Identifying time-resolved features of nocturnal sleep characteristics of narcolepsy using machine learning.

The differential diagnosis of narcolepsy type 1, a rare, chronic, central disorder of hypersomnolence, is challenging due to overlapping symptoms with other hypersomnolence disorders. While recent years have seen significant growth in our understanding of nocturnal polysomnography narcolepsy type 1 features, there remains a need for improving methods to differentiate narcolepsy type 1 nighttime sleep features from those of individuals without narcolepsy type 1. We aimed to develop a machine learning framework for identifying sleep features to discriminate narcolepsy type 1 from clinical controls, narcolepsy type 2 and idiopathic hypersomnia. The population included polysomnography data from 350 drug-free individuals (114 narcolepsy type 1, 90 narcolepsy type 2, 105 idiopathic hypersomnia, and 41 clinical controls) collected at the National Reference Centers for Narcolepsy in Montpelier, France. Several sets of nocturnal sleep features were explored, as well as the value of time-resolving sleep architecture by analysing sleep per quarter-night. Several patterns of nighttime sleep evolution emerged that differed between narcolepsy type 1, clinical controls, narcolepsy type 2 and idiopathic hypersomnia, with increased nighttime instability observed in patients with narcolepsy type 1. Using machine learning models, we identified rapid eye movement sleep onset as the best single polysomnography feature to distinguish narcolepsy type 1 from controls, narcolepsy type 2 and idiopathic hypersomnia. By combining multiple feature sets capturing different aspects of sleep across quarter-night periods, we were able to further improve between-group discrimination and could identify the most discriminative sleep features. Our results highlight salient polysomnography features and the relevance of assessing their time-dependent changes during sleep that could aid diagnosis and measure the impact of novel therapeutics in future clinical trials.

A concerning trend in geriatric pharmacy that merits evidence-based intervention.

The effects of polypharmacy on geriatric populations are an emerging concern that merits more exploration. The primary goal of this review was to evaluate the current body of knowledge on polypharmacy and explore the preventive and corrective measures to avoid negative outcomes. Even if a medication has an appropriate indication, polypharmacy in the geriatric population is associated with an increased risk of drug-drug or drug-condition interactions. Recent efforts to prevent polypharmacy include the development of interprofessional teams in clinics dedicated to medication review and reconciliation, deprescription plans aimed to safely discontinue potentially inappropriate medications, and inpatient screening tools that provide prescribing recommendations. In conclusion, polypharmacy affects a high percentage of the geriatric population. Current efforts to address and prevent polypharmacy are ongoing but have not been widely adopted.

Resolving delayed sleep-wake phase disorder with a pandemic: two case reports.

Two patients with delayed sleep-wake phase disorder (DSWPD) demonstrated improvement in sleep quality and duration, reduction in symptoms, and elimination of the need for hypnotic or stimulant medications after changing their sleep schedules in response to the coronavirus disease 2019 (COVID-19) pandemic lockdown work schedule changes. These cases highlight the impact of work schedules on patient health and raise questions about approaches to workplace schedule requirements postpandemic. CITATION: Epstein LJ, Cai A, Klerman EB, Czeisler CA. Resolving delayed sleep-wake phase disorder with a pandemic: two case reports. J Clin Sleep Med. 2022;18(1):315-318.

Friends or Foes? Rapid Determination of Dissimilar Colistin and Ciprofloxacin Antagonism of Pseudomonas aeruginosa Phages.

