Effect of recombinant bovine granulocyte colony-stimulating factor treatment during the peripartum period on postpartum diseases, reproductive performance, and milk production in Holstein cattle.

To boost the immune function around parturition, recombinant bovine granulocyte colony-stimulating factor (rbG-CSF) has been used to increase the number of neutrophils. Therefore, the aim of this study was to quantify the effect of rbG-CSF administration on the incidence of postpartum pathologies, reproductive performance, and milk production during the first three months of lactation. A total of 199 Holstein cows from one herd were included and were randomly allocated into two groups: Control (n = 103) and rbG-CSF (n = 96). Cows in the rbG-CSF group received 2 doses of a rbG-CSF injectable formulation, one 7 days before the expected date of calving and the other within 24 h after calving. For 6 weeks following calving, animals were examined weekly to assess the presence of postpartum pathologies. Milk production, protein and fat content, and somatic cell count were determined monthly by the regional dairy herd improvement association. Data about the reproductive performance were collected from on-farm software. To analyse the effect of treatment on the incidence of postpartum pathologies, Pearson's χ2 test and multivariable logistic regressions were performed. The effect on reproductive performance was analysed using Cox proportional hazard regression analysis for days open, binary logistic regression for first service conception rate and Oneway ANOVA test for the number of artificial inseminations. The effects of treatment on milk yield and milk composition were checked using GLM repeated measures analysis. No statistically significant differences were observed between treatment groups for any of the parameters evaluated. Only parity had a significant effect on days open and milk production (p < 0.05). In conclusion, in the present study no evidence was found that rbG-CSF could have an effect on the reproductive and productive parameters evaluated.

Neutralizing the threat: harnessing broadly neutralizing antibodies against HIV-1 for treatment and prevention.

Broadly neutralizing antibodies (bnAbs) targeting the human immunodeficiency virus-1 (HIV-1) have played a crucial role in elucidating and characterizing neutralization-sensitive sites on the HIV-1 envelope spike and in informing vaccine development. Continual advancements in identifying more potent bnAbs, along with their capacity to trigger antibody-mediated effector functions, coupled with modifications to extend their half-life, position them as promising candidates for both HIV-1 treatment and prevention. While current pharmacological interventions have made significant progress in managing HIV-1 infection and enhancing quality of life, no definitive cure or vaccines have been developed thus far. Standard treatments involve daily oral anti-retroviral therapy, which, despite its efficacy, can lead to notable long-term side effects. Recent clinical trial data have demonstrated encouraging therapeutic and preventive potential for bnAb therapies in both HIV-1-infected individuals and those without the infection. This review provides an overview of the advancements in HIV-1-specific bnAbs and discusses the insights gathered from recent clinical trials regarding their application in treating and preventing HIV-1 infection.

Assessing the reduction of viral infectivity in HPV16/18-positive women after one, two, and three doses of Gardasil-9 (RIFT): Study protocol.

Human Papillomavirus (HPV) prophylactic vaccination has proven effective in preventing new infections, but it does not treat existing HPV infections or associated diseases. Hence, there is still an important reservoir of HPV in adults, as vaccination programs are mainly focused on young women. The primary objective of this non-randomized, open-label trial is to evaluate if a 3-dose regimen of Gardasil-9 in HPV16/18-positive women could reduce the infective capacity of their body fluids. We aim to assess if vaccine-induced antibodies could neutralize virions present in the mucosa, thus preventing the release of infective particles and HPV transmission to sexual partners. As our main endpoint, the E1^E4-HaCaT model will be used to assess the infectivity rate of cervical, anal and oral samples, obtained from women before and after vaccination. HPV DNA positivity, virion production, seroconversion, and the presence of antibodies in the exudates, will be evaluated to attribute infectivity reduction to vaccination. Our study will recruit two different cohorts (RIFT-HPV1 and RIFT-HPV2) of non-vaccinated adult women. RIFT-HPV1 will include subjects with an HPV16/18 positive cervical test and no apparent cervical lesions or cervical lesions eligible for conservative treatment. RIFT-HPV2 will include subjects with an HPV16/18 positive anal test and no apparent anal lesions or anal lesions eligible for conservative treatment, as well as women with an HPV16/18 positive cervical test and HPV-associated vulvar lesions. Subjects complying with inclusion criteria for both cohorts will be recruited to the main cohort, RIFT-HPV1. Three doses of Gardasil-9 will be administered intramuscularly at visit 1 (0 months), visit 2 (2 months) and visit 3 (6 months). Even though prophylactic HPV vaccines would not eliminate a pre-existing infection, our results will determine if HPV vaccination could be considered as a new complementary strategy to prevent HPV-associated diseases by reducing viral spread. Trial registration: https://clinicaltrials.gov/ct2/show/NCT05334706.

