Optimizing Triage and Hospitalization in Adult General Medical Emergency Patients. The Triage Project

Background: Patients presenting to the emergency department (ED) currently face inacceptable delays in initial treatment, and long, costly hospital stays due to suboptimal initial triage and site-of-care decisions. Accurate ED triage should focus not only on initial treatment priority, but also on prediction of medical risk and nursing needs to improve site-of-care decisions and to simplify early discharge management. Different triage scores have been proposed, such as the Manchester triage system (MTS). Yet, these scores focus only on treatment priority, have suboptimal performance and lack validation in the Swiss health care system. Because the MTS will be introduced into clinical routine at the Kantonsspital Aarau, we propose a large prospective cohort study to optimize initial patient triage. Specifically, the aim of this trial is to derive a three-part triage algorithm to better predict (a) treatment priority; (b) medical risk and thus need for in-hospital treatment; (c) post-acute care needs of patients at the most proximal time point of ED admission. Methods/design: Prospective, observational, multicenter, multi-national cohort study. We will include all consecutive medical patients seeking ED care into this observational registry. There will be no exclusions except for non-adult and non-medical patients. Vital signs will be recorded and left over blood samples will be stored for later batch analysis of blood markers. Upon ED admission, the post-acute care discharge score (PACD) will be recorded. Attending ED physicians will adjudicate triage priority based on all available results at the time of ED discharge to the medical ward. Patients will be reassessed daily during the hospital course for medical stability and readiness for discharge from the nurses and if involved social workers perspective. To assess outcomes, data from electronic medical records will be used and all patients will be contacted 30 days after hospital admission to assess vital and functional status, re-hospitalization, satisfaction with care and quality of life measures. We aim to include between 5000 and 7000 patients over one year of recruitment to derive the three-part triage algorithm. The respective main endpoints were defined as (a) initial triage priority (high vs. low priority) adjudicated by the attending ED physician at ED discharge, (b) adverse 30 day outcome (death or intensive care unit admission) within 30 days following ED admission to assess patients risk and thus need for in-hospital treatment and (c) post acute care needs after hospital discharge, defined as transfer of patients to a post-acute care institution, for early recognition and planning of post-acute care needs. Other outcomes are time to first physician contact, time to initiation of adequate medical therapy, time to social worker involvement, length of hospital stay, reasons fordischarge delays, patient’s satisfaction with care, overall hospital costs and patients care needs after returning home. Discussion: Using a reliable initial triage system for estimating initial treatment priority, need for in-hospital treatment and post-acute care needs is an innovative and persuasive approach for a more targeted and efficient management of medical patients in the ED. The proposed interdisciplinary , multi-national project has unprecedented potential to improve initial triage decisions and optimize resource allocation to the sickest patients from admission to discharge. The algorithms derived in this study will be compared in a later randomized controlled trial against a usual care control group in terms of resource use, length of hospital stay, overall costs and patient’s outcomes in terms of mortality, re-hospitalization, quality of life and satisfaction with care.

Vitamin D time profile based on the contribution of non-genetic and genetic factors in HIV-infected individuals of European ancestry

BACKGROUND Vitamin D deficiency is prevalent in HIV-infected individuals and vitamin D supplementation is proposed according to standard care. This study aimed at characterizing the kinetics of 25(OH)D in a cohort of HIV-infected individuals of European ancestry to better define the influence of genetic and non-genetic factors on 25(OH)D levels. These data were used for the optimization of vitamin D supplementation in order to reach therapeutic targets. METHODS 1,397 25(OH)D plasma levels and relevant clinical information were collected in 664 participants during medical routine follow up visits. They were genotyped for 7 SNPs in 4 genes known to be associated with 25(OH)D levels. 25(OH)D concentrations were analyzed using a population pharmacokinetic approach. The percentage of individuals with 25(OH)D concentrations within the recommended range of 20-40ng/ml during 12 months of follow up and several dosage regimens were evaluated by simulation. RESULTS A one-compartment model with linear absorption and elimination was used to describe 25(OH)D pharmacokinetics, while integrating endogenous baseline plasma concentrations. Covariate analyses confirmed the effect of seasonality, body mass index, smoking habits, the analytical method, darunavir/r and the genetic variant in GC (rs2282679) on 25(OH)D concentrations. 11% of the interindividual variability in 25(OH)D levels was explained by seasonality and other non-genetic covariates and 1% by genetics. The optimal supplementation for severe vitamin D deficient patients was 300000 IU two times per year. CONCLUSIONS This analysis allowed identifying factors associated with 25(OH)D plasma levels in HIV-infected individuals. Improvement of dosage regimen and timing of vitamin D supplementation is proposed based on those results.

