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Plants make up more than 80 percent of the human diet. As a result, they are critical for food security and ensuring that we all have access to enough, cheap, clean, and nutritional food to lead healthy and active living. This research focuses on plant diseases as they create a major threat to food security. Expert people are hired in traditional farming to physically evaluate line by line for host disease plants, which would be labor-intensive, time taking and potentially error-prone activity because it is done by people manually. This work focus on, supervised machine learning algorithms like RF, SVM, DT, KNN, NB, and KNN with image processing methods and also analysis algorithm results with each other and finds the best algorithm for plant disease classification. RF algorithm achieved 89 percent accuracy compared with other algorithms.

Gut microbiome in allogeneic hematopoietic stem cell transplantation and specific changes associated with acute graft vs host disease

Background Recent data suggest that novel biologic agents are associated with increased risk of thrombotic microangiopathy (TMA). Ruxolitinib, an approved treatment for graft-vs-host-disease (GVHD), has been associated with thrombocytopenia of unclear etiology. Methods We investigated factors and outcomes associated with transplant-associated thrombotic microangiopathy (TA-TMA) in patients with GVHD. We retrospectively enrolled consecutive allogeneic hematopoietic cell transplantation recipients with overlap or chronic GVHD at our Joint Accreditation Committee ISCT-Europe & EBMT-accredited unit (January 2016-June 2019). Ruxolitinib has been administered off-label since 2016. Results Among 160 patients with GVHD, 18 were diagnosed with TA-TMA. TA-TMA developed at a median of 150 posttransplant days (range, 98-3013). Among pre- and posttransplant factors, TA-TMA was associated only with ruxolitinib administration and severe GVHD. Interestingly, these 2 variables did not correlate with each other. In the multivariate analysis, both were independent predictors of TA-TMA. Time-dependent analysis confirmed ruxolitinib's association with TA-TMA. With a follow-up of 38.4 months (4.6-83.9) in surviving patients, 5-year overall survival was 52.9%, independently predicted by TA-TMA, severe acute GVHD, and CD34+ cells infused. Ruxolitinib was not associated with survival outcomes. Conclusions Our data suggest that ruxolitinib and GVHD severity are associated with TA-TMA. Given the expanding use of ruxolitinib in GVHD and ongoing trials on chronic GVHD, further studies are warranted to confirm these findings.

BACKGROUND Although acute graft-vs-host disease (aGvHD) is a rare complication of liver transplantation, it is poorly understood and has an extremely high mortality rate. No standardized diagnostic criteria or treatment regimens currently exist. CASE SUMMARY The present study investigated the etiology, diagnosis, and treatment of aGvHD following liver transplantation. Presentation, diagnosis, disease course, histology, and treatment of an aGvHD case are reported, and associated literature is reviewed. A 64-year-old female required LTx due to primary biliary cirrhosis. The donor was a 12-year-old male. Three weeks following liver transplantation, the recipient developed pyrexia, diarrhea, rashes, and antibiotic-unresponsive pancytopenia. Clinical symptoms together with laboratory investigations suggested a diagnosis of aGvHD, which was confirmed via peripheral blood fluorescent in situ hybridization. Donor XY chromosome fluorescent in situ hybridization indicating early chimerism achieved 93% sensitivity in the detection of GvHD. Existing immunosuppressants were discontinued, and high-dose intravenous methylprednisolone was initiated along with antibiotics. While diarrhea resolved, the patient’s general condition continued to deteriorate until demise due to multi-system organ failure at 37 d post-liver transplantation. This case illustrates the life-threatening nature of aGvHD. CONCLUSION Herein, we have summarized a post-LTx aGvHD case and reviewed associated literature in order to increase awareness and provide potentially risk-mitigating recommendations.

Within-host processes (representing the entry, establishment, growth, and development of a parasite inside its host) may play a key role in parasite transmission but remain challenging to observe and quantify. We develop a general model for measuring host defenses and within-host disease dynamics. Our stochastic model breaks the infection process down into the stages of parasite exposure, entry, and establishment and provides associated probabilities for a host's ability to resist infections with barriers and clear internal infections. We tested our model on

Hematopoietic stem cell transplantation (HSCT) is widely performed as a treatment for malignant blood disorders, such as leukemia. To achieve good clinical outcomes in HSCT, it is necessary to minimize the unfavorable effects of acute graft-vs-host disease (GVHD) and induce the more tolerable, chronic form of the disease. For better management of GVHD, sensitive and specific biomarkers that predict the severity and prognosis of the disease have been intensively investigated using proteomics, transcriptomics, genomics, cytomics, and tandem mass spectrometry methods. Here, I will briefly review the current understanding of GVHD biomarkers and future prospects.

Allogeneic hematopoietic stem cell transplantation (alloSCT) carries the promise of cure for many malignant and non-malignant diseases of the lympho-hematopoietic system. Although outcome has improved considerably since the pioneering Seattle achievements more than 5 decades ago, non-relapse mortality (NRM) remains a major burden of alloSCT. There is increasing evidence that endothelial dysfunction is involved in many of the life-threatening complications of alloSCT, such as sinusoidal obstruction syndrome/venoocclusive disease, transplant-associated thrombotic microangiopathy, and refractory acute graft-versus host disease. This review delineates the role of the endothelium in severe complications after alloSCT and describes the current status of search for biomarkers predicting endothelial complications, including markers of endothelial vulnerability and markers of endothelial injury. Finally, implications of our current understanding of transplant-associated endothelial pathology for prevention and management of complications after alloSCT are discussed.

