KV cache offloading enables long-context LLM inference by storing caches in CPU DRAM, but PCIe bandwidth limitations create severe bottlenecks. In this paper, we develops an analytical framework that derives κ_crit, the critical cached-to-prefill token ratio where execution becomes memory-bound and show typical workloads exceed this threshold by orders of magnitude. Empirical characterization reveals 99% of latency spent on transfers and serving offloaded requests results in GPU's consuming only 28% of their rated TDP, motivating our proposed optimizations for hardware interconnects, model architectures, and scheduling algorithms.

Immune checkpoint inhibitor(ICI) induced cardiac immune related adverse events are challenging to study; Leveraging large data bases like TriNetX global health network may provide needed insights. We performed a retrospective cohort study including patients diagnosed neoplasm and 18 and older when receiving ICI therapy from 1/1/2011 to 12/31/2022. Queried ICD 9/10 codes identified patients experiencing myocarditis, pericarditis, pericardial effusion, and cardiac tamponade within 1 year of ICI initiation. Survival analyses compared one-year overall survival (OS) of patients experiencing cardiac irAEs against propensity score matched populations not experiencing them. In 88,928 identified ICI patients, the incidence of myocarditis(0.48

Fair-CO2 is a system for fairly attributing operational and embodied carbon in cloud data centers to user workloads. It leverages the Shapley value, a game theory solution for fair shared cost attribution with theoretical fairness guarantees. We propose the standard Shapley value solution as a ground truth for attribution in cloud data centers, addressing two key gaps in existing carbon attribution methods that lead to unfair attributions: the effect of dynamic demand on embodied carbon, and interference effects in colocated scenarios. However, the computational cost of the Shapley value solution scales exponentially with the number of workloads and becomes intractable for large systems. Fair-CO2 addresses the scalability challenges of the Shapley value while preserving its fairness benefits via two core components: demand-aware embodied carbon attribution and interference-aware resource cost attribution. Using Monte Carlo simulations of workload schedules and colocation scenarios, we show that Fair-CO2 can approximate the ground truth Shapley attribution solution at scale. We also show how users, once provided a fair way of estimating their workload carbon footprint, can dynamically optimize workload deployment for carbon savings.

Oral budesonide exerts local effects with negligible systemic glucocorticoid activity, due to rapid first-pass metabolism, therefore, could potentially be efficacious in preventing gastrointestinal (GI) acute GVHD (aGVHD). We explored the use of budesonide, added to posttransplant cyclophosphamide (PTCy), tacrolimus, and mycophenolate mofetil, for prevention of GI aGVHD after allogeneic hematopoietic stem cell transplantation (AHSCT) in a prospective observational study and treated 80 patients with a median age of 53 years (range 19-74). Results were compared with a publicly available CIBMTR dataset of 646 patients who received PTCy-based GVHD prophylaxis (CIBMTR Study # GV17-02) (control). Cumulative incidence (CI) of 3-month grade 2-4 and grade 3-4 aGVHD in the budesonide and control groups were 3.8% vs. 34.4% (p < 0.001) and 1.3% vs. 9.8% (p = 0.029), respectively. One-year GRFS (70.5% vs. 31.5%, p < 0.001), PFS (73.4% vs. 52.8%, p = 0.003), and OS (80.1% vs. 64.2%, p = 0.038) were significantly higher in the budesonide group compared with control group. Propensity score-adjusted analyses showed that the addition of budesonide significantly decreased risk of aGVHD grade 2-4 (HR 0.29, p < 0.001), grade 3-4 (HR 0.12, p = 0.045), and cGVHD (HR 0.22, p < 0.001), which resulted in better GRFS (HR 0.38, p < 0.001), PFS (HR 0.58, p = 0.012), and OS (HR 0.72, p = 0.044). Similar results were found when using propensity score-matched analysis restricted to recipients of haploidentical transplantation. In conclusion, addition of budesonide to PTCy-based GVHD prophylaxis is safe and effective in preventing severe acute GI GVHD with significantly improved GRFS. These results could facilitate transition to peripheral blood grafts for all allogeneic transplant recipients.

