Randomized clinical trials (RCTs) are conducted to guide clinicians' selection of therapies for individual patients. Currently, RCTs in critical care often report an overall mean effect and selected ...individual subgroups. Yet work in other fields suggests that such reporting practices can be improved. Specifically, this Critical Care Perspective reviews recent work on so-called "heterogeneity of treatment effect" (HTE) by baseline risk and extends that work to examine its applicability to trials of acute respiratory failure and severe sepsis. Because patients in RCTs in critical care medicine-and patients in intensive care units-have wide variability in their risk of death, these patients will have wide variability in the absolute benefit that they can derive from a given therapy. If the side effects of the therapy are not perfectly collinear with the treatment benefits, this will result in HTE, where different patients experience quite different expected benefits of a therapy. We use simulations of RCTs to demonstrate that such HTE could result in apparent paradoxes, including: (1) positive trials of therapies that are beneficial overall but consistently harm or have little benefit to low-risk patients who met enrollment criteria, and (2) overall negative trials of therapies that still consistently benefit high-risk patients. We further show that these results persist even in the presence of causes of death unmodified by the treatment under study. These results have implications for reporting and analyzing RCT data, both to better understand how our therapies work and to improve the bedside applicability of RCTs. We suggest a plan for measurement in future RCTs in the critically ill.
The epidemiology of chronic critical illness is not well characterized. We sought to determine the prevalence, outcomes, and associated costs of chronic critical illness in the United States.
...Population-based cohort study using data from the United States Healthcare Costs and Utilization Project from 2004 to 2009.
Acute care hospitals in Massachusetts, North Carolina, Nebraska, New York, and Washington.
Adult and pediatric patients meeting a consensus-derived definition for chronic critical illness, which included one of six eligible clinical conditions (prolonged acute mechanical ventilation, tracheotomy, stroke, traumatic brain injury, sepsis, or severe wounds) plus at least 8 days in an ICU.
None.
Out of 3,235,741 admissions to an ICU during the study period, 246,151 (7.6%) met the consensus definition for chronic critical illness. The most common eligibility conditions were prolonged acute mechanical ventilation (72.0% of eligible admissions) and sepsis (63.7% of eligible admissions). Among patients meeting chronic critical illness criteria through sepsis, the infections were community acquired in 48.5% and hospital acquired in 51.5%. In-hospital mortality was 30.9% with little change over the study period. The overall population-based prevalence was 34.4 per 100,000. The prevalence varied substantially with age, peaking at 82.1 per 100,000 individuals 75-79 years old but then declining coincident with a rise in mortality before day 8 in otherwise eligible patients. Extrapolating to the entire United States, for 2009, we estimated a total of 380,001 cases; 107,880 in-hospital deaths and $26 billion in hospital-related costs.
Using a consensus-based definition, the prevalence, hospital mortality, and costs of chronic critical illness are substantial. Chronic critical illness is particularly common in the elderly although in very old patients the prevalence declines, in part because of an increase in early mortality among potentially eligible patients.
Recent retrospective epidemiological studies demonstrated that new-onset cardiovascular disease is one of the most emerging issues among sepsis survivors. Sepsis incident may also accelerate ...cardiovascular dysfunction/disease existing prior to sepsis. This review summarizes recent key literature on long-term cardiovascular outcomes after sepsis and pneumonia, and highlights potential biologic and pathophysiologic mechanisms that contribute to long-term cardiovascular disease after a sepsis incident. Prospective pre-clinical and clinical studies are warranted to characterize cardiovascular dysfunction after sepsis, the role of chronic biologic sequelae in pathophysiology of post-sepsis cardiovascular disease, and design interventions to prevent and reduce long-term cardiovascular burden of sepsis.
Abstract This study develops a Malthusian model for the evolution of human society from hunting-gathering to agriculture and from agriculture to industrial production. Human society evolves across ...these stages as the population grows. However, under endogenous population growth, the population may stop growing at any stage. If it fails to reach the first threshold, the population remains as hunter-gatherers. If it reaches the first threshold, an agricultural society emerges. Then, if the population fails to reach the industrial threshold, it remains in an agricultural Malthusian trap without experiencing industrialization. Interestingly, high agricultural productivity triggers not only the Neolithic Revolution but also the subsequent industrialization. Using cross-country data to test this result, we employ an index of prehistoric biogeographic conditions that affect agricultural productivity as an instrument for the timing of transitions to agriculture and find that an earlier transition to agriculture has a positive effect on industrialization in the modern era.
