Autolysin-mediated peptidoglycan hydrolysis is required for the surface display of Staphylococcus aureus cell wall-anchored proteins.

Peptidoglycan hydrolases, or autolysins, play a critical role in cell wall remodeling and degradation, facilitating bacterial growth, cell division, and cell separation. In Staphylococcus aureus, the so-called "major" autolysin, Atl, has long been associated with host adhesion; however, the molecular basis underlying this phenomenon remains understudied. To investigate, we used the type V glycopeptide antibiotic complestatin, which binds to peptidoglycan and blocks the activity of autolysins, as a chemical probe of autolysin function. We also generated a chromosomally encoded, catalytically inactive variant of the Atl enzyme. Autolysin-mediated peptidoglycan hydrolysis, in particular Atl-mediated daughter cell separation, was shown to be critical for maintaining optimal surface levels of S. aureus cell wall-anchored proteins, including the fibronectin-binding proteins (FnBPs) and protein A (Spa). As such, disrupting autolysin function reduced the affinity of S. aureus for host cell ligands, and negatively impacted early stages of bacterial colonization in a systemic model of S. aureus infection. Phenotypic studies revealed that Spa was sequestered at the septum of complestatin-treated cells, highlighting that autolysins are required to liberate Spa during cell division. In summary, we reveal the hydrolytic activities of autolysins are associated with the surface display of S. aureus cell wall-anchored proteins. We demonstrate that by blocking autolysin function, type V glycopeptide antibiotics are promising antivirulence agents for the development of strategies to control S. aureus infections.

Bringing traits back into the equation: A roadmap to understand species redistribution.

Ecological and evolutionary theories have proposed that species traits should be important in mediating species responses to contemporary climate change; yet, empirical evidence has so far provided mixed evidence for the role of behavioral, life history, or ecological characteristics in facilitating or hindering species range shifts. As such, the utility of trait-based approaches to predict species redistribution under climate change has been called into question. We develop the perspective, supported by evidence, that trait variation, if used carefully can have high potential utility, but that past analyses have in many cases failed to identify an explanatory value for traits by not fully embracing the complexity of species range shifts. First, we discuss the relevant theory linking species traits to range shift processes at the leading (expansion) and trailing (contraction) edges of species distributions and highlight the need to clarify the mechanistic basis of trait-based approaches. Second, we provide a brief overview of range shift-trait studies and identify new opportunities for trait integration that consider range-specific processes and intraspecific variability. Third, we explore the circumstances under which environmental and biotic context dependencies are likely to affect our ability to identify the contribution of species traits to range shift processes. Finally, we propose that revealing the role of traits in shaping species redistribution may likely require accounting for methodological variation arising from the range shift estimation process as well as addressing existing functional, geographical, and phylogenetic biases. We provide a series of considerations for more effectively integrating traits as well as extrinsic and methodological factors into species redistribution research. Together, these analytical approaches promise stronger mechanistic and predictive understanding that can help society mitigate and adapt to the effects of climate change on biodiversity.

A genetic platform to investigate the functions of bacterial drug efflux pumps.

Efflux pumps are a serious challenge for the development of antibacterial agents. Overcoming efflux requires an in-depth understanding of efflux pump functions, specificities and the development of inhibitors. However, the complexities of efflux networks have limited such studies. To address these challenges, we generated Efflux KnockOut-35 (EKO-35), a highly susceptible Escherichia coli strain lacking 35 efflux pumps. We demonstrate the use of this strain by constructing an efflux platform comprising EKO-35 strains individually producing efflux pumps forming tripartite complexes with TolC. This platform was profiled against a curated diverse compound collection, which enabled us to define physicochemical properties that contribute to transport. We also show the E. coli drug efflux network is conditionally essential for growth, and that the platform can be used to investigate efflux pump inhibitor specificities and efflux pump interplay. We believe EKO-35 and the efflux platform will have widespread application for the study of drug efflux.

Symptom-based staging for logopenic variant primary progressive aphasia.

