The Majority of SARS-CoV-2 Plasma Cells are Excluded from the Bone Marrow Long-Lived Compartment 33 Months after mRNA Vaccination.

The goal of any vaccine is to induce long-lived plasma cells (LLPC) to provide life-long protection. Natural infection by influenza, measles, or mumps viruses generates bone marrow (BM) LLPC similar to tetanus vaccination which affords safeguards for decades. Although the SARS-CoV-2 mRNA vaccines protect from severe disease, the serologic half-life is short-lived even though SARS-CoV-2-specific plasma cells can be found in the BM. To better understand this paradox, we enrolled 19 healthy adults at 1.5-33 months after SARS-CoV-2 mRNA vaccine and measured influenza-, tetanus-, or SARS-CoV-2-specific antibody secreting cells (ASC) in LLPC (CD19-) and non-LLPC (CD19+) subsets within the BM. All individuals had IgG ASC specific for influenza, tetanus, and SARS-CoV-2 in at least one BM ASC compartment. However, only influenza- and tetanus-specific ASC were readily detected in the LLPC whereas SARS-CoV-2 specificities were mostly excluded. The ratios of non-LLPC:LLPC for influenza, tetanus, and SARS-CoV-2 were 0.61, 0.44, and 29.07, respectively. Even in five patients with known PCR-proven history of infection and vaccination, SARS-CoV-2-specific ASC were mostly excluded from the LLPC. These specificities were further validated by using multiplex bead binding assays of secreted antibodies in the supernatants of cultured ASC. Similarly, the IgG ratios of non-LLPC:LLPC for influenza, tetanus, and SARS-CoV-2 were 0.66, 0.44, and 23.26, respectively. In all, our studies demonstrate that rapid waning of serum antibodies is accounted for by the inability of mRNA vaccines to induce BM LLPC.

The Majority of SARS-CoV-2 Plasma Cells are Excluded from the Bone Marrow Long-Lived Compartment 33 Months after mRNA Vaccination.

The goal of any vaccine is to induce long-lived plasma cells (LLPC) to provide life-long protection. Natural infection by influenza, measles, or mumps viruses generates bone marrow (BM) LLPC similar to tetanus vaccination which affords safeguards for decades. Although the SARS-CoV-2 mRNA vaccines protect from severe disease, the serologic half-life is short-lived even though SARS-CoV-2-specific plasma cells can be found in the BM. To better understand this paradox, we enrolled 19 healthy adults at 1.5-33 months after SARS-CoV-2 mRNA vaccine and measured influenza-, tetanus-, or SARS-CoV-2-specific antibody secreting cells (ASC) in LLPC (CD19 - ) and non-LLPC (CD19 + ) subsets within the BM. All individuals had IgG ASC specific for influenza, tetanus, and SARS-CoV-2 in at least one BM ASC compartment. However, only influenza- and tetanus-specific ASC were readily detected in the LLPC whereas SARS-CoV-2 specificities were mostly excluded. The ratios of non-LLPC:LLPC for influenza, tetanus, and SARS-CoV-2 were 0.61, 0.44, and 29.07, respectively. Even in five patients with known PCR-proven history of infection and vaccination, SARS-CoV-2-specific ASC were mostly excluded from the LLPC. These specificities were further validated by using multiplex bead binding assays of secreted antibodies in the supernatants of cultured ASC. Similarly, the IgG ratios of non-LLPC:LLPC for influenza, tetanus, and SARS-CoV-2 were 0.66, 0.44, and 23.26, respectively. In all, our studies demonstrate that rapid waning of serum antibodies is accounted for by the inability of mRNA vaccines to induce BM LLPC.

SARS-CoV-2-specific plasma cells are not durably established in the bone marrow long-lived compartment after mRNA vaccination.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines are effective at protecting from severe disease, but the protective antibodies wane rapidly even though SARS-CoV-2-specific plasma cells can be found in the bone marrow (BM). Here, to explore this paradox, we enrolled 19 healthy adults at 2.5-33 months after receipt of a SARS-CoV-2 mRNA vaccine and measured influenza-, tetanus- or SARS-CoV-2-specific antibody-secreting cells (ASCs) in long-lived plasma cell (LLPC) and non-LLPC subsets within the BM. Only influenza- and tetanus-specific ASCs were readily detected in the LLPCs, whereas SARS-CoV-2 specificities were mostly absent. The ratios of non-LLPC:LLPC for influenza, tetanus and SARS-CoV-2 were 0.61, 0.44 and 29.07, respectively. In five patients with known PCR-proven history of recent infection and vaccination, SARS-CoV-2-specific ASCs were mostly absent from the LLPCs. We show similar results with measurement for secreted antibodies from BM ASC culture supernatant. While serum IgG titers specific for influenza and tetanus correlated with IgG LLPCs, serum IgG levels for SARS-CoV-2, which waned within 3-6 months after vaccination, were associated with IgG non-LLPCs. In all, our studies suggest that rapid waning of SARS-CoV-2-specific serum antibodies could be accounted for by the absence of BM LLPCs after these mRNA vaccines.