This article presents a holistic research agenda to address the significant environmental impact of information and communication technology (ICT), which accounts for 2.1%-3.9% of global greenhouse gas emissions. It proposes several research thrusts to achieve sustainable computing: accurate carbon accounting models, life cycle design strategies for hardware, efficient use of renewable energy, and integrated design and management strategies for next-generation hardware and software systems. If successful, the research would flatten and reverse growth trajectories for computing power and carbon, especially for rapidly growing applications like artificial intelligence. The research takes a holistic approach because strategies that reduce operational carbon may increase embodied carbon, and vice versa. Achieving these goals will require interdisciplinary collaboration between computer scientists, electrical engineers, environmental scientists, and economists.

300 Background: Proteasome inhibitors (PI) represent a significant advancement in the treatment of multiple myeloma (MM). While recent studies have stressed the cardiovascular (CV) risk associated with carfilzomib (CARF) use, the risk with ixazomib (IXA) is underreported and no large comparative analysis is available. This study aims to compare CV and dose-limiting toxicities in MM patients treated with CARF and IXA. Methods: We conducted a retrospective cohort study analyzing TriNetX electronic medical records, including MM patients age 18 years and older who initiated CARF or IXA between January 1, 2016 to December 31, 2023. Patients with a prior history of heart failure (HF) or arrhythmias were excluded. We evaluated the incidence of new onset of HF and arrhythmia within three months of initiating PIs. Secondary outcomes included the incidence of diarrhea, nausea and vomiting during this period. Propensity score matching (PSM) was performed using 1:1 nearest neighbor matching to balance baseline characteristics. Matching covariates included patients’ demographics (age, sex, race/ethnicity), cardiovascular comorbidities and medications (cardiovascular and chemotherapy). Hazard ratios (HRs) for the outcomes were calculated using Cox proportional hazards models with a significance threshold of p<0.05. Results: We identified 950 and 2,872 patients in the IXA- and CARF-treated cohorts, respectively. After PSM, each cohort included 753 patients, with a mean age of 65 years, 52% male and 65% white. Matched populations had no significant differences with respect to matching criteria. The new onset of HF within three months was 2.8% in the IXA group and 5.4% in the CARF group (HR: 0.50, 95% CI: 0.30–0.85, p=0.009). The new onset of arrhythmias was also significantly lower in the IXA group (4.3%) compared to the CARF group (6.6%) (HR:0.63, 95% CI:0.40–0.98, p=0.04). There was no significant difference in the incidence of diarrhea (HR: 0.92, 95% CI: 0.68–1.26, p=0.61), while nausea/vomiting was significantly lower in the IXA group (HR:0.71, 95% CI:0.54–0.93, p=0.013). Conclusions: Our study indicates that ixazomib is associated with a significantly lower risk of cardiac side effects compared to carfilzomib in the treatment of MM, with similar gastrointestinal side effects. Enhanced cardiac monitoring may be necessary for patients on carfilzomib. Further research is needed to validate these cardiovascular risk differences.

Mixture-of-Experts (MoE) models have recently gained steam in achieving the state-of-the-art performance in a wide range of tasks in computer vision and natural language processing. They effectively expand the model capacity while incurring a minimal increase in computation cost during training. However, deploying such models for inference is difficult due to their large model size and complex communication pattern. In this work, we provide a characterization of two MoE workloads, namely Language Modeling (LM) and Machine Translation (MT) and identify their sources of inefficiencies at deployment. We propose three optimization techniques to mitigate sources of inefficiencies, namely (1) Dynamic gating, (2) Expert Buffering, and (3) Expert load balancing. We show that dynamic gating improves maximum throughput by 6.21-11.55$\times$ for LM, 5.75-10.98$\times$ for MT Encoder and 2.58-5.71$\times$ for MT Decoder. It also reduces memory usage by up to 1.36$\times$ for LM and up to 1.1$\times$ for MT. We further propose Expert Buffering, a new caching mechanism that only keeps hot, active experts in GPU memory while buffering the rest in CPU memory. This reduces static memory allocation by 1.47$\times$. Finally, we propose a load balancing methodology that provides additional robustness to the workload. Our code is available at https://github.com/hyhuang00/moe_inference.

