Context:
Late adolescence is marked by a delay in sleep timing, which is partly driven by a delay shift of the circadian timing system. This study examined whether the sensitivity of the circadian ...system to light—the primary entraining stimulus to the circadian system—differs between pre- to mid-pubertal and late to postpubertal adolescents.
Objective:
The study was designed to determine the influence of puberty on the sensitivity of the circadian system to light in humans.
Methods:
Melatonin suppression to low and moderate light levels was assessed in 38 pre- to mid-pubertal (9.1–14.7 years) and 29 late to postpubertal (11.5–15.9 years) adolescents. They received 1 hour of four light levels on consecutive nights: approximately 0.1 (near-dark baseline condition), 15, 150, and 500 lux. One group received evening light beginning at 11:00 pm (n = 39); a second group received morning light beginning at 3:00 am (n = 28). Salivary melatonin was sampled every 30 minutes. Melatonin suppression for 15, 150, and 500 lux was calculated relative to unsuppressed baseline levels in the 0.1 lux setting, within individuals.
Results:
The pre- to mid-pubertal group showed significantly greater melatonin suppression to 15 lux (9.2 ± 20.5%), 150 lux (26.0 ± 17.7%), and 500 lux (36.9 ± 11.4%) during evening light exposure compared to the late to postpubertal group (−5.3 ± 17.7%, 12.5 ± 17.3%, and 23.9 ± 21.7%, respectively; P < .05). No significant differences were seen between developmental groups in morning melatonin suppression.
Conclusion:
These results indicate support for a greater sensitivity to evening light in early pubertal children. The increased sensitivity to light in younger adolescents suggests that exposure to evening light could be particularly disruptive to sleep regulation for this group.
IMPORTANCE: Infection is frequent among patients in the intensive care unit (ICU). Contemporary information about the types of infections, causative pathogens, and outcomes can aid the development of ...policies for prevention, diagnosis, treatment, and resource allocation and may assist in the design of interventional studies. OBJECTIVE: To provide information about the prevalence and outcomes of infection and the available resources in ICUs worldwide. DESIGN, SETTING, AND PARTICIPANTS: Observational 24-hour point prevalence study with longitudinal follow-up at 1150 centers in 88 countries. All adult patients (aged ≥18 years) treated at a participating ICU during a 24-hour period commencing at 08:00 on September 13, 2017, were included. The final follow-up date was November 13, 2017. EXPOSURES: Infection diagnosis and receipt of antibiotics. MAIN OUTCOMES AND MEASURES: Prevalence of infection and antibiotic exposure (cross-sectional design) and all-cause in-hospital mortality (longitudinal design). RESULTS: Among 15 202 included patients (mean age, 61.1 years SD, 17.3 years; 9181 were men 60.4%), infection data were available for 15 165 (99.8%); 8135 (54%) had suspected or proven infection, including 1760 (22%) with ICU-acquired infection. A total of 10 640 patients (70%) received at least 1 antibiotic. The proportion of patients with suspected or proven infection ranged from 43% (141/328) in Australasia to 60% (1892/3150) in Asia and the Middle East. Among the 8135 patients with suspected or proven infection, 5259 (65%) had at least 1 positive microbiological culture; gram-negative microorganisms were identified in 67% of these patients (n = 3540), gram-positive microorganisms in 37% (n = 1946), and fungal microorganisms in 16% (n = 864). The in-hospital mortality rate was 30% (2404/7936) in patients with suspected or proven infection. In a multilevel analysis, ICU-acquired infection was independently associated with higher risk of mortality compared with community-acquired infection (odds ratio OR, 1.32 95% CI, 1.10-1.60; P = .003). Among antibiotic-resistant microorganisms, infection with vancomycin-resistant Enterococcus (OR, 2.41 95% CI, 1.43-4.06; P = .001), Klebsiella resistant to β-lactam antibiotics, including third-generation cephalosporins and carbapenems (OR, 1.29 95% CI, 1.02-1.63; P = .03), or carbapenem-resistant Acinetobacter species (OR, 1.40 95% CI, 1.08-1.81; P = .01) was independently associated with a higher risk of death vs infection with another microorganism. CONCLUSIONS AND RELEVANCE: In a worldwide sample of patients admitted to ICUs in September 2017, the prevalence of suspected or proven infection was high, with a substantial risk of in-hospital mortality.
Normal functioning of the brain is dependent upon a complex web of communication between numerous cell types. Within neuronal networks, the faithful transmission of information between neurons relies ...on an equally complex organization of inter- and intra-cellular signaling systems that act to modulate protein activity. In particular, post-translational modifications (PTMs) are responsible for regulating protein activity in response to neurochemical signaling. The key second messenger, cyclic adenosine 3′,5′-monophosphate (cAMP), regulates one of the most ubiquitous and influential PTMs, phosphorylation. While cAMP is canonically viewed as regulating the addition of phosphate groups through its activation of cAMP-dependent protein kinases, it plays an equally critical role in regulating removal of phosphate through indirect control of protein phosphatase activity. This dichotomy of regulation by cAMP places it as one of the key regulators of protein activity in response to neuronal signal transduction throughout the brain. In this review we focus on the role of cAMP in regulation of the serine/threonine phosphatases protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) and the relevance of control of PP1 and PP2A to regulation of brain function and behavior.
