The fact that IgA comprises the body's major isotype of antibody on a biosynthetic basis is not widely appreciated because IgG, not IgA, is the predominant isotype in serum. Nevertheless, the bulk of ...the body's Ig-producing cells reside in the various mucosal and exocrine sites, especially along the intestinal tract, and most of them make IgA antibodies against environmental antigens, including the local microbial flora. These antibodies can then function in multiple ways as a first line of immune defense at boundaries with the external environment. It has long been recognized that a major source of the precursors of the IgA plasma cells in the intestine is the organized lymphoid tissue of the Peyer's patches. Here B cells in the germinal centers are thought to switch from IgM to IgA under the influence of T cells and cytokines, in particular TGF- beta . They then migrate from the Peyer's patches to the draining mesenteric lymph nodes, where they continue to divide and differentiate. Finally they exist the lymph nodes and pass via the thoracic duct lymph into the blood, which carries them to the lamina propria of the gut. Here they complete their differentiation into the mature IgA-secreting plasma cells so characteristic of this location. During this process such Th2 cytokines as IL-5, IL-6, and IL-10 are thought to be important in inducing the switched B cells to make IgA for secretion. With regard to this IgA cell cycle, two points are worth emphasizing. One, the precursors of the plasma cells become committed to producing IgA well before they reach the intestinal lamina propria, and two, trafficking to lamina propria is independent of specific antigen even though the presence of antigen in the lamina propria can enhance the proliferation of the newly arrived B cells.
Abstract
Background
Mitral regurgitation (MR) and cardiac amyloidosis (CA) both primarily affect older patients. Data on co-existence and prognostic implications of MR and CA are currently lacking.
...Purpose
We aimed to identify prevalence, clinical characteristics and outcomes of MR-CA compared to lone MR.
Methods
Consecutive patients undergoing transcatheter edge-to-edge repair (TEER) for MR were screened for concomitant CA at two Austrian centers using a multi-parametric approach including core-lab 99mTc-DPD bone scintigraphy and echocardiography, and immunoglobulin light-chain assessment. Transthyretin-CA (ATTR) was diagnosed by DPD (Perugini Grade-1: early infiltration; Grades-2/3: clinical CA) and absence of monoclonal protein, and light-chain-(AL)-CA via tissue biopsy. Mass spectroscopy was performed in case of conflicting immunohistochemical results. All-cause mortality and hospitalization for heart failure (HHF) served as composite endpoint.
Results
In total, 120 patients (76.9±8.1 years, 55.8% male) were recruited. Clinical CA was diagnosed in n=14 (11.7%; 12 ATTR, 1 AL, 1 combined ATTR/AL), and early amyloid infiltration in n=9 (7.5%). MR-CA had higher troponin levels, thicker left ventricular walls, and a higher prevalence of carpal tunnel syndrome and left anterior fascicular block compared to lone MR (all p<0.05). Independent predictors of MR-CA were increased posterior wall thickness, and presence of left anterior fascicular block on ECG. Procedural success (MR reduction ≥1 grade) and periprocedural complications of TEER were similar in MR-CA and lone MR (p for all=n.s.).
After a median of 1.7 years, 25.8% had experienced death and/or HHF. MR-CA had worse outcomes compared to lone MR with regard to the composite endpoint (HR 2.2, 95% confidence interval 95% CI 1.0–4.7, p=0.039), driven by a 2.5-fold higher risk for HHF (HR 2.5, 95% CI 1.1–5.9), but comparable mortality (HR 1.6, 95% CI 0.4–6.1; Graphical abstract).
Conclusions
Dual pathology of MR-CA is common in elderly MR patients undergoing TEER, and has worse post-interventional outcomes compared to lone MR. Given technical feasibility of TEER in MR-CA, valvular repair should be considered as an option to improve forward volume in a state with typically low output. Future studies should evaluate the prognostic benefits of TEER and CA-specific treatment in MR-CA.
Funding Acknowledgement
Type of funding sources: None.
Early intervention with budesonide is an effective strategy for mild persistent asthma, which has been shown to provide additional clinical benefits at a low incremental cost using USA cost data. The ...present authors analysed whether this strategy would be cost-effective using cost data for other countries. Based on the 3-yr prospective, randomised, double-blind inhaled Steroid Treatment As Regular Therapy (START) in early asthma study (comparing budesonide and placebo combined with usual asthma therapy), the cost-effectiveness was estimated separately for eight different countries, from both healthcare payer and societal perspectives, of adding budesonide to usual asthma therapy. Local unit costs were applied to data for the total trial population. Incremental cost-effectiveness ratios (ICER) were estimated as cost per symptom-free day (SFD) gained. Budesonide increased SFDs by an average of 14.1 days annually. From a healthcare payer perspective, budesonide would reduce the total cost of asthma care in Australia. In Sweden, Canada, France, Spain, UK, China and the USA, the ICER ranged from US$2.4-11.3 per SFD. From a societal perspective, budesonide would be cost-saving in Australia, Canada and Sweden. In conclusion, for countries where costs with budesonide are higher, the policy implication has to be determined by that health system's willingness to pay for an additional symptom-free day. However, where budesonide therapy increases symptom-free days and reduces total costs, the policy conclusion clearly favours early intervention.
