Integrating Mechanics and Bioactivity: A Detailed Assessment of Elasticity and Viscoelasticity at Different Scales in 2D Biofunctionalized PEGDA Hydrogels for Targeted Bone Regeneration.

Methods for promoting and controlling the differentiation of human mesenchymal stem cells (hMSCs) in vitro before in vivo transplantation are crucial for the advancement of tissue engineering and regenerative medicine. In this study, we developed poly(ethylene glycol) diacrylate (PEGDA) hydrogels with tunable mechanical properties, including elasticity and viscoelasticity, coupled with bioactivity achieved through the immobilization of a mixture of RGD and a mimetic peptide of the BMP-2 protein. Despite the key relevance of hydrogel mechanical properties for cell culture, a standard for its characterization has not been proposed, and comparisons between studies are challenging due to the different techniques employed. Here, a comprehensive approach was employed to characterize the elasticity and viscoelasticity of these hydrogels, integrating compression testing, rheology, and atomic force microscopy (AFM) microindentation. Distinct mechanical behaviors were observed across different PEGDA compositions, and some consistent trends across multiple techniques were identified. Using a photoactivated cross-linker, we controlled the functionalization density independently of the mechanical properties. X-ray photoelectrin spectroscopy and fluorescence microscopy were employed to evaluate the functionalization density of the materials before the culturing of hMSCs on them. The cells cultured on all functionalized hydrogels expressed an early osteoblast marker (Runx2) after 2 weeks, even in the absence of a differentiation-inducing medium compared to our controls. Additionally, after only 1 week of culture with osteogenic differentiation medium, cells showed accelerated differentiation, with clear morphological differences observed among cells in the different conditions. Notably, cells on stiff but stress-relaxing hydrogels exhibited an overexpression of the osteocyte marker E11. This suggests that the combination of the functionalization procedure with the mechanical properties of the hydrogel provides a potent approach to promoting the osteogenic differentiation of hMSCs.

The treatment of bacterial biofilms cultivated on knee arthroplasty implants using the bioelectric effect.

Introduction: The formation of bacterial biofilms on knee arthroplasty implants can have catastrophic consequences. The aim of this study was to analyze the effectiveness of the bioelectric effect in the elimination of bacterial biofilms on cultivated knee arthroplasty implants. Methods: A novel device was designed to deliver a bioelectric effect on the surface of knee arthroplasty implants. 4-femoral prosthetic implants were cultivated with a staphylococcus aureus inoculum for 15 days. The components were divided into four different groups: A (not treated), B (normal saline 20-minutes), C (bioelectric effect 10-minutes), D (bioelectric effect 20-minutes). The implants were sonicated, and the detached colonies were quantified as the number of colony-forming unit (CFUs). The implants were sterilised and the process was repeated in a standardized manner four more times, to obtain a total of five samples per group. Results: The number of the CFUs after a 10-minute exposure to the bioelectric effect was of 208.2 ± 240.4, compared with 6,041.6 ± 2010.7 CFUs in group A, representing a decrease of 96.5% ± 4.3 (p = 0.004). And a diminution of 91.8% ± 7.9 compared with 2,051.0 ± 1,364.0 CFUs in group B (p = 0.109). The number of bacterial colonies after a 20-minute exposure to the bioelectric effect was 70 ± 126.7 CFUs, representing a decrease of 98.9% ± 1.9 (p = 0.000) compared with group A. And a decrease of 97.8% ± 3.0 (p = 0.019) compared with group B. Conclusions: The bioelectric effect was effective in the elimination of bacterial biofilm from knee arthroplasty implants. This method could be used in the future as part of conventional surgical procedures.

Nobiletin as a novel agent to enhance porcine in vitro embryo development and quality.

