Intentional blood group (BG)-incompatible (ABOi) heart transplantation in childhood is emerging in many centers. Safety limits remain undetermined. In this multicenter study we have compiled ...experience on clinical and immunologic boundaries.
Data from six centers in Europe and North America on ABOi transplantation were collected in a standardized survey.
Fifty-eight ABOi transplants were performed in 57 patients. Median age at transplant was 6.8 months (0.03 to 90 months); post-transplant follow-up was 37.7 months (0.46 to 117 months), accumulating 188 patient-years. Forty-seven percent of the patients received pretransplant mechanical circulatory support. Donors were either blood group A (n = 25), B (n = 18) or AB (n = 15). The median peak antibody titer to the donor BG pretransplant was 1:8 (0 to 1:64) for anti-A and 1:4 (0 to 1:32) for anti-B. Titers against the donor BG were lower post- than pretransplant in B recipients (p = 0.02), whereas third-party antibodies in BG O recipients developed normally post-transplant. Induction immunosuppression included anti-thymocyte globulin (61%), basiliximab (32%) or none (7%). All patients received calcineurin inhibitors, including 62% with mycophenolate mofetil, 10% with azathioprine, 2% with everolimus and 24% with steroids. There were 4 episodes of cellular rejection (Grade≥2R) and 7 antibody-mediated rejections. Five patients underwent antibody removal post-transplant. One patient developed severe graft vasculopathy. Freedom from death or retransplantation was 100%/96%/69% at 1/5/10 years. No graft loss was attributed to BG antibodies.
Successful ABOi heart transplantation can be performed at an older age and with higher isohemagglutinin titers than initially assumed and using similar immunosuppressive regimens as for ABO-compatible transplants. Rejection and graft vasculopathy are rare. Persistently low titers of antibodies to the donor BG post-transplant suggest elements of tolerance and/or accommodation.
Organ transplantation from ABO blood group–incompatible (ABOi) donors requires accurate detection, effective removal and subsequent surveillance of antidonor antibodies. Because ABH antigen subtypes ...are expressed differently in various cells and organs, measurement of antibodies specific for the antigen subtypes in the graft is essential. Erythrocyte agglutination, the century‐old assay used clinically, does not discriminate subtype‐specific ABO antibodies and provides limited information on antibody isotypes. We designed and created an ABO‐glycan microarray and demonstrated the precise assessment of both the presence and, importantly, the absence of donor‐specific antibodies in an international study of pediatric heart transplant patients. Specific IgM, IgG, and IgA isotype antibodies to nonself ABH subtypes were detected in control participants and recipients of ABO‐compatible transplants. Conversely, in children who received ABOi transplants, antibodies specific for A subtype II and/or B subtype II antigens—the only ABH antigen subtypes expressed in heart tissue—were absent, demonstrating the fine specificity of B cell tolerance to donor/graft blood group antigens. In contrast to the hemagglutination assay, the ABO‐glycan microarray allows detailed characterization of donor‐specific antibodies necessary for effective transplant management, representing a major step forward in precise ABO antibody detection.
