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Abstract The consumption of red wine induces headaches in some subjects who can drink other alcoholic beverages without suffering. The cause for this effect has been attributed to a number of components, often the high level of phenolics in red wine, but a mechanism has been elusive. Some alcohol consumers exhibit flushing and experience headaches, and this is attributed to a dysfunctional ALDH2 variant, the enzyme that metabolizes acetaldehyde, allowing it to accumulate. Red wine contains much higher levels of quercetin and its glycosides than white wine or other alcoholic beverages. We show that quercetin-3-glucuronide, a typical circulating quercetin metabolite, inhibits ALDH2 with an IC50 of 9.6 µM. Consumption of red wine has been reported to result in comparable levels in circulation. Thus, we propose that quercetin-3-glucoronide, derived from the various forms of quercetin in red wines inhibits ALDH2, resulting in elevated acetaldehyde levels, and the subsequent appearance of headaches in susceptible subjects. Human-subject testing is needed to test this hypothesis.

The work studied the methanogenic microbial consortium in a coal mine from the Bogotá basin in Colombia. Ex situ coal-enrichment cultures were established for in vitro growth and de novo gas production. Biogenic gas produced by cultures was analyzed by gas chromatography using thermal conductivity and flame ionization detectors. Cultures were used to isolate microbial specimens and to generate 16S rRNA gene libraries employing bacterial and archaeal primer sets. The gas chromatographic analysis showed methane production at 37 oC, but not at 60 oC, where CO2 was the major component of the biogenic gas. 16S rRNA gene sequence analysis of microbial isolates and clone libraries established that the methanogenic microbial consortium was formed by bacteria species from Bacillus and Gracilibacter genera plus archaea from the Methanothermobacter genus. This methanogenic microbial consortium was potentially responsible for biogenic gas generation in La Ciscuda coal mine. The results suggested that these methanogens produced methane by hydrogenotrophic or CO2 reduction pathways.

ABSTRACT Endoplasmic reticulum (ER)-shaping atlastin proteins (ATLs) have been demonstrated to play a functional role during flavivirus replication in mammalian cells. For dengue virus (DENV), atlastin is required in the formation of the replication organelles and RNA replication, virion assembly, production of the infectious virus particles, and trafficking or directing the association of vesicle packets with furin. Here, we investigated the involvement of atlastin in DENV replication in the mosquito Aedes aegypti and explored the possibility of its manipulation by the endosymbiotic bacterium Wolbachia to interfere with DENV replication. Results showed the expression of Ae. aegypti atlastin gene (AaATL) was upregulated in DENV-infected Aag2 cells, and its silencing led to reduced DENV replication. Contrary to our assumption that AaATL could be downregulated by Wolbachia, we did not find evidence for that in Wolbachia-infected cell lines, but this was the case in mosquitoes. Further, silencing AaATL did not have any effect on Wolbachia density. Our results also suggest that aae-miR-989 miRNA negatively regulates AaATL. The oversupply of the miRNA mimic led to reduced DENV replication consistent with the positive role of AaATL in DENV replication. Overall, the results favor AaATL’s involvement in DENV replication; however, there is no support that the protein is involved in Wolbachia-mediated DENV inhibition. In addition, the results contribute to discerning further possible overlapping functions of ATLs in mosquitoes and mammalian cells. IMPORTANCE Atlastin is a protein associated with the endoplasmic reticulum and has been shown to play a role in replication of flaviviruses in mammalian cells. This study aimed to investigate the role of mosquito Aedes aegypti atlastin (AaATL) in dengue virus replication and maintenance of Wolbachia, an endosymbiotic bacterium, in the mosquito. Our results suggest that AaATL facilitates dengue virus replication in mosquito cells, considering silencing the gene led to reductions in virus replication and virion production. Further, AaATL was found to be regulated by a mosquito microRNA, aae-miR-989. Despite an effect on dengue virus, AaATL silencing did not affect Wolbachia replication and maintenance in mosquito cells. The results shed light on the role of atlastins in mosquito-pathogen interactions and their overlapping roles in mosquito and mammalian cells.

A differential benefit of external focus of attention (FOA) relative to internal focus has been demonstrated across a wide variety of athletic and rehabilitative pursuits; however, very little research has been undertaken in the performing arts. Given the unique aesthetic context of the arts and obvious transdisciplinary parallels, particular attention is warranted. This study examines nine pianists’ pedaling while performing Bartók’s Romanian Folk Dance Sz. 56, No. 2, and directing attention to three different focus conditions relative to a baseline condition. Differences in global pedal use and technique emerged and appeared to be modulated by level of expertise and the length of time spent preparing the piece. The two most experienced pianists and the least experienced pianist demonstrated greatest consistency in pedaling, as measured by Z scores calculated across eight performance parameters. Results corroborate previous FOA research demonstrating performance variability when adopting different focus strategies. Implications include the need to deliberately align focus strategies in music training and performance. To the authors’ knowledge, this is the first study to examine performance effects of external against internal FOA on pianists’ pedaling. The critical conceptual aspect of the work is beginning to illuminate the relationships between a performer’s attention and motor output, and perceived artistic or musical effects.

The objectives of the study are to investigate the incidence of new or worsening headache after cochlear implant (CI) surgery and activation and to determine whether there are predictors of associated headache. We performed a cross-sectional survey of patients who had CI surgery. The frequency and severity of headache, onset of headache relative to surgery and device activation, medication use, family history, headache triggers, and accompanying cranial autonomic symptoms were recorded and analyzed. Thirty-seven subjects were enrolled. In the time period after CI surgery but before CI activation, none reported a new headache and four (11%) reported a worsening headache. After CI activation, six (16%) developed new headache and five (14%) developed worsening headache. These 11 subjects also experienced a significantly higher mean of 6.3 headache days/month following CI activation ( p < 0.009). Providers should be aware that new or worsening headache can be reported following CI activation, although not immediately following CI surgery.

Variation in one form or another is an inevitable aspect of human motor performance as the body negotiates the degrees of freedom problem while also adapting to ever-changing task constraints. The constraints to action model suggests that movement patterns arise from within a framework of environmental, task, and personal constraints. Like athletes, musicians adapt to a wide variety of constraints such as the presence and effect of spectators; acoustics in different performing spaces; humidity affecting tuning; and interpersonal interactions characterizing chamber and ensemble music. A crucial constraint particular to piano performance is adapting to the unique attributes of a wide variety of keyboard instruments. Pianists often refer to the distinct “feel” of a particular instrument: its responsiveness and sensitivity; key resistance; and the evenness and predictability of the instrument. Movement control both within and across pianos is essential for optimal performance, and in that sense, each instrument presents a type of task constraint. In this study, seven pianists performed 10 bimanual, two-octave, C major scales on 3 different piano keyboards to facilitate comparison of performance characteristics across instruments. Pianists performed 4 keystrokes per second, paced by a metronome set at 60 BPM. No timing differences were observed among keyboards as consistent patterns emerged, specifically anticipatory adjustments prior to thumb strokes. These results suggest that pianists are able to produce performances of similar musical structure across different instruments.

La durabilidad de la resistencia genética del arroz a Pyricularia grisea Sacc. había estado comprometida en Colombia, por una rápida adaptación aparente del patógeno a los genes dispuestos para contrarrestar su incidencia. Las variedades mejoradas se veían afectadas por la enfermedad en el curso de pocos años y, en ocasiones, a sólo meses de haber sido liberadas. La exclusión de linajes es una estrategia de mejoramiento que propone la identificación y posterior ‘piramidación’ de genes con habilidad para reconocer de manera complementaria las avirulencias de las familias genéticas (linajes) del patógeno. Poblaciones ecológicamente distintitas, caracterizadas molecularmente mediante la sonda MGR-586, exhiben una estructura clonal en la que cada aislamiento del linaje comparte históricamente el mismo espectro de virulencia. La resistencia obtenida con la piramidación de genes complementarios funciona como factor de exclusión hacia la totalidad de la virulencia en la población del patógeno en un ecosistema determinado. Así, en Colombia, los genes Pi-1 (t) y Pi-2 (t) son diferencial y complementariamente excluyentes de la virulencia de las poblaciones de P. grisea. Fueron obtenidas líneas con estos genes piramidados mediante el cruzamiento de dos líneas isogénicas; la presencia y condición homocigota de los genes de resistencia en las nuevas líneas fue establecida a través de marcadores moleculares. El comportamiento de las pirámides fue evaluado en el laboratorio, en cámaras de crecimiento con aislamientos representativos de los linajes colombianos y, en el campo, en una región dedicada tradicionalmente a la producción de arroz donde las epidemias de piricularia son frecuentes.Tanto en las inoculaciones artificiales, como en las áreas de cultivo, las pirámides conservaron la resistencia. La estructura de virulencia entre la población del patógeno en el campo permaneció estable durante tres años, aunque estacional y transitoriamente se identificaron algunos aislamientos virulentos a las pirámides en la estación experimental.

