Development and Validation of a Multiclass Model Defining Molecular Archetypes of Kidney Transplant Rejection: A Large Cohort Study of the Banff Human Organ Transplant Gene Expression Panel.

Gene expression profiling from formalin-fixed paraffin-embedded (FFPE) renal allograft biopsies is a promising approach for feasibly providing a molecular diagnosis of rejection. However, large-scale studies evaluating the performance of models using NanoString platform data to define molecular archetypes of rejection are lacking. We tested a diverse retrospective cohort of over 1400 FFPE biopsy specimens, rescored according to Banff 2019 criteria and representing 10 of 11 United Network of Organ Sharing regions, using the Banff Human Organ Transplant panel from NanoString and developed a multiclass model from the gene expression data to assign relative probabilities of 4 molecular archetypes: No Rejection, Antibody-Mediated Rejection, T Cell-Mediated Rejection, and Mixed Rejection. Using Least Absolute Shrinkage and Selection Operator regularized regression with 10-fold cross-validation fitted to 1050 biopsies in the discovery cohort and technically validated on an additional 345 biopsies, our model achieved overall accuracy of 85% in the discovery cohort and 80% in the validation cohort, with ≥75% positive predictive value for each class, except for the Mixed Rejection class in the validation cohort (positive predictive value, 53%). This study represents the technical validation of the first model built from a large and diverse sample of diagnostic FFPE biopsy specimens to define and classify molecular archetypes of histologically defined diagnoses as derived from Banff Human Organ Transplant panel gene expression profiling data.

A Robust and Low-Cost Sulfonated Hypercrosslinked Polymer for Atmospheric Water Harvesting.

The availability of freshwater is rapidly declining due to over-exploitation and climate change, with multiple parts of the globe already facing significant freshwater scarcity. Here, a sulfonated hypercrosslinked polymer able to repeatedly harvest significant amounts of water via direct air capture is reported. Water uptake from relative humidities as low as 10% is demonstrated, mimicking some of the harshest environments on Earth. A water harvesting device is used to show repeated uptake and harvesting without significant detriment to adsorbent performance. Desorption is triggered using simulated sunlight, presenting a low-energy route to water harvesting and adsorbent regeneration. The synthesis of sulfonated hypercrosslinked polymer requires only low-cost and readily available reagents, offering excellent potential for scale-up. Due to an almost limitless supply of water vapor from air in most regions around the globe, this approach can transform our ability to address water security concerns.

Measurement of Physicochemical Properties and CO2, N2, Ar, O2, and H2O Unary Adsorption Isotherms of Purolite A110 and Lewatit VP OC 1065 for Application in Direct Air Capture.

Direct air capture (DAC) using solid adsorbents has gained significant attention as a carbon dioxide removal (CDR) technology to help limit global temperature rise to below 2 °C. One large area of focus is the development of new adsorbent materials for DAC. However, the necessary data needed to employ these materials in process models for adsorbent screening are rarely available. Here, we showcase Purolite A110, a commercially available amine-functionalized polymeric resin, as a new candidate adsorbent for DAC and compare its properties to a current benchmark, Lewatit VP OC 1065. For both materials, we report their chemical features and composition, skeletal, particle, and bed density, total pore volume, particle porosity, BET area, thermal stability, and specific heat capacity. We determine their equilibrium sorption properties by measuring the volumetric CO2 isotherms at 288, 298, 308, 333, 343, 353, and 393 K, N2 and H2O isotherms at 288, 298, and 308 K, and Ar and O2 isotherms at 298 K. For CO2, N2, and H2O, we also present the corresponding isotherm model fitting parameters and heats of adsorption. These data can help facilitate process modeling and optimization studies to properly assess these adsorbents at scale.

Clinical outcomes from the Assessing Donor-derived cell-free DNA Monitoring Insights of kidney Allografts with Longitudinal surveillance (ADMIRAL) study.

The use of routine monitoring of donor-derived cell-free DNA (dd-cfDNA) after kidney transplant may allow clinicians to identify subclinical allograft injury and intervene prior to development of clinically evident graft injury. To evaluate this, data from 1092 kidney transplant recipients monitored for dd-cfDNA over a three-year period was analyzed to assess the association of dd-cfDNA with histologic evidence of allograft rejection. Elevation of dd-cfDNA (0.5% or more) was significantly correlated with clinical and subclinical allograft rejection. dd-cfDNA values of 0.5% or more were associated with a nearly three-fold increase in risk development of de novo donor-specific antibodies (hazard ratio 2.71) and were determined to be elevated a median of 91 days (interquartile range of 30-125 days) ahead of donor specific antibody identification. Persistently elevated dd-cfDNA (more than one result above the 0.5% threshold) predicted over a 25% decline in the estimated glomerular filtration rate over three years (hazard ratio 1.97). Therefore, routine monitoring of dd-cfDNA allowed early identification of clinically important graft injury. Biomarker monitoring complemented histology and traditional laboratory surveillance strategies as a prognostic marker and risk-stratification tool post-transplant. Thus, persistently low dd-cfDNA levels may accurately identify allograft quiescence or absence of injury, paving the way for personalization of immunosuppression trials.

