A computational account of the development and evolution of psychotic symptoms.

The mechanisms of psychotic symptoms like hallucinations and delusions are often investigated in fully-formed illness, well after symptoms emerge. These investigations have yielded key insights, but are not well-positioned to reveal the dynamic forces underlying symptom formation itself. Understanding symptom development over time would allow us to identify steps in the pathophysiological process leading to psychosis, shifting the focus of psychiatric intervention from symptom alleviation to prevention. We propose a model for understanding the emergence of psychotic symptoms within the context of an adaptive, developing neural system. We will make the case for a pathophysiological process that begins with cortical hyperexcitability and bottom-up noise transmission, which engenders inappropriate belief formation via aberrant prediction error signaling. We will argue that this bottom-up noise drives learning about the (im)precision of new incoming sensory information because of diminished signal-to-noise ratio, causing an adaptive relative over-reliance on prior beliefs. This over-reliance on priors predisposes to hallucinations and covaries with hallucination severity. An over-reliance on priors may also lead to increased conviction in the beliefs generated by bottom-up noise and drive movement toward conversion to psychosis. We will identify predictions of our model at each stage, examine evidence to support or refute those predictions, and propose experiments that could falsify or help select between alternative elements of the overall model. Nesting computational abnormalities within longitudinal development allows us to account for hidden dynamics among the mechanisms driving symptom formation and to view established symptomatology as a point of equilibrium among competing biological forces.

Factors affecting anatomical and visual outcomes in Terson syndrome managed by surgery or observation.

OBJECTIVES: To investigate visual outcomes and prognostic factors of patients with Terson syndrome (TS) managed with observation or pars plana vitrectomy (PPV). METHODS: retrospective review of medical records of 117 eyes from 81 patients (43 females) with TS. Main outcome measures were final best corrected visual acuity (BCVA), intraoperative findings and long-term sequelae. RESULTS: 46 (39.3%) eyes were managed conservatively and 71 (60.7%) eyes underwent PPV. Median follow-up was 8.4 months. The PPV group had significantly worse (p < 0.001) baseline BCVA (median 2.3 versus 0.7 logMAR, Snellen equivalent 20/4000 versus 20/100). Final BCVA did not differ between the two groups (p = 0.38). Final BCVA ≥ 0.3 logMAR (20/40) in the surgery group was associated with post-operative retinal detachment (p = 0.013) and macular abnormalities (p = 0.014), and in the observation group with ocular comorbidity (p = 0.008). Retinal breaks were detected intraoperatively in 25 (35.2%) eyes and were associated with an interval longer than 3 months between ocular diagnosis and surgery (p = 0.04), but not with larger gauge instrumentation and posterior vitreous detachment. Incidence of ERM did not differ among patients managed conservatively and after PPV (p = 0.9) and between eyes undergoing early or delayed surgery (p = 0.09). The most common post-operative complications were cataract in 16 (22.5%) eyes and ERM in 8 (11.3%) eyes. CONCLUSIONS: visual outcomes in TS are similar with both management strategies. Surgery allows faster and greater visual recovery but carries high risk of intraoperative retinal tears if delayed for longer than 3 months from initial presentation. ERM and retinal detachment are not correlated with timing of surgery or management strategy.

EASIX and cardiac adverse events after allogeneic hematopoietic cell transplantation.

This study investigates the interaction between endothelial activation, indirectly measured using EASIX, and the probability of presenting cardiac adverse events (CAE) during the first year after allo-HCT. The 437 consecutive adults undergoing PB allo-HCT from 2012 and 2021 were included. EASIX was retrospectively calculated before and during the first 6 months after allo-HCT and transformed to log2-base to conduct the statistical analysis. The median age was 53, 46 (10.5%) patients had previous history of cardiac disease, MAC allo-HCTs were performed in 186 (42.6%) patients, and PTCY was administered in 242 (55.5%). The 1-year incidence of CAE was 12.6% (n = 55). The most prevalent cardiac events were heart failure and arrhythmias, 32.7% and 23.6% respectively, and the day +100 mortality rate of these patients was 40.5%. During the first 6 months after allo-HCT, EASIX trends were significantly higher in patients who developed CAE. Regression analyses confirmed that higher log2-EASIX values were predictors for higher risk for CAE during the first year after allo-HCT. This analysis identifies a significant association between higher endothelial activation, indirectly measured using EASIX, and higher risk for cardiac toxicity diagnosed during the first year after allo-HCT and extends the applicability of EASIX for identifying patients at risk for CAE.

Perceptual-Auditory and Acoustic Analysis of Breathiness in Cis and Transgender Men and Women.