Triple isotope (δD, δ17O, δ18O) study on precipitation, drip water and speleothem fluid inclusions for a Western Central European cave (NW Switzerland)

Deuterium (δD) and oxygen (δ18O) isotopes are powerful tracers of the hydrological cycle and have been extensively used for paleoclimate reconstructions as they can provide information on past precipitation, temperature and atmospheric circulation. More recently, the use of δ17O excess derived from precise measurement of δ17O and δ18O gives new and additional insights in tracing the hydrological cycle whereas uncertainties surround this proxy. However, 17O excess could provide additional information on the atmospheric conditions at the moisture source as well as about fractionations associated with transport and site processes. In this paper we trace water stable isotopes (δD,δ17O and δ18O) along their path from precipitation to cave drip water and finally to speleothem fluid inclusions for Milandre cave in northwestern Switzerland. A two year-long daily resolved precipitation isotope record close to the cave site is compared to collected cave drip water (3 months average resolution) and fluid inclusions of modern and Holocene stalagmites. Amount weighted mean δD,δ18O and δ17O are -71.0‰, -9.9‰, -5.2‰ for precipitation, -60.3‰, -8.7‰, -4.6‰ for cave drip water and -61.3‰, -8.3‰, -4.7‰ for recent fluid inclusions respectively. Second order parameters have also been derived in precipitation and drip water and present similar values with 18 per meg for 17O excess whereas d-excess is 1.5‰ more negative in drip water. Furthermore, the atmospheric signal is shifted towards enriched values in the drip water and fluid inclusions (Δ of ~ + 10‰ for δD). The isotopic composition of cave drip water exhibits a weak seasonal signal which is shifted by around 8 - 10 months (groundwater residence time) when compared to the precipitation. Moreover, we carried out the first δ17O measurement in speleothem fluid inclusions, as well as the first comparison of the δ17 O behaviour from the meteoric water to the fluid inclusions entrapment in speleothems. This study on precipitation, drip water and fluid inclusions will be used as a speleothem proxy calibration for Milandre cave in order to reconstruct paleotemperatures and moisture source variations for Western Central Europe.

A legacy of human-induced ecosystem changes: spatial processes drive the taxonomic and functional diversities of testate amoebae in Sphagnum peatlands of the Galápagos

Aim Our aims were to compare the composition of testate amoeba (TA) communities from Santa Cruz Island, Galápagos Archipelago, which are likely in existence only as a result of anthropogenic habitat transformation, with similar naturally occurring communities from northern and southern continental peatlands. Additionally, we aimed at assessing the importance of niche-based and dispersal-based processes in determining community composition and taxonomic and functional diversity. Location The humid highlands of the central island of Santa Cruz, Galápagos Archipelago. Methods We survey the alpha, beta and gamma taxonomic and functional diversities of TA, and the changes in functional traits along a gradient of wet to dry habitats. We compare the TA community composition, abundance and frequency recorded in the insular peatlands with that recorded in continental peatlands of Northern and Southern Hemispheres. We use generalized linear models to determine how environmental conditions influence taxonomic and functional diversity as well as the mean values of functional traits within communities. We finally apply variance partitioning to assess the relative importance of niche- and dispersal-based processes in determining community composition. Results TA communities in Santa Cruz Island were different from their Northern Hemisphere and South American counterparts with most genera considered as characteristic for Northern Hemisphere and South American Sphagnum peatlands missing or very rare in the Galápagos. Functional traits were most correlated with elevation and site topography and alpha functional diversity to the type of material sampled and site topography. Community composition was more strongly correlated with spatial variables than with environmental ones. Main conclusions TA communities of the Sphagnum peatlands of Santa Cruz Island and the mechanisms shaping these communities contrast with Northern Hemisphere and South American peatlands. Soil moisture was not a strong predictor of community composition most likely because rainfall and clouds provide sufficient moisture. Dispersal limitation was more important than environmental filtering because of the isolation of the insular peatlands from continental ones and the young ecological history of these ecosystems.