Background and objectives Irradiation of red cell components is indicated for recipients at risk of transfusion-associated graft vs. host disease. Current technologies available comprise of a gamma (γ) or an x source of radiation. The benefits of x vs. γ include non-radioactivity and hence no decay of the source. We aimed to compare the effect of the two technologies on red cell component storage quality post-irradiation. Materials and methods Paired units of red cell concentrates (RCC), neonatal red cell splits (RCS), red cells for intra-uterine transfusion (IUT) or neonatal exchange transfusion (ExTx) were either γ- or x-irradiated. Units were sampled and tested for five storage parameters until the end of shelf life. Equivalence analysis of storage quality parameters was performed for pairs of the same components (RCC, RCS, IUT or ExTx) that were either γ- or x-irradiated. Results Nearly all component comparisons studied showed equivalence between γ and x irradiation for haemolysis, ATP, 2,3-DPG, potassium release and lactate production. The exceptions found that were deemed non-equivalent were higher haemolysis with x irradiation for ExTx, lower 2,3-DPG with x irradiation for RCS irradiated early and higher ATP with x irradiation for IUT. However, these differences were considered not clinically significant. Conclusion This study has demonstrated that a range of red cell components for use in different age groups are of acceptable quality following x irradiation, with only small differences deemed clinically insignificant in a few of the measured parameters.

The trafficking and function of intestine-derived high-density lipoprotein (HDL) have not been identified. In a recent issue of Science, Han et al. (2021) find that intestine-derived HDL neutralizes intestinal-leaked LPS in the portal vein, serving as a host disease tolerance strategy to restrain liver damage of enteric origin under physiological conditions.

Hematopoietic stem cell‐ (HSC) and induced pluripotent stem (iPS) cell‐derived natural killer (NK) cells containing engineered functions, such as chimeric antigen receptors (CAR), offer great promise for the treatment of seemingly incurable oncological malignancies. Today, some of the main challenges of CAR cell‐based therapeutics are the long manufacturing time and safety of the cell sources used. Additional challenges include avoiding graft vs host disease (GVHD) and cytokine release syndrome (CRS). Here, we show compelling evidence for the use of NK cell therapeutics as a reliable off‐the‐shelf option, as they address key issues. Furthermore, we highlight how iPS cells and directed differentiation toward HSC and NK cells address industrial scalability and safety., Main areas of improvement in the creation of reliable off‐the‐shelf chimeric antigen receptor‐natural killer (CAR‐NK)‐based therapies. Superdonor induced pluripotent stem (iPS) cell and hematopoietic stem cell (HSC) sources, defined xeno‐free differentiation protocols, CAR genes inserted at defined genetic dose in safe harbor loci, and CAR proteins with effective on‐off switch transition and endodomains.

BACKGROUND Central nervous system graft-vs-host disease (CNS-GVHD) is a rare cause of CNS disorders after allogeneic hematopoietic stem cell transplantation. Currently, establishing a diagnosis of CNS-GVHD is challenging because the diagnostic criteria and diagnostic methods are not well defined and many confounding factors need to be ruled out. CASE SUMMARY Here, we present two patients with CNS-GVHD. Both patients with a history of acute GVHD or chronic GVHD developed neurological symptoms that could not be explained by other causes, and had abnormal cerebrospinal fluid (CSF) studies as determined by CSF and blood immune biomarker examinations, suggestive of suspected CNS-GVHD. Due to the lack of specific magnetic resonance imaging abnormalities and the rapid clinical deterioration of the patients, we did not attempt to perform a brain biopsy, but prompted the initiation of empirical immunosuppressive therapy. In view of the rapid and favorable response to local and systematic immunosuppressive treatment and the aforementioned neurologic manifestations together with CSF abnormalities and other negative findings, a final diagnosis of CNS-GVHD was made. CONCLUSION CSF and blood immune biomarker examinations facilitated the diagnosis of CNS-GVHD, which are particularly suitable for patients who are critically ill and require urgent treatment and for those who are unsuitable for invasive diagnostic procedures.

Background: Directed blood donation is defined as the donation of blood or its components for the purpose of transfusion into a specified individual. Directed blood donation holds historic significance, and although practices as of 2021 encourage voluntary, nonrenumerated blood donations, public interest in directed donation remains. Requests to discuss the risks and benefits of directed donations are a common inquiry for transfusion medicine, transplant, and hematology/oncology professionals. This narrative review discusses the history of directed donation and summarizes directed donation considerations in the context of modern transfusion practices. Methods: We conducted a systematic search of PubMed for published literature on the topic of directed blood donation and gathered information about its benefits and potential harms with respect to the variety of products used in transfusion medicine. Results: The drawbacks of directed donation include transfusion-transmitted infection risk, alloimmunization risk, increased transfusion-associated graft vs host disease risk, decreased expediency in treatment, and increased administrative burdens. However, a role remains for directed blood donation in specific patient populations, such as individuals with rare blood types or immunoglobulin A deficiencies, because of the difficulties in finding compatible blood for transfusion. Conclusion: Clinicians should consider the risks and benefits when discussing directed blood donations with patients and family members.

