REPRODUCTIVE CYCLE STAGE ASSESSMENT IN THE TWO-TOED SLOTH (CHOLOEPUS HOFFMANNI), PRELIMINARY RESULTS.

The number of two-toed sloths (Choloepus hoffmanni) has significantly decreased in the last years. Deepening the knowledge of this tropical mammal's reproductive physiology is essential to improve captive breeding within conservation programs for this species. However, several aspects of its reproductive biology remain unexplored and have not been described sufficiently. The aim of this work was to describe the estrous cycle and reproductive physiology of two adult female C. hoffmanni by vaginal cytology, appearance of the external genitalia, and behavior. Vaginal cytology assay showed that the average duration of the estrous cycle was 15.1 ± 4.53 d. Positive correlations (P < 0.05) were found between the peak presence of superficial cells (estrous phase) and four parameters: aggressive behavior, pursuing behavior, vulvar swelling, and vaginal discharge. This pilot study, conducted on just two animals, forms a basis for a study design that may be employed for a more comprehensive assessment of the two-toed sloth reproductive physiology and behavior.

Human neutrophil elastase inhibitors: Classification, biological-synthetic sources and their relevance in related diseases.

BACKGROUND: Human neutrophil elastase is a multifunctional protease enzyme whose function is to break the bonds of proteins and degrade them to polypeptides or amino acids. In addition, it plays an essential role in the immune mechanism against bacterial infections and represents a key mediator in tissue remodeling and inflammation. However, when the extracellular release of this enzyme is dysregulated in response to low levels of its physiological inhibitors, it ultimately leads to the degradation of proteins, in particular elastin, as well as other components of the extracellular matrix, producing injury to epithelial cells, which can promote sustained inflammation and affect the innate immune system, and, therefore, be the basis for the development of severe inflammatory diseases, especially those associated with the cardiopulmonary system. OBJECTIVE: This review aims to provide an update on the elastase inhibitory properties of several molecules, either synthetic or biological sources, as well as their classification and relevance in related pathologies since a clear understanding of the function of these molecules with the inhibitory capacity of this protease can provide valuable information for the development of pharmacological therapies that manage to modify the prognosis and survival of various inflammatory diseases. METHODS: Collected data from scientific databases, including PubMed, Google Scholar, Science Direct, Nature, Wiley, Scopus, and Scielo. Articles published in any country and language were included. RESULTS: We reviewed and included 132 articles conceptualizing neutrophil elastase activity and known inhibitors. CONCLUSION: Understanding the mechanism of action of elastase inhibitors based on particular aspects such as their kinetic behavior, structure-function relationship, chemical properties, origin, pharmacodynamics, and experimental progress has allowed for a broad classification of HNE inhibitors.

YKL-40 serum levels are predicted by inflammatory state, age and diagnosis of idiopathic inflammatory myopathies.

YKL-40 increase according to the aging process, and its functions have been associated with tissue remodeling and systemic inflammation. In Rheumatoid Arthritis (RA) it has been proposed as a possible biomarker of activity and severity, however; in the field of idiopathic inflammatory myopathies (IIM) the role of YKL-40 in IIM is not clear. Thus, we aimed to evaluate if there is an association between the serum levels and muscle tissue expression of YKL-40 with age, IIM phenotype, muscle strength and myositis disease activity. The main finding was that age is the most important variable that affects the YKL-40 serum levels. In muscle biopsy, we observed that YKL-40 is mainly expressed in infiltrating lymphoid cells than in muscle tissue. Using ANCOVA according to the b-coefficients, YKL-40 serum levels are predicted by inflammatory state, age, and IIM diagnosis.

Efectos adversos de la radiación cósmica en personal aeronáutico: Revisión Sistemática / Side effects of cosmic radiation on aeronautic personnel: Systematic Review