Identification and characterization of distinct classes of cAMP-pulse-induced genes in Dictyostelium discoideum development

The unicellular amoeba Dictyostelium discoideum embarks on a developmental program upon starvation. During development, extracellular oscillatory cAMP signaling orchestrates the chemotaxis-mediated aggregation of ∼105 amoebae and is required for optimal induction of so-called pulse-induced genes. This requirement for pulsatile CAMP reflects adaptation of the cAMP-receptor-mediated pathways that regulate these genes. Through examination of a collection of pulse-induced genes, we defined two distinct gene classes based on their induction kinetics and the impact of mutations that impair PKA signaling. The first class (represented by D2 and prtA) is highly dependent on PKA signaling, whereas the second class (represented by carA, gpaB, and acaA) is not. Analysis of expression kinetics revealed that these classes are sequentially expressed with the PKA-independent genes peaking in expression before the PKA-dependent class. Experiments with cycloheximide, an inhibitor of translation, demonstrated that the pulse induction of both classes depends on new protein synthesis early in development. carA and gpaB also exhibit pulse-independent, starvation-induced expression which, unlike their pulse induction, was found to be insensitive to cycloheximide added at the outset of starvation. This result indicates that the mechanism of starvation induction pre-exists in growing cells and is distinct from the pulse induction mechanism for these genes. In order to identify cis-acting elements that are critical for induction of carA, we constructed a GFP reporter controlled by a 914-base-pair portion of its promoter and verified that its expression was PKA-independent, pulse-inducible, and developmentally regulated like the endogenous carA gene. By a combination of truncation, internal deletion, and site-directed mutation, we defined several distinct functional elements within the carA promoter, including a 39-bp region required for pulse induction between base pairs -321 and -282 (relative to the transcription start site), a 131-bp region proximal to the start site that is sufficient for starvation induction, and two separate enhancer domains. Identification of factors that interact with these promoter elements and genetic approaches exploiting the GFP reporter described here should help complete our understanding of the mechanisms regulating these genes, including adaptation mechanisms that likely also govern chemotaxis of Dictyostelium and mammalian cells. ^

Proteomic identification and functional characterization of prohibitin 1 and 2 in T cell activation, expansion, survival and disease

Several immune pathologies are the result of aberrant regulation of T lymphocytes. Pronounced T cell proliferation can result in autoimmunity or hematologic malignancy, whereas loss of T cell activity can manifest as immunodeficiency. Thus, there is a critical need to characterize the signal transduction pathways that mediate T cell activation so that novel and rational strategies to detect and effectively control T cell mediated disease can be achieved. ^ The first objective of this dissertation was to identify and characterize novel T cell regulatory proteins that are differentially expressed upon antigen induced activation. Using a functional proteomics approach, two members of the prohibitin (Phb) family of proteins, Phb1 and Phb2, were determined to be upregulated upon activation of primary human T cells. Furthermore, their regulated expression was dependent upon CD3 and CD28 signaling pathways which synergistically increased their expression. In contrast to previous reports of Phb nuclear localization, both proteins were determined to localize to the mitochondrial inner membrane of human T cells. Additionally, novel Phb phosphorylation sites were identified and characterized using mass spectrometry, phosphospecific antibodies and site directed mutagenesis. ^ Prohibitins have been proposed to play important roles in cancer development however the mechanism of action has not been elucidated. The second objective of this dissertation was to define the functional role of Phbs in T cell activity, survival and disease. Compared to levels in normal human T cells, Phb expression was higher in the human tumor T cell line Kit225 and subcellularly localized to the mitochondrion. Ablation of Phb expression by siRNA treatment of Kit225 cells resulted in disruption of mitochondrial membrane potential and significantly enhanced their sensitivity to cell death, suggesting they serve a protective function in T cells. Furthermore, Q-RT-PCR analysis of human oncology cDNA expression libraries indicated the Phbs may represent hematological cancer biomarkers. Indeed, Phb1 and Phb2 protein levels were 6-10 fold higher in peripheral blood mononuclear cells isolated from malignant lymphoma and multiple myeloma patients compared to healthy individuals. ^ Taken together, Phb1 and Phb2 are novel phosphoproteins upregulated during T cell activation and transformation to function in the maintenance of mitochondrial integrity and perhaps energy metabolism, thus representing previously unrecognized intracellular biomarkers and therapeutic targets for regulating T cell activation and hematologic malignancies. ^

