Thoracic ectopia cordis: A case report.

Ectopia cordis is a congenital heart malformation of the sternal wall, with a prevalence of 0.1% among heart conditions and an incidence of 5.5 to 7.9 per million births. It is characterized by the heart being located outside the thoracic cavity, and it may be accompanied by other congenital anomalies such as omphalocele, Cantrell´s pentalogy, or Fallot´s tetralogy. We present a case of thoracic ectopia cordis in a male neonate. After birth, we also observed a midline thoracic malformation and respiratory difficulties with clinical and paraclinical features consistent with tetralogy of Fallot. It was decided to provide skin flap coverage, and due to the poor prognosis of the heart condition, palliative care was chosen. Unfortunately, the neonate passed away after seven days. This clinical case study contributes to understanding this rare condition and may help improve diagnosis and treatment of affected patients.

La ectopia cordis es una malformación cardíaca congénita de la pared esternal, con una prevalencia del 0,1%, e incidencia del 5,5 al 7,9 por millón de nacimientos. Se caracteriza por situar al corazón fuera de la cavidad torácica, puede acompañarse de otras anomalías congénitas como onfalocele, pentalogía de Cantrell o tetralogía de Fallot. Presentamos un caso de ectopia cordis torácica en un recién nacido de sexo masculino. Después del nacimiento, también observamos una malformación de la línea media torácica y dificultad respiratoria con características clínicas y paraclínicas compatibles con tetralogía de Fallot. Se realizó una cobertura con colgajo cutáneo, y debido al mal pronóstico, se optó por cuidados paliativos; con fallecimiento después de siete días. Este estudio de caso clínico contribuye a la comprensión de esta rara enfermedad, y puede ayudar a mejorar el diagnóstico y tratamiento de los pacientes afectados.

Chemotherapy-induced neuropathy and pain in pediatric oncology patients: impact of combination therapies.

Chemotherapy-induced peripheral neuropathy (CIPN) and associated pain are prevalent adverse effects of pediatric cancer treatment, significantly affecting the patient's quality of life. Their impact and risk factors have yet to be assessed in our country. This study aimed to assess the prevalence and clinical characteristics of CIPN, as well as to explore associations with patient- and treatment-related variables, within a cohort of Argentinean pediatric oncology patients. Sixty-six patients diagnosed with malignant hematopoietic tumors and receiving the neurotoxic agent vincristine were included in this observational study. Variables analyzed included age, gender, anthropometric measurements, tumor type, chemotherapy treatment, development of pain and other symptoms, severity, and analgesic treatment. The study population consisted of 39 boys and 27 girls. Most patients received two or three neurotoxic drugs. Symptoms consistent with CIPN were identified in 15 children, reflecting a prevalence of 23%. The main symptom was pain in the lower limbs, with some patients reporting jaw or generalized body pain. Pain was categorized as moderate or severe in 60% and 27% of cases, respectively. NSAIDs, anticonvulsants, and/or opioids were prescribed. Among the patient- and treatment-related variables analyzed as potential risk factors, the use of vincristine in conjunction with cytarabine and the administration of a higher number of neurotoxic drugs demonstrated significant association with the development of CIPN. CONCLUSIONS: Combination therapy stands out as a risk factor for clinical CIPN. The high prevalence of moderate/severe pain underscores the importance of close vigilance given its potential to compromise the patient's overall well-being. WHAT IS KNOWN: • Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent adverse effect and dose-limiting factor in pediatric cancer treatment. • Prevalence varies among regions and risk factors are still under study. WHAT IS NEW: • Prevalence of symptomatic CIPN is 23% among pediatric patients undergoing treatment for hematopoietic tumors in a referral hospital in Argentina. Most patients report moderate or severe pain. • Combining vincristine with cytarabine and using a higher number of neurotoxic drugs in combination therapies exhibit significant association with the development of CIPN-related symptoms.

Unlocking Transplant Tolerance with Biomaterials.

For patients suffering from organ failure due to injury or autoimmune disease, allogeneic organ transplantation with chronic immunosuppression is considered the god standard in terms of clinical treatment. However, the true "holy grail" of transplant immunology is operational tolerance, in which the recipient exhibits a sustained lack of alloreactivity toward unencountered antigen presented by the donor graft. This outcome is resultant from critical changes to the phenotype and genotype of the immune repertoire predicated by the activation of specific signaling pathways responsive to soluble and mechanosensitive cues. Biomaterials have emerged as a medium for interfacing with and reprogramming these endogenous pathways toward tolerance in precise, minimally invasive, and spatiotemporally defined manners. By viewing seminal and contemporary breakthroughs in transplant tolerance induction through the lens of biomaterials-mediated immunomodulation strategies-which include intrinsic material immunogenicity, the depot effect, graft coatings, induction and delivery of tolerogenic immune cells, biomimicry of tolerogenic immune cells, and in situ reprogramming-this review emphasizes the stunning diversity of approaches in the field and spotlights exciting future directions for research to come.