Introducción: El personal de vuelo y astronautas estan sometidos a exposición ocupacional a radiación cósmica que podría producir la aparición de efectos patológicos. Hasta el momento, la evidencia disponible se orienta al estudio de patologías específicas sin recoger todos los posibles efectos adversos.Método: Revisión sistemática (RS) de la literatura publicada hasta enero 2023. Las bases de datos consultadas fue-ron PubMed, EMBASE, LILACS y Cochrane. Los descriptores utilizados fueron “Adverse effects”, “Cosmic Radiation”, y “Aeronautic”. Se incluyeron estudios con información sobre eventos adversos de la radiación cósmica en trabaja-dores expuestos. Se evaluó la calidad de la evidencia.Resultados: Se incluyeron 27 estudios (11 RS y 16 observacionales). Algunos estudios encontraron que los traba-jadores aeronáuticos tenían mayor riesgo neoplásico (cáncer de mama, cerebro, leucemia y melanoma) y de cata-ratas nucleares. Sin embargo, otros estudios no describieron el desarrollo de enfermedades neoplásicas ni otras patologías estudiadas (genéticas, ginecológicas o cardiovasculares) por radiaciones ionizantes. La calidad de las RS (AMSTAR–2) fue críticamente baja en la mayoría, y los estudios observacionales (STROBE) obtuvieron una media de alrededor del 72%.Conclusiones: La evidencia disponible no permite encontrar causalidad directa entre exposición a radiación cós-mica y aparición de patologías en personal expuesto. Se consideran necesarios nuevos estudios bien diseñados (AU)

Introduction: Aircrew and astronauts are subject to cosmic radiation as part of their jobs and could be associated with various pathological effects. Until now, available evidence is oriented to the study of specific pathologies with-out consideration of all possible adverse effects.Method: A systematic review (SR) from literature found until 2023 January. The databases included were PubMed, EMBASE, LILACS and Cochrane. The following descriptors used “Adverse effects” “Cosmic Radiation” and “Aeronau-tic”. Included studies had information on adverse effects of cosmic radiation in exposed workers. We assessed the quality of the evidence.Results: 27 studies were included (11 SR and 16 observational). Some articles determined that aeronautic person-nel have a higher cancer risk (breast, brain, leukemia and melanoma) and nuclear cataracts. However, other studies did not describe neoplastic diseases or other studied pathologies (genetics, gynecological, cardiovascular) due to ionizing radiation. The quality of the SR (AMSTAR-2) was critically low in the vast majority and the average quality for observational studies (STROBE) around 72%.Conclusions: Available evidence does not allow us to find direct causality between exposure to cosmic radiation and the appearance of pathologies in exposed personnel. New well-designed studies considered necessary. (AU)

Pleiotrophin and the Expression of Its Receptors during Development of the Human Cerebellar Cortex.

During embryonic and fetal development, the cerebellum undergoes several histological changes that require a specific microenvironment. Pleiotrophin (PTN) has been related to cerebral and cerebellar cortex ontogenesis in different species. PTN signaling includes PTPRZ1, ALK, and NRP-1 receptors, which are implicated in cell differentiation, migration, and proliferation. However, its involvement in human cerebellar development has not been described so far. Therefore, we investigated whether PTN and its receptors were expressed in the human cerebellar cortex during fetal and early neonatal development. The expression profile of PTN and its receptors was analyzed using an immunohistochemical method. PTN, PTPRZ1, and NRP-1 were expressed from week 17 to the postnatal stage, with variable expression among granule cell precursors, glial cells, and Purkinje cells. ALK was only expressed during week 31. These results suggest that, in the fetal and neonatal human cerebellum, PTN is involved in cell communication through granule cell precursors, Bergmann glia, and Purkinje cells via PTPRZ1, NRP-1, and ALK signaling. This communication could be involved in cell proliferation and cellular migration. Overall, the present study represents the first characterization of PTN, PTPRZ1, ALK, and NRP-1 expression in human tissues, suggesting their involvement in cerebellar cortex development.

Anti-Drug Antibodies in the Biological Therapy of Autoimmune Rheumatic Diseases.

Autoimmune rheumatic diseases are a cluster of heterogeneous disorders that share some clinical symptoms such as pain, tissue damage, immune deregulation, and the presence of inflammatory mediators. Biologic disease-modifying antirheumatic drugs are some of the most effective treatments for rheumatic diseases. However, their molecular and pharmacological complexity makes them potentially immunogenic and capable of inducing the development of anti-drug antibodies. TNF inhibitors appear to be the main contributors to immunogenicity because they are widely used, especially in rheumatoid arthritis. Immunogenicity response on these treatments is crucial since the appearance of ADAs has consequences in terms of safety and efficacy. Therefore, this review proposes an overview of the immunogenicity of biological agents used in autoimmune rheumatic diseases highlighting the prevalence of anti-drug antibodies.

First pan-specific vNAR against human TGF-ß as a potential therapeutic application: in silico modeling assessment.