Objective: There are significant disparities in outcomes among Hispanic patients with acute lymphoblastic leukemia (ALL). Recent studies have demonstrated favorable outcomes of pegaspargase-containing ALL regimens (PEG-CAR) in young adults however, outcomes in Hispanic ethnicity continue to be underreported.Methods: We evaluated outcomes of newly diagnosed, adult B-cell ALL Hispanic and non-Hispanic patients consecutively treated with a PEG-CAR or HyperCVAD between January 2011 and November 2022. The primary endpoint was event-free survival (EFS) while secondary endpoints included cumulative incidence of relapse and overall survival (OS).Results: Among 105 included patients, 48 (45.7%) were treated with a PEG-CAR and 57 (54.3%) with HyperCVAD. Median age was 38 years (range, 18-75 years), 61% were Hispanic, and 35.2% had poor-genetic risk. Hispanic patients demonstrated significantly worse 5-year EFS with a PEG-CAR compared to that seen with HyperCVAD (HR, 2.58; 95% CI, 1.32-5.04; p = .006) whereas non-Hispanic patients had better outcomes with PIR (52.4% vs. 42.0%). Hispanic ethnicity (p = .015) and male sex (p = .019) were independent predictors for poor OS.Conclusions: Hispanic patients with B-cell ALL had worse EFS with a PEG-CAR as compared with HyperCVAD. Future studies will aim to confirm these findings and establish a tailored treatment approach for this high-risk population.

PURPOSE To describe the impact of an inpatient clinical oncology pharmacy technician program. METHODS A retrospective study was conducted to observe outcomes in patients discharged from the hematology/oncology or bone marrow transplant (BMT) units at Indiana University Health in the year before (April 1, 2016-March 31, 2017) compared with the year after (April 1, 2018-March 31, 2019) the implementation of expanded technician services. The technician performed admission medication histories and ensured access to discharge medications. RESULTS There were 1,169 and 1,112 encounters included in the pre- and post-technician cohorts. The median age was lower (54 v 61 years; P < .001), and there was a higher percentage of male patients (62% v 52.3%; P < .001) in the pre- compared with post-technician cohort. There were a higher percentage of oncology (36.4% v 31%; P = .007) and no difference in hematology (37.4% v 40.2%; P = .17) nor BMT encounters (26.3% v 28.8%; P = .18) in the pre- compared with post-technician cohort. The discharge prescription capture rate increased (42.7% v 78.5%; P < .001) from the pre- to post-technician cohort, resulting in a 34.2% increase ($314,639.46 in US dollars [USD]-$422,129.20 USD) in retail pharmacy revenue. More admission medication histories were completed by pharmacy staff (64.4% v 91.9%; P < .001), and there was an increase in the Hospital Consumer Assessment of Healthcare Providers and Systems-derived patient satisfaction results for both hematology/oncology (79% v 88%; P < .001) and BMT units (77% v 84%; P = .02) in the pre- compared with post-technician cohort. There was no difference in rates of unplanned readmissions (16.4% v 18.2%; P = .69) in the pre-compared with post-technician cohort. CONCLUSION The overall capture rate of discharge prescriptions, revenue for the retail pharmacy, and patient satisfaction scores significantly increased after the implementation of expanded, inpatient clinical pharmacy technician services.

