Complement protein C3a enhances adaptive immune responses towards FVIII products.

The most serious complication in the treatment of hemophilia A (HA) is the development of factor (F)VIII inhibitors or antidrug antibodies (ADA) occurring in 25-35% of patients with severe HA. The immunological mechanisms underlying the development of ADA against FVIII products have not been completely understood yet. Immunological danger signals associated with events such as infection or surgery have been suggested to play a critical role. In previous studies, we demonstrated that plasma-derived (pd)FVIII but not recombinant (r)FVIII can activate human monocyte-derived dendritic cells (DC) in a danger signal-dependent manner, which subsequently mediate the proliferation of autologous CD4+ T cells. In this study, we investigated the ability of plasma components, naturally present in pdFVIII products, to mediate T-cell responses. In fact, we show that addition of plasma to rFVIII plus lipopolysaccharide (LPS)-stimulated DC induces proliferation of autologous CD4+ T cells. Interestingly, although DC pulsed with LPS plus plasma induce T-cell proliferation upon co-culture, the addition of FVIII significantly increases the number of proliferating as well as FVIII-specific CD4+ T cells. Total proliferating CD4+ T cells and FVIII-specific subsets were identified mainly as central memory T cells. Experiments using blocking antibodies and receptor antagonists revealed that the complement proteins C3a and, to a lesser extent, C5a are critically involved in these LPS-mediated T-cell responses. Collectively, our results indicate that complement proteins are potent drivers of T-cell responses to FVIII. Data presented provide a model how event-related substitution of FVIII in HA patients might contribute to inhibitor development.

Nivolumab in Advanced Hepatocellular Carcinoma: Safety Profile and Select Treatment-Related Adverse Events From the CheckMate 040 Study.

BACKGROUND: CheckMate 040 assessed the efficacy and safety of nivolumab in patients with advanced hepatocellular carcinoma (HCC). Understanding the safety profile of nivolumab is needed to support the management of treatment-related adverse events (TRAEs). This analysis assessed the safety of nivolumab monotherapy in the phase I/II, open-label CheckMate 040 study. MATERIALS AND METHODS: Select TRAEs (sTRAEs; TRAEs with potential immunologic etiology requiring more frequent monitoring) occurring between first dose and 30 days after last dose were analyzed in patients in the dose-escalation and -expansion phases. Time to onset (TTO), time to resolution (TTR), and recurrence of sTRAEs were assessed, and the outcome of treatment with immune-modulating medication (IMM) was evaluated. RESULTS: The analysis included 262 patients. The most common sTRAE was skin (35.5%), followed by gastrointestinal (14.5%) and hepatic (14.1%) events; the majority were grade 1/2, with 10.7% of patients experiencing grade 3/4 events. One patient had grade 5 pneumonitis. Median (range) TTO ranged from 3.6 (0.1-59.9) weeks for skin sTRAEs to 47.6 (47.1-48.0) weeks for renal sTRAEs. Overall, 68% of sTRAEs resolved, with median (range) TTR ranging from 3.7 (0.1-123.3+) weeks for gastrointestinal sTRAEs to 28.4 (0.1-79.1) weeks for endocrine sTRAEs. Most gastrointestinal and all hepatic events resolved with treatment in accordance with established toxicity management algorithms. In 57 patients (40%), sTRAEs were managed with IMM. Reoccurrence of sTRAEs was uncommon following rechallenge with nivolumab. CONCLUSION: Nivolumab demonstrated a manageable safety profile in this analysis of patients with advanced HCC. A majority of sTRAEs resolved with treatment. IMPLICATIONS FOR PRACTICE: Nivolumab is a viable treatment option for patients with previously treated advanced hepatocellular carcinoma as it has demonstrated durable tumor responses and promising survival. Nivolumab has a manageable safety profile. The most common select treatment-related adverse events (sTRAEs) in this analysis were skin related (35%). Gastrointestinal and hepatic sTRAEs were observed in approximately 14% of patients. The majority of sTRAEs resolved (68%). Safety events are easier to manage if addressed early. Patient education on signs and symptoms to watch out for and the importance of early reporting and consultation should be emphasized.