Phage therapy is a century-old technique employing viruses (phages) to treat bacterial infections, and in the clinic it is often used in combination with antibiotics. Antibiotics, however, interfere with critical bacterial metabolic activities that can be required by phages. Explicit testing of antibiotic antagonism of phage infection activities, though, is not a common feature of phage therapy studies. Here we use optical density-based 'lysis-profile' assays to assess the impact of two antibiotics, colistin and ciprofloxacin, on the bactericidal, bacteriolytic, and new-virion-production activities of three Pseudomonas aeruginosa phages. Though phages and antibiotics in combination are more potent in killing P. aeruginosa than either acting alone, colistin nevertheless substantially interferes with phage bacteriolytic and virion-production activities even at its minimum inhibitory concentration (1× MIC). Ciprofloxacin, by contrast, has little anti-phage impact at 1× or 3× MIC. We corroborate these results with more traditional measures, particularly colony-forming units, plaque-forming units, and one-step growth experiments. Our results suggest that ciprofloxacin could be useful as a concurrent phage therapy co-treatment especially when phage replication is required for treatment success. Lysis-profile assays also appear to be useful, fast, and high-throughput means of assessing antibiotic antagonism of phage infection activities.

Evidence-based management of arrhythmogenic right ventricular cardiomyopathy in pregnancy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic disorder resulting in fibrofatty replacement of the myocardium. Genetic mutations in genes encoding for desmosome proteins result in a ventricular myocardium prone to arrhythmias and heart failure. Although ARVC is known for a few decades, most of the outcomes in pregnancy are reported recently. Pregnancy leads to significant physiological changes with excess mechanical stress on the myocardium. All the retrospective studies suggest that pregnancy is well tolerated in these patients despite the high risk of arrhythmias and heart failure. Our review focuses on the most up-to-date evidence on the management of ARVC patients during the antepartum and postpartum period.

Development of Neuroregenerative Gene Therapy to Reverse Glial Scar Tissue Back to Neuron-Enriched Tissue.

Injuries in the central nervous system (CNS) often causes neuronal loss and glial scar formation. We have recently demonstrated NeuroD1-mediated direct conversion of reactive glial cells into functional neurons in adult mouse brains. Here, we further investigate whether such direct glia-to-neuron conversion technology can reverse glial scar back to neural tissue in a severe stab injury model of the mouse cortex. Using an adeno-associated virus (AAV)-based gene therapy approach, we ectopically expressed a single neural transcription factor NeuroD1 in reactive astrocytes in the injured areas. We discovered that the reactive astrocytes were efficiently converted into neurons both before and after glial scar formation, and the remaining astrocytes proliferated to repopulate themselves. The astrocyte-converted neurons were highly functional, capable of firing action potentials and establishing synaptic connections with other neurons. Unexpectedly, the expression of NeuroD1 in reactive astrocytes resulted in a significant reduction of toxic A1 astrocytes, together with a significant decrease of reactive microglia and neuroinflammation. Furthermore, accompanying the regeneration of new neurons and repopulation of new astrocytes, new blood vessels emerged and blood-brain-barrier (BBB) was restored. These results demonstrate an innovative neuroregenerative gene therapy that can directly reverse glial scar back to neural tissue, opening a new avenue for brain repair after injury.

Toxin-Induced Acute Delirium.

Acute delirium is a transient state of cerebral dysfunction reflecting an underlying medical decompensation. Toxicity from medications and other substances are a common cause of delirium. History and laboratory testing may be limited by alteration and lack of specific tests for certain compounds. Classes of compounds produce a constellation of symptoms and examination findings recognized as a toxidrome. Cessation of the offending agent, supportive care, and specific antidotal therapy are key to treatment. This article reviews the presentations of the anticholinergic toxidrome, sympathomimetic toxidrome, hallucinogenic toxidrome, γ-aminobutyric acid withdrawal, and Wernicke encephalopathy, as well as their mechanisms and basic management.

Approach to critical illness myopathy and polyneuropathy in the older SARS-CoV-2 patients.

One of the major concerns of the health care community and the public surrounding the SARS-CoV-2 pandemic is the availability and use of ventilators. Unprecedented surges of patients presented to intensive care units across the country, with older adults making up a large proportion of the patient population. This paper illustrates contemporary approaches to critical illness myopathy (CIM), critical illness polyneuropathy (CIP), and critical illness polyneuromyopathy (CIPNM) in older patients, including incidence, risk factors, mechanisms for pathology, diagnosis, contemporary treatment approaches, and outcomes. We hope that the following analysis may help educate clinicians and ultimately decrease the duration of the mechanical ventilation required by these patients, resulting in improved clinical outcomes and an increase in ventilator availability for other patients in need.