BACKGROUND/AIMS: Hematopoietic stem cell transplantation (HSCT) is an established curative modality for various hematological malignancies and other diseases. Hepatobiliary dysfunction and subsequent sequelae constitute a common cause of morbidity and mortality in post-transplant scenario. However, data among Indian HSCT recipients is lacking. METHODS: One hundred and one HSCT recipients (37 prospective and 64 retrospective) were followed up for hepatobiliary dysfunction in the post-transplant period. The causes for hepatobiliary dysfunction were categorized as sinusoidal obstruction syndrome (SOS), formerly known as veno-occlusive disease (VOD); acute and chronic graft-versus- host disease (GVHD); drug-induced liver injury (DILI); viral infections and miscellaneous causes including bacterial, fungal and unknown causes based on clinical and laboratory evidence. RESULTS: Among the 101 transplants, 56.44% (n = 57) were allogenic transplants, and 43.56% (n = 44) were autologous transplants. Hepatobiliary dysfunction was observed among 71 (70.30%) patients in first 30 days and overall, among 78 (77.23%) patients. Incidence of hepatobiliary dysfunction was higher among allogenic transplant patients compared to autologous transplants (91.23% vs. 59.09%, p

BACKGROUND Multipotent mesenchymal stromal cells (MSCs) are widely used in the clinic due to their unique properties, namely, their ability to differentiate in all mesenchymal directions and their immunomodulatory activity. Healthy donor MSCs were used to prevent the development of acute graft vs host disease (GVHD) after allogeneic bone marrow transplantation (allo-BMT). The administration of MSCs to patients was not always effective. The MSCs obtained from different donors have individual characteristics. The differences between MSC samples may affect their clinical efficacy. AIM To study the differences between effective and ineffective MSCs. METHODS MSCs derived from the bone marrow of a hematopoietic stem cells donor were injected intravenously into allo-BMT recipients for GVHD prophylaxis at the moment of blood cell reconstitution. Aliquots of 52 MSC samples that were administered to patients were examined, and the same cells were cultured in the presence of peripheral blood mononuclear cells (PBMCs) from a third-party donor or treated with the pro-inflammatory cytokines IL-1β, IFN and TNF. Flow cytometry revealed the immunophenotype of the nontreated MSCs, the MSCs cocultured with PBMCs for 4 d and the MSCs exposed to cytokines. The proportions of CD25-, CD146-, CD69-, HLA-DR- and PD-1-positive CD4+ and CD8+ cells and the distribution of various effector and memory cell subpopulations in the PBMCs cocultured with the MSCs were also determined. RESULTS Differences in the immunophenotypes of effective and ineffective MSCs were observed. In the effective samples, the mean fluorescence intensity (MFI) of HLA-ABC, HLA-DR, CD105, and CD146 was significantly higher. After MSCs were treated with IFN or cocultured with PBMCs, the HLA-ABC, HLA-DR, CD90 and CD54 MFI showed a stronger increase in the effective MSCs, which indicated an increase in the immunomodulatory activity of these cells. When PBMCs were cocultured with effective MSCs, the proportions of CD4+ and CD8+central memory cells significantly decreased, and the proportion of CD8+CD146+ lymphocytes increased more than in the subpopulations of lymphocytes cocultured with MSC samples that were ineffective in the prevention of GVHD; in addition, the proportion of CD8+effector memory lymphocytes decreased in the PBMCs cocultured with the effective MSC samples but increased in the PBMCs cocultured with the ineffective MSC samples. The proportion of CD4+CD146+ lymphocytes increased only when cocultured with the inefficient samples. CONCLUSION For the first time, differences were observed between MSC samples that were effective for GVHD prophylaxis and those that were ineffective. Thus, it was shown that the immunomodulatory activity of MSCs depends on the individual characteristics of the MSC population.

Background A new protocol has been developed on the Amicus Separator that enables the device to perform online extracorporeal photopheresis (ECP) procedures when used in conjunction with the Phelix photoactivation device and associated disposable kit. The objective of this study was to evaluate the safety and performance of the Amicus ECP System in adult subjects with steroid‐refractory or dependent chronic graft vs host disease (cGVHD). Study Design and Methods Eight subjects with mild to severe cGVHD underwent 31 procedures. Subject safety evaluations were performed pre and post procedure and adverse events (AEs) were recorded during treatment and 24 hours after the last procedure. In vitro evaluations of the treated cells included hematology counts and lymphocyte apoptosis, viability and proliferation as measures for ECP procedure validation. Results For n = 23 evaluable procedures, median (range) procedure time was 88 (78‐110) minutes, during which 2.9 (0.6‐4.7) × 109 TNCs (approximately 90% MNCs) were treated and reinfused to the subjects. All subject safety evaluations (vitals, cell counts, plasma hemoglobin and bacterial and endotoxin testing) were within expected ranges. All device or procedure related AEs were mild in nature. After 24 hours in culture, 86 (52‐98)% of treated lymphocytes were apoptotic compared to 27 (15‐51)% in controls. Inhibition of lymphocyte proliferation was >91% in all procedures. Conclusion ECP procedures were safely completed in adult subjects with SR‐cGVHD treated using the new online Amicus ECP system.

Intestinal graft-vs.-host disease (GVHD) is a serious complication of allo-hematopoietic stem cell transplantation (allo-HSCT). Villous atrophy in the terminal ileum is considered a useful diagnostic indicator for GVHD. However, the inter- and intra-observer agreement regarding the ileocolonoscopic findings indicative of acute intestinal GVHD, i.e., villous atrophy in the terminal ileum, are currently insufficient in multiple institutions. Thus, the present study aimed to investigate the incidence of villous atrophy in the terminal ileum to diagnose acute intestinal GVHD and determine the inter- and intra-observer agreement regarding this result for experienced endoscopists from multiple institutions. Consecutive patients who underwent allo-HSCT were referred to our institution between May 2008 and September 2015. A total of 54 patients underwent total ileocolonoscopy after allo-HSCT due to suspected intestinal acute GVHD. Subsequently, three observers from different institutions evaluated the cases for the presence of villous atrophy in the terminal ileum. In this study, the pathology results were a gold standard to evaluate the predictive value of ileocolonoscopy detection. Definitive pathological and non-pathological GVHD was diagnosed in 22 and 32 cases, respectively. The results of examining whether villous atrophy could predict GVHD were as follows. For three observers (A, B and C), the sensitivity of villous atrophy in the terminal ileum was 86.4, 77.3 and 79.2%, respectively, whereas the specificity was 62.5, 62.5 and 86.7%, respectively. The positive predictive value (PPV) and negative predictive value (NPV) of villous atrophy for GVHD were as follows: The PPV of appearance was 61.3, 58.6 and 82.6%, respectively, whereas the NPV was 87.0, 80.0 and 83.9%, respectively. Kappa coefficients for the inter-observer reliability were 0.85, 0.63 and 0.63 for observers A and B, A and C, and B and C, respectively. The intra-observer kappa coefficient was 0.88 for observer A, 0.73 for observer B and 0.75 for observer C. A substantial observer agreement was achieved for the analysis of villous atrophy in the terminal ileum and the agreement for the predictive histological diagnosis was also excellent. Based on the results of the present study, identification of villous atrophy in the terminal ileum was a clinically effective diagnostic parameter, even if different endoscopists were involved in the diagnosis at multiple institutions. The present study was registered as a trial with the University Hospital Medical Information Network (UMIN; registration no. UMIN000025390).

