Pediatric And Adult Lung Transplantation For Cystic Fibrosis

AbstractObjective: This paper was undertaken to review the experience at our institution with bilateral sequential lung transplantation for cystic fibrosis.Methods: Since 1989, 103 bilateral sequential lung transplants for cystic fibrosis have been performed (46 pediatric, 48 adult, 9 redo); the mean age was 21 ± 10 years. Cardiopulmonary bypass was used in all but one pediatric (age <18) transplant, and in 15% of adults.Results: Hospital mortality was 4.9%, with 80% of early deaths related to infection. Bronchial anastomotic complications occurred with equal frequency in the pediatric and the adult populations (7.3%). One- and 3-year actuarial survival are 84% and 61%, respectively (no significant difference between pediatric and adult age groups; average follow-up 2.1 ± 1.6 years). Mean forced expiratory volume in 1 second increased from 25% ± 9% before transplantation to 79% ± 35% 1 year after transplantation. Acute rejection occurred 1.7 times per patient-year, with most episodes taking place within the first 6 months after transplantation. The need for treatment of lower respiratory tract infections occurred 1.2 times per patient in the first year after transplantation. Actuarial freedom from bronchiolitis obliterans was 63% at 2 years and 43% at 3 years. Redo transplantation was performed only in the pediatric population and was associated with an early mortality of 33%. Eight living donor transplants (four primary transplants, four redo transplants) were performed with an early survival of 87.5%.Conclusion: Patients with end-stage cystic fibrosis can undergo bilateral lung transplantation with morbidity and mortality comparable to that seen in pulmonary transplantation for other disease entities. (J Thorac Cardiovasc Surg 1998;115:404-14

Securing the legacy of TESS through the care and maintenance of TESS planet ephemerides

Much of the science from the exoplanets detected by the TESS mission relies on precisely predicted transit times that are needed for many follow-up characterization studies. We investigate ephemeris deterioration for simulated TESS planets and find that the ephemerides of 81% of those will have expired (i.e. 1$\sigma$ mid-transit time uncertainties greater than 30 minutes) one year after their TESS observations. We verify these results using a sample of TESS planet candidates as well. In particular, of the simulated planets that would be recommended as JWST targets by Kempton et al. (2018), $\sim$80% will have mid-transit time uncertainties $>$ 30 minutes by the earliest time JWST would observe them. This rapid deterioration is driven primarily by the relatively short time baseline of TESS observations. We describe strategies for maintaining TESS ephemerides fresh through follow-up transit observations. We find that the longer the baseline between the TESS and the follow-up observations, the longer the ephemerides stay fresh, and that 51% of simulated primary mission TESS planets will require space-based observations. The recently-approved extension to the TESS mission will rescue the ephemerides of most (though not all) primary mission planets, but the benefits of these new observations can only be reaped two years after the primary mission observations. Moreover, the ephemerides of most primary mission TESS planets (as well as those newly discovered during the extended mission) will again have expired by the time future facilities such as the ELTs, Ariel and the possible LUVOIR/OST missions come online, unless maintenance follow-up observations are obtained.Comment: 16 pages, 10 figures, accepted to AJ; main changes are cross-checking results against the sample of real TOIs, and addressing the impact of the TESS extended missio

Securing the Legacy of TESS through the Care and Maintenance of TESS Planet Ephemerides

Much of the science from the exoplanets detected by the Transiting Exoplanet Survey Satellite (TESS) mission relies on precisely predicted transit times that are needed for many follow-up characterization studies. We investigate ephemeris deterioration for simulated TESS planets and find that the ephemerides of 81% of those will have expired (i.e., 1σ mid-transit time uncertainties greater than 30 minutes) 1 yr after their TESS observations. We verify these results using a sample of TESS planet candidates as well. In particular, of the simulated planets that would be recommended as James Webb Space Telescope (JWST) targets by Kempton et al., ~80% will have mid-transit time uncertainties >30 minutes by the earliest time JWST would observe them. This rapid deterioration is driven primarily by the relatively short time baseline of TESS observations. We describe strategies for maintaining TESS ephemerides fresh through follow-up transit observations. We find that the longer the baseline between the TESS and the follow-up observations, the longer the ephemerides stay fresh, and that 51% of simulated primary mission TESS planets will require space-based observations. The recently approved extension to the TESS mission will rescue the ephemerides of most (though not all) primary mission planets, but the benefits of these new observations can only be reaped 2 yr after the primary mission observations. Moreover, the ephemerides of most primary mission TESS planets (as well as those newly discovered during the extended mission) will again have expired by the time future facilities such as the ELTs, Ariel, and the possible LUVOIR/Origins Space Telescope missions come online, unless maintenance follow-up observations are obtained