Specificities and commonalities of the Planctomycetes plasmidome.

Plasmids, despite their critical role in antibiotic resistance and modern biotechnology, are understood in only a few bacterial groups in terms of their natural ecological dynamics. The bacterial phylum Planctomycetes, known for its unique molecular and cellular biology, has a largely unexplored plasmidome. This study offers a thorough exploration of the diversity of natural plasmids within Planctomycetes, which could serve as a foundation for developing various genetic research tools for this phylum. Planctomycetes plasmids encode a broad range of biological functions and appear to have coevolved significantly with their host chromosomes, sharing many homologues. Recent transfer events of insertion sequences between cohabiting chromosomes and plasmids were also observed. Interestingly, 64% of plasmid genes are distantly related to either chromosomally encoded genes or have homologues in plasmids from other bacterial groups. The planctomycetal plasmidome is composed of 36% exclusive proteins. Most planctomycetal plasmids encode a replication initiation protein from the Replication Protein A family near a putative iteron-containing replication origin, as well as active type I partition systems. The identification of one conjugative and three mobilizable plasmids suggests the occurrence of horizontal gene transfer via conjugation within this phylum. This comprehensive description enhances our understanding of the plasmidome of Planctomycetes and its potential implications in antibiotic resistance and biotechnology.

Somatic Mutations in Latin American Breast Cancer Patients: A Systematic Review and Meta-Analysis.

(1) Background: Somatic mutations may be connected to the exposome, potentially playing a role in breast cancer's development and clinical outcomes. There needs to be information regarding Latin American women specifically, as they are underrepresented in clinical trials and have limited access to somatic analysis in their countries. This study aims to systematically investigate somatic mutations in breast cancer patients from Latin America to gain a better understanding of tumor biology in the region. (2) Methods: We realize a systematic review of studies on breast cancer in 21 Latin American countries using various databases such as PubMed, Google Scholar, Web of Science, RedAlyc, Dianlet, and Biblioteca Virtual en Salud. Of 392 articles that fit the criteria, 10 studies have clinical data which can be used to create a database containing clinical and genetic information. We compared mutation frequencies across different breast cancer subtypes using statistical analyses and meta-analyses of proportions. Furthermore, we identified overexpressed biological processes and canonical pathways through functional enrichment analysis. (3) Results: 342 mutations were found in six Latin American countries, with the TP53 and PIK3CA genes being the most studied mutations. The most common PIK3CA mutation was H1047R. Functional analysis provided insights into tumor biology and potential therapies. (4) Conclusion: evaluating specific somatic mutations in the Latin American population is crucial for understanding tumor biology and determining appropriate treatment options. Combining targeted therapies may improve clinical outcomes in breast cancer. Moreover, implementing healthy lifestyle strategies in Latin America could enhance therapy effectiveness and clinical outcomes.

Bending the Rules: Amplifying PD-L1 Immunoregulatory Function Through Flexible Polyethylene Glycol Synthetic Linkers.

Immune checkpoint signaling, such as programmed cell death protein-1 (PD-1), is a key target for immunotherapy due to its role in dampening immune responses. PD-1 signaling in T cells is regulated by complex physicochemical and mechanical cues. However, how these mechanical forces are integrated with biochemical responses remains poorly understood. Our previous work demonstrated that the use of an immobilizing polyethylene glycol (PEG) linker on synthetic microgels for the presentation of a chimeric form of PD-L1, SA-PD-L1, lead to local regulatory responses capable of abrogating allograft rejection in a model of cell-based transplantation. We herein provide evidence that enhanced immune regulating function can be obtained when presentation of SA-PD-L1 is achieved through a longer more flexible PEG chain. Presentation of SA-PD-L1 through a linker of high molecular weight, and thus longer length (10 kDa, 60 nm in length), led to enhance conversion of naive T cells into T regulatory cells (Tregs) in vitro. In addition, using a subcutaneous implant model and protein tethered through three different linker sizes (6, 30, and 60 nm) to the surface of PEG hydrogels, we demonstrated that longer linkers promoted PD-1 immunomodulatory role in vivo through three main functions: (1) augmenting immune cell recruitment at the transplant site; (2) promoting the accumulation of naive Tregs expressing migratory markers; and (3) dampening CD8+ cytolytic molecule production while augmenting expression of exhaustion phenotypes locally. Notably, accumulation of Treg cells at the implant site persisted for over 30 days postimplantation, an effect not observed when protein was presented with the shorter version of the linkers (6 and 30 nm). Collectively, these studies reveal a facile approach by which PD-L1 function can be modulated through external tuning of synthetic presenting linkers. Impact statement Recently, there has been a growing interest in immune checkpoint molecules as potential targets for tolerance induction, including programmed cell death protein-1 (PD-1). However, how the mechanics of ligand binding to PD-1 receptor affect downstream activation signaling pathways remains unresolved. By taking advantage of the effect of polyethylene glycol chain length on molecule kinetics in an aqueous solution, we herein show that PD-L1 function can be amplified by adjusting the length of the grafting linker. Our results uncover a potential facile mechanism that can be exploited to advance the role of immune checkpoint ligands, in particular PD-L1, in tolerance induction for immunosuppression-free cell-based therapies.