In vitro embryo production (IVP) is of great importance to the porcine industry, as well as for basic research and biomedical applications. Despite the large efforts made in laboratories worldwide to address suboptimal culture conditions, porcine IVP remains inefficient. Nobiletin (Nob, 5,6,7,8,3',4' hexamethoxyflavone) supplementation to in vitro culture (IVC) medium, enhances in vitro embryo development in various species. However, its impact on the quality and developmental capacity of in vitro-produced pig embryos is yet to be established. This study evaluated the effects of different concentrations (2.5 and 5 µM) of Nob during the early culture of in vitro-produced pig embryos on embryo developmental competence, mitochondrial activity, lipid content, intracellular Reactive Oxygen Species (ROS) and Glutathione (GSH) content, Total Cell Number (TCN) per blastocyst, and expression of genes related to embryo development, quality and oxidative stress. Embryos cultured in medium without Nob supplementation and in medium supplemented with 0.01 % dimethyl sulfoxide (DMSO-vehicle for Nob) constituted the Control and DMSO groups, respectively. Embryo development rates were evaluated on Days 2, 6 and 7 of IVC. Additionally, a representative group of embryos was selected to assess mitochondrial activity, lipid, ROS and GSH content (on Days 2 and 6 of IVC), TCN assessment and gene expression analyses (on Day 6 of IVC). No significant differences were observed in any of the parameters evaluated on Day 2 of IVC. In contrast, embryos cultured under the presence of Nob 2.5 showed higher developmental rates on Days 6 and 7 of IVC. In addition, Day 6 embryos showed increased mitochondrial activity, with decreased levels of ROS and GSH in the Nob 2.5 group compared to the other groups. Both Nob 2.5 and Nob 5 embryos showed higher TCN compared to the Control and DMSO groups. Furthermore, Nob 2.5 and Nob 5 upregulated the expression of Superoxide dismutase type 1 (SOD1) and Glucose-6-phosphate dehydrogenase (G6PDH) genes, which could help to counteract oxidative stress during IVC. In conclusion, the addition of Nob during the first 48 h of IVC increased porcine embryo development rates and enhanced their quality, including the upregulation of relevant genes that potentially improved the overall efficiency of the IVP system.

Reproductive physiology of the boar: What defines the potential fertility of an ejaculate?

Despite decades of research and handling of semen for use in artificial insemination (AI) and other assisted reproductive technologies, 5-10% of selected boar sires are still considered sub-fertile, escaping current assessment methods for sperm quality and resilience to preservation. As end-product, the ejaculate (emitted spermatozoa sequentially exposed to the composite seminal plasma, the SP) ought to define the homeostasis of the testes, the epididymis, and the accessory sexual glands. Yet, linking findings in the ejaculate to sperm production biology and fertility is suboptimal. The present essay critically reviews how the ejaculate of a fertile boar can help us to diagnose both reproductive health and resilience to semen handling, focusing on methods -available and under development- to identify suitable biomarkers for cryotolerance and fertility. Bulk SP, semen proteins and microRNAs (miRNAs) have, albeit linked to sperm function and fertility after AI, failed to enhance reproductive outcomes at commercial level, perhaps for just being components of a complex functional pathway. Hence, focus is now on the interaction sperm-SP, comparing in vivo with ex vivo, and regarding nano-sized lipid bilayer seminal extracellular vesicles (sEVs) as priority. sEVs transport fragile molecules (lipids, proteins, nucleic acids) which, shielded from degradation, mediate cell-to-cell communication with spermatozoa and the female internal genital tract. Such interaction modulates essential reproductive processes, from sperm homeostasis to immunological female tolerance. sEVs can be harvested, characterized, stored, and manipulated, e.g. can be used for andrological diagnosis, selection of breeders, and alternatively be used as additives to improve cryosurvival and fertility.

Enrichment of Immune Dysregulation Disorders in Adult Patients with Human Inborn Errors of Immunity.

Human inborn errors of immunity (IEI) comprise a group of diseases resulting from molecular variants that compromise innate and adaptive immunity. Clinical features of IEI patients are dominated by susceptibility to a spectrum of infectious diseases, as well as autoimmune, autoinflammatory, allergic, and malignant phenotypes that usually appear in childhood, which is when the diagnosis is typically made. However, some IEI patients are identified in adulthood due to symptomatic delay of the disease or other reasons that prevent the request for a molecular study. The application of next-generation sequencing (NGS) as a diagnostic technique has given rise to an ever-increasing identification of IEI-monogenic causes, thus improving the diagnostic yield and facilitating the possibility of personalized treatment. This work was a retrospective study of 173 adults with IEI suspicion that were sequenced between 2005 and 2023. Sanger, targeted gene-panel, and whole exome sequencing were used for molecular diagnosis. Disease-causing variants were identified in 44 of 173 (25.43%) patients. The clinical phenotype of these 44 patients was mostly related to infection susceptibility (63.64%). An enrichment of immune dysregulation diseases was found when cohorts with molecular diagnosis were compared to those without. Immune dysregulation disorders, group 4 from the International Union of Immunological Societies Expert Committee (IUIS), were the most prevalent among these adult patients. Immune dysregulation as a new item in the Jeffrey Model Foundation warning signs for adults significantly increases the sensitivity for the identification of patients with an IEI-producing molecular defect.