Natural killer cells preferentially target and kill malignant and virally infected cells. Both these properties present compelling clinical utility in the field of haemopoietic progenitor cell transplantation (HPCT), potentially promoting a graft vs leukaemia effect in the absence of graft vs host disease and protecting against cytomegalovirus activation. Killer Ig-like receptors (KIR) play a central role in the cytotoxic action of natural killer cells, providing opportunity for improving transplantation outcomes by prioritising potential donors with optimal characteristics. Numerous algorithms for assessing KIR gene content as part of HPCT donor selection protocols exist, but no single model has been found to be universally applicable in all transplant centres. This review summarises several of the predominant strategies in KIR assessment algorithms, discussing their basic scientific principles, clinical utility and benefits to post-transplant outcomes. Finally, the review will consider how future donor selection protocols could develop towards unifying the concepts of KIR proteomics and genetics for optimising patient care.

Previously, the outcome of paediatric Philadelphia-chromosome-positive (Ph+) ALL treated with conventional chemotherapy alone was poor, necessitating the use of haematopoietic stem cell transplantation (HSCT) for the best outcomes. The recent addition of tyrosine kinase inhibitors (TKIs) alongside the chemotherapy regimens for Ph+ ALL has markedly improved outcomes, replacing the need for HSCT for lower risk patients. An additional poor prognosis group of Philadelphia-chromosome-like (Ph-like) ALL has also been identified. This group also can be targeted by TKIs in combination with chemotherapy, but the role of HSCT in this population is not clear. The impact of novel targeted immunotherapies (chimeric antigen receptor T cells and bispecific or drug-conjugated antibodies) has improved the outcome of patients, in combination with chemotherapy, and made the role of HSCT as the optimal curative therapy for Ph+ ALL and Ph-like ALL less clear. The prognosis of patients with Ph+ ALL and persistent minimal residual disease (MRD) at the end of consolidation despite TKI therapy or with additional genetic risk factors remains inferior when HSCT is not used. For such high-risk patients, HSCT using total-body-irradiation-containing conditioning is currently recommended. This review aims to provide an update on the current and future role of HSCT for Ph+ ALL and addresses key questions related to the management of these patients, including the role of HSCT in first complete remission, MRD evaluation and related actions post HSCT, TKI usage post HSCT, and the putative role of HSCT in Ph-like ALL.

International audience; There is growing theoretical evidence that spatial structure can affect the ecological and evolutionary outcomes of host-parasite interactions. Locally restricted interactions have been shown in particular to affect host resistance and tolerance. In this study we investigate the evolution of several types of host disease resistance strategies, alone or in combination, in spatially structured populations. We construct a spatially explicit, individual-based stochastic model where hosts and parasites interact with each other in a spatial lattice, and interactions are restricted to a given neighbourhood of varying size. We investigate several host resistance strategies, including constitutive (expressed in all resistant hosts), induced (expressed only upon infection), and combinations thereof. We show that a costly constitutive resistance cannot reach fixation, whereas an inducible resistance strategy may become fixed in the population if the cost remains low, particularly if it impacts host recovery. We also demonstrate that mixed strategies can be maintained in the host population, and that a higher investment in a recovery-boosting inducible resistance allows for a higher investment in a constitutive response. Our simulations reveal that the spatial structure of the population impacts the selection for resistance in a complex fashion. While single strategies of resistance are generally favoured in less structured populations, mixed strategies can sometimes prevail only in highly structured environments, e.g. when combining constitutive and transmission-blocking induced responses Overall these results shed new light on the dynamics of disease resistance in a spatially-structured host-pathogen system, and advance our theoretical understanding of the evolutionary dynamics of disease resistance, a necessary step to elaborate more efficient and sustainable strategies for disease management.

Chronic cutaneous graft‐vs‐host disease (GVHD) has several atypical variants. We describe two cases of GVHD with clinical and histopathologic features of pityriasis rubra pilaris (PRP), which responded to additional immunosuppression. Recognition of this newly described PRP‐like clinical presentation of GVHD may prompt early consideration of additional steroid‐sparing therapies.

Dear Editor, A recent paper from Dr Elliot published in Transfusion, entitled ‘Missed irradiation of cellular blood components from vulnerable patients: Insight from 10 years of SHOT data’ updates on Transfusion-associated graft-versus-host disease and blood safety [...]

Autologous stem-cell transplant is used to treat a variety of neoplastic syndromes such as multiple myeloma, chronic myeloid leukemia, and non-Hodgkin's lymphoma. In spite of its efficacy compared to other treatments, it predisposes patients to opportunistic infections and in rare cases, autologous graft versus host disease. In recent years, one opportunistic infection in particular, invasive aspergillosis, has become increasingly more common although survival rates remain low due to difficulty in diagnosis.

