Combined Bone Marrow and Kidney Transplantation for the Induction of Specific Tolerance

The induction of specific tolerance, in order to avoid the detrimental effects of lifelong systemic immunosuppressive therapy after organ transplantation, has been considered the “Holy Grail” of transplantation. Experimentally, tolerance has been achieved through clonal deletion, through costimulatory blockade, through the induction or infusion of regulatory T-cells, and through the establishment of hematopoietic chimerism following donor bone marrow transplantation. The focus of this review is how tolerance has been achieved following combined bone marrow and kidney transplantation. Preclinical models of combined bone marrow and kidney transplantation have shown that tolerance can be achieved through either transient or sustained hematopoietic chimerism. Combined transplants for patients with multiple myeloma have shown that organ tolerance and prolonged disease remissions can be accomplished with such an approach. Similarly, multiple clinical strategies for achieving tolerance in patients without an underlying malignancy have been described, in the context of either transient or durable mixed chimerism or sustained full donor hematopoiesis. To expand the chimerism approach to deceased donor transplants, a delayed tolerance approach, which will involve organ transplantation with conventional immunosuppression followed months later by bone marrow transplantation, has been successful in a primate model. As combined bone marrow and organ transplantation become safer and increasingly successful, the achievement of specific tolerance may become more widely applicable

Active surveillance for rheumatic heart disease in endemic regions: a systematic review and meta-analysis of prevalence among children and adolescents

Background Rheumatic heart disease accounts for up to 250 000 premature deaths every year worldwide and can be regarded as a physical manifestation of poverty and social inequality. We aimed to estimate the prevalence of rheumatic heart disease in endemic countries as assessed by diff erent screening modalities and as a function of age. Methods We searched Medline, Embase, the Latin American and Caribbean System on Health Sciences Information, African Journals Online, and the Cochrane Database of Systematic Reviews for population-based studies published between Jan 1, 1993, and June 30, 2014, that reported on prevalence of rheumatic heart disease among children and adolescents (≥5 years to <18 years). We assessed prevalence of clinically silent and clinically manifest rheumatic heart disease in random eff ects meta-analyses according to screening modality and geographical region. We assessed the association between social inequality and rheumatic heart disease with the Gini coeffi cient. We used Poisson regression to analyse the eff ect of age on prevalence of rheumatic heart disease and estimated the incidence of rheumatic heart disease from prevalence data. Findings We included 37 populations in the systematic review and meta-analysis. The pooled prevalence of rheumatic heart disease detected by cardiac auscultation was 2·9 per 1000 people (95% CI 1·7–5·0) and by echocardiography it was 12·9 per 1000 people (8·9–18·6), with substantial heterogeneity between individual reports for both screening modalities (I²=99·0% and 94·9%, respectively). We noted an association between social inequality expressed by the Gini coeffi cient and prevalence of rheumatic heart disease (p=0·0002). The prevalence of clinically silent rheumatic heart disease (21·1 per 1000 people, 95% CI 14·1–31·4) was about seven to eight times higher than that of clinically manifest disease (2·7 per 1000 people, 1·6–4·4). Prevalence progressively increased with advancing age, from 4·7 per 1000 people (95% CI 0·0–11·2) at age 5 years to 21·0 per 1000 people (6·8–35·1) at 16 years. The estimated incidence was 1·6 per 1000 people (0·8–2·3) and remained constant across age categories (range 2·5, 95% CI 1·3–3·7 in 5-year-old children to 1·7, 0·0–5·1 in 15-year-old adolescents). We noted no sexrelated diff erences in prevalence (p=0·829). Interpretation We found a high prevalence of rheumatic heart disease in endemic countries. Although a reduction in social inequalities represents the cornerstone of community-based prevention, the importance of early detection of silent rheumatic heart disease remains to be further assessed

Test-retest reliability and effects of repeated testing and satiety on performance of an Emotional Test Battery

The P1vital® Oxford Emotional Test Battery (ETB) comprises five computerized tasks designed to assess cognition and emotional processing in human participants. It has been used in between-subjects experimental designs; however, it is unclear whether the battery can be used in crossover designs. This is of particular importance given the increasing use of ETB tasks for repeated assessment of depressed patients in clinical trials and clinical practice. In addition, although satiety state has been reported to affect performance on some cognitive and emotional tasks, it is not known whether it can influence performance on the ETB. Two studies explored these issues. In Experiment 1, 30 healthy women were tested on the ETB on 4 separate occasions (each a week apart) in a within-subjects design. In Experiment 2, another 30 healthy women were randomized to either a satiated or a hungry condition, where they were given an ad libitum lunch of cheese sandwiches, before (satiated) or after (hungry) they were asked to complete the ETB. Experiment 1 demonstrated good test-retest reliability for the ETB. One of the tasks was free from practice effects, whilst performance on the other four tasks stabilized after the first two sessions. In Experiment 2, eating to satiety only affected performance on a single ETB task. These results suggest that the ETB can be used in crossover designs after two initial training sessions. Further, as a robust satiety manipulation had only a limited effect on a single ETB task, it is unlikely that appetitive state will confound ETB performance