Graft versus tumor relies on tumor-associated antigens (TAAs) that are presented to donor T cells via human leukocyte antigens (HLAs). The HLA evolutionary divergence (HED) between alleles of a single individual can dictate the ability to present TAAs. The impact of HED in haploidentical donor transplantation (HIDT) has not been studied. We studied the effect of HED on transplant outcomes following HIDT. We analyzed 322 consecutive recipient/donor pairs with a median follow-up of 57.2 months. Pairwise divergence of HLA class I and II showed that HLA-B, -DRB1, and -DQB1 contributing most to mean HED. The mean HED was class I 6.85 (HLA-A 7.08, -B 8.24, and -C 5.07), class II 8.58 (HLA-DRB1 10.97, -DQB1 10.06 and -DPB1 4.06). A high HED in class I mismatched recipient/donor haplotype (RD MM) was significant for worse DFS (HR 1.11, p = 0.020), and relapse (HR 1.11, p = 0.02). Also, a high HED in RD MM HLA-B haplotype had worse OS (HR 1.07, p = 0.02), DFS (HR 1.09, p = 0.002), higher relapse (HR 1.10, p = 0.003), and similar NRM to low HED. The multivariate analysis showed that high HED in RD MM HLA-B (≥7.8 vs <7.8) had worse DFS (HR 1.53, p = 0.01), higher relapse (HR 1.61, p = 0.024), and similar NRM and OS., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Following conventional graft-versus-host disease (GVHD) prophylaxis, the development of acute and/or chronic GVHD is associated with lower relapse rates. However, the effects of GVHD on relapse and non-relapse mortality following post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis have not been well studied. To this end, we analyzed the impact of acute and chronic GVHD following PTCy-based haploidentical donor transplantation (HIDT). The analysis included 335 consecutive HIDT recipients transplanted at a single institution between 2005 and 2021. Landmark analysis (LA) and time-dependent multivariable analysis (MVA) were utilized to study the impact of GVHD development on transplant outcome. Landmarks were defined as Day +100 for acute GVHD and one-year for chronic GVHD. Recipient characteristics included a median age of 50 (19-80) years, most commonly transplanted for acute leukemia[/MDS [242]. PBSC was the graft source in 81%, and regimen intensity was myeloablative in 49%. Median follow-up was 65 (23-207) months. In landmark analysis, development of grade 3 to 4 acute GVHD (versus 0-1) was associated with inferior 3-year overall survival (OS 47% versus 64%, P = .041), due to higher NRM (25% versus 10%, P = .013). In contrast, development of grade 2 acute GVHD had no significant effect on NRM or survival. When restricted to acute leukemia/MDS patients, development of grade II acute GVHD was associated with improved OS (79% versus 58%, P = .027) and a trend towards lower relapse (24% versus 36%, P = .08). Development of moderate-to-severe chronic GVHD resulted in significantly higher NRM (15% versus 4%, P = .010), but had no impact on relapse, DFS or OS. In Cox multivariate analysis (MVA), grade 3 to 4 acute GVHD and moderate-to-severe chronic GVHD were both associated with significantly higher NRM (HR 3.38, P < .001 and HR3.35, P < .001, respectively). In addition, grade 3 to 4 acute GVHD predicted worse OS (HR 1.80, P = .007) and DFS (HR 1.55, P = .041). In contrast, relapse was not impacted by acute or chronic GVHD in MVA. Grade 2 acute GVHD was not associated with transplant outcome in MVA. In summary, both grade 3 to 4 acute and moderate-to-severe chronic GVHD were associated with higher NRM after PTCy-based HIDT, without an effect on relapse risk. Methods of early identification of such patients in order to augment GVHD prophylaxis are clearly needed., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The development of chronic graft-versus-host disease (GVHD) in 1-year survivors after matched related or unrelated hematopoietic cell transplantation was shown to be associated with higher nonrelapse mortality (NRM) and worse overall survival (OS). The impact of chronic GVHD requiring immunosuppression (IS) for recipients of haploidentical transplantation (HIDT) with post-transplantation cyclophosphamide (PTCy) who have survived to 1 year post-transplantation has not been studied previously and was investigated for this analysis. A total of 322 adult patients who underwent HIDT at our center were included in this study. The effect of IS-free status on post-transplantation outcomes was assessed. The median follow-up for survivors was 63.9 months (range, 18.3 to 165 months). A total of 163 patients (65%) were IS-free at 1 year post-HIDT. Baseline characteristics of this group were similar to those of patients still requiring IS, except for higher percentages of female donor-male recipient pairs (28% versus 15%; P =.03) and female donors (48% versus 30%; P =.008). Logistic regression to identify patients more likely to be on IS at 1 year post-HIDT identified the use of a female donor as a significant risk factor (odds ratio, 2.11; P = .009). In a Cox regression analysis, patients requiring IS at 1 year post-transplantation had higher NRM (hazard ratio [HR], 4.18; 95% confidence interval [CI], 1.80 to 6.72; P < .001) and showed a trend toward worse disease-free survival (DFS) (HR, 1.59; 95% CI, .95 to 2.66; P =.08), with no impact on OS (HR, 1.44; 95% CI, .90 to 2.31; P = .13) or relapse (HR, .77; 95% CI, .37 to 1.61; P = .49). These results indicate that use of a female donor is a significant risk factor for requiring IS at 1 year post-HIDT. Additionally, chronic GVHD requiring IS at 1-year post-HIDT no significant effect on relapse but is associated with higher NRM and a trend toward worse DFS., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The presence of an HLA-DPB1 nonpermissive mismatch (NPMM) by the TCE-3 model has been associated with improved survival following haploidentical donor transplantation (HIDT) using post-transplantation cyclophosphamide (PTCy). With the development of a revised model (TCE-Core) that further separates TCE-3 "group 3" alleles into "core" (C) and "noncore" (NC) alleles, a formerly permissive mismatch (PMM) resulting from group 3 alleles in both donor and recipient is now considered a C-NPMM if 1 or more of those alleles is NC. We aimed to study the additional effect of HLA-DPB1 C-NPMM according to the TCE-Core algorithm, as well as the directional vector of the mismatch, on outcomes following HIDT. To this end, we analyzed 242 consecutive HIDT recipients with acute leukemia or myelodysplastic syndrome who underwent transplantation between 2005 and 2021 (median age, 51 years; range, 19 to 80 years). The median follow-up was 62 months (range, 23 to 199 months). Of the 136 HIDTs classified as PMM by TCE-3, 73 were reclassified as a C-NPMM by the TCE-Core algorithm, of which 36 were in the graft-versus host (GVH) vector (37 were host-versus-graft [HVG] only). Given comparable survival between conventional NPMM and C-NPMM, GVH/bidirectional were analyzed together (nonpermissive). HVG-only C-NPMM were combined with HLA-DPB1-matched and PMM (permissive) because of similar outcomes. The presence of a TCE-Core-defined nonpermissive HLA-DP mismatch resulted in superior 5-year overall survival (OS) (66% versus 47%) and disease-free survival (DFS) (60% versus 43%). Compared to the conventional TCE-3 algorithm, TCE-Core identified a higher percentage of nonpermissive transplants (38% versus 23%) and better discriminated outcomes between nonpermissive and permissive status, with a larger difference in survival outcomes using TCE-Core compared to TCE-3 (OS Δ, 18.3% versus 12.7%; DFS Δ, 16.5% versus 8.5%). In multivariable analysis (MVA), a nonpermissive TCE-Core mismatch led to improved OS (hazard ratio [HR], .54; P = .003) and DFS (HR, .62; P = .013), largely due to decreased relapse risk (HR, .63; P = .049). In contrast, nonrelapse mortality (NRM) and graft-versus-host disease (GVHD) outcomes were not significantly impacted. In summary, the presence of nonpermissive TCE-Core HLA-DP mismatch strongly predicts survival following PTCy-based HIDT, owing to a reduction in relapse risk without a corresponding increase in GVHD or NRM. As a donor selection tool, TCE-Core appears to better discriminate HIDT outcomes while at the same time identifying a larger percentage of the potential donor pool., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Allogeneic transplant remains the best postremission therapy for patients with nonfavorable risk acute myeloid leukemia (AML). However, some patients are ineligible because of psychosocial barriers, such as lack of appropriate caregiver support. We hypothesized that immune checkpoint inhibition after autologous transplant might represent effective postremission therapy in such patients. We conducted a phase 2 study of autologous transplantation followed by administration of pembrolizumab (8 cycles starting day +1). Twenty patients with nonfavorable AML in complete remission were treated (median age, 64 years; CR1, 80%); 55% were non-White and adverse-risk AML was present in 40%. Treatment was well tolerated, with only 1 nonrelapse death. Immune-related adverse events occurred in 9 patients. After a median follow-up of 80 months, 14 patients remain alive, with 10 patients in continuous remission. The estimated 2-year LFS was 48.4%, which met the primary end point of 2-year LFS >25%; the 2-year overall survival (OS), nonrelapse mortality, and cumulative incidences of relapse were 68%, 5%, and 46%, respectively. In comparison with a propensity score-matched cohort group of patients with AML receiving allogeneic transplant, the 3-year OS was similar (73% vs 76%). Patients in the study had inferior LFS (51% vs 75%) but superior postrelapse survival (45% vs 14%). In conclusion, programmed cell death protein-1 blockade after autologous transplant is a safe and effective alternative postremission strategy in patients with nonfavorable risk AML who are ineligible for allogeneic transplant, a context in which there is significant unmet need. This trial was registered at www.clinicaltrials.gov as #NCT02771197., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Few patients with nonfavorable risk (NFR) acute leukemia and myeloid dysplasia syndrome (AL/MDS) undergo allogeneic transplantation (HCT). We assessed whether this could be improved by integrating HCT/leukemia care and the use of haploidentical donors. Of 256 consecutive patients aged <75 years who received initial therapy at our center for NFR AL/MDS from 2016 to 2021, 147 (57%) underwent planned HCT (70% for patients aged <60 years). In the logistic regression analysis, age (OR 1.50 per 10-year increment; P < .001) and race (Black vs White [OR 2.05; P = .023]) were significant factors for failure to receive HCT. Reasons for no HCT included comorbidities (37%), poor KPS, lack of caregiver support, refractory malignancy (19% each), and patient refusal (17%). Lack of donor or insurance were rarely cited (3% each). In older patients (≥60 years), comorbidities (49 vs 15%; P < .001) and KPS (25% vs 10%; P = .06) were more common, and lack of caregivers was less common (13% vs 30%; P = .031). In Black vs White patients, lack of caregivers (37% vs 11%; P = .002) was more frequent. The median time from initial treatment to HCT was 118 days and was similar for Black and White patients. Landmark analysis showed that HCT within 6 months of the initial treatment produced better survival. Multivariable analysis showed that HCT resulted in a significant survival benefit (HR 0.60; P = .020). With the above approach, most of the currently treated patients aged <75 years can access planned HCT. Black patients remain at greater risk of not receiving HCT., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Steroid refractory acute graft-versus-host disease (SR aGvHD) is a major limitation of successful allogeneic hematopoietic stem cell transplantation (HSCT). Extracorporeal photopheresis (ECP) has been used to treat SR aGvHD effectively and with low treatment related toxicity. In this study, we retrospectively analyzed the outcomes of 103 Steroid Refractory aGvHD (SR aGvHD) patients to identify factors associated with improved outcomes including the use of ECP. A total of 79 patients received ECP as part of their SR aGVHD treatment compared to 24 patients who did not. Both groups had similar aGVHD grade and maximum organ stage at onset of aGVHD and treatment initiation. Patients in the group that received ECP had better OS (p = 0.01), DFS (p = 0.008), lower relapse (p = 0.05) and similar NRM compared to the group that did not receive ECP. Patients that received ECP treatment also had shorter hospital stays in the first 180 days after onset of SR aGvHD (20 vs. 38 days, p = 0.03). Multivariable analysis for OS indicated patient CMV status (CMV+ versus CMV-, HR 2.34, CI 1.16-4.69), regimen intensity (Myelo vs. non-Myeloablative, HR 0.39, CI 0.20-0.75), and the use of ECP (ECP vs. no ECP, HR 0.39, CI 0.20-0.75) were associated with OS. In summary, the use of ECP in the treatment of SR aGvHD results in improved overall survival secondary to lower relapse rates compared to other therapeutic modalities that do not incorporate ECP., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The role of NK cell alloreactivity on outcomes after T cell-replete haploidentical donor transplantation (HIDT) remains uncertain. After transplantation, newly formed NK cells are licensed through interactions of donor inhibitory KIR (iKIR) and NKG2A receptors with their cognate ligands on recipient cells. Donor NKG2A recognizes HLA-E bound by recipient HLA class I leader peptides, a process requiring methionine (M) at position -21 of the leader sequence. An rs1050458C/T dimorphism results in approximately 40% of individuals expressing at least one copy of -21M HLA-B (M/M or M/T [M+]), allowing ligand expression. We assessed the impact of recipient HLA-B-leader genotype (M+ versus M- [T/T]) and HLA-C-group iKIR missing ligand (ML, C1C1/C2C2 versus C1C2) on relapse and disease-free survival (DFS) in recipients of post-transplantation cyclophosphamide (PTCy)-based HIDT. Based on preclinical data, we hypothesized that the relative impact of each variable may depend on disease lineage (lymphoid versus myeloid). To this end, we analyzed outcomes of 322 consecutive PTCy-based HIDT recipients with hematologic malignancy who underwent transplantation at a single institution using standardized supportive care measures with mature follow-up (median 45 months). Primary endpoints were relapse and DFS of patients based on HLA-B-leader genotype and HLA-C-group iKIR ML. Planned subgroup analysis included patient with lymphoid versus myeloid malignancy. M+ HLA-B-leader genotype and HLA-C-group iKIR ML were seen in 42% and 49% of recipients, respectively. The presence of a recipient M+ B-leader (versus M-) improved overall survival (OS) and DFS and lowered cumulative incidence of relapse (CIR), an effect primarily seen in lymphoid malignancies (80% versus 51%, 72% versus 41%, 16% versus 42%, respectively). In contrast, myeloid malignancy patients benefited most from HLA-C-group iKIR ML with better OS and DFS and lower CIR (67% versus 51%, 64% versus 44%, 25% versus 45%, respectively). Multivariate analysis confirmed the disease-specific associations of improved relapse/DFS with M+ HLA-B-leader in lymphoid malignancy (hazard ratio [HR] 0.20, P < .001/HR 0.34, P <.001) and HLA-C-group iKIR ML in myeloid malignancy (HR 0.44, P = .004/HR 0.54, P = .009). Neither HLA-B-leader nor iKIR ML was associated with the incidence of non-relapse mortality or acute or chronic graft-versus-host disease. Two distinct NK cell education pathways predict relapse and DFS after HIDT-PTCy in a disease-specific manner: the presence of recipient M+ HLA-B-leader genotype improves outcome in patients with lymphoid malignancies, whereas HLA-C-group iKIR ML improves outcome in patients with myeloid malignancies. These findings strengthen the essential role of NK cells for optimal GVL in the context of HIDT-PTCy and may suggest different approaches to improving transplant outcome depending on disease type., Competing Interests: Conflict of interest statement There are no conflicts of interest to report., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Single-agent high-dose melphalan (Mel) followed by autologous stem cell transplantation (ASCT) remains a standard of care in eligible patients with multiple myeloma (MM), and efforts to improve transplant outcomes by intensifying transplant conditioning have mostly failed. Bendamustine combines both alkylating and antimetabolite properties, can induce responses in MM resistant to other alkylators and represents a promising agent to combine with Mel prior to ASCT. We performed a phase II study to test the safety and efficacy of the high-dose chemotherapy combination of bendamustine, etoposide, cytarabine, and melphalan (BeEAM) in newly diagnosed MM patients up to 70 years of age. The primary study endpoint was the day 100 complete response rate. Sixty-five patients with a median (range) age of 59 (40-69) years underwent transplantation from 2015 to 2020. Other characteristics included Karnofsky performance status <80%, hematopoietic cell transplantation-comorbidity index ≥3, International Staging System III, and high-risk fluorescein in situ hybridization (FISH) in 35%, 46%, 26%, and 44%, respectively. ASCT after BeEAM was well tolerated, and there were no non-relapse deaths through 1 year after transplantation. Although at least 1 nonhematologic grade 3 toxicity was reported in 58 (89%) patients (including grade 3 febrile neutropenia in 48% and stomatitis/esophagitis in 28%), there were no grade ≥3 renal or hepatic toxicity and no grade ≥4 non-hematologic toxicity. The day 100 response rate was ≥CR1 and ≥ very good partial response (VGPR1) in 40% and 89%, respectively. With a median follow-up of 44 (13-70) months, the 3-year overall survival was 92%, 96%, and 90% for all patients and those with standard- and high-risk FISH, respectively. The corresponding values for 3-year progression-free survival was 57%, 72%, and 40%, respectively. When BeEAM-conditioned patients were compared to historical Mel-conditioned cohort, no significant differences were noted in relapse or survival outcomes in univariate or multivariable analysis. In summary, BeEAM was shown to be a safe and effective conditioning regimen before up-front autologous transplant for MM. Although the BeEAM regimen does not appear to offer a significant advantage over single-agent Mel, further studies combining bendamustine and melphalan in the front-line setting may be warranted., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