Identifying risk for status epilepticus with the ADAN scale: a prospective multicenter validation study. / Escala ADAN para la identificación del estado epiléptico: estudio de validación prospectivo y multicéntrico.

OBJECTIVES: Status epilepticus (SE) is a serious event associated with high mortality. This study aims to validate the recently developed ADAN (Abnormal speech, ocular Deviation, Automatisms, and Number of motor epileptic seizures) scale for detecting high risk for SE. MATERIAL AND METHODS: Prospective, multicenter, observational study in adults with suspected epileptic seizures. Consecutive recruitment took place over a 27-month period in 4 hospital emergency departments (EDs). The main endpoint was the proportion of patients with criteria for SE based on the collection and analysis of clinical characteristics and the ADAN scale criteria on arrival at the ED. RESULTS: Of the 527 patients recruited, 203 (38.5%) fulfilled the criteria that predicted SE. Multiple regression analysis demonstrated that the 4 ADAN criteria were the only variables independently associated with a final diagnosis of SE (P .001). The predictive power of the scale was 90.9% (95% CI, 88.4%-93.4%) for a final SE diagnosis. We established 3 risk groups based on ADAN scores: low (score, 0-1: 8.7%), moderate (2, 46.6%), and high (> 2, 92.6%). A cut point of more than 1 had a sensitivity of 88.2% for predicting SE, specificity of 77.8%, positive predictive value of 71.3%, and negative predictive value of 91.3%. CONCLUSION: The ADAN scale is a prospectively validated, simple clinical tool for identifying patients in the ED who are at high risk for SE.

OBJETIVO: El estado epiléptico (EE) es una enfermedad grave con elevada mortalidad. Este estudio tiene como objetivo validar la escala ADAN, propuesta recientemente para identificar pacientes con alto riesgo de desarrollar un EE. METODO: Se realizó un estudio prospectivo, multicéntrico y observacional que incluyó a pacientes adultos con sospecha de crisis epilépticas. Se llevó a cabo un reclutamiento consecutivo durante 27 meses en los servicios de urgencias (SU) de cuatro hospitales. La variable principal fue la proporción de pacientes que cumplían criterios para EE. Se han recopilado y analizado las características clínicas y la puntuación en la escala ADAN a su llegada al SU. RESULTADOS: Se reclutaron 527 pacientes, de los cuales 203 (38,5%) cumplieron criterios de EE. En el análisis de regresión múltiple, se demostró que el habla anormal, la desviación ocular, los automatismos y el número de crisis epilépticas motoras fueron las únicas variables independientemente asociadas con un diagnóstico final de EE (p 0,001). La capacidad predictiva de la escala fue del 90,9% (intervalo de confianza del 95%, 88,4-93,4) para identificar el EE como diagnóstico final. Se establecieron tres grupos de riesgo: bajo (0 1 puntos: 8,7%), moderado (2: 46,6%) y alto (> 2: 92,6%). Una puntuación de corte > 1 punto proporcionó una sensibilidad del 88,2%, especificidad del 77,8%, valor predictivo positivo del 71,3% y valor predictivo negativo del 91,3% para predecir el EE. CONCLUSIONES: La escala ADAN es una herramienta clínica simple y validada de manera prospectiva para identificar, en los SU, a los pacientes con elevado riesgo de EE.

Exploratory study of blood biomarkers in patients with post-stroke epilepsy.