OBJECTIVE: To verify breathiness in the cisgender and transgender men and women's voices, compare values of acoustic and perceptual indicators of breathiness and fundamental frequency (f0) between groups, and compare them between the voices attributed as female and male. STUDY DESIGN: Cross sectional retrospective study. METHODS: The study was approved by the Research Ethics Committee (4,937,140). Sustained vowel /a/ and continuous speech recordings of 21 cisgender men (CISM), 31 transgender men (TM), 32 cisgender women (CISW), and 31 transgender women (TW) were analyzed. Three judges conducted a perceptive-auditory analysis regarding the degree breathiness, using a visual analog scale, and attributed gender (female or male). The ABI (Acoustic Breathiness Index) was extracted using the PRAAT software (6.1.16). The f0, Harmonic-Noise Ratio (HNR), Voice Turbulence Index (VTI), and Soft Phonation Index (SPI) were analyzed using the Multi-Dimensional Voice Program (KayPentax). RESULTS: The ABI value for CISM was lower than for TM and CISW. CISW had a higher f0 than; TM had a higher f0 than CISM; and TW had a higher f0 than CISM. The groups did not differ for HNR and VTI. Regarding the SPI, CISM had higher values than CISW. Regarding the auditory perception, TM presented more intense breathiness than CISM in the vowel. Regarding gender attribution by voice, the voices CISM and CISW were 100% identified as male and female. On the other hand, in the vowel analysis, 45.2% of the TM voices were perceived as female, and 59.4% of TW voices as male. CONCLUSION: Breathiness occurs differently between groups and the voices perceived as male and female. Even when TM is submitted to the use of testosterone and undergoes vocal changes, the transglottal airflow remains, which is a female characteristic of phonation.

Toward a coordinated understanding of hydro-biogeochemical root functions in tropical forests for application in vegetation models.

Tropical forest root characteristics and resource acquisition strategies are underrepresented in vegetation and global models, hampering the prediction of forest-climate feedbacks for these carbon-rich ecosystems. Lowland tropical forests often have globally unique combinations of high taxonomic and functional biodiversity, rainfall seasonality, and strongly weathered infertile soils, giving rise to distinct patterns in root traits and functions compared with higher latitude ecosystems. We provide a roadmap for integrating recent advances in our understanding of tropical forest belowground function into vegetation models, focusing on water and nutrient acquisition. We offer comparisons of recent advances in empirical and model understanding of root characteristics that represent important functional processes in tropical forests. We focus on: (1) fine-root strategies for soil resource exploration, (2) coupling and trade-offs in fine-root water vs nutrient acquisition, and (3) aboveground-belowground linkages in plant resource acquisition and use. We suggest avenues for representing these extremely diverse plant communities in computationally manageable and ecologically meaningful groups in models for linked aboveground-belowground hydro-nutrient functions. Tropical forests are undergoing warming, shifting rainfall regimes, and exacerbation of soil nutrient scarcity caused by elevated atmospheric CO2. The accurate model representation of tropical forest functions is crucial for understanding the interactions of this biome with the climate.

Las características de las raíces de los bosques tropicales y las estrategias de adquisición de recursos están subrepresentadas en modelos de vegetación, lo que dificulta la predicción del efecto de cambio de clima para estos ecosistemas ricos en carbono. Los bosques tropicales a menudo tienen combinaciones únicas a nivel mundial de alta biodiversidad taxonómica y funcional, estacionalidad de precipitación, y suelos infértiles, dando lugar a patrones distintos en los rasgos y funciones de las raíces en comparación con los ecosistemas de latitudes más altas. Integramos los avances recientes en nuestra comprensión de la función subterránea de los bosques tropicales en modelos de vegetación, centrándonos en la adquisición de agua y nutrientes. Ofrecemos comparaciones de avances recientes en la comprensión empírica y de modelos de las características de las raíces que representan procesos funcionales importantes en los bosques tropicales. Nos centramos en: (1) estrategias de raíces finas para adquisición de recursos del suelo, (2) acoplamiento y compensaciones entre adquisición del agua y de nutrientes, y (3) vínculos entre funciones sobre tierra y debajo del superficie en bosques tropicales. Sugerimos vías para representar estas comunidades de plantas extremadamente diversas en grupos computacionalmente manejables y ecológicamente significativos en modelos. Los bosques tropicales se están calentando, tienen cambios en los regímenes de lluvias, y tienen una exacerbación de la escasez de nutrientes del suelo causada por el elevado CO2 atmosférico. La representación precisa de las funciones de los bosques tropicales en modelos es crucial para comprender las interacciones de este bioma con el clima.