Interactions and structural analysis of the zinc -binding motif in decorin, a small leucine rich proteoglycan in extracellular matrix

Decorin, a dermatan/chondroitin sulfate proteoglycan, is ubiquitously distributed in the extracellular matrix (ECM) of mammals. Decorin belongs to the small leucine rich proteoglycan (SLRP) family, a proteoglycan family characterized by a core protein dominated by Leucine Rich Repeat motifs. The decorin core protein appears to mediate the binding of decorin to ECM molecules, such as collagens and fibronectin. It is believed that the interactions of decorin with these ECM molecules contribute to the regulation of ECM assembly, cell adhesions, and cell proliferation. These basic biological processes play critical roles during embryonic development and wound healing and are altered in pathological conditions such as fibrosis and tumorgenesis. ^ In this dissertation, we discover that decorin core protein can bind to Zn2+ ions with high affinity. Zinc is an essential trace element in mammals. Zn2+ ions play a catalytic role in the activation of many enzymes and a structural role in the stabilization of protein conformation. By examining purified recombinant decorin and its core protein fragments for Zn2+ binding activity using Zn2+-chelating column chromatography and Zn2+-equilibrium dialysis approaches, we have located the Zn2+ binding domain to the N-terminal sequence of the decorin core protein. The decorin N-terminal domain appears to contain two Zn2+ binding sites with similar high binding affinity. The sequence of the decorin N-terminal domain does not resemble any other reported zinc-binding motifs and, therefore, represents a novel Zn 2+ binding motif. By investigating the influence of Zn2+ ions on decorin binding interactions, we found a novel Zn2+ dependent interaction with fibrinogen, the major plasma protein in blood clots. Furthermore, a recombinant peptide (MD4) consisting of a 41 amino acid sequence of mouse decorin N-terminal domain can prolong thrombin induced fibrinogen/fibrin clot formation. This suggests that in the presence of Zn2+ the decorin N-terminal domain has an anticoagulation activity. The changed Zn2+-binding activities of the truncated MD4 peptides and site-directed mutagenesis generated mutant peptides revealed that the functional MD4 peptide might contain both a structural zinc-binding site in the cysteine cluster region and a catalytic zinc site that could be created by the flanking sequences of the cysteine cluster region. A model of a loop-like structure for MD4 peptide is proposed. ^

(Table 1) Sr, Nd, and Pb isotopic composition of ODP Leg 129 basalts

Basaltic rocks recovered from three drill sites in the western Pacific during Ocean Drilling Program Leg 129 have fairly distinct Sr, Nd, and Pb isotopic compositions. The Cretaceous alkali olivine dolerites from Site 800 in the northern part of Pigafetta Basin have fairly low 87Sr/86Sri (0.70292-0.70320) and 143Nd/144Ndi (0.51277-0.51281) and high present-day Pb isotopic ratios (206Pb/204Pb = 20.53-21.45; 207Pb/204Pb = 15.70-15.77; 208Pb/204Pb = 40.02-40.68). The Middle Jurassic tholeiites from Site 801 in the southern part of the basin have low 87Sr/86Sri (0.70237-0.70248), high 143Nd/144Ndi (0.51298-0.51322), and moderate present-day Pb isotopic ratios (206Pb/204Pb = 18.20-19.12; 207Pb/204Pb = 15.47-15.60; 208Pb/204Pb = 37.56-38.18); isotopic compositions of the alkali olivine basalts overlying the tholeiites fall between those of the tholeiites and Site 800 dolerites. The Cretaceous tholeiites from Site 802 in the East Mariana Basin have high 87Sr/86Sri (0.70360-0.70372), fairly low 143Nd/144Ndi (0.51277-0.51280), and fairly low and homogeneous present-day Pb isotopic ratios (206Pb/204Pb = 18.37-18.39; 207Pb/204Pb = 15.49-15.51; 208Pb/204Pb = 38.34-38.39). Isotopic compositions of Site 801 tholeiites are indistinguishable from those of modern mid-ocean ridge basalts, consistent with the proposal that these tholeiites are a part of the oldest Pacific crust. The diverse isotopic compositions of the younger basalts appear to be the result of Jurassic Pacific plate migration over the geologically anomalous south-central Pacific region, wherein they acquired their distinct isotopic compositions. The anomalous region was volcanically more active during the Cretaceous than at present.

