Quantification of cerebral perfusion and cerebrovascular reserve using Turbo‐QUASAR arterial spin labeling MRI

PurposeTo compare cerebral blood flow (CBF) and cerebrovascular reserve (CVR) quantification from Turbo‐QUASAR (quantitative signal targeting with alternating radiofrequency labeling of arterial regions) arterial spin labeling (ASL) and single post‐labeling delay pseudo‐continuous ASL (PCASL).MethodsA model‐based method was developed to quantify CBF and arterial transit time (ATT) from Turbo‐QUASAR, including a correction for magnetization transfer effects caused by the repeated labeling pulses. Simulations were performed to assess the accuracy of the model‐based method. Data from an in vivo experiment conducted on a healthy cohort were retrospectively analyzed to compare the CBF and CVR (induced by acetazolamide) measurement from Turbo‐QUASAR and PCASL on the basis of global and regional differences. The quality of the two ASL data sets was examined using the coefficient of variation (CoV).ResultsThe model‐based method for Turbo‐QUASAR was accurate for CBF estimation (relative error was 8% for signal‐to‐noise ratio = 5) in simulations if the bolus duration was known. In the in vivo experiment, the mean global CVR estimated by Turbo‐QUASAR and PCASL was between 63% and 64% and not significantly different. Although global CBF values of the two ASL techniques were not significantly different, regional CBF differences were found in deep gray matter in both pre‐ and postacetazolamide conditions. The CoV of Turbo‐QUASAR data was significantly higher than PCASL.ConclusionBoth ASL techniques were effective for quantifying CBF and CVR, despite the regional differences observed. Although CBF estimated from Turbo‐QUASAR demonstrated a higher variability than PCASL, Turbo‐QUASAR offers the advantage of being able to measure and control for variation in ATT

The predictive value of the modified early warning score for admission to the intensive care unit in patients with a hematologic malignancy – A multicenter observational study

Objectives: The modified early warning score (MEWS) is used to detect clinical deterioration of hospitalized patients. We aimed to investigate the predictive value of MEWS and derived quick Sequential Organ Failure Assessment (qSOFA) scores for intensive care unit admission in patients with a hematologic malignancy admitted to the ward. Design: Retrospective, observational study in two Dutch university hospitals. Setting: Data from adult patients with a hematologic malignancy, admitted to the ward over a 2-year period, were extracted from electronic patient files. Main outcome measures: Intensive care admission. Results: We included 395 patients with 736 hospital admissions; 2% (n = 15) of admissions resulted in admission to the intensive care unit. A higher MEWS (OR 1.5; 95 %CI 1.3–1.80) and qSOFA (OR 4.4; 95 %CI 2.1–9.3) were associated with admission. Using restricted cubic splines, a rise in the probability of admission for a MEWS ≥ 6 was observed. The AUC of MEWS for predicting admission was 0.830, the AUC of qSOFA was 0.752. MEWS was indicative for intensive care unit admission two days before admission. Conclusions: MEWS was a sensitive predictor of ICU admission in patients with a hematologic malignancy, superior to qSOFA. Future studies should confirm cut-off values and identify potential additional characteristics, to further enhance identification of critically ill hemato-oncology patients. Implications for Clinical Practice: The Modified Early Warning Score (MEWS) can be used as a tool for healthcare providers to monitor clinical deterioration and predict the need for intensive care unit admission in patients with a hematologic malignancy. Yet, consistent application and potential reevaluation of current thresholds is crucial. This will enable bedside nurses to more effectively identify patients needing adjunctive care, facilitating timely interventions and improved outcome.</p

Long-Term Outcome of Patients With a Hematologic Malignancy and Multiple Organ Failure Admitted at the Intensive Care