Retrospective cohort study comparing the risk of severe hepatotoxicity in hospitalized patients treated with echinocandins for invasive candidiasis in the presence of confounding by indication.

BACKGROUND: To compare the risk of severe hepatotoxicity with anidulafungin versus caspofungin and micafungin in hospitalized adults. METHODS: This retrospective cohort study combined data from two large US- based hospital electronic medical record databases. Severe hepatotoxicity was a Grade ≥ 3 liver function test (LFT) post-echinocandin initiation. Adjusted incidence rate ratios (IRRs) were estimated for anidulafungin versus caspofungin and micafungin, overall and in patients with normal baseline LFT (Grade 0). RESULTS: Treatments included anidulafungin (n = 1700), caspofungin (n = 4431), or micafungin (n = 6547). The proportions with LFT Grade ≥ 3 pre-echinocandin initiation were: anidulafungin 40.4% versus caspofungin 25.9% (p <  0.001) and micafungin 25.6% (p <  0.001). Rates of severe underlying diseases or comorbidities were: critical care admissions: 75.3% versus 52.6 and 48.6%; and organ failures: 69.4% versus 46.7 and 51.5%. Adjusted IRRs of severe hepatotoxicity for anidulafungin versus caspofungin and micafungin were 1.43 (p = 0.002) and 1.19 (p = 0.183) overall, and 0.88 (P = 0.773) and 0.97 (P = 0.945) for normal baseline LFT, respectively. CONCLUSIONS: Accounting for confounders, severe hepatotoxicity risk was not significantly different across echinocandins in this real-world head-to-head study. Anidulafungin was used more frequently in patients with more comorbidities. Those with normal baseline LFT (least susceptible to confounding by indication), showed no elevated hepatotoxicity risk for anidulafungin.

From source to sink: part 1-characterization and Lagrangian tracking of riverine microplastics in the Mediterranean Basin.

The Mediterranean Sea is one of the most critically polluted areas due to its semi-enclosed structure and its highly anthropized shoreline. Rivers are significant vectors for pollutant transfers from the continental to the marine environment. In this context, a 3D Lagrangian simulation of the dispersion of riverine microplastics (MPs) was performed, which included the application of a recently developed model that reassessed the MP fluxes discharged by rivers. MP physical properties from river samples were further investigated to approximate vertical displacement in modeled ocean currents. The use of a high-resolution circulation model, integrating Stokes drift, turbulent diffusion, and MP sinking and rising velocities, enabled us to establish stock balances. Our simulation suggested that 65% of river inputs may be made of floating MPs drifting in the surface layer and 35% of dense MPs sinking to deeper layers. The Eastern Mediterranean tends to accumulate floating MPs, primarily originating from the Western Mediterranean Basin, where major river sources are concentrated. After 2 years of simulation, modeled stranding sequestered 90% of the MP inputs, indicating relatively short average residence times from a few days to months at most for particles at sea. Although spatial distribution patterns stabilized after this period and a steady state may have been approached, the surface concentrations we modeled generally remained below field observations. This suggested either an underestimation of sources (rivers and unaccounted sources), by a factor of 6 at most, or an overestimation of MP withdrawal through stranding, to be reduced from 90 to around 60% or less if unaccounted sinks were considered.

From source to sink: part 2-seasonal dispersion of microplastics discharged in the NW Mediterranean Sea by the Rhone River in southern France.

