Pharmacological Inhibition of MALT1 Ameliorates Autoimmune Pathogenesis and Can Be Uncoupled From Effects on Regulatory T-Cells.

MALT1 forms part of a central signaling node downstream of immunoreceptor tyrosine-based activation motif (ITAM)-containing receptors, across a broad range of immune cell subsets, and regulates NF-κB driven transcriptional responses via dual scaffolding-protease activity. Allosteric inhibition of MALT1 activity has demonstrated benefit in animal models of inflammation. However, development of MALT1 inhibitors to treat autoimmune and inflammatory diseases (A&ID) has been hindered by reports linking MALT1 inhibition and genetic loss-of-function to reductions in regulatory T-cell (Treg) numbers and development of auto-inflammatory syndromes. Using an allosteric MALT1 inhibitor, we investigated the consequence of pharmacological inhibition of MALT1 on proinflammatory cells compared to regulatory T-cells. Consistent with its known role in ITAM-driven responses, MALT1 inhibition suppressed proinflammatory cytokine production from activated human T-cells and monocyte-derived macrophages, and attenuated B-cell proliferation. Oral administration of a MALT1 inhibitor reduced disease severity and synovial cytokine production in a rat collagen-induced arthritis model. Interestingly, reduction in splenic Treg numbers was less pronounced in the context of inflammation compared with naïve animals. Additionally, in the context of the disease model, we observed an uncoupling of anti-inflammatory effects of MALT1 inhibition from Treg reduction, with lower systemic concentrations of inhibitor needed to reduce disease severity compared to that required to reduce Treg numbers. MALT1 inhibition did not affect suppressive function of human Tregs in vitro. These data indicate that anti-inflammatory efficacy can be achieved with MALT1 inhibition without impacting the number or function of Tregs, further supporting the potential of MALT1 inhibition in the treatment of autoimmune disease.

No Evidence for Axions from Chandra Observation of the Magnetic White Dwarf RE J0317-853.

Axions with couplings g_{aγγ}∼few×10^{-11} GeV^{-1} to electromagnetism may resolve a number of astrophysical anomalies, such as unexpected ∼TeV transparency, anomalous stellar cooling, and x-ray excesses from nearby neutron stars. We show, however, that such axions are severely constrained by the nonobservation of x rays from the magnetic white dwarf (MWD) RE J0317-853 using ∼40 ks of data acquired from a dedicated observation with the Chandra X-ray Observatory. Axions may be produced in the core of the MWD through electron bremsstrahlung and then convert to x rays in the magnetosphere. The nonobservation of x rays constrains the axion-photon coupling to g_{aγγ}≲5.5×10^{-13}sqrt[C_{aγγ}/C_{aee}] GeV^{-1} at 95% confidence for axion masses m_{a}≲5×10^{-6} eV, with C_{aee} and C_{aγγ} the dimensionless coupling constants to electrons and photons. Considering that C_{aee} is generated from the renormalization group, our results robustly disfavor g_{aγγ}≳4.4×10^{-11} GeV^{-1} even for models with no ultraviolet contribution to C_{aee}.

Upper Limit on the QCD Axion Mass from Isolated Neutron Star Cooling.

The quantum chromodynamics (QCD) axion may modify the cooling rates of neutron stars (NSs). The axions are produced within the NS cores from nucleon bremsstrahlung and, when the nucleons are in superfluid states, Cooper pair breaking and formation processes. We show that four of the nearby isolated magnificent seven NSs along with PSR J0659 are prime candidates for axion cooling studies because they are coeval, with ages of a few hundred thousand years known from kinematic considerations, and they have well-measured surface luminosities. We compare these data to dedicated NS cooling simulations incorporating axions, profiling over uncertainties related to the equation of state, NS masses, surface compositions, and superfluidity. Our calculations of the axion and neutrino emissivities include high-density suppression factors that also affect SN 1987A and previous NS cooling limits on axions. We find no evidence for axions in the isolated NS data, and within the context of the Kim-Shifman-Vainshtein-Zakharov QCD axion model, we constrain m_{a}≲16 meV at 95% confidence level. An improved understanding of NS cooling and nucleon superfluidity could further improve these limits or lead to the discovery of the axion at weaker couplings.