BACKGROUND AND PURPOSE: Logopenic variant primary progressive aphasia (lvPPA) is a major variant presentation of Alzheimer's disease (AD) that signals the importance of communication dysfunction across AD phenotypes. A clinical staging system is lacking for the evolution of AD-associated communication difficulties that could guide diagnosis and care planning. Our aim was to create a symptom-based staging scheme for lvPPA, identifying functional milestones relevant to the broader AD spectrum. METHODS: An international lvPPA caregiver cohort was surveyed on symptom development under an 'exploratory' survey (34 UK caregivers). Feedback from this survey informed the development of a 'consolidation' survey (27 UK, 10 Australian caregivers) in which caregivers were presented with six provisional clinical stages and feedback was analysed using a mixed-methods approach. RESULTS: Six clinical stages were endorsed. Early symptoms included word-finding difficulty, with loss of message comprehension and speech intelligibility signalling later-stage progression. Additionally, problems with hearing in noise, memory and route-finding were prominent early non-verbal symptoms. 'Milestone' symptoms were identified that anticipate daily-life functional transitions and care needs. CONCLUSIONS: This work introduces a new symptom-based staging scheme for lvPPA, and highlights milestone symptoms that could inform future clinical scales for anticipating and managing communication dysfunction across the AD spectrum.

Conception and implementation of an MRI-compatible device to elicit the bulbocavernosus reflex for an open spinal cord study.

OBJECTIVE: Functional MRI (fMRI) can be employed to assess neuronal activity in the central nervous system. However, investigating the spinal cord using fMRI poses several technical difficulties. Enhancing the fMRI signal intensity in the spinal cord can improve the visualization and analysis of different neural pathways, particularly those involved in bladder function. The bulbocavernosus reflex (BCR) is an excellent method for evaluating the integrity of the sacral spinal cord. Instead of stimulating the glans penis or clitoris, the BCR can be simulated comfortably by tapping the suprapubic region. In this study, we explain the necessity and development of a device to elicit the simulated BCR (sBCR) via suprapubic tapping while conducting an fMRI scan. METHODS: The device was successfully tested on a group of 20 healthy individuals. Two stimulation task block protocols were administered (empty vs. full bladder). Each block consisted of 40 s of suprapubic tapping followed by 40 s of rest, and the entire sequence was repeated four times. RESULTS: Our device can reliably and consistently elicit sBCR noninvasively as demonstrated by electromyographic recording of pelvic muscles and anal winking. Participants did note mild to moderate discomfort and urge to void during the full bladder task. CONCLUSION: Our device demonstrates an efficacious approach to elicit sBCR within an MRI bore to assess sacral spinal cord functional activity without generating any significant motion artifacts. SIGNIFICANCE: This device can explore the mechanisms and processes controlling urinary, digestive, or sexual function within this region in humans.

Symptom-led staging for semantic and non-fluent/agrammatic variants of primary progressive aphasia.

INTRODUCTION: Here we set out to create a symptom-led staging system for the canonical semantic and non-fluent/agrammatic variants of primary progressive aphasia (PPA), which present unique diagnostic and management challenges not well captured by functional scales developed for Alzheimer's disease and other dementias. METHODS: An international PPA caregiver cohort was surveyed on symptom development under six provisional clinical stages and feedback was analyzed using a mixed-methods sequential explanatory design. RESULTS: Both PPA syndromes were characterized by initial communication dysfunction and non-verbal behavioral changes, with increasing syndromic convergence and functional dependency at later stages. Milestone symptoms were distilled to create a prototypical progression and severity scale of functional impairment: the PPA Progression Planning Aid ("PPA-Squared"). DISCUSSION: This work introduces a symptom-led staging scheme and functional scale for semantic and non-fluent/agrammatic variants of PPA. Our findings have implications for diagnostic and care pathway guidelines, trial design, and personalized prognosis and treatment for PPA. HIGHLIGHTS: We introduce new symptom-led perspectives on primary progressive aphasia (PPA). The focus is on non-fluent/agrammatic (nfvPPA) and semantic (svPPA) variants. Foregrounding of early and non-verbal features of PPA and clinical trajectories is featured. We introduce a symptom-led staging scheme for PPA. We propose a prototype for a functional impairment scale, the PPA Progression Planning Aid.