We previously reported the results of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1101, a randomized comparison of hematopoietic cell transplantation (HCT) performed with double umbilical cord blood units (dUCB) or with haploidentical bone marrow (haplo-BMT) with post-transplantation cyclophosphamide (PTCy) in the nonmyeloablative setting. Those results showed similar progression-free survival in the 2 treatment groups but lower nonrelapse mortality and better overall survival in the haplo-BM arm. In this secondary analysis, we sought to investigate whether transplantation center's previous experience with haplo-BM and/or dUCB HCT had an impact on outcomes. All patients randomized in BMT CTN 1101 were included. Center experience was assigned based on the number of transplantations with each platform performed in the year before initiation of the study according to the Center for International Blood and Marrow Transplant Research. Centers were then classified as a dUCB center (>10 dUCB HCTs; n = 117 patients, 10 centers), a haplo-BM center (>10 haplo-BM HCTs and ≤10 dUCB HCTs; n = 110 patients, 2 centers), or other center (≤10 haplo and ≤10 dUCB HCTs; n = 140 patients, 21 centers). After adjusting for age, Karnofsky Performance Status, and Disease Risk Index, we found that haplo-BM centers had lower overall mortality with this donor type compared with dUCB centers (hazard ratio [HR], 2.56; 95% confidence interval [CI], 1.44 to 4.56). In contrast, there were no differences in overall mortality between haplo-BM and dUCB in centers that were experienced with dUCB HCT (HR, 1.02; 95% CI, .59 to 1.79) or had limited to no experience with either dUCB or haplo-BM HCT (HR, 1.36; 95% CI, .83 to 2.21). The higher risk of treatment failure and overall mortality in dUCB HCT in haplo BM-experienced centers was driven by a significantly higher risk of relapse (HR, 1.78; 95% CI, 1.07 to 2.97). With the exception of worse outcomes among dUCB HCT recipients in haplo-BM centers, transplantation center experience in the year before initiation of BMT CTN 1101 had a limited impact on the outcomes of this randomized clinical trial., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Randomized clinical trials offer the highest-quality data for modifying clinical practice. Results of a phase III randomized trial of nonmyeloablative transplantation for adults with high-risk hematologic malignancies with 2 umbilical cord blood (UCB) units (n = 183) or HLA-haploidentical relative bone marrow (Haplo-BM; n = 154) revealed a 2-year progression-free survival (PFS) of 41% after Haplo-BM transplantation and 35% after 2-unit UCB transplantation (P = .41), with overall survival (OS) of 57% and 46%, respectively (P = .04). We sought to examine the generalizability of BMT CTN 1101 to a contemporaneous cohort beyond the trial's prespecified 2-year outcomes. All transplantations were performed between June 2012 and June 2018 in the United States. We hypothesized that the results of a rigorous phase III randomized trial would be generalizable. Changes in graft selection for HLA-haploidentical relative transplantation during the trial period allowed comparison of outcomes after transplantation with Haplo-BM with those after haploidentical peripheral blood (Haplo-PB). The trial's broad eligibility criteria were applied to the data source of the Center for International Blood and Marrow Transplant Research to select nontrial subjects. Extended follow-up of trial subjects was obtained from this data source. Three separate analyses were performed: (1) trial subjects beyond the trial's 2-year endpoint; (2) comparison of trial subjects with a contemporaneous cohort of nontrial subjects (195 2-unit UCB, 358 Haplo-BM, and 403 Haplo-PB); and (3) comparison of nontrial subjects by donor and graft type. Multivariate analyses were performed using Cox proportional hazards models for comparison of outcomes by treatment groups. With longer follow-up of the trial cohorts, 5-year PFS (37% versus 29%; P = .08) and OS (42% versus 36%; P = .06) were not significantly different between the treatment groups. We then compared the trial results with outcomes of comparable real-world transplantations. Five-year OS did not differ between trial and nontrial 2-unit UCB transplantations (36% versus 41%; P = .48) or between trial and nontrial Haplo-BM transplantations (42% versus 47%; P = .80), confirming generalizability. The randomized trial did not accrue as planned and therefore lacked the statistical power to detect a 15% difference in PFS. With substantially larger numbers of nontrial Haplo-BM transplantations, 5-year survival was higher after nontrial Haplo-BM compared with trial 2-unit UCB (47% versus 36%; P = .012). Nontrial patients who underwent Haplo-PB transplantation had higher 5-year survival (54%) compared with trial Haplo-BM (hazard ratio [HR], 0.76; P = .044) and nontrial Haplo-BM (HR, 0.78; P = .026). Similarly, survival was better after Haplo-PB compared with trial UCB (HR, 0.57; P < .0001) and nontrial UCB (HR, 0.63; P = .0002). When considering alternative donor low-intensity conditioning regimen transplantation, a haploidentical relative is preferred, and PB is the preferred graft source., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. All rights reserved.)