Objectives: Historically, patients with a hematologic malignancy have one of the highest mortality rates among cancer patients admitted to the ICU. Therefore, physicians are often reluctant to admit these patients to the ICU. The aim of our study was to examine the survival of patients who have a hematologic malignancy and multiple organ failure admitted to the ICU. Design: This retrospective cohort study, part of the HEMA-ICU study group, was designed to study the survival of patients with a hematologic malignancy and organ failure after admission to the ICU. Patients were followed for at least 1 year. Setting: Five university hospitals in the Netherlands. Patients: One-thousand ninety-seven patients with a hematologic malignancy who were admitted at the ICU. Interventions: None. Measurements and Main Results: Primary outcome was 1-year survival. Organ failure was categorized as acute kidney injury, respiratory failure, hepatic failure, and hemodynamic failure; multiple organ failure was defined as failure of two or more organs. The World Health Organization performance score measured 3 months after discharge from the ICU was used as a measure of functional outcome. The 1-year survival rate among these patients was 38%. Multiple organ failure was inversely associated with long-term survival, and an absence of respiratory failure was the strongest predictor of 1-year survival. The survival rate among patients with 2, 3, and 4 failing organs was 27%, 22%, and 8%, respectively. Among all surviving patients for which World Health Organization scores were available, 39% had a World Health Organization performance score of 0-1 3 months after ICU discharge. Functional outcome was not associated with the number of failing organs. Conclusions: Our results suggest that multiple organ failure should not be used as a criterion for excluding a patient with a hematologic malignancy from admission to the ICU.</p

EVALUACIÓN DE RESULTADOS QUIRÚRGICOS DESDE LA PERSPECTIVA DEL PACIENTE

RESUMENMedir la calidad de vida relacionada a salud y los síntomas de los pacientes es un problema difícil. Las medición de los problemas de salud mediante escalas o cuestionarios se ha desarrollado para crear los Instrumentos de Evaluación desde la Perspectiva del Paciente o PRO's por su nombre en inglés: Patient-reported outcomes. Los PROs evalúan la calidad de vida en forma genérica o específica en un continuo, entregando instrumentos que pueden evaluar la gravedad de una enfermedad o el impacto de una intervención desde la perspectiva del paciente en frecuentes escenarios clínicos. El objetivo de la presente revisión es entregar a clínicos e investigadores una introducción hacia los PROs y resumir sus principales propiedades.SUMMARYQuantifying health-related quality of life and specific patient symptoms it is a difficult problem. Health measurement scales has developed to include rigorous techniques to develop patient-reported outcome measures (PROs). PROs assess objectively the QoL in a continuum, providing instruments to measure the severity of a given disease or the impact of a therapeutic intervention from patient perspective in different clinical problems. The following review aims to introduce the PROs to clinicians and researchers and summarize its main properties

One-year safety and efficacy of mitapivat in sickle cell disease:follow-up results of a phase 2, open-label study

Targeting the primary pathogenic event of sickle cell disease (SCD), the polymerization of sickle hemoglobin (HbS), may prevent downstream clinical events. Mitapivat, an oral pyruvate kinase (PK) activator, has therapeutic potential by increasing adenosine triphosphate (ATP) and decreasing 2,3-diphosphoglycerate (2,3-DPG), a glycolytic red blood cell (RBC) intermediate. In the previously reported 8-week dose-finding period of this phase 2, investigator-initiated, open-label study, mitapivat was well tolerated and showed efficacy in SCD. Here, the 1-year fixed-dose extension period is reported in which 9 of 10 included patients (90%) aged ≥16 years with SCD (HbSS, HbS/β0, or HbS/β+) continued with mitapivat. Mostly mild treatment-emergent adverse events (AEs) (most commonly, transaminase increase and headache) were still reported. Apart from the reported nontreatment-related serious AE (SAE) of a urinary tract infection in the dose-finding period, 1 nontreatment-related SAE occurred in the fixed-dose extension period in a patient who died of massive pulmonary embolism due to COVID-19. Importantly, sustained improvement in Hb level (mean increase, 1.1 ± 0.7 g/dL; P = .0014) was seen, which was accompanied by decreases in markers of hemolysis. In addition, the annualized rate of vaso-occlusive events reduced significantly from a historic baseline of 1.33 ± 1.32 to 0.64 ± 0.87 (P = .0489) when combining the dose-finding period and fixed-dose extension period. Cellularly, the ATP:2,3-DPG ratio and Hb-oxygen affinity significantly increased and RBC sickling (point of sickling) nonsignificantly reduced. Overall, this study demonstrated 1-year safety and efficacy of treatment with mitapivat in SCD, supporting further evaluation in ongoing phase 2/3 study (RISE UP, NCT05031780). This trial was registered at https://www.clinicaltrialsregister.eu/as NL8517 and EudraCT 2019-003438-18.</p