MicroRNA expression in specific segments of the pig periovulatory internal genital tract is differentially regulated by semen or by seminal plasma.

microRNAs play pivotal roles during mammalian reproduction, including the cross-talk between gametes, embryos and the maternal genital tract. Mating induces changes in the expression of mRNA transcripts in the female, but whether miRNAs are involved remains to be elucidated. In the current study, we mapped 181 miRNAs in the porcine peri-ovulatory female reproductive tract: Cervix (Cvx), distal and proximal uterus (Dist-Ut, Prox-Ut), Utero-tubal-junction (UTJ), isthmus (Isth), ampulla (Amp), and infundibulum (Inf) when exposed to semen (natural mating (NM) or artificial insemination (AI-P1)) or to infusions of sperm-free seminal plasma (SP): the first 10 mL of the sperm rich fraction (SP-P1) or the entire ejaculate (SP-E). Among the most interesting findings, NM decreased mir-671, implicated in uterine development and pregnancy loss prior to embryo implantation, in Cvx, Dist-UT, Prox-UT, Isth, and Inf, while it increased in Amp. NM and SP-E induced the downregulation of miR-let7A-1 (Dist-UT, Prox-UT), a regulator of immunity during pregnancy. miR-34C-1, a regulator of endometrial receptivity gene expression, was increased in Dist-UT, UTJ and Amp (NM), in Prox-UT (AI-P1), and in Amp (SP-P1). miR-296, a modulator of the inflammatory response and apoptosis, was upregulated in the UTJ (all treatments). NM elicited the highest miRNA activity in the sperm reservoir (UTJ), suggesting that key-regulators such as miR-34c or miR-296 may modulate the metabolic processes linked to the adequate preparation for gamete encounter in the oviduct. Our results suggest that SP should be maintained in AI to warrant miRNA regulation within the female genital tract for reproductive success.

Funduplicatura con disección extensa de la unión esofagogástrica: lecciones aprendidas y resultados tras 178 pacientes consecutivos / Fundoplication with extensive dissection of the esophagogastric junction: Lessons learned and outcomes from 178 consecutives patients

Introducción: La cirugía antirreflujo se asocia con frecuencia a tasas significativas de recurrencia y complicaciones, habiéndose propuesto varias técnicas quirúrgicas para minimizarlas. El objetivo del estudio es evaluar los resultados a tres años de una funduplicatura con disección extensa de la unión esofagogástrica (UEG). Métodos: Estudio observacional retrospectivo que incluyó a 178 pacientes con enfermedad por reflujo gastroesofágico (ERGE) o hernia de hiato (HH) a los que se les realizó una funduplicatura con disección extensa de la UEG entre 2015 y 2020. La recidiva herniaria, los síntomas y la calidad de vida al primer año y a los tres siguientes de la cirugía fueron evaluados mediante tránsito baritado, endoscopia y cuestionarios para síntomas y calidad de vida (Gastro Esophageal Reflux Disease-Health Related Quality of Life [GERD-HRQL]). Resultados: La tasa de pirosis fue de 7,5 y 10,7% al año y a los tres siguientes, respectivamente, regurgitación de 3,8 y 6,9% y disfagia de 3,7 y 7,6%. La presencia de hernia hiatal se evidenció preoperatoriamente en 55,1% y en 7,8 y 9,6% en el seguimiento y la mediana de la escala GERD-HRQL fue de 27, 2 y 0, respectivamente. No aparecieron casos de telescopaje de la funduplicatura ni síntomas que sugieran lesión vagal. No se encontraron diferencias al comparar los distintos tipos de funduplicatura en términos de recidiva del reflujo, complicaciones o recurrencia de la hernia. Conclusiones: La funduplicatura con disección extensa de la UEG contribuye a su correcto posicionamiento y mejor anclaje, lo que asocia bajas tasas de recidiva herniaria y del reflujo, así como disminuye la posibilidad de telescopaje y lesión vagal.(AU)