Exploring functional interplay amongst Escherichia coli efflux pumps.

Bacterial efflux pumps exhibit functional interplay that can translate to additive or multiplicative effects on resistance to antimicrobial compounds. In diderm bacteria, two different efflux pump structural types - single-component inner membrane efflux pumps and cell envelope-spanning multicomponent systems - cooperatively export antimicrobials with cytoplasmic targets from the cell. Harnessing our recently developed efflux platform, which is built upon an extensively efflux-deficient strain of Escherichia coli, here we explore interplay amongst a panel of diverse E. coli efflux pumps. Specifically, we assessed the effect of simultaneously expressing two efflux pump-encoding genes on drug resistance, including single-component inner membrane efflux pumps (MdfA, MdtK and EmrE), tripartite complexes (AcrAB, AcrAD, MdtEF and AcrEF), and the acquired TetA(C) tetracycline resistance pump. Overall, the expression of two efflux pump-encoding genes from the same structural type did not enhance resistance levels regardless of the antimicrobial compound or efflux pump under investigation. In contrast, a combination of the tripartite efflux systems with single-component pumps sharing common substrates provided multiplicative increases to antimicrobial resistance levels. In some instances, resistance was increased beyond the product of resistance provided by the two pumps individually. In summary, the developed efflux platform enables the isolation of efflux pump function, facilitating the identification of interactions between efflux pumps.

Geographic hotspot detection for late-stage hepatocellular carcinoma: novel approach to cancer control.

IMPORTANCE: As hepatocellular carcinoma (HCC)-associated mortality continues to rise in the United States, there is a crucial need for strategies to shift diagnoses from late to early stage in order to improve survival. OBJECTIVE: To describe a population-based geospatial approach to identifying areas with high late-stage HCC burden for intervention. DESIGN: Cross-sectional study between 2008 and 2017. SETTING: Los Angeles County. PARTICIPANTS: All incident cases of HCC with residential address at diagnosis in Los Angeles County were identified from a population-based cancer registry. Late stage included AJCC 7th Edition stages III-IV and unstaged cases. EXPOSURE: Sociodemographic factors. MAIN OUTCOME(S): Geographic "hotspots" or areas with a high density of late-stage HCC, identified using kernel density estimation in ArcMap 10.3.1. RESULTS: 51.8% of 7,519 incident cases of HCC were late stage. We identified a total of 23 late-stage hotspots, including 30.0% of all late-stage cases. Cases within hotspots were more often racial/ethnic minorities, foreign-born, under or uninsured, and of lower socioeconomic status. The age-adjusted incidence rate of late-stage HCC was twofold higher within hotspots (6.85 per 100,000 in hotspots vs 3.38 per 100,000 outside of hotspots). The calculated population-attributable risk was 43%, suggesting that a substantial proportion of late-stage HCC burden could be averted by introducing interventions in hotspot areas. We mapped the relationship between hotspots and federally qualified health centers primary care clinics and subspecialty clinics in Los Angeles County to demonstrate how clinic partnerships can be selected to maximize impact of interventions and resource use. Hotspots can also be utilized to identify "high-risk" neighborhoods that are easily recognizable by patients and the public and to facilitate community partnerships. CONCLUSION AND RELEVANCE: Reducing late-stage HCC through geographic late-stage hotspots may be an efficient approach to improving cancer control and equity.

Applying assessments of adaptive capacity to inform natural-resource management in a changing climate.