High levels of donor-derived cell-free DNA in a case of graft-versus-host-disease following liver transplantation.

The diagnosis of graft-versus-host-disease (GVHD) after solid organ transplantation is made difficult by its variable clinical presentation and lack of sensitive and specific biomarkers to evaluate the immune state of transplant recipients. Emerging noninvasive diagnostic techniques like the quantification of donor-derived cell-free DNA (dd-cfDNA) for surveillance may improve the current standard-of-care. Herein, we report the use of this methodology in a patient with GVHD and corresponding levels of dd-cfDNA without any evidence of graft injury. Correlation of dd-cfDNA levels with the clinical course and its novel application here could lead to improvements in the rapid diagnosis of GVHD and in monitoring of response to treatment.

Valuing the Cancer Mortality Risk Reduction from Lowering the Arsenic Maximum Contaminant Level in New Hampshire Municipal Water Supplies.

This study uses a 2018 stated preference survey to elicit a willingness to pay (WTP) to reduce the cancer morbidity and mortality risk from arsenic exposure through drinking water. Respondents who use a public water supply are willing to pay $35.43 per month for the risk reduction associated with lowering the maximum allowable level of arsenic in drinking water from 10 to a hypothetical level of 3 ppb; households on private wells are willing to pay $29.19. Respondents from households with children were willing to pay significantly more than respondents from households without children. We derive values of a statistical life (VSL) of $4.61 million and $3.48 million per household member, respectively, in households using municipal or well water. Shortly after the initial release of these findings, New Hampshire became the second state to set a maximum allowable level for arsenic below the national limit of 10 ppb.

Noninvasive detection of graft injury after heart transplant using donor-derived cell-free DNA: A prospective multicenter study.

Standardized donor-derived cell-free DNA (dd-cfDNA) testing has been introduced into clinical use to monitor kidney transplant recipients for rejection. This report describes the performance of this dd-cfDNA assay to detect allograft rejection in samples from heart transplant (HT) recipients undergoing surveillance monitoring across the United States. Venous blood was longitudinally sampled from 740 HT recipients from 26 centers and in a single-center cohort of 33 patients at high risk for antibody-mediated rejection (AMR). Plasma dd-cfDNA was quantified by using targeted amplification and sequencing of a single nucleotide polymorphism panel. The dd-cfDNA levels were correlated to paired events of biopsy-based diagnosis of rejection. The median dd-cfDNA was 0.07% in reference HT recipients (2164 samples) and 0.17% in samples classified as acute rejection (35 samples; P = .005). At a 0.2% threshold, dd-cfDNA had a 44% sensitivity to detect rejection and a 97% negative predictive value. In the cohort at risk for AMR (11 samples), dd-cfDNA levels were elevated 3-fold in AMR compared with patients without AMR (99 samples, P = .004). The standardized dd-cfDNA test identified acute rejection in samples from a broad population of HT recipients. The reported test performance characteristics will guide the next stage of clinical utility studies of the dd-cfDNA assay.

Ultrafast mid-infrared fiber laser mode-locked using frequency-shifted feedback.

We demonstrate ultrashort pulse generation from a fluoride fiber laser co-doped with holmium and praseodymium. To date, the majority of work focused on short pulse generation from this class of fiber laser has employed loss modulators in the cavity, both real and artificial. In this Letter, we alternatively employ a frequency shifting element: an acousto-optic modulator (AOM) in the cavity. This results in mode-locked output of sub-5 ps pulses with 10 nJ of energy at a center wavelength of 2.86 µm and a pulse repetition frequency of 30.1 MHz, equating to a peak power of 1.9 kW. Additional experimental investigation of the relationship between frequency shift and cavity round trip offer insight into the complex underlying dynamics. As a complementary mode-locking technique to conventional loss modulation, this method of pulse-formation may greatly expand the design flexibility of pulsed mid-infrared fiber lasers.

Optimized laser-written ZBLAN fiber Bragg gratings with high reflectivity and low loss.