ADAMTS13 recovery in acute thrombotic thrombocytopenic purpura after caplacizumab therapy.

ABSTRACT: Caplacizumab prevents the interaction between von Willebrand factor and platelets and is used to treat immune thrombotic thrombocytopenic purpura (iTTP). Its administration has been associated with a delay in ADAMTS13 activity restoration after plasma exchange (PEX) suspension. We analyzed the outcomes of 113 iTTP episodes, 75 of which were treated with caplacizumab, in 108 patients from the Spanish Registry of Thrombotic Thrombocytopenic Purpura. Caplacizumab shortened the time to platelet count normalization and reduced PEX requirement, exacerbations, and relapses. There was no difference in the time to achieve ADAMTS13 activity ≥20% after PEX end between caplacizumab-treated and nontreated episodes (median [interquartile range], 14.5 [7.7-27.2] vs 13.0 [8.0-29.0] days, P = .653). However, considering the 36 episodes in which caplacizumab was started ≤3 days after iTTP diagnosis, the time for ADAMTS13 restoration from PEX end was higher than in those episodes in which caplacizumab was started >3 days after iTTP diagnosis (20.0 [12.0-43.0] vs 11.0 [3.5-20.0] days, P = .003) or than in non-caplacizumab-treated episodes (P = .033). This finding could be related to a significantly shorter duration of PEX in early caplacizumab-treated episodes than in late caplacizumab-treated episodes (5.5 [4.0-9.0] vs 15.0 [11.0-21.5] days, P < .001) or non-caplacizumab-treated episodes (11.0 [6.0-26.0] days, P < .001). There were no differences in time to ADAMTS-13 restoration from PEX start (28.0 [17.2-47.5], 27.0 [19.0-37.5] and 29.5 [15.2-45.0] days in early caplacizumab-treated, late caplacizumab-treated and non-caplacizumab-treated episodes). Early administered caplacizumab does not prevent the requirement for immunosuppression but has beneficial effects by shortening PEX requirement without major safety concerns.

VEGF-delivering PEG hydrogels promote vascularization in the porcine subcutaneous space.

For cell therapies, the subcutaneous space is an attractive transplant site due to its large surface area and accessibility for implantation, monitoring, biopsy, and retrieval. However, its poor vascularization has catalyzed research to induce blood vessel formation within the site to enhance cell revascularization and survival. Most studies focus on the subcutaneous space of rodents, which does not recapitulate important anatomical features and vascularization responses of humans. Herein, we evaluate biomaterial-driven vascularization in the porcine subcutaneous space. Additionally, we report the first use of cost-effective fluorescent microspheres to quantify perfusion in the porcine subcutaneous space. We investigate the vascularization-inducing efficacy of vascular endothelial growth factor (VEGF)-delivering synthetic hydrogels based on 4-arm poly(ethylene) glycol macromers with terminal maleimides (PEG-4MAL). We compare three groups: a non-degradable hydrogel with a VEGF-releasing PEG-4MAL gel coating (Core+VEGF gel); an uncoated, non-degradable hydrogel (Core-only); and naïve tissue. After 2 weeks, Core+VEGF gel has significantly higher tissue perfusion, blood vessel area, blood vessel density, and number of vessels compared to both Core-only and naïve tissue. Furthermore, healthy vital signs during surgery and post-procedure metrics demonstrate the safety of hydrogel delivery. We demonstrate that VEGF-delivering synthetic hydrogels induce robust vascularization and perfusion in the porcine subcutaneous space.

