Chronic liver disease after allogeneic hematopoietic cell transplantation.

BACKGROUND AIMS: There are few descriptions of the epidemiology of chronic liver disease (CLD) after allogeneic hematopoietic stem cell transplantation (allo-HCT). Among those transplanted before 2000, viral hepatitis was the dominant cause of CLD. Recently, the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD, previously known as nonalcoholic fatty liver disease) is increasing in the general population. In addition, survivors of allo-HCT are known to be at increased risk of metabolic syndrome. We set out to describe the epidemiology of CLD in a modern cohort of allo-HCT recipients. We hypothesized that MASLD would be the most common cause of CLD in the cohort. METHODS: We undertook a retrospective cohort and nested case-control study of 2-year survivors of allo-HCT in Alberta transplanted between 2008 and 2018. RESULTS: Among 392 2-year survivors of allo-HCT between 2008 and 2018, the prevalence of CLD was 41.8% and MASLD was identified in 56% of those with CLD, followed by iron overload in 47% of those with CLD. The prevalence of MASLD among the entire cohort was 46%. Although most patients developed CLD before 2 years post-transplant, there was a 13% cumulative incidence of new CLD after 2 years posttransplant. Grade 2-4 acute graft-versus-host disease and/or moderate-to-severe chronic graft-versus-host disease and pretransplant CLD were strongly associated with CLD. In the case-control study examining the association between cardiovascular risk factors and CLD, type 2 diabetes was associated with CLD. Cirrhosis developed in 1.5% of survivors, and MASLD was an underlying etiology in one half of these cases. There was no difference in overall survival and non-relapse mortality between those who did and did not develop CLD. CONCLUSIONS: MASLD is the main cause of CLD in recent long-term survivors of allo-HCT and may be associated with post-transplant corticosteroid exposure and type 2 diabetes. We note a shift in the underlying etiology of CLD post-HCT: previous studies describe viral hepatitis as the most common cause of CLD. The high prevalence of MASLD in allo-HCT recipients has important implications for survivorship care.

The Development of the Canadian Physiotherapy Assessment of Clinical Performance (ACP) 2.0 - Alignment with the 2017 Competency Profile.

Purpose: Clinical education and assessment of students' performance during clinical placements are key components of Canadian entry-to-practice physiotherapy curriculum and important in developing entry-level physiotherapy practitioners. The Canadian Physiotherapy Assessment of Clinical Performance (ACP) is the measure currently used to assess physiotherapy student performance on clinical placements in most of the entry-to-practice physiotherapy programmes across Canada. The release of the 2017 Competency Profile by the National Physiotherapy Advisory Group resulted in a revision of the existing ACP. The purpose of this study is to report the process used to develop a revised version of the ACP based on the 2017 Competency Profile, henceforth called the ACP 2.0. Method: Using a multistage process, we sought input from Canadian clinical education academics, an expert consultant panel, as well as physiotherapists across Canada using a questionnaire, meetings, and an online survey, respectively. Results: Twelve of 15 clinical education academics responded to a questionnaire. The expert consultant panel (n = 12) met three times. There were 144 physiotherapists who initiated the national, online, survey and met the inclusion criteria; 84 completed the survey. In the ACP 2.0, rating scales and comments boxes were grouped, and additional text was added to 12 items for further clarification. The ACP 2.0 came to have 18 items and 9 comment boxes in addition to summative comments, in contrast to the original ACP's 21 items and 9 comment boxes. Conclusions: In November 2020, Canadian clinical education academics reviewed the proposed draft ACP 2.0 and unanimously accepted it for implementation in Canadian physiotherapy university programmes.