The human subventricular zone (SVZ) has a defined cytological and neurochemical architecture, with four constituent laminae that act in concert to support its neurogenic activity. Lipidomic ...specialisation has previously been demonstrated in the neurologically normal human SVZ, with enrichment of functionally important lipid classes in each lamina. The SVZ is also responsive to neurodegenerative disorders, where thickening of the niche and enhanced proliferation of resident cells were observed in Huntington's disease (HD) brains. In this study, we hypothesised lipidomic changes in the HD SVZ. Using matrix‐assisted laser desorption/ionisation (MALDI) imaging mass spectrometry, this analysis shows differences in the lipidomic architecture in the post‐mortem Vonsattel grade III cases. Relative to matched, neurologically normal specimens (N = 4), the lipidomic signature of the HD SVZ (N = 4) was characterized by loss of sulfatides and triglycerides in the myelin layer, with an ectopic and focal accumulation of sphingomyelins and ceramide‐1‐phosphate observed in this lamina. A striking loss of lipidomic patterning was also observed in the ependymal layer, where the local abundance of phosphatidylinositols was significantly reduced in HD. This comprehensive spatially resolved lipidomic analysis of the human HD SVZ identifies alterations in lipid architecture that may shed light on the mechanisms of SVZ responses to neurodegeneration in HD.
Open Practices
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In Huntington's disease the lipidome of the subventricular zone has not been studied. We used matrix‐assisted laser desorption/ionisation imaging mass spectrometry combined with histological techniques to demonstrate lipid changes in the Huntington's disease subventricular zone. Ceramide and sphingomyelins were elevated, sulfatides and triglycerides were elevated in the myelin layer and phosphatidylinositols were reduced in the ependymal layer.
Open Science: This manuscript was awarded with the Open Materials Badge.
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Transcriptome profiling has become routine in studies of many biological processes. However, the favored approaches such as short-read Illumina RNA sequencing are giving way to long-read sequencing ...platforms better suited to interrogating the complex transcriptomes typical of many RNA and DNA viruses. Here, we provide a guide-tailored to molecular virologists-to the ins and outs of viral transcriptome sequencing and discuss the strengths and weaknesses of the major RNA sequencing technologies as tools to analyze the abundance and diversity of the viral transcripts made during infection.
This study develops a Schumpeterian growth model with endogenous entry of heterogeneous firms to analyze the effects of monetary policy on economic growth via a cash-in-advance constraint on R&D ...investment. Our results can be summarized as follows. In the special case of a zero entry cost, an increase in the nominal interest rate decreases R&D, the arrival rate of innovations and economic growth as in previous studies. However, in the general case of a positive entry cost, an increase in the nominal interest rate affects the distribution of innovations that are implemented and would have an inverted-U effect on economic growth if the entry cost is sufficiently large. We also calibrate the model to aggregate data of the US economy and find that the growth-maximizing inflation rate is about 3%, which is consistent with recent empirical estimates. Finally, we also explore the welfare effects of inflation and consider a number of extensions to the benchmark model.
Sepsis: a roadmap for future research Cohen, Jonathan, Prof; Vincent, Jean-Louis, Prof; Adhikari, Neill K J, MDCM ...
The Lancet infectious diseases,
05/2015, Letnik:
15, Številka:
5
Journal Article
Recenzirano
Summary Sepsis is a common and lethal syndrome: although outcomes have improved, mortality remains high. No specific anti-sepsis treatments exist; as such, management of patients relies mainly on ...early recognition allowing correct therapeutic measures to be started rapidly, including administration of appropriate antibiotics, source control measures when necessary, and resuscitation with intravenous fluids and vasoactive drugs when needed. Although substantial developments have been made in the understanding of the basic pathogenesis of sepsis and the complex interplay of host, pathogen, and environment that affect the incidence and course of the disease, sepsis has stubbornly resisted all efforts to successfully develop and then deploy new and improved treatments. Existing models of clinical research seem increasingly unlikely to produce new therapies that will result in a step change in clinical outcomes. In this Commission, we set out our understanding of the clinical epidemiology and management of sepsis and then ask how the present approaches might be challenged to develop a new roadmap for future research.