The authors design a novel ABH‐glycan microarray and demonstrate its effectiveness and accuracy in confirming donor‐specific B cell tolerance in a cohort of ABO‐incompatible pediatric heart transplant patients.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
IMPORTANCE: Trials often assess primary outcomes of traumatic brain injury at 6 months. Longer-term data are needed to assess outcomes for patients receiving surgical vs medical treatment for ...traumatic intracranial hypertension. OBJECTIVE: To evaluate 24-month outcomes for patients with traumatic intracranial hypertension treated with decompressive craniectomy or standard medical care. DESIGN, SETTING, AND PARTICIPANTS: Prespecified secondary analysis of the Randomized Evaluation of Surgery With Craniectomy for Uncontrollable Elevation of Intracranial Pressure (RESCUEicp) randomized clinical trial data was performed for patients with traumatic intracranial hypertension (>25 mm Hg) from 52 centers in 20 countries. Enrollment occurred between January 2004 and March 2014. Data were analyzed between 2018 and 2021. Eligibility criteria were age 10 to 65 years, traumatic brain injury (confirmed via computed tomography), intracranial pressure monitoring, and sustained and refractory elevated intracranial pressure for 1 to 12 hours despite pressure-controlling measures. Exclusion criteria were bilateral fixed and dilated pupils, bleeding diathesis, or unsurvivable injury. INTERVENTIONS: Patients were randomly assigned 1:1 to receive a decompressive craniectomy with standard care (surgical group) or to ongoing medical treatment with the option to add barbiturate infusion (medical group). MAIN OUTCOMES AND MEASURES: The primary outcome was measured with the 8-point Extended Glasgow Outcome Scale (1 indicates death and 8 denotes upper good recovery), and the 6- to 24-month outcome trajectory was examined. RESULTS: This study enrolled 408 patients: 206 in the surgical group and 202 in the medical group. The mean (SD) age was 32.3 (13.2) and 34.8 (13.7) years, respectively, and the study population was predominantly male (165 81.7% and 156 80.0%, respectively). At 24 months, patients in the surgical group had reduced mortality (61 33.5% vs 94 54.0%; absolute difference, −20.5 95% CI, −30.8 to −10.2) and higher rates of vegetative state (absolute difference, 4.3 95% CI, 0.0 to 8.6), lower or upper moderate disability (4.7 −0.9 to 10.3 vs 2.8 −4.2 to 9.8), and lower or upper severe disability (2.2 −5.4 to 9.8 vs 6.5 1.8 to 11.2; χ27 = 24.20, P = .001). For every 100 individuals treated surgically, 21 additional patients survived at 24 months; 4 were in a vegetative state, 2 had lower and 7 had upper severe disability, and 5 had lower and 3 had upper moderate disability, respectively. Rates of lower and upper good recovery were similar for the surgical and medical groups (20 11.0% vs 19 10.9%), and significant differences in net improvement (≥1 grade) were observed between 6 and 24 months (55 30.0% vs 25 14.0%; χ22 = 13.27, P = .001). CONCLUSIONS AND RELEVANCE: At 24 months, patients with surgically treated posttraumatic refractory intracranial hypertension had a sustained reduction in mortality and higher rates of vegetative state, severe disability, and moderate disability. Patients in the surgical group were more likely to improve over time vs patients in the medical group. TRIAL REGISTRATION: ISRCTN Identifier: 66202560
To determine and compare outcomes with accepted benchmarks in trauma care at 7 academic level I trauma centers in which patients were treated on the basis of a series of standard operating procedures ...(SOPs).
Injury remains the leading cause of death for those younger than 45 years. This study describes the baseline patient characteristics and well-defined outcomes of persons hospitalized in the United States for severe blunt trauma.
We followed 1637 trauma patients from 2003 to 2009 up to 28 hospital days using SOPs developed at the onset of the study. An extensive database on patient and injury characteristics, clinical treatment, and outcomes was created. These data were compared with existing trauma benchmarks.
The study patients were critically injured and were in shock. SOP compliance improved 10% to 40% during the study period. Multiple organ failure and mortality rates were 34.8% and 16.7%, respectively. Time to recovery, defined as the time until the patient was free of organ failure for at least 2 consecutive days, was developed as a new outcome measure. There was a reduction in mortality rate in the cohort during the study that cannot be explained by changes in the patient population.
This study provides the current benchmark and the overall positive effect of implementing SOPs for severely injured patients. Over the course of the study, there were improvements in morbidity and mortality rates and increasing compliance with SOPs. Mortality was surprisingly low, given the degree of injury, and improved over the duration of the study, which correlated with improved SOP compliance.
The Arcminute Microkelvin Imager Zwart, J. T. L.; Barker, R. W.; Biddulph, P. ...
