-
Stem Cell Reports Sep 2021Human neurons engineered from induced pluripotent stem cells (iPSCs) through neurogenin 2 (NGN2) overexpression are widely used to study neuronal differentiation...
Human neurons engineered from induced pluripotent stem cells (iPSCs) through neurogenin 2 (NGN2) overexpression are widely used to study neuronal differentiation mechanisms and to model neurological diseases. However, the differentiation paths and heterogeneity of emerged neurons have not been fully explored. Here, we used single-cell transcriptomics to dissect the cell states that emerge during NGN2 overexpression across a time course from pluripotency to neuron functional maturation. We find a substantial molecular heterogeneity in the neuron types generated, with at least two populations that express genes associated with neurons of the peripheral nervous system. Neuron heterogeneity is observed across multiple iPSC clones and lines from different individuals. We find that neuron fate acquisition is sensitive to NGN2 expression level and the duration of NGN2-forced expression. Our data reveal that NGN2 dosage can regulate neuron fate acquisition, and that NGN2-iN heterogeneity can confound results that are sensitive to neuron type.
Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Cell Differentiation; Cell Line; Cells, Cultured; Computational Biology; Gene Expression Profiling; Gene Expression Regulation, Developmental; Humans; Induced Pluripotent Stem Cells; Mice; Nerve Tissue Proteins; Neurogenesis; Neurons; RNA-Seq; Transcriptome
PubMed: 34358451
DOI: 10.1016/j.stemcr.2021.07.006 -
The Lancet. Neurology Oct 2022Prospective epidemiological studies in industrial societies indicate that 7 h of sleep per night in people aged 18 years or older is optimum, with higher and lower... (Review)
Review
Prospective epidemiological studies in industrial societies indicate that 7 h of sleep per night in people aged 18 years or older is optimum, with higher and lower amounts of sleep predicting a shorter lifespan. Humans living a hunter-gatherer lifestyle (eg, tribal groups) sleep for 6-8 h per night, with the longest sleep durations in winter. The prevalence of insomnia in hunter-gatherer populations is low (around 2%) compared with the prevalence of insomnia in industrial societies (around 10-30%). Sleep deprivation studies, which are done to gain insights into sleep function, are often confounded by the effects of stress. Consideration of the duration of spontaneous daily sleep across species of mammals, which ranges from 2 h to 20 h, can provide important insights into sleep function without the stress of deprivation. Sleep duration is not related to brain size or cognitive ability. Rather, sleep duration across species is associated with their ecological niche and feeding requirements, indicating a role for wake-sleep balance in food acquisition and energy conservation. Brain temperature drops from waking levels during non-rapid eye movement (non-REM) sleep and rises during REM sleep. Average daily REM sleep time of homeotherm orders is negatively correlated with average body and brain temperature, with the largest amount of REM sleep in egg laying (monotreme) mammals, moderate amounts in pouched (marsupial) mammals, lower amounts in placental mammals, and the lowest amounts in birds. REM sleep might, therefore, have a key role in the regulation of temperature and metabolism of the brain during sleep and in the facilitation of alert awakening.
Topics: Animals; Female; Humans; Mammals; Placenta; Pregnancy; Prospective Studies; Sleep; Sleep Initiation and Maintenance Disorders
PubMed: 36115365
DOI: 10.1016/S1474-4422(22)00210-1 -
Frontiers in Pharmacology 2021A program to identify novel intravenous sedatives with a short and predictable duration of action was initiated in the late 1990's by Glaxo Wellcome. The program... (Review)
Review
A program to identify novel intravenous sedatives with a short and predictable duration of action was initiated in the late 1990's by Glaxo Wellcome. The program focussed on the identification of ester-based benzodiazepine derivatives that are rapidly broken down by esterases. Remimazolam was identified as one of the lead compounds. The project at Glaxo was shelved for strategic reasons at the late lead optimization stage. Via the GSK ventures initiative, the program was acquired by the small biotechnology company, TheraSci, and, through successive acquisitions, developed as the besylate salt at CeNeS and PAION. The development of remimazolam besylate has been slow by industry standards, primarily because of the resource limitations of these small companies. It has, however, recently been approved for anesthesia in Japan and South Korea, procedural sedation in the United States, China, and Europe, and for compassionate use in intensive care unit sedation in Belgium. A second development program of remimazolam was later initiated in China, using a slightly different salt form, remimazolam tosylate. This salt form of the compound has also recently been approved for procedural sedation in China. Remimazolam has the pharmacological profile of a classical benzodiazepine, such as midazolam, but is differentiated from other intravenous benzodiazepines by its rapid conversion to an inactive metabolite resulting in a short onset/offset profile. It is differentiated from other intravenous hypnotic agents, such as propofol, by its low liability for cardiovascular depression, respiratory depression, and injection pain. The benzodiazepine antagonist flumazenil can reverse the effects of remimazolam in case of adverse events and further shorten recovery times. The aim of this review is to provide an analysis of, and perspective on, published non-clinical and clinical information on 1) the pharmacology, metabolism, pharmacokinetics, and pharmacodynamic profile of remimazolam, 2) the profile of remimazolam compared with established agents, 3) gaps in the current understanding of remimazolam, 4) the compound's discovery and development process and 5) likely future developments in the clinical use of remimazolam.