Gravitino Swampland Conjecture.

We extend the swampland from effective field theories (EFTs) inconsistent with quantum gravity to EFTs inconsistent with quantum supergravity. This enlarges the swampland to include EFTs that become inconsistent when the gravitino is quantized. We propose the "gravitino swampland conjecture": the gravitino sound speed must be nonvanishing in all EFTs that are low-energy limits of quantum supergravity. This seemingly simple statement has important consequences for both theories and observations. The conjecture is consistent with and supported by the Kachru-Kallosh-Linde-Trivedi and large volume scenarios for moduli stabilization in string theory.

Identification of Pru du 6 as a potential marker allergen for almond allergy.

BACKGROUND: Oral food challenges have demonstrated that diagnosis of almond allergy based on extract-sIgE tests displays low specificity. Molecular allergy diagnosis is expected to improve accuracy, but its value in diagnosing almond allergy remains unknown. The aim of this study was to identify relevant almond allergens and examine their ability to improve almond allergy diagnosis. METHODS: IgE-reactive proteins were purified from almond kernels. IgE binding to almond extract and the allergens was analyzed by quantitative ELISA using sera from 18 subjects with a proven almond allergy. The control group consisted of sera from 18 subjects allergic to peanut and/or tree nuts but tolerant to almond. RESULTS: Three IgE-binding proteins were identified: legumin (Pru du 6), alpha-hairpinin (Pru du 8), and mandelonitrile lyase (Pru du 10). Positive IgE (≥0.35 kU/L) to almond extract showed 94% sensitivity but only 33% specificity. IgE to Pru du 6 maintained high sensitivity (83%) and provided superior specificity (78%). Sera from almond-allergic subjects had significantly higher IgE levels to almond extract (P < .0001) and Pru du 6 (P < .0001) than sera from tolerant donors. Sensitization to Pru du 6 was highly specific for almond allergy, while frequencies of sensitization to legumins from peanut, walnut, hazelnut, and cashew were similar in both groups. IgE to Pru du 8 and Pru du 10 was less sensitive (41% and 67%), but showed specificities of 100% and 61%. CONCLUSION: The use of almond allergens markedly increases the diagnostic specificity compared to the extract. Pru du 6 is a potential new molecular marker for almond allergy.

The JAK1 Selective Inhibitor ABT 317 Blocks Signaling Through Interferon-γ and Common γ Chain Cytokine Receptors to Reverse Autoimmune Diabetes in NOD Mice.

Cytokines that signal through the JAK-STAT pathway, such as interferon-γ (IFN-γ) and common γ chain cytokines, contribute to the destruction of insulin-secreting ß cells by CD8+ T cells in type 1 diabetes (T1D). We previously showed that JAK1/JAK2 inhibitors reversed autoimmune insulitis in non-obese diabetic (NOD) mice and also blocked IFN-γ mediated MHC class I upregulation on ß cells. Blocking interferons on their own does not prevent diabetes in knockout NOD mice, so we tested whether JAK inhibitor action on signaling downstream of common γ chain cytokines, including IL-2, IL-7 IL-15, and IL-21, may also affect the progression of diabetes in NOD mice. Common γ chain cytokines activate JAK1 and JAK3 to regulate T cell proliferation. We used a JAK1-selective inhibitor, ABT 317, to better understand the specific role of JAK1 signaling in autoimmune diabetes. ABT 317 reduced IL-21, IL-2, IL-15 and IL-7 signaling in T cells and IFN-γ signaling in ß cells, but ABT 317 did not affect GM-CSF signaling in granulocytes. When given in vivo to NOD mice, ABT 317 reduced CD8+ T cell proliferation as well as the number of KLRG+ effector and CD44hiCD62Llo effector memory CD8+ T cells in spleen. ABT 317 also prevented MHC class I upregulation on ß cells. Newly diagnosed diabetes was reversed in 94% NOD mice treated twice daily with ABT 317 while still on treatment at 40 days and 44% remained normoglycemic after a further 60 days from discontinuing the drug. Our results indicate that ABT 317 blocks common γ chain cytokines in lymphocytes and interferons in lymphocytes and ß cells and are thus more effective against diabetes pathogenesis than IFN-γ receptor deficiency alone. Our studies suggest use of this class of drug for the treatment of type 1 diabetes.