Immunotherapies based on antibody fragments have been developed and applied to human diseases, describing novel antibody formats. The vNAR domains have a potential therapeutic use related to their unique properties. This work used a non-immunized Heterodontus francisci shark library to obtain a vNAR with recognition of TGF-ß isoforms. The isolated vNAR T1 selected by phage display demonstrated binding of the vNAR T1 to TGF-ß isoforms (-ß1, -ß2, -ß3) by direct ELISA assay. These results are supported by using for the first time the Single-Cycle kinetics (SCK) method for Surface plasmon resonance (SPR) analysis for a vNAR. Also, the vNAR T1 shows an equilibrium dissociation constant (KD) of 9.61 × 10-8 M against rhTGF-ß1. Furthermore, the molecular docking analysis revealed that the vNAR T1 interacts with amino acid residues of TGF-ß1, which are essential for interaction with type I and II TGF-ß receptors. The vNAR T1 is the first pan-specific shark domain reported against the three hTGF-ß isoforms and a potential alternative to overcome the challenges related to the modulation of TGF-ß levels implicated in several human diseases such as fibrosis, cancer, and COVID-19.

Pharmaco-invasive Strategy in Myocardial Infarction: Descriptive Analysis, Presentation of Ischemic Symptoms and Mortality Predictors. / Estratégia Fármaco-Invasiva no Infarto do Miocárdio: Análise Descritiva, Apresentação de Sintomas Isquêmicos e Preditores de Mortalidade.

BACKGROUND: ST-segment elevation myocardial infarction (STEMI) is defined by symptoms accompanied by typical electrocardiogram changes. However, the characterization of ischemic symptoms is unclear, especially in subgroups such as women and the elderly. OBJECTIVES: To analyze the typification of ischemic symptoms, temporal metrics and observe the occurrence of in-hospital outcomes, in the analysis of predictive scores, in patients with STEMI, in a drug-invasive strategy. METHODS: Study involving 2,290 patients. Types of predefined clinical presentations: typical pain, atypical pain, dyspnea, syncope. We measured the time between the onset of symptoms and demand for care and the interval between arrival at the medical unit and thrombolysis. Odds-ratios (OR; CI-95%) were estimated in a regression model. ROC curves were constructed for mortality predictors. The adopted significance level (alpha) was 5%. RESULTS: Women had a high prevalence of atypical symptoms; longer time between the onset of symptoms and seeking care; delay between arrival at the emergency room and fibrinolysis. Hospital mortality was 5.6%. Risk prediction by Killip-Kimball classification: AUC: [0.77 (0.73-0.81)] in class ≥II. Subgroups studied [OR (CI-95%)]: women [2.06 (1.42-2.99); p=0.01]; chronic renal failure [3.39 (2.13-5.42); p<0.001]; elderly [2.09 (1.37-3.19) p<0.001]; diabetics [1.55 (1.04-2.29); p=0.02]; obese 1.56 [(1.01-2.40); p=0.04]: previous stroke [2.01 (1.02-3.96); p=0.04] correlated with higher mortality rates. CONCLUSION: Despite higher mortality rates in some subgroups, significant disparity persists in women, with delays in symptom recognition and prompt thrombolysis. We highlight the applicability of the Killip-Kimball score in prediction, regardless of the clinical presentation.

FUNDAMENTO: O infarto do miocárdio com elevação do segmento-ST (IAMCSST) é definido por sintomas acompanhados por alterações típicas do eletrocardiograma. Entretanto, a caracterização dos sintomas isquêmicos não é clara, principalmente em subgrupos, como mulheres e idosos. OBJETIVOS: Analisar a tipificação dos sintomas isquêmicos, métricas temporais e observar a ocorrência de desfechos intra-hospitalares, em análise dos escores preditivos, em pacientes com IAMCSST, em estratégia fármaco-invasiva. MÉTODOS: Estudo envolvendo 2.290 pacientes. Tipos de apresentações clínicas pré-definidas: dor típica, dor atípica, dispnéia, sincope. Medimos o tempo entre o início dos sintomas à demanda pelo atendimento e o intervalo entre a chegada à unidade-médica e trombólise. Odds-ratios (OR; IC-95%) foram estimadas em modelo de regressão. Curvas ROCs foram construídas para preditores de mortalidade. Nível de significância adotado (alfa) foi de 5%. RESULTADOS: Mulheres apresentaram alta prevalência de sintomas atípicos; maior tempo entre o início dos sintomas e a procura por atendimento; atraso entre a chegada ao pronto-socorro e a fibrinólise. A mortalidade hospitalar foi de 5,6%. Predição de risco pela classificação Killip-Kimball: AUC: [0,77 (0,73-0,81)] em classe ≥II. Subgrupos estudados [OR (IC-95%)]: mulheres [2,06 (1,42-2,99); p=0,01]; insuficiência renal crônica [3,39 (2,13-5,42); p<0,001]; idosos [2,09 (1,37-3,19) p<0,001]; diabéticos [1,55 (1,04-2,29); p=0,02]; obesos 1,56 [(1,01-2,40); p=0,04]; acidente vascular cerebral prévio [2,01 (1,02-3,96); p=0,04] correlacionaram-se com maiores taxas de mortalidade. CONCLUSÃO: Apesar das mais altas taxas de mortalidade em alguns subgrupos, disparidade significativa persiste nas mulheres, com atrasos no reconhecimento dos sintomas e trombólise imediata. Destaca-se a aplicabilidade do escore Killip-Kimball na predição, independentemente da apresentação clínica.