Objectif: l'enseignement clinique et l'évaluation du rendement des étudiants pendant les stages cliniques sont des éléments clés du programme canadien d'entrée en pratique de la physiothérapie et sont importants pour former des praticiens de la physiothérapie prêts à entrer en pratique. L'évaluation du rendement clinique de la physiothérapie au Canada (ÉPC) est la mesure actuellement en usage pour évaluer le rendement des étudiants en physiothérapie lors de leur stage clinique dans la plupart des programmes d'entrée en pratique de la physiothérapie au Canada. La publication du Profil des compétences par le Groupe consultatif national en physiothérapie en 2017 a donné lieu à une révision de l'ÉPC. La présente étude vise à rendre compte du processus utilisé pour mettre au point une version révisée de l'ÉPC d'après le Profil des compétences de 2017, désormais appelée l'ÉPC 2.0. Méthodologie: au moyen d'un processus échelonné, les chercheurs ont demandé l'apport d'universitaires canadiens en enseignement clinique, d'un groupe d'experts consultants et de physiothérapeutes des diverses régions du Canada dans le cadre d'un questionnaire, de réunions et d'un sondage en ligne, respectivement. Résultats: au total, 12 des 15 universitaires en enseignement clinique ont répondu à un questionnaire. Le groupe d'experts consultants (n = 12) s'est réuni trois fois. Enfin, 144 physiothérapeutes qui respectaient les critères d'inclusion ont entrepris le sondage national en ligne, et 84 l'ont terminé. Dans l'ÉPC 2.0, les échelles d'évaluation et les encadrés de commentaires ont été regroupés et du texte a été ajouté à 12 des points afin de les clarifier. L'ÉPC 2.0 comporte finalement 18 points et neuf encadrés de commentaires en plus des commentaires sommatifs, par rapport aux 21 points et aux neuf encadrés de commentaires de l'ÉPC original. Conclusions: en novembre 2020, les universitaires en enseignement clinique canadiens ont révisé le projet d'ÉPC 2.0 et en ont adopté la mise en œuvre à l'unanimité au sein des programmes universitaires de physiothérapie du Canada.

Injectable MSC Spheroid and Microgel Granular Composites for Engineering Tissue.

Many cell types require direct cell-cell interactions for differentiation and function; yet, this can be challenging to incorporate into 3-dimensional (3D) structures for the engineering of tissues. Here, a new approach is introduced that combines aggregates of cells (spheroids) with similarly-sized hydrogel particles (microgels) to form granular composites that are injectable, undergo interparticle crosslinking via light for initial stabilization, permit cell-cell contacts for cell signaling, and allow spheroid fusion and growth. One area where this is important is in cartilage tissue engineering, as cell-cell contacts are crucial to chondrogenesis and are missing in many tissue engineering approaches. To address this, granular composites are developed from adult porcine mesenchymal stromal cell (MSC) spheroids and hyaluronic acid microgels and simulations and experimental analyses are used to establish the importance of initial MSC spheroid to microgel volume ratios to balance mechanical support with tissue growth. Long-term chondrogenic cultures of granular composites produce engineered cartilage tissue with extensive matrix deposition and mechanical properties within the range of cartilage, as well as integration with native tissue. Altogether, a new strategy of injectable granular composites is developed that leverages the benefits of cell-cell interactions through spheroids with the mechanical stabilization afforded with engineered hydrogels.

Upfront allogeneic transplantation versus JAK inhibitor therapy for patients with myelofibrosis: a North American collaborative study.

Allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy for myelofibrosis (MF) and is recommended for patients with higher risk disease. However, there is a risk of early mortality, and optimal timing is unknown. JAK inhibitor (JAKi) therapy may offer durable improvement in symptoms, splenomegaly and quality of life. The aim of this multicentre, retrospective observational study was to compare outcomes of patients aged 70 years or below with MF in chronic phase who received upfront JAKi therapy vs. upfront HCT in dynamic international prognostic scoring system (DIPSS)-stratified categories. For the whole study cohort, median overall survival (OS) was longer for patients who received a JAKi vs. upfront HCT, 69 (95% CI 57-89) vs. 42 (95% CI 20-not reached, NR) months, respectively (p = 0.01). In patients with intermediate-2 and high-risk disease, median OS was 55 (95% CI 36-73) months with JAKi vs. 36 (95% CI 20-NR) months for HCT (p = 0.27). An upfront HCT strategy was associated with early mortality and difference in median OS was not observed in any risk group by 5 years of follow-up. Within the limitations of a retrospective observational study, we did not observe any benefit of a universal upfront HCT approach for higher-risk MF.