A meta-analysis confirmed the benefit of thromboprophylaxis with a direct oral anticoagulant for high-risk nonsurgical patients after hospital discharge.

This study validated the Canadian Syncope Risk Score for predicting 30-day serious outcomes in patients presenting to the ED within 24 hours of syncope.

We report a first in-depth comparison of immune reconstitution in patients with HIV-related lymphoma following autologous hematopoietic cell transplant (AHCT) recipients (n=37, lymphoma, BEAM conditioning), HIV(-) AHCT recipients (n=30, myeloma, melphalan conditioning) at 56, 180, and 365 days post-AHCT, and 71 healthy control subjects. Principal component analysis showed that immune cell composition in HIV(+) and HIV(-) AHCT recipients clustered away from healthy controls and from each other at each time point, but approached healthy controls over time. Unsupervised feature importance score analysis identified activated T cells, cytotoxic memory and effector T cells [higher in HIV(+)], and naïve and memory T helper cells [lower HIV(+)] as a having a significant impact on differences between HIV(+) AHCT recipient and healthy control lymphocyte composition (p<0.0033). HIV(+) AHCT recipients also demonstrated lower median absolute numbers of activated B cells and lower NK cell sub-populations, compared to healthy controls (p<0.0033) and HIV(-) AHCT recipients (p<0.006). HIV(+) patient T cells showed robust IFNγ production in response to HIV and EBV recall antigens. Overall, HIV(+) AHCT recipients, but not HIV(-) AHCT recipients, exhibited reconstitution of pro-inflammatory immune profiling that was consistent with that seen in patients with chronic HIV infection treated with antiretroviral regimens. Our results further support the use of AHCT in HIV(+) individuals with relapsed/refractory lymphoma., Competing Interests: PS, Seattle Genetics, Research funding. AK, Celgene, Consultancy, Speakers Bureau, Millennium/Takeda, Consultancy, Speakers Bureau, Onyx, Consultancy, Speakers Bureau, Janssen, Consultancy, Speakers Bureau. Hofmeister, Signal Genetics, Inc., Membership on an entity’s Board of Directors or advisory committees, Celgene, Research Funding; Arno Therapeutics, Inc., Research Funding, Incyte, Corp, Membership on an entity’s Board of Directors or advisory committees, Janssen, Pharmaceutical Companies of Johnson & Johnson, Research Funding, Karyopharm Therapeutics, Research Funding, Takeda Pharmaceutical Company, Research Funding, Teva, Membership on an entity’s Board of Directors or advisory committees. SF, Mustang Therapeutics, Other, Construct licensed by City of Hope. WN, Atara Biotherapeutics, employment, stock ownership. GL, Boehringer Ingelheim, Research Funding, Beckman Coulter, Research Funding, Stemline Therapeutics Inc., Research Funding, Genentech. RB, Prelude Therapeutics, Research Funding and Scientific Advisory Board, Viracta, Scientific Advisory Board. AN, Janssen, Membership on a Board or Advisory Committee; Medscape, Honoraria; Morphosys, Membership on a Board or Advisory Committee; Pharmacyclics, Research Funding, Honoraria; Rafael Pharma, Research Funding; Epizyme, Membership on a Board or Advisory Committee; Physician Education Resource, Consulting. MM and AMM are employed by EMMES Company. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Shindiapina, Pietrzak, Seweryn, McLaughlin, Zhang, Makowski, Ahmed, Schlotter, Pearson, Kitzler, Mozhenkova, Le-Rademacher, Little, Akpek, Ayala, Devine, Kaplan, Noy, Popat, Hsu, Morris, Mendizabal, Krishnan, Wachsman, Williams, Sharma, Hofmeister, Forman, Navarro, Alvarnas, Ambinder, Lozanski and Baiocchi.)