Background: Induction chemotherapy in acute myeloid leukemia (AML) has historically combined an anthracycline with standard-dose cytarabine (“7+3”) in fit patients and is considered the standard of care despite complete remission (CR) rates of 50-70%. Recently, the addition of venetoclax (V) to the chemotherapy combination of cladribine, cytarabine, and idarubicin (“CLIA”) demonstrated an impressive 94% composite CR (CCR) rate with 82% undetectable measurable-residual disease (MRD) among de novo AML patients. Based on these findings, we adopted the utilization of CLIA+V for intensive induction therapy since May 2023 at our institution. Methods: We retrospectively reviewed all newly diagnosed AML patients who received intensive upfront chemotherapy between 2017 and 2024. Patients diagnosed with acute promyelocytic leukemia, core-binding factor AML, and CML myeloid blast phase were excluded from this review as well as patients with FLT3(+), Ph(+), and IDH1/2 (+) mutations who received oral targeted therapies. Outcomes of interest included CCR defined as CR or CR with incomplete count recovery (CRi) after chemotherapy induction, event-free survival (EFS), relapse-free survival (RFS), and overall survival (OS). Time-to-event endpoints were summarized via the Kaplan-Meier method, and treatment groups were compared using a 2-sided log-rank test. Adverse events (ADEs) in alignment with National Cancer Institute Common Terminology Criteria for Adverse Events V5.0 were also evaluated to compare the tolerability and safety of each respective regimen. Results: A total of 50 patients were included in this analysis, 14 in the CLIA+V arm and 36 in the 7+3 arm. The median [IQR] age was 54 [42-63] years and 54% were male. More than half of the study population had European LeukemiaNet (ELN) 2022 adverse-risk AML (58%), and was significantly higher among CLIA+V treated patients (92.9% vs 44.4%; P=0.003). All other baseline characteristics were similar between the two cohorts. Median follow-up time for survivors was 7.6 months for CLIA+V and 54 months for 7+3 treated patients. Two patients in the 7+3 cohort expired prior to bone marrow assessment and were excluded from the response evaluation. CCR was significantly higher among patients who received CLIA+V compared to 7+3 (100% vs 50%; P=0.001). MRD testing by multicolor-flow cytometry post-induction therapy was performed in 85.7% (n=12/14) of CLIA+V and 76.5% (n=13/17) of 7+3 patients, respectively, who achieved CCR; MRD-negative CCR was significantly higher in the former (91.7% [n=11/12] vs 46.2% [n=6/13]; P=0.03). Median number of cycles required to achieve CR1 was 1 (range, 1-1) for CLIA+V and 2 (range, 1-4) for 7+3 treated patients (P=0.001). A greater percentage of patients who received CLIA+V induction therapy proceeded to allogeneic hematopoietic stem cell transplantation (alloHSCT) (78.6% vs 31.6%; P=0.004). Patients who received CLIA+V had higher EFS (92.3% vs 31.6% at 6-months; P<0.001), RFS (92% vs 21.1% at 6-months; P=0.023), and OS (92.3% vs 68.4% at 6-months; P=0.05) compared to those who received 7+3 induction chemotherapy. Patients who received CLIA+V had similar rates of grade ≥2 febrile neutropenia (78.6% vs 61.1%; P=0.33) and infection (21.4% vs 25%; P>0.99), as well as cardiovascular- (14.3% vs 13.9%; P>0.99), gastrointestinal- (35.7% vs 22.2%; P=0.33), and nephrotoxicity (0% vs 11.1%; P=0.57), compared to those who received 7+3, while a lower rate of grade ≥2 hepatotoxicity (0% vs 41.7%; P=0.004) was seen in the former. Early mortality (within 30-days of chemotherapy initiation) was not increased in patients receiving CLIA+V (0% vs 13.2%; P=0.31). Conclusion: This single center analysis shows that induction therapy using CLIA+V resulted in significantly higher CCR, MRD-negativity, and proportion of patients proceeding to alloHSCT compared to 7+3 among newly diagnosed AML patients without increased toxicity. Survival outcomes were also improved among CLIA+V treated patients however, longer follow-up time is needed.

ABSTRACTIntroductionBlastoid variant‐mantle cell lymphoma (BV‐MCL) represents an aggressive subset of patients with no established standard of care treatment approach.MethodsWe performed a retrospective analysis of the clinical characteristics and outcomes of 17 de novo BV‐MCL patients treated at our institution between May 2009 and September 2023. In addition, we reviewed the literature supporting 2nd/3rd generation Bruton's Tyrosine‐kinase (BTKi)‐based therapies for upfront management.ResultsThe complete response rate to frontline and salvage therapy was 66.7% and 25%, respectively. Two‐year overall survival (OS) was low at 62.5% (95% CI, 34.7%–81.1%). Variables associated with higher OS included receipt of consolidative HSCT (p = 0.017), TP53‐wild type (p = 0.031), intermediate‐ versus high‐risk Mantle Cell Lymphoma Prognostic Index score (p = 0.026), and achieving complete response with induction therapy (p = 0.027).DiscussionTreatment outcomes with chemo‐immunotherapy in BV‐MCL patients are poor, especially among TP53‐mutated patients. Recent findings describing positive outcomes with novel BTKi‐based therapies are encouraging and should be considered in this high‐risk population.