Separated twins or just siblings? A multi-planet system around an M dwarf including a cool sub-Neptune

We report the discovery of two TESS sub-Neptunes orbiting the early M dwarf TOI-904 (TIC 261257684). Both exoplanets, TOI-904 b and c, were initially observed in TESS sector 12 with twin sizes of 2.49R$_\oplus$ and 2.31R$_\oplus$, respectively. Through observations in five additional sectors in the TESS primary mission and the first and second extended missions, the orbital periods of both planets were measured to be 10.887$\pm$0.001 and 83.999$\pm$0.001 days, respectively. Reconnaissance radial velocity measurements (taken with EULER/CORALIE) and high resolution speckle imaging with adaptive optics (obtained from SOAR/HRCAM and Gemini South/ZORRO) show no evidence of an eclipsing binary or a nearby companion, which together with the low false positive probabilities calculated with the statistical validation software TRICERATOPS establish the planetary nature of these candidates. The outer planet, TOI-904 c, is the longest-period M dwarf exoplanet found by TESS, with an estimated equilibrium temperature of 217K. As the three other validated planets with comparable host stars and orbital periods were observed by Kepler around much dimmer stars (J$_{mag}$ $>$ 12), TOI-904 c, orbiting a brighter star (J$_{mag}$ $=$ 9.6), is the coldest M dwarf planet easily accessible for atmospheric follow-up. Future mass measurements and transmission spectroscopy of the similar sized planets in this system could determine whether they are also similar in density and composition, suggesting a common formation pathway, or whether they have distinct origins.Comment: 18 pages, 6 figures, Accepted by the Astrophysical Journal Letter

Interleukin-22 Protects Intestinal Stem Cells from Immune-Mediated Tissue Damage and Regulates Sensitivity to Graft versus Host Disease

SummaryLittle is known about the maintenance of intestinal stem cells (ISCs) and progenitors during immune-mediated tissue damage or about the susceptibility of transplant recipients to tissue damage mediated by the donor immune system during graft versus host disease (GVHD). We demonstrate here that deficiency of recipient-derived IL-22 increased acute GVHD tissue damage and mortality, that ISCs were eliminated during GVHD, and that ISCs as well as their downstream progenitors expressed the IL-22 receptor. Intestinal IL-22 was produced after bone marrow transplant by IL-23-responsive innate lymphoid cells (ILCs) from the transplant recipients, and intestinal IL-22 increased in response to pretransplant conditioning. However, ILC frequency and IL-22 amounts were decreased by GVHD. Recipient IL-22 deficiency led to increased crypt apoptosis, depletion of ISCs, and loss of epithelial integrity. Our findings reveal IL-22 as a critical regulator of tissue sensitivity to GVHD and a protective factor for ISCs during inflammatory intestinal damage

Factors affecting glomerular filtration rate, as measured by iohexol disappearance, in men with or at risk for HIV infection

Objective: Formulae used to estimate glomerular filtration rate (GFR) underestimate higher GFRs and have not been well-studied in HIV-infected (HIV(+)) people; we evaluated the relationships of HIV infection and known or potential risk factors for kidney disease with directly measured GFR and the presence of chronic kidney disease (CKD). Design: Cross-sectional measurement of iohexol-based GFR (iGFR) in HIV(+) men (n = 455) receiving antiretroviral therapy, and HIV-uninfected (HIV(-)) men (n = 258) in the Multicenter AIDS Cohort Study. Methods: iGFR was calculated from disappearance of infused iohexol from plasma. Determinants of GFR and the presence of CKD were compared using iGFR and GFR estimated by the CKD-Epi equation (eGFR). Results: Median iGFR was higher among HIV(+) than HIV(-) men (109 vs. 106 ml/min/1.73 m2, respectively, p = .046), and was 7 ml/min higher than median eGFR. Mean iGFR was lower in men who were older, had chronic hepatitis C virus (HCV) infection, or had a history of AIDS. Low iGFR (≤90 ml/min/1.73 m2) was associated with these factors and with black race. Other than age, factors associated with low iGFR were not observed with low eGFR. CKD was more common in HIV(+) than HIV(-) men; predictors of CKD were similar using iGFR and eGFR. Conclusions: iGFR was higher than eGFR in this population of HIV-infected and -uninfected men who have sex with men. Presence of CKD was predicted equally well by iGFR and eGFR, but associations of chronic HCV infection and history of clinically-defined AIDS with mildly decreased GFR were seen only with iGFR. © 2014 Margolick et al