IMPORTANCE: The risk of cardiovascular disease (CVD) after infection is poorly understood. OBJECTIVE: To determine whether hospitalization for pneumonia is associated with an increased short-term and ...long-term risk of CVD. DESIGN, SETTINGS, AND PARTICIPANTS: We examined 2 community-based cohorts: the Cardiovascular Health Study (CHS, n = 5888; enrollment age, ≥65 years; enrollment period, 1989–1994) and the Atherosclerosis Risk in Communities study (ARIC, n = 15 792; enrollment age, 45-64 years; enrollment period, 1987–1989). Participants were followed up through December 31, 2010. We matched each participant hospitalized with pneumonia to 2 controls. Pneumonia cases and controls were followed for occurrence of CVD over 10 years after matching. We estimated hazard ratios (HRs) for CVD at different time intervals, adjusting for demographics, CVD risk factors, subclinical CVD, comorbidities, and functional status. EXPOSURES: Hospitalization for pneumonia. MAIN OUTCOMES AND MEASURES: Incident CVD (myocardial infarction, stroke, and fatal coronary heart disease). RESULTS: Of 591 pneumonia cases in CHS, 206 had CVD events over 10 years after pneumonia hospitalization. CVD risk after pneumonia was highest in the first year. CVD occurred in 54 cases and 6 controls in the first 30 days (HR, 4.07; 95% CI, 2.86-5.27); 11 cases and 9 controls between 31 and 90 days (HR, 2.94; 95% CI, 2.18-3.70); and 22 cases and 55 controls between 91 days and 1 year (HR, 2.10; 95% CI, 1.59-2.60). Additional CVD risk remained elevated into the tenth year, when 4 cases and 12 controls developed CVD (HR, 1.86; 95% CI, 1.18-2.55). In ARIC, of 680 pneumonia cases, 112 had CVD over 10 years after hospitalization. CVD occurred in 4 cases and 3 controls in the first 30 days (HR, 2.38; 95% CI, 1.12-3.63); 4 cases and 0 controls between 31 and 90 days (HR, 2.40; 95% CI, 1.23-3.47); 11 cases and 8 controls between 91 days and 1 year (HR, 2.19; 95% CI, 1.20-3.19); and 8 cases and 7 controls during the second year (HR, 1.88; 95% CI, 1.10-2.66). After the second year, the HRs were no longer statistically significant. CONCLUSIONS AND RELEVANCE: Hospitalization for pneumonia was associated with increased short-term and long-term risk of CVD, suggesting that pneumonia may be a risk factor for CVD.
Shape memory alloys (SMAs) have recently emerged as promising material candidates for structural seismic resisting purposes. Most of the existing SMA-based strategies, however, are based on the wire ...or rod form of SMAs, where issues such as gripping complexity and fracture may exist. This paper presents a proof-of-concept study on an innovative type of SMA-based self-centring system, namely, a superelastic SMA ring spring system. The proposed system includes a series of inner high-strength steel (HSS) rings and outer superelastic SMA rings stacked in alternation with mating taper faces, where the resisting load is provided by the wedging action which tends to expand the outer rings and concurrently to squeeze the inner rings. The superelastic effect of the SMA offers energy dissipation and a driving force for recentring, and the frictional effect over the taper face further contributes to the overall resisting load and energy dissipation. The feasibility of the new system is carefully examined via numerical studies considering the parameters of ring thickness, taper angle, and coefficient of friction. The key hysteretic responses, including resisting load, stiffness, stress distributions, source of residual deformation, energy dissipation, and equivalent viscous damping, are discussed in detail. The behaviour of the SMA ring springs is also studied via analytical models, and the analytical predictions are found to agree well with the numerical results. Finally, two practical applications of the new system, namely self-centring HS-SMA ring spring connections, and self-centring SMA ring spring dampers, are discussed via comprehensive numerical studies.
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