Artificial nighttime lighting impacts Plasmodium falciparum mature stage V gametocytes infectivity in Anopheles stephensi.

BACKGROUND: Malaria is one of the most important vector-borne diseases of humans with an estimated 241 million cases worldwide in 2020. As an urban and periurban mosquito species, Anopheles stephensi is exposed to artificial human stimuli like light that can alter many aspects of mosquito behaviour, physiology and metabolism. Therefore, fluctuations in the light environment may influence the host, parasite and/or mosquito biology and hence modulate risk for disease transmission. In this study, the effect of artifitial light at night on mosquito infectivity by Plasmodium falciparum during the first hours of blood digestion was tested. METHODS: A total of three independent standard membrane feeding assays were performed to artificially fed septic and aseptic mosquitoes with P. falciparum infected blood. After blood feeding, females were transferred to incubators with different photoperiod cycles, so digestion occurred under day artificial light or dark. At 7 and 16 days post blood feeding, mosquitoes were dissected for midguts and salivary glands, respectively. Percentage of mosquitoes fed, percentage of prevalence and P. falciparum oocyst intensity between septic and aseptic mosquitoes in the two different photoperiod regimes, were compared using a Kruskal-Wallis test followed by a Dunn´s multiple comparison test . RESULTS: The exposition of mosquitoes to light after they took an infected blood meal has a negative effect on the successful progression of P. falciparum in the mosquito midgut. Antibiotic treatment significantly incremented the number of oocysts per midgut. Photophase significantly reduced the median oocyst intensity in both septic and aseptic mosquitoes. The percentage of oocyst reduction, understood as the percentage of reduction in the mean oocyst intensity of the parasite in the mosquito midgut between photophase and scotophase, was 51% in the case of aseptic mosquitoes and 80% for septic mosquitoes, both in the photophase condition. CONCLUSION: Although there are still many gaps in the understanding of parasite-mosquito interactions, these results support the idea that light can, not only, influence mosquito biting behaviour but also parasite success in the mosquito midgut. Hence, light can be considered an interesting additional mosquito-control strategy to reduce mosquito-borne diseases.

T-TAS® 01 as a new tool for the evaluation of hemostasis in thrombocytopenic patients after platelet transfusion.

BACKGROUND: Current laboratory tests fail to evaluate the hemostatic function of platelets in patients with thrombocytopenia. We investigated the use of the Total Thrombus-Formation Analysis System (T-TAS® 01 [Fujimori Kogyo Co, Tokyo, Japan]) to evaluate hemostasis under conditions of experimental thrombocytopenia, and in patients before and after platelet transfusion. MATERIALS AND METHODS: Specific T-TAS 01 chips, for thrombocytopenic conditions, were used. The area under the curve (AUC) and occlusion time (OT, min) were measured in: (i) experimentally induced thrombocytopenia (183±15 to 6.3±1.2×103 platelets/µL) in blood samples from healthy donors (No.=13), and (ii) blood from oncohematological thrombocytopenic patients (No.=48), before and after platelet transfusion. The influences of hematocrit and number of transfusions were analyzed in these patients. RESULTS: Progressive reductions of AUC and prolongations of OT related significantly to decreasing platelet counts (p<0.05 for all) in experimental thrombocytopenia. In samples from thrombocytopenic patients, platelet counts, AUC and OT were, respectively, 10.8±0.6×103/µL, 175.2±59, and 27.2±1 min before transfusion; and 22±1.5×103/µL, 400.8±83 and 22.9±1.5 min after platelet transfusion (p<0.01 for all). A hematocrit below 25% or exposure to ten or more previous platelet transfusions had a negative impact on the T-TAS 01 performance in patients. In vitro correction of the hematocrit improved the hemostatic response in thrombocytopenic patients. DISCUSSION: T-TAS 01 measurements were sensitive to low platelet counts in the experimental setting. The technology was sensitive to evaluate the hemostatic capacity of platelet transfusions. Exposure to multiple medications, repeated platelet transfusions and lower hematocrits may interfere with the hemostatic performance in oncohematological patients with thrombocytopenia.

Antithrombotic and prohemorrhagic actions of different concentrations of apixaban in patients exposed to single and dual antiplatelet regimens.