The Economic Implications of COVID-19 in the United States.

The novel coronavirus disease 2019 (COVID-19) first reported in Wuhan, China, in 2019 has evolved into a pandemic and public health emergency, leading to extensive fatalities and halting global economies. Older adults have emerged as a critically vulnerable population as earlier data suggests a disproportionately increased incidence of COVID-19 in this population, as well as worse health outcomes. Disease attenuating behaviors such as social distancing has been encouraged and mandated across different countries leading to downstream economic ramifications. This paper seeks to outline the economic implications of COVID-19 in the U.S. (particularly in terms of vocational, retail, and service industries), highlighting the role of nursing homes in disease dissemination. We also discuss potential costs associated with COVID-19 management focusing on the senior population who rely on Medicare benefits for health insurance.

COVID-19: Catastrophic Cause of Acute Lung Injury.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak that began in 2019 and spread rapidly across the globe has been observed to cause acute lung injury and multiorgan system failure. While common symptoms are flu-like, this population has been observed to decompensate at an alarmingly rapid rate to severe hypoxia. SARS-CoV-2 infects host cells by targeting the angiotensin-converting enzyme 2 (ACE2) receptor, which is present on endothelial cells in the lung, heart, kidney, and gastrointestinal tissue. The pathophysiology of acute respiratory distress syndrome (ARDS) in SARS-CoV-2 infection has a component of lung perfusion dysregulation and is described as a "cytokine storm" that causes increased vascular permeability and disease severity. Older adults and those with comorbid conditions, particularly hypertension, diabetes, and history of ischemic heart disease, are especially vulnerable. These high-risk populations are often on angiotensin-modulating therapies, which are theorized to increase ACE2 expressivity, but current evidence for or against discontinuation is equivocal. The standard for SARS-CoV-2 testing is through reverse transcription polymerase chain reaction, which has presented problems due to low sensitivity and possible co-infection with other pathogens. Treatment for ARDS in the setting of SARS-CoV-2 should follow pre-established goals of care and the wishes of the patient and family members or caregivers and consider the high risk for polypharmacy, cognitive decline, malnutrition, and depression, particularly in older adults. Treatment recommendations have outlined ventilation goals to minimize further lung injury. Compassionate use of pharmacologic therapies such as remdesivir has shown promise, and further clinical trials of anticytokine agents are underway.

Regeneration of Functional Neurons After Spinal Cord Injury via in situ NeuroD1-Mediated Astrocyte-to-Neuron Conversion.

Spinal cord injury (SCI) often leads to impaired motor and sensory functions, partially because the injury-induced neuronal loss cannot be easily replenished through endogenous mechanisms. In vivo neuronal reprogramming has emerged as a novel technology to regenerate neurons from endogenous glial cells by forced expression of neurogenic transcription factors. We have previously demonstrated successful astrocyte-to-neuron conversion in mouse brains with injury or Alzheimer's disease by overexpressing a single neural transcription factor NeuroD1. Here we demonstrate regeneration of spinal cord neurons from reactive astrocytes after SCI through AAV NeuroD1-based gene therapy. We find that NeuroD1 converts reactive astrocytes into neurons in the dorsal horn of stab-injured spinal cord with high efficiency (~95%). Interestingly, NeuroD1-converted neurons in the dorsal horn mostly acquire glutamatergic neuronal subtype, expressing spinal cord-specific markers such as Tlx3 but not brain-specific markers such as Tbr1, suggesting that the astrocytic lineage and local microenvironment affect the cell fate after conversion. Electrophysiological recordings show that the NeuroD1-converted neurons can functionally mature and integrate into local spinal cord circuitry by displaying repetitive action potentials and spontaneous synaptic responses. We further show that NeuroD1-mediated neuronal conversion can occur in the contusive SCI model with a long delay after injury, allowing future studies to further evaluate this in vivo reprogramming technology for functional recovery after SCI. In conclusion, this study may suggest a paradigm shift from classical axonal regeneration to neuronal regeneration for spinal cord repair, using in vivo astrocyte-to-neuron conversion technology to regenerate functional new neurons in the gray matter.

