High-frequency ultrasound accuracy in preoperative cutaneous melanoma assessment: A meta-analysis.

BACKGROUND: High-frequency ultrasound (HFUS) can safely and efficiently visualize cutaneous tumour characteristics including depth. OBJECTIVES: We aimed to evaluate its accuracy in measuring melanoma depth against the gold standard, histopathology, for treatment planning. METHODS: A review of publications was conducted in March 2023 through five electronic databases. Thirty-six included articles studied patients who received HFUS (≥10 MHz) measurements, melanoma biopsy or excision, and reported a tumour depth correlation coefficient between HFUS and histopathology. We analysed correlation coefficients between HFUS and histopathology, measured tumour depths and shed light on reasons for mismeasurements. Additionally, we identified the reporting of critical metrics including, lesion characteristics, melanoma subtype, type of correlation coefficient, 95% confidence intervals for Pearson coefficients and sample size. RESULTS: The most common tumour imaged was superficial spreading melanoma on the trunk and extremities, followed by head/face. Maximum ultrasound frequencies ranged from 13 MHz to 100 MHz with participants ranging from 5 to 264. Histopathology and HFUS correlation coefficients ranged from 0.417 to 0.997 (median: 0.94, mean: 0.89 and SD: 0.13). Lower frequency probes (10-20 MHz) were less accurate in assessing melanoma thickness, with a cumulative mean correlation coefficient of 0.87 compared to 0.94 (20-25 MHz) and 0.98 (≥70 MHz). Studies demonstrated higher sonographic accuracy in melanomas >0.75 mm. Additionally, ultrasound may report increased melanoma depth compared to histopathology for reasons including lymphocytic infiltration, presence of a nevus and shrinkage during specimen processing. Furthermore, we found a gap in the reporting of details such as fundamental characteristics of lesion populations. Specifically, 86% (31 out of 36) of the studies failed to report one or more critical metrics, such as mean, median or range of lesion depths. CONCLUSIONS: HFUS may serve as a supplementary tool for preoperative melanoma assessment, with increased accuracy in thicker tumours. Frequencies <20 MHz are less reliable in assessing depth. Frequencies ≥70 MHz demonstrate stronger correlations to histopathology. Higher ultrasound accuracy was seen for melanomas with Breslow depth >0.75 mm.

Incidence and Outcomes of BK Virus Nephropathy in Kidney Transplant Recipients With Steroid-Free Maintenance Immunosuppression.

BACKGROUND: BK virus nephropathy (BKVN) is a significant complication in kidney transplant recipients, resulting in graft dysfunction and potentially leading to graft loss. This study aims to investigate the incidence and outcomes of BKVN in kidney transplant recipients receiving steroid-free maintenance immunosuppression in a Latin -American cohort. METHODS: Case series study of BKVN among kidney transplant recipients who underwent transplantation between 2008 and 2023. The primary outcome was graft loss caused by BKVN, excluding death with function. Secondary outcomes included graft function and acute rejection episodes. The statistical analysis involved descriptive statistics and the Kaplan-Meier (K-M) method to plot the overall probabilities of not initiating dialysis. RESULTS: During the 15-year period, 2236 kidney transplants were performed, BKVN was histologically diagnosed in 38 kidney recipients and 33 cases were analyzed. Median age was 50 years and men were 48.5% of patients. A total of 45.4% of BKVN occurred within the first 12 months of transplant. The incidence of BKVN was 1.6% but it varied by era. The rate of graft loss was 75.7% (25 cases). The K-M graft survival probability at 6 months and 12 months after diagnosis of BKVN was 38.3% (95% CI 24.7-59.4) and 22.3% (95% CI 11.7-42.8), respectively. CONCLUSION: BKVN affected 1.6% of transplant recipients and it was associated with high-rate of graft loss. We observed that significant graft disfunction at the time of diagnosis resulted in worse outcomes with a reduced probability of graft survival.

Effects of PreOperative radiotherapy in a preclinical glioblastoma model: a paradigm-shift approach.

