Nova LMC 2009a as observed with XMM–Newton, compared with other novae

ABSTRACT We examine four high-resolution reflection grating spectrometers (RGS) spectra of the February 2009 outburst of the luminous recurrent nova LMC 2009a. They were very complex and rich in intricate absorption and emission features. The continuum was consistent with a dominant component originating in the atmosphere of a shell burning white dwarf (WD) with peak effective temperature between 810¿000 K and a million K, and mass in the 1.2–1.4 M¿ range. A moderate blue shift of the absorption features of a few hundred km s-1 can be explained with a residual nova wind depleting the WD surface at a rate of about 10-8 M¿ yr-1. The emission spectrum seems to be due to both photoionization and shock ionization in the ejecta. The supersoft X-ray flux was irregularly variable on time-scales of hours, with decreasing amplitude of the variability. We find that both the period and the amplitude of another, already known 33.3-s modulation varied within time-scales of hours. We compared N LMC 2009a with other Magellanic Clouds novae, including four serendipitously discovered as supersoft X-ray sources (SSS) among 13 observed within 16 yr after the eruption. The new detected targets were much less luminous than expected: we suggest that they were partially obscured by the accretion disc. Lack of SSS detections in the Magellanic Clouds novae more than 5.5 yr after the eruption constrains the average duration of the nuclear burning phase.Peer ReviewedPostprint (author's final draft

Restoration by ketamine of stress-induced maladaptive changes in synaptic function and brain architecture

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CUIDADOS PALIATIVOS E COVID-19: PERCEPÇÃO DOS PROFISSIONAIS DE SAÚDE DE UNIDADE DE TERAPIA INTENSIVA

Objetivo: apreender as percepções dos profissionais de saúde que atuam em Unidade de Terapia Intensiva sobre os cuidados paliativos na assistência aos pacientes com Covid-19. Método: estudo descritivo-exploratório, qualitativo, realizado com profissionais que atuavam em Unidade de Terapia Intensiva de um hospital público. A coleta ocorreu em 2021, por meio de entrevistas semiestruturadas. Os dados foram organizados e analisados mediante o software IRAMUTEQ®, considerando o referencial da Análise de Conteúdo. Resultados: participaram 10 profissionais. Dos discursos emergiram três categorias: Ainda falta muito conhecimento: barreira para a implementação dos cuidados paliativos; Cuidado paliativo não é decreto de morte!: percepção ampliada do conceito; Ajuda a manter a dignidade da pessoa: cuidados paliativos no contexto da pandemia da Covid-19. Considerações finais: no contexto da pandemia, os profissionais sentiram insegurança e despreparo para implementação de cuidados paliativos, especialmente em decorrência do conhecimento incipiente, embora o compreendesse como importante ferramenta para manter a dignidade humana. Descritores: Cuidados Paliativos. Equipe de Assistência ao Paciente. COVID-19. Unidades de Terapia Intensiva

Automated Quantitative Pupillometry for the Prognostication of Coma After Cardiac Arrest

Background: Sedation and therapeutic hypothermia (TH) delay neurological responses and might reduce the accuracy of clinical examination to predict outcome after cardiac arrest (CA). We examined the accuracy of quantitative pupillary light reactivity (PLR), using an automated infrared pupillometry, to predict outcome of post-CA coma in comparison to standard PLR, EEG, and somato-sensory evoked potentials (SSEP). Methods: We prospectively studied over a 1-year period (June 2012-June 2013) 50 consecutive comatose CA patients treated with TH (33°C, 24h). Quantitative PLR (expressed as the % of pupillary response to a calibrated light stimulus) and standard PLR were measured at day 1 (TH and sedation; on average 16h after CA) and day 2 (normothermia, off sedation: on average 46h after CA). Neurological outcome was assessed at 90days with Cerebral Performance Categories (CPC), dichotomized as good (CPC 1-2) versus poor (CPC 3-5). Predictive performance was analyzed using area under the ROC curves (AUC). Results: Patients with good outcome [n=23 (46%)] had higher quantitative PLR than those with poor outcome [n=27; 16 (range 9-23) vs. 10 (1-30)% at day 1, and 20 (13-39) vs. 11 (1-55)% at day 2, both p0.20). Conclusions: Quantitative PLR is more accurate than standard PLR in predicting outcome of post-anoxic coma, irrespective of temperature and sedation, and has comparable prognostic accuracy than EEG and SSEP