Riesgos a la Salud Mental de las Personas Cuidadoras durante la Pandemia por COVID-19 en México / Mental Health Risks of Caregivers during the COVID-19 Pandemic in Mexico

Resumen Diversos estudios han reportado que el cuidado informal de adultos mayores, personas con alguna enfermedad o discapacidad, e incluso el cuidado de menores de edad, tiene un impacto en la salud física y mental de las personas cuidadoras (PC). El objetivo del presente estudio fue identificar los riesgos a la salud mental de las PC, teniendo como referencia el concepto de "carga de cuidado" que alude a las demandas físicas, emocionales, sociales y/o económicas de las actividades de cuidado, y la tensión que estas producen. Los participantes respondieron a un tamizaje entre abril y diciembre de 2020, vía una plataforma electrónica, mismo que tuvo por objeto identificar y atender problemas de salud mental que pudieran presentarse o agravarse por la pandemia y las medidas de confinamiento adoptadas para mitigarla. Más de 51,000 personas reportaron ser PC de menores, adultos mayores y/o enfermos crónicos, lo que permitió identificar variaciones en la carga de cuidado considerando el impacto de distintos perfiles de cuidadores (según el tipo y número de personas dependientes). Las condiciones de salud mental evaluadas fueron estrés agudo, ansiedad generalizada, ansiedad por la salud y depresión. Los resultados confirman que las PC que cuidan más de un tipo de persona dependiente tienen mayores probabilidades de riesgo a desarrollar alguna de las condiciones de salud mental. Así mismo, quienes cuidaban alguna persona con enfermedad crónica fueron los más vulnerables, mientras que tener un menor de edad al cuidado actuó en alguna medida como un factor protector.

Abstract Several studies have reported that informal care of older adults, chronically ill, and children's, has an impact on physical and mental health of caregivers. The goal of this study was to identify mental health risks of caregivers, considering the concept of caregiver burden that points to the physical, emotional, social and/or economic demands of care activities, and the tension they produce. Participants answered a mental health screening (via an electronic platform) that intended to identify and attend mental health problems that could arise or be aggravated during the pandemic and confinement measures adopted to mitigate it. More than 51,000 people reported being caregivers of children, older people and/or chronically ill, which allows to identify variations in caregiver burden considering type and number of dependent people. The mental health conditions evaluated were acute stress, generalized anxiety, health anxiety, and depression. Results confirmed that caregivers who take care of more than one type of dependent are more likely to be at risk of developing any of the mental health conditions measured. Likewise, those who care for a chronically ill, were the most vulnerable and, to take care of children was at some extent a protective factor.

Discovery of ABBV-3373, an Anti-TNF Glucocorticoid Receptor Modulator Immunology Antibody Drug Conjugate.

Using a convergent synthetic route to enable multiple points of diversity, a series of glucocorticoid receptor modulators (GRM) were profiled for potency, selectivity, and drug-like properties in vitro. Despite covering a large range of diversity, profiling the nonconjugated small molecule was suboptimal and they were conjugated to a mouse antitumor necrosis factor (TNF) antibody using the MP-Ala-Ala linker. Screening of the resulting antibody drug conjugates (ADCs) provided a better assessment of efficacy and physical properties, reinforcing the need to conduct structure-activity relationship studies on the complete ADC. DAR4 ADCs were screened in an acute mouse contact hypersensitivity model measuring biomarkers to ensure a sufficient therapeutic window. In a chronic mouse arthritis model, mouse anti-TNF GRM ADCs were efficacious after a single dose of 10 mg/kg i.p. for over 30 days. Data on the unconjugated payloads and mouse surrogate anti-TNF ADCs identified payload 17 which was conjugated to a human anti-TNF antibody and advanced to the clinic as ABBV-3373.

