The use of extracorporeal carbon dioxide removal (ECCO2R) is well established as a therapy for patients suffering from acute respiratory failure. Development of next generation low blood flow (<500 ...mL/min) ECCO2R devices necessitates more efficient gas exchange devices. Since over 90% of blood CO2 is transported as bicarbonate (HCO3(-)), we previously reported development of a carbonic anhydrase (CA) immobilized bioactive hollow fiber membrane (HFM) which significantly accelerates CO2 removal from blood in model gas exchange devices by converting bicarbonate to CO2 directly at the HFM surface. This present study tested the hypothesis that dilute sulfur dioxide (SO2) in oxygen sweep gas could further increase CO2 removal by creating an acidic microenvironment within the diffusional boundary layer adjacent to the HFM surface, facilitating dehydration of bicarbonate to CO2. CA was covalently immobilized onto poly (methyl pentene) (PMP) HFMs through glutaraldehyde activated chitosan spacers, potted in model gas exchange devices (0.0151 m(2)) and tested for CO2 removal rate with oxygen (O2) sweep gas and a 2.2% SO2 in oxygen sweep gas mixture. Using pure O2 sweep gas, CA-PMP increased CO2 removal by 31% (258 mL/min/m(2)) compared to PMP (197 mL/min/m(2)) (P<0.05). Using 2.2% SO2 acidic sweep gas increased PMP CO2 removal by 17% (230 mL/min/m(2)) compared to pure oxygen sweep gas control (P<0.05); device outlet blood pH was 7.38 units. When employing both CA-PMP and 2.2% SO2 sweep gas, CO2 removal increased by 109% (411 mL/min/m(2)) (P<0.05); device outlet blood pH was 7.35 units. Dilute acidic sweep gas increases CO2 removal, and when used in combination with bioactive CA-HFMs has a synergistic effect to more than double CO2 removal while maintaining physiologic pH. Through these technologies the next generation of intravascular and paracorporeal respiratory assist devices can remove more CO2 with smaller blood contacting surface areas.
A clinical need exists for more efficient respiratory assist devices which utilize low blood flow rates (<500 mL/min) to regulate blood CO2 in patients suffering from acute lung failure. Literature has demonstrated approaches to chemically increase hollow fiber membrane (HFM) CO2 removal efficiency by shifting equilibrium from bicarbonate to gaseous CO2, through either a bioactive carbonic anhydrase enzyme coating or bulk blood acidification with lactic acid. In this study we demonstrate a novel approach to local blood acidification using an acidified sweep gas in combination with a bioactive coating to more than double CO2 removal efficiency of HFM devices. To our knowledge, this is the first report assessing an acidic sweep gas to increase CO2 removal from blood using HFM devices.
Extracorporeal CO
2
removal from circulating blood is a promising therapeutic modality for the treatment of acute respiratory failure. The enzyme carbonic anhydrase accelerates CO
2
removal within ...gas exchange devices by locally catalyzing HCO
3
−
into gaseous CO
2
within the blood. In this work, we covalently immobilized carbonic anhydrase on the surface of polypropylene hollow fiber membranes using glutaraldehyde activated chitosan tethering to amplify the density of reactive amine functional groups for enzyme immobilization. XPS and a colorimetric amine assay confirmed higher amine densities on the chitosan coated fiber compared to control fiber. Chitosan/CA coated fibers exhibited accelerated CO
2
removal in scaled-down gas exchange devices in buffer and blood (115 % enhancement vs. control, 37 % enhancement vs. control, respectively). Carbonic anhydrase immobilized directly on hollow fiber membranes without chitosan tethering resulted in no enhancement in CO
2
removal. Additionally, fibers coated with chitosan/carbonic anhydrase demonstrated reduced platelet adhesion when exposed to blood compared to control and heparin coated fibers.
Artificial lung devices comprised of hollow fiber membranes (HFMs) coated with the enzyme carbonic anhydrase (CA), accelerate removal of carbon dioxide (CO
2
) from blood for the treatment of acute ...respiratory failure. While previous work demonstrated CA coatings increase HFM CO
2
removal by 115 % in phosphate buffered saline (PBS), testing in blood revealed a 36 % increase compared to unmodified HFMs. In this work, we sought to characterize the CO
2
mass transport processes within these biocatalytic devices which impede CA coating efficacy and develop approaches towards improving bioactive HFM efficiency. Aminated HFMs were sequentially reacted with glutaraldehyde (GA), chitosan, GA and afterwards incubated with a CA solution, covalently linking CA to the surface. Bioactive CA-HFMs were potted in model gas exchange devices (0.0119 m
2
) and tested for esterase activity and CO
2
removal under various flow rates with PBS, whole blood, and solutions containing individual blood components (plasma albumin, red blood cells or free carbonic anhydrase). Results demonstrated that increasing the immobilized enzyme activity did not significantly impact CO
2
removal rate, as the diffusional resistance from the liquid boundary layer is the primary impediment to CO
2
transport by both unmodified and bioactive HFMs under clinically relevant conditions. Furthermore, endogenous CA within red blood cells competes with HFM immobilized CA to increase CO
2
removal. Based on our findings, we propose a bicarbonate/CO
2
disequilibrium hypothesis to describe performance of CA-modified devices in both buffer and blood. Improvement in CO
2
removal rates using CA-modified devices in blood may be realized by maximizing bicarbonate/CO
2
disequilibrium at the fiber surface via strategies such as blood acidification and active mixing within the device.