Introduction: Antireflux surgery is commonly associated with significant recurrence and complication rates, and several surgical techniques have been proposed to minimize them. The aim of this study is to evaluate the results of a fundoplication with extensive dissection of the esophagogastric junction 1 and 3 years after the procedure.Methods: Retrospective observational study including 178 patients with gastroesophageal reflux disease or hiatal hernia who underwent fundoplication with extensive dissection of the esophagogastric junction between 2015 and 2020. Hernia recurrence, symptoms and quality of life at 1 and 3 years after surgery were assessed by barium transit, endoscopy and questionnaires for symptoms and quality of life (GERD-HRQL). Results: Heartburn rate was 7.5% and 10.7% at 1 and 3 years respectively, regurgitation 3.8% and 6.9% and dysphagia was 3.7% and 7.6%. The presence of hiatal hernia was evident preoperatively in 55.1% and in 7.8% and 9.6% at follow-up and the median GERD-HRQL scale was 27, 2 and 0, respectively. There were no cases of slippage of the fundoplication or symptoms suggestive of vagal injury. No differences were found when comparing the different types of fundoplication in terms of reflux and recurrence or complications. Conclusions: Fundoplication with extensive dissection of the esophagogastric junction contributes to correct positioning and better anchorage of the fundoplication, which is associated with low rates of hiatal hernia and reflux recurrence, as well as absence of slippage and lower possibility of vagal injury.(AU)

Fundoplication with extensive dissection of the esophagogastric junction: Lessons learned and outcomes from 178 consecutives patients.

INTRODUCTION: Antireflux surgery is commonly associated with significant recurrence and complication rates, and several surgical techniques have been proposed to minimize them. The aim of this study is to evaluate the results of a fundoplication with extensive dissection of the esophagogastric junction 1 and 3 years after the procedure. METHODS: Retrospective observational study including 178 patients with gastroesophageal reflux disease or hiatal hernia who underwent fundoplication with extensive dissection of the esophagogastric junction between 2015 and 2020. Hernia recurrence, symptoms and quality of life at 1 and 3 years after surgery were assessed by barium transit, endoscopy and questionnaires for symptoms and quality of life (GERD-HRQL). RESULTS: Heartburn rate was 7.5% and 10.7% at 1 and 3 years respectively, regurgitation 3.8% and 6.9% and dysphagia was 3.7% and 7.6%. The presence of hiatal hernia was evident preoperatively in 55.1% and in 7.8% and 9.6% at follow-up and the median GERD-HRQL scale was 27, 2 and 0 respectively. There were no cases of slippage of the fundoplication or symptoms suggestive of vagal injury. No differences were found when comparing the different types of fundoplication in terms of reflux and recurrence or complications. CONCLUSIONS: Fundoplication with extensive dissection of the esophagogastric junction contributes to correct positioning and better anchorage of the fundoplication, which is associated with low rates of hiatal hernia and reflux recurrence, as well as absence of slippage and lower possibility of vagal injury.

Impact of an Intervention to Promote the Vaccination of Patients with Inflammatory Bowel Disease.

Patients with inflammatory bowel disease (IBD) have a dysregulated immune system, being at high risk of opportunistic infections. Low vaccination rates hinder the prevention of such diseases. Therefore, we implemented an intervention to increase vaccination rates, and we aimed to evaluate the effect. We determined the change in professionals and the change in the vaccination rates after the intervention. A quasi-experimental study was carried out using data from 31 December 2016 to 31 December 2021. First, healthcare professionals specializing in IBD agreed on a vaccination protocol; then, this protocol was passed on to the professionals involved in vaccination. We evaluated the perception of knowledge, capacity, and intention to vaccinate patients with IBD among the professionals before and after the intervention with a survey. We also described the effectiveness of the intervention for already diagnosed patients and compared the vaccination rates between patients diagnosed prior to the intervention and newly diagnosed patients. The intervention resulted in an improved perception of knowledge, capacity, and intention to vaccinate patients with IBD among the professionals (p < 0.05). Moreover, during the post-intervention period, in the 315 patients, the vaccination rate increased for all immune-preventable diseases (p < 0.05). The professionals positively valued the intervention, and compliance with the recommended vaccination protocol in patients with IBD improved significantly.

In-depth blood immune profiling of Good syndrome patients.