Allogeneic hematopoietic cell transplantation for blastic plasmacytoid dendritic cell neoplasm: a CIBMTR analysis.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with a poor prognosis and considered incurable with conventional chemotherapy. Small observational studies reported allogeneic hematopoietic cell transplantation (allo-HCT) offers durable remissions in patients with BPDCN. We report an analysis of patients with BPDCN who received an allo-HCT, using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). We identified 164 patients with BPDCN from 78 centers who underwent allo-HCT between 2007 and 2018. The 5-year overall survival (OS), disease-free survival (DFS), relapse, and nonrelapse mortality (NRM) rates were 51.2% (95% confidence interval [CI], 42.5-59.8), 44.4% (95% CI, 36.2-52.8), 32.2% (95% CI, 24.7-40.3), and 23.3% (95% CI, 16.9-30.4), respectively. Disease relapse was the most common cause of death. On multivariate analyses, age of ≥60 years was predictive for inferior OS (hazard ratio [HR], 2.16; 95% CI, 1.35-3.46; P = .001), and higher NRM (HR, 2.19; 95% CI, 1.13-4.22; P = .02). Remission status at time of allo-HCT (CR2/primary induction failure/relapse vs CR1) was predictive of inferior OS (HR, 1.87; 95% CI, 1.14-3.06; P = .01) and DFS (HR, 1.75; 95% CI, 1.11-2.76; P = .02). Use of myeloablative conditioning with total body irradiation (MAC-TBI) was predictive of improved DFS and reduced relapse risk. Allo-HCT is effective in providing durable remissions and long-term survival in BPDCN. Younger age and allo-HCT in CR1 predicted for improved survival, whereas MAC-TBI predicted for less relapse and improved DFS. Novel strategies incorporating allo-HCT are needed to further improve outcomes.

Corticosteroids as graft-versus-host disease prophylaxis for allogeneic hematopoietic cell transplant recipients with calcineurin inhibitor intolerance.

BACKGROUND AIMS: Although calcineurin inhibitors (CNIs) have a well-established role in the prevention of graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT), their use can be limited by significant toxicities, which may result in premature treatment discontinuation. The optimal management of patients with CNI intolerance is unknown. The objective of this study was to determine the effectiveness of corticosteroids as GVHD prophylaxis for patients with CNI intolerance. METHODS: This retrospective single-center study included consecutive adult patients with hematologic malignancies who underwent myeloablative peripheral blood allogeneic HCT with anti-thymocyte globulin, CNI, and methotrexate GVHD prophylaxis in Alberta, Canada. Multivariable competing-risks regression was used to compare cumulative incidences of GVHD, relapse, and non-relapse mortality between recipients of corticosteroid versus continuous CNI prophylaxis, and multivariable Cox proportional hazards regression was applied to compare overall survival, relapse-free survival (RFS) and moderate-to-severe chronic GVHD and RFS. RESULTS: Among 509 allogeneic HCT recipients, 58 (11%) patients developed CNI intolerance and were switched to corticosteroid prophylaxis at median 28 days (range 1-53) after HCT. Compared with patients who received continuous CNI prophylaxis, recipients of corticosteroid prophylaxis had significantly greater cumulative incidences of grade 2-4 acute GVHD (subhazard ratio [SHR] 1.74, 95% confidence interval [CI] 1.08-2.80, P = 0.024), grade 3-4 acute GVHD (SHR 3.22, 95% CI 1.55-6.72, P = 0.002), and GVHD-related non-relapse mortality (SHR 3.07, 95% CI 1.54-6.12, P = 0.001). There were no significant differences in moderate-to-severe chronic GVHD (SHR 0.84, 95% CI 0.43-1.63, P = 0.60) or relapse (SHR 0.92, 95% CI 0.53-1.62, P = 0.78), but corticosteroid prophylaxis was associated with significantly inferior overall survival (hazard ratio [HR] 1.77, 95% CI 1.20-2.61, P = 0.004), RFS (HR 1.54, 95% CI 1.06-2.25, P = 0.024), and chronic GVHD and RFS (HR 1.46, 95% CI 1.04-2.05, P = 0.029). CONCLUSIONS: Allogeneic HCT recipients with CNI intolerance are at increased risks of acute GVHD and poor outcomes despite institution of corticosteroid prophylaxis following premature CNI discontinuation. Alternative GVHD prophylaxis strategies are needed for this high-risk population.

Granular Hydrogels in Biofabrication: Recent Advances and Future Perspectives.