Hereditary haemochromatosis (HH), which affects some 1 in 400 and has an estimated carrier frequency of 1 in 10 individuals of Northern European descent, results in multi-organ dysfunction caused by ...increased iron deposition, and is treatable if detected early. Using linkage-disequilibrium and full haplotype analysis, we have identified a 250-kilobase region more than 3 megabases telomeric of the major histocompatibility complex (MHC) that is identical-by-descent in 85% of patient chromosomes. Within this region, we have identified a gene related to the MHC class I family, termed HLA-H, containing two missense alterations. One of these is predicted to inactivate this class of proteins and was found homozygous in 83% of 178 patients. A role of this gene in haemochromatosis is supported by the frequency and nature of the major mutation and prior studies implicating MHC class I-like proteins in iron metabolism.
Objective
To investigate whether antidrug antibodies and/or drug non‐trough levels predict the long‐term treatment response in a large cohort of patients with rheumatoid arthritis (RA) treated with ...adalimumab or etanercept and to identify factors influencing antidrug antibody and drug levels to optimize future treatment decisions.
Methods
A total of 331 patients from an observational prospective cohort were selected (160 patients treated with adalimumab and 171 treated with etanercept). Antidrug antibody levels were measured by radioimmunoassay, and drug levels were measured by enzyme‐linked immunosorbent assay in 835 serial serum samples obtained 3, 6, and 12 months after initiation of therapy. The association between antidrug antibodies and drug non‐trough levels and the treatment response (change in the Disease Activity Score in 28 joints) was evaluated.
Results
Among patients who completed 12 months of followup, antidrug antibodies were detected in 24.8% of those receiving adalimumab (31 of 125) and in none of those receiving etanercept. At 3 months, antidrug antibody formation and low adalimumab levels were significant predictors of no response according to the European League Against Rheumatism (EULAR) criteria at 12 months (area under the receiver operating characteristic curve 0.71 95% confidence interval (95% CI) 0.57, 0.85). Antidrug antibody–positive patients received lower median dosages of methotrexate compared with antidrug antibody–negative patients (15 mg/week versus 20 mg/week; P = 0.01) and had a longer disease duration (14.0 versus 7.7 years; P = 0.03). The adalimumab level was the best predictor of change in the DAS28 at 12 months, after adjustment for confounders (regression coefficient 0.060 95% CI 0.015, 0.10, P = 0.009). Etanercept levels were associated with the EULAR response at 12 months (regression coefficient 0.088 95% CI 0.019, 0.16, P = 0.012); however, this difference was not significant after adjustment. A body mass index of ≥30 kg/m2 and poor adherence were associated with lower drug levels.
Conclusion
Pharmacologic testing in anti–tumor necrosis factor–treated patients is clinically useful even in the absence of trough levels. At 3 months, antidrug antibodies and low adalimumab levels are significant predictors of no response according to the EULAR criteria at 12 months.
We report results from a study of the spin and parity of Ξ c ( 2970 ) + using a 980 fb −1 data sample collected by the Belle detector at the KEKB asymmetric-energy e+e− collider. The decay angle ...distributions in the chain Ξc (2970)+→ Ξc (2645) 0π+ → Ξ+c π− π+ are analyzed to determine the spin of this charmed-strange baryon. The angular distributions strongly favor the Ξc (2970)+ spin J = 1/2 over 3/2 or 5/2, under an assumption that the lowest partial wave dominates in the decay. We also measure the ratio of Ξc (2970)+ decay branching fractions R = B Ξc (2970)+ → Ξc (2645)0π+/B Ξc (2970)+ → Ξ0c π+ = 1.67 ± 0.29 (stat)+0.15 −0.09 (syst) ± 0.25 (IS), where the last uncertainty is due to possible isospin-symmetry-breaking effects. This R value favors the spin-parity J P = 1/2+ with the spin of the light-quark degrees of freedom sl = 0. This is the first determination of the spin and parity of a charmed-strange baryon.
We present the results of the first Dalitz plot analysis of the decay D0 → K−π+η. The analysis is performed on a data set corresponding to an integrated luminosity of 953 fb−1 collected by the ...Belle detector at the asymmetric-energy e+e− KEKB collider. The Dalitz plot is well described by a combination of the six resonant decay channels K* ( 892 )0η, K−a0 ( 980 )+, K−a2 ( 1320 )+, K* ( 1410 )0η, K* ( 1680 )−π+ and K2* ( 1980 )−π+, together with Kπ and Kη S-wave components. The decays K* ( 1680 )− → K−η and K2* ( 1980 )− → K−η are observed for the first time. We measure ratio of the branching fractions, ... (B PDG). Using the Dalitz fit result, the ratio ... is measured to be ...; this is much lower than the theoretical expectations ( ≈ 1 ) made under the assumption that K*( 1680 ) is a pure 13D1 state. The product branching fraction ... is determined. In addition, the π η ′ contribution to the a0( 980 )± resonance shape is confirmed with 10.1 σ statistical significance using the three-channel Flatté model. We also measure ... . This is consistent with, and more precise than, the current world average ( 1.02 ± 0.30 ) % , deviates with a significance of more than 3 σ from the theoretical predictions of (0.51–0.92)%. (ProQuest: ... denotes formulae omited.).
We present an analysis of the exclusive B+ → π+ π− ℓ+ νℓ decay, where ℓ represents an electron or a muon, with the assumption of charge-conjugation symmetry and lepton universality. The study ...exploits the full Υ ( 4 S ) data sample collected by the Belle detector, corresponding to 711 fb−1 of integrated luminosity. Events are selected by fully reconstructing one B meson in hadronic decay modes, subsequently determining the properties of the other B meson. We extract the signal yields using a binned maximum-likelihood fit to the missing-mass squared distribution in bins of the invariant mass of the two pions or the momentum transfer squared. We measure a total branching fraction of B(B+ → π+ π− ℓ+ νℓ) = 22.7+1.9 −1.6 (stat) ± 3.5(syst) × 10−5, where the uncertainties are statistical and systematic, respectively. This result is the first reported measurement of this decay.
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