Introduction: Good syndrome (GS) is a rare adult-onset immunodeficiency first described in 1954. It is characterized by the coexistence of a thymoma and hypogammaglobulinemia, associated with an increased susceptibility to infections and autoimmunity. The classification and management of GS has been long hampered by the lack of data about the underlying immune alterations, a controversy existing on whether it is a unique diagnostic entity vs. a subtype of Common Variable Immune Deficiency (CVID). Methods: Here, we used high-sensitive flow cytometry to investigate the distribution of up to 70 different immune cell populations in blood of GS patients (n=9) compared to age-matched CVID patients (n=55) and healthy donors (n=61). Results: All 9 GS patients displayed reduced B-cell counts -down to undetectable levels (<0.1 cells/µL) in 8/9 cases-, together with decreased numbers of total CD4+ T-cells, NK-cells, neutrophils, and basophils vs. age-matched healthy donors. In contrast, they showed expanded TCRγδ+ T-cells (p ≤ 0.05). Except for a deeper B-cell defect, the pattern of immune cell alteration in blood was similar in GS and (age-matched) CVID patients. In depth analysis of CD4+ T-cells revealed significantly decreased blood counts of naïve, central memory (CM) and transitional memory (TM) TCD4+ cells and their functional compartments of T follicular helper (TFH), regulatory T cells (Tregs), T helper (Th)2, Th17, Th22, Th1/Th17 and Th1/Th2 cells. In addition, GS patients also showed decreased NK-cell, neutrophil, basophil, classical monocyte and of both CD1c+ and CD141+ myeloid dendritic cell counts in blood, in parallel to an expansion of total and terminal effector TCRγδ+ T-cells. Interestingly, those GS patients who developed hypogammaglobulinemia several years after the thymoma presented with an immunological and clinical phenotype which more closely resembled a combined immune humoral and cellular defect, with poorer response to immunoglobulin replacement therapy, as compared to those in whom the thymoma and hypogammaglobulinemia were simultaneously detected. Discussion: Our findings provide a more accurate definition of the immune cell defects of GS patients and contribute to a better discrimination among GS patients between those with a pure B-cell defect vs. those suffering from a combined immunodeficiency with important consequences on the diagnosis and management of the disease.

Hypopyon Uveitis as a Manifestation of Primary Choroidal Lymphoma.

A 78-year-old female was referred to our hospital due to a decrease of visual acuity in her left eye. On examination, presence of left choroidal folds and subretinal fluid was disclosed. After being misdiagnosed as neovascular age-related macular degeneration treatment with intravitreal injections of Aflibercept was started. Despite improvement of fluid, persistence of choroidal folds encouraged a magnetic resonance imaging revealing a left retrobulbar nodular lesion. Furthermore, development of hypopyon during follow-up allowed a flow cytometry analysis of an aqueous humour sample that confirmed infiltration by a non-Hodgkin mature B-cell lymphoproliferative process. Finally, treatment with Rituximab and intravenous corticosteroids achieved complete resolution. Primary choroidal lymphoma may occur with an atypical presentation, including hypopyon uveitis. Thus, familiarity with its clinical features is fundamental for an early recognition and correct management.

Population Older than 69 Had Similar Fatality Rates Independently If They Were Admitted in Nursing Homes or Lived in the Community: A Retrospective Observational Study during COVID-19 First Wave.

The aim of this study is to assess the influence of living in nursing homes on COVID-19-related mortality, and to calculate the real specific mortality rate caused by COVID-19 among people older than 20 years of age in the Balaguer Primary Care Centre Health Area during the first wave of the pandemic. We conducted an observational study based on a database generated between March and May 2020, analysing COVID-19-related mortality as a dependent variable, and including different independent variables, such as living in a nursing home or in the community (outside nursing homes), age, sex, symptoms, pre-existing conditions, and hospital admission. To evaluate the associations between the independent variables and mortality, we calculated the absolute and relative frequencies, and performed a chi-square test. To avoid the impact of the age variable on mortality and to assess the influence of the "living in a nursing home" variable, we established comparisons between infected population groups over 69 years of age (in nursing homes and outside nursing homes). Living in a nursing home was associated with a higher incidence of COVID-19 infection, but not with higher mortality in patients over 69 years of age (p = 0.614). The real specific mortality rate caused by COVID-19 was 2.270/00. In the study of the entire sample, all the comorbidities studied were associated with higher mortality; however, the comorbidities were not associated with higher mortality in the infected nursing home patients group, nor in the infected community patients over 69 years of age group (except for neoplasm history in this last group). Finally, hospital admission was not associated with lower mortality in nursing home patients, nor in community patients over 69 years of age.