INTRODUCTION: In addition to clinical factors, blood-based biomarkers can provide useful information on the risk of developing post-stroke epilepsy (PSE). Our aim was to identify serum biomarkers at stroke onset that could contribute to predicting patients at higher risk of PSE. PATIENTS AND METHODS: From a previous study in which 895 acute stroke patients were followed-up, 51 patients developed PSE. We selected 15 patients with PSE and 15 controls without epilepsy. In a biomarker discovery setting, 5 Olink panels of 96 proteins each, were used to determine protein levels. Biomarkers that were down-regulated and overexpressed in PSE patients, and those that showed the strongest interactions with other proteins were validated using an enzyme-linked immunosorbent assay in samples from 50 PSE patients and 50 controls. A ROC curve analysis was used to evaluate the predictive ability of significant biomarkers to develop PSE. RESULTS: Mean age of the PSE discovery cohort was 68.56 ± 15.1, 40% women and baseline NIHSS 12 [IQR 1-25]. Nine proteins were down-expressed: CASP-8, TNFSF-14, STAMBP, ENRAGE, EDA2R, SIRT2, TGF-alpha, OSM and CLEC1B. VEGFa, CD40 and CCL4 showed greatest interactions with the remaining proteins. In the validation analysis, TNFSF-14 was the single biomarker showing statistically significant downregulated levels in PSE patients (p = 0.006) and it showed a good predictive capability to develop PSE (AUC 0.733, 95% CI 0.601-0.865). DISCUSSION AND CONCLUSION: Protein expression in PSE patients differs from that of non-epileptic stroke patients, suggesting the involvement of several different proteins in post-stroke epileptogenesis. TNFSF-14 emerges as a potential biomarker for predicting PSE.

COVID-19 Vaccination in Patients with Inborn Errors of Immunity Reduces Hospitalization and Critical Care Needs Related to COVID-19: a USIDNET Report.

BACKGROUND: The CDC and ACIP recommend COVID-19 vaccination for patients with inborn errors of immunity (IEI). Not much is known about vaccine safety in IEI, and whether vaccination attenuates infection severity in IEI. OBJECTIVE: To estimate COVID-19 vaccination safety and examine effect on outcomes in patients with IEI. METHODS: We built a secure registry database in conjunction with the US Immunodeficiency Network to examine vaccination frequency and indicators of safety and effectiveness in IEI patients. The registry opened on January 1, 2022, and closed on August 19, 2022. RESULTS: Physicians entered data on 1245 patients from 24 countries. The most common diagnoses were antibody deficiencies (63.7%). At least one COVID-19 vaccine was administered to 806 patients (64.7%), and 216 patients received vaccination prior to the development of COVID-19. The most common vaccines administered were mRNA-based (84.0%). Seventeen patients were reported to seek outpatient clinic or emergency room care for a vaccine-related complication, and one patient was hospitalized for symptomatic anemia. Eight hundred twenty-three patients (66.1%) experienced COVID-19 infection. Of these, 156 patients required hospitalization (19.0%), 47 required ICU care (5.7%), and 28 died (3.4%). Rates of hospitalization (9.3% versus 24.4%, p < 0.001), ICU admission (2.8% versus 7.6%, p = 0.013), and death (2.3% versus 4.3%, p = 0.202) in patients who had COVID-19 were lower in patients who received vaccination prior to infection. In adjusted logistic regression analysis, not having at least one COVID-19 vaccine significantly increased the odds of hospitalization and ICU admission. CONCLUSION: Vaccination for COVID-19 in the IEI population appears safe and attenuates COVID-19 severity.

Attachment styles and associated psychosocial factors in patients at ultra-high risk for psychosis: A systematic review.

BACKGROUND: Patients with an ultra-high risk of psychosis (UHR) are more likely to transition to psychosis. Attachment style has also been associated with psychosis and other symptoms. AIMS: To review attachment styles in UHR patients and to analyze related psychosocial factors. Ours is the first systematic review of attachment in this population. METHOD: We performed a systematic review of attachment and related psychosocial factors in UHR patients following the PRISMA methodology. RESULTS: We identified five studies. The results revealed high rates of insecure attachment in this population (more than 80%). The UHR sample presented high levels of depression, anxiety, social anxiety, emotional reactivity, trauma, and poor mentalization. Premorbid social adjustment was a predictor of improvement in disorganization and negative symptoms. The rate of transition to psychosis was 10%. Attachment patterns accounted for 16.8% of the variance. This vulnerability for psychosis was also associated with poor mentalization. CONCLUSION: Early detection of patients with UHR and insecure attachment is crucial, since early intervention to address symptoms, mentalization, and attachment is feasible and may lead to an improvement in the remaining associated psychosocial related factors (secure style: better global functioning and less affective and anxious symptoms). PROSPERO ID440957.

Epileptiform electroencephalogram discharges increase seizure recurrence risk in patients with acute symptomatic seizure due to a structural brain lesion.

