Concern over antibiotic resistance is growing, and new classes of antibiotics, particularly against Gram-negative bacteria, are needed. However, even if the scientific hurdles can be overcome, it ...could take decades for sufficient numbers of such antibiotics to become available. As an interim solution, antibiotic resistance could be 'broken' by co-administering appropriate non-antibiotic drugs with failing antibiotics. Several marketed drugs that do not currently have antibacterial indications can either directly kill bacteria, reduce the antibiotic minimum inhibitory concentration when used in combination with existing antibiotics and/or modulate host defence through effects on host innate immunity, in particular by altering inflammation and autophagy. This article discusses how such 'antibiotic resistance breakers' could contribute to reducing the antibiotic resistance problem, and analyses a priority list of candidates for further investigation.
To examine temporal trend in the national incidence of bronchiolitis hospitalizations, use of mechanical ventilation, and hospital charges between 2000 and 2009.
We performed a serial, ...cross-sectional analysis of a nationally representative sample of children hospitalized with bronchiolitis. The Kids Inpatient Database was used to identify children <2 years of age with bronchiolitis by International Classification of Diseases, Ninth Revision, Clinical Modification code 466.1. Primary outcome measures were incidence of bronchiolitis hospitalizations, mechanical ventilation (noninvasive or invasive) use, and hospital charges. Temporal trends were evaluated accounting for sampling weights.
The 4 separated years (2000, 2003, 2006, and 2009) of national discharge data included 544 828 weighted discharges with bronchiolitis. Between 2000 and 2009, the incidence of bronchiolitis hospitalization decreased from 17.9 to 14.9 per 1000 person-years among all US children aged <2 years (17% decrease; P(trend) < .001). By contrast, there was an increase in children with high-risk medical conditions (5.9%-7.9%; 34% increase; P(trend) < .001) and use of mechanical ventilation (1.9%-2.3%; 21% increase; P(trend) = .008). Nationwide hospital charges increased from $1.34 billion to $1.73 billion (30% increase; P(trend) < .001); this increase was driven by a rise in the geometric mean of hospital charges per case from $6380 to $8530 (34% increase; P(trend) < .001).
Between 2000 and 2009, we found a significant decline in bronchiolitis hospitalizations among US children. By contrast, use of mechanical ventilation and hospital charges for bronchiolitis significantly increased over this same period.
IMPORTANCE It is unclear whether advanced airway management such as endotracheal intubation or use of supraglottic airway devices in the prehospital setting improves outcomes following ...out-of-hospital cardiac arrest (OHCA) compared with conventional bag-valve-mask ventilation. OBJECTIVE To test the hypothesis that prehospital advanced airway management is associated with favorable outcome after adult OHCA. DESIGN, SETTING, AND PARTICIPANTS Prospective, nationwide, population-based study (All-Japan Utstein Registry) involving 649 654 consecutive adult patients in Japan who had an OHCA and in whom resuscitation was attempted by emergency responders with subsequent transport to medical institutions from January 2005 through December 2010. MAIN OUTCOME MEASURES Favorable neurological outcome 1 month after an OHCA, defined as cerebral performance category 1 or 2. RESULTS Of the eligible 649 359 patients with OHCA, 367 837 (57%) underwent bag-valve-mask ventilation and 281 522 (43%) advanced airway management, including 41 972 (6%) with endotracheal intubation and 239 550 (37%) with use of supraglottic airways. In the full cohort, the advanced airway group incurred a lower rate of favorable neurological outcome compared with the bag-valve-mask group (1.1% vs 2.9%; odds ratio OR, 0.38; 95% CI, 0.36-0.39). In multivariable logistic regression, advanced airway management had an OR for favorable neurological outcome of 0.38 (95% CI, 0.37-0.40) after adjusting for age, sex, etiology of arrest, first documented rhythm, witnessed status, type of bystander cardiopulmonary resuscitation, use of public access automated external defibrillator, epinephrine administration, and time intervals. Similarly, the odds of neurologically favorable survival were significantly lower both for endotracheal intubation (adjusted OR, 0.41; 95% CI, 0.37-0.45) and for supraglottic airways (adjusted OR, 0.38; 95% CI, 0.36-0.40). In a propensity score–matched cohort (357 228 patients), the adjusted odds of neurologically favorable survival were significantly lower both for endotracheal intubation (adjusted OR, 0.45; 95% CI, 0.37-0.55) and for use of supraglottic airways (adjusted OR, 0.36; 95% CI, 0.33-0.39). Both endotracheal intubation and use of supraglottic airways were similarly associated with decreased odds of neurologically favorable survival. CONCLUSION AND RELEVANCE Among adult patients with OHCA, any type of advanced airway management was independently associated with decreased odds of neurologically favorable survival compared with conventional bag-valve-mask ventilation.