Estratégia Fármaco-Invasiva no Infarto do Miocárdio: Análise Descritiva, Apresentação de Sintomas Isquêmicos e Preditores de Mortalidade / Pharmaco-invasive Strategy in Myocardial Infarction: Descriptive Analysis, Presentation of Ischemic Symptoms and Mortality Predictors

Resumo Fundamento O infarto do miocárdio com elevação do segmento-ST (IAMCSST) é definido por sintomas acompanhados por alterações típicas do eletrocardiograma. Entretanto, a caracterização dos sintomas isquêmicos não é clara, principalmente em subgrupos, como mulheres e idosos. Objetivos Analisar a tipificação dos sintomas isquêmicos, métricas temporais e observar a ocorrência de desfechos intra-hospitalares, em análise dos escores preditivos, em pacientes com IAMCSST, em estratégia fármaco-invasiva. Métodos Estudo envolvendo 2.290 pacientes. Tipos de apresentações clínicas pré-definidas: dor típica, dor atípica, dispnéia, sincope. Medimos o tempo entre o início dos sintomas à demanda pelo atendimento e o intervalo entre a chegada à unidade-médica e trombólise. Odds-ratios (OR; IC-95%) foram estimadas em modelo de regressão. Curvas ROCs foram construídas para preditores de mortalidade. Nível de significância adotado (alfa) foi de 5%. Resultados Mulheres apresentaram alta prevalência de sintomas atípicos; maior tempo entre o início dos sintomas e a procura por atendimento; atraso entre a chegada ao pronto-socorro e a fibrinólise. A mortalidade hospitalar foi de 5,6%. Predição de risco pela classificação Killip-Kimball: AUC: [0,77 (0,73-0,81)] em classe ≥II. Subgrupos estudados [OR (IC-95%)]: mulheres [2,06 (1,42-2,99); p=0,01]; insuficiência renal crônica [3,39 (2,13-5,42); p<0,001]; idosos [2,09 (1,37-3,19) p<0,001]; diabéticos [1,55 (1,04-2,29); p=0,02]; obesos 1,56 [(1,01-2,40); p=0,04]; acidente vascular cerebral prévio [2,01 (1,02-3,96); p=0,04] correlacionaram-se com maiores taxas de mortalidade. Conclusão Apesar das mais altas taxas de mortalidade em alguns subgrupos, disparidade significativa persiste nas mulheres, com atrasos no reconhecimento dos sintomas e trombólise imediata. Destaca-se a aplicabilidade do escore Killip-Kimball na predição, independentemente da apresentação clínica.

Abstract Background ST-segment elevation myocardial infarction (STEMI) is defined by symptoms accompanied by typical electrocardiogram changes. However, the characterization of ischemic symptoms is unclear, especially in subgroups such as women and the elderly. Objectives To analyze the typification of ischemic symptoms, temporal metrics and observe the occurrence of in-hospital outcomes, in the analysis of predictive scores, in patients with STEMI, in a drug-invasive strategy. Methods Study involving 2,290 patients. Types of predefined clinical presentations: typical pain, atypical pain, dyspnea, syncope. We measured the time between the onset of symptoms and demand for care and the interval between arrival at the medical unit and thrombolysis. Odds-ratios (OR; CI-95%) were estimated in a regression model. ROC curves were constructed for mortality predictors. The adopted significance level (alpha) was 5%. Results Women had a high prevalence of atypical symptoms; longer time between the onset of symptoms and seeking care; delay between arrival at the emergency room and fibrinolysis. Hospital mortality was 5.6%. Risk prediction by Killip-Kimball classification: AUC: [0.77 (0.73-0.81)] in class ≥II. Subgroups studied [OR (CI-95%)]: women [2.06 (1.42-2.99); p=0.01]; chronic renal failure [3.39 (2.13-5.42); p<0.001]; elderly [2.09 (1.37-3.19) p<0.001]; diabetics [1.55 (1.04-2.29); p=0.02]; obese 1.56 [(1.01-2.40); p=0.04]: previous stroke [2.01 (1.02-3.96); p=0.04] correlated with higher mortality rates. Conclusion Despite higher mortality rates in some subgroups, significant disparity persists in women, with delays in symptom recognition and prompt thrombolysis. We highlight the applicability of the Killip-Kimball score in prediction, regardless of the clinical presentation.

ß-Caryophyllene, a Dietary Cannabinoid, Protects Against Metabolic and Immune Dysregulation in a Diet-Induced Obesity Mouse Model.