Ground-penetrating radar (GPR) is an established geophysical technique used extensively for the accurate reconstruction of the shallow (<10 m) subsurface. Reconstructions have largely been completed and presented as 2D vertical and horizontal planes, leaving limited visualization of subsurface 3D shapes and their spatial relationships. With technological advancements, particularly the availability and integration of various software platforms, 3D modelling of GPR data is now emerging as the new standard. However, despite these developments, there remains an inadequate examination and testing of these techniques, particularly in determining if their application is beneficial and warranted. In this study we conducted a GPR grid survey on a churchyard cemetery to generate and evaluate 2D and 3D-modelled reconstructions of the cemetery burial sites. Data collection and processing was completed using a Sensors and Software Incorporated pulseEKKO™ Pro SmartCart GPR system and EKKO&#95;Project™ software, respectively. The modelling component was achieved using Schlumberger's Petrel™ E & P software platform, which is tailored to the petroleum industry. The subsurface patterns present in the 2D and 3D models closely matched the cemetery plot plan, validating our data collection, processing, and modelling methods. Both models were adequate for 2D horizontal visualization of reflection patterns at any specific depth. The 3D model was used to identify the presence of a companion burial plot (stacked caskets) and possible leachate plumes below and encircling burial sites, both of which were not evident in the 2D model, highlighting the benefits of 3D modelling when discerning subsurface objects. We expect our findings to be of value to similar GPR studies, with particular significance to geoforensic studies and criminal investigations., (Copyright © 2021. Published by Elsevier B.V.)

Global health partnerships (GHPs) have encountered many challenges during the coronavirus disease 2019 (COVID-19) pandemic. New perspectives and insights are needed to guide GHPs when navigating current and future collaborations. This study aimed to understand perspectives and insights of international partners regarding how the COVID-19 pandemic impacted their GHPs with institutions in the United States. We performed a cross-sectional qualitative study conducted through virtual semi-structured interviews performed between June 12, 2020 and July 22, 2020. We queried academic institutions based in the United States to refer individuals from their corresponding international GHP organizations. We invited these individuals to participate in virtual interviews that were audio-recorded and transcribed. We analyzed data qualitatively to identify themes. Eighty-four United States partners provided e-mail addresses for international partners. Ten individuals from these GHPs completed the interview. Participants reported overall positive experiences with their United States-based partners during the pandemic. The following themes emerged: imbalanced decision-making; worry about partnership continuity; opportunity to optimize communication within partnerships; interest in incorporating technology to facilitate engagement; and a desire for increased bilateral exchanges. Several challenges appeared to exist before COVID-19 and were highlighted by the pandemic. Most respondents were optimistic regarding the future of their GHPs. However, concerns were expressed regarding the implications of fewer in-person international experiences with United States trainees and the desire for stronger communication. Although our results do not represent the perspectives and insights of all GHPs, they provide considerations for the future. We urge institutions in the United States to re-examine and strive for equitable relationships with their international partners.

Observing fetal development in utero is vital to further the understanding of later-life diseases. Magnetic resonance imaging (MRI) offers a tool for obtaining a wealth of information about fetal growth, development, and programming not previously available using other methods. This review provides an overview of MRI techniques used to investigate the metabolic and cardiovascular consequences of the developmental origins of health and disease (DOHaD) hypothesis. These methods add to the understanding of the developing fetus by examining fetal growth and organ development, adipose tissue and body composition, fetal oximetry, placental microstructure, diffusion, perfusion, flow, and metabolism. MRI assessment of fetal growth, organ development, metabolism, and the amount of fetal adipose tissue could give early indicators of abnormal fetal development. Noninvasive fetal oximetry can accurately measure placental and fetal oxygenation, which improves current knowledge on placental function. Additionally, measuring deficiencies in the placenta's transport of nutrients and oxygen is critical for optimizing treatment. Overall, the detailed structural and functional information provided by MRI is valuable in guiding future investigations of DOHaD.

T-replete haploidentical donor transplants using posttransplant cyclophosphamide (haplo) have greatly expanded donor availability and are increasingly utilized. Haplo were originally performed using truly nonmyeloablative conditioning and a bone marrow graft. We have also developed myeloablative conditioning and peripheral blood stem cell (PBSC) grafts for use with haplo. However, some patients may not tolerate myeloablative conditioning but may still benefit from a more dose-intensified preparative regimen to control malignancy and diminish graft rejection. To this end, we enrolled 25 patients on a prospective phase II trial utilizing a regimen of fludarabine 30 mg/m 2 /day × 5 days and Melphalan 140 mg/m 2 on day -1 (flu/Mel) followed by infusion of unmanipulated PBSC graft from a haploidentical donor. GVHD prophylaxis included cyclophosphamide 50 mg/kg/day on days 3 and 4, mycophenolate mofetil on day 35, and tacrolimus on day 180. Median age was 57 years (range from 35 to 68). Transplantation diagnosis included AML ( n  = 11), ALL ( n  = 4), MDS/MPD ( n  = 6), NHL/CLL ( n  = 3), and MM ( n  = 1). Using the refined Disease Risk Index (DRI), patients were low ( n  = 1), intermediate ( n  = 13), and high/very high ( n  = 11). 22 out of 25 patients engrafted with a median time to neutrophil and platelet engraftment of 18 days and 36 days, respectively. All engrafting patients achieved full peripheral blood T-lymphocyte and myeloid donor chimerism at day 30. The 180-day cumulative incidence for acute GVHD grades II-IV and III-IV was seen in 20% (95% CI 8%-37%) and 8% (95% CI 2%-22%), respectively. The 2-year cumulative incidence of chronic GVHD was 16% (95% CI 5%-33%) (moderate-severe 12% (95% CI 3%-27%)). After a median follow-up of 28.3 months, the estimated 2-year OS, DFS, NRM, and relapse were 56% (95%CI 33-74%), 44% (95%CI 23%-64%), 20% (95% CI 8%-37%), and 36% (95% CI 17%-55%), respectively. Among patients with high/very high risk DRI, 2-year OS was 53% compared to 69% for low/intermediate DRI. When compared with a contemporaneous cohort of patients at our center receiving haploidentical transplant with nonablative fludarabine, Cytoxan, and total body irradiation flu/Cy/TBI regimen, the outcomes were statistically similar to the 2-year OS at 56% vs. 63% p =0.75 and DFS at 44% vs. 46% p =0.65., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Melhem M. Solh et al.)

Results of 2 parallel phase 2 trials of transplantation of unrelated umbilical cord blood (UCB) or bone marrow (BM) from HLA-haploidentical relatives provided equipoise for direct comparison of these donor sources. Between June 2012 and June 2018, 368 patients aged 18 to 70 years with chemotherapy-sensitive lymphoma or acute leukemia in remission were randomly assigned to undergo UCB (n = 186) or haploidentical (n = 182) transplant. Reduced-intensity conditioning comprised total-body irradiation with cyclophosphamide and fludarabine for both donor types. Graft-versus-host disease prophylaxis for UCB transplantation was cyclosporine and mycophenolate mofetil (MMF) and for haploidentical transplantation, posttransplant cyclophosphamide, tacrolimus, and MMF. The primary end point was 2-year progression-free survival (PFS). Treatment groups had similar age, sex, self-reported ethnic origin, performance status, disease, and disease status at randomization. Two-year PFS was 35% (95% confidence interval [CI], 28% to 42%) compared with 41% (95% CI, 34% to 48%) after UCB and haploidentical transplants, respectively (P = .41). Prespecified analysis of secondary end points recorded higher 2-year nonrelapse mortality after UCB, 18% (95% CI, 13% to 24%), compared with haploidentical transplantation, 11% (95% CI, 6% to 16%), P = .04. This led to lower 2-year overall survival (OS) after UCB compared with haploidentical transplantation, 46% (95% CI, 38-53) and 57% (95% CI 49% to 64%), respectively (P = .04). The trial did not demonstrate a statistically significant difference in the primary end point, 2-year PFS, between the donor sources. Although both donor sources extend access to reduced-intensity transplantation, analyses of secondary end points, including OS, favor haploidentical BM donors. This trial was registered at www.clinicaltrials.gov as #NCT01597778.