Association between use of enhanced recovery after surgery protocols and postoperative complications after gastric surgery for cancer (POWER 4): a nationwide, prospective multicentre study.

INTRODUCTION: The effectiveness of the Enhanced Recovery After Surgery (ERAS) protocols in gastric cancer surgery remains controversial. METHODS: Multicentre prospective cohort study of adult patients undergoing surgery for gastric cancer. Adherence with 22 individual components of ERAS pathways were assessed in all patients, regardless of whether they were treated in a self-designed ERAS centre. Each centre had a three-month recruitment period between October 2019 and September 2020. The primary outcome was moderate-to-severe postoperative complications within 30 days after surgery. Secondary outcomes were overall postoperative complications, adherence to the ERAS pathway, 30 day-mortality and hospital length of stay (LOS). RESULTS: A total of 743 patients in 72 Spanish hospitals were included, 211 of them (28.4 %) from self-declared ERAS centres. A total of 245 patients (33 %) experienced postoperative complications, graded as moderate-to-severe complications in 172 patients (23.1 %). There were no differences in the incidence of moderate-to-severe complications (22.3% vs. 23.5%; OR, 0.92 (95% CI, 0.59 to 1.41); P = 0.068), or overall postoperative complications between the self-declared ERAS and non-ERAS groups (33.6% vs. 32.7%; OR, 1.05 (95 % CI, 0.70 to 1.56); P = 0.825). The overall rate of adherence to the ERAS pathway was 52% [IQR 45 to 60]. There were no differences in postoperative outcomes between higher (Q1, > 60 %) and lower (Q4, ≤ 45 %) ERAS adherence quartiles. CONCLUSIONS: Neither the partial application of perioperative ERAS measures nor treatment in self-designated ERAS centres improved postoperative outcomes in patients undergoing gastric surgery for cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03865810.

Longitudinal change in cerebro-placental ratio (CPR) between 37 and 40 weeks of pregnancy is associated with non-reassuring fetal status and increased risk of cesarean section.

OBJECTIVE: To evaluate in low-risk pregnancies if longitudinal change in cerebro-placental ratio (CPR) between 37 and 40 weeks of pregnancy is associated with cesarean section (CS) for non-reassuring fetal status (NRFS) during labor. METHODS: This is a prospective observational study of women with singleton low-risk pregnancies who underwent an ultrasound scan at 36 + 0 to 37 + 6 and 39 + 0 to 41 + 6 weeks of pregnancy, when the CPR was calculated from the middle cerebral artery (MCA) and umbilical artery (UA) pulsatility indices. Managing professionals were kept blinded to the Doppler results. The association of the longitudinal change between both CPR (z-velocity) to CS for NRFS was evaluated by logistic regression. RESULTS: A total of 401 pregnancies were included. The mean time interval between both CPR evaluations was 21 days (SD 7). A CS for fetal distress was performed in 7% of pregnancies. Independent of the CPR at 37 weeks, the likelihood of CS for fetal distress was significantly decreased by the longitudinal changes from 37 to 40 weeks (OR 0.61, 95%CI 0.4-0.92; p=.018). This association remained significant after further adjustment for potential confounders (nulliparity, maternal weight at booking and estimated fetal weight at 37): (OR 0.64, 95%CI 0.41-0.98; p=.044). CONCLUSIONS: The longitudinal change of CPR between 37 and 40 weeks is associated with the need for CS for NRFS during labor.

Novel Germline TET2 Mutations in Two Unrelated Patients with Autoimmune Lymphoproliferative Syndrome-Like Phenotype and Hematologic Malignancy.