Monthly notices of the Royal Astronomical Society,
12/2008, Volume:
391, Issue:
4
Journal Article
Peer reviewed
Open access
The Arcminute Microkelvin Imager is a pair of interferometer arrays operating with six frequency channels spanning 13.9–18.2 GHz, for observations on angular scales of 30 arcsec–10 arcmin and for ...declinations greater than −15°; the Small Array has a sensitivity of 30 mJy s−1/2 and the Large Array has a sensitivity of 3 mJy s−1/2. The telescope is aimed principally at Sunyaev–Zel'dovich imaging of clusters of galaxies. We discuss the design of the telescope and describe and explain its electronic and mechanical systems.
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
By the end of the 1980s, there was strong epidemiologic evidence of a continuous association between plasma cholesterol levels and the risk of coronary heart disease (CHD).
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Most patients with ...CHD have cholesterol levels that are not markedly elevated.
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However, most randomized, controlled trials of cholesterol-lowering therapy have involved patients with at least moderate hypercholesterolemia, and the treatments used have had limited efficacy in lowering cholesterol. Taken together, those trials have demonstrated a clear reduction in the incidence of coronary events, both among persons with a history of CHD
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and among those without such a history.
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However, the reduction . . .
Broadly cross-reactive neutralizing antibodies (bNabs) represent powerful tools to combat human immunodeficiency virus type 1 (HIV-1) infection. Here, we examined whether HIV-1-specific bNabs are ...capable of cross-neutralizing distantly related simian immunodeficiency viruses (SIVs) infecting central (Pan troglodytes troglodytes) (SIVcpzPtt) and eastern (Pan troglodytes schweinfurthii) (SIVcpzPts) chimpanzees (n = 11) as well as western gorillas (Gorilla gorilla gorilla) (SIVgor) (n = 1). We found that bNabs directed against the CD4 binding site (n = 10), peptidoglycans at the base of variable loop 3 (V3) (n = 5), and epitopes at the interface of surface (gp120) and membrane-bound (gp41) envelope glycoproteins (n = 5) failed to neutralize SIVcpz and SIVgor strains. In addition, apex V2-directed bNabs (n = 3) as well as llama-derived (heavy chain only) antibodies (n = 6) recognizing both the CD4 binding site and gp41 epitopes were either completely inactive or neutralized only a fraction of SIVcpzPtt strains. In contrast, one antibody targeting the membrane-proximal external region (MPER) of gp41 (10E8), functional CD4 and CCR5 receptor mimetics (eCD4-Ig, eCD4-Ig(mim2), CD4-218.3-E51, and CD4-218.3-E51-mim2), as well as mono- and bispecific anti-human CD4 (iMab and LM52) and CCR5 (PRO140, PRO140-10E8) receptor antibodies neutralized >90% of SIVcpz and SIVgor strains with low-nanomolar (0.13 to 8.4 nM) potency. Importantly, the latter antibodies blocked virus entry not only in TZM-bl cells but also in Cf2Th cells expressing chimpanzee CD4 and CCR5 and neutralized SIVcpz in chimpanzee CD4(+) T cells, with 50% inhibitory concentrations (IC50s) ranging from 3.6 to 40.5 nM. These findings provide new insight into the protective capacity of anti-HIV-1 bNabs and identify candidates for further development to combat SIVcpz infection.
SIVcpz is widespread in wild-living chimpanzees and can cause AIDS-like immunopathology and clinical disease. HIV-1 infection of humans can be controlled by antiretroviral therapy; however, treatment of wild-living African apes with current drug regimens is not feasible. Nonetheless, it may be possible to curb the spread of SIVcpz in select ape communities using vectored immunoprophylaxis and/or therapy. Here, we show that antibodies and antibody-like inhibitors developed to combat HIV-1 infection in humans are capable of neutralizing genetically diverse SIVcpz and SIVgor strains with considerable breadth and potency, including in primary chimpanzee CD4(+) T cells. These reagents provide an important first step toward translating intervention strategies currently developed to treat and prevent AIDS in humans to SIV-infected apes.
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