The concurrent profiles of the gut microbiome and metabolome can be used in the diagnosis of complex diseases. However, the establishment of robust predictive models is challenging due to the high dimensionality of data and complex interactions among microbiome, metabolites, and host. Using deep neural networks consisting of an autoencoder for extracting latent representations and a multilayer neural network for disease prediction, we show that gut metabolome is more predictive of inflammatory bowel disease (IBD) than gut microbiome. In addition, we design a new multi-task autoencoder to extract the latent profiles from the combined microbiome and metabolome data. We further demonstrate that the combined latent profiles can further improve the performance of prediction. In summary, our work shows that autoencoders are useful apparatuses in generating low dimensional profiles that contribute to the improved performance and robustness for IBD prediction.

BACKGROUND Standard first-line treatment of cGVHD includes systemic corticosteroids; however, about 50% of patients (pts) are steroid refractory or dependent (SR/D) and require additional treatment. The best second-line therapy option has not yet been defined. RUX, an oral JAK1/2 inhibitor, was superior to BAT in SR acute GVHD (aGVHD) in a phase 3 study (REACH2). Here we present the primary analysis of the REACH3 study (NCT03112603), a phase 3, open-label, randomized study evaluating RUX vs BAT in pts with SR/D cGVHD. METHODS Eligible pts were ≥ 12 years old, had received allogeneic hematopoietic cell transplant, and had developed moderate or severe SR/D cGVHD. Pts transitioning from aGVHD to cGVHD without tapering steroids were excluded. Pts treated with JAK inhibitors for aGVHD were allowed if they achieved complete response (CR) or partial response (PR) and had been off JAK inhibitor treatment for ≥ 8 weeks prior to cycle 1 day 1. Those treated with ≥ 2 prior lines of systemic therapy for cGVHD in addition to corticosteroids ± calcineurin inhibitors (CNI) were ineligible. Pts were randomized (1:1) to RUX 10 mg bid or investigator-selected BAT (10 options) and were treated for 6 cycles (cycle = 28 days). Pts continued receiving their regimen of corticosteroids ± CNI. Viral prophylaxis and antibiotics were allowed as needed for infection prevention and treatment. Addition or initiation of a new BAT was allowed only after lack of response, intolerable toxicity, or cGVHD flare and was considered treatment failure. Crossover from BAT to RUX was allowed on or after cycle 7 day 1 (C7D1) in pts who did not achieve or maintain CR/PR, developed toxicity to BAT, or had a cGVHD flare. The primary endpoint was overall response rate (ORR) at C7D1. ORR was defined as the proportion of pts achieving CR or PR, per NIH consensus criteria. Key secondary endpoints were failure-free survival (FFS; defined as time to the earliest of recurrence of underlying disease, start of new systemic treatment for cGVHD, or death) and improvement in symptoms based on change in the modified Lee symptom score (mLSS; 0 [no symptoms] to 100 [worst symptoms]) at C7D1. An mLSS responder was defined as having achieved a ≥ 7-point reduction from baseline in the total symptom score. The primary and key secondary endpoints were α-controlled via an overall hierarchical testing procedure. RESULTS A total of 329 pts were randomized to RUX (n = 165) or BAT (n = 164). Baseline characteristics were balanced in the 2 arms; 61% were male, and median age was 49 years (range, 12-76 years). Twelve pts were < 18 years old. Overall, 48% and 52% of pts had moderate and severe cGVHD, respectively. At data cutoff (May 8, 2020), 125 pts (38%) were on randomized treatment (RUX, 50%; BAT, 26%). Eighty-two (50%) and 122 (74%) pts discontinued RUX and BAT, respectively; 61 (37%) had crossed over to RUX. Reasons for discontinuation included lack of efficacy (15% RUX vs 43% BAT), adverse events (AEs; 17% vs 5%), and relapse (5% vs 4%). The study met its primary endpoint with the efficacy boundary crossed at interim analysis (ORR, P = 0.0003). At C7D1, ORR was significantly higher in the RUX arm vs BAT (50% vs 26%; odds ratio, 2.99; P < 0.0001a); the CR rate was higher with RUX (7% vs 3%; Table). Both key secondary endpoints showed superiority of RUX vs BAT. FFS was significantly longer for RUX-treated pts (median FFS, not reached vs 5.7 months; HR, 0.370 [95% CI, 0.268-0.510]; P < 0.0001; Figure), and the mLSS responder rate was higher (24% vs 10%; odds ratio, 3.00; P = 0.0003). Overall, 31 RUX (19%) and 27 BAT (16%) pts died; the main cause of death was cGVHD (RUX, n = 22 [13%]; BAT, n = 13 [8%], including 2 deaths after crossover to RUX). Rates of AEs up to C7D1 were comparable in the 2 arms (RUX, 98% [grade ≥ 3, 57%]; BAT, 92% [grade ≥ 3, 58%]. The most common AEs (≥ 15%) in the RUX vs BAT arms were anemia (29% vs 13%), hypertension (16% vs 13%), pyrexia (16% vs 9%), and ALT increase (15% vs 4%). Infections of any type occurred in 64% of RUX and 56% of BAT pts (19% vs 18% grade 3, grading based on Cordonnier et al 2006), and included fungal (12% vs 6%), viral (34% vs 29%), and bacterial (28% vs 26%) infections. CONCLUSIONS This is the first successful randomized phase 3 trial of RUX in pts with SR/D cGVHD. RUX demonstrated superior efficacy vs BAT, measured by a higher ORR, longer FFS, and greater symptom improvement. RUX was effective for moderate or severe SR/D cGVHD and its safety profile is consistent with that expected for this drug and this population. Disclosures Zeiser: Malinckrodt: Honoraria; Novartis: Honoraria; Incyte: Honoraria. Polverelli:Novartis: Consultancy. Chakraverty:Mallinckrodt Pharmaceuticals (Therakos (UK) Ltd): Honoraria; Neovii: Honoraria. Flowers:Novartis: Current Employment. Dawkins:Incyte: Current Employment. Hollaender:Novartis Pharma AG: Current Employment. Gowda:Novartis Pharmaceuticals Corporation: Current Employment. Stefanelli:Novartis AG: Current Employment, Current equity holder in publicly-traded company. Lee:Takeda: Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; Amgen: Research Funding; Kadmon: Research Funding; Incyte: Consultancy, Research Funding; Syndax: Research Funding; AstraZeneca: Research Funding. Teshima:Sharp & Dohme Corp: Consultancy, Honoraria; Astellas Pharma Inc.: Research Funding; Bristol-Myers Squibb: Honoraria; Japan Society for the Promotion of Science KAKENHI (17H04206): Other; The Center of Innovation Program from Japan Science and Technology Agency: Other; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Merck: Consultancy, Honoraria; Janssen Pharmaceutical K.K.: Other; NIPPON SHINYAKU CO., LTD.: Honoraria; Fuji Pharma Co., Ltd.: Honoraria; TEIJIN PHARMA LIMITED: Honoraria; Sanofi K.K.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Novartis Pharma K.K.: Consultancy, Other: Manuscript preparation, Research Funding; Pfizer Japan Inc.: Honoraria; Takeda Pharmaceutical Company Limited: Consultancy, Honoraria. Locatelli:Jazz Pharmaceeutical: Speakers Bureau; Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: Ruxolitinib for the treatment of chronic GVHD.

