Vision-controlled jetting for composite systems and robots.

Recreating complex structures and functions of natural organisms in a synthetic form is a long-standing goal for humanity1. The aim is to create actuated systems with high spatial resolutions and complex material arrangements that range from elastic to rigid. Traditional manufacturing processes struggle to fabricate such complex systems2. It remains an open challenge to fabricate functional systems automatically and quickly with a wide range of elastic properties, resolutions, and integrated actuation and sensing channels2,3. We propose an inkjet deposition process called vision-controlled jetting that can create complex systems and robots. Hereby, a scanning system captures the three-dimensional print geometry and enables a digital feedback loop, which eliminates the need for mechanical planarizers. This contactless process allows us to use continuously curing chemistries and, therefore, print a broader range of material families and elastic moduli. The advances in material properties are characterized by standardized tests comparing our printed materials to the state-of-the-art. We directly fabricated a wide range of complex high-resolution composite systems and robots: tendon-driven hands, pneumatically actuated walking manipulators, pumps that mimic a heart and metamaterial structures. Our approach provides an automated, scalable, high-throughput process to manufacture high-resolution, functional multimaterial systems.

Bridging anatomical gaps between brain and immune system.

It is increasingly clear that the central nervous system (CNS) relies significantly on both adaptive and innate immune cells for its repair and lifelong maintenance. These interactions hold profound implications for brain aging and neurodegeneration. Recent work by Smyth et al. describes newfound anatomical connections between the brain and dura mater, which they named the arachnoid cuff exit points.

The developmental pathway for CD103(+)CD8+ tissue-resident memory T cells of skin.

Tissue-resident memory T cells (T(RM) cells) provide superior protection against infection in extralymphoid tissues. Here we found that CD103(+)CD8(+) T(RM) cells developed in the skin from epithelium-infiltrating precursor cells that lacked expression of the effector-cell marker KLRG1. A combination of entry into the epithelium plus local signaling by interleukin 15 (IL-15) and transforming growth factor-ß (TGF-ß) was required for the formation of these long-lived memory cells. Notably, differentiation into T(RM) cells resulted in the progressive acquisition of a unique transcriptional profile that differed from that of circulating memory cells and other types of T cells that permanently reside in skin epithelium. We provide a comprehensive molecular framework for the local differentiation of a distinct peripheral population of memory cells that forms a first-line immunological defense system in barrier tissues.

Alternative CNDOL Fockians for fast and accurate description of molecular exciton properties.

CNDOL is an a priori, approximate Fockian for molecular wave functions. In this study, we employ several modes of singly excited configuration interaction (CIS) to model molecular excitation properties by using four combinations of the one electron operator terms. Those options are compared to the experimental and theoretical data for a carefully selected set of molecules. The resulting excitons are represented by CIS wave functions that encompass all valence electrons in the system for each excited state energy. The Coulomb-exchange term associated to the calculated excitation energies is rationalized to evaluate theoretical exciton binding energies. This property is shown to be useful for discriminating the charge donation ability of molecular and supermolecular systems. Multielectronic 3D maps of exciton formal charges are showcased, demonstrating the applicability of these approximate wave functions for modeling properties of large molecules and clusters at nanoscales. This modeling proves useful in designing molecular photovoltaic devices. Our methodology holds potential applications in systematic evaluations of such systems and the development of fundamental artificial intelligence databases for predicting related properties.

Giant brainstem cavernoma in pediatrics: diagnosis and treatment-case report.

INTRODUCTION: Brain cavernomas or cavernous angiomas are a rare vascular malformation in the general population, even more so in pediatric patients. Their incidence in this group is less than 5% of all vascular malformations. They are typically found in the cerebral hemispheres in cortico-subcortical locations and, more rarely, in the brainstem. OBJECTIVE: To describe the diagnosis, treatment, and follow-up of a case involving a pediatric patient with a giant cavernoma in the brainstem at J.P. Garrahan Hospital. MATERIALS AND METHODS: The clinical history of the case was retrieved from the database of J.P. Garrahan Pediatric Hospital. Additionally, a literature search was conducted in high-impact factor journals using the PubMed database. CONCLUSION: Both the authors of this study and experts consulted through the literature agree that, given the eloquence of the affected area and its challenging accessibility, close monitoring and an expectant approach are advisable for such patients. Nevertheless, when the onset of the case warrants it, surgical intervention is deemed necessary in emergency situations and following the acute phase for complete resolution of the pathology.