Development of emergency department (ED) triage systems that accurately differentiate and prioritize critically ill from stable patients remains challenging. We used machine learning models to ...predict clinical outcomes, and then compared their performance with that of a conventional approach-the Emergency Severity Index (ESI).
Using National Hospital and Ambulatory Medical Care Survey (NHAMCS) ED data, from 2007 through 2015, we identified all adult patients (aged ≥ 18 years). In the randomly sampled training set (70%), using routinely available triage data as predictors (e.g., demographics, triage vital signs, chief complaints, comorbidities), we developed four machine learning models: Lasso regression, random forest, gradient boosted decision tree, and deep neural network. As the reference model, we constructed a logistic regression model using the five-level ESI data. The clinical outcomes were critical care (admission to intensive care unit or in-hospital death) and hospitalization (direct hospital admission or transfer). In the test set (the remaining 30%), we measured the predictive performance, including area under the receiver-operating-characteristics curve (AUC) and net benefit (decision curves) for each model.
Of 135,470 eligible ED visits, 2.1% had critical care outcome and 16.2% had hospitalization outcome. In the critical care outcome prediction, all four machine learning models outperformed the reference model (e.g., AUC, 0.86 95%CI 0.85-0.87 in the deep neural network vs 0.74 95%CI 0.72-0.75 in the reference model), with less under-triaged patients in ESI triage levels 3 to 5 (urgent to non-urgent). Likewise, in the hospitalization outcome prediction, all machine learning models outperformed the reference model (e.g., AUC, 0.82 95%CI 0.82-0.83 in the deep neural network vs 0.69 95%CI 0.68-0.69 in the reference model) with less over-triages in ESI triage levels 1 to 3 (immediate to urgent). In the decision curve analysis, all machine learning models consistently achieved a greater net benefit-a larger number of appropriate triages considering a trade-off with over-triages-across the range of clinical thresholds.
Compared to the conventional approach, the machine learning models demonstrated a superior performance to predict critical care and hospitalization outcomes. The application of modern machine learning models may enhance clinicians' triage decision making, thereby achieving better clinical care and optimal resource utilization.
The single largest risk factor for etiology of neurodegenerative diseases like Alzheimer’s disease is increased age. Therefore, understanding the changes that occur as a result of aging is central to ...any possible prevention or cure for such conditions. Microglia, the resident brain glial population most associated with both protection of neurons in health and their destruction is disease, could be a significant player in age related changes. Microglia can adopt an aberrant phenotype sometimes referred to either as dystrophic or senescent. While aged microglia have been frequently identified in neurodegenerative diseases such as Alzheimer’s disease, there is no conclusive evidence that proves a causal role. This has been hampered by a lack of models of aged microglia. We have recently generated a model of senescent microglia based on the observation that all dystrophic microglia show iron overload. Iron‐overloading cultured microglia causes them to take on a senescent phenotype and can cause changes in models of neurodegeneration similar to those observed in patients. This review considers how this model could be used to determine the role of senescent microglia in neurodegenerative diseases.