Somatic mutations in the ten-eleven translocation methylcytosine dioxygenase 2 gene (TET2) have been associated to hematologic malignancies. More recently, biallelic, and monoallelic germline mutations conferring susceptibility to lymphoid and myeloid cancer have been described. We report two unrelated autoimmune lymphoproliferative syndrome-like patients who presented with T-cell lymphoma associated with novel germline biallelic or monoallelic mutations in the TET2 gene. Both patients presented a history of chronic lymphoproliferation with lymphadenopathies and splenomegaly, cytopenias, and immune dysregulation. We identified the first compound heterozygous patient for TET2 mutations (P1) and the first ALPS-like patient with a monoallelic TET2 mutation (P2). P1 had the most severe form of autosomal recessive disease due to TET2 loss of function resulting in absent TET2 expression and profound increase in DNA methylation. Additionally, the immunophenotype showed some alterations in innate and adaptive immune system as inverted myeloid/plasmacytoid dendritic cells ratio, elevated terminally differentiated effector memory CD8 + T-cells re-expressing CD45RA, regulatory T-cells, and Th2 circulating follicular T-cells. Double-negative T-cells, vitamin B12, and IL-10 were elevated according to the ALPS-like suspicion. Interestingly, the healthy P1's brother carried a TET2 mutation and presented some markers of immune dysregulation. P2 showed elevated vitamin B12, hypergammaglobulinemia, and decreased HDL levels. Therefore, novel molecular defects in TET2 confirm and expand both clinical and immunological phenotype, contributing to a better knowledge of the bridge between cancer and immunity.

What is behind the gender gap in economics distance education: Age, work-life balance and COVID-19.

There is an ongoing debate about whether gender equality in education has been achieved or not. Research efforts have focused on primary and secondary education, while there are fewer studies on higher education, and few studies refer to distance education. To contribute to address this gap, this article presents a gender analysis of educational outcomes in economics at Spain's leading distance university, UNED, which is also the largest university in the European Union in terms of enrolment. The aim of the article is to assess whether there is a gender gap in academic results and to identify the sociodemographic and academic variables that may be causing such a gap by analysing how they shape such differences. Finally, the impact of COVID-19 is also considered. The results confirm that women underperformed significantly in our sample in terms of passing and scoring, especially among those between 30 and 45 years of age, who are more likely to have young children. When considering a distribution of family tasks biased against women, along with the higher average age of distance learning university students, gender gaps could probably be greater in nonface-to-face education. COVID-19 narrowed the gender gap during the lockdown period, as some men and women staying at home together were able to improve task sharing capabilities. After the lockdown, however, women's results worsened compared to pre-COVID-19 levels. A possible explanation is that they had to continue performing the same family duties in addition to substituting education and caring services (e.g., nurseries and day centres for the elderly) that did not resume activity immediately or continuously.

SPION nanoparticles for delivery of dopaminergic isoquinoline and benzazepine derivatives.

Superparamagnetic iron nanoparticles (SPIONs) have become one of the most useful colloidal systems in nanomedicine. We report here the preparation of new hybrid core@shell systems based on SPION nanoparticles coated with a SiO2 shell (SPION@SiO2) and functionalized with carboxyl groups (SPION@SiO2-COOH). A series of new N-alkylamino- and N-alkylamido-terminated 1-phenyl- tetrahydroisoquinolines (THIQs) and 3-tetrahydrobenzazepines (THBs) derivatives presenting -SMe and -Cl groups, respectively, with potential dopaminergic activity, are synthesized and incorporated to the hybrid system. We include the synthetic details for THIQs and THBs derivatives preparation and investigate the influence of the terminal-functional group as well as the number of carbon atoms linked to THIQ and THB molecules during the coupling to the SPION@SiO2-COOH. Nuclear magnetic resonance (NMR) and electron ionization mass spectrometry (EI-MS) are used to characterize the synthesized THIQs and THBs. High-angle annular dark-field transmission electron microscopy (HAADF-TEM), energy dispersive X-ray transmission electron microscopy (EDX-TEM), and proton high-resolution magic angle spinning NMR spectroscopy1H HRMAS-NMR) are used to confirm the presence of THB and THIQ molecules onto the surface of the nanoparticles. The hybrid SPION@SiO2-THIQ and THB systems show significant activity toward the D2 receptor, reaching Ki values of about 20 nM, thus having potential application in the treatment of central nervous system (CNS) diseases.

Enhancing Night and Day Circadian Contrast through Sleep Education in Prediabetes and Type 2 Diabetes Mellitus: A Randomized Controlled Trial.