Pediatric hemispheric cerebellar low-grade gliomas: clinical approach, diagnosis, and management challenges-experience at a tertiary care children's hospital.

PURPOSE: This study aims to provide an exhaustive analysis of pediatric low-grade gliomas (pLGGs) in the cerebellar hemispheres, focusing on incidence, clinical characteristics, surgical outcomes, and prognosis. It seeks to enhance understanding and management of pLGGs in the pediatric population. METHODS: We conducted an observational, descriptive, retrospective, and cross-sectional study at a pediatric hospital, reviewing medical records of 30 patients with cerebellar hemispheric pLGGs treated from December 2014 to January 2023. Data collection included demographics, clinical presentation, imaging findings, surgical approach, postoperative complications, histopathological diagnosis, hydrocephalus management, and follow-up. Molecular markers and adjuvant therapies were also analyzed. RESULTS: The cohort predominantly presented with cerebellar symptoms, with 60% showing hydrocephalus at diagnosis. MRI with gadolinium was crucial for diagnosis. Surgical focus was on achieving gross total resection (GTR), accomplished in 70% of cases. Postsurgical hydrocephalus was less common, and cerebellar mutism was not reported. While a complete molecular analysis was not performed in all cases, available data suggest significant influence of molecular markers on prognosis and therapeutic options of pLGGs. CONCLUSIONS: This study highlights the unique clinical and molecular characteristics of cerebellar hemispheric pLGGs in children. The lower incidence of postoperative hydrocephalus and absence of cerebellar mutism are notable findings. Emphasizing a multidisciplinary approach, our findings contribute to a deeper understanding of pediatric pLGGs, underscoring the need for personalized treatment strategies and vigilant follow-up.

Exploring the Combined Action of Adding Pertuzumab to Branded Trastuzumab versus Trastuzumab Biosimilars for Treating HER2+ Breast Cancer.

The binding activity of various trastuzumab biosimilars versus the branded trastuzumab towards the glycosylated extracellular domain of the human epidermal growth factor receptor 2 (HER2) target in the presence of pertuzumab was investigated. We employed size exclusion chromatography with tetra-detection methodology to simultaneously determine absolute molecular weight, concentration, molecular size, and intrinsic viscosity. All trastuzumab molecules in solution exhibit analogous behavior in their binary action towards HER2 regardless of the order of addition of trastuzumab/pertuzumab. This analogous behavior of all trastuzumab molecules, including biosimilars, highlights the robustness and consistency of their binding activity towards HER2. Furthermore, the addition of HER2 to a mixture of trastuzumab and pertuzumab leads to increased formation of high-order HER2 complexes, up to concentrations of one order of magnitude higher than in the case of sequential addition. The observed increase suggests a potential synergistic effect between these antibodies, which could enhance their therapeutic efficacy in HER2-positive cancers. These findings underscore the importance of understanding the complex interplay between therapeutic antibodies and their target antigens, providing valuable insights for the development of more effective treatment strategies.

Variation of Plasma Damage-Associated Molecular Patterns in Patients with Advanced Solid Tumors after Standard of Care Systemic Treatment.