The most important risk factor for neurodegenerative diseases like Alzheimer’s disease is aging. While the potential role aberrant microglia play in neurodegeneration has been studied for some time, new evidence suggests that that microglial aging might be more important. When microglia become senescent they lose many of their supportive roles and compromise neuronal survival. This review focuses on senescent microglia. New models of senescent microglia could advance study of aging and neurodegeneration.
Oxidative stress has long been implicated in cardiovascular disease, but more recently, the role of reactive oxygen species (ROS) in normal physiological signaling has been elucidated. Signaling ...pathways modulated by ROS are complex and compartmentalized, and we are only beginning to identify the molecular modifications of specific targets. Here, we review the current literature on ROS signaling in the cardiovascular system, focusing on the role of ROS in normal physiology and how dysregulation of signaling circuits contributes to cardiovascular diseases, including atherosclerosis, ischemia–reperfusion injury, cardiomyopathy, and heart failure. In particular, we consider how ROS modulate signaling pathways related to phenotypic modulation, migration and adhesion, contractility, proliferation and hypertrophy, angiogenesis, endoplasmic reticulum stress, apoptosis, and senescence. Understanding the specific targets of ROS may guide the development of the next generation of ROS-modifying therapies to reduce morbidity and mortality associated with oxidative stress.
Summary Background Encephalitis has many causes, but for most patients the cause is unknown. We aimed to establish the cause and identify the clinical differences between causes in patients with ...encephalitis in England. Methods Patients of all ages and with symptoms suggestive of encephalitis were actively recruited for 2 years (staged start between October, 2005, and November, 2006) from 24 hospitals by clinical staff. Systematic laboratory testing included PCR and antibody assays for all commonly recognised causes of infectious encephalitis, investigation for less commonly recognised causes in immunocompromised patients, and testing for travel-related causes if indicated. We also tested for non-infectious causes for acute encephalitis including autoimmunity. A multidisciplinary expert team reviewed clinical presentation and hospital tests and directed further investigations. Patients were followed up for 6 months after discharge from hospital. Findings We identified 203 patients with encephalitis. Median age was 30 years (range 0–87). 86 patients (42%, 95% CI 35–49) had infectious causes, including 38 (19%, 14–25) herpes simplex virus, ten (5%, 2–9) varicella zoster virus, and ten (5%, 2–9) Mycobacterium tuberculosis ; 75 (37%, 30–44) had unknown causes. 42 patients (21%, 15–27) had acute immune-mediated encephalitis. 24 patients (12%, 8–17) died, with higher case fatality for infections from M tuberculosis (three patients; 30%, 7–65) and varicella zoster virus (two patients; 20%, 2–56). The 16 patients with antibody-associated encephalitis had the worst outcome of all groups—nine (56%, 30–80) either died or had severe disabilities. Patients who died were more likely to be immunocompromised than were those who survived (OR=3·44). Interpretation Early diagnosis of encephalitis is crucial to ensure that the right treatment is given on time. Extensive testing substantially reduced the proportion with unknown cause, but the proportion of cases with unknown cause was higher than that for any specific identified cause. Funding The Policy Research Programme, Department of Health, UK.
The United States is battling obesity and heart failure (HF) epidemics. Although studies have suggested relationships between obesity and HF morbidity, little is known regarding the effects of ...substantial weight reduction in obese patients with HF.
This study investigated whether bariatric surgery is associated with a decreased rate of HF exacerbation.
We performed a self-controlled case series study of obese patients with HF who underwent bariatric surgery, using the population-based emergency department (ED) and inpatient sample in California, Florida, and Nebraska. Primary outcome was ED visit or hospitalization for HF exacerbation from 2005 to 2011. We used conditional logistic regression to compare the outcome event rate during sequential 12-month periods, using pre-surgery months 13 to 24 as the reference period.
