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Obsessive in gambling and in love, the soldier Hermann is the protagonist of Tchaikovsky's Pique Dame, based on a story by Pushkin. He is smitten with the aristocratic Lisa and fixated on learning the winning secret of 'the three cards' from her grandmother, the Countess, played by iconic contralto Ewa Podles. This opulent production from Barcelona's Liceu captures St Petersburg in the era of Catherine the Great, while the house's Music Director Michael Boden conducts a large and impressive cast.

Recorded live at the Royal Opera House in Brussels, dramatic staging brings to life the conflict between individual aspiration, tradition, and duty.

Chimeric antigen receptor (CAR)T-cell CD19 therapy is an effective treatment for relapsed/refractory B-cell acute lymphoblastic leukemia. It can be associated with life-threatening toxicities which often require PICU admission. Purpose: to describe clinical characteristics, treatment and outcome of these patients. Prospective observational cohort study conducted in a tertiary pediatric hospital from 2016-2021. Children who received CAR-T admitted to PICU were included. We collected epidemiological, clinical characteristics, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), treatment, length of stay and mortality. CAR T-cells (4-1BB constructs) were infused in 59 patients. Twenty-four (40.7%) required PICU admission, length of stay was 4 days (IQR 3-6). Median age was 8.3 years (range 4-24). Patients admitted to PICU presented higher disease burden before infusion: 24% blasts in bone marrow (IQR 5-72) vs. 0 (0-6.9), p<0.001. No patients with <5% blasts were admitted to PICU. Main reasons for admissions were CRS (n=20, 83.3%) and ICANS (n=3, 12.5%). Fourteen patients (58.3%) required inotropic support, 14(58.3%) respiratory. Sixteen patients (66.6%) received tocilizumab, 10(41.6%) steroids, 6(25.0%) anakinra, and 5(20.8%) siltuximab. Ten patients (41.6%) presented neurotoxicity, six of them severe (ICANS 3-4). Two patients died at PICU (8.3%) because of refractory CRS-hemophagocytic lymphohistyocitosis (carHLH) syndrome. There were no significant differences in relapse rate after CAR-T in patients requiring PICU, it was more frequently CD19 negative (p=0.344). PICU admission after CAR-T therapy was mainly due to CRS. Supportive treatment allowed effective management and high survival. Some patients presenting with carHLH, can suffer a fulminant course.

Children with acute leukaemia (AL) are a high-risk population for infections and life-threatening conditions requiring paediatric intensive care unit (PICU) admission, presenting an increased mortality rate. A few literature exists about PICU outcomes in this kind of patients, especially with haematopoietic stem cell transplant (HSCT) background. We investigated the clinical and epidemiological characteristics of these patients as well as their outcomes. A retrospective, single-centre analytical/observational study was conducted from January 2011 to December 2018 in the PICU of a tertiary care hospital. AL patients from 28 days to 18 years old admitted to the PICU were included, excluding those with histories of HSCT or CAR T-cell therapy. We collected epidemiological and clinical characteristics, laboratory and microbiology results and outcomes. Forty-three patients with AL required urgent admission (35 lymphoblastic and 8 myeloblastic) for 63 different episodes. The main reasons were sepsis (21, 33.3%), hyperleukocytosis (12, 19%), respiratory failure (11, 17.5%) and seizures (8, 12.7%). Nineteen (30.2%) required inotropic support, and fifteen (23.8%) required mechanical ventilation. Three patients died at the hospital (3/43, 6.9%). Sixty-day mortality was 9.3%, and 1-year mortality was 13.9%. There was no differences regarding the type of AL and 60-day mortality (log-rank 2.652, p = 0.103).Conclusion: In our study, the main cause of admission for AL patients was infection, which was associated to more severity and longer hospital admission. What is Known:• Acute leukaemia is the most common childhood cancer. Admission to a paediatric intensive care unit is required in 30% of children with acute leukaemia.• Regarding the outcomes of children with acute leukaemia that require admission to the intensive care unit data are scarce.What is New:• Mortality in acute leukaemia patients admitted to the paediatric intensive care unit is lower than that of patients with a history of stem cell therapy but higher than that of patients with solid tumours.• The main reason for admission was sepsis, which is related in literature to more severity and long length of stay.