The present study examined negative life events (NLEs) and sexual assault victimization as predictors of positive and negative psychological functioning in a sample of 151 female college students. Results obtained from conducting regression analyses indicated several notable patterns. NLEs, compared with sexual assault victimization, were a stronger negative predictor of positive functioning based on indices related to subjective well-being (e.g., life satisfaction, positive affect). Alternatively, sexual assault victimization, compared with NLEs, was a stronger positive predictor of negative functioning based on indices related to posttraumatic stress disorder symptoms (e.g., anxiety) and related conditions (e.g., alcohol use). Furthermore, both NLEs and sexual assault victimization were found to be positive predictors of negative functioning based on indices related to suicide risk (e.g., depressive symptoms, suicidal behaviors). Overall, our findings indicate that both NLEs and sexual assault victimization represent important and distinct predictors of psychological functioning in female college students.

We assessed differences in presentation and response to therapy in 394 consecutive patients who developed acute or chronic graft-versus-host disease (GVHD) after receiving their first allogeneic transplantation (HSCT) from a 10/10 HLA allele-matched unrelated donor (MUD; n = 179) using calcineurin inhibitors or a T cell-replete haploidentical donor (haplo; n = 215) and post-transplantation cyclophosphamide at our center between 2005 and 2017. The median duration of follow-up for survivors was 52.5 months. The cumulative incidences for grade II-IV and grade III-IV acute GVHD at day 180 post HCT were similar, at 39% and 14%, respectively, for haplo-HSCT compared with 50% and 16% for MUD HSCT (P not significant). Haplo-HSCT recipients had a lower cumulative incidence of moderate to severe chronic GVHD, at 22% (severe, 19%), compared with 31% (severe, 29%) for MUD HSCT recipients (P = .026). The time to onset of moderate to severe chronic GVHD was faster for haplo-HSCT recipients (213 days versus 280 days; P = .011). Among patients with grade II-IV acute GVHD, there was no significant between-group difference in organ involvement, with skin the most affected (75% for haplo-HSCT versus 70% for MUD HSCT), followed by the gastrointestinal tract (71% versus 69%) and liver (14% versus 17% MUD). For chronic GVHD, haplo-HSCT recipients had less involvement of the eyes (46% versus 75% for MUD; P < .001) and of the joints/fascia (12% versus 36%; P = .001). Also for cGVHD patients, haplo-HSCT recipients and MUD HSCT recipients had similar all-cause mortality (22% versus 18%; P = .89), but the former were more likely to be off immunosuppression at 2 years post-HCT (63% versus 43%; P = .03) compared with MUD., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

HLA disparity is the major predictor of outcome following unrelated donor (UD) transplantation, where a single mismatch (mm) at the HLA-A, HLA-B, HLA-C, or HLA-DRB1 locus leads to increased mortality, and mismatching at multiple loci compounds this effect. In contrast, HLA disparity has not been shown to increase mortality in the context of haploidentical transplant using posttransplant cyclophosphamide (PTCy). To better define the consequences of loci-specific HLA mm, we analyzed 208 consecutive patients undergoing haploidentical transplantation for hematologic malignancy using PTCy at our institution (median age, 52 years [range, 19-75 years]; peripheral blood stem cell, 66%; reduced-intensity conditioning, 59%). Median follow-up was 65.4 months (range, 34.3-157.2 months). In univariate analysis, a single class II HLA mm at HLA-DR, HLA-DQ or a nonpermissive (np) HLA-DP mm had a protective effect on disease-free and overall survival (OS), primarily a result of reduced relapse risk. Furthermore, this survival effect was cumulative, so that patients with 3 class II mm (HLA-DR, HLA-DQ, and np HLA-DP) had the best OS. In multivariate analysis, HLA-DR mm and np HLA-DP mm were both independently associated with improved OS (hazard ratio [HR], 0.43; P =.001; and HR, 0.47; P =.011, respectively). In contrast, single or multiple mm at HLA-A, HLA-B, or HLA-C loci had no effect on acute graft-versus-host disease (GVHD), nonrelapse mortality (NRM), relapse, or survival, although the presence of an HLA-A mm was associated with increased chronic GVHD incidence. The association of class II mm with lower relapse occurred without a corresponding increase in NRM or acute or chronic GVHD. These findings will require validation in larger registry studies., (© 2020 by The American Society of Hematology.)

To evaluate the impact of psychosocial risks on post-hematopoietic stem cell transplantation (HSCT) outcomes, we prospectively conducted psychosocial assessment of 556 consecutive allogeneic HSCT patients who received their first allogeneic transplant at our center between 2003 and 2017. The Transplant Evaluation Rating Scale (TERS) score was prospectively assessed by a psychologist before transplantation, and patients were categorized as low, intermediate, or high risk based on their TERS score. Patients in the high-risk TERS group had significantly longer hospital stays during the first 180 days and 1 year post-allogeneic HSCT compared with the low-risk group (16 vs 13 and 21 vs 16 days; P = .05 and .02, respectively). The survival estimates for low-, intermediate-, and high-risk TERS groups at 3 year were as follows: overall survival (OS), 73%, 60%, and 65%; disease-free survival (DFS), 63%, 55%, and 60%; nonrelapse mortality (NRM), 11%, 20%, and 17%; and relapse, 26%, 25%, and 23%, respectively. In a multivariable analysis, intermediate- and high-risk TERS scores predicted for inferior OS, similar DFS, and higher NRM compared with low-risk TERS score. In a subset analysis of patients with low/intermediate risk per Disease Risk Index, multivariable analysis showed that high- and intermediate-risk TERS scores predicted for significantly worse OS, worse DFS, higher NRM, and similar relapse rates compared with low-risk TERS score. Our findings show that psychosocial factors as measured by TERS score are strong predictors of morbidity and mortality after HSCT among patients with low/intermediate disease risk., (© 2020 by The American Society of Hematology.)

Proteasome inhibition results in extensive immunomodulatory effects that augment natural killer cell cytotoxicity and inhibit aspects of T-cell, B-cell, and dendritic cell function. We performed a phase 2 study that examined the effects of ixazomib for graft-versus-host disease (GVHD) prophylaxis (up to 12 cycles) with posttransplant cyclophosphamide and tacrolimus after standard nonmyeloablative haploidentical donor transplantation (HIDT). Ixazomib was started on day +5 (4 mg on days 1, 8, and 15 of a 28-day cycle), with dose reductions allowed in future cycles for toxicity. All patients received peripheral blood stem cells. Twenty-five patients were enrolled with a median age of 62 years (range, 35-77 years) who had acute leukemia (4), myelodysplastic syndrome (7), non-Hodgkin lymphoma/Hodgkin lymphoma/chronic lymphocytic leukemia (8), and myeloma (6). The hematopoietic cell transplant comorbidity index was ≥3 in 68% of the patients. After a median follow-up of 33.5 months, the cumulative incidence of relapse/progression at 1 year was 24% and 44% at 3 years, which failed to meet the statistically predefined goal of decreasing 1-year risk of relapse. Engraftment occurred in all patients with no secondary graft failure, and 3-year nonrelapse mortality (NRM) was 12%. Cumulative incidence of grade 3 to 4 acute GVHD was 8%, whereas moderate-to-severe chronic GVHD occurred in 19%. Nineteen patients survive with an estimated 1-year overall survival (OS) of 84% and 3-year OS of 74%. Hematologic and cutaneous toxicities were common but manageable. The substitution of ixazomib for mycophenolate mofetil (MMF) post-HIDT results in reliable engraftment, comparable rates of clinically significant GVHD, relapse and NRM, and favorable OS. This trial was registered at www.clinicaltrials.gov as # NCT02169791., (© 2020 by The American Society of Hematology.)