We evaluated modifications in the hemostatic balance of different concentrations of apixaban (APIX) in 25 healthy donors and 53 patients treated with aspirin (ASA, n = 21), ASA and clopidogrel (ASA + CLOPI, n = 11), or ASA and ticagrelor (ASA + TICA, n = 21). Blood samples from participants were spiked ex vivo with apixaban 0 (APIX0), 40 (APIX40), and 160 ng/mL (APIX160). We assessed the effects of APIX on (1) clot formation, by ROTEM thromboelastometry; (2) thrombin generation primed by platelets; and (3) platelet and fibrin interactions with a thrombogenic surface, in a microfluidic model with circulating blood. APIX caused dose-related prolongations of clotting time with minimal impact on other ROTEM parameters. Thrombin generation was significantly inhibited by APIX160, with ASA + TICA actions showing the strongest inhibition (p < 0.01 vs APIX0). Microfluidic studies showed that APIX160 was more potent at suppressing platelet and fibrin interactions (p < 0.001 vs. APIX0). APIX40 demonstrated a consistent antithrombotic action but with a favorable protective effect on the structural quality of fibrin. APIX potentiated the antithrombotic effects of current antiplatelet regimens. APIX at 40 ng/mL, enhanced the antithrombotic action of single or dual antiplatelet regimens but was more conservative for hemostasis than the 160 ng/mL concentration.

Endothelial activation and damage as a common pathological substrate in different pathologies and cell therapy complications.

The endothelium is a biologically active interface with multiple functions, some of them common throughout the vascular tree, and others that depend on its anatomical location. Endothelial cells are continually exposed to cellular and humoral factors, and to all those elements (biological, chemical, or hemodynamic) that circulate in blood at a certain time. It can adapt to different stimuli but this capability may be lost if the stimuli are strong enough and/or persistent in time. If the endothelium loses its adaptability it may become dysfunctional, becoming a potential real danger to the host. Endothelial dysfunction is present in multiple clinical conditions, such as chronic kidney disease, obesity, major depression, pregnancy-related complications, septic syndromes, COVID-19, and thrombotic microangiopathies, among other pathologies, but also in association with cell therapies, such as hematopoietic stem cell transplantation and treatment with chimeric antigen receptor T cells. In these diverse conditions, evidence suggests that the presence and severity of endothelial dysfunction correlate with the severity of the associated disease. More importantly, endothelial dysfunction has a strong diagnostic and prognostic value for the development of critical complications that, although may differ according to the underlying disease, have a vascular background in common. Our multidisciplinary team of women has devoted many years to exploring the role of the endothelium in association with the mentioned diseases and conditions. Our research group has characterized some of the mechanisms and also proposed biomarkers of endothelial damage. A better knowledge would provide therapeutic strategies either to prevent or to treat endothelial dysfunction.

Speech therapy assistance to the transgender population: an experience report / Atendimento fonoaudiológico à população transgênera: um relato de experiência

An incompatible voice with one's own identity is a theme frequently pointed out by the transgender population in speech therapy sessions. Speech therapy is a technique that allows the adjustment of the speaker's voice within a range of possibilities. The speech-language pathologist's role is to provide training, guidance, and counseling to this population, taking into account the specificities of each individual. In light of this, this study aims to report the experience of undergraduate students and speech-language professionals in providing care to the transgender population in a communication laboratory. Initially, key concepts, such as the differences between sex, gender, gender identity, and sexual orientation, are presented. Topics addressed include the violence suffered by the transgender population, the pursuit of vocal adaptation, the creation and development of the communication clinic, the support and assistance provided by professionals to the transgender population and their families, as well as the procedures adopted by the clinic. Among the conclusions, it is highlighted that speech therapy has demonstrated the importance of individual-centered care, legitimizing the guarantee of promoting the users' health. Furthermore, the importance of the speech-language professional in the vocal and communicative improvement of this population, which is often stigmatized, is emphasized (AU).

Voz incompatível com a própria identidade é um tema frequentemente apontado pela população transgênera em atendimentos fonoaudiológicos. A fonoterapia é uma técnica que permite a adequação da voz do falante, dentro de um campo de possibilidades. Ao fonoaudiólogo cabe o treinamento, a orientação e o aconselhamento dessa população, levando em conta as especificidades de cada indivíduo. Diante disso, este estudo tem como objetivo relatar a experiência de estudantes de graduação e profissionais de Fonoaudiologia no atendimento voltado à população transgênera em um laboratório de comunicação. Inicialmente são apresentados conceitos-chave, tais como as diferenças entre sexo, gênero, identidade de gênero, e orientação sexual. São abordados temas como a violência sofrida pela população trans, a busca pela adequação vocal, a criação e o desenvolvimento do ambulatório de comunicação, o acolhimento e o suporte prestado pelos profissionais à população trans e a seus familiares, além dos procedimentos adotados pelo ambulatório. Dentre as conclusões, destaca-se que a assistência fonoaudiológica tem mostrado a importância do cuidado centrado no indivíduo, legitimando a garantia da promoção de saúde dos usuários. Ademais, é destacada a importância do profissional de fonoaudiologia no aprimoramento vocal e comunicativo dessa população que é frequentemente estigmatizada (AU).

