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Objectives The aim of the study was to provide evidence for, at which vital and laboratory values, increased risk of 7-day mortality in acute adult patients on arrival to an emergency department (ED).Design A population-based cohort study.Setting ED at Odense University Hospital, Denmark.Participants All patients ≥18 years with a first-time contact within the study period, 1 April 2012 to 31 March 2015.Primary and secondary outcome measures Primary outcome was 7-day all-cause mortality.Variables were first recorded vital and laboratory values included in risk stratification scores; respiratory frequency, blood pressure, heart rate, Glasgow Coma Scale, temperature, saturation, creatinine, PaO2, platelet count and bilirubin. The association between values and mortality was described using a restricted cubic spline. A predefined 7-day mortality of 2.5% was chosen as a relevant threshold.Results We included 40 423 patients, 52.5% women, median age 57 (IQR 38–74) years and 7-day mortality 2.8%. Seven-day mortality of 2.5% had thresholds of respiratory frequency 18/min, systolic blood pressure 192 mm Hg, heart rate 102 beats/min, temperature 39.8°C, saturation 98 µmol/L for PaO2 12.3 kPa, platelet count 327×109/L and bilirubin >12 µmol/L.Conclusion Vital values on arrival, outside the normal ranges for the measures, are indicative of increased risk of short-term mortality, and most of the value thresholds are included in the lowest urgency level in triage and risk stratification scoring systems.

Abstract Background Acutely ill patients are a heterogeneous group, and some of these suffer from organ failure. As the prognosis of organ failure improves with early treatment, it is important to identify these patients as early as possible. Most studies on organ failure have been performed in intensive care settings, or on selected groups of patients, where a high prevalence and mortality have been reported. Before patients arrive to the intensive care unit, or the general ward, most of them have passed through the emergency department (ED), where diagnosis and treatment has been initiated. The prevalence and prognosis of acutely ill patients, with organ failure, at arrival have been studied in some selected groups, but methods and results differ. This systematic review aims to identify, summarize, and analyze studies of prevalence and prognosis of new onset organ failure in acutely ill undifferentiated patients, at arrival to hospital. The result of the review will assist physicians working in an ED, when assessing patients’ risk of organ failure and their associated prognosis. Methods The information sources used are electronic databases, PubMed, Cochrane Library, EMBASE, and CINAHL; references in included studies and review articles; and authors’ personal files. One author will perform the title and abstract screening and exclude obviously ineligible studies. By an independent full-text screening, two authors will decide on the eligibility for the remaining studies. Eligible studies will include an unselected group of acutely ill adult patients at arrival to hospital, with one or more organ failures (respiratory, renal, cerebral, circulatory, hepatic, or coagulation failure). Included studies will have assessed the prevalence or prognosis, defined as mortality or ICU transfer, of new onset organ failure. From included studies, bibliographical and study description data, patient characteristics, and data related to prevalence of organ failure and prognosis will be extracted. We will assess risk of bias in included studies using the Quality in Prognosis Studies tool for prognostic studies and the Newcastle-Ottawa Scale for observational studies. We expect heterogeneity and to conduct a qualitative synthesis of the results. If, however, heterogeneity is low, we will conduct a random effects meta-analysis stratified by basic study design. Discussion This review will summarize and analyze studies of prevalence and prognosis of acutely ill patients, with organ failure at arrival to hospital, assist ED physicians assessing the risk of organ failure in unselected patients, and guide recommendations for further research. Systematic review registration PROSPERO CRD42017060871