OBJECTIVE: The risk factors for seizure recurrence after acute symptomatic seizure due to a structural brain lesion are not well established. The aim of this study was to analyze possible associations between demographic, clinical, and electroencephalographic variables and epilepsy development in patients with acute symptomatic seizure due to an acute structural brain lesion. METHODS: We designed an observational prospective study of patients with acute symptomatic seizure due to an acute structural brain lesion (hemorrhagic stroke, ischemic stroke, traumatic brain injury, or meningoencephalitis) who underwent EEG during their initial admission between January 2015 and January 2020. We analyzed prospectively recorded demographic, clinical, electroencephalographic (EEG), and treatment-related variables. All variables were compared between patients with and without seizure recurrence during 2 years of follow up. RESULTS: We included 194 patients (41.2 % women; mean [SD] age, 57.3 [15.8] years) with acute symptomatic seizure due to an acute structural brain lesion. They all underwent EEG during admission and were followed for at least 2 years. The identifiable causes were hemorrhagic stroke (44.8 %), ischemic stroke (19.5 %), traumatic brain injury (18.5 %), and meningoencephalitis (17 %). Fifty-six patients (29 %) experienced a second seizure during follow-up. Seizure recurrence was associated with epileptiform discharges on EEG (52% vs 32 %; OR 2.3 [95 % CI, 1.2-4.3], p = 0.008) and onset with status epilepticus (17% vs 0.05 %, OR 4.03 [95 % CI 1.45-11.2], p = 0.009). CONCLUSIONS: Epileptiform discharges on EEG and status epilepticus in patients with acute symptomatic seizure due to an acute structural brain lesion are associated with a higher risk of epilepsy development.

Prevalence, Risk Factors, and Relationship between Reproductive Performance and the Presence of Antibodies against Coxiellosis in Dairy Farm Milk Tanks in the Northwest of Spain.

Q fever is a zoonotic disease that has been associated with reproductive problems in animals. As there is little epidemiological data regarding the distribution and risk factors of this disorder in cattle, the objective of this study was to evaluate the prevalence of Coxiella burnetii among dairy herds in the northwest of Spain, and to determine the on-farm risk factors associated with the disease and its effects on reproductive performance. Bulk tank milk (BTM) samples were collected from 262 commercial dairy herds from A Coruña, Lugo, and Pontevedra provinces. Data about location, mean age, and herd management features were obtained. A commercial indirect ELISA kit was used to determine the presence of antibodies against C. burnetii in BTM samples. The relationship between seropositivity to C. burnetii and the risk factors was checked using a Pearson's χ2 test and a classification tree analysis. In addition, a one-way ANOVA test and the Mann-Whitney U test were used to check the impact of seropositivity to C. burnetii on reproductive performance. A total of 60.1% of the farms tested positive for coxiellosis, the herd size, the external purchase of livestock, and the geographical area were identified as the main risk factors. Conception rate and first-service conception rate were significantly lower (p < 0.05) in positive farms (37.1 and 32.9%) compared to negative farms (39.8 and 36.1%). Similarly, positive farms had significant higher incidence of endometritis (13.7% vs. 11.2%, p < 0.05). Consequently, a high seropositivity and slightly negative effects of coxiellosis on reproductive performance were observed, which intensifies the need for further research, including the identification an active infection in positive herds and the characterization of the genotype.

Assessment of Luteal Function Using Rectal Palpation, B-Mode Ultrasonography, and Progesterone Determination to Improve Recipient Selection in Embryo Transfer Programs.

Proper selection of recipients determines the success of embryo transfer (ET) programs. Therefore, the objectives of this study were to assess the accuracy of rectal palpation (RP) in selecting recipients according to the size and firmness of their corpus luteum (CL) compared to ultrasonography (US) and progesterone determination (P4); to check if US or P4 provide additional information to RP with regard to selecting animals with higher odds of maintaining the pregnancy; and to verify the reliability of the presence of a cavity and the volume of the CL within the ovary (%CLOV) as predictors of the ET outcome. In Experiment 1, measurements for the largest and minor diameter (LADCL and MIDCL), CL area, and P4 at ET day were collected, as well as the RP score, in 94 heifers. In Experiment 2, measurements for the LADCL, MIDCL, CL volume, %CLOV, and presence of a cavity were collected, as well as data about the procedure and metabolic markers, in 108 heifers. No differences were found in Experiment 1, whereas in Experiment 2, just a tendency was observed for the variable of veterinarian. Consequently, these results suggest that RP and US are useful methods to select recipients with, that US and P4 do not offer additional data to use to select animals with higher odds of maintaining pregnancy, and that neither %CLOV nor cavitary CL were good indicators for pregnancy rates.