Percepción del impacto económico en pacientes con cáncer en un hospital de tercer nivel, La Paz - Bolivia: un estudio exploratorio cualitativo / Perception of the economic impact in patients diagnosed with cancer in a third level hospital, La Paz - Bolivia: a qualitative exploratory study

Los pacientes con cáncer experimentan además del impacto de la enfermedad, el impacto económico, y este es más evidente en los pacientes con escasos recursos económicos, los motivos son multifactoriales. OBJETIVO: describir la percepción sobre el impacto económico en los pacientes bolivianos con cáncer en el Hospital de Clínicas Universitario- La Paz. MÉTODOS: el diseño es cualitativo exploratorio, muestreo por bola de nieve, se realizaron entrevistas a profundidad dirigidas a pacientes con cáncer del hospital de Clínicas Universitario de La Paz- Bolivia entre diciembre de 2018 a febrero de 2019. RESULTADOS: se entrevistaron a 11 pacientes y 9 familiares. Se han identificado el impacto de los gastos en los pacientes con cáncer en las siguientes categorías: Ahorros y deudas, vivienda, trabajo, familia, tratamiento, esfera psicológica, gastos a futuro, y en el cuidado de otros enfermos en la casa. Las percepciones son variables, algunos pacientes muestran mayor preocupación por su economía que por su enfermedad, relatan además el cambio que significó en su económica recibir el diagnóstico de cáncer en distintas áreas. CONCLUSIÓN: se ha encontrado, en el presente trabajo, que la percepción del impacto económico para los pacientes con cáncer es multidimensional. Se ha evidenciado además, que el impacto depende del estadio de la enfermedad y del contexto social que vive el paciente, siendo este variable y dando como resultado necesidades de acompañamiento variable por parte de los equipos oncológicos

Cancer patients experience, is about disease´s and economic impact, and this impact is more evident in patients with limited economic resources in low-income countries, the reasons are multifactorial. OBJECTIVE: describe the perception of the economic impact on Bolivian patients with cancer at the Hospital de Clínicas Universitario-La Paz. METHODS: the design is qualitative and exploratory, sampling was by snowball, in-depth interviews were conducted at cancer patients at the Clínicas Universitario de La Paz hospital - Bolivia between December 2018 and February 2019. RESULTS: 11 patients and 9 family members were interviewed. The impact of expenses on cancer patients has been identified in the following categories: Savings and debts, housing, work, family, treatment, psychological sphere, future expenses, and caring for other patients at home. Perceptions are variable, some patients show more significant concern about their finances than about their illness, and they also report the change that receiving the diagnosis of cancer meant in their finances in different areas. CONCLUSION: in this investigation, the perception of economic impact on cancer patients is multidimensional. It has also been shown that the impact depends on the stage of the disease, and the social context in which the patient lives, this being variable and resulting in variable support needs from the oncology teams

Manejo multidisciplinario en un caso refractario de obstrucción intestinal maligna / Multidisciplinary management in a refractory case of malignant intestinal obstruction

Se denomina obstrucción intestinal maligna (OIM) a aquella alteración del tránsito intestinal por obstrucción mecánica o funcional, que genera alteración de la motilidad y acumulación de secreciones, causada por tumores malignos. Es una urgencia oncológica y paliativa de difícil manejo, esta entidad representa un reto para el equipo de salud, debido al gran impacto sobre la calidad de vida del paciente y su familia. Se presenta el caso de una paciente femenina de 73 años, con características clínicas de obstrucción intestinal maligna, evaluada inicialmente por oncología médica quienes diagnostican carcinoma seroso de alto grado de ovario y carcinomatosis peritoneal, se solicita manejo conjunto con un equipo multidisciplinario para tratar la obstrucción intestinal maligna refractaria a medicación convencional, donde se opta por sedación superficial intermitente; así mismo se aborda preferencias y cuidados de final de vida en domicilio con la paciente y su familia. Este caso es un ejemplo del manejo integral de casos refractarios a la obstrucción intestinal maligna, donde se logra aliviar el sufrimiento del paciente y su familia, cuando la cirugía no es una opción

Malignant intestinal obstruction (MIO) is defined as that alteration of intestinal transit due to mechanical or functional obstruction, which generates impaired motility and accumulation of secretions, caused by malignant tumors. It is an oncological and palliative emergency that is difficult to manage, this entity represents a challenge for the health team, due to the great impact on the quality of life of the patient and his family. The case of a 73-year-old female patient is presented, with clinical characteristics of malignant intestinal obstruction, initially evaluated by medical oncology who diagnosed high-grade serous ovarian carcinoma and peritoneal carcinomatosis, joint management with a multidisciplinary team is requested to treat malignant intestinal obstruction refractory to conventional medication, where intermittent superficial sedation is chosen; Likewise, preferences and end-of-life care at home are addressed with the patient and her family This case is an example of the comprehensive management of cases refractory to malignant intestinal obstruction, where it is possible to alleviate the suffering of the patient and her family, when surgery is not an option

An Optimal Integral Controller for Adaptive Optics Systems.