Dosis de radiación por radiografías y factores asociados en neonatos de la Unidad de Recién Nacidos del Hospital Universitario San Ignacio, Bogotá, Colombia / X-ray radiation dose and associated factors in neonates from the newborn unit of Hospital Universitario San Ignacio, Bogotá, Colombia

Introducción. Las radiografías continúan usándose ampliamente, subestimando los riesgos. Esto sucede, especialmente, en las unidades de cuidado neonatal, lo que implica que los neonatos reciben una dosis de radiación ionizante mayor que los adultos. Objetivo. Cuantificar las dosis de radiación recibidas al tomar radiografías y evaluar los posibles factores asociados con el aumento de la dosis. Materiales y métodos. Se llevó a cabo un estudio observacional de 160 neonatos de la Unidad de Recién Nacidos del Hospital Universitario San Ignacio, Bogotá, Colombia. Se consideró como variable dependiente la dosis de entrada en piel por cada radiografía. Se hizo la caracterización de los pacientes, seguida de un análisis multivariado con regresión lineal múltiple para identificar factores asociados. Resultados. Se analizaron 160 pacientes y 492 radiografías en total. Entre los hallazgos más frecuentes, se encuentran: pacientes de sexo masculino (n=87; 54,4 %), nacimiento por cesárea (n=122; 76,3 %) e indicación de toma de radiografías por dificultad respiratoria (n=123; 24,9 %). El 1,8 % (n=9) de los pacientes no tenían una indicación para la toma de la radiografía. La radiografía más frecuente fue la de tórax (n=322; 65,4 %). La mayoría de las radiografías se tomaron con el equipo computarizado (n=352; 71,5 %) y no con el digital (n=140, 28,4 %). La mediana de la dosis de entrada en piel con el equipo computarizado fue de 0,112 mGy (0,022; 0,134 mGy) y, con el equipo digital, de 0,020 mGy (0,019, 0,022 mGy). Conclusiones. Se cuantificaron las dosis de radiación absorbida en neonatos, general y específica, con el equipo computarizado y el digital. Se identificaron mayores dosis con el equipo computarizado. Se reconoció la interacción entre el equipo computarizado con menores edades gestacionales corregidas como principal factor para el aumento de la dosis. Además, se reconoció la relación entre el equipo computarizado y una menor edad gestacional corregida, como principal factor para una mayor dosis.

Introduction. Radiographs are still widely used, underestimating the risks. This situation is frequent in neonatal care units, generating radiation doses than in adults. Objective. To quantify the received radiation doses when performing radiographs on neonates and the possible factors associated with higher doses. Materials and methods. We performed an observational study of 160 neonates from the newborn unit of the Hospital Universitario San Ignacio, Bogotá, Colombia. We considered the input dose of each radiograph as the dependent variable. Patients were characterized and a multivariate analysis with multiple linear regression was performed to identify associated factors. Results. We analyzed 160 newborns and 492 radiographs. The most frequent findings were male patients (n=87, 54.4%), cesarean delivery (n=122, 76.3%), and radiograph indication for respiratory distress (n=123, 24.9%). One-point eight percent of the patients (n=9) did not have radiograph indication. The most frequently taken radiograph was chest (322, 65.4%). Most radiographs were taken with a computerized equipment (n=352, 71.5%), compared to a digital one (n=140, 28.4%). The median input dose with computerized equipment was 0.112 mGy (0.022, 0.134 mGy), and with the digital equipment was 0.020 mGy (0.019, 0.022 mGy). Conclusions. The general and specific absorbed radiation doses were measured in neonates with a computerized and a digital equipment. We identified higher doses with the computerized equipment. In addition, it was recognized the correlation between computerized radiography equipment with lower corrected gestational ages as the main factor for dose increase.

Quality indicators of hospitalized children influenced by clinical pharmacist services: A systematic review.