The fludarabine, high dose cytarabine and G-CSF with or without idarubicin combination regimen, referred to as FLAG+/-Ida, is commonly used as a salvage regimen for relapsed/refractory AML but its use as initial induction therapy has been more limited. The impact of choice of induction regimen on post remission survival remains unclear. We retrospectively analyzed 304 consecutive AML patients, with non-favorable NCCN risk who received initial treatment at our center with either 7 + 3 (n = 86) or FLAG+/-Ida (n = 218). Patients in the FLAG+/-Ida group were more likely to achieve remission after one course of induction (74 % vs 62 %, p < 0.001) and had a faster time to achieve CR (30 days vs 37.5, p < 0.001) compared to 7 + 3. The time from diagnosis to transplant was shorter among CR patients after FLAG+/-Ida compared to 7 + 3 (115 vs. 151 days, p < 0.003). The 3-year post-remission OS and DFS was significantly better for patients receiving FLAG-Ida at 54 % and 49 % compared to 39 % and 32 % for 7 + 3 respectively (P = 0.01). Factors associated with post-remission survival included age at CR1, NCCN risk, induction regimen (FLAG+/-Ida vs 3 + 7 h 0.62, p = 0.01) and receipt of HCT. Our data, with the limitations inherent to a retrospective analysis, shows that achieving CR after FLAG+/-Ida has better post remission survival than 7 + 3., Competing Interests: Declaration of Competing Interest The authors have no financial conflict of interest related to this manuscript, (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Due to perceived intolerance, many elderly AML patients do not receive therapy, and few are considered for hematopoietic cell transplantation (HCT). To better understand "real-world" outcomes, 323 consecutive AML patients ≥ 60 years referred from 2009 to 2017 were evaluated (median age 70 [60-88] years); favorable (fav) in 48 (15%), intermediate (int) in 112 (35%) and poor risk in 161 (50%). Remission induction therapy, either intensive chemotherapy (IC, n = 205) or hypomethylating agents (HMA, n = 57), was given to all but 61 (19%) patients. With median f/u of 34 months, 2-year overall survival (OS) for the whole cohort was 31%; 40 and 33% for IC- and HMA-treated vs. 0% for untreated patients. Early mortality was 14%. Remission (CR/CRi) was achieved in 60% of patients, with approximately half of these surviving 2 years. In transplant-eligible patients (60-75-year-old, int/poor risk, achieving remission), 54 (46%) of 118 received HCT. Transplanted patients had improved 2- and 3-year post-remission survival of 59% and 40% compared to 26% and 18% in similar patients not receiving HCT (HR = 0.59, 95% CI 0.37-0.93, p = 0.023). These results suggest that survival of elderly AML patients may be improved through a coordinated approach of remission induction therapy for most patients followed by HCT when feasible.

Although myeloablative conditioning (MAC) before haploidentical donor transplant (HIDT) with post-transplant cyclophosphamide is being increasingly used, the optimal preparative regimen remains unclear. In our initial trial, the feasibility of HIDT following a MAC preparative regimen using fludarabine and 12 Gy of total-body irradiation was demonstrated in 30 patients. We now present long-term outcome results, including an additional 52 patients, now with 47 months (16 to 96) median follow-up. Median patient age was 42 (19 to 61) years. The most common diagnoses were acute myelogenous leukemia (51%) and acute lymphoblastic leukemia (33%), and 39% had a high/very high disease risk index (DRI). Engraftment was universal with no cases of primary or secondary graft failure. Grade 3 to 4 acute graft-versus-host disease (GVHD) and moderate to severe chronic GVHD occurred in 17% and 23%, respectively. Nonrelapse mortality (NRM) was 7% at 1 year and 13% at 4 years. Estimated 4-year overall survival (OS), disease-free survival, and cumulative incidence of relapse (CIR) were 67%, 60%, and 27%, respectively. CIR was significantly higher in patients with high/very high- versus low/intermediate-risk DRI (38% versus 20%, P= .032), which led to inferior 4-year OS (50% versus 77%, P = .001). Median time to systemic immunosuppressive therapy (IST) discontinuation was 7.8 months, with 84% of patients off IST at 2 years post-transplant. Current GHVD-free, relapse-free survival (CGRFS) at 2, 3, and 4 years was 60%, 57%, and 60%, respectively. This approach to MAC HIDT results in universal engraftment; low rates of NRM, infection, and clinically significant GVHD; and relatively rapid IST discontinuation, resulting in high rates of CGRFS and survival., (Copyright © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Fever is a common early complication after infusion of stem cells in patients undergoing T-replete HLA haploidentical transplantation using post-transplant cyclophosphamide (PTCY). We analyzed the records of 172 haploidentical transplant patients to identify risk factors and to assess the impact of such fevers on transplant morbidity and mortality. One hundred and seventy-two patients received haploidential hematopoietic stem cell transplantation (haplo-HSCT) using PBSC (n = 103) or marrow (n = 69) grafts. One hundred and forty patients (81%) experienced fever (T ≥ 100.5 °F or >38 °C) with median onset on d + 2. Compared to patients who did not develop fevers, patients with fevers received higher median CD34+ cell dose (5.00 vs. 3.08 × 10 6 /kg, p < 0.001), CD3+ cell dose (12.8 vs. 4.5 × 10 7 /kg), were more likely to have received a myeloablative regimen (50% vs. 9%, p < 0.001), and PBSC source (71% vs. 9%, p < 0.001). Cox model showed that fever had no impact on TRM, GVHD, OS, and DFS. In the logistic regression to identify correlation with fevers, higher degree of HLA mismatches and use of PBSC were all predictors of developing fever. Fevers between infusion of the T-Cell replete graft and administration of PTCY are very common in Haplo-HSCT. This complication is transient and had no impact on post-transplant morbidity and mortality.

T cell replete HLA-mismatched haploidentical transplantation (HIDT) with post-transplant cyclophosphamide is increasingly becoming an acceptable treatment approach for patients lacking timely access to a suitably matched related donor transplant (MRDT) or matched unrelated donor transplant (MUDT). Multiple recent registry and single-center studies have shown comparable overall survival (OS) and disease-free survival (DFS) rates among HIDT, MRDT, and MUDT with a significantly lower risk of acute and chronic graft-versus-host disease (GVHD) among HIDT recipients. Candidates for allogeneic hematopoietic stem cell transplantation (HSCT) often have access to multiple donor sources, and a relevant question is whether outcomes can be improved with a younger HLA-mismatched haploidentical donor (≤35 years) rather than an older matched related donor (≥35 years) or matched unrelated donor (≥35 years). We analyzed 406 consecutive allogenic HSCT recipients, with a median age of 54 years (range, 19 to 77), after a MRDT with a donor age of ≥35 years (n = 222), MUDT with a donor age of ≥35 years (n = 91), and HIDT with a donor age of ≤35 years (n = 93). Median follow-up time for survivors was 51.5 months. Compared with MRDT and MUDT, HIDT recipients had a similar median age at time of HSCT, hematopoietic cell transplant comorbidity index, disease risk index distribution, and donor recipient sex matching. The survival estimates and relapse incidence at 3 years post-HSCT were OS (64% for MRDT, 54% for MUDT, and 62% for HIDT), DFS (55% for MRDT, 44% for MUDT, and 58% for HIDT), Transplant related mortality (TRM) (19% for MRDT, 16% for MUDT, and 18% for HIDT), and relapse (26% for MRDT, 37% for MUDT, and 24% for HIDT). HIDT recipients had better 3-year relapse rates compared with MUDT recipients (24% versus 37%, P= .048), with similar DFS and OS in a univariate analysis. MRDT recipients had a better relapse rate (26% versus 37%, P = .042) compared with MUDT recipients. Recipients of HIDT also had significantly lower rates of moderate to severe chronic GVHD compared with MRDT and MUDT recipients (P = .01). Multivariable analysis showed no effect of donor on OS, DFS, relapse, and TRM. Recipients of HIDT from a young donor ≤35 years had similar OS, lower rates of chronic GVHD, and better chronic GVHD-free, relapse-free survival compared with patients undergoing transplantation with an MRD or a MUD donor ≥35 years. This study suggests that given a situation where a choice between a young haploidentical relative and an older matched unrelated donor is to be made, one can achieve similar survival with a haploidentical donor and significantly lower rates of chronic GVHD., (Copyright © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Initial therapy of chronic GVHD (cGvHD) has not changed for over three decades, despite limited efficacy and long-term toxicity. We have previously shown in a small pilot study the feasibility of rituximab-based first-line therapy of cGVHD. To better assess safety and efficacy, we now evaluate 69 patients that received rituximab as part of their initial treatment. Median follow-up for surviving patients was 47 (11-81) months. Resolution of cGVHD occurred in 49 patients with median time to IST discontinuation of 349 (138-920) days. The cumulative incidence (CI) of cGHVD resolution was 41%, 69 and 77% at 1-, 2- and 3-years, respectively. No systemic corticosteroids were used in 27 patients, and 67% received ≤ 10 mg/kg cumulative exposure. Overall survival (OS) at 1-, 2- and 3-years following cGVHD diagnosis was 87, 79 and 77% respectively; corresponding rates of non-relapse mortality (NRM) were 10%, 16 and 19%. The probability of being alive and free of cGVHD at 1-, 2-, and 3-years was 36, 55, and 57% respectively. This study demonstrates the feasibility and efficacy of rituximab-based first-line cGVHD treatment. This approach demonstrates significant activity and avoids long courses of corticosteroids in most patients.