Dose-Reduced Busulfan, Cyclophosphamide, and Autologous Stem Cell Transplantation for Human Immunodeficiency Virus–Associated Lymphoma: AIDS Malignancy Consortium Study 020

AbstractIntensive chemotherapy for human immunodeficiency virus (HIV)-associated non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) has resulted in durable remissions in a substantial proportion of patients. High-dose chemotherapy and autologous stem cell transplantation (AuSCT), moreover, has resulted in sustained complete remissions in selected patients with recurrent chemosensitive disease. Based on a favorable experience with dose-reduced high-dose busulfan, cyclophosphamide, and AuSCT for older patients with non-HIV–associated aggressive lymphomas, an AIDS Malignancy Consortium multicenter trial was undertaken using the same dose-reduced busulfan and cyclophosphamide preparative regimen with AuSCT for recurrent HIV-associated NHL and HL. Of the 27 patients in the study, 20 received an AuSCT. The median time to achievement of an absolute neutrophil count (ANC) of ≥ 0.5×109/L was 11 days (range, 9-16 days). The median time to achievement of an unsupported platelet count of ≥ 20×109/L was 13 days (range, 6-57 days). One patient died on day +33 posttransplantation from hepatic veno-occlusive disease (VOD) and multiorgan failure. No other fatal regimen-related toxicity occurred. Ten of 19 patients (53%) were in complete remission at the time of their day +100 post-AuSCT evaluation. Of the 20 patients, 10 were alive and event-free at a median of 23 weeks post-AuSCT. Median overall survival (OS) was not reached by 13 of the 20 patients alive at the time of last follow-up. This multi-institutional trial demonstrates that a regimen of dose-reduced high-dose busulfan, cyclophosphamide, and AuSCT is well tolerated and is associated with favorable disease-free survival (DFS) and OS probabilities for selected patients with HIV-associated NHL and HL

Durability of Near-Complete Skin Clearance in Patients with Psoriasis Using Systemic Biologic Therapies: Real-World Evidence from the CorEvitas Psoriasis Registry

INTRODUCTION: Near-complete skin clearance has become a rapidly achievable treatment goal for patients with psoriasis receiving systemic biologic therapies. However, real-world evidence for durability of near-complete skin clearance and risk factors associated with loss of near-complete skin clearance is limited. METHODS: This study described durability of near-complete skin clearance (≥ 90% improvement in Psoriasis Area and Severity Index from initiation; PASI90) and identified clinical factors or patient characteristics associated with loss of PASI90 among patients with psoriasis from the CorEvitas Psoriasis Registry (April 2015-August 2021). Included patients had PASI \u3e 5 at biologic initiation and achieved PASI90 at approximately 6 months from initiation (index). A Kaplan-Meier estimate described time to loss of treatment response over 24 months follow-up from index. Proportional hazards regression was used to identify independent predictors of loss of treatment response. RESULTS: This study included 687 patient initiations (instances of patients initiating a biologic). Following achievement of PASI90, treatment response was maintained in more than half of patient initiations (54%). Treatment response was maintained at 6, 12, and 18 months from index in an estimated 73% (95% [confidence interval] CI 70-77%), 60% (95% CI 56-63%), and 50% (95% CI 47-54%) of patient initiations, respectively. Adjusted hazards regression suggested non-White race, full-time employment, greater body weight, concomitant psoriatic arthritis, prior use of biologics, and clinically meaningful skin symptoms were associated with loss of treatment response. CONCLUSIONS: Among real-world patients with psoriasis who achieved PASI90 with biologic therapy, about one-quarter lost response at 6 months, and half lost response at 18 months. Prior use of a biologic therapy and clinically meaningful skin symptoms at index, including itch and skin pain, were associated with loss of treatment response. Therefore, dermatologists may consider focusing on patient-reported symptoms as part of any intervention designed to reduce the likelihood of loss of response to biologic therapies