As the largest individual contributor of freshwater inflow to the basin, the Rhone River is likely to be one of the main sources of microplastics (MPs) to the Mediterranean Sea. In order to predict the fate of MPs discharged by the Rhone River, an innovative 3D Lagrangian dispersion of its particles associated with vertical velocities was modeled in Mediterranean ocean currents. Through winter and summer scenarios, the seasonal variability of transfers and the corresponding accumulation areas were depicted in the Northwestern Basin according to hydrodynamic conditions on the continental shelf of the Gulf of Lion and to the frontal dynamics from the Pyrenees to the North Balearic fronts. Our results indicated that MP transfers were driven by mesoscale and sub-mesoscale structures, resulting in steep concentration gradients across fronts during summer, while winter energetic mixing favored a more efficient and homogeneous spreading. After a year of drift, high MP retention (up to 50%) occurred in the coastal zone of the Gulf of Lion near the river mouth, with a large contribution of sinking MPs and an increase in stranding during the highest freshwater inflows of the winter season. Conversely, up to 60% of the floating MPs were exported to the Algerian Basin and then to the Eastern Mediterranean. This west-to-east transfer led to significant stranding on the islands, prevailing on the northern coasts of the Balearic Islands in winter (6% of floating inputs) and on the western coasts of Corsica and Sardinia in summer (13%). The southern Mediterranean coasts, from Algeria to Tunisia, represented also a major sink for floating debris with stranding ranging from 9 to 35% of MPs discharged in winter and in summer, respectively. We estimated that 3.5 to 5 t of the Rhone MPs remained in the surface layer at the end of the year, with high concentrations in the Ionian Sea.

Standardization of monitoring data reassesses spatial distribution of aquatic microplastics concentrations worldwide.

Microplastics are found in continental and oceanic waters worldwide, but their spatial distribution shows an intricate pattern. Their driving factors remain difficult to identify and widely discussed due to insufficient and unstandardized monitoring data. Here, based on in situ experiments and hundreds of river samples from the Qinghai-Tibet Plateau, we formulate a model to standardize aquatic microplastic measurements. The model was applied to existing data on a global scale. These data are standardized to a 20 µm mesh size, resulting in a new spatial distribution of aquatic microplastic densities, with average concentrations of 554.93 ± 1352.42 items/m3 in Europe, 2558.90 ± 4799.62 in North America and 1741.94 ± 3225.09 in Asia. Excessive contaminations (microplastic concentration > 104 items/m3) are in the Yangtze River, the Charleston Harbor Estuary, the Bodega Bay and the Winyah Bay. We show that, based on these standardized concentrations, new driving factors could be used to predict the global or regional microplastic distribution in continental waters, such as the Human Development Index with a correlation of 75.86% on a global scale, the nighttime lights with a correlation of 37.26 ± 0.30% in Europe and 39.02 ± 0.54% in Asia, and the Mismanagement Plastic Waste with a correlation of 61.21 ± 19.86% in North America. Mapping standardized concentrations of aquatic microplastics enables a better comparison of contamination levels between regions and reveals more accurate hotspots to better adapt remediation efforts and future plastic pollution scenarios.

Contribution of mechanoreceptors to spinal cord injury-induced mechanical allodynia.

ABSTRACT: Evidence from previous studies supports the concept that spinal cord injury (SCI)-induced neuropathic pain (NP) has its neural roots in the peripheral nervous system. There is uncertainty about how and to which degree mechanoreceptors contribute. Sensorimotor activation-based interventions (eg, treadmill training) have been shown to reduce NP after experimental SCI, suggesting transmission of pain-alleviating signals through mechanoreceptors. The aim of the present study was to understand the contribution of mechanoreceptors with respect to mechanical allodynia in a moderate mouse contusion SCI model. After genetic ablation of tropomyosin receptor kinase B expressing mechanoreceptors before SCI, mechanical allodynia was reduced. The identical genetic ablation after SCI did not yield any change in pain behavior. Peptidergic nociceptor sprouting into lamina III/IV below injury level as a consequence of SCI was not altered by either mechanoreceptor ablation. However, skin-nerve preparations of contusion SCI mice 7 days after injury yielded hyperexcitability in nociceptors, not in mechanoreceptors, which makes a substantial direct contribution of mechanoreceptors to NP maintenance unlikely. Complementing animal data, quantitative sensory testing in human SCI subjects indicated reduced mechanical pain thresholds, whereas the mechanical detection threshold was not altered. Taken together, early mechanoreceptor ablation modulates pain behavior, most likely through indirect mechanisms. Hyperexcitable nociceptors seem to be the main drivers of SCI-induced NP. Future studies need to focus on injury-derived factors triggering early-onset nociceptor hyperexcitability, which could serve as targets for more effective therapeutic interventions.