Corrigendum: Analysis of a Large Standardized Food Challenge Data Set to Determine Predictors of Positive Outcome Across Multiple Allergens.

[This corrects the article DOI: 10.3389/fimmu.2018.02689.].

Filtered Dark Matter at a First Order Phase Transition.

We describe a new mechanism of dark matter production. If dark matter particles acquire mass during a first order phase transition, it is energetically unfavorable for them to enter the expanding bubbles. Instead, most of them are reflected and quickly annihilate away. The bubbles eventually merge as the phase transition completes and only the dark matter particles that have entered the bubbles survive to constitute the observed dark matter today. This mechanism can produce dark matter with masses from the TeV scale to above the PeV scale, surpassing the Griest-Kamionkowski bound.

STAT3 phosphorylation mediates the stimulatory effects of interferon alpha on B cell differentiation and activation in SLE.

OBJECTIVE: Type I IFNs play a well-known role in the pathogenesis of SLE, through activation of CD4 T and antigen-presenting cells. Here, we investigated the effects of IFN alpha (IFNα) on SLE B cell activation and differentiation. METHODS: Peripheral blood mononuclear cells (PBMCs) and purified total or naïve B cells were obtained from healthy controls and SLE patients. The effects of IFNα on B cell differentiation were studied by flow cytometry. The role of STAT3 in B cell responses to IFNα was studied using pharmacological inhibitors and PBMCs from STAT3-deficient individuals. RESULTS: Incubation of normal PBMCs with IFNα induces a B cell differentiation pattern as observed spontaneously in SLE PBMCs. IFNα displays direct stimulatory effects on purified naïve B cells from healthy individuals, as evidenced by a significant induction of cell surface CD38 and CD95 in the presence of the cytokine. In purified naïve B cells, IFNα also induces STAT3 phosphorylation. IFNα-induced naïve B cell differentiation in total PBMCs is significantly inhibited in the presence of STAT3 inhibitors, or in PBMCs from individuals with STAT3 loss of function mutations. Spontaneous levels of STAT3, but not STAT1, phosphorylation are significantly higher in total B cells from SLE patients compared with controls. Pharmacological STAT3 inhibition in SLE PBMCs inhibits naïve B cell activation and differentiation. CONCLUSION: IFNα displays direct stimulatory effects on B cell differentiation and activation in SLE. STAT3 phosphorylation mediates the effects of IFNα stimulation in naïve B cells, an observation that opens new therapeutic perspectives in SLE.

X-Ray Signatures of Axion Conversion in Magnetic White Dwarf Stars.

White dwarf (WD) stars may radiate keV-energy axions produced in their stellar cores. This has been extensively studied as an extra channel by which WDs may cool, with some analyses even suggesting that axions can help explain the observed WD luminosity function. We show that the radiated axions may convert into x rays in the strong magnetic fields surrounding the WDs, leading to observable x-ray signatures. We use Suzaku observations of the WD RE J0317-853 to set the strongest constraints to date on the combination of the axion-electron (g_{aee}) times axion-photon (g_{aγγ}) couplings, and we show that dedicated observations of magnetic WDs by telescopes such as Chandra, XMM-Newton, and NuSTAR could increase the sensitivity to |g_{aee}g_{aγγ}| by over an order of magnitude, allowing for a definitive test of the axionlike-particle explanation of the stellar cooling anomalies.