To investigate the incidence and risk factors as well as prognosis of autoimmune hemolytic anemia (AIHA) following allogeneic hematopoietic stem cell transplantation (allo‐HSCT), a total of 1377 adult hematological malignancies at three institutions were enrolled in this study. The 3‐year cumulative incidence of AIHA was 2.2 ± 0.4%. Multivariate analysis showed that haploidentical donors (HRDs) and chronic graft vs host disease (cGVHD) were the independent risk factors for AIHA. Patients with AIHA treated initially with corticosteroids combined with cyclosporine A (CsA) had a higher complete response rate than those with corticosteroids monotherapy (66.7% vs 11.1%; P = .013). The 3‐year cumulative incidence of malignant diseases relapse was 4.4 ± 4.3% and 28.0 ± 1.3% (P = .013), treatment‐related mortality (TRM) was 8.9 ± 6.3% and 17.4 ± 1.2% (P = .431), disease‐free survival (DFS) was 56.1 ± 1.5% and 86.7 ± 7.2% (P = .011), and overall survival (OS) was 86.3 ± 7.4% and 64.1 ± 1.5% (P = .054), respectively, in the patients with AIHA and those without AIHA. Our results indicate that HRDs and cGVHD are risk factors for AIHA and corticosteroids combined with CsA are superior to corticosteroids as initial treatment for AIHA. Autoimmune hemolytic anemia does not contribute to increase TRM and could reduce the malignant diseases relapse and increase DFS., Autoimmune hemolytic anemia (AIHA) occurs more frequently than other autoimmune hematological diseases (AHDs) after allogeneic hematopoietic stem cell transplantation. Haploidentical donors and chronic graft vs host disease are risk factors for AIHA and corticosteroids combined with cyclosporine A are superior to corticosteroids as initial treatment for AIHA. AIHA does not contribute to increase treatment‐related mortality and could reduce the malignant diseases relapse and increase disease‐free survival.

Objectives: Acute graft versus host disease (aGVHD) is a common complication of allogeneic hematopoietic cell transplant (HCT) and is associated with morbidity and mortality. Identifying th...

Despite major strides in reducing cardiovascular disease (CVD) burden with modification of classic CVD risk factors, significant residual risks remain. Recent discoveries that linked intestinal microbiota and CVD have broadened our understanding of how dietary nutrients may affect cardiovascular health and disease. Although next-generation sequencing techniques can identify gut microbial community participants and provide insights into microbial composition shifts in response to physiological responses and dietary exposures, provisions of prebiotics or probiotics have yet to show therapeutic benefit for CVD. Our evolving understanding of intestinal microbiota-derived physiological modulators (e.g., short-chain fatty acids) and pathogenic mediators (e.g., trimethylamine N-oxide) of host disease susceptibility have created novel potential therapeutic opportunities for improved cardiovascular health. This review discusses the roles of human intestinal microbiota in normal physiology, their associations with CVD susceptibilities, and the potential of modulating intestinal microbiota composition and metabolism as a novel therapeutic target for CVD.

Background Immunosuppressive prophylaxis is usually given to decrease the development of acute graft versus host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Belatacept is a Cytotoxic T-lymphocyte-associated protein 4, blocking agent, an immunosuppressive agent used for organ rejection prevention in adult renal transplant recipients. Methods We describe two children in whom belatacept was successfully used for GvHD prophylaxis. Case 1 was noncompliant with prior immunosuppressive therapy for aplastic anemia, and Case 2 developed severe thrombotic microangiopathy (TMA) precluding the use of calcineurin inhibitors (CNI) or mTOR inhibitors. Results and conclusion Belatacept was found to be a safe alternative in preventing GvHD in 2 patients in whom traditional prophylactic therapies were not possible to use.