BACKGROUND: Immunogenic cell death (ICD) is known for releasing damage-associated molecular patterns (DAMPs) from tumor cells. We aimed to find ICD signals by assessing the variation of plasmatic DAMPs (HMGB1, S100A8) before-after standard of care (SoC) systemic treatment in patients with advanced solid tumors. METHODS: Patients scheduled to start a new line of systemic treatment were included. Plasmatic concentrations of HMGB1 and S100A8 were measured (ng/mL) before and after three months of treatment. RESULTS: Fifty-two patients were included. Forty-four patients (85%) had metastases, and 8 (15%) were treated for stage III tumors. The most frequent tumor sites were colorectal (35%) and lung (25%). Forty-two patients (81%) received this treatment in the first-line setting. Thirty-six patients (69%) were treated chemotherapy (CT) alone, ten (19%) CT plus targeted therapy, two (3.8%) carboplatin-pemetrexed-pembrolizumab, three (5.8%) pembrolizumab alone and one (1.9%) cetuximab alone. Median plasmatic concentration of S100A8 was significantly higher before than after treatment in the whole population (3.78 vs. 2.91 ng/mL; p = 0.011) and more markedly in the subgroups of patients who experienced RECIST-assessed tumor response (5.70 vs. 2.63 ng/mL; p = 0.002). Median plasmatic concentration of HMGB1was not significantly different before and after treatment (10.23 vs. 11.85 ng/mL; p = 0.382) and did not differ depending on tumor response. Median PFS was not significantly different between patients whose plasma HMBG1 concentration decreased or increased (8.0 vs. 10.6 months; p = 0.29) after treatment. Median PFS was significantly longer in those patients in whom the plasma concentration of S100A8 decreased after treatment (12 vs. 4.7 months; p < 0.001). Median OS was not significantly different between patients whose plasma HMBG1 concentration decreased or increased (13.1 vs. 14.7 months; p = 0.46) after treatment. Median OS was significantly longer in those patients in whom the plasma concentration of S100A8 decreased after treatment (16.7 vs. 9.0 months; p < 0.001). CONCLUSIONS: Signals of ICD were not observed. S100A8 behaves as an inflammatory marker with decreased concentration after treatment, mostly in RECIST-responders. PFS and OS were significantly prolonged in those patients who experienced a decrease of S100A8 compared with those patients who experienced increase of plasma S100A8 at three months.

Combining Molecular Quantum Mechanical Modeling and Machine Learning for Accelerated Reaction Screening and Discovery.

Molecular quantum mechanical modeling, accelerated by machine learning, has opened the door to high-throughput screening campaigns of complex properties, such as the activation energies of chemical reactions and absorption/emission spectra of materials and molecules; in silico. Here, we present an overview of the main principles, concepts, and design considerations involved in such hybrid computational quantum chemistry/machine learning screening workflows, with a special emphasis on some recent examples of their successful application. We end with a brief outlook of further advances that will benefit the field.

Inflammatory myofibroblastic tumor of the lung involving the central nervous system in pediatric patients.

INTRODUCTION: The inflammatory myofibroblastic tumor (IMT) is a very rare lesion with an incidence of less than 0.1% of total neoplasms and with main affection in the lungs. Involvement in the central nervous system is extremely rare, but with a much more aggressive course than IMT diagnosed in the rest of the body. We report the 2 cases presented in our neurosurgery department to date; both were treated satisfactorily without intercurrences in 10 years of follow-up. HISTORICAL BACKGROUND: The World Health Organization described the IMT as a distinctive lesion composed of myofibroblastic spindle cells accompanied by an inflammatory infiltrate of plasma cells, lymphocytes, and eosinophils. CLINICAL PRESENTATION: Clinical manifestations of patients with CNS IMT vary and may consist of headache, vomiting, seizures, and blindness. Seizures are the most common symptom in patients with focal lesions. DIAGNOSIS: The true origin of this entity remains to be elucidated, but to date, etiologies ranging from chromosomal alterations to autoimmune or postinfectious mechanisms have been described. Due to its rarity and non-specificity in imaging, the final diagnosis of IMT in the brain parenchyma relies on pathological examination. MANAGEMENT: Treatment options are controversial and include total or subtotal removal, high-dose steroids, and radiation therapy. In the last decade, the development of ALK Tyrosine Kinase Inhibitors allows the possibility of chemotherapy in those patients harboring ALK mutations. CONCLUSION: IMT is a rare tumor that can exceptionally be found in the CNS. The cause is still unknown although the different studies focus on a neoplastic origin. The diagnosis is based in the use of different modalities of imaging and with histological confirmation. Optimal management is gross total resection whenever possible, is the only established curative treatment. Further research with longer follow-up is needed to clarify the natural history of this rare tumor.

Understanding Attachment, Emotional Regulation, and Childhood Adversity and Their Link to Chemsex.