Granular hydrogels, which are formed by densely packing microgels, are promising materials for bioprinting due to their extrudability, porosity, and modularity. However, the multidimensional parameter space involved in granular hydrogel design makes material optimization challenging. For example, design inputs such as microgel morphology, packing density, or stiffness can influence multiple rheological properties that govern printability and the behavior of encapsulated cells. This review provides an overview of fabrication methods for granular hydrogels, and then examines how important design inputs can influence material properties associated with printability and cellular responses across multiple scales. Recent applications of granular design principles in bioink engineering are described, including the development of granular support hydrogels for embedded printing. Further, the paper provides an overview of how key physical properties of granular hydrogels can influence cellular responses, highlighting the advantages of granular materials for promoting cell and tissue maturation after the printing process. Finally, potential future directions for advancing the design of granular hydrogels for bioprinting are discussed.

High resolution lithography 3D bioprinting.

Lithography bioprinting can fabricate constructs with high resolution for potential use in tissue engineering applications. Seminal work by Grigoryan and colleagues developed bioresins with precise control over the x, y, and z-planes during lithography bioprinting and applied this technique to fabricating physiologically biomimetic alveolar lung models.

Abstracts of the Cell Therapy Transplant Canada 2022 Annual Conference.

On behalf of Cell Therapy Transplant Canada (CTTC), we are pleased to present the Abstracts of the CTTC 2022 Annual Conference. The conference was held in-person 15-18 June 2022, in Niagara Falls, Ontario. Poster authors presented their work during a lively and engaging welcome reception on Thursday, 16 June, and oral abstract authors were featured during the oral abstract session in the afternoon on Friday, 17 June 2022. Thirty-three (33) abstracts were selected for presentation as posters and six (6) as oral presentations. The top abstracts in each of four (4) categories, (1) Basic/Translational sciences, (2) Clinical Trials/Observations, (3) Laboratory/Quality, and (4) Pharmacy/Nursing/Other Transplant Support, received awards for both the oral and poster presentations. All of these were marked as "Award Recipient" with the relevant category. We congratulate all the presenters on their research and contribution to the field.

Donor Genetic Predisposition to High Interleukin-10 Production Appears Protective against Acute Graft-Versus-Host Disease.

The persistence of graft-versus-host disease (GVHD) as the principal complication of allogeneic hematopoietic cell transplantation (HCT) demonstrates that HLA matching alone is insufficient to prevent alloreactivity. We performed molecular and functional characterization of 22 candidate cytokine genes for their potential to improve matching in 315 myeloablative, 10/10 HLA-matched donor−recipient pairs. Recipients of a graft carrying the -1082GG IL10 gene promoter region variant had a three-fold lower incidence of grade II−IV acute GVHD compared to IL10-1082AA graft recipients (SHR = 0.25, p = 0.005). This was most evident in matched unrelated donor (MUD) transplants, where the greatest alloreactivity is expected. IL10-1082GG transplants did not experience an increased incidence of relapse, and, consequently, overall survival was two-fold higher in IL10-1082GG MUD transplants (HR = 0.17, p = 0.023). Longitudinal post-transplant measurements demonstrated that -1082GG is a high-IL10-producing and -expressing genotype with attenuated CD8+ T-cell reconstitution. High post-transplant donor chimerism in T- and myeloid-cells (>95%) confirmed a predominant donor, rather than recipient, genotype effect on immune function and aGVHD. To date, this is the first study to report corroborating genome-to-cellular evidence for a non-HLA donor immunogenetic variant that appears to be protective against GVHD. The incorporation of IL10 variants in donor selection criteria and clinical-management decisions has the potential to improve patient outcomes.

Cumulative incidence of subsequent malignancy after allo-HCT conditioned with or without low-dose total body irradiation.

Subsequent malignancies (SMs) present a significant burden of morbidity and are a common cause of late mortality in survivors of allogeneic hematopoietic cell transplant (allo-HCT). Previous studies have described total body irradiation (TBI) as a risk factor for the development of SMs in allo-HCT survivors. However, most studies of the association between TBI and SM have examined high-dose TBI regimens (typically ≥600 cGy), and thus little is known about the association between low-dose TBI regimens and risk of SMs. Our goal, therefore, was to compare the cumulative incidence of SMs in patients of Alberta, Canada, who received busulfan/fludarabine alone vs busulfan/fludarabine plus 400 cGy TBI. Of the 674 included patients, 49 developed a total of 56 malignancies at a median of 5.9 years' posttransplant. The cumulative incidence of SMs at 15 years' post-HCT in the entire cohort was 11.5% (95% confidence interval [CI], 8.5-15.6): 13.4% (95% CI, 9.1-19.3) in the no-TBI group and 10.8% (95% CI, 6.6-17.4) in the TBI group. In the multivariable model, TBI was not associated with SMs, whereas there was an association with number of pre-HCT cycles of chemotherapy. The standardized incidence ratio for the entire cohort, compared with the age-, sex-, and calendar year-matched general population, was 1.75. allo-HCT conditioning that includes low-dose TBI does not seem to increase risk of SMs compared with chemotherapy-alone conditioning.