Adaptive capacity (AC)-the ability of a species to cope with or accommodate climate change-is a critical determinant of species vulnerability. Using information on species' AC in conservation planning is key to ensuring successful outcomes. We identified connections between a list of species' attributes (e.g., traits, population metrics, and behaviors) that were recently proposed for assessing species' AC and management actions that may enhance AC for species at risk of extinction. Management actions were identified based on evidence from the literature, a review of actions used in other climate adaptation guidance, and our collective experience in diverse fields of global-change ecology and climate adaptation. Selected management actions support the general AC pathways of persist in place or shift in space, in response to contemporary climate change. Some actions, such as genetic manipulations, can be used to directly alter the ability of species to cope with climate change, whereas other actions can indirectly enhance AC by addressing ecological or anthropogenic constraints on the expression of a species' innate abilities to adapt. Ours is the first synthesis of potential management actions directly linked to AC. Focusing on AC attributes helps improve understanding of how and why aspects of climate are affecting organisms, as well as the mechanisms by which management interventions affect a species' AC and climate change vulnerability. Adaptive-capacity-informed climate adaptation is needed to build connections among the causes of vulnerability, AC, and proposed management actions that can facilitate AC and reduce vulnerability in support of evolving conservation paradigms.

Aplicación de Evaluaciones de la Capacidad Adaptativa para Informar la Gestión de Recursos Naturales en un Clima Cambiante Resumen La capacidad adaptativa (CA) - la habilidad que tiene una especie para sobrellevar o acomodarse al cambio climático - es una determinante crítica de la vulnerabilidad de una especie. El uso de la información sobre la CA de una especie dentro de la planeación de la conservación es de suma importancia para asegurar resultados exitosos. Identificamos las conexiones entre una lista de atributos de las especies (p. ej.: características, métricas poblacionales, comportamientos) que fueron propuestos recientemente para la evaluación de la CA de las especies y las acciones de gestión que pueden mejorar la CA para las especies que se encuentran en riesgo de extinción. Las acciones de gestión fueron identificadas con base en la evidencia de la literatura, una revisión de acciones usadas en otras guías de adaptación climática y nuestra experiencia colectiva en diferentes campos de la ecología del cambio global y la adaptación climática. Ciertas acciones de gestión respaldan las vías generales de CA de persistir en el lugar o cambiar en el espacio como respuesta al cambio climático contemporáneo. Algunas acciones, como la manipulación genética, pueden usarse para alterar directamente la habilidad que tienen las especies para sobrellevar el cambio climático, mientras que otras acciones pueden mejorar indirectamente la CA al combatir las restricciones ecológicas o antropogénicas que existen sobre la expresión de las habilidades innatas de una especie para adaptarse. Nuestra síntesis es la primera que aborda acciones potenciales de gestión conectadas directamente con la CA. Enfocarse en los atributos de la CA ayuda a mejorar el conocimiento sobre cómo y por qué los aspectos climáticos están afectando a los organismos, así como los mecanismos mediante los cuales las intervenciones de gestión afectan la CA y la vulnerabilidad al cambio climático de la especie. La adaptación climática orientada por la capacidad adaptativa es necesaria para establecer conexiones entre las causas de la vulnerabilidad, la CA y las acciones de gestión propuestas que pueden facilitar la CA y reducir la vulnerabilidad como apoyo a los paradigmas cambiantes de la conservación.

Increased Mortality and Costs Associated with Adverse Events in Intensive Care Unit Patients.

Background: Adverse events (AEs) are defined as unintended complications occurring to patients as a result of medical care. AEs are especially prevalent in the intensive care unit (ICU) setting and may lead to negative patient outcomes. Although many studies have examined the impact of AEs on patient outcomes, few have investigated their associated costs. Methods: The study population consisted of 17 173 adult patients (≥18 years of age) who were admitted to the ICU at The Ottawa Hospital (TOH) between 2011 and 2016. AEs were categorized using an established International Classification of Diseases 10th revision (ICD-10) patient safety indicators (PSI) system for AE detection. Logistic regression was performed to determine the association between AEs and in-hospital outcomes, including mortality. In addition, we constructed a generalized linear model to assess the independent association between AEs and total hospital costs. Results: Patients who experienced an AE had longer total hospital and ICU lengths of stay, required more invasive ICU interventions, had more complex discharge plans, and experienced higher rates of in-hospital mortality compared to those who did not experience an AE. Average total hospital costs and ICU-specific costs were higher among patients who experienced an AE ($72 718; $46 715) relative to their counterparts ($20 543; $16 217), but the per day cost was comparable in both groups. After controlling for age, sex, patient comorbidities, and illness severity, AEs were significantly associated with an increased odds of mortality (OR = 1.13, 95% CIs = 1.04, 1.22) and total average costs (Cost Ratio = 1.04, 95% CIs = 1.06, 1.08). The most impactful AE subtypes from a cost- and patient-perspective were hospital-acquired infections (HAI) and cardiac-related AEs. Conclusion: Incidence of AEs among ICU patients is associated with higher patient mortality and elevated costs. Specific causes of these AEs should be investigated, with further protocols and interventions developed to reduce their occurrence.