BACKGROUND: Care for children who are hospitalized can be optimized if the pharmacist, in conjunction with the multidisciplinary team, promotes the rational use of medicines. In this sense, the evaluation of the quality of these clinical services through indicators is important in the planning, decision making of pharmacists and managers of these services. OBJECTIVE: To characterize which health indicators were influenced by the pharmaceutical clinical services for the care of children in hospitals. METHODS: A systematic review was performed. The search for data was made on the bases: Cochrane, Embase, Lilacs, Pubmed and Web of Science. Then, the search included studies in which evaluated the impact of pharmaceutical clinical services on clinical, economic and humanistic outcomes. RESULTS: The search resulted in 11 included studies. In this review, four pharmaceutical clinical services were found: pharmacotherapy review, multiprofessional team interventions, antimicrobial stewardship program and pharmaceutical services at discharge hospital. The most influenced outcome indicators were length of hospital stay, with average time in the group that received the pharmacotherapy review service, and interventions multiprofessional team with a 6.45-day vs. 10.83 days in the control group; hospital readmissions with a significant reduction of non-scheduled readmission of 30 days in the ntimicrobial stewardship program; reduction of hospital costs and caregiver satisfaction. CONCLUSION: In this study, we can highlight that pharmacotherapy review, multiprofessional team interventions and Antimicrobial Stewardship Program that significantly reduced the clinical results of length of hospital stay and hospital readmission, as well as a significant reduction of hospital costs.

Characterization of the endotheliopathy, innate-immune activation and hemostatic imbalance underlying CAR-T cell toxicities: laboratory tools for an early and differential diagnosis.

BACKGROUND: Chimeric antigen receptor (CAR)-T cell-based immunotherapy constitutes a revolutionary advance for treatment of relapsed/refractory hematological malignancies. Nevertheless, cytokine release and immune effector cell-associated neurotoxicity syndromes are life-threatening toxicities in which the endothelium could be a pathophysiological substrate. Furthermore, differential diagnosis from sepsis, highly incident in these patients, is challenging. Suitable laboratory tools could be determinant for their appropriate management. METHODS: Sixty-two patients treated with CAR-T cell immunotherapy for hematological malignancies (n=46 with CD19-positive diseases, n=16 with multiple myeloma) were included. Plasma samples were obtained: before CAR-T cell infusion (baseline); after 24-48 hours; at suspicion of any toxicity onset and 24-48 hours after immunomodulatory treatment. Biomarkers of endothelial dysfunction (soluble vascular cell adhesion molecule 1 (sVCAM-1), soluble TNF receptor 1 (sTNFRI), thrombomodulin (TM), soluble suppression of tumorigenesis-2 factor (ST2), angiopoietin-2 (Ang-2)), innate immunity activation (neutrophil extracellular traps (NETs), soluble C5b-9 (sC5b-9)) and hemostasis/fibrinolysis (von Willebrand Factor antigen (VWF:Ag), ADAMTS-13 (A13), α2-antiplasmin (α2-AP), plasminogen activator inhibitor-1 antigen (PAI-1 Ag)) were measured and compared with those in cohorts of patients with sepsis and healthy donors. RESULTS: Patients who developed CAR-T cell toxicities presented increased levels of sVCAM-1, sTNFRI and ST2 at the clinical onset versus postinfusion values. Twenty-four hours after infusion, ST2 levels were good predictors of any CAR-T cell toxicity, and combination of ST2, Ang-2 and NETs differentiated patients requiring intensive care unit admission from those with milder clinical presentations. Association of Ang-2, NETs, sC5b-9, VWF:Ag and PAI-1 Ag showed excellent discrimination between severe CAR-T cell toxicities and sepsis. CONCLUSIONS: This study provides relevant contributions to the current knowledge of the CAR-T cell toxicities pathophysiology. Markers of endotheliopathy, innate immunity activation and hemostatic imbalance appear as potential laboratory tools for their prediction, severity and differential diagnosis.

Differential protein expression in endothelial cells exposed to serum from patients with acute graft-vs-host disease, depending on steroid response.

Graft-versus-host disease (GVHD) is a complication of allogeneic haematopoietic cell transplantation. Endothelial injury is crucial as pathophysiological substrate for GVHD. GVHD first-line treatment is high-dose corticosteroids, although some patients are steroid-refractory. Through the present study, we compared the endothelial proteomic profiles in response to serum from steroid-refractory acute GVHD (SR-aGVHD) and steroid-sensitive acute GVHD (SS-aGVHD) patients. Blood samples from SR-aGVHD (n = 4) and SS-aGVHD (n = 8) patients were collected at aGVHD diagnosis. Endothelial cell cultures were exposed (48 h) to patients' serum. Protein extraction and proteomic analysis were performed. Differences were statistically evaluated by multivariate analysis. Forty-four proteins contributed to separate all samples into the two study groups, among which 15 participated significantly (p < 0.05), 10 exhibiting a fold change >1.2. Differentially expressed proteins were mainly associated with oxidative phosphorylation (Cytochrome C oxidase subunit 6B1, CX6B1), inflammation and angiogenesis (Apolipoprotein D, APOD), cell survival (Rapamycin-insensitive companion of mTOR, RICTR), and oxidative stress (Riboflavin kinase, RIFK). This pilot study used a novel approach to distinguish the aGVHD response to steroid treatment. The proteins differentially expressed could constitute potential biomarkers for steroid-treatment response. These findings signify a step forward to identify the mechanisms of response to steroids, of high clinical relevance considering the SR-aGVHD elevated mortality.