Allogeneic transplant and CAR-T therapy after autologous transplant failure in DLBCL: a noncomparative cohort analysis.

Allogeneic transplant (alloHCT) and chimeric antigen receptor modified (CAR)-T cell therapy are potentially cuarative options of diffuse large B-cell lymphoma (DLBCL) relapsing after an autologous (auto)HCT. Although the Center for International Blood and Marrow Transplant Research (CIBMTR) prognostic model can predict outcomes of alloHCT in DLBCL after autoHCT failure, corresponding models of CAR-T treatment in similar patient populations are not available. In this noncomparative registry analysis, we report outcomes of patients with DLBCL (≥18 years) undergoing a reduced intensity alloHCT or CAR-T therapy with axicabtagene ciloleucel during 2012 to 2019 after a prior auto-HCT failure and apply the CIBMTR prognostic model to CAR-T recipients. A total of 584 patients were included. The 1-year relapse, nonrelapse mortality, overall survival (OS), and progression-free survival for CAR-T treatment after autoHCT failure were 39.5%, 4.8%, 73.4%, and 55.7%, respectively. The corresponding rates in the alloHCT cohort were 26.2%, 20.0%, 65.6%, and 53.8%, respectively. The 1-year OS of alloHCT recipients classified as low-, intermediate- and high/very high-risk groups according to the CIBMTR prognostic score was 73.3%, 59.9%, and 46.3%, respectively (P = .002). The corresponding rates for low-, intermediate-, and high/very high-risk CAR-T patients were 88.4%, 76.4%, and 52.8%, respectively (P < .001). This registry analysis shows that both CAR-T and alloHCT can provide durable remissions in a subset of patients with DLBCL relapsing after a prior autoHCT. The simple CIBMTR prognostic score can be used to identify patients at high risk of treatment failure after either procedure. Evaluation of novel relapse mitigations strategies after cellular immunotherapies are warranted in these high-risk patients.

Risk Factors for the Incidence of and the Mortality due to Post-Transplant Lymphoproliferative Disorder after Hematopoietic Cell Transplantation.

Post-transplant lymphoproliferative disorder (PTLD) is a potentially serious complication that occurs following hematopoietic cell transplantation (HCT), in which B cells transformed by Epstein-Barr virus (EBV) proliferate uncontrollably. It is unknown whether risk factors for the incidence of PTLD are identical to those for mortality due to PTLD, a clinically more important outcome. We sought to determine the risk factors influencing the incidence of PTLD and those influencing mortality due to PTLD in a cohort of 1184 allogenic HCT recipients. All patients were predisposed to PTLD, because their graft-versus-host disease (GVHD) prophylaxis included antithymocyte globulin. The overall PTLD incidence was 9.0%, and mortality due to PTLD was 1.1%. In multivariate analysis, risk factors for PTLD incidence include donor+/recipient- (D+/R-) EBV serostatus (subhazard ratio [SHR], 3.3; P = .002), use of a donor other than an HLA-matched sibling donor (non-MSD) (SHR, 1.7; P = .029), receipt of total body irradiation (TBI; SHR, 3.3; P = .008), and the absence of GVHD (SHR, 3.3; P < .001). The sole risk factor for mortality due to PTLD among all patients was D+/R- serostatus (SHR, 5.8; P = .022). Risk factors for mortality due to PTLD among patients who developed PTLD were use of a bone marrow (BM) graft (compared with peripheral blood stem cells [PBSCs]; SHR, 22.8; P < .001) and extralymphatic involvement (SHR, 14.6; P < .001). Interestingly, whereas the absence of GVHD was a risk factor for PTLD incidence, there was a trend toward the presence of GVHD as a risk factor for PTLD mortality (SHR, 4.2; P = .093). Likewise, whereas use of a BM graft was a risk factor for PTLD mortality, there was a trend toward use of a PBSC graft as a risk factor for PTLD incidence (SHR, 0.44; P = .179). Some risk factors for the incidence of PTLD are identical to the risk factors for mortality due to PTLD (ie, D+/R- serostatus), whereas other risk factors are disparate. Specifically, TBI was identified as a risk factor for PTLD incidence but not for PTLD mortality; the absence of GVHD was a risk factor for PTLD incidence, whereas the presence of GVHD was possibly a risk factor for PTLD mortality; and receipt of a PBSC graft was possibly a risk factor for PTLD incidence, whereas receipt of a BM graft was a risk factor for PTLD mortality.