"Does your baby watch TV?": The associations between at-home TV watching and laboratory challenge cortisol are different for young infants and their mothers.

This longitudinal study examined associations between at-home TV watching and the biological stress response (cortisol) during a laboratory infant cognitive challenge task in 240 3- and 5-month infants and their mothers. Cortisol levels were lower in mothers of 5-month-old infants whose infants were exposed to TV at home, compared to mothers of infants that were not TV-exposed. Cortisol patterns were different across three laboratory sampling intervals for 3-month-old infants as a function of TV watching, revealing a sharp increase in laboratory cortisol only for infants who were exposed to TV at home. In contrast, there was no effect of TV exposure in 5-month-old infants' cortisol. Infant temperament and demographic measures were included as control variables in regression models to predict maternal and infant cortisol. At 3 months, for the T3 cortisol sampling interval, and at 5 months across all three sampling intervals, maternal cortisol levels were significantly predicted by infant TV exposure after accounting for variance due to these control variables. Our findings show the strong influence of the infant TV-exposure factor in the biological stress response of mothers of young infants, and suggest that infant TV exposure may influence self-regulation in 3-month-old infants.

INVESTIGATION OF THE USE OF SERUM BIOMARKERS FOR THE DETECTION OF CARDIAC DISEASE IN MARINE MAMMALS.

Cardiac disease has been extensively documented in marine mammals; however, it remains difficult to diagnose antemortem. Assays measuring cardiac troponin I (cTnI) and N-terminal pro-brain natriuretic peptide (NT-proBNP) are used as sensitive and specific biomarkers of cardiac disease in many species, but have not been widely investigated in marine mammals. This study aimed to provide a set of reference values for cTnI and NT-proBNP in belugas (BW) (Delphinapterus leucas), sea otters (SO) (Enhydra lutris), Steller sea lions (SSL) (Eumetopias jubatus), and California sea lions (CSL) (Zalophus californianus) with and without cardiac disease, and to determine if these biomarkers are useful indicators of cardiac disease in these species. First, existing immunoassays for cTnI and NT-proBNP were successfully validated utilizing species-specific heart lysate spiked serum. Cohorts were defined by histopathology as animals with no evidence of cardiac disease ("control"), with confirmed cardiac disease ("disease"), and with concurrent renal and cardiac disease ("renal") for which serum samples were then analyzed. Serum concentration ranges for cTnI (ng/ml) and NT-proBNP (pmol/L) were determined for control and disease cohorts. There was significantly higher cTnI (P= 0.003) and NT-proBNP (P= 0.004) concentrations in the CSL disease cohort, as well as positive trends in BW, SO, and SSL disease cohorts that did not reach statistical significance. NT-proBNP concentrations were significantly higher in the CSL renal cohort compared with the control (P < 0.001) and disease (P= 0.007) cohorts. These results suggest that cTnI and NT-proBNP may be clinically useful in the antemortem diagnosis of cardiac disease in CSL, and warrant further investigation in BW, SO, and SL.

Social Network and Behavioral Synchrony Influences On Maternal and Infant Cortisol Response.