PubMed: 34354587
DOI: 10.3389/fphar.2021.690875 -
Frontiers in Cellular and Infection... 2021The emergence of carbapenem-resistant Enterobacterales (CRE) has become a major public health concern. Moreover, its colonization among residents of long-term care... (Review)
Review
The emergence of carbapenem-resistant Enterobacterales (CRE) has become a major public health concern. Moreover, its colonization among residents of long-term care facilities (LTCFs) is associated with subsequent infections and mortality. To further explore the various aspects concerning CRE in LTCFs, we conducted a literature review on CRE colonization and/or infections in long-term care facilities. The prevalence and incidence of CRE acquisition among residents of LTCFs, especially in California, central Italy, Spain, Japan, and Taiwan, were determined. There was a significant predominance of CRE in LTCFs, especially in high-acuity LTCFs with mechanical ventilation, and thus may serve as outbreak centers. The prevalence rate of CRE in LTCFs was significantly higher than that in acute care settings and the community, which indicated that LTCFs are a vital reservoir for CRE. The detailed species and genomic analyses of CRE among LTCFs reported that is the primary species in the LTCFs in the United States, Spain, and Taiwan. KPC-2-containing strains with sequence type 258 is the most common sequence type of KPC-producing in the LTCFs in the United States. IMP-11- and IMP-6-producing CRE were commonly reported among LTCFs in Japan. OXA-48 was the predominant carbapenemase among LTCFs in Spain. Multiple risk factors associated with the increased risk for CRE acquisition in LTCFs were found, such as comorbidities, immunosuppressive status, dependent functional status, usage of gastrointestinal devices or indwelling catheters, mechanical ventilation, prior antibiotic exposures, and previous culture reports. A high CRE acquisition rate and prolonged CRE carriage duration after colonization were found among residents in LTCFs. Moreover, the patients from LTCFs who were colonized or infected with CRE had poor clinical outcomes, with a mortality rate of up to 75% in infected patients. Infection prevention and control measures to reduce CRE in LTCFs is important, and could possibly be controlled active surveillance, contact precautions, cohort staffing, daily chlorhexidine bathing, healthcare-worker education, and hand-hygiene adherence.
Topics: Bacterial Proteins; Carbapenems; Enterobacteriaceae Infections; Humans; Italy; Japan; Klebsiella pneumoniae; Long-Term Care; Spain; Taiwan; United States; beta-Lactamases
PubMed: 33968793
DOI: 10.3389/fcimb.2021.601968 -
The Journal of Allergy and Clinical... Mar 2023Atopic march refers to the sequential development of allergic diseases from infancy through adolescence, typically beginning with atopic dermatitis (AD), followed by... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Atopic march refers to the sequential development of allergic diseases from infancy through adolescence, typically beginning with atopic dermatitis (AD), followed by food allergy and then airway diseases, later evolving to broader or worsened spectrum of allergic diatheses. No intervention has shown to alter its course.
OBJECTIVE
We sought to determine the rate of acquisition of new or worsened allergic events for dupilumab versus placebo in patients with AD.
METHODS
Allergy-associated events from 12 clinical trials were grouped into 17 allergy categories, and IgE changes from baseline were defined. A new/worsened event was considered one step of atopic march. Treatment effect was assessed by incidence rate ratios (IRRs), dupilumab versus placebo, by meta-analysis.