Time Variability in Simulated Ultracompact and Hypercompact HII Regions

Ultracompact and hypercompact HII regions appear when a star with a mass larger than about 15 solar masses starts to ionize its own environment. Recent observations of time variability in these objects are one of the pieces of evidence that suggest that at least some of them harbor stars that are still accreting from an infalling neutral accretion flow that becomes ionized in its innermost part. We present an analysis of the properties of the HII regions formed in the 3D radiation-hydrodynamic simulations presented by Peters et al. as a function of time. Flickering of the HII regions is a natural outcome of this model. The radio-continuum fluxes of the simulated HII regions, as well as their flux and size variations are in agreement with the available observations. From the simulations, we estimate that a small but non-negligible fraction (~ 10 %) of observed HII regions should have detectable flux variations (larger than 10 %) on timescales of ~ 10 years, with positive variations being more likely to happen than negative variations. A novel result of these simulations is that negative flux changes do happen, in contrast to the simple expectation of ever growing HII regions. We also explore the temporal correlations between properties that are directly observed (flux and size) and other quantities like density and ionization rates.Comment: Monthly Notices of the Royal Astronomical Society, in press. The movie of free-free optical depth can be found at http://www.ita.uni-heidelberg.de/~tpeters/tau.av

Rationale, design and conduct of a randomised controlled trial evaluating a primary care-based complex intervention to improve the quality of life of heart failure patients: HICMan (Heidelberg Integrated Case Management) : study protocol

Background: Chronic congestive heart failure (CHF) is a complex disease with rising prevalence, compromised quality of life (QoL), unplanned hospital admissions, high mortality and therefore high burden of illness. The delivery of care for these patients has been criticized and new strategies addressing crucial domains of care have been shown to be effective on patients' health outcomes, although these trials were conducted in secondary care or in highly organised Health Maintenance Organisations. It remains unclear whether a comprehensive primary care-based case management for the treating general practitioner (GP) can improve patients' QoL. Methods/Design: HICMan is a randomised controlled trial with patients as the unit of randomisation. Aim is to evaluate a structured, standardized and comprehensive complex intervention for patients with CHF in a 12-months follow-up trial. Patients from intervention group receive specific patient leaflets and documentation booklets as well as regular monitoring and screening by a prior trained practice nurse, who gives feedback to the GP upon urgency. Monitoring and screening address aspects of disease-specific selfmanagement, (non)pharmacological adherence and psychosomatic and geriatric comorbidity. GPs are invited to provide a tailored structured counselling 4 times during the trial and receive an additional feedback on pharmacotherapy relevant to prognosis (data of baseline documentation). Patients from control group receive usual care by their GPs, who were introduced to guidelineoriented management and a tailored health counselling concept. Main outcome measurement for patients' QoL is the scale physical functioning of the SF-36 health questionnaire in a 12-month follow-up. Secondary outcomes are the disease specific QoL measured by the Kansas City Cardiomyopathy questionnaire (KCCQ), depression and anxiety disorders (PHQ-9, GAD-7), adherence (EHFScBS and SANA), quality of care measured by an adapted version of the Patient Chronic Illness Assessment of Care questionnaire (PACIC) and NTproBNP. In addition, comprehensive clinical data are collected about health status, comorbidity, medication and health care utilisation. Discussion: As the targeted patient group is mostly cared for and treated by GPs, a comprehensive primary care-based guideline implementation including somatic, psychosomatic and organisational aspects of the delivery of care (HICMAn) is a promising intervention applying proven strategies for optimal care. Trial registration: Current Controlled Trials ISRCTN30822978

Diversity and composition of tropical butterflies along an Afromontane agricultural gradient in the Jimma Highlands, Ethiopia

Afromontane landscapes are typically characterized by a mosaic of smallholder farms and the biodiversity impacts of these practices will vary in accordance to local management and landscape context. Here, we assess how tropical butterfly diversity is maintained across an agricultural landscape in the Jimma Highlands of Ethiopia. We used transect surveys to sample understory butterfly communities within degraded natural forest, semi-managed coffee forest (SMCF), exotic timber plantations, open woodland, croplands and pasture. Surveys were conducted in 29 one-hectare plots and repeated five times between January and June 2013. We found that natural forest supports higher butterfly diversity than all agricultural plots (measured with Hill's numbers). SMCF and timber plantations retain relatively high abundance and diversity, but these metrics drop off sharply in open woodland, cropland and pasture. SMCF and timber plantations share the majority of their species with natural forest and support an equivalent abundance of forest-dependent species, with no increase in widespread species. There was some incongruence in the responses of families and sub-families, notably that Lycaenidae are strongly associated with open woodland and pasture. Adult butterflies clearly utilize forested agricultural practices such as SMCF and timber plantations, but species diversity declines steeply with distance from natural forest suggesting that earlier life-stages may depend on host plants and/or microclimatic conditions that are lost under agricultural management. From a management perspective, the protection of natural forest remains a priority for tropical butterfly conservation, but understanding functioning of the wider landscape mosaic is important as SMCF and timber plantations may act as habitat corridors that facilitate movement between forest fragments