Background: Although evidence shows that engaging in chemsex can be associated with poor mental health, little is known about the relationship between psychological factors and this type of drug use. We aim to explore associations between engagement in chemsex and several psychological variables (adverse life events, attachment styles, emotional regulation skills, self-care patterns) in a sample of gay, bisexual, and other men who have sex with men (GBMSM) with drug-related problems. Methods: A group of GBMSM engaged in chemsex (n = 41) and a control group of GBMSM (n = 39) completed an online survey to assess drug-related problems and the abovementioned psychological variables, in which both groups were compared. All analyses were adjusted for covariates showing significant differences between groups. Results: Compared to the control group, participants engaged in chemsex showed significantly higher frequencies of an avoidant-insecure attachment style and early adverse life events, regardless of all covariates (HIV status, job situation, and place of birth). Poorer emotional regulation and self-care patterns and a higher frequency of sexual abuse were also found in participants engaged in chemsex, though we cannot rule out the influence of HIV status on this second group of variables. Conclusions: Some people with drug-related problems engaged in chemsex might have suffered early adverse events and might have an avoidant-insecure attachment style. Moreover, those who have been diagnosed with HIV might show higher emotional dysregulation and poorer self-care patterns. These variables should be routinely evaluated in this population.

Wearable and Noninvasive Device for Integral Congestive Heart Failure Management in the IoMT Paradigm.

Noninvasive remote monitoring of hemodynamic variables is essential in optimizing treatment opportunities and predicting rehospitalization in patients with congestive heart failure. The objective of this study is to develop a wearable bioimpedance-based device, which can provide continuous measurement of cardiac output and stroke volume, as well as other physiological parameters for a greater prognosis and prevention of congestive heart failure. The bioimpedance system, which is based on a robust and cost-effective measuring principle, was implemented in a CMOS application specific integrated circuit, and operates as the analog front-end of the device, which has been provided with a radio-frequency section for wireless communication. The operating parameters of the proposed wearable device are remotely configured through a graphical user interface to measure the magnitude and the phase of complex impedances over a bandwidth of 1 kHz to 1 MHz. As a result of this study, a cardiac activity monitor was implemented, and its accuracy was evaluated in 33 patients with different heart diseases, ages, and genders. The proposed device was compared with a well-established technique such as Doppler echocardiography, and the results showed that the two instruments are clinically equivalent.

Binding Affinity of Trastuzumab and Pertuzumab Monoclonal Antibodies to Extracellular HER2 Domain.

The binding affinity of trastuzumab and pertuzumab to HER2 has been studied using both experimental and in silico methods. The experiments were conducted using the antibodies in their complete IgG form, as used in clinical therapy, and the extracellular domain of the HER2 protein in solution. This approach provides a precise, reproducible, and reliable view of the interaction between them in physicochemical conditions similar to those found in the tumoral environment. Dynamic light scattering and size exclusion chromatography coupled with tetra detection were utilized to characterize the protein complexes, measure their concentrations, and calculate the equilibrium-free binding energy, ΔGbind. In addition, PRODIGY, a QSAR-like model with excellent predictive ability, was employed to obtain in silico ΔGbind estimations. The results obtained indicate that pertuzumab exhibits a slightly higher binding affinity to HER2 than trastuzumab. The difference in binding affinity was explained based on the contribution of the different interfacial contact (IC) descriptors to the ΔGbind value estimated by the PRODIGY model. Furthermore, experiments revealed that the pertuzumab IgG antibody binds preferentially to two HER2 proteins, one per Fab fragment, while trastuzumab mainly forms a monovalent complex. This finding was interpreted based on a geometrical model that identified steric crowding in the trastuzumab-HER2 complex as compared with the pertuzumab-HER2 complex.

Urgent endoscopy versus early endoscopy: Does urgent endoscopy play a role in acute non-variceal upper gastrointestinal bleeding? / Endoscopia urgente frente a endoscopia precoz: ¿tiene algún papel la endoscopia urgente en la hemorragia digestiva alta aguda no varicosa?