Treatment and Management Experience of Idiopathic Granulomatous Mastitis in a Low-income Country.

OBJECTIVE: Reporting our experience of the management and treatment of Idiopathic granulomatous mastitis (IGM) in a low-income country by describing patients characteristics and therapy with emphasis on conservative surgical excision and postoperative care as the cornerstone of treatment. METHODS: A retrospective cohort of women with histopathological diagnosis of IGM from 2014 to 2018 at Instituto Nacional Materno Perinatal in Lima, Peru. Patients' characteristics, clinical presentation, treatment, management, postoperative care, and follow-up were analyzed. RESULTS: Thirty-eight patients with histopathological diagnosis of IGM were identified. Their average age was 35.9 years and 23 (60.5%) reported previous use of hormonal contraceptives. Nine (23.7%) patients had chronic mastitis with previous treatment. The time from the onset of symptoms to the first clinic consult was 5.1 months on average. Twenty-one (55.3%) patients had the lesion in the right breast, with a mean size of 6.9 cm. Conservative surgical excision was performed in all patients. Additionally, 86.8% required corticosteroids and 78.9% were treated with antibiotics. Complete remission was obtained at 141 days on average (range 44 to 292 days). Six (15.8%) women reported ipsilateral recurrence and 5 (13.2%), contralateral. The latency time was 25.5 months on average. CONCLUSION: The conservative surgical treatment demonstrated and close follow-up made for a high cure rate, but with recurrence similar to that reported in the literature. Use of gloves is an alternative to manage post operative wounds in a low-income country. The most frequent adverse effect was breast surgical scar.

Treatment and Management Experience of Idiopathic Granulomatous Mastitis in a Low-income Country / Experiência de tratamento e manejo da mastite granulomatosa idiopática em um país de baixa renda

Abstract Objective Reporting our experience of the management and treatment of Idiopathic granulomatous mastitis (IGM) in a low-income country by describing patients characteristics and therapy with emphasis on conservative surgical excision and postoperative care as the cornerstone of treatment. Methods A retrospective cohort of women with histopathological diagnosis of IGM from 2014 to 2018 at Instituto Nacional Materno Perinatal in Lima, Peru. Patients' characteristics, clinical presentation, treatment, management, postoperative care, and follow-up were analyzed. Results Thirty-eight patients with histopathological diagnosis of IGM were identified. Their average age was 35.9 years and 23 (60.5%) reported previous use of hormonal contraceptives. Nine (23.7%) patients had chronic mastitis with previous treatment. The time from the onset of symptoms to the first clinic consult was 5.1 months on average. Twenty-one (55.3%) patients had the lesion in the right breast, with a mean size of 6.9 cm. Conservative surgical excision was performed in all patients. Additionally, 86.8% required corticosteroids and 78.9% were treated with antibiotics. Complete remission was obtained at 141 days on average (range 44 to 292 days). Six (15.8%) women reported ipsilateral recurrence and 5 (13.2%), contralateral. The latency time was 25.5 months on average. Conclusion The conservative surgical treatment demonstrated and close follow-up made for a high cure rate, but with recurrence similar to that reported in the literature. Use of gloves is an alternative to manage post operative wounds in a low-income country. The most frequent adverse effect was breast surgical scar.

Serious neurological adverse events following immunization against SARS-CoV-2: a narrative review of the literature.