PURPOSE OF REVIEW:The purpose of this review is to highlight the importance of a multidisciplinary thrombotic microangiopathies (TMA) Team. This goal will be accomplished through review of the complement system, discuss various causes of thrombotic microangiopathies (TMA), and aspects of their diagnosis and management. In so doing, readers will gain an appreciation for the complexity of this family of disorders and realize the benefit of a dedicated multidisciplinary TMA Team.RECENT FINDINGS:TMA causes derive from multiple specialty areas, are difficult to timely recognize, pose complex challenges, and require multidisciplinary management. Hematopoietic stem cell transplant-associated TMA (TA-TMA) and TA-TMA related multiorgan dysfunction syndrome (TA-TMA MODS) are areas of burgeoning research; use of complement testing and eculizumab precision-dosing has been found to better suppress complement activity in TA-TMA than standard eculizumab dosing. Newer tests are available to risk-stratify obstetric patients at risk for severe pre-eclampsia, whose features resemble those of TA-TMA MODS. Numerous disorders may produce TMA-like findings, and a systematic approach aids in their identification. TMA Teams elevate institutional awareness of increasingly recognized TMAs, will help expedite diagnostic and therapeutic interventions, and create pathways to future TMA-related research and facilitate access to clinical trials.SUMMARY:Establishment of a TMA-Team is valuable in developing the necessary institutional expertise needed to promptly recognize and appropriately manage patients with TMA.

Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening, hyperinflammatory syndrome for which etoposide-based regimens have historically been the standard of care. Recent reports have described positive outcomes with the utilization of ruxolitinib or anakinra although these studies are often limited to small samples. Objectives: We aimed to compare the efficacy of ruxolitinib, anakinra, and etoposide-based therapies for the management of HLH in adult patients. Design: We performed a population-based, multicenter, retrospective cohort study utilizing the TriNetX Networks database. Methods: Adult patients (⩾18 years) diagnosed with HLH who received first-line treatment with ruxolitinib, anakinra, or etoposide between 2008 and 2023 were analyzed. The primary endpoint was overall survival (OS) at 1 year. A 1:1 propensity-score matching analysis was utilized. Results: Anakinra ( p = 0.020) but not ruxolitinib ( p = 0.19) resulted in a significantly higher 1-year OS when compared with etoposide-based therapies. Conclusions: Anakinra is effective for the management of adult patients with HLH.

Soil rhizobia promote nitrogen fixation in legume hosts, maximizing their tolerance to different biotic stressors, plant biomass, crop growth, and yield. While the presence of soil rhizobia is considered beneficial for plants, few studies have assessed whether variation in rhizobia abundance affects the tolerance of legumes to stressors. To address this, we assessed the effects of variable soil rhizobia inoculum concentrations on interactions between a legume host (Pisum sativum), a vector insect (Acyrthosiphon pisum), and a virus (Pea enation mosaic virus, PEMV). We showed that increased rhizobia abundance reduces the inhibitory effects of PEMV on the nodule formation and root growth in 2-week-old plants. However, these trends were reversed in 4-week-old plants. Rhizobia abundance did not affect shoot growth or virus prevalence in 2- or 4-week-old plants. Our results show that rhizobia abundance may indirectly affect legume tolerance to a virus, but effects varied based on plant age. To assess the mechanisms that mediated interactions between rhizobia, plants, aphids, and PEMV, we measured the relative expression of gene transcripts related to plant defense signaling. Rhizobia concentrations did not strongly affect the expression of defense genes associated with phytohormone signaling. Our study shows that an abundance of soil rhizobia may impact a plant’s ability to tolerate stressors such as vector-borne pathogens, as well as aid in developing sustainable pest and pathogen management systems for legume crops. More broadly, understanding how variable rhizobia concentrations can optimize legume-rhizobia symbiosis may enhance the productivity of legume crops.