Can the Inflaton Also Be a Weakly Interacting Massive Particle?

We propose a class of models in which a stable inflaton is produced as a thermal relic in the early Universe and constitutes the dark matter. We show that inflaton annihilations can efficiently reheat the Universe, and identify several examples of inflationary potentials that can accommodate all cosmic microwave background observables and in which the inflaton dark matter candidate has a weak scale mass. As a simple example, we consider annihilations that take place through a Higgs portal interaction, leading to encouraging prospects for future direct detection experiments.

ABBV-105, a selective and irreversible inhibitor of Bruton's tyrosine kinase, is efficacious in multiple preclinical models of inflammation.

OBJECTIVES: Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase required for intracellular signaling downstream of multiple immunoreceptors. We evaluated ABBV-105, a covalent BTK inhibitor, using in vitro and in vivo assays to determine potency, selectivity, and efficacy to validate the therapeutic potential of ABBV-105 in inflammatory disease. METHODS: ABBV-105 potency and selectivity were evaluated in enzymatic and cellular assays. The impact of ABBV-105 on B cell function in vivo was assessed using mechanistic models of antibody production. Efficacy of ABBV-105 in chronic inflammatory disease was evaluated in animal models of arthritis and lupus. Measurement of BTK occupancy was employed as a target engagement biomarker. RESULTS: ABBV-105 irreversibly inhibits BTK, demonstrating superior kinome selectivity and is potent in B cell receptor, Fc receptor, and TLR-9-dependent cellular assays. Oral administration resulted in rapid clearance in plasma, but maintenance of BTK splenic occupancy. ABBV-105 inhibited antibody responses to thymus-independent and thymus-dependent antigens, paw swelling and bone destruction in rat collagen induced arthritis, and reduced disease in an IFNα-accelerated lupus nephritis model. BTK occupancy in disease models correlated with in vivo efficacy. CONCLUSION: ABBV-105, a selective BTK inhibitor, demonstrates compelling efficacy in pre-clinical mechanistic models of antibody production and in models of rheumatoid arthritis and lupus.

Analysis of a Large Standardized Food Challenge Data Set to Determine Predictors of Positive Outcome Across Multiple Allergens.

Background: Double-blind placebo-controlled food challenges (DBPCFCs) remain the gold standard for the diagnosis of food allergy; however, challenges require significant time and resources and place the patient at an increased risk for severe allergic adverse events. There have been continued efforts to identify alternative diagnostic methods to replace or minimize the need for oral food challenges (OFCs) in the diagnosis of food allergy. Methods: Data was extracted for all IRB-approved, Stanford-initiated clinical protocols involving standardized screening OFCs to a cumulative dose of 500 mg protein to any of 11 food allergens in participants with elevated skin prick test (SPT) and/or specific IgE (sIgE) values to the challenged food across 7 sites. Baseline population characteristics, biomarkers, and challenge outcomes were analyzed to develop diagnostic criteria predictive of positive OFCs across multiple allergens in our multi-allergic cohorts. Results: A total of 1247 OFCs completed by 427 participants were analyzed in this cohort. Eighty-five percent of all OFCs had positive challenges. A history of atopic dermatitis and multiple food allergies were significantly associated with a higher risk of positive OFCs. The majority of food-specific SPT, sIgE, and sIgE/total IgE (tIgE) thresholds calculated from cumulative tolerated dose (CTD)-dependent receiver operator curves (ROC) had high discrimination of OFC outcome (area under the curves > 0.75). Participants with values above the thresholds were more likely to have positive challenges. Conclusions: This is the first study, to our knowledge, to not only adjust for tolerated allergen dose in predicting OFC outcome, but to also use this method to establish biomarker thresholds. The presented findings suggest that readily obtainable biomarker values and patient demographics may be of use in the prediction of OFC outcome and food allergy. In the subset of patients with SPT or sIgE values above the thresholds, values appear highly predictive of a positive OFC and true food allergy. While these values are relatively high, they may serve as an appropriate substitute for food challenges in clinical and research settings.