Obesity is an abnormal or excessive accumulation of fat in the body that exacerbates metabolic and inflammatory processes, and impairs the health of afflicted individuals. ß-caryophyllene is a natural sesquiterpene that is a dietary cannabinoid with anti-inflammatory properties and potential activity against metabolic diseases. In the present study, we evaluated the effect of ß-caryophyllene on C57BL/6 mice using a diet-induced obesity model. Male mice were randomly assigned to the following groups over a 16-week period: (1) standard diet as lean control, (2) high-fat diet (HFD) as obese control, and (3) HFD + ß-caryophyllene with ß-caryophyllene at 50 mg/kg. Treatment with ß-caryophyllene improved various metabolic parameters including increased total body weight, fasting glucose levels, oral-glucose tolerance, insulin tolerance, fasting triglycerides, adipocyte hypertrophy, and liver macrovesicular steatosis. ß-caryophyllene also modulated the levels and expression of immune response factors including adiponectin, leptin, insulin, interleukin-6, tumor necrosis factor-a, and Toll-like receptor-4. Our data indicate that chronic supplementation with ß-caryophyllene can improve relevant metabolic and immunological processes in obese mice. This protocol was approved by the Institutional Committee for Care and Use of Laboratory Animals from the University of Guadalajara with protocol code CUCEI/CINV/CICUAL-01/2022.

Effects of Etanercept on TNF-α Inhibition in Rats with Adenine-Induced Chronic Kidney Disease.

Introduction: Chronic kidney disease (CKD) constitutes a chronic inflammatory state associated with an increase in inflammatory mediators and profibrotic molecules such as tumor necrosis factor-α (TNF-α). Etanercept (ETA) is a TNF inhibitor widely used in treatment of autoimmune inflammatory diseases. However, the effects of TNF-α inhibition in the establishment of CKD have not been fully elucidated. We evaluate the effects of TNF inhibition by ETA in adenine- (Ad-) induced CKD in rats. Methods: Rats were divided into three groups: control, renal injury model, and model plus ETA (2 mg/kg, 3 times per week (w); sc). Renal injury was induced by Ad administration (100 mg/kg, daily for 2 or 4 w; orogastric). Serum TNF-α levels and biochemical parameters for renal function were evaluated. Histopathological changes in the kidney were assessed using H&E and Masson's trichrome staining and also immunostaining for tubular cells. Results: Ad administration produced a renal functional decline, tubular atrophy, interstitial inflammation, and fibrosis for 2 w, followed by renal anemia, several renal dysfunctions, tubular atrophy, and fibrosis at 4 w. A significant increase in serum TNF-α levels was observed from 2 w of Ad administration and remained elevated up to 4 w. Treatment with ETA partially reduced kidney damage but was very effective to blocking serum TNF-α. Conclusion: Although inhibition of TNF by ETA was very effective in reducing serum TNF-α, this strategy was partially effective in preventing Ad-induced CKD.

Screening Tool for Mental Health Problems During COVID-19 Pandemic: Psychometrics and Associations With Sex, Grieving, Contagion, and Seeking Psychological Care.