Cerebral metabolic effects of exogenous lactate supplementation on the injured human brain

Purpose: Experimental evidence suggests that lactate is neuroprotective after acute brain injury; however, data in humans are lacking. We examined whether exogenous lactate supplementation improves cerebral energy metabolism in humans with traumatic brain injury (TBI). Methods: We prospectively studied 15 consecutive patients with severe TBI monitored with cerebral microdialysis (CMD), brain tissue PO2 (PbtO2), and intracranial pressure (ICP). Intervention consisted of a 3-h intravenous infusion of hypertonic sodium lactate (aiming to increase systemic lactate to ca. 5mmol/L), administered in the early phase following TBI. We examined the effect of sodium lactate on neurochemistry (CMD lactate, pyruvate, glucose, and glutamate), PbtO2, and ICP. Results: Treatment was started on average 33±16h after TBI. A mixed-effects multilevel regression model revealed that sodium lactate therapy was associated with a significant increase in CMD concentrations of lactate [coefficient 0.47mmol/L, 95% confidence interval (CI) 0.31-0.63mmol/L], pyruvate [13.1 (8.78-17.4)μmol/L], and glucose [0.1 (0.04-0.16) mmol/L; all p<0.01]. A concomitant reduction of CMD glutamate [−0.95 (−1.94 to 0.06) mmol/L, p=0.06] and ICP [−0.86 (−1.47 to −0.24) mmHg, p<0.01] was also observed. Conclusions: Exogenous supplemental lactate can be utilized aerobically as a preferential energy substrate by the injured human brain, with sparing of cerebral glucose. Increased availability of cerebral extracellular pyruvate and glucose, coupled with a reduction of brain glutamate and ICP, suggests that hypertonic lactate therapy has beneficial cerebral metabolic and hemodynamic effects after TBI

A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function

ASS1 Overexpression:A Hallmark of Sonic Hedgehog Hepatocellular Adenomas; Recommendations for Clinical Practice

Until recently, 10% of hepatocellular adenomas (HCAs) remained unclassified (UHCA). Among the UHCAs, the sonic hedgehog HCA (shHCA) was defined by focal deletions that fuse the promoter of Inhibin beta E chain with GLI1. Prostaglandin D2 synthase was proposed as immunomarker. In parallel, our previous work using proteomic analysis showed that most UHCAs constitute a homogeneous subtype associated with overexpression of argininosuccinate synthase (ASS1). To clarify the use of ASS1 in the HCA classification and avoid misinterpretations of the immunohistochemical staining, the aims of this work were to study (1) the link between shHCA and ASS1 overexpression and (2) the clinical relevance of ASS1 overexpression for diagnosis. Molecular, proteomic, and immunohistochemical analyses were performed in UHCA cases of the Bordeaux series. The clinico-pathological features, including ASS1 immunohistochemical labeling, were analyzed on a large international series of 67 cases. ASS1 overexpression and the shHCA subgroup were superimposed in 15 cases studied by molecular analysis, establishing ASS1 overexpression as a hallmark of shHCA. Moreover, the ASS1 immunomarker was better than prostaglandin D2 synthase and only found positive in 7 of 22 shHCAs. Of the 67 UHCA cases, 58 (85.3%) overexpressed ASS1, four cases were ASS1 negative, and in five cases ASS1 was noncontributory. Proteomic analysis performed in the case of doubtful interpretation of ASS1 overexpression, especially on biopsies, can be a support to interpret such cases. ASS1 overexpression is a specific hallmark of shHCA known to be at high risk of bleeding. Therefore, ASS1 is an additional tool for HCA classification and clinical diagnosis