Abstract Background In order to dispatch ambulances with the correct level of urgency, the dispatch center has to balance the perceived urgency and traffic safety considerations with the available resources. As urgency is not clear in all clinical situations, some high urgency patients may end up with a suboptimal mode of transport. Patients with severe sepsis or septic shock suffer from highly time dependent conditions but they present with a wide range of symptoms, which might be difficult to identify in the dispatch system. The aim of the study is to investigate the modes of prehospital transport among acute admitted patients with sepsis, severe sepsis and septic shock. Methods We included all adult patients (≥15 years) presenting to an acute medical unit at Odense University Hospital with a first-time admission of community-acquired sepsis between September 2010-August 2011. Cases and prehospital ambulance transport were identified by structured manual chart review. In all cases it was registered, whether the ordinary ambulance was assisted by the mobile emergency care unit (MECU), manned by anesthesiologists. Results We included 1,713 patients median age 72 years (IQR 57–81), 793 (46.3%) male, 621 (36.3%) had sepsis, 1,071 (62.5%) severe sepsis, and 21 (1.2%) septic shock. In the group of sepsis patients, 390 (62.8%) arrived without public prehospital transport, 197 (31.7%) were transported by ambulance, and 34 (5.5%) were assisted by MECU. In the group of severe sepsis patients, the same percentage 62.8% arrived without public pre-hospital transport, a lower percentage 28.2% were transported by ambulance, and a larger percentage 9.0% were transported by MECU. Among 21 patients with septic shock, 10 arrived without public pre-hospital transport (47.7%), 7 (33.3%) were transported by ambulance, and 4 (19.0%) by MECU. The 30-day mortality hazard ratio was associated with mode of transport, with the adjusted highest hazard ratio found in the group of MECU transported patients 1.76 (95%Cl 1.16–2.66). Conclusions A substantial proportion of patients with severe sepsis and septic shock arrive to hospital without public prehospital transport or by unspecialized ambulances.

Objectives The aim was to describe population-based incidence and emergency department-based prevalence and 1-year all-cause mortality of patients with new organ failure present at arrival.Design This was a population-based cohort study of all citizens in four municipalities (population of 230 000 adults).Setting Emergency department at Odense University Hospital, Denmark.Participants We included all adult patients who arrived from 1 April 2012 to 31 March 2015.Primary and secondary outcome measures Organ failure was defined as a modified Sequential Organ Failure Assessment score≥2 within six possible organ systems: cerebral, circulatory, renal, respiratory, hepatic and coagulation.The primary outcome was prevalence of organ failure, and secondary outcomes were 0–7 days, 8–30 days and 31–365 days all-cause mortality.Results We identified in total 175 278 contacts, of which 70 399 contacts were further evaluated for organ failure. Fifty-two per cent of these were women, median age 62 (IQR 42–77) years. The incidence of new organ failure was 1342/100 000 person-years, corresponding to 5.2% of all emergency department contacts.The 0–7-day, 8–30-day and 31–365-day mortality was 11.0% (95% CI: 10.2% to 11.8%), 5.6% (95% CI: 5.1% to 6.2%) and 13.2% (95% CI: 12.3% to 14.1%), respectively, if the patient had one or more new organ failures at first contact in the observation period, compared with 1.4% (95% CI: 1.3% to 1.6%), 1.2% (95% CI: 1.1% to 1.3%) and 5.2% (95% CI: 5.0% to 5.4%) for patients without. Seven-day mortality ranged from hepatic failure, 6.5% (95% CI: 4.9% to 8.6%), to cerebral failure, 33.8% (95% CI: 31.0% to 36.8%), the 8–30-day mortality ranged from cerebral failure, 3.9% (95% CI: 2.8% to 5.3%), to hepatic failure, 8.6% (95% CI: 6.6% to 10.8%) and 31–365-day mortality ranged from cerebral failure, 9.3% (95% CI: 7.6% to 11.2%), to renal failure, 18.2% (95% CI: 15.5% to 21.1%).Conclusions The study revealed an incidence of new organ failure at 1342/100 000 person-years and a prevalence of 5.2% of all emergency department contacts. One-year all-cause mortality was 29.8% among organ failure patients.