Sparsifying priors for Bayesian uncertainty quantification in model discovery.

We propose a probabilistic model discovery method for identifying ordinary differential equations governing the dynamics of observed multivariate data. Our method is based on the sparse identification of nonlinear dynamics (SINDy) framework, where models are expressed as sparse linear combinations of pre-specified candidate functions. Promoting parsimony through sparsity leads to interpretable models that generalize to unknown data. Instead of targeting point estimates of the SINDy coefficients, we estimate these coefficients via sparse Bayesian inference. The resulting method, uncertainty quantification SINDy (UQ-SINDy), quantifies not only the uncertainty in the values of the SINDy coefficients due to observation errors and limited data, but also the probability of inclusion of each candidate function in the linear combination. UQ-SINDy promotes robustness against observation noise and limited data, interpretability (in terms of model selection and inclusion probabilities) and generalization capacity for out-of-sample forecast. Sparse inference for UQ-SINDy employs Markov chain Monte Carlo, and we explore two sparsifying priors: the spike and slab prior, and the regularized horseshoe prior. UQ-SINDy is shown to discover accurate models in the presence of noise and with orders-of-magnitude less data than current model discovery methods, thus providing a transformative method for real-world applications which have limited data.

Analogues of cannabinoids as multitarget drugs in the treatment of Alzheimer's disease.

Given that neuronal degeneration in Alzheimer's disease (AD) is caused by the combination of multiple neurotoxic insults, current directions in the research of novel therapies to treat this disease attempts to design multitarget strategies that could be more effective than the simply use of acetylcholinesterase inhibitors; currently, the most used therapy for AD. One option, explored recently, is the synthesis of new analogues of cannabinoids that could competitively inhibit the acetylcholinesterase (AChE) enzyme and showing the classic neuroprotective profile of cannabinoid compounds. In this work, molecular docking has been used to design some cannabinoid analogues with such multitarget properties, based on the similarities of donepezil and Δ9-tetrahydrocannabinol. The analogues synthesized, compounds 1 and 2, demonstrated to have two interesting characteristics in different in vitro assays: competitive inhibition of AChE and competitive antagonism at the CB1/CB2 receptors. They are highly lipophilic, highlighting that they could easily reach the CNS, and apparently presented a low toxicity. These results open the door to the synthesis of new compounds for a more effective treatment of AD.

[Psychosocial risks, occupational stress and burnout syndrome in university workers from a Bioanalysis School]. / Riesgos psicosociales, estrés laboral y síndrome burnout en trabajadores universitarios de una escuela de bioanálisis.

OBJECTIVE: To evaluate psychosocial risks, occupational stress and burnout syndrome in university workers from a Venezuelan bioanalysis school. MATERIALS AND METHODS: Descriptive, cross-sectional study performed with a sample of 75 workers. The analysis of psychosocial risks, occupational stress and burnout syndrome was done using the CoPsoQ-istas21 methodology. RESULTS: The main psychosocial risks were work rhythm (80.8%) and insecure working conditions (54.9%). The most unfavorable health situations included double presence (52.7%); the intermediate situations were related to role conflict (38.9%); and the most favorable situations were associated with recognition (98.6%) and vertical confidence (94.3%). Both occupational stress (3%) and burnout syndrome (5%) were observed in the most unfavorable situations. There were direct relationships between seniority and wage scale (r=0.361; p<0.001); between occupational stress and burnout syndrome (r=0.512; p<0.01); and between work satisfaction and self-perceived health status (r=0.485; p<0.01). CONCLUSIONS: The description of positions and functions performed by workers should be analyzed and reinforced; moreover, staff performance indicators should be built and better mechanisms for work planning and systems of information should be established to help improve the School's managerial model.

