Early Diagnosis of Delirium in Palliative Care Patients Decreases Mortality and Necessity of Palliative Sedation: Results of a Prospective Observational Study.

INTRODUCTION: Delirium in end-of-life patients is reported to be between 13% and 42% and up to 80% in the terminal phase. It is a serious clinical situation, often a cause of death due to the frequent ineffectiveness of treatments. This study aimed to assess whether and how much precocity of diagnosis, hitherto little considered, could affect the outcomes and prognosis of delirium in palliative care settings. METHODS: Patients consecutively admitted to a palliative care unit (PCU) between October 2018 and December 2019, cared for both in hospice and home programs, were analyzed. All patients were subjected to a careful procedure aimed at recognizing the onset of delirium. The first step was the detection of prodromal "sentinel" symptoms related to incoming delirium. PCU staff and family members/caregivers were trained to observe the patients and immediately identify the appearance of even one symptom. The final diagnosis was performed with the 4AT (4 A's test). Patients were then included in the categories of "early" or "slow" diagnosis (cut-off: four hours) depending on the time between sentinel symptom observation and the final diagnosis of delirium. RESULTS: Among 503 admitted patients, 95 developed delirium. Confusion was the most frequent sentinel symptom (49.5%). The early diagnosis was more frequent in hospice than in home care (p-value<0.0001). Delirium was positively resolved in 43 patients, of which 25 with an early diagnosis (p-value=0.038). Time to resolution was shorter in the case of early diagnosis (7.1 vs. 13.7 hours in hospice patients; p-value=0.018). Palliative sedation was performed on 25 patients, but only 8 of them had an early diagnosis. CONCLUSION: Time of diagnosis was important in determining the clinical outcomes of patients in charge of PCU who experienced delirium. The early diagnosis reduced both mortality and the necessity of palliative sedation.

ATAD2 controls chromatin-bound HIRA turnover.

Taking advantage of the evolutionary conserved nature of ATAD2, we report here a series of parallel functional studies in human, mouse, and Schizosaccharomyces pombe to investigate ATAD2's conserved functions. In S. pombe, the deletion of ATAD2 ortholog, abo1, leads to a dramatic decrease in cell growth, with the appearance of suppressor clones recovering normal growth. The identification of the corresponding suppressor mutations revealed a strong genetic interaction between Abo1 and the histone chaperone HIRA. In human cancer cell lines and in mouse embryonic stem cells, we observed that the KO of ATAD2 leads to an accumulation of HIRA. A ChIP-seq mapping of nucleosome-bound HIRA and FACT in Atad2 KO mouse ES cells demonstrated that both chaperones are trapped on nucleosomes at the transcription start sites of active genes, resulting in the abnormal presence of a chaperone-bound nucleosome on the TSS-associated nucleosome-free regions. Overall, these data highlight an important layer of regulation of chromatin dynamics ensuring the turnover of histone-bound chaperones.

Factors for Timely Identification of Possible Occurrence of Delirium in Palliative Care: A Prospective Observational Study.

Delirium occurs in 50-80% of end-of-life patients but is often misdiagnosed. Identification of clinical factors potentially associated with delirium onset can lead to a correct early diagnosis. To this aim, we conducted a prospective cohort study on patients from an Italian palliative care unit (PCU) admitted in 2018-2019. We evaluated the presence of several clinical factors at patient admission and compared their presence in patients who developed delirium and in those who did not develop it during follow-up. Among 503 enrolled patients, after a median follow-up time of 16 days (interquartile range 6-40 days), 95 (18.9%) developed delirium. Hazard ratios (HR) and corresponding 95% confidence intervals were computed using Cox proportional hazard models. In univariate analyses, factors significantly more frequent in patients with delirium were care in hospice, compromised performance status, kidney disease, fever, renal failure, hypoxia, dehydration, drowsiness, poor well-being, breathlessness, and "around the clock" therapy with psychoactive drugs, particularly haloperidol. In multivariate analyses, setting of care (HR 2.28 for hospice versus home care, 95% CI 1.45-3.60; p < 0.001), presence of breathlessness (HR 1.71, 95% CI 1.03-2.83, p = 0.037), and administration of psychoactive drugs, particularly haloperidol (HR 2.17 for haloperidol, 95% CI 1.11-4.22 and 1.53 for other drugs, 95% CI 0.94-2.48; p = 0.048) were significantly associated with the risk of developing delirium. The study indicates that some clinical factors are associated with the probability of delirium onset. Their evaluation in PC patients could help healthcare professionals to identify the development of delirium in those patients in a timely manner.

Lessons from yeast on emerging roles of the ATAD2 protein family in gene regulation and genome organization.

ATAD2, a remarkably conserved, yet poorly characterized factor is found upregulated and associated with poor prognosis in a variety of independent cancers in human. Studies conducted on the yeast Saccharomyces cerevisiae ATAD2 homologue, Yta7, are now indicating that the members of this family may primarily be regulators of chromatin dynamics and that their action on gene expression could only be one facet of their general activity. In this review, we present an overview of the literature on Yta7 and discuss the possibility of translating these findings into other organisms to further define the involvement of ATAD2 and other members of its family in regulating chromatin structure and function both in normal and pathological situations.

Homology modeling of human serum carnosinase, a potential medicinal target, and MD simulations of its allosteric activation by citrate.

Recent biochemical and clinical evidence implicates human serum carnosinase in a variety of pathological conditions, such as neurological disorders and diabetic nephropathy, suggesting that this enzyme is of potential interest as a novel medicinal target. The present study was undertaken with a view to model the serum carnosinase and its catalytic site and to unravel the molecular mechanism by which citrate ions increase the catalytic efficiency of serum carnosinase. A homology model of the enzyme was obtained on the basis of beta-alanine synthetase, and its active center was found to bind known substrates carnosine, homocarnosine, and anserine in a binding mode conducive to catalysis. Citrate ions were shown to bind at only three well-defined sites involving both ion pairs and hydrogen bonds. Molecular dynamics simulations evidenced that citrate binding had a remarkable conformational influence on the 3D structure of carnosinase, increasing the binding affinity (i.e., binding score) of carnosine to the catalytic site. This is one of the first reports documenting the molecular mechanism of an allosteric enzyme activator using MD simulations.