INTRODUCTION: The main clinical practice guidelines recommend endoscopy within 24hours after admission to the Emergency Department in patients with non-variceal upper gastrointestinal bleeding. However, it is a wide time frame and the role of urgent endoscopy (<6hours) is controversial. MATERIAL AND METHODS: Prospective observational study carried out at La Paz University Hospital, where all patients were selected, from January 1, 2015 to April 30, 2020, who attended the Emergency Room and underwent endoscopy for suspected upper gastrointestinal bleeding. Two groups of patients were established: urgent endoscopy (<6hours) and early endoscopy (6-24hours). The primary endpoint of the study was 30-day mortality. RESULTS: A total of 1096 were included, of whom 682 underwent urgent endoscopy. Mortality at 30days was 6% (5% vs 7.7%, P=.064) and rebleeding was 9.6%. There were no statistically significant differences in mortality, rebleeding, need for endoscopic treatment, surgery and/or embolization, but there were differences in the necessity for transfusion(57.5% vs 68.4%, P<.001) and the number of concentrates of transfused red blood cells (2.85±4.01 vs 3.51±4.09, P=.008). CONCLUSION: Urgent endoscopy, in patients with acute upper gastrointestinal bleeding, as well as the high-risk subgroup (GBS ≥12), was not associated with lower 30-day mortality than early endoscopy. However, urgent endoscopy in patients with high-risk endoscopic lesions (ForrestI-IIB), was a significant predictor of lower mortality. Therefore, more studies are required for the correct identification of patients who benefit from this medical approach (urgent endoscopy).

Targeting the immune system towards novel therapeutic avenues to fight brain aging and neurodegeneration.

The incidence of age-related dementia is growing with increased longevity, yet there are currently no disease-modifying therapies for these devastating disorders. Studies over the last several years have led to an evolving awareness of the role of the immune system in supporting brain maintenance and repair, displaying a diverse repertoire of functions while orchestrating the crosstalk between the periphery and the brain. Here, we provide insights into the current understanding of therapeutic targets that could be adopted to modulate immune cell fate, either systemically or locally, to defeat brain aging and neurodegeneration.

Minocycline prevents chronic restraint stress-induced vulnerability to developing cocaine self-administration and associated glutamatergic mechanisms: a potential role of microglia.

Stressful experience-induced cocaine-related behaviors are associated with a significant impairment of glutamatergic mechanisms in the Nucleus Accumbens core (NAcore). The hallmarks of disrupted glutamate homeostasis following restraint stress are the enduring imbalance of glutamate efflux after a cocaine stimulus and increased basal concentrations of extracellular glutamate attributed to GLT-1 downregulation in the NAcore. Glutamate transmission is tightly linked to microglia functioning. However, the role of microglia in the biological basis of stress-induced addictive behaviors is still unknown. By using minocycline, a potent inhibitor of microglia activation with anti-inflammatory properties, we determined whether microglia could aid chronic restraint stress (CRS)-induced glutamate homeostasis disruption in the NAcore, underpinning stress-induced cocaine self-administration. In this study, adult male rats were restrained for 2 h/day for seven days (day 1-7). From day 16 until completing the experimental protocol, animals received a vehicle or minocycline treatment (30 mg/Kg/12h i.p.). On day 21, animals were assigned to microscopic, biochemical, neurochemical or behavioral studies. We confirm that the CRS-induced facilitation of cocaine self-administration is associated with enduring GLT-1 downregulation, an increase of basal extracellular glutamate and postsynaptic structural plasticity in the NAcore. These alterations were strongly related to the CRS-induced reactive microglia and increased TNF-α mRNA and protein expression, since by administering minocycline, the impaired glutamate homeostasis and the facilitation of cocaine self-administration were prevented. Our findings are the first to demonstrate that minocycline suppresses the CRS-induced facilitation of cocaine self-administration and glutamate homeostasis disruption in the NAcore. A role of microglia is proposed for the development of glutamatergic mechanisms underpinning stress-induced vulnerability to cocaine addiction.

A 20-Year Journey from Axonal Injury to Neurodegenerative Diseases and the Prospect of Immunotherapy for Combating Alzheimer's Disease.

The understanding of the dialogue between the brain and the immune system has undergone dramatic changes over the last two decades, with immense impact on the perception of neurodegenerative diseases, mental dysfunction, and many other brain pathologic conditions. Accumulated results have suggested that optimal function of the brain is dependent on support from the immune system, provided that this immune response is tightly controlled. Moreover, in contrast to the previous prevailing dogma, it is now widely accepted that circulating immune cells are needed for coping with brain pathologies and that their optimal effect is dependent on their type, location, and activity. In this perspective, we describe our own scientific journey, reviewing the milestones in attaining this understanding of the brain-immune axis integrated with numerous related studies by others. We then explain their significance in demonstrating the possibility of harnessing the immune system in a well-controlled manner for the treatment of neurodegenerative diseases.

