Treatment of circadian rhythm disorders, whether precipitated by intrinsic factors (e.g., sleep disorders, blindness, mental disorders, aging) or by extrinsic factors (e.g., shift work, jet-lag) has led to the development of a new type of agents called 'chronobiotics', among which melatonin is the prototype. The term 'chronobiotic' defines as a substance capable of shifting the phase of the circadian time system thus re-entraining circadian rhythms. Melatonin administration synchronizes the sleep-wake cycle in blind people and in individuals suffering from delayed sleep phase syndrome or jet lag, as well in shift-workers. The effect of melatonin on sleep is probably the consequence of increasing sleep propensity (by inducing a fall in body temperature) and of a synchronizing effect on the circadian clock (chronobiotic effect). We successfully employed the timely use of three factors (melatonin treatment, exposure to light, physical exercise) to hasten the resynchronization after transmeridian flights comprising 12-13 time zones, from an average of 8-10 days to about 2 days. Daily melatonin production decreases with age, and in several pathologies, attaining its lowest values in Alzheimer's dementia patients. About 45% of dementia patients have severe disruptions in their sleep-wakefulness cycle. Both in aged subjects having very minimal sleep disorders as well as in demented patients with a very severe disorganization of the sleep-wake cycle, melatonin treatment reduced the variability of sleep onset and restored sleep.

Background: To describe short-term outcomes and independent predictors of 28-dayx mortality in adult patients with hematologic malignancies and septic shock defined by the new Third International Consensus Definitions (Sepsis-3) criteria. Methods: We performed a retrospective cohort study of patients admitted to the medical ICU with septic shock from April 2016 to March 2019. Demographic and clinical features and short-term outcomes were collected. We used descriptive statistics to summarize patient characteristics, logistic regression to identify predictors of 28-day mortality, and Kaplan-Meier plots to assess survival. Results: Among the 459 hematologic patients with septic shock admitted to the ICU, 109 (23.7%) had received hematopoietic stem cell transplant. The median age was 63 years (range, 18–89 years), and 179 (39%) were women. Nonsurvivors had a higher Charlson comorbidity index (P=.007), longer length of stay before ICU admission (P=.01), and greater illness severity at diagnosis and throughout the hospital course (P<.001). The mortality rate at 28 days was 67.8% and increased with increasing sequential organ failure assessment score on admission (odds ratio [OR], 1.11; 95% CI, 1.03–1.20), respiratory failure (OR, 3.12; 95% CI, 1.49–6.51), and maximum lactate level (OR, 1.16; 95% CI, 1.10–1.22). Aminoglycosides administration (OR, 0.42; 95% CI, 0.26–0.69), serum albumin (OR, 0.51; 95% CI, 0.31–0.86), and granulocyte colony-stimulating factor (G-CSF) (OR, 0.40; 95% CI, 0.24–0.65) were associated with lower 28-day mortality. Life support limitations were present in 81.6% of patients at death. At 90 days, 19.4% of the patients were alive. Conclusions: Despite efforts to enhance survival, septic shock in patients with hematologic malignancies is still associated with high mortality rates and poor 90-day survival. These results demonstrate the need for an urgent call to action with higher awareness, including the further evaluation of interventions such as earlier ICU admission, aminoglycosides administration, and G-CSF treatment.

The circadian time system involves periodic gene expression at the cellular level, synchronized by a hierarchically superior structure located in the hypothalamic suprachiasmatic nuclei. Treatment of circadian rhythm disorders has led to the development of a new type of agent called "chronobiotics," among which melatonin is the prototype. In elderly insomniacs, melatonin treatment decreased sleep latency and increased sleep efficiency, particularly slow-wave sleep. The effect of melatonin on sleep is the consequence of increasing sleep propensity (by augmenting the amplitude of circadian clock oscillation via MT1 receptors) and of synchronizing the circadian clock via MT2 receptors. Daily melatonin production decreases with age and in several pathologies, attaining its lowest values in Alzheimer's disease (AD) patients. About 45% of AD patients have disruptions in their sleep and "sundowning" agitation. Generally, melatonin treatment decreases sundowning in AD patients and reduced variability of sleep onset time. Both open and controlled studies have indicated a significant decrease of cognitive deterioration in AD patients treated with melatonin. The mechanisms accounting for the possible therapeutic effect of melatonin in AD patients may be manifold. On one hand, melatonin treatment promotes slow-wave sleep in the elderly and could be beneficial by augmenting the restorative phases of sleep. On the other hand, melatonin protects neurons against beta-amyloid toxicity. By its combined chronobiotic and cytoprotective properties melatonin provides an innovative neuroprotective strategy to reduce the cost of lifetime treatment of some neuropsychiatric disorders.

Background. Pembrolizumab is a checkpoint inhibitor that targets the programmed cell death-1 receptor (PD-1) and has shown to be effective against several malignancies, including lung cancer. However, life-threatening immune-related adverse events can result from these immunotherapy treatments. Case presentation. A 62-year-old man with HIV, metastatic adenocarcinoma of the lung, and no previous history of diabetes presented to the emergency department with new-onset nausea, vomiting, and generalized weakness. Glucose was 1191 mg/dl, hemoglobin A1c 11%, and potassium 6.9 mEq/L. He had metabolic acidosis with a lactate of 6.6 mmol/L and anion gap of 38 mEq/L, and ketones were detected on the urinalysis. Severe diabetic ketoacidosis was diagnosed, and the patient was admitted to the intensive care unit. Additional investigations showed low C-peptide and negative anti-glutamic acid decarboxylase antibody, anti-insulin antibody, and anti-islet-antigen 2Ab antibody. After ruling out other possible etiologies, pembrolizumab was considered to be the cause of the diabetes and ketoacidosis. Conclusions. Life-threatening adverse drug events associated with checkpoint inhibitors such as pembrolizumab are on the rise. We recommend to closely follow and monitor patients receiving these immunotherapies. This strategy could lead to early detection and prevention, as well as reduction of more serious life-threatening complications requiring intensive care.

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