A biomarker-guided, prospective, phase 2 trial of pre-emptive graft-versus-host disease therapy using anti-thymocyte globulin.

BACKGROUND AIMS: Intensified immunosuppressive prophylaxis for graft-versus-host disease (GVHD) may be toxic and therefore warranted only in patients at high risk of developing GVHD. In patients who underwent allogeneic hematopoietic cell transplant at the authors' center, high serum soluble IL-2 receptor alpha (sIL-2Rα) and low IL-15 levels on day 7 post-transplant were found to predict a high risk of developing clinically significant GVHD (sGVHD), defined as grade 2-4 acute GVHD or moderate to severe chronic GVHD. METHODS: This was a prospective, phase 2 trial in which high-risk patients (serum sIL-2Rα >4500 ng/L or IL-15 <31 ng/L) received rabbit anti-thymocyte globulin (ATG) 3 mg/kg on day 8 post-transplant. Controls consisted of patients who had their sIL-2Rα/IL-15 levels measured but did not participate in the trial. A total of 68 trial patients and 143 controls were accrued to this study. The primary endpoint was incidence of sGVHD. RESULTS: There was a reduction in sGVHD in high-risk trial patients (received day 8 ATG) compared with high-risk controls (did not receive day 8 ATG) (sub-hazard ratio [SHR] = 0.48, P < 0.05). There was no significant difference between the groups in overall survival or relapse; however, there was a greater incidence of non-GVHD-associated non-relapse mortality in high-risk trial patients (SHR = 3.73, P < 0.05), mostly related to infections. This may be due in part to the biomarkers ineffectively stratifying GVHD risk. CONCLUSIONS: Pre-emptive ATG therapy is both feasible and effective at reducing sGVHD without increasing relapse. Further mitigation strategies are needed to reduce the risk of infection associated with intensified GVHD prophylaxis. This study was registered at ClinicalTrials.gov (NCT01994824).

3D bioprinting of high cell-density heterogeneous tissue models through spheroid fusion within self-healing hydrogels.

Cellular models are needed to study human development and disease in vitro, and to screen drugs for toxicity and efficacy. Current approaches are limited in the engineering of functional tissue models with requisite cell densities and heterogeneity to appropriately model cell and tissue behaviors. Here, we develop a bioprinting approach to transfer spheroids into self-healing support hydrogels at high resolution, which enables their patterning and fusion into high-cell density microtissues of prescribed spatial organization. As an example application, we bioprint induced pluripotent stem cell-derived cardiac microtissue models with spatially controlled cardiomyocyte and fibroblast cell ratios to replicate the structural and functional features of scarred cardiac tissue that arise following myocardial infarction, including reduced contractility and irregular electrical activity. The bioprinted in vitro model is combined with functional readouts to probe how various pro-regenerative microRNA treatment regimes influence tissue regeneration and recovery of function as a result of cardiomyocyte proliferation. This method is useful for a range of biomedical applications, including the development of precision models to mimic diseases and the screening of drugs, particularly where high cell densities and heterogeneity are important.

Bioprinting for the Biologist.

Building tissues from scratch to explore entirely new cell configurations could revolutionize fundamental understanding in biology. Bioprinting is an emerging technology to do this. Although typically applied to engineer tissues for therapeutic tissue repair or drug screening, there are many opportunities for bioprinting within biology, such as for exploring cellular crosstalk or cellular morphogenesis. The overall goals of this Primer are to provide an overview of bioprinting with the biologist in mind, outline the steps in extrusion bioprinting (the most widely used and accessible technology), and discuss alternative bioprinting technologies and future opportunities for bioprinting in biology.

Injectable hyaluronic acid and platelet lysate-derived granular hydrogels for biomedical applications.