Human sewage can introduce pollutants into food webs and threaten ecosystem integrity. Among the many sewage-associated pollutants, pharmaceuticals and personal care products (PPCPs) are consistent indicators of sewage in ecosystems and can also cause potent ecological consequences, even at minute concentrations (e.g., ng/L). Despite increased study over the past three decades, PPCPs in terrestrial ecosystems have been less studied than those in aquatic ecosystems. To evaluate PPCP prevalence and drivers in a terrestrial ecosystem, we analyzed managed and native bees collected from agroecosystems in Washington State (USA) for PPCPs. Caffeine, paraxanthine, cotinine, and acetaminophen were detected in all three evaluated taxa ( Bombus vosnesenskii , Agapostemon texanus , and Apis mellifera ), with B. vosnesenskii and A. texanus having a higher probability of PPCP detection relative to A. mellifera . The probability of PPCP presence in all three taxa increased in landscapes with more human development and greater plant abundance, with significant but negative interactions among these factors. These results suggest that human activity, availability of resources, and species-specific pollinator traits affect the introduction and mobilization of PPCPs in terrestrial ecosystems. Consequently, monitoring PPCPs and their ecological responses in terrestrial ecosystems creates opportunities to synthesize effects of sewage pollution across terrestrial and aquatic ecosystem types and organisms.

BackgroundLetermovir (LT) given during the first 100 days after allogeneic transplant has been shown to decrease CMV reactivation. However, a significant proportion of patients (pts) develop late CMV reactivation after LT discontinuation, particularly in haploidentical transplant (haploSCT) recipients. Extended prophylactic duration may be warranted. Here we report on the efficacy of extended duration LT prophylaxis (LT-P) in haploSCT.MethodsWe conducted a retrospective study of pts undergoing haploSCT between 8/2020- 8/2023 using flu-mel based conditioning regimen. LT-P up to 1-year post-SCT was given if either a recipient (R) or donor (D) had CMV+ serology. Clinically significant CMV infection (CS-CMVi) was defined as CMV disease/viremia leading to preemptive treatment.ResultsA total of 41 pts with a median age 50 years (22-73) were included. Median KPS and HCT-CI were 90 (70-100) and 2 (0-7), respectively. The most common diagnosis was acute leukemia (21 pts). MAC and RIC regimens were used in 10 and 31 pts, respectively. Twenty-six pts received a peripheral stem cell graft. CMV serology statuses were R+/D+ (26 pts), R+/D- (14 pts) and R-/D+ (1 pt). Median duration of LT-P was 289 days (145-472).Twenty-three pts developed CS-CMVi (56.1%): 22 with CMV viremia and 1 with CMV pneumonitis at a median onset of 33 days (6-319) with a median initial viral load (VL) of 138 copies/mL (50-8485). Median time of peak CMV reactivation was 55 days post-transplant (10-322) and median peak VL was 650 copies/mL (109-30904). Cumulative incidence of CS-CMVi at 100 days post-SCT was 40.2% (95% CI 25%-54.9%) and 62.9% (95% CI 42.9%-76.3%) at 1 year. A significantly higher cumulative incidence of CS-CMVi was observed in R+/D+ compared to the R+/D- (51.8% vs. 21.4% at 100 days; P=0.02).Twelve of 23 pts (52.2%) had CS-CMVi beyond day 100 post-SCT. Seven of 23 pts developed CS-CMVi within 35 days after LT discontinuation (14-42). Cumulative incidence of CS-CMVi at 100 days post-LT discontinuation was 46.67% (95% CI 21.2%-68.8%). Ten pts developed a second episode of CS-CMVi after initial treatment including 1 patient with CMV pneumonitis who later died of superimposed bacterial pneumonia and respiratory failure at 305 days post-SCT, accounting for 2.4% of CMV-related deaths.At 1-year, there was no difference in PFS (67.2% vs. 67.8%, P=0.71), OS (71.4% vs. 75.2%, P=0.96), NRM (18.5% vs. 17.6%, P=0.69) and relapse (14.4% vs. 14.7%, P=0.99) between pts with or without CS-CMVi. However, patients without CS-CMVi had a higher mean absolute number of CD19+ lymphocytes at day 180 post-SCT (108.2/µL vs. 9/µL, P=0.02) while no differences were seen in absolute numbers of CD3, CD4, CD8, and CD56 at days 30, 100, and 180 post-SCT.ConclusionApproximately 47% of haplo pts developed CS-CMVi at day 100 post-LT discontinuation, with no reactivation observed beyond 1-year post-transplant. Extended LT-P might be needed in haploSCT.