BackgroundVital signs, i.e. respiratory rate, oxygen saturation, pulse, blood pressure and temperature, are regarded as an essential part of monitoring hospitalized patients. Changes in vital signs prior to clinical deterioration are well documented and early detection of preventable outcomes is key to timely intervention. Despite their role in clinical practice, how to best monitor and interpret them is still unclear.ObjectiveTo evaluate the ability of vital sign trends to predict clinical deterioration in patients hospitalized with acute illness.Data sourcesPubMed, Embase, Cochrane Library and CINAHL were searched in December 2017.Study selectionStudies examining intermittently monitored vital sign trends in acutely ill adult patients on hospital wards and in emergency departments. Outcomes representing clinical deterioration were of interest.Data extractionPerformed separately by two authors using a preformed extraction sheet.ResultsOf 7,366 references screened, only two were eligible for inclusion. Both were retrospective cohort studies without controls. One examined the accuracy of different vital sign trend models using discrete-time survival analysis in 269,999 admissions. One included 44,531 medical admissions examining trend in Vitalpac Early Warning Score weighted vital signs. They stated that vital sign trends increased detection of clinical deterioration. Critical appraisal was performed using evaluation tools. The studies had moderate risk of bias, and a low certainty of evidence. Additionally, four studies examining trends in early warning scores, otherwise eligible for inclusion, were evaluated.ConclusionsThis review illustrates a lack of research in intermittently monitored vital sign trends. The included studies, although heterogeneous and imprecise, indicates an added value of trend analysis. This highlights the need for well-controlled trials to thoroughly assess the research question.

INTRODUCTION:Patients in an emergency department are diverse. Some are more seriously ill than others and some even arrive in multi-organ failure. Knowledge of the prevalence of organ failure and its prognosis in unselected patients is important from a diagnostic, hospital planning, and from a quality evaluation point of view, but is not reported systematically. OBJECTIVES:To analyse the prevalence and prognosis of new onset organ failure in unselected acute patients at arrival to hospital. METHODS:A systematic review of studies of prevalence and prognosis of acutely ill patients with organ failure at arrival to hospital. We searched PubMed, Cochrane Library, Embase and Cinahl, and read references in included studies. Two authors decided independently on study eligibility and extracted data. Results were summarised qualitatively. RESULTS:Four studies were included with a total of 678,960 patients. The number of different organ failures reported in the studies ranged from one to six, and the settings were emergency departments and wards. The definitions of organ failure varied between studies. The prevalence of organ failure was 7%, 14%, 14%, and 23%, and in-hospital mortality was 5%, 11% and 15% respectively. The relative risk of in-hospital mortality for patients with organ failure compared to patients without organ failure varied from 2.58 to 8.65. Numbers of organ failures per 1,000 visits varied from 71 to 256. CONCLUSION:The results of this review indicate that clinicians have good reasons to be alert when a patient arrives to the emergency department; as a state of organ failure seems both frequent and highly severe. However, most studies identified were performed in patients after a diagnosis was established, and only very few studies were performed in unselected patients. SYSTEMATIC REVIEW REGISTRATION NUMBER:PROSPERO: CRD42017060871.

Abstract Impairment of autophagy leads to an accumulation of misfolded proteins and damaged organelles and has been implicated in plethora of human diseases. Loss of autophagy in actively respiring cells has also been shown to trigger metabolic collapse mediated by the depletion of nicotinamide adenine dinucleotide (NAD) pools, resulting in cell death. Here we found that the deficit in the autophagy-NAD axis underpins the loss of viability in cell models of a neurodegenerative lysosomal storage disorder, Niemann-Pick type C1 (NPC1) disease. Defective autophagic flux in NPC1 cells resulted in mitochondrial dysfunction due to impairment of mitophagy, leading to the depletion of both the reduced and oxidised forms of NAD as identified via metabolic profiling. Consequently, exhaustion of the NAD pools triggered mitochondrial depolarisation and apoptotic cell death. Our chemical screening identified two FDA-approved drugs, celecoxib and memantine, as autophagy activators which effectively restored autophagic flux, NAD levels, and cell viability of NPC1 cells. Of biomedical relevance, either pharmacological rescue of the autophagy deficiency or NAD precursor supplementation restored NAD levels and improved the viability of NPC1 patient fibroblasts and induced pluripotent stem cell (iPSC)-derived cortical neurons. Together, our findings identify the autophagy-NAD axis as a mechanism of cell death and a target for therapeutic interventions in NPC1 disease, with a potential relevance to other neurodegenerative disorders.