X-ray fluorescence (XRF) scannings and grain size analysis at sites in the Gulf of Cádiz

Contourites in the Gulf of Cádiz preserve a unique archive of Mediterranean Outflow Water (MOW) variability over the past 5.3 Ma. In our study we investigate the potential of geochemical data obtained by XRF scanning to decipher bottom current processes and paleoclimatic evolution at two different sites drilled through contourite deposits in the northern Gulf of Cadiz: Site U1387, which is bathed by the upper MOW core, and Site U1389, located more proximal to the Straits of Gibraltar. The lack of major downslope transport at both locations during the Pleistocene makes them ideal locations for the purpose of our study. The results indicate that the Zr/Al ratio, representing the relative enrichment of heavy minerals (zircon) over less dense alumosilicates under strong bottom current flow, is the most useful indicator for a semi-quantitative assessment of current strength. While most elements are biased by current-related processes, the bromine record, representing organic content, preserves the most pristine climate signal rather independent of grain size changes. Hence, Br can be used for chronostratigraphy and site-to-site correlation in addition to stable isotope stratigraphy. Based on these findings we reconstructed MOW variability for Marine Isotope Stages 1-5 using the Zr/Al ratio from Site U1387. The results reveal abrupt, millennial-scale variations of MOW strength during Greenland Stadials (GS) and Interstadials (GI) with strong MOW during GS and glacial Terminations and a complex behavior during Heinrich Stadials. Millennial-scale variability persisting during periods of poorly expressed GS/GI cyclicities implies a strong internal oscillation of the Mediterranean/North Atlantic climate system.

Radiochemistry at DSDP Leg 54 and 70 Holes

Use of the hydraulic piston corer during DSDP Leg 70 in the Galapagos mounds area allowed recovery of an undisturbed sedimentary sequence down to the basement. It thus became possible to establish the chronology of different events. Several holes on and off the mounds were studied, using uranium series disequilibrium methods of age determination and oxygen isotope stratigraphy. The following sequence was thereby established: 1) From 600,000 to 300,000 years ago there was normal pelagic sedimentation, with an injection of uranium-rich solution, probably of hydrothermal origin, between 400,000 and 300,000 years ago. 2) From 300,000 to 90,000 years ago, nontronitic clay formed, replacing a pre-existing sediment. 3) From 60,000 to 20,000 years ago, manganese oxide deposits formed, probably also replacing pre-existing sediments. 4) About 19,000 years ago there occurred a uranium injection from seawater, attributed to the end of the hydrothermal circulation. In some holes, especially Hole 424, Leg 54, younger manganese oxides have been found, indicating that some mounds may be presently active.

Planktonic foraminifera at DSDP Holes 72-516 and 72-518

Quantitative analysis was performed on the Quaternary planktonic foraminiferal fauna from Site 516, near the crest of the Rio Grande Rise, and Site 518, on the lower western flank of the Rise. From Hole 516, 46 samples were taken, and from Hole 518, 80 samples were taken. The mean interval between samples is 20 to 25 cm. About 50 species of Quaternary and Pliocene planktonic foraminifers were identified. Quaternary sediments, dated by the initial evolutionary appearance of Globorotalia truncatulinoides and other criteria, have thickness, of 9.8 m in Hole 516 and 16 m in Hole 518. The Globorotalia truncatulinoides Zone is subdivided into four subzones or biostratigraphic horizons (from lower to upper): (1) Globorotalia crassaformis viola, (2) Globorotalia crassaformis hessi, (3) Globigerina calida calida, and (4) Globigerinoides ruber (pink). Thickness of these horizons in Hole 516 establishes the age of the boundaries between them as 1.47, 0.81, and 0.28 Ma, respectively. All the Quaternary planktonic foraminiferal complexes sampled are subtropical. The region of the Rio Grande Rise, therefore, has been within the southern subtropical gyre continuously for the last 2 Ma. The average annual surface water temperatures were reconstructed for the Quaternary at both sites. A micropaleontologic method for the paleotemperature analysis of the thanatocoenosis registers an average Quaternary temperature of 21.2°C at Site 516 and 21.7°C at Site 518. The temperature fluctuations increase up to 3.5°C during the accumulation of the two last horizons (since 0.81 Ma). Temperature peaks are tentatively compared with oxygen isotopic stages and with continental glaciations. Levels at which planktonic foraminiferal species disappear correspond to coldwater intervals. In the Quaternary of Site 518, some layers show signs of dissolution. Corrosive to CaCO3, the northward flow of Antarctic Bottom Water through the Vema Channel increases during the cold periods. Site 518 has two layers of redeposited foraminiferal sand with Pliocene foraminifers. The average rate of the Quaternary sedimentation in Hole 516 is 0.52 cm per thousand years, and in Hole 518 it is 0.84 cm per thousand years.