This study examined the contributions of mothers' social network stability and mother-infant behavioral synchrony on cortisol response in infants and their mothers during separation. The quality and stability of mothers' social network system and mother-infant bond have both been shown to affect infant neuroendocrine response. Yet, no studies have directly addressed how these two forms of social relationships might differentially affect infants' and mothers' neuroendocrine responses during separation. First-time mothers (N = 133) and their 3-month-old infants participated in the study. Maternal social network stability, mother-infant behavioral synchrony, and mother and infant cortisol response during an infant challenge task were assessed. Behavioral synchrony accounted for significant variance in infants' cortisol response, and after adjusting for synchrony, mothers' network stability measures did not explain variance in infant cortisol. Social network stability, but not synchrony, accounted for significant variance in mothers' cortisol response. These results demonstrate that, when mothers and infants experience brief separation, the quality of their bond is associated with a lower stress response for infants; but for mothers, it is the longevity of her social relationships outside of the mother-infant relationship context that is associated with her lower stress response.

Costs and Outcomes of Patients Admitted to the Intensive Care Unit With Cancer.

INTRODUCTION: Cancer is associated with significant health-care expenditure, but few studies have examined the cost of patients with cancer in the intensive care unit (ICU). We aimed to describe the costs and outcomes of patients admitted to the ICU with cancer. METHODS: We conducted a retrospective cohort study of patients admitted between 2011 and 2016 to 2 tertiary-care ICUs. We included patients with a cancer-related most responsible diagnosis using International Classification of Disease, 10th Revision, Canada codes. We compared costs and outcomes of patients having cancer with noncancer controls matched for age, sex, and Elixhauser comorbidity score. We used logistic regression to determine predictors of mortality among patients with cancer. RESULTS: There were 1022 patients with cancer during the study period. Mean age was 63.2 years and 577 (56.5%) were male. Inhospital mortality for all patients with cancer was 24.0%. Total cost per patient was higher for patients with cancer compared to noncancer patients (CAD$57 084 vs CAD$40 730; P < .001) but there were no differences in the cost per day (CAD$2868 vs CAD$2887; P = .76) or ICU cost (CAD$30 495 vs CAD$29 382; P = .42). Among patients with cancer, the cost per day was higher for nonsurvivors (CAD$3477 vs CAD$2677; P < .001). Liver disease (odds ratio [OR]: 2.96; 95% confidence interval [CI]: 1.22-7.81), mechanical ventilation (OR: 1.73; 95% CI: 1.25-2.39), hematologic malignancy (OR: 3.88; 95% CI: 2.31-6.54), and unknown primary site (OR: 2.13; 95% CI: 1.36-3.35) were independently associated with mortality in patients with cancer. CONCLUSION: Patients admitted to the ICU with cancer did not differ in cost per day, ICU cost, or mortality compared to matched noncancer controls. Among patients with cancer, nonsurvivors had significantly higher cost per day compared to survivors. Hematologic and unknown primaries, liver disease, and mechanical ventilation were independently associated with mortality in patients with cancer.

Frailty Is Associated With Decreased Time Spent at Home After Critical Illness: A Population-Based Study.

BACKGROUND: Frailty is characterized by vulnerability to stressors due to an accumulation of multiple functional deficits. Frailty is increasingly recognized as a risk factor for accelerated functional decline, increasing dependency, and risk of mortality. The objective of this study was to examine the association of frailty, at the time of critical care admission, with days alive at home and health care costs post-discharge. METHODS: This retrospective cohort study used linked administrative data (2010-2016) in Ontario, Canada. We identified all patients admitted at the intensive care unit (ICU), aged 19 years and above, assessed using the Resident Assessment Instrument for Home Care (RAI-HC), within 6 months prior to index hospitalization including an ICU stay. Patients were stratified as robust, pre-frail, or frail based on a validated Frailty Index. The primary outcome was days alive at home in the year after admission. Secondary outcomes included mortality, health care-associated costs, ICU interventions, long-term care admissions, and hospital readmissions. RESULTS: Frail patients spent significantly fewer days at home within 1 year of index hospitalization (mean 159 days vs 223 days in robust cohort, P < .001). Mortality was higher among frail patients at 1 year (59.6% in the frail cohort vs 45.9% in robust patients; odds ratio for death 1.59 [1.49-1.69]). Frail patients also had higher rates of long-term care admission within 1 year (30.1% vs 10.6% in robust patients). Total health care-associated costs per person alive were $30 450 higher the year after admission in the frail cohort. CONCLUSIONS: Frailty prior to ICU admission among patients who were eligible for RAI-HC assessment was associated with higher mortality and fewer days spent at home following admission. Frail patients had markedly higher rates of long-term care admission and increased costs per life saved following critical illness. These findings add to the discussion of risk-benefit trade-offs for ICU admission.