Abstract Digital pathology has seen a proliferation of deep learning models in recent years, but many models are not readily reusable. To address this challenge, we developed WSInfer: an open-source software ecosystem designed to streamline the sharing and reuse of deep learning models for digital pathology. The increased access to trained models can augment research on the diagnostic, prognostic, and predictive capabilities of digital pathology.

Electron microscopy (EM) images of axons and their ensheathing myelin from both the central and peripheral nervous system are used for assessing myelin formation, degeneration (demyelination) and regeneration (remyelination). The g-ratio is the gold standard measure of assessing myelin thickness and quality, and traditionally is determined from measurements made manually from EM images-a time-consuming endeavour with limited reproducibility. These measurements have also historically neglected the innermost uncompacted myelin sheath, known as the inner tongue. Nonetheless, the inner tongue has been shown to be important for myelin growth and some studies have reported that certain conditions can elicit its enlargement. Ignoring this fact may bias the standard g-ratio analysis, whereas quantifying the uncompacted myelin has the potential to provide novel insights in the myelin field. In this regard, we have developed AimSeg, a bioimage analysis tool for axon, inner tongue and myelin segmentation. Aided by machine learning classifiers trained on transmission EM (TEM) images of tissue undergoing remyelination, AimSeg can be used either as an automated workflow or as a user-assisted segmentation tool. Validation results on TEM data from both healthy and remyelinating samples show good performance in segmenting all three fibre components, with the assisted segmentation showing the potential for further improvement with minimal user intervention. This results in a considerable reduction in time for analysis compared with manual annotation. AimSeg could also be used to build larger, high quality ground truth datasets to train novel deep learning models. Implemented in Fiji, AimSeg can use machine learning classifiers trained in ilastik. This, combined with a user-friendly interface and the ability to quantify uncompacted myelin, makes AimSeg a unique tool to assess myelin growth.

MYC activation can sensitise cells to apoptosis upon glutamine withdrawal. Here the authors show that MYC activation enhances global transcription and translation that creates a metabolic demand, while glutamine limitation causes a metabolic demand and supply imbalance through loss of TCA energetics and thus, sensitises cells to apoptosis.

Technological advancements in biology and microscopy have empowered a transition from bioimaging as an observational method to a quantitative one. However, as biologists are adopting quantitative bioimaging and these experiments become more complex, researchers need additional expertise to carry out this work in a rigorous and reproducible manner. This Essay provides a navigational guide for experimental biologists to aid understanding of quantitative bioimaging from sample preparation through to image acquisition, image analysis, and data interpretation. We discuss the interconnectedness of these steps, and for each, we provide general recommendations, key questions to consider, and links to high-quality open-access resources for further learning. This synthesis of information will empower biologists to plan and execute rigorous quantitative bioimaging experiments efficiently. As bioimaging has moved from an observational method to a quantitative one, additional considerations are needed to carry out this work in a rigorous and reproducible manner. This Essay provides a navigational guide for biologists new to quantitative bioimaging, with recommendations and pointers to open source resources.

Cell wall deficient “L- form” bacteria are of growing medical interest as a possible source of recurrent or persistent infection, largely because of their complete resistance to cell wall active antibiotics such as β-lactams. Antibiotics that specifically kill L-forms would be of potential interest as therapeutics, but also as reagents with which to explore the role of L-forms in models of recurrent infection. To look for specific anti-L-form antibiotics, we screened a library of several hundred FDA-approved drugs and identified compounds highly selective for L-form killing. Among the compounds identified were representatives of two different classes of calcium channel blockers: dihydropyridines, e.g., manidipine; and diphenylmethylpiperazine, e.g., flunarizine. Mode of action studies suggested that both classes of compound work by decreasing membrane fluidity. This leads to a previously recognized phenotype of L-forms in which the cells can continue to enlarge but fail to divide. We identified a considerable degree of variation in the activity of different representatives of the two classes of compounds, suggesting that it may be possible to modify them for use as drugs for L-form-dependent infections.