PURPOSE: PreOperative radiotherapy (RT) is commonly used in the treatment of brain metastasis and different cancer types but has never been used in primary glioblastoma (GBM). Here, we aim to establish, describe, and validate the use of PreOperative RT for the treatment of GBM in a preclinical model. METHODS: Rat brains were locally irradiated with 30-Gy, hypofractionated in five doses 2 weeks before or after the resection of intracranial GBM. Kaplan-Meier analysis determined survival. Hematoxylin-eosin staining was performed, and nuclei size and p21 senescence marker were measured in both resected and recurrent rodent tumors. Immunohistochemistry assessed microglia/macrophage markers, and RNAseq analyzed gene expression changes in recurrent tumors. Akoya Multiplex Staining on two human patients from our ongoing Phase I/IIa trial served as proof of principle. RESULTS: PreOperative RT group median survival was significantly higher than PostOperative RT (p < 0.05). Radiation enlarged cytoplasm and nuclei in PreOperative RT resected tumors (p < 0.001) and induced senescence in PostOperative RT recurrent tumors (p < 0.05). Gene Set Enrichment Analysis (GSEA) suggested a more proliferative profile in PreOperative RT group. PreOperative RT showed lower macrophage/microglia recruitment in recurrent tumors (p < 0.01) compared to PostOperative RT. Akoya Multiplex results indicated TGF-ß accumulation in the cytoplasm of TAMs and CD4 + lymphocyte predominance in PostOperative group. CONCLUSIONS: This is the first preclinical study showing feasibility and longer overall survival using neoadjuvant radiotherapy before GBM resection in a mammalian model. This suggests strong superiority for new clinical radiation strategies. Further studies and trials are required to confirm our results.

SLCO1B1 and ABCG2 genotype-informed phenotypes are related to variation in ramipril exposure.

Ramipril is an angiotensin-converting enzyme inhibitor used for hypertension and heart failure management. To date, scarce literature is available on pharmacogenetic associations affecting ramipril. The goal of this study was to investigate the effect of 120 genetic variants in 34 pharmacogenes (i.e., genes encoding for enzymes like CYPs or UGTs and transporters like ABC or SLC) on ramipril pharmacokinetic variability and adverse drug reaction (ADR) incidence. Twenty-nine healthy volunteers who had participated in a single-dose bioequivalence clinical trial of two formulations of ramipril were recruited. A univariate and multivariate analysis searching for associations between genetic variants and ramipril pharmacokinetics was performed. SLCO1B1 and ABCG2 genotype-informed phenotypes strongly predicted ramipril exposure. Volunteers with the SLCO1B1 decreased function (DF) phenotype presented around 1.7-fold higher dose/weight-corrected area under the curve (AUC/DW) than volunteers with the normal function (NF) phenotype (univariate p-value [puv] < 0.001, multivariate p-value [pmv] < 0.001, ß = 0.533, R2 = 0.648). Similarly, volunteers with ABCG2 DF + poor function (PF) phenotypes presented around 1.6-fold higher AUC/DW than those with the NF phenotype (puv = 0.011, pmv < 0.001, ß = 0.259, R2 = 0.648). Our results suggest that SLCO1B1 and ABCG2 are important transporters to ramipril pharmacokinetics, and their genetic variation strongly alters its pharmacokinetics. Further studies are required to confirm these associations and their clinical relevance.

The Value of Protocol Biopsy in Kidney Transplantation on Monitoring Transplant Outcomes: A Systematic Review and Meta-Analysis.

BACKGROUND: There is a great debate about the role of biopsies per protocol in kidney transplant recipients, and the published studies show contradictory results. We aimed to assess the safety and effectiveness of protocol biopsies in kidney transplant recipients in improving short- and long-term outcomes. METHODS: We conducted searches until July of 2023 to identify all randomized clinical trials (RCT). Studies were identified through search strategies for CENTRAL, MEDLINE, EMBASE, and LILACS. Titles and abstracts were screened independently by 2 authors; 2 authors independently assessed retrieved abstracts and the full text. Assessment of risk of bias was carried out using the Cochrane risk of bias tool. The outcomes of interest were: Acute rejection, graft loss, mortality, glomerular filtration rate, and safety outcomes. Meta-analysis was performed for variables of interest when appropriate. Quality of evidence was assessed using GRADE methodology. RESULTS: We screened 5,695 records. Four trials met all eligibility criteria. No benefit of protocol biopsy was found in detecting acute rejection (3 studies RR: 2.0, 95% CI: 0.68-5.85, p = .2) or preventing graft loss at 12 months (2 studies, RR 0.33, 95% CI 0.06-1.72, p = .19). No differences were found between the groups in the glomerular filtration rate at 6 months post-transplantation (2 studies, MD 2.97, 95% CI 1.4-7.3, p = .18). A total of 23 safety events were present in the biopsy group compared to six in the control group. CONCLUSION: No benefit was found in performing protocol biopsy following kidney transplantation.