After replicating in surface epithelia, herpes simplex virus type-1 (HSV-1) enters the axonal terminals of peripheral neurons. The viral genome translocates to the nucleus, where it establishes a ...specialized infection known as latency, re-emerging periodically to seed new infections. Studies using cultured neuron models that faithfully recapitulate the molecular hallmarks of latency and reactivation defined in live animal models have provided fresh insight into the control of latency and connections to neuronal physiology. With this comes a growing appreciation for how the life cycles of HSV-1 and other herpesviruses are governed by key host pathways controlling metabolic homeostasis and cell identity.
IMPORTANCE: Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, ...biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination. OBJECTIVE: To evaluate and, as needed, update definitions for sepsis and septic shock. PROCESS: A task force (n = 19) with expertise in sepsis pathobiology, clinical trials, and epidemiology was convened by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. Definitions and clinical criteria were generated through meetings, Delphi processes, analysis of electronic health record databases, and voting, followed by circulation to international professional societies, requesting peer review and endorsement (by 31 societies listed in the Acknowledgment). KEY FINDINGS FROM EVIDENCE SYNTHESIS: Limitations of previous definitions included an excessive focus on inflammation, the misleading model that sepsis follows a continuum through severe sepsis to shock, and inadequate specificity and sensitivity of the systemic inflammatory response syndrome (SIRS) criteria. Multiple definitions and terminologies are currently in use for sepsis, septic shock, and organ dysfunction, leading to discrepancies in reported incidence and observed mortality. The task force concluded the term severe sepsis was redundant. RECOMMENDATIONS: Sepsis should be defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. For clinical operationalization, organ dysfunction can be represented by an increase in the Sequential Sepsis-related Organ Failure Assessment (SOFA) score of 2 points or more, which is associated with an in-hospital mortality greater than 10%. Septic shock should be defined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Patients with septic shock can be clinically identified by a vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia. This combination is associated with hospital mortality rates greater than 40%. In out-of-hospital, emergency department, or general hospital ward settings, adult patients with suspected infection can be rapidly identified as being more likely to have poor outcomes typical of sepsis if they have at least 2 of the following clinical criteria that together constitute a new bedside clinical score termed quickSOFA (qSOFA): respiratory rate of 22/min or greater, altered mentation, or systolic blood pressure of 100 mm Hg or less. CONCLUSIONS AND RELEVANCE: These updated definitions and clinical criteria should replace previous definitions, offer greater consistency for epidemiologic studies and clinical trials, and facilitate earlier recognition and more timely management of patients with sepsis or at risk of developing sepsis.
Both quality improvement and clinical research efforts over the past few decades have focused on consensus definition of sepsis and acute respiratory distress syndrome (ARDS). Although clinical ...definitions based on readily available clinical data have advanced recognition and timely use of broad supportive treatments, they likely hinder the identification of more targeted therapies that manipulate select biological mechanisms underlying critical illness. Sepsis and ARDS are by definition heterogeneous, and patients vary in both their underlying biology and their severity of illness. We have long been able to identify subtypes of sepsis and ARDS that confer different prognoses. The key is that we are now on the verge of identifying subtypes that may confer different response to therapy. In this perspective, inspired by a 2015 American Thoracic Society International Conference Symposium entitled "Lumpers and Splitters: Phenotyping in Critical Illness," we highlight promising approaches to uncovering patient subtypes that may predict treatment responsiveness and not just differences in prognosis. We then discuss how this information can be leveraged to improve the success and translatability of clinical trials by using predictive enrichment and other design strategies. Last, we discuss the challenges and limitations to identifying biomarkers and endotypes and incorporating them into routine clinical practice.
Sepsis is life-threatening organ dysfunction due to a dysregulated host response to infection. It is considered a major cause of health loss, but data for the global burden of sepsis are limited. As ...a syndrome caused by underlying infection, sepsis is not part of standard Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimates. Accurate estimates are important to inform and monitor health policy interventions, allocation of resources, and clinical treatment initiatives. We estimated the global, regional, and national incidence of sepsis and mortality from this disorder using data from GBD 2017.