Barau's petrel, Pterodroma baraui, as a bioindicator of plastic pollution in the South-West Indian Ocean: A multifaceted approach.

Marine plastic pollution is well described by bioindicator species in temperate and polar regions but remains understudied in tropical oceans. We addressed this gap by evaluating the seabird Barau's petrel as bioindicator of plastic pollution in the South-West Indian Ocean. We conducted a multifaceted approach including necropsies of birds to quantify plastic ingestion; GPS tracking of breeding adults to identify their foraging areas; manta trawling of plastic debris to measure plastic pollution at sea and modelling of plastic dispersal. We developed a spatial risk index of seabird exposure to plastic ingestion. Seventy-one percent of the analysed birds had ingested plastic. GPS tracking coupled with manta trawling and dispersal modelling show that adults consistently foraged at places with high level of plastic concentration. The highest ingestion risk occurred in the northwest of Reunion Island and at latitude 30°S. Our findings confirm that Barau's petrel is a reliable bioindicator of plastic pollution in the region.

RUNX1 interacts with lncRNA SMANTIS to regulate monocytic cell functions.

Monocytes, the circulating macrophage precursors, contribute to diseases like atherosclerosis and asthma. Long non-coding RNAs (lncRNAs) have been shown to modulate the phenotype and inflammatory capacity of monocytes. We previously discovered the lncRNA SMANTIS, which contributes to cellular phenotype expression by controlling BRG1 in mesenchymal cells. Here, we report that SMANTIS is particularly highly expressed in monocytes and lost during differentiation into macrophages. Moreover, different types of myeloid leukemia presented specific SMANTIS expression patterns. Interaction studies revealed that SMANTIS binds RUNX1, a transcription factor frequently mutated in AML, primarily through its Alu-element on the RUNT domain. RNA-seq after CRISPR/Cas9-mediated deletion of SMANTIS or RUNX1 revealed an association with cell adhesion and both limited the monocyte adhesion to endothelial cells. Mechanistically, SMANTIS KO reduced RUNX1 genomic binding and altered the interaction of RUNX1 with EP300 and CBFB. Collectively, SMANTIS interacts with RUNX1 and attenuates monocyte adhesion, which might limit monocyte vascular egress.

Trapped microplastics within vertical redeposited sediment: Experimental study simulating lake and channeled river systems during resuspension events.

Plastic waste and its fragments (microplastics; <5 mm) have been observed in almost all types of environments. However, the mechanisms underlying the flow and transport processes of plastics are unknown. This is particularly valid for river sediments, where complex interactions occur between particles and influence their vertical and horizontal distribution patterns. In this study, we investigated the vertical redistribution of 14 pristine microplastics (MPs) with different densities, sizes, and shapes within disturbed sediment without lateral transport (i.e., low-velocity flow). MPs were spiked into sediments (height: 8 cm) in a column with a height of 1 m (diameter: 6 cm) filled to the top with water. The sediment was perturbed by turning the column upside-down to simulate remobilization and the subsequent deposition of sediment. After the complete sedimentation of the particles, the water column was filtered and the sediment was cut into vertical sections. MPs were then extracted from the sediment using sieves and a density separation method, and were counted under a stereomicroscope. Low-density polymers were mainly recovered in the water column and at the surface of the sediment, whereas high-density polymers were found within all sediment sections. The vertical distribution of high-density polymers changes primarily with the sediment grain size. The distribution of each polymer type changes depending on the size and/or shape of the particles with complex interactions. The observed distributions were compared with the expected distributions based only on the vertical velocity formulas. Overall, the formulas used did not explain the sedimentation of a portion of low-density polymers and predicted a lower distribution in the sediment than those observed in the experiment. In conclusion, this study highlights the importance of considering MPs as multi-dimensional particles and provides clues to understand their fate in low-velocity flow systems, considering that they undergo scavenging in sediments.

