes con errores innatos de la inmunidad.

Inborn errors of immunity (IEI) are a heterogeneous group of hereditary disorders that affect in number and/or function different components of the immune system, resulting in an increased risk and severity of infections, autoimmune diseases, allergic manifestations, autoinflammation and malignancy. Inactivated vaccines are generally safe in these patients, but may be ineffective in some cases, due to difference in immunogenicity. However, live viral and bacterial vaccines may lead to disease, with high morbidity and mortality, so it is essential a previous immunological work-out. In this document, the Pediatric Immunology Work Group of the Sociedad Argentina de Pediatría summarizes recommendations about immunizations in patients with IEI, their household contacts, as well as in patients under immunosuppressive treatment and hematopoietic stem cell transplant recipients.

Los errores innatos de la inmunidad (EII) constituyen un grupo heterogéneo de enfermedades hereditarias que afectan el número y/o la función de los distintos componentes del sistema inmune, lo que predispone a un incremento de la tasa y gravedad de infecciones, enfermedades autoinmunes, manifestaciones alérgicas, autoinflamación y malignidad. En estos pacientes, la inmunización con vacunas inactivadas es generalmente segura, pero puede no ser efectiva en determinados grupos de EII, sin generar el efecto protector deseado. La aplicación de vacunas vivas atenuadas (virales y bacterianas) puede llevar al desarrollo de enfermedad asociada a la inmunización, con elevada morbimortalidad, por lo que amerita previamente consultar al especialista. El presente informe resume las conclusiones del Grupo de Trabajo de Inmunología de la Sociedad Argentina de Pediatría respecto a la vacunación en pacientes con EII y sus convivientes, en pacientes bajo inmunosupresión farmacológica y en receptores de trasplante de células precursoras hematopoyéticas.

Targeting cargo to an unconventional secretory system within megakaryocytes allows the release of transgenic proteins from platelets.

BACKGROUND: Platelets are essential for hemostasis and thrombosis and play vital roles during metastatic cancer progression and infection. Hallmarks of platelet function are activation, cytoskeletal rearrangements, and the degranulation of their cellular contents upon stimulation. While α-granules and dense granules are the most studied platelet secretory granules, the dense tubular system (DTS) also functions as a secretory system for vascular thiol isomerases. However, how DTS cargo is packaged and transported from megakaryocytes (MKs) to platelets is poorly understood. OBJECTIVES: To underpin the mechanisms responsible for DTS cargo transport and leverage those for therapeutic protein packaging into platelets. METHODS: A retroviral expression system combined with immunofluorescence confocal microscopy was employed to track protein DTS cargo protein disulfide isomerase fused to enhanced green fluorescent protein (eGFP-PDI) during platelet production. Murine bone marrow transplantation models were used to determine the release of therapeutic proteins from platelets. RESULTS: We demonstrated that the endoplasmic reticulum retrieval motif Lys-Asp-Glu-Leu (KDEL) located at the C-terminus of protein disulfide isomerase was essential for the regular transport of eGFP-PDI-containing granules. eGFP-PDIΔKDEL, in which the retrieval signal was deleted, was aberrantly packaged, and its expression was upregulated within clathrin-coated endosomes. Finally, we found that ectopic transgenic proteins, such as tissue factor pathway inhibitor and interleukin 2, can be packaged into MKs and proplatelets by adding a KDEL retrieval sequence. CONCLUSION: Our data corroborate the DTS as a noncanonical secretory system in platelets and demonstrate that in vitro-generated MKs and platelets may be used as a delivery system for transgenic proteins during cellular therapy.

The Effect of the COVID-19 Pandemic on the Family and Community Medicine Residency Training Program: The Philippine Experience.