The pathogenesis of multiple sclerosis (MS) involves alterations to multiple pathways and processes, which represent a significant challenge for developing more-effective therapies. Systems biology approaches that study pathway dysregulation should offer benefits by integrating molecular networks and dynamic models with current biological knowledge for understanding disease heterogeneity and response to therapy. In MS, abnormalities have been identified in several cytokine-signaling pathways, as well as those of other immune receptors. Among the downstream molecules implicated are Jak/Stat, NF-Kb, ERK1/3, p38 or Jun/Fos. Together, these data suggest that MS is likely to be associated with abnormalities in apoptosis/cell death, microglia activation, blood-brain barrier functioning, immune responses, cytokine production, and/or oxidative stress, although which pathways contribute to the cascade of damage and can be modulated remains an open question. While current MS drugs target some of these pathways, others remain untouched. Here, we propose a pragmatic systems analysis approach that involves the large-scale extraction of processes and pathways relevant to MS. These data serve as a scaffold on which computational modeling can be performed to identify disease subgroups based on the contribution of different processes. Such an analysis, targeting these relevant MS-signaling pathways, offers the opportunity to accelerate the development of novel individual or combination therapies.

Correspondence to Dr Julio Delgado; jdelgado@clinic.cat ; Dr Manel Juan; mjuan@clinic.cat The prognosis of patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) remains poor, particularly for those relapsing after allogeneic hematopoietic cell transplantation (alloHCT).1 Novel agents such as inotuzumab ozogamicin or blinatumomab achieve increased response rates, but these are generally transient unless followed by alloHCT. Patients with ≥5% lymphoblasts in the BM had a higher incidence of CRS (any grade: 82% vs 39%, p=0.0022; grade ≥3: 27% vs 0%, p=0.0036) compared with those with <5% lymphoblasts. [...]the incidence and severity of CRS was also associated with single dose versus fractionated administration of ARI-0001 cells (any grade: 87% vs 45%, p=0.0064; grade ≥3: 27% vs 5%, p=0.047). [...]ARI-0001 infusions were documented in nine patients (three more than previously reported5: four due to CD19 +relapse and five in patients with early BCA loss). According to these analyses, the 3-month time point was the closest to statistical significance (HR 1.83; 95% CI 0.82 to 4.11; p=0.15, (online supplemental table 3).

Sarcopenia and frailty are often overlooked in assessing kidney transplant (KT) candidates with chronic kidney disease (CKD), potentially leading to poor post-transplant outcomes. This study aimed to identify metabolites associated with frailty and sarcopenia in KT candidates from the FRAILMar study. Between June 2016 and June 2020, we evaluated frailty and sarcopenia in 173 KT candidates using the Physical Frailty Phenotype and EGWSOP-2 criteria, respectively. Seventy-five metabolic markers from targeted pathways, previously linked to CKD, sarcopenia or frailty, were measured in serum samples. These markers were analyzed using adjusted and weighted generalized linear models. Metabolomic data were integrated with multi-modal data, such as comorbidities, using a factor-based integration algorithm to identify metabolic phenotypes. Increased metabolites related to energy metabolism and essential amino acids were associated with frailty, mainly Krebs cycle intermediates. Sarcopenic KT candidates showed lower levels of aromatic amino acids, and lower protein/muscle metabolism, energy metabolism and neurotransmission compared with non-sarcopenic patients. Unsupervised multi-modal integration revealed a high-risk metabolic phenotype characterized by the presence of sarcopenia, diabetes mellitus and low body mass index, with alterations in branched-chain amino acids and high activity of lactate dehydrogenase enzyme. Frailty and sarcopenia are common among KT candidates, and their metabolic status reveals notable disruptions in energy and amino acid metabolism. These findings highlight the value of a detailed metabolic assessment to more accurately evaluate patient health status prior to transplantation.