CAR-Ts redirected against the Thomsen-Friedenreich antigen CD176 mediate specific elimination of malignant cells from leukemia and solid tumors.

Introduction: Chimeric antigen receptor-engineered T cells (CAR-Ts) are investigated in various clinical trials for the treatment of cancer entities beyond hematologic malignancies. A major hurdle is the identification of a target antigen with high expression on the tumor but no expression on healthy cells, since "on-target/off-tumor" cytotoxicity is usually intolerable. Approximately 90% of carcinomas and leukemias are positive for the Thomsen-Friedenreich carbohydrate antigen CD176, which is associated with tumor progression, metastasis and therapy resistance. In contrast, CD176 is not accessible for ligand binding on healthy cells due to prolongation by carbohydrate chains or sialylation. Thus, no "on-target/off-tumor" cytotoxicity and low probability of antigen escape is expected for corresponding CD176-CAR-Ts. Methods: Using the anti-CD176 monoclonal antibody (mAb) Nemod-TF2, the presence of CD176 was evaluated on multiple healthy or cancerous tissues and cells. To target CD176, we generated two different 2nd generation CD176-CAR constructs differing in spacer length. Their specificity for CD176 was tested in reporter cells as well as primary CD8+ T cells upon co-cultivation with CD176+ tumor cell lines as models for CD176+ blood and solid cancer entities, as well as after unmasking CD176 on healthy cells by vibrio cholerae neuraminidase (VCN) treatment. Following that, both CD176-CARs were thoroughly examined for their ability to initiate target-specific T-cell signaling and activation, cytokine release, as well as cytotoxicity. Results: Specific expression of CD176 was detected on primary tumor tissues as well as on cell lines from corresponding blood and solid cancer entities. CD176-CARs mediated T-cell signaling (NF-κB activation) and T-cell activation (CD69, CD137 expression) upon recognition of CD176+ cancer cell lines and unmasked CD176, whereby a short spacer enabled superior target recognition. Importantly, they also released effector molecules (e.g. interferon-γ, granzyme B and perforin), mediated cytotoxicity against CD176+ cancer cells, and maintained functionality upon repetitive antigen stimulation. Here, CD176L-CAR-Ts exhibited slightly higher proliferation and mediator-release capacities. Since both CD176-CAR-Ts did not react towards CD176- control cells, their response proved to be target-specific. Discussion: Genetically engineered CD176-CAR-Ts specifically recognize CD176 which is widely expressed on cancer cells. Since CD176 is masked on most healthy cells, this antigen and the corresponding CAR-Ts represent a promising approach for the treatment of various blood and solid cancers while avoiding "on-target/off-tumor" cytotoxicity.

Response to Comment on "The missing ocean plastic sink: Gone with the rivers".

Mai et al. are mistaken in their assertions that we incorrectly calculated the residence time for floating microplastic stock at the ocean surface, and that most of our results are not novel. Their claim that our field-measured data and methods were not rigorous is wrong, as shown by a more careful consideration of what was done.

Electroosmotic Flow Induced Lift Forces on Polymer Chains in Nanochannels.

A major objective of research in nanofluidics is to achieve better selectivity in manipulating the fluxes of nano-objects and in particular of biopolymers. Numerical simulations allow one to better understand the physical mechanisms at play in such situations. We performed hybrid mesoscale simulations to investigate the properties of polymers under flows in slit pores at the nanoscale. We use multiparticle collision dynamics, an algorithm that includes hydrodynamics and thermal fluctuations, to investigate the properties of fully flexible and stiff polymers under several types of flow, showing that Poiseuille flows and electroosmotic flows can lead to quantitatively and qualitatively different behaviors of the chain. In particular, a counterintuitive phenomenon occurs in the presence of an electroosmotic flow: When the monomers are attracted by the solid surfaces through van der Waals forces, shear-induced forces lead to a stronger repulsion of the polymers from these surfaces. Such focusing of the chain in the middle of the channel increases its flowing velocity, a phenomenon that may be exploited to separate different types of polymers.