Amnesia of the Operating Room in the B-Unaware and BAG-RECALL Clinical Trials.

BACKGROUND: Patient memories of the operating room (OR) may serve as the informational basis for assessing satisfaction with individual anesthesiologists. Furthermore, the provision of clinically important information may assume that perioperative memories are retained. Studies assessing the extent of perioperative amnesia and factors associated with perioperative amnesia are sparse. Therefore, we assessed patient amnesia of the OR and of the preoperative holding area in hospitals where midazolam is typically administered in the preoperative holding area and evaluated whether midazolam dose administered in the preoperative holding area and patient age were associated with amnesia of the OR before induction of anesthesia. METHODS: This was a retrospective study among 7750 adult patients who had general anesthesia and participated in the B-Unaware and Bispectral Index or Anesthetic Gas to Reduce Explicit Recall (BAG-RECALL) clinical trials. The last location the patient remembered before induction of anesthesia and the first location they remembered after induction of anesthesia were determined through a modified Brice questionnaire administered over the phone 30 days postoperatively. Regarding the preoperative period, patients were excluded if their last memory was unclear with respect to location before induction of anesthesia or if they were recruited at Winnipeg, where midazolam was typically first administered in the OR. Midazolam dose (mg/kg) administered in the preoperative holding area was divided into quartiles. Poisson regression models were used to calculate age- and multivariable-adjusted odds ratios (95% confidence intervals [CIs]) for the association between midazolam dose and amnesia of the OR before induction of anesthesia. RESULTS: Of the 5339 patients included, 59.5% (95% CI, 58.2­60.9) of patients had amnesia of the OR before induction of anesthesia. In addition, 44.1% (95% CI, 42.8­45.7) last remembered the preoperative holding area, and 15.4% (95% CI, 14.4­16.4) only had preoperative memories before the holding area. The percentages of patients with amnesia of the OR before induction of anesthesia differed according to age groups: 50.7% (95% CI, 47.7%­53.7%) in patients aged 18 to 47 years versus 70.0% (95% CI, 67.0%­72.9%) in patients aged 73 to 99 years. Patients in the highest midazolam quartile had an adjusted prevalence ratio of 1.31 (95% CI, 1.22­1.42) for amnesia of the OR compared with those who did not receive midazolam. CONCLUSIONS: In hospitals where patients typically receive midazolam in the preoperative holding area, the majority of patients do not remember the OR, and a clinically relevant number of patients does not remember the preoperative holding area. If additional studies produce results indicating that a substantial proportion of patients has amnesia of the anesthesiologist, these findings would argue against the validity of assessing patient satisfaction with individual anesthesiologists providing exclusively OR care in such hospitals. Furthermore, if additional studies yield findings suggesting patient amnesia of the preoperative holding area, these results would suggest reconsideration of providing clinically important information only in the preoperative holding area. Older age and midazolam-induced anterograde amnesia are probably associated with impaired perioperative memories.

Does power magnify the expression of dispositions?

Conventional wisdom holds that power holders act more in line with their dispositions than do people who lack power. Drawing on principles of construct accessibility, we propose that this is the case only when no alternative constructs are activated. In three experiments, we assessed participants' chronic dispositions and subsequently manipulated participants' degree of power. Participants then either were or were not primed with alternative (i.e., inaccessible or counterdispositional) constructs. When no alternatives were activated, the responses of power holders--perceptions of other people (Experiment 1), preferences for charitable donations (Experiment 2), and strategies in an economic game (Experiment 3)--were more in line with their chronically accessible constructs than were the responses of low-power participants. However, when alternatives had been activated, power holders' responses were no longer more congruent with their dispositions than were the responses of low-power participants. We propose a single mechanism according to which power increases reliance on accessible constructs--that is, constructs that easily come to mind-regardless of whether these constructs are chronically or temporarily accessible.