Characterizing Long COVID: Deep Phenotype of a Complex Condition.

BACKGROUND: Numerous publications describe the clinical manifestations of post-acute sequelae of SARS-CoV-2 (PASC or long COVID ), but they are difficult to integrate because of heterogeneous methods and the lack of a standard for denoting the many phenotypic manifestations. Patient-led studies are of particular importance for understanding the natural history of COVID-19, but integration is hampered because they often use different terms to describe the same symptom or condition. This significant disparity in patient versus clinical characterization motivated the proposed ontological approach to specifying manifestations, which will improve capture and integration of future long COVID studies. METHODS: The Human Phenotype Ontology (HPO) is a widely used standard for exchange and analysis of phenotypic abnormalities in human disease but has not yet been applied to the analysis of COVID-19. FINDINGS: We identified 303 articles published before April 29, 2021, curated 59 relevant manuscripts that described clinical manifestations in 81 cohorts three weeks or more following acute COVID-19, and mapped 287 unique clinical findings to HPO terms. We present layperson synonyms and definitions that can be used to link patient self-report questionnaires to standard medical terminology. Long COVID clinical manifestations are not assessed consistently across studies, and most manifestations have been reported with a wide range of synonyms by different authors. Across at least 10 cohorts, authors reported 31 unique clinical features corresponding to HPO terms; the most commonly reported feature was Fatigue (median 45.1%) and the least commonly reported was Nausea (median 3.9%), but the reported percentages varied widely between studies. INTERPRETATION: Translating long COVID manifestations into computable HPO terms will improve analysis, data capture, and classification of long COVID patients. If researchers, clinicians, and patients share a common language, then studies can be compared/pooled more effectively. Furthermore, mapping lay terminology to HPO will help patients assist clinicians and researchers in creating phenotypic characterizations that are computationally accessible, thereby improving the stratification, diagnosis, and treatment of long COVID. FUNDING: U24TR002306; UL1TR001439; P30AG024832; GBMF4552; R01HG010067; UL1TR002535; K23HL128909; UL1TR002389; K99GM145411

Mucosal Targeting of a BoNT/A Subunit Vaccine Adjuvanted with a Mast Cell Activator Enhances Induction of BoNT/A Neutralizing Antibodies in Rabbits

We previously reported that the immunogenicity of Hcβtre, a botulinum neurotoxin A (BoNT/A) immunogen, was enhanced by fusion to an epithelial cell binding domain, Ad2F, when nasally delivered to mice with cholera toxin (CT). This study was performed to determine if Ad2F would enhance the nasal immunogenicity of Hcβtre in rabbits, an animal model with a nasal cavity anatomy similar to humans. Since CT is not safe for human use, we also tested the adjuvant activity of compound 48/80 (C48/80), a mast cell activating compound previously determined to safely exhibit nasal adjuvant activity in mice.New Zealand White or Dutch Belted rabbits were nasally immunized with Hcβtre or Hcβtre-Ad2F alone or combined with CT or C48/80, and serum samples were tested for the presence of Hcβtre-specific binding (ELISA) or BoNT/A neutralizing antibodies.Hcβtre-Ad2F nasally administered with CT induced serum anti-Hcβtre IgG ELISA and BoNT/A neutralizing antibody titers greater than those induced by Hcβtre + CT. C48/80 provided significant nasal adjuvant activity and induced BoNT/A-neutralizing antibodies similar to those induced by CT.Ad2F enhanced the nasal immunogenicity of Hcβtre, and the mast cell activator C48/80 was an effective adjuvant for nasal immunization in rabbits, an animal model with a nasal cavity anatomy similar to that in humans