Integral controllers are commonly employed in astronomical adaptive optics. This work presents a novel tuning procedure for integral controllers in adaptive optics systems which relies on information about the measured disturbances. This tuning procedure consists of two main steps. First, it models and identifies measured disturbances as continuous-time-damped oscillators using Whittles´s likelihood and the wavefront sensor output signal. Second, it determines the integral controller gain of the adaptive optics system by minimizing the output variance. The effectiveness of this proposed method is evaluated through theoretical examples and numerical simulations conducted using the Object-Oriented Matlab Adaptive Optics toolbox. The simulation results demonstrate that this approach accurately estimates the disturbance model and can reduce the output variance. Our proposal results in improved performance and better astronomical images even in challenging atmospheric conditions. These findings significantly contribute to adaptive optics system operations in astronomical observatories and establish our procedure as a promising tool for fine-tuning integral controllers in astronomical adaptive optics systems.

Delayed graft rejection in autoimmune islet transplantation via biomaterial immunotherapy.

The induction of operational immune tolerance is a major goal in beta-cell replacement strategies for the treatment of type 1 diabetes. Our group previously reported long-term efficacy via biomaterial-mediated programmed death ligand 1 (PD-L1) immunotherapy in islet allografts in nonautoimmune models. In this study, we evaluated autoimmune recurrence and allograft rejection during islet transplantation in spontaneous nonobese diabetic (NOD) mice. Graft survival and metabolic function were significantly prolonged over 60 days in recipients of syngeneic islets receiving the biomaterial-delivered immunotherapy, but not in control animals. The biomaterial-mediated PD-L1 immunotherapy resulted in delayed allograft rejection in diabetic NOD mice compared with controls. Discrimination between responders and nonresponders was attributed to the enriched presence of CD206+ program death 1+ macrophages and exhausted signatures in the cytotoxic T cell compartment in the local graft microenvironment. Notably, draining lymph nodes had similar remodeling in innate and adaptive immune cell populations. This work establishes that our biomaterial platform for PD-L1 delivery can modulate immune responses to transplanted islets in diabetic NOD mice and, thus, can provide a platform for the development of immunologic strategies to curb the allo- and autoimmune processes in beta-cell transplant recipients.

La prueba cardiopulmonar de ejercicio contribuye a determinar con precisión el riesgo en pacientes con hipertensión pulmonar de bajo riesgo / Cardiopulmonary Exercise Testing Contributes to Accurate Risk Assessment in Patients with Low-risk Pulmonary Hypertension

RESUMEN Introducción : Las guías europeas de hipertensión arterial pulmonar (HAP) estratifican el riesgo valiéndose de características clínicas y estudios complementarios entre los cuales está la prueba cardiopulmonar de ejercicio (PCPE), de la cual toma en cuenta 3 parámetros: el consumo de O2 (VO2) pico, su porcentaje respecto del predicho y la pendiente ventilación minuto/ producción de dióxido de carbono (VE/VCO2). Sin embargo, ninguno de los modelos que validaron esta forma de estratificar el riesgo incluyeron la PCPE entre sus variables. Objetivos : Determinar qué proporción de pacientes con HAP del grupo I considerados de bajo riesgo y que caminan >440 metros en la prueba de caminata de 6 minutos (PC6M) tienen en la PCPE parámetros considerados de riesgo moderado o alto. Material y métodos : Se incluyeron pacientes >18 años con diagnóstico de HAP del grupo I considerados de bajo riesgo con una PC6M >400 metros a los que se les realizó una PCPE en la que se registró el VO2 pico, su porcentaje respecto del VO2 predicho y la pendiente VE/VCO2. Se determinó qué proporción de pacientes presentaban estos parámetros en un estrato de riesgo mayor a bajo riesgo (VO2 pico <15 ml/kg/min, su porcentaje respecto del predicho <65% y la pendiente VE/VCO2 >36). Resultados : Se incluyeron 18 pacientes. A pesar de ser pacientes de bajo riesgo y con buena clase funcional todos presentaron un VO2 pico menor al 85% del predicho, lo cual determina un deterioro al menos leve de la capacidad funcional. Un único paciente (6%) presentó los tres parámetros evaluados en bajo riesgo, 8 pacientes (44%) tuvieron al menos un parámetro alterado, 7 pacientes (39%) presentaron 2 parámetros alterados y en 2 pacientes (11%) todos los parámetros estuvieron alterados. Los parámetros que más frecuentemente se vieron alterados fueron el porcentaje respecto del VO2 predicho y la pendiente VE/VCO2, en el 67% de los casos. Solo 4 pacientes presentaron un VO2 pico <15 ml/k/m. Ningún paciente presentó valores de VO2 pico o porcentaje respecto del predicho en la categoría de alto riesgo. Sin embargo, 6 pacientes (33%) presentaron una pendiente VE/VCO2 considerada de alto riesgo. Conclusión : El 94% de los pacientes considerados de bajo riesgo presentaron al menos una variable en la PCPE que no corresponde a un perfil de riesgo bajo. La pendiente VE/VCO2 y el porcentaje de VO2 pico respecto del predicho fueron las variables más frecuentemente alteradas. La pendiente VE/VCO2 fue la única que mostró valores considerados de alto riesgo. La PCPE podría tener un lugar en la estratificación de precisión de pacientes de bajo riesgo. El valor de este hallazgo deberá ser evaluado en estudios prospectivos, al tiempo que genera las bases para el planteo de hipótesis respecto de la estratificación de riesgo y la intensidad del tratamiento en pacientes que aparentan estar en bajo riesgo.