Amid the coronavirus disease 2019 (COVID-19) pandemic, massive immunization campaigns became the most promising public health measure. During clinical trials, certain neurological adverse effects following immunization (AEFIs) were observed; however, acceptable safety profiles lead to emergency authorization for the distribution and use of the vaccines. To contribute to pharmacovigilance and lessen the potential negative impact that vaccine hesitancy would have on immunization programs, we conducted a review of the scientific literature concerning the epidemiological data, clinical presentation, and potential mechanisms of these neurological AEFIs. There is some epidemiological evidence linking COVID-19 vaccines to cerebral venous sinus thrombosis, arterial ischemic stroke, convulsive disorder, Guillain-Barré syndrome, facial nerve palsy, and other neurological conditions. Cerebral venous sinus thrombosis has been associated with a thrombotic thrombocytopenia induced by the vaccine, similar to that induced by heparin, which suggests similar pathogenic mechanisms (likely involving antibodies against platelet factor 4, a chemokine released from activated platelets). Arterial ischemic stroke is another thrombotic condition observed among some COVID-19 vaccine recipients. Vaccine-induced convulsive disorder might be the result of structural abnormalities potentially caused by the vaccine or autoimmune mechanisms. Guillain-Barré syndrome and facial nerve palsy may also be linked to the immunization event, possibly due to immune mechanisms such as uncontrolled cytokine release, autoantibody production, or bystander effect. However, these events are mostly uncommon and the evidence for the association with the vaccine is not conclusive. Furthermore, the potential pathophysiological mechanisms remain largely unknown. Nevertheless, neurological AEFIs can be serious, life-threatening or even fatal. In sum, COVID-19 vaccines are generally safe and the risk of neurological AEFIs does not outweigh the benefits of immunization. However, early diagnosis and treatment of neurological AEFIs are of utmost importance, and both health professionals and the public should be aware of these conditions.

A review of undesired effects involving the nervous system following the administration of COVID-19 vaccines Among the range of complications that can occur after a vaccine, some of them can affect the nervous system and its vasculature. This narrative review aims to evaluate some serious neurological conditions following COVID-19 vaccination. We searched biomedical journal databases where physicians around the globe reported different complications after the administration of different COVID-19 vaccines. Besides reports of cases in individual patients or small groups, we reviewed studies that included bigger groups of patients (e.g. vaccinated versus non-vaccinated) and compared the occurrence of these events between them. We found that after the administration of a certain type of vaccine (e.g. ChAdOx1-S/Oxford, AstraZeneca vaccine), serious neurological complications were rare, with abnormal clot formation involving cerebral blood vessels being one of the most important among them. Nonetheless, other conditions have been observed after the administration of the vaccines; however, it is not certain yet if the vaccines are the actual cause of these complications. There are some hypotheses that could explain why these adverse reactions take place after a vaccine. For instance, an abnormal immune response to the vaccine leads to the production of antibodies (i.e. proteins made by the immune system in response to the presence of a foreign substance). These antibodies trigger a response that could eventually result in clot formation. Besides, the immune response can also produce other adverse effects, including convulsive disorder, Guillain­Barré syndrome, and facial nerve palsy. Scientific evidence suggests that vaccines are safe overall. While mild complications, such as pain at the site of injection or bruising might occur, more serious events remain rare. Furthermore, the complications derived from COVID-19 are far more likely in non-vaccinated individuals than the complications associated with the vaccine. Thus, vaccination continues to be the safest and most effective strategy to control the ongoing pandemic. However, both health professionals and the public should be aware of the possibility of serious neurological adverse reactions occurring after vaccination to allow early diagnosis and treatment.

Comparison between transrectal palpation, B-mode and Doppler ultrasonography to assess luteal function in Holstein cattle.

Introduction: Over the years, the most common methods for monitoring reproductive health in cattle have varied from transrectal palpation to B-mode ultrasonography. Nowadays, some portable ultrasound equipment includes the Doppler mode. Therefore, the aim of this study was to compare the accuracy of the different methods to assess corpus luteum (CL) functionality. Methods: In Experiment 1, 53 Holstein lactating cows undergoing a synchronization protocol were examined via transrectal palpation and B-mode scanning. Measurements for the largest diameter (LAD) and subjective size of CL (SCLS) were collected. Data were analyzed using correlation analysis and ROC Curves. In Experiment 2, 30 Holstein non-lactating cows with a CL were administered PGF2α and examined several times after injection, first in B-mode and then with Power Doppler. Measurements for LAD, CL area (CLA) and subjective and objective CL blood flow were collected. Blood samples were taken in both experiments to determine P4 concentration. Data were analyzed using correlation analysis and the GLM repeated measures test. Results: Results for Experiment 1 showed that LAD was more accurate than SCLS. In Experiment 2, CLA was the best measurement to assess CL function, although both subjective and objective CL blood flow offer accurate information 24 h after PGF2α administration. Discussion: Consequently, ultrasonography provides more accurate information about CL function than transrectal palpation. Although CLA seems to be an earlier indicator of luteal function than blood flow, 24 h after the onset of luteolysis, both parameters are valid.