We report the direct femtosecond laser inscription of type-I fiber Bragg gratings (FBGs) into the core of soft-glass ZBLAN fibers. We investigate and compare various fabrication methods such as single pass (line by line), double pass, and stacking (plane by plane) to create the highest reflectivity FBGs (99.98%) for mid-infrared (mid-IR) applications. In addition, we experimentally demonstrate how the parameters that influence the coupling coefficient, i.e., refractive index modulation and overlap factor, can be controlled in these gratings to specifically tailor the FBG properties. The performance of the direct-written type-I gratings after 6 h of annealing is further analyzed, and the reflectivity increases by approximately 10 dB. To the best of our knowledge, this is the first demonstration of temperature-stable mid-IR FBGs with highest coupling coefficient (464 m-1) and lowest loss (<0.5 dB/cm) without the use of an expensive phase mask.

Dysprosium-doped ZBLAN fiber laser tunable from 2.8 µm to 3.4 µm, pumped at 1.7 µm.

We demonstrate a mid-infrared dysprosium-doped fluoride fiber laser with a continuously tunable output range of 573 nm, pumped by a 1.7 µm Raman fiber laser. To the best of our knowledge, this represents the largest tuning range achieved to date from any rare-earth-doped fiber laser and, critically, spans the 2.8-3.4 µm spectral region, which contains absorption resonances of many important functional groups and is uncovered by other rare-earth ions. Output powers up to 170 mW are achieved, with 21% slope efficiency. We also discuss the relative merits of the 1.7 µm pump scheme, including possible pump excited-state absorption.

Emission beyond 4 µm and mid-infrared lasing in a dysprosium-doped indium fluoride (InF3) fiber.

Optical emission from rare-earth-doped fluoride fibers has thus far been limited to less than 4 µm. We extend emission beyond this limit by employing an indium fluoride (InF3) glass fiber as the host, which exhibits an increased infrared transparency over commonly used zirconium fluoride (ZBLAN). Near-infrared pumping of a dysprosium-doped InF3 fiber results in broad emission centered around 4.3 µm, representing the longest emission yet achieved from a fluoride fiber. The first laser emission in an InF3 fiber is also demonstrated from the 3 µm dysprosium transition. Finally, a frequency domain excited state lifetime measurement comparison between fluoride hosts suggests that multiphonon effects are significantly reduced in indium fluoride fiber, paving the way to more efficient, longer wavelength lasers compared to ZBLAN fibers.

Estimating the Learning Curve of a Novel Medical Device: Bipolar Sealer Use in Unilateral Total Knee Arthroplasties.

BACKGROUND: The use of cost-effectiveness analysis for medical devices has proven to be challenging because of the existence of the learning effects in the device-operator interactions. The need for the relevant analytical framework for assessing the economic value of such technologies has been recognized. OBJECTIVES: To present a modified difference-in-differences (DID) cost-effectiveness methodology that facilitates visualization of a new health technology's learning curve. METHODS: Using the Premier Perspective database (Premier Inc., Charlotte, NC), we examined the impact of physicians adopting a bipolar sealer (BPS) to control blood loss in primary unilateral total knee arthroplasties on hospital lengths of stay and total hospitalization costs when compared with two control groups. In our DID approach, we substituted month-from-adoption for the calendar-month-of-adoption in both graphical representations and ordinary least-squares regression results to estimate the effect of the BPS. RESULTS: The results clearly demonstrated a learning curve associated with the adoption of the BPS technology. Although the reductions in length of stay were immediate, the first postadoption year costs increased by $1335 (extrahospital controls) to $1565 (within-hospital controls). Importantly, and also consistent with a learning curve hypothesis, these initial higher costs were offset by subsequent cost savings in the second and third years postadoption. CONCLUSIONS: The presented modified DID approach is a suitable and versatile analytical tool for economic evaluation of a slowly diffusing medical device or health technology. It provides a better understanding of the potential learning effects associated with relevant interventions.

Cell-Free DNA and Active Rejection in Kidney Allografts.