In vitro and in vivo characterization of the JAK1 selectivity of upadacitinib (ABT-494).

BACKGROUND: Anti-cytokine therapies such as adalimumab, tocilizumab, and the small molecule JAK inhibitor tofacitinib have proven that cytokines and their subsequent downstream signaling processes are important in the pathogenesis of rheumatoid arthritis. Tofacitinib, a pan-JAK inhibitor, is the first approved JAK inhibitor for the treatment of RA and has been shown to be effective in managing disease. However, in phase 2 dose-ranging studies tofacitinib was associated with dose-limiting tolerability and safety issues such as anemia. Upadacitinib (ABT-494) is a selective JAK1 inhibitor that was engineered to address the hypothesis that greater JAK1 selectivity over other JAK family members will translate into a more favorable benefit:risk profile. Upadacitinib selectively targets JAK1 dependent disease drivers such as IL-6 and IFNγ, while reducing effects on reticulocytes and natural killer (NK) cells, which potentially contributed to the tolerability issues of tofacitinib. METHODS: Structure-based hypotheses were used to design the JAK1 selective inhibitor upadacitinib. JAK family selectivity was defined with in vitro assays including biochemical assessments, engineered cell lines, and cytokine stimulation. In vivo selectivity was defined by the efficacy of upadacitinib and tofacitinib in a rat adjuvant induced arthritis model, activity on reticulocyte deployment, and effect on circulating NK cells. The translation of the preclinical JAK1 selectivity was assessed in healthy volunteers using ex vivo stimulation with JAK-dependent cytokines. RESULTS: Here, we show the structural basis for the JAK1 selectivity of upadacitinib, along with the in vitro JAK family selectivity profile and subsequent in vivo physiological consequences. Upadacitinib is ~ 60 fold selective for JAK1 over JAK2, and > 100 fold selective over JAK3 in cellular assays. While both upadacitinib and tofacitinib demonstrated efficacy in a rat model of arthritis, the increased selectivity of upadacitinib for JAK1 resulted in a reduced effect on reticulocyte deployment and NK cell depletion relative to efficacy. Ex vivo pharmacodynamic data obtained from Phase I healthy volunteers confirmed the JAK1 selectivity of upadactinib in a clinical setting. CONCLUSIONS: The data presented here highlight the JAK1 selectivity of upadacinitinib and supports its use as an effective therapy for the treatment of RA with the potential for an improved benefit:risk profile.

Radical gastric cancer surgery results in widespread upregulation of pro-tumourigenic intraperitoneal cytokines.

BACKGROUND: Radical surgical resection is the mainstay of curative treatment for oesophagogastric malignancy. However, survival and recurrence rates remain poor. Theoretical data suggests that the inflammatory response to surgery can promote tumour recurrence. The local and systemic inflammatory response to radical oesophagogastric cancer surgery has not been fully characterized. We aimed to measure this response, particularly factors associated with tumour implantation. METHODS: Consecutive patients undergoing radical junctional or gastric cancer resection over 12 months were recruited. Repeated serum and adipose tissue were collected intra-operatively. Adipose tissue was collected adjacent and remote to the tumour, and cytokine messenger RNA (mRNA) expression was measured. Post-operatively, daily serum was collected for 7 days, and analysed for inflammatory cell profile and cytokine concentration. RESULTS: There were nine patients recruited (67.1 ± 2.1 years). mRNA expression of interleukin-6 (IL-6), CC-chemokine ligand-2 and IL-1ß increased in adipose tissue intra-operatively (P < 0.05), equally both adjacent and remote from the tumour site. Serum IL-6 concentration increased from 23.3 pg/mL to 161.8 pg/mL intra-operatively (P < 0.05) before falling steadily to 35.7 pg/mL post-operatively (P < 0.05). Serum tumour necrosis factor-α was elevated throughout, and IL-1ß levels were unaffected. Leukocyte and neutrophil populations increased, while T-cell and dendritic cell populations decreased intra-operatively (P < 0.05). CONCLUSION: Radical surgery dramatically upregulates the expression of pro-tumourigenic cytokines in the peritoneum. There is also a marked systemic immune and inflammatory response to surgery, including downregulation of T-cell and dendritic cell populations. This offers two potential pathways that may facilitate tumour progression - local inflammation promoting peritoneal adherence and implantation, and secondary suppression of immunosurveillance due to circulating inflammatory response.