BACKGROUND: Evidence supports a causal relationship between circadian disturbance and impaired glucose homeostasis. METHODS: To determine the effect of an educational intervention delivered by primary care nurses to improve sleep hygiene, a parallel, open-label clinical trial in subjects aged 18 and older with impaired fasting glucose (IFG) or type 2 diabetes mellitus (T2DM) was performed. Study variables were sex, age, fasting glucose, glycated haemoglobin A1c (HbA1c), Pittsburgh Sleep Quality Index (PSQI), sleep duration and efficiency, body mass index, antidiabetic treatment, diet and physical exercise. An individual informative educational intervention was carried out following a bidirectional feedback method. The intervention aimed to develop skills to improve sleep through nine simple tips. An analysis of covariance was performed on all the mean centred outcome variables controlling for the respective baseline scores. RESULTS: In the intervention group, PSQI dropped, the duration and quality of sleep increased, and a decrease in fasting glucose and in HbA1c levels was observed. CONCLUSION: The proposed intervention is effective for improving sleep quality, length and efficiency, and for decreasing fasting glucose and HbA1c levels in only 3 months. These findings support the importance of sleep and circadian rhythm education focused on improving IFG and T2DM.

Is Sleeve Gastrectomy as Effective in Older Patients as in Younger Patients? A Comparative Analysis of Weight Loss, Related Comorbidities, and Medication Requirements.

BACKGROUND: Bariatric surgery in the older population has been the subject of ongoing debate but several studies have recently demonstrated its short-term advantages in this age group. It is not yet clear, however, whether these benefits are long-lasting. METHODS: We retrospectively analyzed patients with morbid obesity who underwent laparoscopy sleeve gastrectomy (LSG). These patients were divided into two groups: those above 60 years of age (older group) and those of 60 years or under (younger group). Variables evaluated included demographics and anthropometrics data, comorbidities, and daily medication requirements. RESULTS: Two hundred fifty-two patients underwent LSG, 57 in the older group and 195 in the younger group. Outcomes related to weight loss in the older subjects were modest compared to those in the younger population (older group %EWL 41.6 vs younger group %EWL 51.1, p < 0.05, older group %TWL 24.9% vs younger group %TWL 25.2%, p < 0.05). During follow-up, both older and younger patients showed an improvement in all the comorbidities: hypertension (older 82.5% vs 38.1%, younger 52.6% vs 29.2%, p < 0.05), type 2 diabetes mellitus (older 38.6% vs 27.3%, 34.9% vs 23.9%, p < 0.05), hyperlipidemia (older 75.4% vs 42.9%, younger 35.9% vs 21.1%, p < 0.05), and OSAHS (older 57.9% vs 30%, younger 40.4% vs 7.1%, p < 0.05). The average number of daily medications used to manage comorbidities decreased in both groups. CONCLUSION: LSG in older patients is effective in terms of weight loss, improvement of comorbidities, and lower daily medication requirements up to 5 years of follow-up.

Pharmacogene Variants Associated with Liver Transplant in a Twelve-Year Clinical Follow-Up.

Some gene polymorphisms have been previously associated individually with tacrolimus efficacy and toxicity, but no long-term study to determine the role of pharmacogene variants in the clinical evolution of liver-transplanted patients has been addressed so far. In the present work, we analyzed the relation between highly-evidenced genetic polymorphisms located in relevant pharmacogenes and the risk of suffering premature death and other comorbidities such as cancer, diabetes mellitus, arterial hypertension, graft rejection, infections and nephrotoxicities in a cohort of 87 patients (8 were excluded due to early loss of follow-up) transplanted at Hospital La Fe in Valencia (Spain) during a 12-year follow-up. Employing a logistic regression model with false discovery rate penalization and Kaplan-Meier analyses, we observed significant association between survival rates and metabolizer genes. In this sense, our results show an association between MTHFR gene variants in donor rs1801133 (HR: 7.90; p-value: 0.032) and recipient rs1801131 (HR: 7.34; p-value: 0.036) and the group of patients who died during the follow-up period, supporting the interest of confirming these results with larger patient cohorts. In addition, donor polymorphisms in UGT1A9 metabolizer gene rs6714486 (OR: 0.13; p-value: 0.032) were associated with a lower risk of suffering from de novo cancer. Genetic variants in CYP2B6 metabolizer gene rs2279343 demonstrated an association with a risk of infection. Other variants in different locations of SLCO1A2, ABCC2 and ABCB1 transporter genes were associated with a lower risk of suffering from type 2 diabetes mellitus, chronic and acute nephrotoxicities and arterial hypertension. Results suggest that pharmacogenetics-derived information may be an important support for personalized drug prescription, clinical follow-up and the evolution of liver-transplanted patients.