Histologic analysis of the allograft biopsy specimen is the standard method used to differentiate rejection from other injury in kidney transplants. Donor-derived cell-free DNA (dd-cfDNA) is a noninvasive test of allograft injury that may enable more frequent, quantitative, and safer assessment of allograft rejection and injury status. To investigate this possibility, we prospectively collected blood specimens at scheduled intervals and at the time of clinically indicated biopsies. In 102 kidney recipients, we measured plasma levels of dd-cfDNA and correlated the levels with allograft rejection status ascertained by histology in 107 biopsy specimens. The dd-cfDNA level discriminated between biopsy specimens showing any rejection (T cell-mediated rejection or antibody-mediated rejection [ABMR]) and controls (no rejection histologically), P<0.001 (receiver operating characteristic area under the curve [AUC], 0.74; 95% confidence interval [95% CI], 0.61 to 0.86). Positive and negative predictive values for active rejection at a cutoff of 1.0% dd-cfDNA were 61% and 84%, respectively. The AUC for discriminating ABMR from samples without ABMR was 0.87 (95% CI, 0.75 to 0.97). Positive and negative predictive values for ABMR at a cutoff of 1.0% dd-cfDNA were 44% and 96%, respectively. Median dd-cfDNA was 2.9% (ABMR), 1.2% (T cell-mediated types ≥IB), 0.2% (T cell-mediated type IA), and 0.3% in controls (P=0.05 for T cell-mediated rejection types ≥IB versus controls). Thus, dd-cfDNA may be used to assess allograft rejection and injury; dd-cfDNA levels <1% reflect the absence of active rejection (T cell-mediated type ≥IB or ABMR) and levels >1% indicate a probability of active rejection.

Direct inscription of Bragg gratings into coated fluoride fibers for widely tunable and robust mid-infrared lasers.

We report the development of a widely tunable all-fiber mid-infrared laser system based on a mechanically robust fiber Bragg grating (FBG) which was inscribed through the polymer coating of a Ho3+-Pr3+ co-doped double clad ZBLAN fluoride fiber by focusing femtosecond laser pulses into the core of the fiber without the use of a phase mask. By applying mechanical tension and compression to the FBG while pumping the fiber with an 1150 nm laser diode, a continuous wave (CW) all-fiber laser with a tuning range of 37 nm, centered at 2870 nm, was demonstrated with up to 0.29 W output power. These results pave the way for the realization of compact and robust mid-infrared fiber laser systems for real-world applications in spectroscopy and medicine.

Noncovalent Surface Modification of Cellulose Nanopapers by Adsorption of Polymers from Aprotic Solvents.

Basic adsorption of hydrophobic polymers from aprotic solvents was introduced as a platform technology to modify exclusively the surfaces of cellulose nanopapers. Dynamic vapor sorption demonstrated that the water vapor uptake ability of the nanopapers remained unperturbed, despite strong repellency to liquid water caused by the adsorbed hydrophobic polymer on the surface. This was enabled by the fact that the aprotic solvents used for adsorption did not swell the nanopaper unlike water that is generally applied as the adsorption medium in such systems. As case examples, the adsorptions of polystyrene (PS) and poly(trifluoroethylene) (PF3E) were followed by X-ray photoelectron spectroscopy and water contact angle measurements, backed up with morphological analysis by atomic force microscopy. The resulting nanopapers are useful in applications like moisture buffers where repellence to liquid water and ability for moisture sorption are desired qualities.

Dose-Dependent Therapeutic Distinction between Active and Passive Targeting Revealed Using Transferrin-Coated PGMA Nanoparticles.

The paradigm of using nanoparticle-based formulations for drug delivery relies on their enhanced passive accumulation in the tumor interstitium. Nanoparticles with active targeting capabilities attempt to further enhance specific delivery of drugs to the tumors via interaction with overexpressed cellular receptors. Consequently, it is widely accepted that drug delivery using actively targeted nanoparticles maximizes the therapeutic benefit and minimizes the off-target effects. However, the process of nanoparticle mediated active targeting initially relies on their passive accumulation in tumors. In this article, it is demonstrated that these two tumor-targeted drug delivery mechanisms are interrelated and dosage dependent. It is reported that at lower doses, actively targeted nanoparticles have distinctly higher efficacy in tumor inhibition than their passively targeted counterparts. However, the enhanced permeability and retention effect of the tumor tissue becomes the dominant factor influencing the efficacy of both passively and actively targeted nanoparticles when they are administered at higher doses. Importantly, it is demonstrated that dosage is a pivotal parameter that needs to be taken into account in the assessment of nanoparticle mediated targeted drug delivery.

Gametocyte Clearance Kinetics Determined by Quantitative Magnetic Fractionation in Melanesian Children with Uncomplicated Malaria Treated with Artemisinin Combination Therapy.