Background: The COVID-19 pandemic had a profound impact on medical education, particularly in Family and Community Medicine training programs. This study aimed to assess the impact in the Philippines by comparing the number of cases and procedures before and during the pandemic, as well as the adaptations made by these programs. Objective: The objective of this study was to determine the effect of the COVID-19 pandemic on Family and Community Medicine training in the Philippines by comparing the average number of cases and procedures done before and during the pandemic and the changes implemented by the different accredited training programs. Methods: A cross-sectional study utilizing an explanatory sequential mixed methods approach was undertaken. The quantitative portion collected data on cases and procedures from the participating institutions' residents using the standardized checklist of the Philippine Academy of Family Physicians. The qualitative portion was done through a focused group discussion (FGD) following a prepared set of FGD questions. Analysis of variation (ANOVA) was used to compare the average cases seen and procedures across the four years and content analysis for the qualitative data. Results: There was a significant decrease in the average number of adult and pediatric cases during the pandemic years (2020-2021) compared to before (2018-2019). Various organ systems cases such as neurology, ophthalmology, dermatology, and gastrointestinal, showed significant differences (p-value <0.05) in the average number of pediatric cases. For adult cases, significant differences (p-value <0.05) were found for several organ system cases when comparing the years before (2018-2019) and during the pandemic (2020-2021), including neurology, ophthalmology, ENT, dermatology, cardiology, gastrointestinal, genitourinary, reproductive health, musculoskeletal, and endocrinology cases. The trainers adjusted training activities to support the hospital's COVID-19 response and that prompted an abrupt shift to online strategies for patient consultations, teaching sessions, and examinations. Conclusion: The COVID-19 pandemic led to a reduction in the variety of cases and procedures in Family and Community Medicine training, impacting the fulfillment of specialty training requirements. However, it also drove innovation through the integration of technology, including online teaching methods. These experiences underscore the importance of resilience and adaptability in medical education and offer valuable lessons for future training programs, potentially leading to improvements in training and patient care through innovative methodologies.

luxA Gene From Enhygromyxa salina Encodes a Functional Homodimeric Luciferase.

Several clades of luminescent bacteria are known currently. They all contain similar lux operons, which include the genes luxA and luxB encoding a heterodimeric luciferase. The aldehyde oxygenation reaction is presumed to be catalyzed primarily by the subunit LuxA, whereas LuxB is required for efficiency and stability of the complex. Recently, genomic analysis identified a subset of bacterial species with rearranged lux operons lacking luxB. Here, we show that the product of the luxA gene from the reduced luxACDE operon of Enhygromyxa salina is luminescent upon addition of aldehydes both in vivo in Escherichia coli and in vitro. Overall, EsLuxA is much less bright compared with luciferases from Aliivibrio fischeri (AfLuxAB) and Photorhabdus luminescens (PlLuxAB), and most active with medium-chain C4-C9 aldehydes. Crystal structure of EsLuxA determined at the resolution of 2.71 Å reveals a (ß/α)8 TIM-barrel fold, characteristic for other bacterial luciferases, and the protein preferentially forms a dimer in solution. The mobile loop residues 264-293, which form a ß-hairpin or a coil in Vibrio harveyi LuxA, form α-helices in EsLuxA. Phylogenetic analysis shows EsLuxA and related proteins may be bacterial protoluciferases that arose prior to duplication of the luxA gene and its speciation to luxA and luxB in the previously described luminescent bacteria. Our work paves the way for the development of new bacterial luciferases that have an advantage of being encoded by a single gene.

Incidence and prevalence of primary biliary cholangitis in the Netherlands - A nationwide cohort study.

Background & Aims: Although primary biliary cholangitis (PBC) is considered a rare disorder, accurate determination of its incidence and prevalence remains challenging due to limited comprehensive population-based registries. We aimed to assess the incidence and prevalence of PBC in the Netherlands over time through the nationwide Dutch PBC Cohort Study (DPCS). Methods: DPCS retrospectively included every identifiable patient with PBC in the Netherlands from 1990 onwards in all 71 Dutch hospitals. Incidence and prevalence were assessed between 2008-2018 by Poisson regression between sex and age groups over time. Results: On the 1st of January 2008, there were 1,458 patients with PBC in the Netherlands. Between 2008-2018, 2,187 individuals were newly diagnosed, 46 were transplanted and 468 died. The yearly incidence of PBC in 2008 was 1.38, increasing to 1.74 per 100,000 persons in 2018. When compared to those aged <45 years, females aged 45-64 years (adjusted incidence rate ratio 4.21, 95% CI 3.76-4.71, p <0.001) and males ≥65 years (adjusted incidence rate ratio 14.41, 95% CI 9.62-21.60, p <0.001) were at the highest risk of being diagnosed with PBC. The male-to-female ratio of patients newly diagnosed with PBC during the study period was 1:14 in those <45 years, 1:10 in patients aged 45-64 years, and 1:4 in those ≥65 years. Point prevalence increased from 11.9 in 2008 to 21.5 per 100,000 persons in 2018. Average annual percent change in this time period was 5.94% (95% CI 5.77-6.15, p <0.05), and was the highest among the population aged ≥65 years (5.69%, 95% CI 5.32-6.36, p <0.001). Conclusions: In this nationwide cohort study, we observed an increase in both the incidence and prevalence of PBC in the Netherlands over the past decade, with marked age and sex differences. Impact and implications: This nationwide Dutch primary biliary cholangitis (PBC) Cohort Study, including all hospitals in the Netherlands, showed that the incidence and prevalence of PBC have increased over the last decade. The age-dependent PBC incidence rate differed for males (highest risk ≥65 years) and females (highest risk between 45 and 65 years), which may be related to a difference in the timing of exposure to environmental triggers of PBC. The largest increase in PBC prevalence over time was observed in the population aged ≥65 years, which may have implications for the use of second-line therapies. These results therefore indicate that further studies are needed to elaborate on the advantages and disadvantages of add-on therapies in the elderly population.