Neuropsychological markers of antidepressant action: a secondary analysis of the ANTLER randomised controlled trial.

BACKGROUND: Antidepressants have been proposed to act via their influence on emotional processing. We investigated the effect of discontinuing maintenance antidepressant treatment on positive and negative self-referential recall and the association between self-referential recall and risk of relapse. METHODS: The ANTLER trial was a large (N = 478) pragmatic double-blind trial investigating the clinical effectiveness of long-term antidepressant treatment for preventing relapse in primary care patients. Participants were randomised to continue their maintenance antidepressants or discontinue via a taper to placebo. We analysed memory for positive and negative personality descriptors, assessed at baseline, 12- and 52-week follow-up. RESULTS: The recall task was completed by 437 participants. There was no evidence of an effect of discontinuation on self-referential recall at 12 [positive recall ratio 1.00, 95% CI (0.90-1.11), p = 0.93; negative recall ratio 1.00 (0.87-1.14), p = 0.87] or 52 weeks [positive recall ratio 1.03 (0.91-1.17), p = 0.62; negative recall ratio 1.00 (0.86-1.15), p = 0.96; ratios larger than one indicate higher recall in the discontinuation group], and no evidence of an association between recall at baseline or 12 weeks and later relapse [baseline, positive hazard ratio (HR) 1.02 (0.93-1.12), p = 0.74; negative HR 1.01 (0.90-1.13), p = 0.87; 12 weeks, positive HR 0.99 (0.89-1.09), p = 0.81; negative HR 0.98 (0.84-1.14), p = 0.78; ratios larger than one indicate a higher frequency of relapse in those with higher recall]. CONCLUSIONS: We found no evidence that discontinuing long-term antidepressants altered self-referential recall or that self-referential recall was associated with risk of relapse. These findings suggest that self-referential recall is not a neuropsychological marker of antidepressant action.

Palliative Medicine Referral and End-of-Life Interventions Among Racial and Ethnic Minority Patients With Advanced or Recurrent Gynecologic Cancer.

BACKGROUND: Referral to palliative medicine (PM) has been shown to improve quality of life, reduce hospitalizations, and improve survival. Limited data exist about PM utilization among racial minorities with gynecologic malignancies. Our objective was to assess differences in palliative medicine referrals and end of life interventions (within the last 30 days of life) by race and ethnicity in a diverse population of gynecologic oncology patients. METHODS: A retrospective cohort study of patients receiving gynecologic oncologic care at a tertiary referral center between 2017 - 2019 was conducted. Patients had either metastatic disease at the time of diagnosis or recurrence. Demographic and clinical data were abstracted. Exploratory analyses were done using chi-square and rank sum tests. Tests were two-sided with significance set at P < .05. RESULTS: A total of 186 patients were included. Of those, 82 (44.1%) were referred to palliative medicine. Underrepresented minorities accounted for 47.3% of patients. English was identified as the primary language for 69.9% of the patients and Spanish in 24.2%. Over 90% of patients had insurance coverage. Ovarian cancer (37.6%) and uterine cancer (32.8%) were the most common sites of origin. Most patients (75%) had advanced stage at the time of diagnosis. Race and language spoken were not associated with referral to PM. Black patients were more likely to have been prescribed appetite stimulants compared to White patients (41% vs 24%, P = .038). Black patients also had a higher number of emergency department visits compared to White patients during the study timeframe. Chemotherapy in the last 30 days of life was also more likely to be given to Black patients compared to White (P = .019). CONCLUSIONS: Race was associated with variation in interventions and healthcare utilization near end-of-life. Understanding the etiologies of these differences is crucial to inform interventions for care optimization as it relates specifically to the health of minority patients.

Mafosfamide, a cyclophosphamide analog, causes a proinflammatory response and increased permeability on endothelial cells in vitro.