Exploring Variable Approaches in Complex Hernia Repair: A Comprehensive Literature Review.

Surgeons have long grappled with categorizing complex hernias, leading to varied interpretations and fluctuating incidence rates. Complex Abdominal Wall Reconstruction (CAWR) addresses repairs for large hernias, with defined factors including size, previous repairs, mesh placement, infections, and comorbidities. This review explores pivotal surgical techniques for complex hernia repair, starting with Preoperative Progressive Pneumoperitoneum (PPP) and progressing to innovative methods like Botulinum Toxin Type A. Mesh fixation, both open and laparoscopic, plays a crucial role, with synthetic and biological mesh options discussed. Hybrid techniques and the "sandwich" approach are proposed for intricate cases. Each technique presents advantages and limitations, emphasizing the ongoing quest for optimal outcomes.

A bioelectronic device for electric field treatment of wounds reduces inflammation in an in vivo mouse model.

Electrical signaling plays a crucial role in the cellular response to tissue injury in wound healing and an external electric field (EF) may expedite the healing process. Here, we have developed a standalone, wearable, and programmable electronic device to administer a well-controlled exogenous EF, aiming to accelerate wound healing in an in vivo mouse model to provide pre-clinical evidence. We monitored the healing process by assessing the re-epithelization rate and the ratio of M1/M2 macrophage phenotypes through histology staining. Following three days of treatment, the M1/M2 macrophage ratio decreased by 30.6% and the re-epithelization in the EF-treated wounds trended towards a non-statically significant 24.2% increase compared to the control. These findings provide point towards the effectiveness of the device in shortening the inflammatory phase by promoting reparative macrophages over inflammatory macrophages, and in speeding up re-epithelialization. Our wearable device supports the rationale for the application of programmed EFs for wound management in vivo and provides an exciting basis for further development of our technology based on the modulation of macrophages and inflammation to better wound healing.

Assessing the feasibility of digital keypress statistics to detect seizures and capture cognitive impairment in patients with epilepsy: A pilot study.

BACKGROUND: Efficient, non-invasive monitoring may provide a more accurate and comprehensive understanding of seizure frequency and the development of some comorbidities in people with epilepsy. Novel keyboard technology measuring digital keypress statistics has demonstrated its practical value for neurodegenerative diseases including Parkinson's Disease and Dementia. Smartphones integrated into daily life may serve as a low-burden longitudinal monitoring system for patients with epilepsy. OBJECTIVE: This study aimed to assess the feasibility of keyboard statistics as an objective measure of seizure frequency for patients with epilepsy, in addition to tracking differences between cognitively normal and cognitively impaired patients. METHODS: Six adult patients admitted to the Epilepsy Monitoring Unit (EMU) at Mayo Clinic in Rochester, Minnesota were studied. The keyboard was installed on the patient's smartphone. In the EMU, typing statistics were correlated to electroencephalogram (EEG) confirmed seizures. After discharge, participants continued using their keyboards and kept a seizure log. We also analyzed the key press/release times and usage of participants' keyboards for adherence. RESULTS: Keyboard sessions during and after seizures assessed for key press/release differences versus baseline showed no statistically significant difference (p = 0.44). Using one-way ANOVA, cognitive impairment's potential impact on keyboard statistics was explored in patients who had neuropsychological testing (N = 3). Significant differences were found between patients with and without cognitive impairment (p < 0.001). No significant difference was noted between patients with mild intellectual disability and normal cognitive function (p = 0.55).

Human Microglia-Like Cells Differentiated from Monocytes with GM-CSF and IL-34 Show Phagocytosis of α-Synuclein Aggregates and C/EBPß-Dependent Proinflammatory Activation.