ABSTRACT Background : European guidelines for pulmonary arterial hypertension (PAH) stratify the risk using clinical characteristics and complementary studies, including the cardiopulmonary exercise test (CPET). This takes into account 3 parameters: peak O2 consumption (peak VO2), its percentage with respect to the predicted VO2, and the minute ventilation/carbon dioxide production (VE/VCO2) slope. However, none of the models that validated this way of stratifying risk included PCPE among their variables. Objectives : To determine what proportion of patients with group I PAH considered to be at low risk and who walk >440 meters in the 6-minute walk test (6MWT) have parameters considered to be of moderate or high risk in the PCPE. Methods : Patients >18 years of age, diagnosed with group I PAH at low risk of events, who walked >440 meters in the 6MWT and had NT-proBNP value <300 pg/dL were included. A CPET was performed in which the peak VO2, its percentage with respect to the predicted VO2, and the VE/VCO2 slope were recorded. It was determined what proportion of patients presented these parameters in a higher than low risk stratum (peak VO2 consumption ≤15 ml/min/Kg, its percentage with respect to the predicted VO2 ≤65% and the VE/VCO2 slope ≥36). Results : Eighteen patients were included. Despite being low-risk patients with a good functional class, all patients presented a peak VO2 less than 85% of predicted, which determines a deterioration of functional capacity. A single patient (6%) presented the three parameters evaluated at low risk, 8 patients (44%) had at least one altered parameter, 7 patients (39%) presented 2 altered parameters and in 2 patients (11%) all parameters were altered. The parameters that were most frequently altered were the percentage of predicted peak VO2 and the VE/VCO2 slope in 67% of the cases. Only 4 patients presented a peak VO2 <15 ml/kg/m. No patient presented peak VO2 values or percentage of predicted VO2 in the high-risk category. However, 6 patients (33%) presented a high-risk VE/VCO2 slope. Conclusion : Majority (92%) of the patients considered low risk and who walk more than 440 meters in 6 minutes presented at least one altered variable in the CPET. The VE/VCO2 slope and the percentage of predicted peak VO2 consumption were the most frequently altered variables. The VE/VCO2 slope was the only one that showed values considered high risk. CPET could have a place in the precision stratification of low-risk patients. The value of this finding should be evaluated in prospective studies.

Motixafortide and G-CSF to mobilize hematopoietic stem cells for autologous transplantation in multiple myeloma: a randomized phase 3 trial.

Autologous hematopoietic stem cell transplantation (ASCT) improves survival in multiple myeloma (MM). However, many individuals are unable to collect optimal CD34+ hematopoietic stem and progenitor cell (HSPC) numbers with granulocyte colony-stimulating factor (G-CSF) mobilization. Motixafortide is a novel cyclic-peptide CXCR4 inhibitor with extended in vivo activity. The GENESIS trial was a prospective, phase 3, double-blind, placebo-controlled, multicenter study with the objective of assessing the superiority of motixafortide + G-CSF over placebo + G-CSF to mobilize HSPCs for ASCT in MM. The primary endpoint was the proportion of patients collecting ≥6 × 106 CD34+ cells kg-1 within two apheresis procedures; the secondary endpoint was to achieve this goal in one apheresis. A total of 122 adult patients with MM undergoing ASCT were enrolled at 18 sites across five countries and randomized (2:1) to motixafortide + G-CSF or placebo + G-CSF for HSPC mobilization. Motixafortide + G-CSF enabled 92.5% to successfully meet the primary endpoint versus 26.2% with placebo + G-CSF (odds ratio (OR) 53.3, 95% confidence interval (CI) 14.12-201.33, P < 0.0001). Motixafortide + G-CSF also enabled 88.8% to meet the secondary endpoint versus 9.5% with placebo + G-CSF (OR 118.0, 95% CI 25.36-549.35, P < 0.0001). Motixafortide + G-CSF was safe and well tolerated, with the most common treatment-emergent adverse events observed being transient, grade 1/2 injection site reactions (pain, 50%; erythema, 27.5%; pruritis, 21.3%). In conclusion, motixafortide + G-CSF mobilized significantly greater CD34+ HSPC numbers within two apheresis procedures versus placebo + G-CSF while preferentially mobilizing increased numbers of immunophenotypically and transcriptionally primitive HSPCs. Trial Registration: ClinicalTrials.gov , NCT03246529.