OBJETIVO: Evaluar los riesgos psicosociales, el estrés laboral y el síndrome burnout en trabajadores universitarios de una escuela de bioanálisis venezolana. METODOLOGÍA: La investigación fue descriptiva y de corte transversal, la muestra estuvo constituida por 75 trabajadores. El análisis de riesgos psicosociales, el estrés laboral y el Síndrome Burnout se realizó a través de la metodología CoPsoQ-istas21. RESULTADOS: Los principales riesgos psicosociales fueron el ritmo de trabajo (80,8%) y la Inseguridad en las condiciones de trabajo (54,9%) en la situación más desfavorable a la salud, la doble presencia (52,7%) y el conflicto de roles (38,9%) en la situación intermedia, y el reconocimiento (98,6%) y la confianza vertical (94,3%) en la situación más favorable. Tanto el estrés laboral (3%) como el síndrome burnout (5%) se presentaron en la situación más desfavorable. Fueron directas las relaciones entre la antigüedad laboral y la escala de sueldos (r = 0,361; p<0,001), entre los niveles de estrés laboral y el síndrome de burnout (r= 0,512; p<0,01), y entre la satisfacción laboral y el estado de salud auto-percibida (r= 0,485; p<0,01). CONCLUSIONES: Se debe analizar y reforzar la descripción de cargos y funciones desempeñados por los trabajadores, construir indicadores de desempeño del personal, establecer mejores mecanismos para la planificación del trabajo y sistemas de información que ayuden a mejorar el modelo gerencial en la escuela.

Relationships between Sprint Ability and Endurance Capacity in Soccer Referees.

The aim of this study was to analyze the association between sprint ability and endurance capacity in soccer referees. Twenty-three Spanish officials participated in this study. Each referee undertook, in this order, a 40 m linear straight sprinting test (40 m Sprint) and the Yo⁻Yo intermittent recovery level 1 test (YYIR1) interspersed with a 8 min of self-administered rest. The results in the 40 m Sprint test showed that the time spent by referees was 5.56 ± 0.27 s and achieved a maximum velocity of 31.46 ± 2.85 km·h-1. Furthermore, during the YYIR1 the referees covered 1213.91 ± 432.26 m. The distance covered at YYIR1 was moderately correlated to the velocity achieved in the 40 m Sprint test (r = -0.404, p < 0.05). These results suggest that the ability to reach high speeds is a limiting factor in YYIR1 performance.

Probabilistic density function method for nonlinear dynamical systems driven by colored noise.

We present a probability density function (PDF) method for a system of nonlinear stochastic ordinary differential equations driven by colored noise. The method provides an integrodifferential equation for the temporal evolution of the joint PDF of the system's state, which we close by means of a modified large-eddy-diffusivity (LED) closure. In contrast to the classical LED closure, the proposed closure accounts for advective transport of the PDF in the approximate temporal deconvolution of the integrodifferential equation. In addition, we introduce the generalized local linearization approximation for deriving a computable PDF equation in the form of a second-order partial differential equation. We demonstrate that the proposed closure and localization accurately describe the dynamics of the PDF in phase space for systems driven by noise with arbitrary autocorrelation time. We apply the proposed PDF method to analyze a set of Kramers equations driven by exponentially autocorrelated Gaussian colored noise to study nonlinear oscillators and the dynamics and stability of a power grid. Numerical experiments show the PDF method is accurate when the noise autocorrelation time is either much shorter or longer than the system's relaxation time, while the accuracy decreases as the ratio of the two timescales approaches unity. Similarly, the PDF method accuracy decreases with increasing standard deviation of the noise.

Parámetros ecocardiográficos relacionados a hipertensión arterial pulmonar en pacientes con leucemia mieloide crónica en tratamiento con dasatinib / Echocardiographic parameters related to pulmonary arterial hypertension in patients with chronic myeloid leukemia under dasatinib treatment

Introducción: La leucemia mieloide crónica (LMC) es un desorden clonal de células madre hematopoyéticas, predomina en el género masculino entre 55 y 65 años. El ecocardiograma transtorácico (ECOTT) para detección temprana de hipertensión arterial pulmonar (HAP) permite hacer modificaciones al tratamiento con dasatinib. Ojetivos: Determinar los parámetros ecocardiográficos y la probabilidad ecocardiográfica para HAP en pacientes con LMC tratados con dasatinib. Métodos: Estudio de correlación, transversal, retrospectivo, unicéntrico; se incluyeron pacientes con LMC tratados con dasatinib. Se utilizó correlación de Spearman y Pearson. Resultados: Se analizaron 16 pacientes, edad promedio 53,5 años; 62,5% hombres, 37,5% mujeres. La dosis de dasatinib fue 50 mg/día en 18,7%, y 100 mg/día en 81,2%, presión media de la arteria pulmonar (mPAP) 26,3 mmHg, velocidad máxima de regurgitación tricuspídea (VmxRT) media 2,9 m/s, presión sistólica de arteria pulmonar (PSAP) media 41 mmHg. El 56,2% presentó disfunción diastólica del ventrículo derecho (DDVD). Se categorizaron 43% en baja probabilidad para HAP, 18,7% intermedia y 37,5% en alta. Relación entre mPAP y VmxRT con p=0,012. Relación entre mPAP y función diastólica del ventrículo derecho (FDVD), con p=0,002. Relación entre probabilidad para HAP y mPAP, con p=0,008. Conclusión: Los parámetros ecocardiográficos mPAP, VmxRT, PSAP, DDVD son útilesy la probabilidad ecocardiográfica para HAP deben realizarse de forma temprana y como seguimiento, ya que se encontró relación positiva con la presencia de HAP, la cual no es dependiente del tiempo de tratamiento ni de la dosis de dasatinib.