Microglia, the main resident immune cells in the central nervous system, are implicated in the pathogenesis of various neurological disorders. Much of our knowledge on microglial biology was obtained using rodent microglial cultures. To understand the role of microglia in human disease, reliable in vitro models of human microglia are necessary. Monocyte-derived microglia-like cells (MDMi) are a promising approach. This study aimed to characterize MDMi cells generated from adult human monocytes using granulocyte-macrophage colony-stimulating factor and interleukin-34. To this end, 49 independent cultures of MDMI were prepared, and various methodological and functional studies were performed. We show that with this protocol, adult human monocytes develop into microglia-like cells, a coating is unnecessary, and high cell density seeding is preferable. When compared to monocytes, MDMi upregulate the expression of many, but not all, microglial markers, indicating that, although these cells display a microglia-like phenotype, they cannot be considered bona fide human microglia. At the functional level, MDMi phagocytose α-synuclein aggregates and responds to lipopolysaccharide (LPS) by nuclear translocation of the transcription factor nuclear factor-kappaB (NFkappaB) and the upregulation of proinflammatory genes. Finally, a long-lasting silencing of the transcription factor CCAAT/enhancer protein ß (C/EBPß) was achieved by small interfering RNA, resulting in the subsequent downregulation of proinflammatory genes. This supports the hypothesis that C/EBPß plays a key role in proinflammatory gene program activation in human microglia. Altogether, this study sheds new light on the properties of MDMi cells and supports these cells as a promising in vitro model for studying adult human microglia-like cells.

Non-response to ACE items is associated with demographic variables and health indicators in the 2021 Behavioral Risk Factor Surveillance System.

Background: Adverse childhood experiences (ACE) encompass traumatic events occurring before age 18, with lasting impacts on health. While ACE disclosure is important for understanding these effects, some individuals decline to respond to ACE-related survey items due to sensitivity, privacy concerns, or psychological distress. This study explores the relationship between non-response to ACE items and health outcomes, shedding light on the implications for those who choose not to disclose. Methods: We performed a secondary analysis of the 2021 Behavioral Risk Factor Surveillance System (BRFSS)-a national telephone survey querying health behaviors and conditions. Sociodemographic factors, ACE exposure, and non-response to ACE items were analyzed. Results: Individuals who decline to respond to ACE items exhibit similar patterns of health behaviors and conditions as those reporting ACE exposure. Non-response is linked to both healthier behaviors (lifetime HIV testing) and riskier behaviors (higher odds of smoking and e-cigarette use). Moreover, non-responders have higher odds of being underweight or obese, experiencing concentration difficulties, reporting poor self-rated health, and reporting multiple health diagnoses including depression, diabetes, high blood pressure, heart attack, and stroke. Conclusions: The study underscores the need to address health disparities associated with ACE, regardless of disclosure status. Healthcare interventions should target respondents and non-respondents of ACE screeners, tailoring strategies to promote healthier coping mechanisms and mitigate maladaptive behaviors. These results emphasize the importance of trauma-informed care, early intervention, and targeted public health initiatives for individuals affected by ACE, irrespective of their disclosure choices.

Pierre Robin Sequence: An Updated Evidence-Based Treatment Proposal.

BACKGROUND: The Pierre Robin sequence (PRS) is characterized by the presence of micrognathia, glossoptosis, and respiratory obstruction during the neonatal period, its prompt recognition allows to mitigate the associated morbidity and mortality. A diagnosis and treatment algorithm was previously proposed based on data from the literature to guide therapeutic efforts; therefore, it was proposed to carry out a new search for relevant evidence to update or complement it. METHODS: A literature review of the subject was conducted in PubMed, Embase, and Cochrane databases, corresponding to the period between November 2016 and September 2021. Using the GRADE methodology, 38 articles from different clinical studies that discussed diagnostic tests or therapeutic approaches, directly or indirectly compared, were selected and evaluated. RESULTS: After evaluating and analyzing the selected articles, the new information was incorporated into an updated algorithm according to the most recent evidence found for the diagnosis and comprehensive management of patients with PRS. CONCLUSION: To date, there is no consensus in the literature on the treatment of patients with PRS nor are there multicenter studies comparing different management modalities. The indications to proceed with surgical strategies do not present changes with respect to the previous article. Nutritional monitoring is the main objective, and the study of oral feeding is essential in all scenarios.

Time is of the essence: Age at autism diagnosis, sex assigned at birth, and psychopathology.