Alcohol-related stimuli modulate functional connectivity during response inhibition in young binge drinkers.

Binge drinking is a pattern of intermittent excessive alcohol consumption that is highly prevalent in young people. Neurocognitive dual-process models have described substance abuse and adolescence risk behaviours as the result of an imbalance between an overactivated affective-automatic system (related to motivational processing) and damaged and/or immature reflective system (related to cognitive control abilities). Previous studies have evaluated the reflective system of binge drinkers (BDs) through neutral response inhibition tasks and have reported anomalies in theta (4-8 Hz) and beta (12-30 Hz) bands. The present study aimed to investigate the influence of the motivational value of alcohol-related stimuli on brain functional networks devoted to response inhibition in young BDs. Sixty eight BDs and 78 control participants performed a beverage Go/NoGo task while undergoing electrophysiological recording. Whole cortical brain functional connectivity (FC) was evaluated during successful response inhibition trials (NoGo). BDs exhibited fast-beta and theta hyperconnectivity in regions related to cognitive control. These responses were modulated differently depending on the motivational content of the stimuli. The increased salience of alcohol-related stimuli may lead to overactivation of the affective-automatic system in BDs, and compensatory neural resources of the reflective system will thus be required during response inhibition. In BDs, inhibition of the response to alcohol stimuli may require higher theta FC to facilitate integration of information related to the task goal (withholding a response), while during inhibition of the response to no-alcoholic stimuli, higher fast-beta FC would allow to apply top-down inhibitory control of the information related to the prepotent response.

Abusive head trauma, protocols, and legal concerns in a South American Country.

The abusive head trauma (AHT) is a form of child abuse and is a frequent entity all over de world. It is particularly unique among medical diagnoses because of the legal implications imposed by the diagnosis. Therefore, it has been the subject of much legal controversy over the decades. Knowledge of the clinical signs and imaging findings of abusive head trauma is vitally important for early diagnosis. An oriented anamnesis, as well as a complete physical examination and obtaining adequate images of the central nervous system, play a significant role in confirming the presumptive diagnosis. The interdisciplinary approach (pediatricians, neurosurgeons, neuroradiologists, social workers, and other specialists) is the key in the management of these patients. The purpose of this article is to familiarize the pediatric neurosurgeon with some of the more common medicolegal issues surrounding AHT as well as to discuss legal commitments and ethical obligations of the neurosurgeon in Argentina (South America) based on 2 clinical cases.

Correlation between endoscopy and intestinal ultrasound for the evaluation of postoperative recurrence of Crohn's disease. / Correlación entre la endoscopia y la ecografía intestinal para la evaluación de la recurrencia posquirúrgica de la enfermedad de Crohn.

OBJECTIVE: Intestinal ultrasound is considered to be a valid alternative for the evaluation of post-operative recurrence (POR) of Crohn's disease. The aim of this study is to assess the correlation between ultrasound and endoscopic findings. METHODS: Patients with Crohn's disease were retrospectively recruited who had undergone ileocecal resection, and for whom a colonoscopy and intestinal ultrasound had been performed for the detection of POR. Recurrence was assessed using the Rutgeerts score (RS). The ultrasound findings analysed were bowel wall thickness (BWT), parietal hyperaemia using power Doppler, loss of layer pattern and mesenteric fat hypertrophy. RESULTS: A total of 31 patients were included, of which 15 (48.4%) had no POR (RS<2b) and 16 (51.6%) had POR (RS≥2b). A statistically significant association was identified between BWT and the presence of endoscopic recurrence (a mean of 2.75mm vs. 5.68mm, P>0.001). There was also a statistically significant difference in hyperaemia between the 2groups (P=0.03). For wall thickness, an area under the ROC curve (AUC) of 92.9% was obtained, and with a cut-off point of 3.4mm, a sensitivity of 100% and specificity of 86.6%. When comparing with the most frequent biomarkers (fecal calprotectin and serum CRP), a higher AUC was obtained for wall thickness (72.3% and 72.3% vs. 92.9%). CONCLUSIONS: In our experience, ultrasound has high diagnostic efficacy in the detection of POR and can be considered a valid non-invasive alternative to endoscopy.