Anti-IgE treatment with oral immunotherapy in multifood allergic participants: a double-blind, randomised, controlled trial.

BACKGROUND: Despite progress in single food oral immunotherapy, there is little evidence concerning the safety and efficacy of treating individuals with multiple food (multifood) allergies. We did a pilot study testing whether anti-IgE (omalizumab) combined with multifood oral immunotherapy benefited multifood allergic patients. METHODS: We did a blinded, phase 2 clinical trial at Stanford University. We enrolled participants, aged 4-15 years, with multifood allergies validated by double-blind, placebo-controlled food challenges to their offending foods. Inclusion criteria included a positive skin prick test of 6 mm or more (wheal diameter, above the negative control), a food-specific serum IgE concentration of more than 4 kU/L for each food, or both, and a positive double-blind, placebo-controlled food challenge at 500 mg or less of food protein. Exclusion criteria included eosinophilic oesophagitis and severe asthma. Participants were randomised (3:1) with a block size of four, to receive multifood oral immunotherapy to two to five foods, together with omalizumab (n=36) or placebo (n=12). 12 individuals who fulfilled the same inclusion and exclusion criteria were included as controls. These individuals were not randomised and received neither omalizumab nor oral immunotherapy. Omalizumab or placebo was administered subcutaneously for 16 weeks, with oral immunotherapy starting at week 8, and was stopped 20 weeks before the exit double-blind, placebo-controlled food challenge at week 36. The primary endpoint was the proportion of participants who passed double-blind, placebo-controlled food challenges to at least two of their offending foods. This completed trial is registered with ClinicalTrials.gov, number NCT02643862. FINDINGS: Between March 25, 2015, and Aug 18, 2016, 165 participants were assessed for eligibility, of whom 84 did not meet the inclusion criteria and 21 declined to participate. We enrolled and randomised 48 eligible participants and the remaining 12 patients were included as nonrandomised, untreated controls. At week 36, a significantly greater proportion of the omalizumab-treated (30 [83%] of 36) versus placebo (four [33%] of 12) participants passed double-blind, placebo-controlled food challenges to 2 g protein for two or more of their offending foods (odds ratio 10·0, 95% CI 1·8-58·3, p=0·0044). All participants completed the study. There were no serious or severe (grade 3 or worse) adverse events. Participants in the omalizumab group had a significantly lower median per-participant percentage of oral immunotherapy doses associated with any adverse events (27% vs 68%; p=0·0082). The most common adverse events in both groups were gastrointestinal events. INTERPRETATION: In multifood allergic patients, omalizumab improves the efficacy of multifood oral immunotherapy and enables safe and rapid desensitisation. FUNDING: US National Institutes of Health (NIH).

Syk Inhibition Induces Platelet Dependent Peri-islet Hemorrhage in the Rat Pancreas.