Outcomes and Resource Utilization Among Patients Admitted to the Intensive Care Unit Following Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

PURPOSE: Chronic obstructive pulmonary disease (COPD) is a common condition, accounting for a significant number of intensive care unit (ICU) admissions. However, little is known about outcomes and costs among ICU patients admitted with acute exacerbations of COPD (AECOPD). We studied predictors of inhospital mortality and costs of ICU admissions for AECOPD. METHODS: Data were obtained from a prospectively maintained registry from 2 ICUs from 2011 to 2016, including adult patients (age ≥ 18) with an ICU discharge diagnosis of AECOPD. The primary outcome was hospital mortality. Secondary outcomes included ICU length of stay, resource utilization, total hospital costs, and cost per survivor. RESULTS: We included 390 patients, of which 27.2% died in hospital. Independent predictors of inhospital mortality included age (odds ratio [OR]: 1.95, CI: 1.58-2.67) and the presence of clinical frailty (OR: 4.12, CI: 2.26-6.95). The mean total hospital costs were Can$35 059, with a cost per survivor of Can$48 191. Factors associated with increased cost included transfer from an inpatient setting, severity of illness, and previous ICU admission. CONCLUSIONS: Approximately a quarter of patients admitted to ICU with AECOPD died during hospitalization, and these patients accrued significant costs. This study identifies important factors associated with poor outcome in this at-risk population, which has value in risk stratification and patient or family discussions addressing goals of care.

Dynamic borrowing from a single prior data source using the conditional power prior.

The conditional power prior is a popular method to borrow information from a single prior data source. The amount of borrowing is controlled by the power parameter which is fixed before running the new study. However, fixing this parameter before running a new study is often difficult and may be unwise because if the outcomes in the current study are much different from the prior data outcomes, the power parameter cannot be changed to reflect a more appropriate degree of borrowing. On the other hand, treating the power parameter as a random variable to be updated via Bayes theorem may relinquish control over how much to borrow in cases where regulatory oversight recommends a conservative approach.Previous authors have determined the power parameter at the end of the current study based on "stochastic" similarity in the outcomes between the current study and the prior data. In this paper, we introduce some modifications to those methods. First, we determine the power parameter based on similarity between a percentage of the current study outcome data available at an interim look and the prior outcome data. This may limit potential for operational bias resulting from the determination of the power parameter after the current study is complete. Next, we introduce a new measure of similarity between the current (interim) and prior data that limits similarity by a pre-specified clinical margin. The proposed clinical similarity region may be readily understood by clinicians who need to assess when such borrowing is clinically appropriate. Through simulations, we show that our approach has low bias and good power, while reducing type I error rate in areas outside of the "similarity region". An example of a hypothetical medical device study illustrates its potential use in practice.

Characteristics and resource utilization of high-cost users in the intensive care unit: a population-based cohort study.