GRFS and CRFS in alternative donor hematopoietic cell transplantation for pediatric patients with acute leukemia.

We report graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) (a composite end point of survival without grade III-IV acute GVHD [aGVHD], systemic therapy-requiring chronic GVHD [cGVHD], or relapse) and cGVHD-free relapse-free survival (CRFS) among pediatric patients with acute leukemia (n = 1613) who underwent transplantation with 1 antigen-mismatched (7/8) bone marrow (BM; n = 172) or umbilical cord blood (UCB; n = 1441). Multivariate analysis was performed using Cox proportional hazards models. To account for multiple testing, P \u3c .01 for the donor/graft variable was considered statistically significant. Clinical characteristics were similar between UCB and 7/8 BM recipients, because most had acute lymphoblastic leukemia (62%), 64% received total body irradiation-based conditioning, and 60% received anti-thymocyte globulin or alemtuzumab. Methotrexate-based GVHD prophylaxis was more common with 7/8 BM (79%) than with UCB (15%), in which mycophenolate mofetil was commonly used. The univariate estimates of GRFS and CRFS were 22% (95% confidence interval [CI], 16-29) and 27% (95% CI, 20-34), respectively, with 7/8 BM and 33% (95% CI, 31-36) and 38% (95% CI, 35-40), respectively, with UCB (P \u3c .001). In multivariate analysis, 7/8 BM vs UCB had similar GRFS (hazard ratio [HR], 1.12; 95% CI, 0.87-1.45; P = .39), CRFS (HR, 1.06; 95% CI, 0.82-1.38; P = .66), overall survival (HR, 1.07; 95% CI, 0.80-1.44; P = .66), and relapse (HR, 1.44; 95% CI, 1.03-2.02; P = .03). However, the 7/8 BM group had a significantly higher risk for grade III-IV aGVHD (HR, 1.70; 95% CI, 1.16-2.48; P = .006) compared with the UCB group. UCB and 7/8 BM groups had similar outcomes, as measured by GRFS and CRFS. However, given the higher risk for grade III-IV aGVHD, UCB might be preferred for patients lacking matched donors. © 2019 American Society of Hematology. All rights reserved

The Extended Environment of M17: A Star Formation History

M17 is one of the youngest and most massive nearby star-formation regions in the Galaxy. It features a bright H II region erupting as a blister from the side of a giant molecular cloud (GMC). Combining photometry from the Spitzer GLIMPSE survey with complementary infrared (IR) surveys, we identify candidate young stellar objects (YSOs) throughout a 1.5 deg x 1 deg field that includes the M17 complex. The long sightline through the Galaxy behind M17 creates significant contamination in our YSO sample from unassociated sources with similar IR colors. Removing contaminants, we produce a highly-reliable catalog of 96 candidate YSOs with a high probability of association with the M17 complex. We fit model spectral energy distributions to these sources and constrain their physical properties. Extrapolating the mass function of 62 intermediate-mass YSOs (M >3 Msun), we estimate that >1000 stars are in the process of forming in the extended outer regions of M17. From IR survey images from IRAS and GLIMPSE, we find that M17 lies on the rim of a large shell structure ~0.5 deg in diameter (~20 pc at 2.1 kpc). We present new maps of CO and 13CO (J=2-1) emission, which show that the shell is a coherent, kinematic structure associated with M17 at v = 19 km/s. The shell is an extended bubble outlining the photodissociation region of a faint, diffuse H II region several Myr old. We provide evidence that massive star formation has been triggered by the expansion of the bubble. The formation of the massive cluster ionizing the M17 H II region itself may have been similarly triggered. We conclude that the star formation history in the extended environment of M17 has been punctuated by successive waves of massive star formation propagating through a GMC complex.Comment: 31 pages, 15 figures, accepted for publication in ApJ. For a version with higher-quality figures, see http://www.astro.wisc.edu/glimpse/Povich2009_M17.pd