We identified 524 patients with HF who underwent bariatric surgery. During the reference period, 16.2% of patients had an ED visit or hospitalization for HF exacerbation. The rate remained unchanged in the subsequent 12-month pre-surgery period (15.3%; p = 0.67). In the first 12-month period after bariatric surgery, we observed a nonsignificantly reduced rate (12.0%; p = 0.052). However, the rate was significantly lower in the subsequent 13 to 24 months after bariatric surgery (9.9%; adjusted odds ratio: 0.57; p = 0.003). By contrast, there was no significant reduction in the rate of HF exacerbation among obese patients who underwent nonbariatric surgery (i.e., cholecystectomy, hysterectomy).
Our findings indicate that bariatric surgery is associated with a decline in the rate of HF exacerbation requiring ED evaluation or hospitalization among obese patients with HF.
The ability of prokaryotic microbes to produce and respond to neurochemicals that are more often associated with eukaryotic systems is increasingly recognized through the concept of microbial ...endocrinology. Most studies have described the phenomena of neurochemical production by bacteria, but there remains an incomplete understanding of the mechanisms by which microbe- or host-derived neuroactive substances can be recognized by bacteria. Based on the evolutionary origins of eukaryotic solute carrier transporters, we hypothesized that bacteria may possess an analogous uptake function for neuroactive biogenic amines. Using specific fluorescence-based assays, Lactobacillus salivarius biofilms appear to express both plasma membrane monoamine transporter (PMAT)- and organic cation transporter (OCT)-like uptake of transporter-specific fluorophores. This phenomenon is not distributed throughout the genus Lactobacillus as L. rhamnosus biofilms did not take up these fluorophores. PMAT probe uptake into L. salivarius biofilms was attenuated by the protonophore CCCP, the cation transport inhibitor decynium-22, and the natural substrates norepinephrine, serotonin and fluoxetine. These results provide the first evidence, to our knowledge, for the existence of PMAT- and OCT-like uptake systems in a bacterium. They also suggest the existence of a hitherto unrecognized mechanism by which a probiotic bacterium may interact with host signals and may provide a means to examine microbial endocrinology-based interactions in health and disease that are part of the larger microbiota-gut-brain axis.
The burden of Congenital Rubella Syndrome (CRS) is typically underestimated in routine surveillance. Updated estimates are needed following the recent WHO position paper on rubella and recent GAVI ...initiatives, funding rubella vaccination in eligible countries. Previous estimates considered the year 1996 and only 78 (developing) countries.
We reviewed the literature to identify rubella seroprevalence studies conducted before countries introduced rubella-containing vaccination (RCV). These data and the estimated vaccination coverage in the routine schedule and mass campaigns were incorporated in mathematical models to estimate the CRS incidence in 1996 and 2000-2010 for each country, region and globally.
The estimated CRS decreased in the three regions (Americas, Europe and Eastern Mediterranean) which had introduced widespread RCV by 2010, reaching <2 per 100,000 live births (the Americas and Europe) and 25 (95% CI 4-61) per 100,000 live births (the Eastern Mediterranean). The estimated incidence in 2010 ranged from 90 (95% CI: 46-195) in the Western Pacific, excluding China, to 116 (95% CI: 56-235) and 121 (95% CI: 31-238) per 100,000 live births in Africa and SE Asia respectively. Highest numbers of cases were predicted in Africa (39,000, 95% CI: 18,000-80,000) and SE Asia (49,000, 95% CI: 11,000-97,000). In 2010, 105,000 (95% CI: 54,000-158,000) CRS cases were estimated globally, compared to 119,000 (95% CI: 72,000-169,000) in 1996.
Whilst falling dramatically in the Americas, Europe and the Eastern Mediterranean after vaccination, the estimated CRS incidence remains high elsewhere. Well-conducted seroprevalence studies can help to improve the reliability of these estimates and monitor the impact of rubella vaccination.
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