Quantitative magnetic fractionation and a published mathematical model were used to characterize between-treatment differences in gametocyte density and prevalence in 70 Papua New Guinean children with uncomplicated Plasmodium falciparum and/or Plasmodium vivax malaria randomized to one of two artemisinin combination therapies (artemether-lumefantrine or artemisinin-naphthoquine) in an intervention trial. There was an initial rise in peripheral P. falciparum gametocyte density with both treatments, but it was more pronounced in the artemisinin-naphthoquine group. Model-derived estimates of the median pretreatment sequestered gametocyte population were 21/µl for artemether-lumefantrine and 61/µl for artemisinin-naphthoquine (P < 0.001). The median time for P. falciparum gametocyte density to fall to <2.5/µl (below which transmission becomes unlikely) was 16 days in the artemether-lumefantrine group and 20 days in artemisinin-naphthoquine group (P < 0.001). Gametocyte prevalence modeling suggested that artemisinin-naphthoquine-treated children became gametocytemic faster (median, 2.2 days) than artemether-lumefantrine-treated children (median, 5.3 days; P < 0.001) and had a longer median P. falciparum gametocyte carriage time per individual (20 versus 13 days; P < 0.001). Clearance of P. vivax gametocytes was rapid (within 3 days) in both groups; however, consistent with the reappearance of asexual forms in the main trial, nearly 40% of children in the artemether-lumefantrine group developed P. vivax gametocytemia between days 28 and 42 compared with 3% of children in the artemisinin-naphthoquine group. These data suggest that artemisinin is less active than artemether against sequestered gametocytes. Greater initial gametocyte release after artemisinin-naphthoquine increases the period of potential P. falciparum transmission by 4 days relative to artemether-lumefantrine, but the longer elimination half-life of naphthoquine than of lumefantrine suppresses P. vivax recurrence and consequent gametocytemia.

Lanthanoid "bottlebrush" clusters: remarkably elongated metal-oxo core structures with controllable lengths.

Large metal-oxo clusters consistently assume spherical or regular polyhedral morphologies rather than high-aspect-ratio structures. Access to elongated core structures has now been achieved by the reaction of lanthanoid salts with a tetrazole-functionalized calixarene in the presence of a simple carboxylate co-ligand. The resulting Ln19 and Ln12 clusters are constructed from apex-fused Ln5O6 trigonal bipyramids and are formed consistently under a range of reaction conditions and reagent ratios. Altering the carboxylate co-ligand structure reliably controls the cluster length, giving access to a new class of rod-like clusters of variable length.

Swellable, water- and acid-tolerant polymer sponges for chemoselective carbon dioxide capture.

To impact carbon emissions, new materials for carbon capture must be inexpensive, robust, and able to adsorb CO2 specifically from a mixture of other gases. In particular, materials must be tolerant to the water vapor and to the acidic impurities that are present in gas streams produced by using fossil fuels to generate electricity. We show that a porous organic polymer has excellent CO2 capacity and high CO2 selectivity under conditions relevant to precombustion CO2 capture. Unlike polar adsorbents, such as zeolite 13x and the metal-organic framework, HKUST-1, the CO2 adsorption capacity for the hydrophobic polymer is hardly affected by the adsorption of water vapor. The polymer is even stable to boiling in concentrated acid for extended periods, a property that is matched by few microporous adsorbents. The polymer adsorbs CO2 in a different way from rigid materials by physical swelling, much as a sponge adsorbs water. This gives rise to a higher CO2 capacities and much better CO2 selectivity than for other water-tolerant, nonswellable frameworks, such as activated carbon and ZIF-8. The polymer has superior function as a selective gas adsorbent, even though its constituent monomers are very simple organic feedstocks, as would be required for materials preparation on the large industrial scales required for carbon capture.

Labeling of cancer cells with magnetic nanoparticles for magnetic resonance imaging.

PURPOSE: The process of invasion and metastasis formation of tumor cells can be studied by following the migration of labeled cells over prolonged time periods. This report investigates the applicability of iron oxide nanoparticles as a magnetic resonance imaging (MRI) contrast agent for cell labeling. METHODS: γFe2 O3 nanoparticles prepared with direct flame spray pyrolysis are biofunctionalized with poly-l-lysine (PLL). The nanoparticles within the cells were observed with transmission electron microscopy, bright-field microscopy, and magnetorelaxometry. MRI of labeled cells suspended in agarose was used to estimate the detection limit. RESULTS: PLL-coated particles are readily taken up, stored in intracellular clusters, and gradually degraded by the cells. During cell division, the nanoparticle clusters are divided and split between daughter cells. The MRI detection limit was found to be 25 cells/mm(3) for R2*, and 70 cells/mm(3) for R2. The iron specificity, however, was higher for R2 images. Due to the degradation of intracellular γFe2 O3 to paramagnetic iron ions within 13 days, the R1, R2, and R2* contrast gradually decreased over this time period to approximately 50% of its initial value. CONCLUSIONS: These results suggest that PLL-coated γFe2 O3 nanoparticles can be used as an MRI contrast agent for long-term studies of cell migration. Magn Reson Med 71:1896-1905, 2014. © 2013 Wiley Periodicals, Inc.