Introduction: The use of dasatinib in patients with CML has improved life expectancy and follow-up with transthoracic echocardiography (ECOTT) for early detection of PAH allows modifications to the treatment. Objectives: To determine the echocardiographic parameters and echocardiographic probability for PAH in patients with CML treated with dasatinib. Methods: Correlation, cross-sectional, retrospective, single-center study; patients with CML treated with dasatinib were included. Spearman and Pearson correlation was used. Results: 16 patients were analyzed, mean age 53.5 years; 62.5% men, 37.5% women. The dasatinib dose was 50 mg / day in 18.7%, and 100 mg / day in 81.2%, mean pulmonary arterial pressure (mPAP) 26.3 mmHg, mean maximum tricuspid regurgitation velocity (VmxRT) 2.9 m / s, mean pulmonary artery systolic pressure (PSAP) 41 mmHg. 56.2% had right ventricular diastolic dysfunction (RVDD). 43% were categorized as low probability for PAH, 18.7% intermediate, and 37.5% as high. Relationship between PAPm and VmxRT with p = 0.012. Relationship between mPAP and RV diastolic function, with p = 0.002. Relationship between probability for PAH and mPAP, with p = 0.008. Conclusions: The echocardiographic parameters PAPm, VmxRT, PSAP, DDVD and echocardiographic probability for PAH are useful and necessary for the diagnosis of PAH. The determination of all these parameters should be carried out early and as a follow-up, since a considerable positive relationship was found for each one with the presence of PAH, which is not dependent on the treatment time or the dose of dasatinib.

Riesgos psicosociales, estrés laboral y síndrome burnout en trabajadores universitarios de una escuela de bioanálisis / Psychosocial risks, occupational stress and burnout syndrome in university workers from a Bioanalysis School

RESUMEN Objetivo Evaluar los riesgos psicosociales, el estrés laboral y el síndrome burnout en trabajadores universitarios de una escuela de bioanálisis venezolana. Metodología La investigación fue descriptiva y de corte transversal, la muestra estuvo constituida por 75 trabajadores. El análisis de riesgos psicosociales, el estrés laboral y el Síndrome Burnout se realizó a través de la metodología CoPsoQ-istas21. Resultados Los principales riesgos psicosociales fueron el ritmo de trabajo (80,8%) y la Inseguridad en las condiciones de trabajo (54,9%) en la situación más desfavorable a la salud, la doble presencia (52,7%) y el conflicto de roles (38,9%) en la situación intermedia, y el reconocimiento (98,6%) y la confianza vertical (94,3%) en la situación más favorable. Tanto el estrés laboral (3%) como el síndrome burnout (5%) se presentaron en la situación más desfavorable. Fueron directas las relaciones entre la antigüedad laboral y la escala de sueldos (r = 0,361; p<0,001), entre los niveles de estrés laboral y el síndrome de burnout (r= 0,512; p<0,01), y entre la satisfacción laboral y el estado de salud auto-percibida (r= 0,485; p<0,01). Conclusiones Se debe analizar y reforzar la descripción de cargos y funciones desempeñados por los trabajadores, construir indicadores de desempeño del personal, establecer mejores mecanismos para la planificación del trabajo y sistemas de información que ayuden a mejorar el modelo gerencial en la escuela.(AU)

ABSTRACT Objective To evaluate psychosocial risks, occupational stress and burnout syndrome in university workers from a Venezuelan bioanalysis school. Materials and Methods Descriptive, cross-sectional study performed with a sample of 75 workers. The analysis of psychosocial risks, occupational stress and burnout syndrome was done using the CoPsoQ-istas21 methodology. Results The main psychosocial risks were work rhythm (80.8%) and insecure working conditions (54.9%). The most unfavorable health situations included double presence (52.7%); the intermediate situations were related to role conflict (38.9%); and the most favorable situations were associated with recognition (98.6%) and vertical confidence (94.3%). Both occupational stress (3%) and burnout syndrome (5%) were observed in the most unfavorable situations. There were direct relationships between seniority and wage scale (r=0.361; p<0.001); between occupational stress and burnout syndrome (r=0.512; p<0.01); and between work satisfaction and self-perceived health status (r=0.485; p<0.01). Conclusions The description of positions and functions performed by workers should be analyzed and reinforced; moreover, staff performance indicators should be built and better mechanisms for work planning and systems of information should be established to help improve the School's managerial model.(AU)