The F4/AS01B HIV-1 Vaccine Candidate Is Safe and Immunogenic, But Does Not Show Viral Efficacy in Antiretroviral Therapy-Naive, HIV-1-Infected Adults: A Randomized Controlled Trial

The impact of the investigational human immunodeficiency virus type 1 (HIV-1) F4/AS01(B) vaccine on HIV-1 viral load (VL) was evaluated in antiretroviral therapy (ART)-naive HIV-1 infected adults.This phase IIb, observer-blind study (NCT01218113), included ART-naive HIV-1 infected adults aged 18 to 55 years. Participants were randomized to receive 2 (F4/AS01(B)_2 group, N=64) or 3 (F4/AS01(B)_3 group, N=62) doses of F4/AS01(B) or placebo (control group, N=64) at weeks 0, 4, and 28. Efficacy (HIV-1 VL, CD4(+) T-cell count, ART initiation, and HIV-related clinical events), safety, and immunogenicity (antibody and T-cell responses) were evaluated during 48 weeks.At week 48, based on a mixed model, no statistically significant difference in HIV-1 VL change from baseline was demonstrated between F4/AS01(B)_2 and control group (0.073 log(10)copies/mL [97.5% confidence interval (CI): -0.088; 0.235]), or F4/AS01(B)_3 and control group (-0.096 log(10)copies/mL [97.5% CI: -0.257; 0.065]). No differences between groups were observed in HIV-1 VL change, CD4(+) T-cell count, ART initiation, or HIV-related clinical events at intermediate timepoints. Among F4/AS01(B) recipients, the most frequent solicited symptoms were pain at injection site (252/300 doses), fatigue (137/300 doses), myalgia (105/300 doses), and headache (90/300 doses). Twelve serious adverse events were reported in 6 participants; 1 was considered vaccine-related (F4/AS01(B)_2 group: angioedema). F4/AS01(B) induced polyfunctional F4-specific CD4(+) T-cells, but had no significant impact on F4-specific CD8(+) T-cell and anti-F4 antibody levels.F4/AS01(B) had a clinically acceptable safety profile, induced F4-specific CD4(+) T-cell responses, but did not reduce HIV-1 VL, impact CD4(+) T-cells count, delay ART initiation, or prevent HIV-1 related clinical events

MCT4 blockade increases the efficacy of immune checkpoint blockade

Background & Aims Intratumoral lactate accumulation and acidosis impair T-cell function and antitumor immunity. Interestingly, expression of the lactate transporter monocarboxylate transporter (MCT) 4, but not MCT1, turned out to be prognostic for the survival of patients with rectal cancer, indicating that single MCT4 blockade might be a promising strategy to overcome glycolysis-related therapy resistance. Methods To determine whether blockade of MCT4 alone is sufficient to improve the efficacy of immune checkpoint blockade (ICB) therapy, we examined the effects of the selective MCT1 inhibitor AZD3965 and a novel MCT4 inhibitor in a colorectal carcinoma (CRC) tumor spheroid model co-cultured with blood leukocytes in vitro and the MC38 murine CRC model in vivo in combination with an antibody against programmed cell death ligand-1(PD-L1). Results Inhibition of MCT4 was sufficient to reduce lactate efflux in three-dimensional (3D) CRC spheroids but not in two-dimensional cell-cultures. Co-administration of the MCT4 inhibitor and ICB augmented immune cell infiltration, T-cell function and decreased CRC spheroid viability in a 3D co-culture model of human CRC spheroids with blood leukocytes. Accordingly, combination of MCT4 and ICB increased intratumoral pH, improved leukocyte infiltration and T-cell activation, delayed tumor growth, and prolonged survival in vivo. MCT1 inhibition exerted no further beneficial impact. Conclusions These findings demonstrate that single MCT4 inhibition represents a novel therapeutic approach to reverse lactic-acid driven immunosuppression and might be suitable to improve ICB efficacy