Monitoring of meat quality and change-point detection by a sensor array and profiling of bacterial communities.

BACKGROUND: Real-time monitoring of food consumer quality remains challenging due to diverse bio-chemical processes taking place in the food matrices, and hence it requires accurate analytical methods. Thresholds to determine spoiled food are often difficult to set. The existing analytical methods are too complicated for rapid in situ screening of foodstuff. RESULTS: We have studied the dynamics of meat spoilage by electronic nose (e-nose) for digitizing the smell associated with volatile spoilage markers of meat, comparing the results with changes in the microbiome composition of the spoiling meat samples. We apply the time series analysis to follow dynamic changes in the gas profile extracted from the e-nose responses and to identify the change-point window of the meat state. The obtained e-nose features correlate with changes in the microbiome composition such as increase in the proportion of Brochothrix and Pseudomonas spp. and disappearance of Mycoplasma spp., and with representative gas sensors towards hydrogen, ammonia, and alcohol vapors with R2 values of 0.98, 0.93, and 0.91, respectively. Integration of e-nose and computer vision into a single analytical panel improved the meat state identification accuracy up to 0.85, allowing for more reliable meat state assessment. SIGNIFICANCE: Accurate identification of the change-point in the meat state achieved by digitalizing volatile spoilage markers from the e-nose unit holds promises for application of smart miniaturized devices in food industry.

Caregivers' perspectives of early developmental tele-assessments in challenging circumstances.

BACKGROUND:  Outbreaks, such as the COVID-19 pandemic in 2020, exacerbate barriers to accessing early childhood developmental care. Tele-assessment may serve as an innovative approach to developmental monitoring to overcome service delivery amidst challenging circumstances. It is vital to collect caregivers' perspectives of this potential service delivery method to inform clinical decision making. OBJECTIVES:  This study aimed to determine caregivers' perspectives of interview-based early developmental tele-assessment in a South African context. METHOD:  Thirty caregivers of children (aged birth - 36 months) completed a caregiver-report developmental assessment via a telecommunications platform, as well as an online questionnaire probing their perspectives on the tele-assessment. RESULTS:  Most participants (96.7%, n = 29 out of 30) rated their overall experience of the tele-assessment as positive; however, 53.8% (n = 14 out of 26 that answered the question) indicated that they would additionally still prefer in-person assessment. CONCLUSION:  Tele-assessment appears to be a viable approach for caregivers to access developmental care during circumstances such as COVID-19.Contribution: This study provided valuable insight into a novel approach using interview-based early developmental tele-assessment and the perspectives of caregivers thereof.

Association of Vessel Fractional Flow Reserve (vFFR) with Luminal Obstruction and Plaque Characteristics as Detected by Optical Coherence Tomography (OCT) in Patients With NSTE-ACS: the FAST OCT Study.