LAY ABSTRACT: Previous research has shown that girls/women are diagnosed later than boys/men with autism. Individuals who are diagnosed later in life, especially girls/women, have greater anxious and depressive symptoms. Previous research has been limited due to narrow inclusionary criteria for enrollment in studies. The present study uses two samples-one clinic-based, large "real-world" sample and another research-based sample with strict criteria for autism diagnosis-to understand the relationships between diagnostic age, sex assigned at birth, and symptoms of anxiety/depression. In both samples, those who were diagnosed later had greater anxious/depressive symptoms, and anxiety was not predicted by sex. In the clinic-based but not research-based sample, those assigned female at birth were diagnosed later than those assigned male at birth. In the clinic-based sample only, individuals assigned female at birth and who were later diagnosed experienced greater symptoms of anxiety/depression compared to those assigned male who benefited from earlier diagnostic timing. Within the research-based sample, those assigned female at birth had greater depressive symptoms than those assigned male. These findings highlight the importance of timely identification of autism, especially for girls/women who are often diagnosed later. Community-based samples are needed to better understand real-world sex-based and diagnostic age-based disparities in mental health.

Estrogens prevent the hypothalamus-periphery crosstalk induced by olanzapine intraperitoneal treatment in female mice: Effects on brown/beige adipose tissues and liver.

Olanzapine (OLA) is a highly obesogenic second-generation antipsychotic (SGA). Recently we demonstrated that, contrarily to OLA oral treatment, intraperitoneal (i.p.) administration resulted in weight loss and absence of hepatic steatosis in wild-type (WT) and protein tyrosine phosphatase 1B (PTP1B)-deficient (KO) male mice. This protection relied on two central-peripheral axes connecting hypothalamic AMPK with brown/inguinal white adipose tissue (BAT/iWAT) uncoupling protein-1 (UCP-1) and hypothalamic JNK with hepatic fatty acid synthase (FAS). Herein, we addressed OLA i.p. treatment effects in WT and PTP1B-KO female mice. Contrarily to our previous results in WT females receiving OLA orally, the i.p. treatment did not induce weight gain or hyperphagia. Molecularly, in females OLA failed to diminish hypothalamic phospho-AMPK or elevate BAT UCP-1 and energy expenditure (EE) despite the preservation of iWAT browning. Conversely, OLA i.p. treatment in ovariectomized mice reduced hypothalamic phospho-AMPK, increased BAT/iWAT UCP-1 and EE, and induced weight loss as occurred in males. Pretreatment of hypothalamic neurons with 17ß-estradiol (E2) abolished OLA effects on AMPK. Moreover, neither hypothalamic JNK activation nor hepatic FAS upregulation were found in WT and PTP1B-KO females receiving OLA via i.p. Importantly, this axis was reestablished upon ovariectomy. In this line, E2 prevented OLA-induced phospho-JNK in hypothalamic neurons. These results support the role of estrogens in sex-related dimorphism in OLA treatment. This study evidenced the benefit of OLA i.p. administration in preventing its obesogenic effects in female mice that could offer clinical value.

A pro-reparative bioelectronic device for controlled delivery of ions and biomolecules.

Wound healing is a complex physiological process that requires precise control and modulation of many parameters. Therapeutic ion and biomolecule delivery has the capability to regulate the wound healing process beneficially. However, achieving controlled delivery through a compact device with the ability to deliver multiple therapeutic species can be a challenge. Bioelectronic devices have emerged as a promising approach for therapeutic delivery. Here, we present a pro-reparative bioelectronic device designed to deliver ions and biomolecules for wound healing applications. The device incorporates ion pumps for the targeted delivery of H+ and zolmitriptan to the wound site. In vivo studies using a mouse model further validated the device's potential for modulating the wound environment via H+ delivery that decreased M1/M2 macrophage ratios. Overall, this bioelectronic ion pump demonstrates potential for accelerating wound healing via targeted and controlled delivery of therapeutic agents to wounds. Continued optimization and development of this device could not only lead to significant advancements in tissue repair and wound healing strategies but also reveal new physiological information about the dynamic wound environment.

Genetic variation in UGT1A1 is not associated with altered liver biochemical parameters in healthy volunteers participating in bioequivalence trials.