The role of tunneling in enzyme catalysis of C–H activation

AbstractRecent data from studies of enzyme catalyzed hydrogen transfer reactions implicate a new theoretical context in which to understand C–H activation. This is much closer to the Marcus theory of electron transfer, in that environmental factors influence the probability of effective wave function overlap from donor to acceptor atoms. The larger size of hydrogen and the availability of three isotopes (H, D and T) introduce a dimension to the kinetic analysis that is not available for electron transfer. This concerns the role of gating between donor and acceptor atoms, in particular whether the system in question is able to tune distance between reactants to achieve maximal tunneling efficiency. Analysis of enzyme systems is providing increasing evidence of a role for active site residues in optimizing the inter-nuclear distance for nuclear tunneling. The ease with which this optimization can be perturbed, through site-specific mutagenesis or an alteration in reaction conditions, is also readily apparent from an analysis of the changes in the temperature dependence of hydrogen isotope effects

Metabolic blood profile and response to treatment with the pyruvate kinase activator mitapivat in patients with sickle cell disease

Mitapivat is an investigational, oral, small-molecule allosteric activator of pyruvate kinase (PK). PK is a regulatory glycolytic enzyme that is key in providing the red blood cell (RBC) with sufficient amounts of adenosine triphosphate (ATP). In sickle cell disease (SCD), decreased 2,3-DPG levels increase the oxygen affinity of hemoglobin, thereby preventing deoxygenation and polymerization of sickle hemoglobin. The PK activator mitapivat has been shown to decrease levels of 2,3-DPG and increase levels of ATP in RBCs in patients with SCD. In this phase 2, investigator-initiated, open-label study (https://www.clinicaltrialsregister.eu/ NL8517; EudraCT 2019-003438-18), untargeted metabolomics was used to explore the overall metabolic effects of 8-week treatment with mitapivat in the dose-finding period. In total, 1773 unique metabolites were identified in dried blood spots of whole blood from ten patients with SCD and 42 healthy controls (HCs). The metabolic phenotype of patients with SCD revealed alterations in 139/1773 (7.8%) metabolites at baseline when compared to HCs (false discovery rate-adjusted p &lt; 0.05), including increases of (derivatives of) polyamines, purines, and acyl carnitines. Eight-week treatment with mitapivat in nine patients with SCD altered 85/1773 (4.8%) of the total metabolites and 18/139 (12.9%) of the previously identified altered metabolites in SCD (unadjusted p &lt; 0.05). Effects were observed on a broad spectrum of metabolites and were not limited to glycolytic intermediates. Our results show the relevance of metabolic profiling in SCD, not only to unravel potential pathophysiological pathways and biomarkers in multisystem diseases but also to determine the effect of treatment.</p

Metabolic blood profile and response to treatment with the pyruvate kinase activator mitapivat in patients with sickle cell disease

Mitapivat is an investigational, oral, small-molecule allosteric activator of pyruvate kinase (PK). PK is a regulatory glycolytic enzyme that is key in providing the red blood cell (RBC) with sufficient amounts of adenosine triphosphate (ATP). In sickle cell disease (SCD), decreased 2,3-DPG levels increase the oxygen affinity of hemoglobin, thereby preventing deoxygenation and polymerization of sickle hemoglobin. The PK activator mitapivat has been shown to decrease levels of 2,3-DPG and increase levels of ATP in RBCs in patients with SCD. In this phase 2, investigator-initiated, open-label study (https://www.clinicaltrialsregister.eu/ NL8517; EudraCT 2019-003438-18), untargeted metabolomics was used to explore the overall metabolic effects of 8-week treatment with mitapivat in the dose-finding period. In total, 1773 unique metabolites were identified in dried blood spots of whole blood from ten patients with SCD and 42 healthy controls (HCs). The metabolic phenotype of patients with SCD revealed alterations in 139/1773 (7.8%) metabolites at baseline when compared to HCs (false discovery rate-adjusted p &lt; 0.05), including increases of (derivatives of) polyamines, purines, and acyl carnitines. Eight-week treatment with mitapivat in nine patients with SCD altered 85/1773 (4.8%) of the total metabolites and 18/139 (12.9%) of the previously identified altered metabolites in SCD (unadjusted p &lt; 0.05). Effects were observed on a broad spectrum of metabolites and were not limited to glycolytic intermediates. Our results show the relevance of metabolic profiling in SCD, not only to unravel potential pathophysiological pathways and biomarkers in multisystem diseases but also to determine the effect of treatment.</p