Desensibilización exitosa a Colistina en paciente peruano con Fibrosis quística / Successful desensitization to colistin in a Peruvian patient with cystic fibrosis

RESUMEN Introducción: La desensibilización farmacológica induce un estado temporal de hiposensibilidad a un medicamento que se realiza a pacientes con reacciones mediadas por Inmunoglobulina E. Reporte de caso: Presentamos el caso de un paciente con exacerbación respiratoria de fibrosis quística que presentó hipersensibilidad inmediata a colistina, un antibiótico esencial para su tratamiento, tanto por la sensibilidad del microorganismo, como la falta de disponibilidad de otros medicamentos. Se realizó el procedimiento en Unidad de Cuidados Intensivos de forma exitosa y el paciente completó el esquema del tratamiento. Conclusión: Actualmente el paciente se encuentra en tratamiento específico para su enfermedad de fondo y no ha presentado nuevos episodios de exacerbación ni neumonías.

ABSTRACT Introduction: Pharmacological desensitization induces a temporary hyposensitivity to the causative drug in patients with Immunoglobulin E-mediated drug reactions. Case of report: We present the case of a patient with respiratory exacerbation of cystic fibrosis who presented immediate hypersensitivity to colistin, an essential antibiotic for its treatment-both due to the sensitivity of the microorganism and the lack of availability of other drugs. The procedure was successfully performed in the Intensive Care Unit, and the patient completed the treatment schedule. Conclusion: Currently, the patient is undergoing specific treatment for his underlying disease and has not presented any new episodes of exacerbation or pneumonia.

Partial loss-of-function mutations in GINS4 lead to NK cell deficiency with neutropenia.

Human NK cell deficiency (NKD) is a primary immunodeficiency in which the main clinically relevant immunological defect involves missing or dysfunctional NK cells. Here, we describe a familial NKD case in which 2 siblings had a substantive NKD and neutropenia in the absence of other immune system abnormalities. Exome sequencing identified compound heterozygous variants in Go-Ichi-Ni-San (GINS) complex subunit 4 (GINS4, also known as SLD5), an essential component of the human replicative helicase, which we demonstrate to have a damaging impact upon the expression and assembly of the GINS complex. Cells derived from affected individuals and a GINS4-knockdown cell line demonstrate delayed cell cycle progression, without signs of improper DNA synthesis or increased replication stress. By modeling partial GINS4 depletion in differentiating NK cells in vitro, we demonstrate the causal relationship between the genotype and the NK cell phenotype, as well as a cell-intrinsic defect in NK cell development. Thus, biallelic partial loss-of-function mutations in GINS4 define a potentially novel disease-causing gene underlying NKD with neutropenia. Together with the previously described mutations in other helicase genes causing NKD, and with the mild defects observed in other human cells, these variants underscore the importance of this pathway in NK cell biology.

Comparison of Models to Predict Mechanical Properties of FR-AM Composites and a Fractographical Study.

Continuous fiber-reinforced additive manufacturing (cFRAM) composites improve the mechanical properties of polymer components. Given the recent interest in their mechanical performance and failure mechanisms, this work aims to describe the principal failure mechanisms and compare the prediction capabilities for the mechanical properties, stiffness constants, and strength of cFRAM using two distinct predictive models. This work presents experimental tensile tests of continuous carbon fiber AM composites varying their reinforced fraction, printing direction, and fiber angle. In the first predictive model, a micromechanical-based model for stiffness and strength predicts their macroscopic response. In the second part, data-driven models using different machine learning algorithms for regression are trained to predict stiffness and strength based on critical parameters. Both models are assessed regarding their accuracy, ease of implementation, and generalization capabilities. Moreover, microstructural images are used for a qualitative evaluation of the parameters and their influence on the macroscopic response and failure surface topology. Finally, we conclude that although predicting the mechanical properties of cFRAM is a complex task, it can be carried on a Gaussian process regression and a micromechanical model, with good accuracy generalized onto different process parameters specimens.

Flexural Fatigue in a Polymer Matrix Composite Material Reinforced with Continuous Kevlar Fibers Fabricated by Additive Manufacturing.