The present study examined the role of vitality as a mediator of the association between dispositional hope and quality of life (QoL) (namely, physical health, psychological health, social relationships, and environment) in a sample of 101 adult primary care patients. Vitality was found to fully mediate the relationship between hope and physical health, social relationships, and environment. In addition, vitality was found to partially mediate the association between hope and psychological health. The present findings are consistent with a model in which vitality represents an important mechanism through which hope affects QoL in adults. Accordingly, these findings point to the importance of fostering both hope and vitality in efforts to promote positive QoL in adults., (© 2019 National Association of Social Workers.)

Understanding the process of successful adaptation to high altitude provides valuable insight into the pathogenesis of conditions associated with impaired oxygen uptake and utilization. Prepubertal children residing at low altitude show a reduced cerebrovascular response to exercise in comparison to adults, and a transient uncoupling of cerebral blood flow to changes in the partial pressure of end-tidal CO 2 (P ET CO 2 ); however, little is known about the cerebrovascular response to exercise in high-altitude native children. We sought to compare the cerebral hemodynamic response to acute exercise between prepubertal children residing at high and low altitude. Prepubertal children (n = 32; 17 female) of Sherpa descent (Sherpa children [SC]) at high altitude (3800 m, Nepal) and maturational-matched (n = 32; 20 female) children (lowland children [LLC]) residing at low altitude (342 m, Canada). Ventilation, peripheral oxygen saturation (S p O 2 ), P ET CO 2, and blood velocity in the middle and posterior cerebral arteries (MCA v and PCA v ) were continuously measured during a graded cycling exercise test to exhaustion. At baseline (BL), P ET CO 2 (-19 ± 4 mmHg, p < 0.001), S p O 2 (-6.0% ± 2.1%, p < 0.001), MCA v (-12% ± 5%, p = 0.02), and PCA v (-12% ± 6%, p = 0.04) were lower in SC when compared with LLC. Despite this, the relative change in MCA v and PCA v during exercise was similar between the two groups (p = 0.99). Linear regression analysis demonstrated a positive relationship between changes in P ET CO 2 with MCA v in SC (R 2  = 0.13, p > 0.001), but not in LLC (R 2  = 0.03, p = 0.10). Our findings demonstrate a similar increase in intra-cranial perfusion during exercise in prepubertal SC, despite differential BL values and changes in P ET CO 2 and S p O 2 .

The impact of conditioning intensity on different disease risk index (DRI) groups has not been evaluated. We retrospectively analyzed acute myelogenous leukemia (AML)/myelodysplastic syndrome (MDS) hematopoietic cell transplantation (HCT) recipients in 2 groups based on DRI, to assess the impact of conditioning intensity on overall survival (OS), disease free survival (DFS), relapse, and nonrelapse mortality (NRM). A total of 380 patients with either high/very high (n = 148) or low/intermediate DRI (n = 232) myeloid malignancy (AML, n = 278; MDS, n = 102) were included in the analysis. Median follow-up for survivors was 35 months. Median age was 58years (range, 18 to 75). Patient and transplant-related characteristics were 41% reduced-intensity conditioning (RIC), 59% myeloablative conditioning (MAC), 13% bone marrow graft, 29% matched related donor, 49% matched unrelated donor, 22% haploidentical donor, and 52% HCT-specific comorbidity index ≥ 3. Among patients with high/very high DRI, there was no difference in OS, DFS, relapse, and NRM between RIC and MAC conditioning groups. For low/intermediate risk DRI recipients of MAC had better 3-year OS estimate (69% versus 57%, P = .001), DFS (65% versus 51%, P = .003), and lower relapse (3-year cumulative incidence, 17% versus 32%; P = .01) but similar NRM (19% versus 17%, P = .04) to RIC recipients. On multivariable analysis MAC was associated with better DFS (hazard ratio [HR], .58; 95% confidence interval [CI], .39-.88; P = .01), lower relapse (HR, .56; 95% CI, .32 to .97; P = .038), and similar NRM (HR, 1.11; 95% CI, .54 to 2.26; P = .781) compared with RIC in the low/intermediate DRI group. Intensity had no impact on HCT outcomes in the high/very high DRI group. MAC improves DFS and relapse compared with RIC among AML/MDS patients with low/intermediate DRI. The finding of no such benefit in high/very high DRI needs to be further explored in a larger cohort with a longer follow-up., (Copyright © 2018. Published by Elsevier Inc.)

We sought to make the first comparisons of duplex Doppler ultrasonography-derived measures of cerebral blood flow during exercise in young and older individuals and to assess whether healthy aging influences the effect of exercise on neurovascular coupling (NVC) and cerebral vascular reactivity to changes in carbon dioxide (CVRco 2 ). In 10 healthy young (23 ± 2 yr; mean ± SD) and 9 healthy older (66 ± 3 yr) individuals, internal carotid artery (ICA) and vertebral artery (VA) blood flows were concurrently measured, along with middle and posterior cerebral artery mean blood velocity (MCAv mean and PCAv mean ). Measures were made at rest and during leg cycling (75 W and 35% maximum aerobic workload). ICA and VA blood flow during dynamic exercise, undertaken at matched absolute (ICA: young 336 ± 95, older 352 ± 155; VA: young 95 ± 43, older 100 ± 30 ml/min) and relative (ICA: young 355 ± 125, older 323 ± 153; VA: young 115 ± 48, older 110 ± 32 ml/min) intensities, were not different between groups ( P > 0.670). The PCAv mean responses to visual stimulation (NVC) were blunted in older versus younger group at rest (16 ± 6% vs. 23 ± 7%, P < 0.026) and exercise; however, these responses were not changed from rest to exercise in either group. The ICA and VA CVRco 2 were comparable in both groups and unaltered during exercise. Collectively, our findings suggest that 1) ICA and VA blood flow responses to dynamic exercise are similar in healthy young and older individuals, 2) NVC is blunted in healthy older individuals at rest and exercise but is not different between rest to exercise in either group, and 3) CVRco 2 is similar during exercise in healthy young and older groups. NEW & NOTEWORTHY Internal carotid artery and vertebral artery blood flow responses to dynamic exercise are similar in healthy young and older individuals. Neurovascular coupling and cerebrovascular carbon dioxide reactivity, two key mechanisms mediating the cerebral blood flow responses to exercise, are generally unaffected by exercise in both healthy young and older individuals.

Background and Objectives: Parenting during residency is increasingly common, and resident parents face unique demands on their time and emotional and cognitive resources. Physicians at all levels of training perceive negative impacts of parenting on career and family life. Surveys of program directors (PDs) in other specialties reveal concern about performance and quality of life of parenting residents. The primary aims of this study were to examine family medicine PDs' perceptions of parenting residents' performance and the adequacy of parenting support structures., Methods: Data were collected from the 2017 Council of Academic Family Medicine (CAFM) Educational Research Alliance (CERA) Family Medicine Residency Program Directors survey. Directors provided the number and status of parenting residents and rated adequacy of parenting resources, resident performance, and impact of parenting on residents using a Likert scale. Results were compared between male/female PDs and male/female residents., Results: Response rate was 57.1%. Less than half of PDs reported adequate parenting support structures in their program (46%). Over 40% of PDs reported that 81%-100% of female residents who take parental leave end up extending their residency training, the most common response category. PDs did not report gender-based differences in performance of parenting residents. PDs most often reported significantly worse well-being for female parenting residents but perceived improved well-being of male parents., Conclusions: Less than half of family medicine PDs feel their program has adequate parenting resources. Female parenting residents commonly extend residency training. PDs perceive parenting negatively impacts well-being of female residents, but not male residents.