Introduction: Bioequivalence clinical trials are conducted in healthy volunteers whose blood tests should be within normal limits; individuals with Gilbert syndrome (GS) are excluded from these studies on suspicion of any liver disease, even if the change is clinically insignificant. GS is a benign genetic disorder characterized by elevated bilirubin levels, the primary cause of which is the presence of polymorphisms in UGT1A1 gene. In this work, subjects with UGT1A1 intermediate (IM) or poor (PM) metabolizer genotype-informed phenotypes were investigated to determine whether they have a higher incidence of liver disease or other biochemical parameters. Methods: The study population comprised 773 healthy volunteers who underwent biochemical analysis at baseline and at the end of the study which were genotyped for UGT1A1*80 (rs887829), as an indicator of UGT1A1*80+*28 (rs887829 and rs3064744), and UGT1A1*6 (rs4148323). Results: Bilirubin levels were higher in subjects IMs and PMs compared to normal metabolizers (NMs). Decreased uric acid levels was observed in PMs compared to NMs. No associations were observed in liver enzyme levels according to UGT1A1 phenotype. Discussion: Considering that there is no hepatic toxicity in subjects with UGT1A1 IM or PM phenotype, who are more likely to develop GS, this study suggests that they could be included in bioequivalence clinical trials as their biochemical parameters are not affected outside normal ranges.

Critical pathway for deceased donors: An analysis in three regions of Colombia / Ruta crítica de donantes fallecidos: un análisis de tres regiones en Colombia

Introduction. The critical pathway for deceased donation offers a methodical framework for guiding the donation process. It not only serves to assess performance but also to identify areas of potential improvement. Therefore, the identification and selection of potential organ donors (POD) is a key process. This study aims to describe the critical pathway for deceased donation in a cohort of POD in three regions (CRT1, CRT2, and CRT5) of Colombia. Methods. We retrospectively reviewed data of POD assessed from January 2022 to December 2022. General characteristics of POD, diagnosis, contraindication causes, and organ procurement were described. Analysis was conducted using the Chi-squared test for categorical variables and the Mann-Whitney test for quantitative variables. Results. Within the cohort of 1451 assessed POD, 441 (30.3%) were diagnosed with brain death. Among potential donors after brain death, 198 (44.9%) were eligible donors (medically suitable). Of these, 157 donors (79.3%) became actual donors (undergoing operative incision for organ recovery), with 147 (93,6 %) having at least one organ recovered (actual donors with organ recovery). Ultimately, 411 utilized organs were utilized. Additionally, there were observed differences in the characteristics of donors from different regions. Conclusion. This study reports the critical pathway for deceased donation in a cohort of POD in three regions of Colombia. This provides useful information and helps to gain insight and understanding into the process of organ donation and organ procurement in order to take actions that could improve the donation rates.

Introducción. La ruta crítica de donantes fallecidos permite un enfoque sistemático para la donación de riñón, y, proporciona una herramienta para evaluar el rendimiento de áreas de mejora potencial. La selección de posibles donantes de órganos (PDO) es un proceso clave. El objetivo de este estudio fue describir la ruta crítica para la donación de fallecidos en una cohorte de PDO en tres regiones de Colombia. Métodos. Estudio retrospectivo de PDO evaluados durante 2022. Se describieron las características generales de los PDO, el diagnóstico y las causas de contraindicación. El análisis se llevó a cabo utilizando la prueba de Chi-cuadrado para las variables categóricas y la prueba de Mann-Whitney para las variables cuantitativas. Resultados. Entre los 1451 POD evaluados, 441 (30,3 %) fueron diagnosticados con muerte cerebral. De los posibles donantes después de la muerte cerebral, 198 (44,9 %) fueron donantes elegibles (adecuados desde el punto de vista médico). Entre ellos, 157 donantes (79,3 %) fueron donantes reales (en quienes se realizó una incisión operatoria con la intención de recuperar órganos) y 147 (93,6 %) tuvieron al menos un órgano recuperado (donantes reales con recuperación de órganos). Finalmente, se identificaron 411 órganos utilizados. Conclusión. Este estudio reporta la ruta crítica para la donación de fallecidos en una cohorte de POD en tres regiones de Colombia. Esto proporciona información útil, ayuda a obtener conocimientos y comprender el proceso de donación y obtención de órganos, para tomar medidas que puedan mejorar las tasas de donación.

Course on Breeding, Handling, and Experimental Procedures of Zebrafish (Danio rerio): Training, Refinement, Paradigm Shift, and Dissemination of Knowledge from Brazil to the World.