Fatigue bending tests, under controlled displacement, were performed on a polymer matrix composite material reinforced with continuous Kevlar fibers. The samples were fabricated using the Fused Filament Fabrication (FFF) technique in a Markforged Two® 3D printer. The static characterization delivered a flexural modulus of elasticity of 4.73 GPa and flexural strength of 110 MPa. The applied loading corresponded to 92.3, 88.5, 86.2, and 84.7% of the static flexural displacement, giving 15, 248, 460, and 711 cycles for failure. Additionally, two numerical models were created: one using orthotropic properties for static loading conditions; and a second one using isotropic in-bulk properties for fatigue modeling. The second model was able to reproduce the experimental fatigue results. Finally, morphological analysis of the fractured surface revealed fiber breakage, fiber tearing, fiber buckling, matrix cracking, and matrix porosity.

Connexins and Pannexins: Important Players in Neurodevelopment, Neurological Diseases, and Potential Therapeutics.

Cell-to-cell communication is essential for proper embryonic development and its dysfunction may lead to disease. Recent research has drawn attention to a new group of molecules called connexins (Cxs) and pannexins (Panxs). Cxs have been described for more than forty years as pivotal regulators of embryogenesis; however, the exact mechanism by which they provide this regulation has not been clearly elucidated. Consequently, Cxs and Panxs have been linked to congenital neurodegenerative diseases such as Charcot-Marie-Tooth disease and, more recently, chronic hemichannel opening has been associated with adult neurodegenerative diseases (e.g., Alzheimer's disease). Cell-to-cell communication via gap junctions formed by hexameric assemblies of Cxs, known as connexons, is believed to be a crucial component in developmental regulation. As for Panxs, despite being topologically similar to Cxs, they predominantly seem to form channels connecting the cytoplasm to the extracellular space and, despite recent research into Panx1 (Pannexin 1) expression in different regions of the brain during the embryonic phase, it has been studied to a lesser degree. When it comes to the nervous system, Cxs and Panxs play an important role in early stages of neuronal development with a wide span of action ranging from cellular migration during early stages to neuronal differentiation and system circuitry formation. In this review, we describe the most recent available evidence regarding the molecular and structural aspects of Cx and Panx channels, their role in neurodevelopment, congenital and adult neurological diseases, and finally propose how pharmacological modulation of these channels could modify the pathogenesis of some diseases.

Bleeding Risk With Combination Intrapleural Fibrinolytic and Enzyme Therapy in Pleural Infection: An International, Multicenter, Retrospective Cohort Study.

BACKGROUND: Combination intrapleural fibrinolytic and enzyme therapy (IET) has been established as a therapeutic option in pleural infection. Despite demonstrated efficacy, studies specifically designed and adequately powered to address complications are sparse. The safety profile, the effects of concurrent therapeutic anticoagulation, and the nature and extent of nonbleeding complications remain poorly defined. RESEARCH QUESTION: What is the bleeding complication risk associated with IET use in pleural infection? STUDY DESIGN AND METHODS: This was a multicenter, retrospective observational study conducted in 24 centers across the United States and the United Kingdom. Protocolized data collection for 1,851 patients treated with at least one dose of combination IET for pleural infection between January 2012 and May 2019 was undertaken. The primary outcome was the overall incidence of pleural bleeding defined using pre hoc criteria. RESULTS: Overall, pleural bleeding occurred in 76 of 1,833 patients (4.1%; 95% CI, 3.0%-5.0%). Using a half-dose regimen (tissue plasminogen activator, 5 mg) did not change this risk significantly (6/172 [3.5%]; P = .68). Therapeutic anticoagulation alongside IET was associated with increased bleeding rates (19/197 [9.6%]) compared with temporarily withholding anticoagulation before administration of IET (3/118 [2.6%]; P = .017). As well as systemic anticoagulation, increasing RAPID score, elevated serum urea, and platelets of < 100 × 109/L were associated with a significant increase in bleeding risk. However, only RAPID score and use of systemic anticoagulation were independently predictive. Apart from pain, non-bleeding complications were rare. INTERPRETATION: IET use in pleural infection confers a low overall bleeding risk. Increased rates of pleural bleeding are associated with concurrent use of anticoagulation but can be mitigated by withholding anticoagulation before IET. Concomitant administration of IET and therapeutic anticoagulation should be avoided. Parameters related to higher IET-related bleeding have been identified that may lead to altered risk thresholds for treatment.