Spleen tyrosine kinase (Syk) is a nonreceptor tyrosine kinase that is an important signaling enzyme downstream of immunoreceptors containing an intracellular immunoreceptor tyrosine activating motif (ITAM). These receptors encompass a wide variety of biological functions involved in autoimmune disease pathogenesis. There has been considerable interest in the development of inhibitors of the Syk pathway for the treatment of rheumatoid arthritis and systemic lupus erythematosus. We report that Syk inhibition mechanistically caused peri-islet hemorrhages and fibrin deposition in the rat pancreas and that this finding is due to a homeostatic functional defect in platelets. In more limited studies, similar lesions could not be induced in mice, dogs, and cynomolgus monkeys at similar or higher plasma drug concentrations. Irradiation-induced thrombocytopenia caused a phenotypically similar peri-islet pancreas lesion and the formation of this lesion could be prevented by platelet transfusion. In addition, Syk inhibitor-induced lesions were prevented by the coadministration of prednisone. A relatively greater sensitivity of rat platelets to Syk inhibition was supported by functional analyses demonstrating rat-specific differences in response to convulxin, a glycoprotein VI agonist that signals through Syk. These data demonstrate that the Syk pathway is critical in platelet-endothelial cell homeostasis in the peri-islet pancreatic microvasculature in rats.

Concurrent Large Para-oesophageal Hiatal Hernia Repair and Laparoscopic Adjustable Gastric Banding: Results from 5-year Follow Up.

OBJECTIVE: The objective of the study is to identify the efficacy and safety of combining laparoscopic adjustable gastric banding with repair of large para-oesophageal hernias. BACKGROUND: Para-oesophageal hernias are more common in the obese with higher recurrence rates following repair. The effect and safety of combining para-oesophageal hernia repair with laparoscopic adjustable gastric banding is unknown. METHODS: One-hundred fourteen consecutive patients undergoing primary laparoscopic adjustable gastric banding with concurrent repair of a large para-oesophageal hernia were prospectively identified and matched to a control group undergoing primary laparoscopic adjustable gastric banding only. Weight loss and complication data were retrieved from a prospectively maintained database, and a standardised bariatric outcome questionnaire was used to assess post-operative symptoms, satisfaction with surgery and satiety scores. RESULTS: At a mean follow up of 4.9 ± 2.1 years, total weight loss was 16.4 ± 9.9% in the hernia repair group and 17.6 ± 12.6% in the control group (p = 0.949), with 17 vs. 11% loss to follow up rates (p = 0.246). No statistically significant difference in revisional surgery rate and symptomatic recurrence of hiatal hernia was documented in four patients in the hernia repair group (3.5%). No statistically significant difference in mean reflux (9.9 vs. 10.3, p = 0.821), dysphagia (20.7 vs. 20.1, p = 0.630) or satiety scores was identified. CONCLUSIONS: Concurrent repair of large para-oesophageal hiatal hernia and laparoscopic adjustable gastric banding placement is safe and effective both in terms of symptom control and weight loss over the intermediate term. In obese patients with large hiatal hernias, consideration should be given to combining repair of the hernia with a bariatric procedure.

Influenza vaccine antibody response and 6-month persistence in lung transplant recipients using two definitions of seroprotection.

BACKGROUND: Lung transplant recipients are among those with the highest risk of influenza infection and complications each year. A few studies show adequate responses after influenza immunization; no studies examined the season-long protection. METHODS: Influenza antibody concentrations were measured using hemagglutination inhibition assays before immunization, 2 to 4 weeks after immunization, and 6 months after immunization in 25 healthy controls and 54 lung transplant patients. Two definitions of seroprotection (40 hemagglutination units (HAU) and 160 HAU which confers about 95% protection) were used. RESULTS: Influenza vaccine responses were high in both groups postimmunization (100% at 40 HAU and 60% healthy and 61% lung transplant at 160 HAU; P = 1.0; chi-square). At 6 months after immunization, seroprotection rates at 40 HAU (95% healthy and 97% lung transplant; P = 1.0) and at 160 HAU (24% healthy and 36% lung transplant; P = 0.40) were observed. CONCLUSION: Seroprotection rates do not differ between healthy and transplant groups over 6 months when 40 HAU or 160 HAU is used. However, the seroprotection rates are disappointingly low when 160 HAU (the antibody concentration associated with 95% protection from infection) is used. Annual influenza vaccine should continue to be a high priority for lung transplant patients.