We used multiple cause-of-death data from 109 million individual death records to calculate mortality related to sepsis among each of the 282 underlying causes of death in GBD 2017. The percentage of sepsis-related deaths by underlying GBD cause in each location worldwide was modelled using mixed-effects linear regression. Sepsis-related mortality for each age group, sex, location, GBD cause, and year (1990–2017) was estimated by applying modelled cause-specific fractions to GBD 2017 cause-of-death estimates. We used data for 8·7 million individual hospital records to calculate in-hospital sepsis-associated case-fatality, stratified by underlying GBD cause. In-hospital sepsis-associated case-fatality was modelled for each location using linear regression, and sepsis incidence was estimated by applying modelled case-fatality to sepsis-related mortality estimates.
In 2017, an estimated 48·9 million (95% uncertainty interval UI 38·9–62·9) incident cases of sepsis were recorded worldwide and 11·0 million (10·1–12·0) sepsis-related deaths were reported, representing 19·7% (18·2–21·4) of all global deaths. Age-standardised sepsis incidence fell by 37·0% (95% UI 11·8–54·5) and mortality decreased by 52·8% (47·7–57·5) from 1990 to 2017. Sepsis incidence and mortality varied substantially across regions, with the highest burden in sub-Saharan Africa, Oceania, south Asia, east Asia, and southeast Asia.
Despite declining age-standardised incidence and mortality, sepsis remains a major cause of health loss worldwide and has an especially high health-related burden in sub-Saharan Africa.
The Bill & Melinda Gates Foundation, the National Institutes of Health, the University of Pittsburgh, the British Columbia Children's Hospital Foundation, the Wellcome Trust, and the Fleming Fund.
Purpose
To determine whether early goal-directed therapy (EGDT) reduces mortality compared with other resuscitation strategies for patients presenting to the emergency department (ED) with septic ...shock.
Methods
Using a search strategy of PubMed, EmBase and CENTRAL, we selected all relevant randomised clinical trials published from January 2000 to January 2015. We translated non-English papers and contacted authors as necessary. Our primary analysis generated a pooled odds ratio (OR) from a fixed-effect model. Sensitivity analyses explored the effect of including non-ED studies, adjusting for study quality, and conducting a random-effects model. Secondary outcomes included organ support and hospital and ICU length of stay.
Results
From 2395 initially eligible abstracts, five randomised clinical trials (
n
= 4735 patients) met all criteria and generally scored high for quality except for lack of blinding. There was no effect on the primary mortality outcome (EGDT: 23.2 % 495/2134 versus control: 22.4 % 582/2601; pooled OR 1.01 95 % CI 0.88–1.16,
P
= 0.9, with heterogeneity
I
2
= 57 %;
P
= 0.055). The pooled estimate of 90-day mortality from the three recent multicentre studies (
n
= 4063) also showed no difference pooled OR 0.99 (95 % CI 0.86–1.15),
P
= 0.93 with no heterogeneity (
I
2
= 0.0 %;
P
= 0.97). EGDT increased vasopressor use (OR 1.25 95 % CI 1.10–1.41;
P
< 0.001) and ICU admission OR 2.19 (95 % CI 1.82–2.65);
P
< 0.001. Including six non-ED randomised trials increased heterogeneity (
I
2
= 71 %;
P
< 0.001) but did not change overall results pooled OR 0.94 (95 % CI 0.82 to 1.07);
P
= 0.33.
Conclusion
EGDT is not superior to usual care for ED patients with septic shock but is associated with increased utilisation of ICU resources.
Characterizing complex viral transcriptomes by conventional RNA sequencing approaches is complicated by high gene density, overlapping reading frames, and complex splicing patterns. Direct RNA ...sequencing (direct RNA-seq) using nanopore arrays offers an exciting alternative whereby individual polyadenylated RNAs are sequenced directly, without the recoding and amplification biases inherent to other sequencing methodologies. Here we use direct RNA-seq to profile the herpes simplex virus type 1 (HSV-1) transcriptome during productive infection of primary cells. We show how direct RNA-seq data can be used to define transcription initiation and RNA cleavage sites associated with all polyadenylated viral RNAs and demonstrate that low level read-through transcription produces a novel class of chimeric HSV-1 transcripts, including a functional mRNA encoding a fusion of the viral E3 ubiquitin ligase ICP0 and viral membrane glycoprotein L. Thus, direct RNA-seq offers a powerful method to characterize the changing transcriptional landscape of viruses with complex genomes.
This study explores the effects of patent protection and R&D subsidies on innovation and income inequality using a Schumpeterian growth model with heterogeneous households. We find that although ...strengthening patent protection and raising R&D subsidies have the same macroeconomic effects of stimulating innovation and economic growth, they have drastically different microeconomic implications on income inequality. Specifically, strengthening patent protection increases income inequality whereas raising R&D subsidies decreases (increases) it if the quality step size is sufficiently small (large). An empirically realistic quality step size is smaller than the threshold, implying a negative effect of R&D subsidies on income inequality. We also calibrate the model to provide a quantitative analysis and find that strengthening patent protection causes a moderate increase in income inequality and a negligible increase in consumption inequality whereas raising R&D subsidies causes a relatively large decrease in both income inequality and consumption inequality.
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