Stable carbon and oxygen isotope ratios of Paleogene planktonic foraminifera from the Maud Rise

The oxygen and carbon isotopic composition has been measured for numerous Paleogene planktonic foraminifer species from Maud Rise, Weddell Sea (ODP Sites 689 and 690), the first such results from the Antarctic. The results provide information about large-scale changes in the evolution of temperatures, seasonally, and structure of the upper water column prior to the development of a significant Antarctic cryosphere. The early Paleocene was marked by cooler surface-water conditions compared to the Cretaceous and possibly a less well developed thermocline. The late Paleocene and early Eocene saw the expansion of the thermocline as Antarctic surface waters became warm-temperate to subtropical. The late Paleocene to early Eocene thermal maximum was punctuated by two brief excursions during which time the entire Antarctic water column warmed and the meridional temperature gradient was reduced. The first of these excursions occurred at the Paleocene/Eocene boundary, in association with a major extinction in deep sea benthic foraminifers. The second excursion occurred within the early Eocene at ~54.0 Ma. These excursions are of global importance and represent the warmest intervals of the entire Cenozoic. The excursions were associated with fundamental changes in deep-water circulation and global heat transport. The thermal maximum of the early Eocene ended with the initiation of a long-term cooling trend at 52.0 Ma. This cooling trend was associated with reduced seasonality, and diminished structure and/or duration of the seasonal thermocline. The cooling trend was punctuated by three major cooling steps at 43.0, 40.0, and -36.0 Ma.

Middle Miocene to recent sedimentological record of ODP sites 177-1088 and 177-1092

During Leg 177 of the Ocean Drilling Program (ODP), well-preserved Middle Miocene to Pleistocene carbonate-rich sediment records were recovered on a north-south transect through the south-eastern Atlantic sector of the Southern Ocean at Site 1088 on the Agulhas Ridge and Site 1092 on Meteor Rise. Both sites were dominated by the deposition of calcareous nannofossil oozes through the Miocene, indicating low biological productivity in warm to temperate surface waters. A continuous increase in the proportions of foraminifera since the latest Miocene (6.5 Ma) points to enhanced nutrient supply, possibly related to the global 'biogenic bloom' event across the Miocene-Pliocene boundary. Since the Late Pliocene, different styles of biological productivity developed between the sites. Enhanced deposition of biosiliceous constituents at the southern Site 1092, particularly in the Early Pleistocene, is consistent with the formation of the Circum-Antarctic Opal Belt since 2.5 Ma in a setting near the Polar Front, whereas carbonate deposition still prevailed at the northern Site 1088 situated near the Subtropical Front. Clay-mineral tracers of water-mass advection together with the pattern of sedimentation rates and hiatuses reflect distinct pulses in the development of regional ocean circulation between 14 and 12 Ma, around 8 Ma and since 2.8 Ma. These pulses can be related to Antarctic ice-sheet extension that mediates the production and flow of southern source water, and stepwise increases in North Atlantic Deep Water production that drives global conveyor circulation. At Site 1088, illite chemistry and silt/clay ratios of the terrigenous sediment fraction reflect the history of terrestrial climate in southern Africa, with humid conditions prior to the Early Late Miocene (9.7 Ma), followed by a dry episode until 7.7 Ma. The latest Miocene and Early Pliocene were characterized by a humid episode until modern aridity was established in the Late Pliocene between 4.0 and 2.8 Ma. These climate changes were related to the latitudinal migration of climate belts in response to tectonically caused reorganizations in atmospheric and ocean circulation.