Bioengineered omental transplant site promotes pancreatic islet allografts survival in non-human primates.

The transplanting islets to the liver approach suffers from an immediate posttransplant loss of islets of more than 50%, progressive graft dysfunction over time, and precludes recovery of grafts should there be serious complications such as the development of teratomas with grafts that are stem cell-derived islets (SC-islets). The omentum features an attractive extrahepatic alternative site for clinical islet transplantation. We explore an approach in which allogeneic islets are transplanted onto the omentum, which is bioengineered with a plasma-thrombin biodegradable matrix in three diabetic non-human primates (NHPs). Within 1 week posttransplant, each transplanted NHP achieves normoglycemia and insulin independence and remains stable until termination of the experiment. Success was achieved in each case with islets recovered from a single NHP donor. Histology demonstrates robust revascularization and reinnervation of the graft. This preclinical study can inform the development of strategies for ß cell replacement including the use of SC-islets or other types of novel cells in clinical settings.

Modulation of the Inflammatory Response by Pre-emptive Administration of IMT504 Reduces Postoperative Pain in Rats and has Opioid-Sparing Effects.

Despite the available knowledge on underlying mechanisms and the development of several therapeutic strategies, optimal management of postoperative pain remains challenging. This preclinical study hypothesizes that, by promoting an anti-inflammatory scenario, pre-emptive administration of IMT504, a noncoding, non-CpG oligodeoxynucleotide with immune modulating properties, will reduce postincisional pain, also facilitating therapeutic opioid-sparing. Male adult Sprague-Dawley rats with unilateral hindpaw skin-muscle incision received pre-emptive (48 and 24 hours prior to surgery) or postoperative (6 hours after surgery) subcutaneous vehicle (saline) or IMT504. Various groups of rats were prepared for pain-like behavior analyses, including subgroups receiving morphine or naloxone, as well as for flow-cytometry or quantitative RT-PCR analyses of the spleen and hindpaws (for analysis of inflammatory phenotype). Compared to vehicle-treated rats, pre-emptive IMT504 significantly reduced mechanical allodynia by 6 hours after surgery, and accelerated recovery of basal responses from 72 hours after surgery and onwards. Cold allodynia was also reduced by IMT504. Postoperative administration of IMT504 resulted in similar positive effects on pain-like behavior. In IMT504-treated rats, 3 mg/kg morphine resulted in comparable blockade of mechanical allodynia as observed in vehicle-treated rats receiving 10 mg/kg morphine. IMT504 significantly increased hindpaw infiltration of mesenchymal stem cells, CD4+T and B cells, and caused upregulated or downregulated transcript expressions of interleukin-10 and interleukin-1ß, respectively. Also, IMT504 treatment targeted the spleen, with upregulated or downregulated transcript expressions, 6 hours after incision, of interleukin-10 and interleukin-1ß, respectively. Altogether, pre-emptive or postoperative IMT504 provides protection against postincisional pain, through participation of significant immunomodulatory actions, and exhibiting opioid-sparing effects. PERSPECTIVE: This preclinical study introduces the noncoding non-CpG oligodeoxynucleotide IMT504 as a novel modulator of postoperative pain and underlying inflammatory events. The opioid-sparing effects observed for IMT504 appear as a key feature that could contribute, in the future, to reducing opioid-related adverse events in patients undergoing surgical intervention.

An update to pain management after spinal cord injury: from pharmacology to circRNAs.

Neuropathic pain (NP) following a spinal cord injury (SCI) is often hard to control and therapies should be focused on the physical, psychological, behavioral, social, and environmental factors that may contribute to chronic sensory symptoms. Novel therapeutic treatments for NP management should be based on the combination of pharmacological and nonpharmacological options. Some of them are addressed in this review with a focus on mechanisms and novel treatments. Several reports demonstrated an aberrant expression of non-coding RNAs (ncRNAs) that may represent key regulatory factors with a crucial role in the pathophysiology of NP and as potential diagnostic biomarkers. This review analyses the latest evidence for cellular and molecular mechanisms associated with the role of circular RNAs (circRNAs) in the management of pain after SCI. Advantages in the use of circRNA are their stability (up to 48 h), and specificity as sponges of different miRNAs related to SCI and nerve injury. The present review discusses novel data about deregulated circRNAs (up or downregulated) that sponge miRNAs, and promote cellular and molecular interactions with mRNAs and proteins. This data support the concept that circRNAs could be considered as novel potential therapeutic targets for NP management especially after spinal cord injuries.