The missing ocean plastic sink: Gone with the rivers.

Plastic floating at the ocean surface, estimated at tens to hundreds of thousands of metric tons, represents only a small fraction of the estimated several million metric tons annually discharged by rivers. Such an imbalance promoted the search for a missing plastic sink that could explain the rapid removal of river-sourced plastics from the ocean surface. On the basis of an in-depth statistical reanalysis of updated data on microplastics-a size fraction for which both ocean and river sampling rely on equal techniques-we demonstrate that current river flux assessments are overestimated by two to three orders of magnitude. Accordingly, the average residence time of microplastics at the ocean surface rises from a few days to several years, strongly reducing the theoretical need for a missing sink.

Less Is More: Novel Hepatocyte-Targeted siRNA Conjugates for Treatment of Liver-Related Disorders.

N-acetyl-galactosamine (GalNAc) conjugation enhances liver specificity for therapeutic oligonucleotides. Here we report on a novel design with improved activity and stability compared with a triantennary design. We applied a versatile monovalent serinol-GalNAc conjugation strategy. First, 1-4 serial serinol-linked GalNAc units were conjugated to terminal positions of small interfering RNA (siRNA) molecules. In primary hepatocytes, 5' antisense GalNAc conjugates were inactive, whereas 3' antisense and 3' or 5' sense conjugates displayed low activity for single GalNAc units, while 2-4 serial GalNAc conjugates were all equally potent. In mice, 5' sense conjugates with 2-4 serial GalNAc units were all as potent as a triantennary GalNAc control (1 mg/kg). Second, increased spacing between two serial 5' sense-conjugated GalNAc units did not affect in vitro activity. Finally, two single GalNAc units were positioned at opposite ends of the sense strand. A single dose (0.3 mg/kg) of this novel conjugate in mice showed a 3-fold reduction of serum target protein level at day 7 and 4-fold lower serum level at day 27, relative to an equimolar dose of a triantennary GalNAc conjugate of the same siRNA. Improved tritosome stability (by liquid chromatography-mass spectrometry [LC-MS] analysis) can at least partially explain the increased activity and duration of action for the novel GalNAc conjugate.

Modeling exposure to air pollution from the WTC disaster based on reports of perceived air pollution.

We examined the utility of a newly developed perceived air pollution (PAP) scale and of a modeled air pollution (MAP) scale derived from it for predicting previously observed birth outcomes of pregnant women enrolled following September 11, 2001. Women reported their home and work locations in the four weeks after September 11, 2001 and the PAP at each site on a four-point scale designed for this purpose. Locations were geocoded and their distance from the World Trade Center (WTC) site determined. PAP values were used to develop a model of air pollution for a 20-mile radius from the WTC site. MAP values were assigned to each geocoded location. We examined the relationship of PAP and MAP values to maternal characteristics and to distance of home and work sites from the WTC site. Both PAP and MAP values were highly correlated with distance from the WTC. Maternal characteristics that were associated with PAP values reported for home or work sites (race, demoralization, material hardship, first trimester on September 11) were not associated with modeled MAP values. Relationships of several birth outcomes to proximity to the WTC, which we previously reported using this data set, were also seen when MAP values were used as the measure of exposure, instead of proximity. MAP developed from reports of PAP may be useful to identify high-risk areas and predict health outcomes when there are multiple sources of pollution and a "distance from source" analysis is impossible.

Computation of the Hydrodynamic Radius of Charged Nanoparticles from Nonequilibrium Molecular Dynamics.

We have used nonequilibrium molecular dynamics to simulate the flow of water molecules around a charged nanoparticle described at the atomic scale. These nonequilibrium simulations allowed us to compute the friction coefficient of the nanoparticle and then to deduce its hydrodynamic radius. We have compared two different strategies to thermostat the simulation box, since the low symmetry of the flow field renders the control of temperature non trivial. We show that both lead to an adequate control of the temperature of the system. To deduce the hydrodynamic radius of the nanoparticle we have employed a partial thermostat, which exploits the cylindrical symmetry of the flow field. Thereby, only a part of the simulation box far from the nanoparticle is thermostated. We have taken into account the finite concentration of the nanoparticle when calculating the friction force acting on it. We have focused on the case of polyoxometalate ions, which are inorganic charged nanoparticles. It appears that, for a given structure of the nanoparticle at the atomic level, the hydrodynamic radius significantly increases with the nanoparticles charge, a phenomenon that had not been quantified so far using molecular dynamics. The presence of an added salt only slightly modifies the hydrodynamic radius.