Background: The COVID-19 pandemic has created a public mental health crisis. Brief, valid electronic tools are required to evaluate mental health status, identify specific risk factors, and offer treatment when needed. Objective: To determine the construct validity, reliability, and measurement invariance of a brief screening tool for mental health symptoms by sex, loss of loved ones, personal COVID-19 status, and psychological care-seeking during the COVID-19 pandemic. Furthermore, the aim involved establishing a predictive pattern between the mental health variables. Method: A total sample of 27,320 Mexican participants, with a mean age of 32 years (SD = 12.24, range = 18-80), 67% women (n = 18,308), 23.10% with a loss of loved ones (n = 6,308), 18.3% with COVID-19 status (n = 5,005), and 18.40% seeking psychological care (n = 5,026), completed a questionnaire through a WebApp, containing socio-demographic data (sex, loss of loved ones, COVID-19 status, and psychological care-seeking) and the dimensions from the Posttraumatic Checklist, Depression-Generalized Anxiety Questionnaires, and Health Anxiety-Somatization scales. We used the confirmatory factor analysis (CFA: through maximum likelihood to continuous variable data, as an estimation method), the invariance measurement, and the structural equational modeling (SEM) to provide evidence of the construct validity of the scale and the valid path between variables. We analyzed the measurement invariance for each dimension by comparison groups to examine the extent to which the items showed comparable psychometric properties. Findings: The tool included eight dimensions: four posttraumatic stress symptoms -intrusion, avoidance, hyperactivation, and numbing, as well as depression, generalized anxiety, health anxiety, and somatization The tool's multidimensionality, was confirmed through the CFA and SEM. The participants' characteristics made it possible to describe the measurement invariance of scales because of the participants' attributes. Additionally, our findings indicated that women reported high generalized anxiety, hyperactivation, and depression. Those who lost loved ones reported elevated levels of intrusion and health anxiety symptoms. Participants who reported having COVID-19 presented with high levels of generalized anxiety symptoms. Those who sought psychological care reported high levels of generalized anxiety, intrusion, hyperactivation, and health anxiety symptoms. Our findings also show that intrusion was predicted by the avoidance dimension, while health anxiety was predicted by the intrusion dimension. Generalized anxiety was predicted by the health anxiety and hyperactivation dimensions, and hyperactivation was predicted by the depression one. Depression and somatization were predicted by the health anxiety dimension. Last, numbing was predicted by the depression and avoidance dimensions. Discussion and Outlook: Our findings indicate that it was possible to validate the factor structure of posttraumatic stress symptoms and their relationship with depression, anxiety, and somatization, describing the specific bias as a function of sociodemographic COVID-19-related variables. We also describe the predictive pattern between the mental health variables. These mental health problems were identified in the community and primary health care scenarios through the CFA and the SEM, considering the PCL, depression, generalized anxiety, health anxiety, and somatization scales adapted during the COVID-19 pandemic. Therefore, future studies should describe the diagnosis of mental health disorders, assessing the cut-off points in the tool to discriminate between the presence and absence of conditions and mental health cut-off points. Community and primary care screening will lead to effective early interventions to reduce the mental health risks associated with the current pandemic. Limitations: Future studies should follow up on the results of this study and assess consistency with diagnoses of mental health disorders and evaluate the effect of remote psychological help. Moreover, in the future, researchers should monitor the process and the time that has elapsed between the occurrence of traumatic events and the development of posttraumatic stress and other mental health risks through brief electronic measurement tools such as those used in this study.

Suicide Risk in Rheumatoid Arthritis Patients is Associated With Suboptimal Vitamin D Levels.

BACKGROUND/OBJECTIVE: Rheumatoid arthritis (RA) patients might experience anxiety and depressive symptoms. Deficient vitamin D levels may be a trigger for these conditions. The aim of this study was to determine the frequency of depression, anxiety symptoms, and suicidal risk or ideation in patients with RA associated with vitamin D serum levels. METHODS: In this cross-sectional study, we recruited RA patients older than 18 years, classified into 3 groups according to serum vitamin D levels: sufficient, ≥30 ng/mL; insufficient, 20-29 ng/mL; and deficient, <20 ng/mL. Based on the self-reported Plutchik and the Hospital Anxiety and Depression Scale, we evaluated the association of suicidal risk, depression, and anxiety with the vitamin D levels in RA and the Rheumatoid Arthritis Quality-of-Life Questionnaire. RESULTS: We studied 72 patients with RA between January and October 2019. We found an inverse correlation between Plutchik score and suicidal risk with inadequate vitamin D levels, but not with the Hospital Anxiety and Depression Scale. Suicidal ideation was associated with a higher score on the Rheumatoid Arthritis Quality-of-Life Questionnaire. CONCLUSIONS: Despite the high prevalence of depressive and anxiety symptoms in RA patients, a Plutchik low correlation coefficient with inadequate serum levels of vitamin D was found. However, in the analysis of covariance, we were able to find that vitamin D levels remain associated with a reduction of suicide ideation. Further studies are needed to identify a risk profile for early psychological interventions to improve the quality of life in RA patients.

Presenilin mutations and their impact on neuronal differentiation in Alzheimer's disease.

The presenilin genes (PSEN1 and PSEN2) are mainly responsible for causing early-onset familial Alzheimer's disease, harboring ~300 causative mutations, and representing ~90% of all mutations associated with a very aggressive disease form. Presenilin 1 is the catalytic core of the γ-secretase complex that conducts the intramembranous proteolytic excision of multiple transmembrane proteins like the amyloid precursor protein, Notch-1, N- and E-cadherin, LRP, Syndecan, Delta, Jagged, CD44, ErbB4, and Nectin1a. Presenilin 1 plays an essential role in neural progenitor maintenance, neurogenesis, neurite outgrowth, synaptic function, neuronal function, myelination, and plasticity. Therefore, an imbalance caused by mutations in presenilin 1/γ-secretase might cause aberrant signaling, synaptic dysfunction, memory impairment, and increased Aß42/Aß40 ratio, contributing to neurodegeneration during the initial stages of Alzheimer's disease pathogenesis. This review focuses on the neuronal differentiation dysregulation mediated by PSEN1 mutations in Alzheimer's disease. Furthermore, we emphasize the importance of Alzheimer's disease-induced pluripotent stem cells models in analyzing PSEN1 mutations implication over the early stages of the Alzheimer's disease pathogenesis throughout neuronal differentiation impairment.