Graft-vs. host disease (GVHD), both acute and chronic are among the chief non-relapse complications of allogeneic transplantation which still cause substantial morbidity and mortality despite significant advances in supportive care over the last few decades. The prevention of GVHD therefore remains critical to the success of allogeneic transplantation. In this review we briefly discuss the pathophysiology and immunobiology of GVHD and the current standards in the field which remain centered around calcineurin inhibitors. We then discuss important translational advances in GVHD prophylaxis, approaching these various platforms from a mechanistic standpoint based on the pathophysiology of GVHD including in-vivo and ex-vivo T-cell depletion alongwith methods of selective T-cell depletion, modulation of T-cell co-stimulatory pathways (checkpoints), enhancing regulatory T-cells (Tregs), targeting T-cell trafficking as well as cytokine pathways. Finally we highlight exciting novel pre-clinical research that has the potential to translate to the clinic successfully. We approach these methods from a pathophysiology based perspective as well and touch upon strategies targeting the interaction between tissue damage induced antigens and T-cells, regimen related endothelial toxicity, T-cell co-stimulatory pathways and other T-cell modulatory approaches, T-cell trafficking, and cytokine pathways. We end this review with a critical discussion of existing data and novel therapies that may be transformative in the field in the near future as a comprehensive picture of GVHD prophylaxis in 2020. While calcineurin inhibitors remain the standard, post-transplant eparinsphamide originally developed to facilitate haploidentical transplantation is becoming an attractive alternative to traditional calcinuerin inhibitor based prophylaxis due to its ability to reduce severe forms of acute and chronic GVHD without compromising other outcomes, even in the HLA-matched setting. In addition T-cell modulation, particularly targeting some important T-cell co-stimulatory pathways have resulted in promising outcomes and may be a part of GVHD prophylaxis in the future. Novel approaches including targeting early events in GVHD pathogenesis such as interactions bvetween tissue damage associated antigens and T-cells, endothelial toxicity, and T-cell trafficking are also promising and discussed in this review. GVHD prophylaxis in 2020 continues to evolve with novel exicitng therapies on the horizon based on a more sophisticated understanding of the immunobiology of GVHD.

Fungal plant-pathogens promote infection of their hosts through the release of ‘effectors’—a broad class of cytotoxic or virulence-promoting molecules. Effectors may be recognised by resistance or sensitivity receptors in the host, which can determine disease outcomes. Accurate prediction of effectors remains a major challenge in plant pathology, but if achieved will facilitate rapid improvements to host disease resistance. This study presents a novel tool and pipeline for the ranking of predicted effector candidates—Predector—which interfaces with multiple software tools and methods, aggregates disparate features that are relevant to fungal effector proteins, and applies a pairwise learning to rank approach. Predector outperformed a typical combination of secretion and effector prediction methods in terms of ranking performance when applied to a curated set of confirmed effectors derived from multiple species. We present Predector (https://github.com/ccdmb/predector) as a useful tool for the ranking of predicted effector candidates, which also aggregates and reports additional supporting information relevant to effector and secretome prediction in a simple, efficient, and reproducible manner.

The potential role of active CMV infection in promoting acute Graft-versus-Host Disease (aGvHD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a matter of debate. We further addressed this issue conducting a retrospective, observational, multicenter study of 632 patients subjected to allogeneic peripheral blood HSCT at 20 Spanish centers. Monitoring of CMV DNA load in plasma or whole blood was performed by real-time PCR assays. Cumulative incidence of CMV DNAemia was 48.9% (95% CI, 45%-52.9%), of any grade aGvHD, 45.6; 95% (CI, 41.3%-50.1%), and of grade II-IV aGvHD, 30.7 (95% CI, 24.9%-36.4%). Overall, development of CMV DNAemia at any level resulted in an increased risk of subsequent all grade (HR, 1.38; 95% CI, 1.08 - 1.76; P = .009) or grade II-IV (HR, 1.58; 95% CI, 1.22 - 2.06; P = .001) aGvHD. The increased risk of aGvHD linked to prior occurrence of CMV DNAemia was similar to the above when only clinically significant episodes were considered for the analyses (HR for all grade aGvHD, 1.48; 95% CI, 1.13 - 1.91; P = .041, and HR for grade II-IV aGvHD, 1.53; 95% CI. 1.13-1.81; P = .04). The CMV DNA doubling time in blood was comparable overall in episodes of CMV DNAemia whether followed by aGvHD or not. Whether CMV replication is a surrogate risk marker of aGvHD or it is causally involved is an important question to be addressed in future experimental research.

Despite decades of experience with hematopoietic stem cell transplantation, we are still faced with the delicate equipoise of achieving stable ocular health post-transplantation. This is because ocular graft-versus-host disease (oGvHD) following hematopoietic stem cell transplantation frequently occurs (≥50%) among transplant patients. To date, our understanding of the pathophysiology of oGvHD especially the involvement of the meibomian gland is still limited as a result of a lack of suitable preclinical models among other. Herein, the current state of the etiology and, pathophysiology of oGvHD based on existing pre-clinical models are reviewed. The need for additional pre-clinical models and knowledge about the involvement of the meibomian glands in oGvHD are emphasized.