AIMS: There is a paucity of data on the performance of angiography-derived vessel fractional flow reserve (vFFR) in coronary artery lesions of patients presenting with non-ST-segment elevation acute coronary syndrome (NSTE-ACS). Optical coherence tomography (OCT) allows for visualization of lumen dimensions and plaque integrity with high resolution. The aim of the present study was to define the association between vFFR and OCT findings in intermediate coronary artery lesions in patients presenting with NSTE-ACS. METHODS AND RESULTS: The FAST OCT study was a prospective, multicenter, single-arm study. Patients presenting with NSTE-ACS with intermediate to severe coronary artery stenosis in one or multiple vessels with TIMI 3 flow suitable for OCT imaging were eligible. Complete pre-procedural vFFR and OCT data were available in 226 vessels (in 188 patients). A significant association between vFFR and minimal lumen area (MLA) was observed, showing an average decrease of 20.4% (95% CI -23.9% - -16.7%) in MLA per 0.10 decrease in vFFR (adjusted p<0.001). vFFR≤0.80 showed a sensitivity of 56.7% and specificity of 92.5% to detect MLA≤2.5 mm². Conversely, vFFR had a poor to moderate discriminative ability to detect plaque instability (sensitivity, 46.9% specificity 71.6%). CONCLUSIONS: In patients with NSTE-ACS, vFFR is significantly associated with OCT-detected MLA and a vFFR≤0.80 is highly predictive for the presence of significant disease based on OCT. Conversely, the sensitivity of vFFR≤0.80 to detect OCT-assessed significant disease was low, indicating that the presence of significant OCT findings cannot be ruled out based on a negative vFFR. CLINICALTRIALS.GOV ID: NCT04683133.

Efficacy of Tixagevimab/Cilgavimab as Pre-Exposure Prophylaxis against Infection from SARS-CoV-2 and Severe COVID-19 among Heavily Immunocompromised Patients: A Single-Center, Prospective, Real-World Study.

BACKGROUND: COVID-19 continues to pose a threat to immunocompromised individuals, even with vaccination. The monoclonal antibodies (mAbs) tixagevimab/cilgavimab (TXG/CIL) provide targeted prophylaxis against SARS-CoV-2 with the benefit of a prolonged half-life. Although approved for COVID-19 prevention, there is limited data on their effectiveness among heavily immunocompromised populations. METHODS: We conducted a prospective, observational study at Laiko General Hospital, Athens, Greece, from August to December 2022 to investigate the efficacy of TXG/CIL as a form of pre-exposure prophylaxis in immunocompromised patients. Data on breakthrough SARS-CoV-2 infections were collected over a six-month follow-up period. RESULTS: Of the 375 participants (mean age 61.3 ± 14.1 years; 59.7% male), 76 (20.3%) developed breakthrough SARS-CoV-2 infections, with an incidence of 3.81 cases/100 patient months. Hospitalization was required for 21 patients (5.6%), with a median stay of 14 days. Seven deaths were recorded, with only one attributed to COVID-19. Previous infection (OR 0.46, 95% CI 0.26-0.82) and hybrid immunity (OR 0.52, 95% CI 0.29-0.92) can protect against new infection. Solid organ malignancy significantly increased the risk of severe outcomes among those infected (OR 7.4, 95% CI 2.2-24.7, p = 0.001). CONCLUSIONS: TXG/CIL provides effective prophylaxis against COVID-19 in immunocompromised patients. Future strategies should focus on developing new mAb combinations to address emerging SARS-CoV-2 variants and protect vulnerable populations.

Phenotypes of regulatory T cells in different stages of COPD.

BACKGROUND: Previous studies have shown that failure to control inflammatory processes mediated by regulatory T (Treg) cells contributes to chronic obstructive pulmonary disease (COPD) development and progression. The activity of Treg cells depends on their phenotypic characteristics: resting Treg (rTreg, CD3+CD4+CD25+FOXP3+CD25++CD45RA+) and activated Treg (aTreg, CD3+CD4+CD25+FOXP3+CD25+++CD45RA-) cells exhibit immunosuppressive activity, while cytokine-secreting T cells (FrIII, CD3+CD4+CD25+FOXP3+CD25++CD45RA-) exhibit proinflammatory activity. Previous findings have shown an increased density of cytokine-secreting T cells in COPD patients experiencing exacerbation. However, the methods for evaluating COPD under stable conditions are lacking. AIM: To evaluate Treg cell phenotypes in patients with different stages of COPD under stable conditions. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from non-obstructed smokers and ex-smokers (NOS group, n = 19) and COPD patients at different stages (COPD I-II group, n = 25; COPD III-IV group, n = 25). The phenotypic characteristics of Treg cells and Th17 cells and their respective intracellular cytokines were analyzed by flow cytometry. RESULTS: Both obstructed groups showed an increase in the proportion of rTregs, while the COPD III-IV group showed additional increases in total Treg and Th17 cells and in IL-10+ cells. There was an increase in proinflammatory mediators (CD3+CD4+IL-17+ cells; CD3+CD4+RORγt+ cells) in the COPD I-II group. In contrast, the NOS group demonstrated high proportions of proinflammatory Treg cells and proinflammatory CD8+ T cells (CD3+CD8+IL-17+). CONCLUSION: Despite the increase in both total Treg cells and the rTreg phenotype from the early stages of COPD, there was a decrease in cells expressing IL-10, suggesting a failure in controlling the inflammatory process. These events precede the progression of the inflammatory process mediated by Th17 cells.