The Chosen Few: Parallel Library Reaction Methodologies for Drug Discovery.

Parallel library synthesis is an important tool for drug discovery because it enables the synthesis of closely related analogues in parallel via robust and general synthetic transformations. In this perspective, we analyzed the synthetic methodologies used in >5000 parallel libraries representing 15 prevalent synthetic transformations. The library data set contains complex substrates and diverse arrays of building blocks used over the last 14 years at AbbVie. The library synthetic methodologies that have demonstrated robustness and generality with proven success are described along with their substrate scopes. The evolution of the synthetic methodologies for library synthesis over the past decade is discussed. We also highlight that the combination of parallel library synthesis with high-throughput experimentation will continue to facilitate the discovery of library-amenable synthetic methodologies in drug discovery.

Mental Health Symptoms, Binge Drinking, and the Experience of Abuse During the COVID-19 Lockdown in Mexico.

Background: The health crisis associated with the COVID-19 pandemic is causally linked to negative mental health symptoms in the same way as other diseases such as Ebola. Objective: The purpose of this paper is to describe the relationship between mental health symptoms, binge drinking, and the experience of abuse during the COVID-19 lockdown. Method: We surveyed 9,361 participants, all Mexican, with an average age of 33 years old (SD = 10.86). In this group of people, we found out that 59% were single (5,523), 71% were women (6,693). Forty-six percentage were complying with lockdown procedures (4,286), 50% were partially complying (4,682), and 4% were not complying at all (393). The invitation to participate was open from April 24th to April 30th during the second stage of the pandemic in Mexico, in 2020, characterized by voluntary complete lockdown staying at home. Thus, we used a cross-sectional online survey design to assess mental health risk factors related to the COVID-19 pandemic. The survey was available on a WebApp designed by Linux®, PHP®, HTML®, CSS®, and JavaScript®. We calculated descriptive and inferential analysis to describe the mental health average distribution as a function of the lockdown, binge drinking, and experience of abuse. To calculate the reliability and validation of the subscales, we used Cronbach's Alpha and Factor Loading. We run the confirmatory factor loading analysis, and we described the relationship between each latent variable and its item factor load, obtained through structural modeling equations, derived from 179 iterations and 207 parameters (t[1,171] = 28,079.418, p < 0.001). We got a CFI of 0.947, a TLC of 0.940, an RMSEA of 0.049 (0.049-0.050), and an SRMR of 0.048. Findings: The results indicated that reported attitudes such as avoidance, sadness, withdrawal, anger, and anxiety were associated with acute stress, which was linked to an anxiety condition caused by uncertainty about achieving or maintaining overall good health. Discussion and Prospects: People in lockdown mentioned a sudden increase in alcohol consumption. They lived episodes of physical and emotional abuse, in contrast with those who stated that they did not go into lockdown or consume alcohol, or experienced abuse. Limitations: Further studies should diagnose mental health conditions as part of the impact of COVID-19, ensure their follow-up, and assess the effect of providing remote psychological care. There is a need to explore methods to curb the increase in the number of people affected by post-traumatic stress disorder.

ChemBead Enabled High-Throughput Cross-Electrophile Coupling Reveals a New Complementary Ligand.

High-throughput experimentation (HTE) methods are central to modern medicinal chemistry. While many HTE approaches to C-N and Csp2 -Csp2 bonds are available, options for Csp2 -Csp3 bonds are limited. We report here how the adaptation of nickel-catalyzed cross-electrophile coupling of aryl bromides with alkyl halides to HTE is enabled by AbbVie ChemBeads technology. By using this approach, we were able to quickly map out the reactivity space at a global level with a challenging array of 3×222 micromolar reactions. The observed hit rate (56 %) is competitive with other often-used HTE reactions and the results are scalable. A key to this level of success was the finding that bipyridine 6-carboxamidine (BpyCam), a ligand that had not previously been shown to be optimal in any reaction, is as general as the best-known ligands with complementary reactivity. Such "cryptic" catalysts may be common and modern HTE methods should facilitate the process of finding these catalysts.