Key Points Question Is ruxolitinib an option for patients with steroid-refractory chronic graft-vs-host disease, and what characteristics are associated with treatment response? Findings In this case series of 41 patients with steroid-refractory chronic graft-vs-host disease who were treated with ruxolitinib, heavily pretreated patients could achieve meaningful responses with a favorable safety profile. No lung involvement and haploidentical donors were associated with response to ruxolitinib. Meaning In this study, monotherapy with ruxolitinib was associated with a meaningful response in patients with steroid-refractory chronic graft-vs-host disease, suggesting a possible therapeutic option for a serious disease with no currently accepted standard-of-care treatment., This case series investigates the clinical response to ruxolitinib in patients with steroid-refractory chronic graft-vs-host disease after allogeneic hematopoietic stem cell transplantation and evaluates its safety profile during the treatment course., Importance Ruxolitinib, a selective inhibitor of the Janus kinases 1/2 signaling pathway, has shown a significant response in steroid-refractory chronic graft-vs-host disease (SR-cGVHD), a major cause of morbidity and mortality in individuals who have undergone allogeneic hematopoietic stem cell transplantation (HSCT). Objectives To investigate the clinical response to ruxolitinib in patients with SR-cGVHD after allogeneic HSCT and to evaluate its safety profile during the treatment course. Design, Setting, and Participants This single-center case series included 41 consecutive patients who were treated with ruxolitinib for SR-cGVHD after allogeneic HSCT between August 2017 and December 2019. Data were collected from each patient’s medical record at the First Affiliated Hospital of Zhejiang University School of Medicine. Data analysis was conducted from March to May 2020. Exposure Ruxolitinib. Main Outcomes and Measures Treatment responses, factors associated with response, and adverse effects during ruxolitinib administration. Findings Overall, 41 patients (median [range] age, 31 [17-56] years; 14 [34.1%] women) were treated with ruxolitinib and included in this study. A total of 15 patients (36.6%) had a complete remission, and 14 (34.1%) had a partial remission, with an overall response rate of 70.7% (29 patients; 95% CI, 56.2%-85.3%). Lung involvement (odds ratio, 0.112; 95% CI, 0.020-0.639; P = .01) and matched related donors (odds ratio, 0.149; 95% CI, 0.022-0.981; P = .048) were associated with less favorable treatment response. Major adverse events associated with ruxolitinib were cytopenias and infectious complications. The median (range) follow-up for this cohort was 14.9 (1.4-32.5) months. Prolonged survival was observed in patients with a male donor (P = .006), complete remission before transplantation (P = .02), baseline moderate cGVHD (P = .02), and skin cGVHD (P = .001). Conclusions and Relevance In this small, single-site case series, ruxolitinib demonstrated a significant response in heavily pretreated patients with SR-cGVHD and a reasonably well-tolerated safety profile. The results add to the body of literature suggesting ruxolitinib as a promising treatment option in SR-cGVHD.

Background This study assessed pharmacoeconomic costs associated with extracorporeal photopheresis (ECP) compared with other available second-line therapies for chronic graft-vs-host disease (cGvHD) in a tertiary Spanish institution. Methods Patients (>= 18 years) diagnosed with steroid-refractory cGvHD were eligible. Data were collected retrospectively from index date until 1 year or relapse. Patients were distributed in two cohorts (ECP vs non-ECP), matched by age ( 40), hematopoietic stem cell transplant (HLA-identical sibling donor or other) and number of previous immunosuppressive lines (1, 2, or >= 3). Costs were assigned using the 2016 diagnosis-related group (DRG) system: DRG 579 (euro22 383) overnight stay due to major complication (ie, sepsis, pneumonia, parenteral nutrition, or respiratory failure), and DRG 875 (euro5154) if no major complication. The primary endpoint was healthcare resource utilization per patient. Results Forty patients (n = 20 per cohort) were included. Median age was 49, and 37.5% were female. Mean total cost per patient was euro25 319 (95% CI: euro17 049-euro33 590) across the two cohorts, with a slightly lower mean cost per ECP-treated patient (euro23 120) compared with the non-ECP cohort (euro27 519; P = .597). Twenty-seven inpatient hospitalizations occurred among ECP-treated patients, vs 33 in the non-ECP cohort. Day hospital and external consultations were more frequent in the ECP cohort. However, fewer inpatient admissions included DRG 579 compared with the non-ECP cohort (44% vs 58%). Inpatient length of stay was slightly shorter in the ECP cohort (30 vs 49 days; P = .298). Conclusions ECP treatment may yield economic savings in Spain through resource savings and moving costs toward outpatient care.

Microbiota is the collection of all the microorganisms that are present in and on all mammals. The microbial communities are vastly diverse and actively contribute to the development and proper functioning of the immune system. Host-microbiota studies have seen an upswing with increasing technologies that help profile several microbial communities. Recent studies have uncovered how microbial metabolites play an important role in regulating host immunity. The host immune system has coevolved with the commensal microbiome for mutual regulation. Some metabolites even play a prominent role in increasing immune responses and decreasing harmful inflammatory responses. Studies involving microbial metabolites help unravel the molecular basis of host-microbiome interactions. Gut microbial metabolites have been shown to play an important role in gut homeostasis. This review throws light on microbial metabolites that play an important role in regulating host immunity and how an impaired microbiota contributes to host disease and metabolic disorders.

Background: Traditional weight-based dosing results in variable rabbit anti-thymocyte-globulin (rATG) clearance that can delay CD4+Tcell immune reconstitution (CD4+IR) leading to higher mortality. Methods: In a retrospective, pharmacokinetic (PK)/pharmacodynamic analysis of patients undergoing their first CD34+ T-cell depleted (TCD) Allogeneic Hematopoietic Cell Transplantation (HCT) after myeloablative conditioning with rATG, we estimated post-HCT rATG exposure as area-under-the-curve (AUC;AU*d/L) using a validated population-PK model. We related rATG exposure to non-relapse mortality (NRM), CD4+IR (CD4+≥50/µL at two consecutive measures within 100 days after HCT), overall survival, relapse, and acute-graft versus host disease (GVHD) to define an optimal rATG-exposure. Cox-proportional hazard models, and multi-state competing risk models were used. Results: 554 patients were included (age 0.1-73 years). Median post-HCT rATG exposure was 47AU*d/L (range 0–101). Low post–HCT AUC ( 55AU*d/L and 30-55AU*d/L groups, respectively, compared to