Post-transplantation cyclophosphamide (PTCy) has decreased GVHD incidence. Endothelial damage in allo-HCT is caused by multiple factors, including conditioning treatments and some immunosupressants, and underlies HCT-complications as GVHD. Nevertheless, the specific impact of PTCy on the endothelium remains unclear. We evaluated the effect of mafosfamide (MAF), an active Cy analog, on endothelial cells (ECs) vs. cyclosporine A (CSA), with known damaging endothelial effect. ECs were exposed to MAF and CSA to explore changes in endothelial damage markers: (i) surface VCAM-1, (ii) leukocyte adhesion on ECs, (iii) VE-cadherin expression, (iv) production of VWF, and (v) activation of intracellular signaling proteins (p38MAPK, Akt). Results obtained (expressed in folds vs. controls) indicate that both compounds increased VCAM-1 expression (3.1 ± 0.3 and 2.8 ± 0.6, respectively, p < 0.01), with higher leukocyte adhesion (5.5 ± 0.6, p < 0.05, and 2.8 ± 0.4, respectively). VE-cadherin decreased with MAF (0.8 ± 0.1, p < 0.01), whereas no effect was observed with CSA. Production of VWF augmented with CSA (1.4 ± 0.1, p < 0.01), but diminished with MAF (0.9 ± 0.1, p < 0.05). p38MAPK activation occurred with both compounds, being more intense and faster with CSA. Both drugs activated Akt, with superior MAF effect at longer exposure. Therefore, the cyclophosphamide analog MAF is not exempt from a proinflammatory effect on the endothelium, though without modifying the subendothelial characteristics.

Laboratory interpretative comments and guidance: clinical and operative outcomes on moderate to severe hyponatraemia patient management.

AIMS: Hyponatraemia is the most common body fluid disorders but often goes unnoticed. Our laboratory incorporated a standardised procedure to help clinicians detect moderate/severe hyponatraemia. The study aims were to evaluate the outcomes on patient care and clinicians' satisfaction. METHODS: The study, observational and retrospective, included 1839 cases, adult and paediatric patients, with sodium concentration <130 mmol/L. The procedure consisted of interpretative comments in the emergency and core laboratories report and the point-of-care testing blood gas network report. We evaluated hyponatraemia length in two equal periods: before and after the implementation. We conducted a survey addressed to the staff of the clinical settings involved to know their satisfaction. RESULTS: The median hyponatraemia length decreased significantly from 4.95 hours (2.08-16.57) in the first period to 2.17 hours (1.06-5.39) in the second period. The lack of hyponatraemia patients follow-up was significantly less after the procedure implementation. The survey was answered by 92 (60 senior specialists and 32 residents) out of 110 clinicians surveyed. Ninety of them (98%) answered positively. CONCLUSIONS: We have demonstrated the reduction in the time for diagnosing and management by physicians, the higher uniformity in the time required to solve hyponatraemia episodes following our laboratory procedure and the clinicians' satisfaction.

One-year surgical outcomes of the PreserFlo MicroShunt in glaucoma: a multicentre analysis.

BACKGROUND/AIMS: To evaluate the efficacy and safety of the PreserFlo MicroShunt glaucoma device in a multicentre cohort study. METHODS: All consecutive patients who received the microshunt with mitomycin-C (MMC) 0.4 mg/mL from May 2019 to September 2020 in three UK tertiary centres. Primary outcome at 1 year was a complete success, with failure defined as intraocular pressure (IOP) >21 mmHg or <20% reduction, IOP≤5 mmHg with any decreased vision on two consecutive visits, reoperation or loss of light perception vision. Secondary outcomes were IOP, best-corrected visual acuity, medications, complications, interventions and reoperations. We also performed subgroup analyses for severe glaucoma and assessed risk factors for failure. RESULTS: 104 eyes had 1-year follow-up. Complete and qualified success at 1 year were achieved in 51.9% (N=54) and 16.4% (N=17), respectively, and failure occurred in 31.7% (N=33). There was a significant reduction in IOP (mmHg) from preoperatively (23.4±0.8, N=104) to 12 months (14.7±0.6, N=104) (p<0.0001). Antiglaucoma medications also decreased from preoperatively (3.4±0.1, N=104) to 12 months (0.7±0.1, N=104) (p<0.0001). Multivariate analyses showed an association between higher mean deviation and failure (HR 1.055, 95% CI 1.0075 to 1.11, p=0.0227). Complications were hypotony (19.2%; N=20), choroidal detachments (10.6%; N=11), hyphaema (5.8%; N=6) and bleb leak (5.8%; N=6). Needling and 5-fluorouracil injections were performed in 12.5% (N=13) and 33.7% (N=35), respectively, and 11.5% (N=12) required revision surgery. CONCLUSION: The PreserFlo MicroShunt with MMC 0.4 mg/mL showed an overall success rate of 68.3% at 1 year, and led to significant IOP and medication reduction with a low rate of adverse effects.