Objetivo Para avaliar riscos psicossociais, estresse no trabalho e síndrome de burnout em trabalhadores de uma universidade de uma escola de bioanálise venezuelana. Metodologia A pesquisa foi descritiva e transversal, a amostra foi composta por 75 trabalhadores. A análise dos riscos psicossociais, estresse no trabalho e Síndrome de Burnout foi realizada pela metodologia CoPsoQ-istas21. Resultados Os principais riscos psicossociais foram o ritmo de trabalho (80,8%) e a insegurança nas condições de trabalho (54,9%) na situação mais desfavorável à saúde, dupla presença (52,7%) e conflitos de papéis (38,9%) na situação intermediária e reconhecimento (98,6%) e confiança vertical (94,3%) na situação mais favorável. Tanto o estresse no trabalho (3%) quanto a síndrome de burnout (5%) foram apresentados na situação mais desfavorável. As relações entre tempo de trabalho e escala salarial (r = 0,361; p <0,001), entre níveis de estresse no trabalho e síndrome de burnout (r = 0,512; p <0,01) e entre satisfação foram diretas. e autopercepção do estado de saúde (r = 0,485; p <0,01). Conclusões A descrição das posições e funções desempenhadas pelos trabalhadores deve ser analisada e reforçada, construindo indicadores de desempenho para a equipe, estabelecendo melhores mecanismos para o planejamento do trabalho e sistemas de informação que ajudem a melhorar o modelo de gestão na escola.(AU)

Sensibilidad y especificidad de la escala de Alvarado en apendicitis aguda en el Hospital Regional de Alta Especialidad de Veracruz / Sensitivity and specificity of the Alvarado score in acute appendicitis, and its anatomopatological correlation at the High Specialty Regional Hospital of Veracruz

Objetivo: Determinar la sensibilidad y especificidad de la escala de Alvarado en el diagnóstico de apendicitis aguda en el Hospital Regional de Alta Especialidad de Veracruz. Sede: Hospital de alta especialidad de Veracruz. Diseño: Estudio transversal, ambispectivo, descriptivo, observacional. Análisis estadístico: Regresión logística binaria, chi cuadrada (χ²), razón de momios y curvas ROC. Resultados: Se incluyeron 384 (293 retrospectivos y 91 prospectivos) pacientes con diagnóstico de probable apendicitis y que fueron operados. Mediante un análisis estadístico se encontró que con la escala de Alvarado en el punto de corte >5 se obtiene una mayor precisión diagnóstica, con sensibilidad de 0.96%, especificidad de 0.72, valor predictivo positivo de 0.93% y valor predictivo negativo de 0.82. El criterio más encontrado fue el dolor en fosa iliaca derecha, positivo en el 100% de pacientes intervenidos con apendicitis; sin embargo, el más específico fue el rebote con 94.3% de los pacientes. Conclusión: Los criterios de Alvarado son una herramienta útil para el diagnóstico de apendicitis aguda, son aplicables en todos los pacientes con dolor abdominal agudo sugestivo de apendicitis como prueba al ingreso y para descartar patología apendicular en 5 puntos o menos.

Objective: To determine the sensitivity and specificity of the Alvarado Score for the diagnosis of acute appendicitis at a high specialty regional hospital. Setting: High specialty regional hospital in the city of Veracruz, Veracruz, Mexico. Design: Cross-sectional, descriptive, ambispective observational study. Statistical analysis: Binary logistic regression, chi square (χ2), odds ratio and ROC curves. Results: The study included 384 (293 retrospective and 91 prospective) patients with a diagnosis of probable appendicitis and who were operated. Statistical analysis revealed that a better diagnostic accuracy is achieved with the Alvarado Score at a cut off >5, with a sensitivity of 0.96%, specificity of 0.72, positive predictive value of 0.93% and negative predictive value of 0.82. The most frequently found criterion was pain in the right iliac fossa positive in 100% of patients with appendicitis subjected to surgery; however, the most specific criterion was the rebound with 94.3% of patients. Conclusion: Criteria of the Alvarado Score are a useful tool for the diagnosis of acute appendicitis, it is applicable to all patients with acute abdominal pain suggestive of appendicitis as an admittance test, and to discard appendicular pathology in 5 points or less.