A Data Driven Approach to Achieving High Value Healthcare.

The purpose of this special issue is to disseminate learning from the High Value Healthcare Collaborative (HVHC). The HVHC is a voluntary, member-led organization based on trusted, working relationships among delivery system leaders. HVHC's mission is to be a provider-based learning health system committed to improving healthcare value through data, evidence, and collaboration. We begin by describing the organization and structure of HVHC in order to lay the context for a series of papers that feature work from this learning health system. HVHC was awarded a grant from the John and Laura Arnold Foundation to develop a generalizable model for dissemination and implementation. Implementation of the 3-hour sepsis bundle was used as a prototypic, complex intervention with an in-depth mixed methods evaluation across 16 member sites. The first four articles in this issue describe, in detail, various data and methodological challenges encountered together with strategies for overcoming these (see Knowlton et al., von Recklinghausen et al., Welch et al., and Taenzer et al.). Next, we illustrate how the Data Trust can support emerging questions relevant to member organizations. The paper by Albritton et al., explores the impact of observation stays on readmission rates. Knighton et al., explore the use of an area-based measure for health literacy to assess risk in disadvantaged populations. Two final papers illustrate the importance of fundamental data sources needed to support advanced data science.

Topology-Sensitive Microfluidic Filter for Polymers of Varying Stiffness.

The separation of polymers based on their size, rigidity, and topology is an essential but also highly challenging task for nanoscience and engineering. Using hybrid molecular dynamics simulations that correctly take into account hydrodynamics, we have designed microfluidic channels for separating linear from ring polymers in dilute solutions. We establish that the transport velocity of the polymers is independent of their topology and rigidity when the channel walls are smooth and repulsive. However, when the walls are decorated with attractive spots arranged on lines parallel to the flow, ring polymers exhibit an order of magnitude higher transport velocity compared to linear chains. The spots induce a homeotropic-like reorientation of ring polymers close to walls leading to a tank treading motion along them, whereas linear chains are immobilized upon adsorption. This mechanism becomes more enhanced with increasing polymer rigidity. The presented technique holds thus promise for reliably separating nanoparticles based on their topology.

Data Cleaning in the Evaluation of a Multi-Site Intervention Project.

CONTEXT: The High Value Healthcare Collaborative (HVHC) sepsis project was a two-year multi-site project where Member health care delivery systems worked on improving sepsis care using a dissemination & implementation framework designed by HVHC. As part of the project evaluation, participating Members provided 5 data submissions over the project period. Members created data files using a uniform specification, but the data sources and methods used to create the data sets differed. Extensive data cleaning was necessary to get a data set usable for the evaluation analysis. CASE DESCRIPTION: HVHC was the coordinating center for the project and received and cleaned all data submissions. Submissions received 3 sequentially more detailed levels of checking by HVHC. The most detailed level evaluated validity by comparing values within-Member over time and between Member. For a subset of episodes Member-submitted data were compared to matched Medicare claims data. FINDINGS: Inconsistencies in data submissions, particularly for length-of-stay variables were common in early submissions and decreased with subsequent submissions. Multiple resubmissions were sometimes required to get clean data. Data checking also uncovered a systematic difference in the way Medicare and some members defined intensive care unit stay. CONCLUSIONS: Data checking is a critical for ensuring valid analytic results for projects using electronic health record data. It is important to budget sufficient resources for data checking. Interim data submissions and checks help find anomalies early. Data resubmissions should be checked as fixes can introduce new errors. Communicating with those responsible for creating the data set provides critical information.