RESULTS
The duration of pooled AD studies was 4 to 52 weeks (1359 patient-years; n = 2296 dupilumab, n = 1229 placebo, median age 35 years). The median age at AD onset was 2 years. Baseline allergic disease burden was comparable between groups. Dupilumab reduced the risk of new/worsening allergies by 34% (IRR 0.66; 95% confidence interval [CI], 0.52-0.84) and new allergies by 37% (IRR 0.63; 95% CI, 0.48-0.83) versus placebo. Including IgE category shift, the IRR for combined new/worsening allergies was reduced by 54% (IRR 0.46; 95% CI, 0.36-0.57). These treatment benefits did not reverse on treatment discontinuation in off-treatment follow-up.
CONCLUSIONS
The acquisition/worsening of allergic conditions suggestive of atopic march was observed in a pooled adult/adolescent AD study population with inadequately controlled AD. Treatment with dupilumab reduced new/worsened allergy events versus placebo; inclusion of IgE category change increased the apparent benefit.
Topics: Adult; Adolescent; Humans; Child, Preschool; Dermatitis, Atopic; Antibodies, Monoclonal, Humanized; Cost of Illness; Immunoglobulin E; Treatment Outcome
PubMed: 36084766
DOI: 10.1016/j.jaci.2022.08.026 -
Frontiers in Immunology 2023Sleep enhances the antibody response to vaccination, but the relationship between sleep and mRNA vaccination against severe acute respiratory syndrome coronavirus 2... (Observational Study)
Observational Study
INTRODUCTION
Sleep enhances the antibody response to vaccination, but the relationship between sleep and mRNA vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is not fully understood.
METHODS
In this prospective observational study, we investigated the influence of sleep habits on immune acquisition induced by mRNA vaccines against SARS-CoV-2 in 48 healthy adults (BNT-162b2, n=34; mRNA-1273, n=14; female, n=30, 62.5%; male, n=18, 37.5%; median age, 39.5 years; interquartile range, 33.0-44.0 years) from June 2021 to January 2022. The study measured sleep duration using actigraphy and sleep diaries, which covered the periods of the initial and booster vaccinations.
RESULTS
Multivariable linear regression analysis showed that actigraphy-measured objective sleep duration 3 and 7 days after the booster vaccination was independently and significantly correlated with higher antibody titers (B=0.003; 95% confidence interval, 0.000-0.005; Beta=0.337; p=0.02), even after controlling for covariates, including age, sex, the type of vaccine, and reactogenicity to the vaccination. Associations between acquired antibody titer and average objective sleep duration before vaccination, and any period of subjective sleep duration measured by sleep diary were negligible.
DISCUSSION
Longer objective, but not subjective, sleep duration after booster vaccination enhances antibody response. Hence, encouraging citizens to sleep longer after mRNA vaccination, especially after a booster dose, may increase protection against SARS-CoV-2.
STUDY REGISTRATION
This study is registered at the University Hospital Medical Information Network Center (UMIN: https://www.umin.ac.jp) on July 30, 2021, #UMIN000045009.
Topics: Adult; Female; Humans; Male; COVID-19; COVID-19 Vaccines; Sleep Duration; Vaccination; Antibody Formation; Antibodies, Viral; mRNA Vaccines; Immunization, Secondary
PubMed: 38149250
DOI: 10.3389/fimmu.2023.1242302 -
Frontiers in Neurology 2019Many clinical applications based on deep learning and pertaining to radiology have been proposed and studied in radiology for classification, risk assessment,... (Review)
Review
Many clinical applications based on deep learning and pertaining to radiology have been proposed and studied in radiology for classification, risk assessment, segmentation tasks, diagnosis, prognosis, and even prediction of therapy responses. There are many other innovative applications of AI in various technical aspects of medical imaging, particularly applied to the acquisition of images, ranging from removing image artifacts, normalizing/harmonizing images, improving image quality, lowering radiation and contrast dose, and shortening the duration of imaging studies. This article will address this topic and will seek to present an overview of deep learning applied to neuroimaging techniques.
PubMed: 31474928
DOI: 10.3389/fneur.2019.00869 -
Journal of Clinical Medicine Feb 2022Two benefits of MR-guided radiotherapy (MRgRT) are the ability to track target structures while treatment is being delivered and the ability to adapt plans daily for...
OBJECTIVE
Two benefits of MR-guided radiotherapy (MRgRT) are the ability to track target structures while treatment is being delivered and the ability to adapt plans daily for some lesions based on changing anatomy. These unique capacities come at two costs: increased capital for acquisition and greatly decreased workflow. An adaptive gated stereotactic body radiotherapy (MRgART) treatment routinely takes ~90 min to perform and requires the presence of both a physician and a physicist. This may significantly limit daily capacity. We previously described how "simple cases" were necessary for proton facilities to allow for debt management. In this manuscript, we seek to determine the optimal scheduling of different MRgRT plans to recoup capital costs.