The design and manufacturing of the first model of an International Linear Collider (ILC) Main Linac superconducting quadrupole is in progress at Fermilab. The quadrupole has a 78 mm aperture, a 36 T ...integrated gradient, and a cold mass length of 700 mm. A superferric magnet configuration with iron poles and four racetrack coils was chosen based on magnet performance, cost, and reliability considerations. Each coil is wound using enamel insulated, 0.5 mm diameter, NbTi superconductor. The quadrupole package also includes shell type dipole steering coils. The results of the quadrupole design, including magnetic and mechanical analyses, are presented. Specific issues related to the quadrupole magnetic center stability, superconductor magnetization and mechanical stability are discussed and analyzed. The magnet quench protection system, current leads, and mounting the quadrupole inside ILC Main Linac cryomodule will also be briefly discussed.
Production and testing of the high-gradient superconducting quadrupole magnets developed by the US-LHC accelerator project is being completed. The production process included relative alignment of ...the two MQXB cold masses of the LQXB in a single cryostat, alignment of corrector magnet assemblies supplied by CERN on each of the triplet elements, and final magnet alignment for transfer to cryostat fiducials. Additionally, all LQXB magnets and one each of the LQXA and LQXC have had alignment measurements at Fermilab's magnet test facility (MTF) during cryogenic testing. This paper gives an overview and summary of the available alignment and strength data taken with the single stretched wire (SSW) system for the LQX magnets. Warm-to-cold changes in alignment parameters are also presented.
The US-LHC accelerator research program (LARP) built and tested the first 3.7-m long Nb{sub 3}Sn quadrupole model of LQ series with a 90 mm bore diameter and a target field gradient of 200 T/m. The ...LQ series, developed in collaboration among FNAL, LBNL and BNL, is a scale up of the previously tested 1-m long technology quadrupoles of TQ series based on similar coils and two different mechanical structures (shell-based TQS and collar-based TQC), with a primary goal of demonstrating the Nb{sub 3}Sn accelerator magnet technology for the luminosity upgrade of LHC interaction regions. In this paper, we present the field quality measurements in the first 3.7-m long LQS01 model based on the modified TQS mechanical structure. The results are compared to the expectations from the magnet geometry and magnetic properties of coils and iron yoke. Moreover, we present a comparison between this magnet and the short models previously measured.
A program to develop model magnets for a helical cooling channel is under way at Fermilab. In the first steps of a planned sequence of magnets, two four-coil helical solenoid models with 300 mm ...aperture have been fabricated and tested. These two models, HSM01 and HSM02, used insulated NbTi Rutherford cable wound onto stainless steel rings with spliceless transitions between coils. Strip heaters were included for quench protection of each coil, and the coils were epoxy-impregnated after winding inside the support structures. Based on the results of the first model the second model was made using a cable with optimized cross-section, improved winding and epoxy-impregnation procedures, enhanced ground insulation, and included heat exchange tubing for a test of conduction cooling. We report on the results and lessons learned from fabrication and tests of these two models.
A Thermosiphon cooling scheme is a productive way of cooling large scale superconducting magnets. The absence of active pumping and the availability of the higher heat capacity parameter "latent ...heat" make this an attractive cooling method. Nevertheless, the design of such a system demands a well-organized study of the effect of various flow parameters, such as, mass flow rates, flow quality, etc., and also a robust mechanical design of the various components of the system. This paper presents an analytical approach to designing a thermosiphon cooling scheme based on homogeneous flow conditions as well as separated flow conditions. The design of the mechanical components such as the piping is also discussed. The design approach presented here has been applied to the reference design of two large superconducting solenoids, the Production Solenoid and the Detector Solenoid of the Mu2e experiment at Fermilab.
Intravesical therapy with bacillus Calmette-Guerin (BCG) has proved to be more effective in the prophylaxis and treatment of superficial bladder tumors and carcinoma in situ than most ...chemotherapeutic agents. Compared to intravesical chemotherapy, instillations with BCG provoke more local and systemic reactions. In addition to the commonly induced granulomatous inflammatory changes in the bladder, which produce irritative symptoms, this therapy may cause systemic side effects varying from mild malaise and fever to, in rare instances, life-threatening or fatal sepsis. We report the incidence and varieties of toxicities in 2,602 patients treated with intravesical BCG. Side effects are classified according to local and systemic toxicity. Treatment options vary according to the severity of toxicity from delaying or withholding instillations to treatment with antituberculous drugs for up to 6 months. In general, 95% of the patients have no serious side effects. Recognition of risk factors, particularly traumatic catheterization or concurrent cystitis, that result in systemic BCG absorption, as well as the prompt and appropriate treatment of early side effects should significantly decrease the incidence of severe toxicity.
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