BACKGROUND: Healthcare expenditure within the intensive care unit (ICU) is costly. A cost reduction strategy may be to target patients accounting for a disproportionate amount of healthcare spending, or high-cost users. This study aims to describe high-cost users in the ICU, including health outcomes and cost patterns. METHODS: We conducted a population-based retrospective cohort study of patients with ICU admissions in Ontario from 2011 to 2018. Patients with total healthcare costs in the year following ICU admission (including the admission itself) in the upper 10th percentile were defined as high-cost users. We compared characteristics and outcomes including length of stay, mortality, disposition, and costs between groups. RESULTS: Among 370,061 patients included, 37,006 were high-cost users. High-cost users were 64.2 years old, 58.3% male, and had more comorbidities (41.2% had ≥3) when likened to non-high cost users (66.1 years old, 57.2% male, 27.9% had ≥3 comorbidities). ICU length of stay was four times greater for high-cost users compared to non-high cost users (22.4 days, 95% confidence interval [CI] 22.0-22.7 days vs. 5.56 days, 95% CI 5.54-5.57 days). High-cost users had lower in-hospital mortality (10.0% vs.14.2%), but increased dispositioning outside of home (77.4% vs. 42.2%) compared to non-high-cost users. Total healthcare costs were five-fold higher for high-cost users ($238,231, 95% CI $237,020-$239,442) compared to non-high-cost users ($45,155, 95% CI $45,046-$45,264). High-cost users accounted for 37.0% of total healthcare costs. CONCLUSION: High-cost users have increased length of stay, lower in-hospital mortality, and higher total healthcare costs when compared to non-high-cost users. Further studies into cost patterns and predictors of high-cost users are necessary to identify methods of decreasing healthcare expenditure.

The SCF Complex Is Essential to Maintain Genome and Chromosome Stability.

The SKP1, CUL1, F-box protein (SCF) complex encompasses a group of 69 SCF E3 ubiquitin ligase complexes that primarily modify protein substrates with poly-ubiquitin chains to target them for proteasomal degradation. These SCF complexes are distinguishable by variable F-box proteins, which determine substrate specificity. Although the function(s) of each individual SCF complex remain largely unknown, those that have been characterized regulate a wide array of cellular processes, including gene transcription and the cell cycle. In this regard, the SCF complex regulates transcription factors that modulate cell signaling and ensures timely degradation of primary cell cycle regulators for accurate replication and segregation of genetic material. SCF complex members are aberrantly expressed in a myriad of cancer types, with altered expression or function of the invariable core SCF components expected to have a greater impact on cancer pathogenesis than that of the F-box proteins. Accordingly, this review describes the normal roles that various SCF complexes have in maintaining genome stability before discussing the impact that aberrant SCF complex expression and/or function have on cancer pathogenesis. Further characterization of the SCF complex functions is essential to identify and develop therapeutic approaches to exploit aberrant SCF complex expression and function.

The Evolutionary Conservation of Escherichia coli Drug Efflux Pumps Supports Physiological Functions.

Bacteria harness an impressive repertoire of resistance mechanisms to evade the inhibitory action of antibiotics. One such mechanism involves efflux pump-mediated extrusion of drugs from the bacterial cell, which significantly contributes to multidrug resistance. Intriguingly, most drug efflux pumps are chromosomally encoded components of the intrinsic antibiotic resistome. In addition, in terms of xenobiotic detoxification, bacterial efflux systems often exhibit significant levels of functional redundancy. Efflux pumps are also considered to be highly conserved; however, the extent of conservation in many bacterial species has not been reported and the majority of genes that encode efflux pumps appear to be dispensable for growth. These observations, in combination with an increasing body of experimental evidence, imply alternative roles in bacterial physiology. Indeed, the ability of efflux pumps to facilitate antibiotic resistance could be a fortuitous by-product of ancient physiological functions. Using Escherichia coli as a model organism, we here evaluated the evolutionary conservation of drug efflux pumps and we provide phylogenetic analysis of the major efflux families. We show the E. coli drug efflux system has remained relatively stable and the majority (∼80%) of pumps are encoded in the core genome. This analysis further supports the importance of drug efflux pumps in E. coli physiology. In this review, we also provide an update on the roles of drug efflux pumps in the detoxification of endogenously synthesized substrates and pH homeostasis. Overall, gaining insight into drug efflux pump conservation, common evolutionary ancestors, and physiological functions could enable strategies to combat these intrinsic and ancient elements.