'Manopause': sexual response changes as a threat to ageing manhood.

When men root manhood in sexual performance, their inability to get and maintain an erection (i.e. erectile dysfunction) may pose a threat to ageing men's ability to enact masculinity. Using data from the 2015-2016 National Social Life, Health and Aging Project (NSHAP) - a nationally representative survey of the USA - this study finds that age and erectile dysfunction interact: men who report 'trouble getting or maintaining an erection' have a higher odds of reporting anxiety before sex. However, this effect gradually declines as the sample of men with erectile dysfunction ages (from ages 49 to 95). Additionally, men who do not report erectile dysfunction have the same odds of sex-anxiety throughout the sample, regardless of their age. The change in sexual performance may cause distress for men, as they feel unable to maintain their dominant masculinity in old age. While previous studies have shown that age and gender interact to affect men's sexual health in mid-life and later-life, this study adds to the feminist gerontology literature by providing indirect evidence that changes in sexual response may become gradually less anxiety-inducing, and thereby, less threatening for men as they age.

Equal Maintenance of Anti-SARS-CoV-2 Antibody Levels Induced by Heterologous and Homologous Regimens of the BNT162b2, ChAdOx1, CoronaVac and Ad26.COV2.S Vaccines: A Longitudinal Study Up to the 4th Dose of Booster.

Several technological approaches have been used to develop vaccines against COVID-19, including those based on inactivated viruses, viral vectors, and mRNA. This study aimed to monitor the maintenance of anti-SARS-CoV-2 antibodies in individuals from Brazil according to the primary vaccination regimen, as follows: BNT162b2 (group 1; 22) and ChAdOx1 (group 2; 18). Everyone received BNT162b2 in the first booster while in the second booster CoronaVac, Ad26.COV2.S, or BNT162b2. Blood samples were collected from 2021 to 2023 to analyze specific RBD (ELISA) and neutralizing antibodies (PRNT50). We observed a progressive increase in anti-RBD and neutralizing antibodies in each subsequent dose, remaining at high titers until the end of follow-up. Group 1 had higher anti-RBD antibody titers than group 2 after beginning the primary regimen, with significant differences after the 2nd and 3rd doses. Group 2 showed a more expressive increase after the first booster with BNT162B2 (heterologous booster). Group 2 also presented high levels of neutralizing antibodies against the Gamma and Delta variants until five months after the second booster. In conclusion, the circulating levels of anti-RBD and neutralizing antibodies against the two variants of SARS-CoV-2 were durable even five months after the 4th dose, suggesting that periodic booster vaccinations (homologous or heterologous) induced long-lasting immunity.

Rabies virus circulation in a highly diverse bat assemblage from a high-risk area for zoonoses outbreaks in the Brazilian Amazon.

Bats are the second most diverse order of mammals and play a central role in ecosystem dynamics. They are also important reservoirs of potentially zoonotic microorganisms, of which rabies virus is the most lethal among the bat-transmitted zoonotic pathogens. Importantly, recent outbreaks of human rabies have been reported from the Brazilian Amazon. Here we present a survey of bat species and rabies virus (RABV) circulation in a bat assemblage in the Marajó region, northern Brazil. Using data from mist-net captures and bioacoustic sampling, 56 bat species were recorded along the Jacundá River basin over a 10-day expedition in November 2022. For the investigation of RABV, we used the direct fluorescent antibody test (DFAT) and the rapid fluorescent focus inhibition test (RFFIT). In total, 159 bat individuals from 22 species were investigated for RABV. Five adults of the common vampire bat, Desmodus rotundus, showed RABV-specific antibodies in serum samples. Additionally, we report on local residents with injuries caused by D. rotundus bites and the occurrence of colonies of non-hematophagous bats from different species roosting inside human residences. This scenario raises concerns about the risks of new cases of human rabies and other zoonotic diseases associated with bats in the region and highlights the need for epidemiological surveillance and mitigation measures to prevent outbreaks of emerging infectious diseases.