MATERIALS/METHODS
We assumed an MR-linac (MRL) was completely scheduled with patients over workdays of varying duration. Treatment times and reimbursement data from our facility for varying complexities of patients were extrapolated for varying numbers treated daily. We then derived the number of adaptive and non-adaptive patients required daily to optimize the schedules. HOPPS data were used to model reimbursement.
RESULTS
A single MRL treating 14 non-gated, non-adaptive IMRT patients over an 8 h workday would take about 4.8 years to cover initial acquisition and installation costs. However, such patients may be more quickly and efficiently treated with a conventional linear accelerator, while MRgART cases may only be treated with an MRL. By treating four of these daily, that same MRL room would cover costs in 2.4 years. Personnel, maintenance costs, and profit further complicate any business case for treating non-adaptive patients or for extending hours.
CONCLUSIONS
In our previously published paper discussing proton therapy, we noted that debt is not variable with capacity; this remains true with MRgRT. Different from protons, a clinically optimal case load of adaptive patients provides an optimal business case as well. This requires a large patient cadre to ensure continuing throughput. As improvements in MRgRT are brought to the clinic, shorter adaptive and non-adaptive treatment times will help improve the timeframe to recoup costs but will require even more appropriate patients.
PubMed: 35160318
DOI: 10.3390/jcm11030869 -
Critical Care (London, England) May 2023The optimal treatment duration and the nature of regimen of antibiotics (monotherapy or combination therapy) for Pseudomonas aeruginosa ventilator‑associated pneumonia... (Randomized Controlled Trial)
Randomized Controlled Trial
Association between combination antibiotic therapy as opposed as monotherapy and outcomes of ICU patients with Pseudomonas aeruginosa ventilator-associated pneumonia: an ancillary study of the iDIAPASON trial.
BACKGROUND
The optimal treatment duration and the nature of regimen of antibiotics (monotherapy or combination therapy) for Pseudomonas aeruginosa ventilator‑associated pneumonia (PA-VAP) remain debated. The aim of this study was to evaluate whether a combination antibiotic therapy is superior to a monotherapy in patients with PA-VAP in terms of reduction in recurrence and death, based on the 186 patients included in the iDIAPASON trial, a multicenter, randomized controlled trial comparing 8 versus 15 days of antibiotic therapy for PA-VAP.
METHODS
Patients with PA-VAP randomized in the iDIAPASON trial (short-duration-8 days vs. long-duration-15 days) and who received appropriate antibiotic therapy were eligible in the present study. The main objective is to compare mortality at day 90 according to the antibiotic therapy received by the patient: monotherapy versus combination therapy. The primary outcome was the mortality rate at day 90. The primary outcome was compared between groups using a Chi-square test. Time from appropriate antibiotic therapy to death in ICU or to censure at day 90 was represented using Kaplan-Meier survival curves and compared between groups using a Log-rank test.
RESULTS
A total of 169 patients were included in the analysis. The median duration of appropriate antibiotic therapy was 14 days. At day 90, among 37 patients (21.9%) who died, 17 received monotherapy and 20 received a combination therapy (P = 0.180). Monotherapy and combination antibiotic therapy were similar for the recurrence rate of VAP, the number of extra pulmonary infections, or the acquisition of multidrug-resistant (MDR) bacteria during the ICU stay. Patients in combination therapy were exposed to mechanical ventilation for 28 ± 12 days, as compared with 23 ± 11 days for those receiving monotherapy (P = 0.0243). Results remain similar after adjustment for randomization arm of iDIAPASON trial and SOFA score at ICU admission.
CONCLUSIONS
Except longer durations of antibiotic therapy and mechanical ventilation, potentially related to increased difficulty in achieving clinical cure, the patients in the combination therapy group had similar outcomes to those in the monotherapy group.
TRIAL REGISTRATION
NCT02634411 , Registered 15 December 2015.
Topics: Humans; Anti-Bacterial Agents; Pneumonia, Ventilator-Associated; Pseudomonas aeruginosa; Respiration, Artificial; Intensive Care Units
PubMed: 37254209
DOI: 10.1186/s13054-023-04457-y