Changes in the expression of endocannabinoid system components in an experimental model of chemotherapy-induced peripheral neuropathic pain: Evaluation of sex-related differences.

Chemotherapy-induced neuropathic pain is a serious clinical problem and one of the major side effects in cancer treatment. The endocannabinoid system (ECS) plays a crucial role in regulating pain neurotransmission, and changes in the expression of different components of the ECS have been reported in experimental models of persistent pain. In addition, sex differences have been observed in ECS regulation and function. The aim of our study was to evaluate whether administration of oxaliplatin, a neurotoxic antineoplastic agent, induced changes in the expression of ECS components in peripheral and central stations of the pain pathway, and if those changes exhibited sexual dimorphism. Adult male and female rats were injected with oxaliplatin or saline, and mechanical and cold hypersensitivity and allodynia were evaluated using Von Frey and Choi Tests. The mRNA levels corresponding to cannabinoid receptors (CB1, CB2), cannabinoid-related receptors (GPR55, 5HT1A, TRPV1) and to the main enzymes involved in the synthesis (DAGL, DAGL, NAPE-PLD) and degradation (MGL, FAAH) of endocannabinoids were assessed in lumbar dorsal root ganglia (DRGs) and spinal cord by using real time RT-PCR. In addition, the levels of the main endocannabinoids, 2-arachidonoylglycerol (2-AG) and anandamide (AEA), were evaluated using commercial ELISA kits. Oxaliplatin administration induced the development of mechanical and cold hypersensitivity and allodynia in male and female animals. Oxaliplatin also induced early and robust changes in the expression of several components of the ECS in DRGs. A marked upregulation of CB1, CB2, 5HT1A and TRPV1 was detected in both sexes. Interestingly, while DAGL mRNA levels remained unchanged, DAGL was downregulated in male and upregulated in female rats. Finally, MGL and NAPE-PLD showed increased levels only in male animals, while FAAH resulted upregulated in both sexes. In parallel, reduced 2-AG and AEA levels were detected in DRGs from male or female rats, respectively. In the lumbar spinal cord, only TRPV1 mRNA levels were found to be upregulated in both sexes. Our results reveal previously unreported changes in the expression of cannabinoid receptors, ligands and enzymes occurring mainly in the peripheral nervous system and displaying certain sexual dimorphism. These changes may contribute to the physiopathology of oxaliplatin-induced neuropathic pain in male and female rats. A better understanding of these dynamic changes will facilitate the development of mechanism- and sex-specific approaches to optimize the use of cannabinoid-based medicines for the treatment of chemotherapy-induced pain.

Risk stratification, prognosis, and survival in a pulmonary arterial hypertension cohort in Latin America. A multicenter study.

BACKGROUND: Pulmonary arterial hypertension (PAH) guidelines suggest that achieving a low-risk profile should be the treatment goal. Our aim was to assess a risk assessment strategy based on three non-invasive variables from the ESC/ERS 2015 guidelines in a Latin American cohort. METHODS: 92 incident patients (mean [SD] age 47, 77% female, 53% idiopathic PAH) were included in this retrospective, multicenter study. Patients were stratified at baseline and at early follow-up, within the first year, using three non-invasive variables (WHO functional class, 6-minute walking distance, BNP/NT-proBNP) from the ESC/ERS 2015 risk assessment instrument. Median (IQR) follow-up was 3.11 years (3.01 years). RESULTS: At baseline assessment, 25% of patients were at low risk, 61.9% at intermediate-risk, and 13% at high-risk. At early follow-up (median 9.5 months), 56.5% of patients were at low-risk, 40.2% at intermediate-risk, and 3.2% at high-risk (p<0.001 vs. baseline). According to risk stratification at early follow-up, one, three and five-year overall survival was 100% in the low-risk group (no deaths at five-year follow-up), and 100%, 84% (95% CI: 72-98%), and 66% (95% CI: 48-90%) respectively in the intermediate-risk group, p = 0.0003. Mortality in the high-risk patients at early follow-up was 1/3 (33.3%). One, three, and five-year event-free survival (death or transplant or first hospitalization due to worsening PAH) based on early follow-up risk assessment was higher in the low-risk group, p = 0.0003. CONCLUSION: Our study validates a risk assessment strategy based on three non-invasive variables and confirms that early achievement of a low-risk profile should be the treatment goal.