Currently, in Brazil, all researchers involved in animal experimentation must undergo training in laboratory animal science to stay updated on biology, methodology, ethics, and legal considerations related to the use of animals. The training program presented in this study not only aims to fulfill a legal obligation but also intends to train students and professionals to effectively care for their biomodels. It seeks to help them understand the importance of this care, both for the welfare of the animals and for the results of their projects. In total, 58 participants were present at the event (pre-event and full-time course). These participants consisted students and professionals from 11 institutions and 5 different countries. These numbers demonstrate the successful attainment of the desired capillarity in the scientific community and the posterior dissemination of knowledge. Through this course, it was possible to train the participants and raise their awareness about the importance of applying scientific knowledge in their daily practices to maintain the animals, ensuring the welfare of the models and refining the research. Finally, the program presented in this study, as well as the strategies adopted, can serve as a model for other institutions aiming to achieve similar results.

Adalimumab as treatment for neurosarcoidosis: A case series.

Sarcoidosis is a disease characterized by non-caseating granulomas that can involve the central nervous system as neurosarcoidosis. This challenging disease is currently managed with high dose steroids, and sometimes the addition of infliximab. Other TNA-alpha inhibitors have not been studied as rigorously. We discovered ten neurosarcoidosis patients who were on an alternative TNA-alpha inhibitor, adalimumab. Eight patients had a positive response clinically and radiographically to adalimumab.

Structural characterization of two nanobodies targeting the ligand-binding pocket of human Arc.

The activity-regulated cytoskeleton-associated protein (Arc) is a complex regulator of synaptic plasticity in glutamatergic neurons. Understanding its molecular function is key to elucidate the neurobiology of memory and learning, stress regulation, and multiple neurological and psychiatric diseases. The recent development of anti-Arc nanobodies has promoted the characterization of the molecular structure and function of Arc. This study aimed to validate two anti-Arc nanobodies, E5 and H11, as selective modulators of the human Arc N-lobe (Arc-NL), a domain that mediates several molecular functions of Arc through its peptide ligand binding site. The structural characteristics of recombinant Arc-NL-nanobody complexes were solved at atomic resolution using X-ray crystallography. Both anti-Arc nanobodies bind specifically to the multi-peptide binding site of Arc-NL. Isothermal titration calorimetry showed that the Arc-NL-nanobody interactions occur at nanomolar affinity, and that the nanobodies can displace a TARPγ2-derived peptide from the binding site. Thus, both anti-Arc-NL nanobodies could be used as competitive inhibitors of endogenous Arc ligands. Differences in the CDR3 loops between the two nanobodies indicate that the spectrum of short linear motifs recognized by the Arc-NL should be expanded. We provide a robust biochemical background to support the use of anti-Arc nanobodies in attempts to target Arc-dependent synaptic plasticity. Function-blocking anti-Arc nanobodies could eventually help unravel the complex neurobiology of synaptic plasticity and allow to develop diagnostic and treatment tools.

Understanding the dynamics of deceased organ donation and utilization in Colombia.

Objective: To obtain a comprehensive overview of organ donation, organ utilization, and discard in the entire donation process in Colombia. Methods: A retrospective study of 1 451 possible donors, distributed in three regions of Colombia, evaluated in 2022. The general characteristics, diagnosis, and causes of contraindication for potential donors were described. Results: Among the 1 451 possible donors, 441 (30.4%) fulfilled brain death criteria, constituting the potential donor pool. Families consented to organ donation in 141 medically suitable cases, while 60 instances utilized legal presumption, leading to 201 eligible donors (13.9%). Of those, 160 (11.0%) were actual donors (in whom operative incision was made with the intent of organ recovery or who had at least one organ recovered). Finally, we identified 147 utilized donors (10.1%) (from whom at least one organ was transplanted). Statistically significant differences were found between age, sex, diagnosis of brain death, and donor critical pathway between regions. A total of 411 organs were transplanted from 147 utilized donors, with kidneys being the most frequently procured and transplanted organs, accounting for 280 (68.1%) of the total. This was followed by 85 livers (20.7%), 31 hearts (7.5%), 14 lungs (3.4%), and 1 pancreas (0.2%). The discard rate of procured deceased donors was 8.1%. Conclusions: About one-tenth of donors are effectively used for transplantation purposes. Our findings highlight areas of success and challenges, providing a basis for future improvements in Colombia.