Towards the repair of damaged tissues, numerous scaffolds have been fabricated to recreate the complex extracellular matrix (ECM) environment to support desired cell behaviors; however, it is often challenging to design scaffolds with the requisite cell-anchorage sites, mechanical stability, and tailorable physicochemical properties necessary for many applications. To address this and to improve on the properties of hyaluronic acid (HA) hydrogels, we combined photocrosslinkable norbornene-modified HA (NorHA) with human platelet lysate (PL). These PL-NorHA hybrid hydrogels supported the adhesion of cells when compared to NorHA hydrogels without PL, exhibited tailorable physicochemical properties based on the concentration of individual components, and released proteins over time. Using microfluidic techniques with on-chip mixing of NorHA and PL and subsequent photocrosslinking, spherical PL-NorHA microgels with a hierarchical fibrillar network were fabricated that exhibited the sustained delivery of PL proteins. Microgels could be jammed into granular hydrogels that exhibited shear-thinning and self-healing properties, enabling ejection from syringes and the fabrication of stable 3D constructs with 3D printing. Again, the inclusion of PL enhanced cellular interactions with the microgel structures. Overall, the combination of biomolecules and fibrin self-assembly arising from the enriched milieu of PL-derived proteins improved the bioactivity of HA-based hydrogels, enabling the formation of dynamic systems with modular design. The granular systems can be engineered to meet the complex demands of functional tissue repair using versatile processing techniques, such as with 3D printing.

Australia: A Continent Without Native Powdery Mildews? The First Comprehensive Catalog Indicates Recent Introductions and Multiple Host Range Expansion Events, and Leads to the Re-discovery of Salmonomyces as a New Lineage of the Erysiphales.

In contrast to Eurasia and North America, powdery mildews (Ascomycota, Erysiphales) are understudied in Australia. There are over 900 species known globally, with fewer than currently 60 recorded from Australia. Some of the Australian records are doubtful as the identifications were presumptive, being based on host plant-pathogen lists from overseas. The goal of this study was to provide the first comprehensive catalog of all powdery mildew species present in Australia. The project resulted in (i) an up-to-date list of all the taxa that have been identified in Australia based on published DNA barcode sequences prior to this study; (ii) the precise identification of 117 specimens freshly collected from across the country; and (iii) the precise identification of 30 herbarium specimens collected between 1975 and 2013. This study confirmed 42 species representing 10 genera, including two genera and 13 species recorded for the first time in Australia. In Eurasia and North America, the number of powdery mildew species is much higher. Phylogenetic analyses of powdery mildews collected from Acalypha spp. resulted in the transfer of Erysiphe acalyphae to Salmonomyces, a resurrected genus. Salmonomyces acalyphae comb. nov. represents a newly discovered lineage of the Erysiphales. Another taxonomic change is the transfer of Oidium ixodiae to Golovinomyces. Powdery mildew infections have been confirmed on 13 native Australian plant species in the genera Acacia, Acalypha, Cephalotus, Convolvulus, Eucalyptus, Hardenbergia, Ixodia, Jagera, Senecio, and Trema. Most of the causal agents were polyphagous species that infect many other host plants both overseas and in Australia. All powdery mildews infecting native plants in Australia were phylogenetically closely related to species known overseas. The data indicate that Australia is a continent without native powdery mildews, and most, if not all, species have been introduced since the European colonization of the continent.

Timing of allogeneic hematopoietic cell transplantation (alloHCT) for chronic myeloid leukemia (CML) patients.

While TKI are the preferred first-line treatment for chronic phase (CP) CML, alloHCT remains an important consideration. The aim is to estimate residual life expectancy (RLE) for patients initially diagnosed with CP CML based on timing of alloHCT or continuation of TKI in various settings: CP1 CML, CP2 + [after transformation to accelerated phase (AP) or blast phase (BP)], AP, or BP. Non-transplant cohort included single-institution patients initiating TKI and switched TKI due to failure. CIBMTR transplant cohort included CML patients who underwent HLA sibling matched (MRD) or unrelated donor (MUD) alloHCT. AlloHCT appeared to shorten survival in CP1 CML with overall mortality hazard ratio (HR) for alloHCT of 2.4 (95% CI 1.2-4.9; p = .02). In BP CML, there was a trend toward higher survival with alloHCT; HR = 0.7 (0.5-1.1; p = .099). AlloHCT in CP2 + [HR = 2.0 (0.8-4.9), p = .13] and AP [HR = 1.1 (0.6-2.1); p = .80] is less clear and should be determined on a case-by-case basis.