BackgroundAvailable data on preemptive treatment (PT) for Human herpesvirus 6 (HHV6) reactivation after allogeneic stem cell transplantation (SCT) remains limited, and treatment guidelines are lacking.ObjectivesWe hypothesized that PT with a 1-week course of foscarnet (FCN) at a lower plasma HHV6 viral load (VL) is effective in treating early HHV6 reactivation, obviating the need for in-hospital management and minimizing complications.MethodsWe reviewed outcomes of adult patients (pts) who received PT with once daily FCN x 1 week for HHV6 reactivation after SCT between 05/2020-9/2023. Plasma HHV6 VL was monitored using qPCR twice monthly in first 100 days and twice weekly after reactivation. We compared viral reactivation, transplant outcomes and recovery of T-cell subsets between the pts who experienced HHV6 reactivation and the control group of pts who did not.ResultsA total of 68 pts (44 haplo, 22 HLA-matched, 2 HLA-mismatched) with a median age of 49 years (range, 22-73) were included, of whom 18 developed HHV6 reactivation (26.5%). Cumulative incidence of HHV6 reactivation at 100-days was 28.1% (95% CI, 18%-39%), and was higher in haplo-donor compared to matched-HLA donor recipients but did not reach statistical significance (35% vs. 13.9%, P=0.08). The most common diagnosis was acute leukemia (13 pts). MAC and RIC were used in 6 and 12 pts, respectively.Median time to HHV6 reactivation was 24 days (range, 6-89), median VL was 2930 copies/mL (range, 188-118000) at first reactivation, and median peak VL was 10000 copies/mL (range, 600-983000). All pts received a short course of FCN dosed at either 90 mg/kg/day (N=14) or 60 mg/kg/day (N=4). Plasma HHV6 DNA was undetectable in all pts after completion of PT (100% response). No encephalitis occurred. The 100-day cumulative incidence of BKV reactivation/infection was higher in the HHV6 group (50% vs. 23.3%, P=0.01), but there was no difference in CMV (34.8% vs. 33.4%, P=0.53) and other virus (24.9% vs. 10.5%, P=0.37) reactivation/infection between 2 groups.All pts achieved neutrophil and platelet engraftment after a median time of 16 (8-24) and 23 (14-168) days, respectively, with no secondary graft failure. Absolute number of lymphocyte subsets (CD3/CD4/CD8/CD19/CD56) at days 100 and 180 showed no difference between the 2 groups. At 1-year, there was no difference between pts with or without HHV6 reactivation with regards to PFS (77.1% vs. 66.2%, P=0.79), OS (91.7% vs. 70%, P=0.57), NRM (8.6% vs. 21%, P=0.67) and relapse (14.3% vs. 12.8%, P=0.91). No complications related to FCN infusion were noted. One pt with a peak HHV6 DNAemia of 983000 experienced recurrent reactivation and received a second course of FCN with resolution of viremia.ConclusionA short course of once-daily FCN has a highly tolerability profile, is effective in clearing HHV6 viremia, may reduce incidence of HHV6-related complications and prevent hospitalization.

Viroids, the agents of several plant diseases, are the smallest and simplest known replicators that consist of covalently closed circular (ccc) RNA molecules between 200 and 400 nucleotides in size. Viroids encode no proteins and rely on host RNA polymerases for replication, but some contain ribozymes involved in replication intermediate processing. Although other viroid-like agents with cccRNAs genomes, such as satellite RNAs, ribozyviruses and retrozymes, have been discovered, until recently, the spread of these agents in the biosphere appeared narrow, and their actual diversity and evolution remained poorly understood. Extensive, targeted metatranscriptome mining dramatically expanded the known diversity of cccRNAs genomes. These searches identified numerous, diverse viroid-like cccRNAs, many found in environments devoid of plant and animal material, suggesting replication in unicellular eukaryotic and/or prokaryotic hosts. Several cccRNAs are targeted by CRISPR systems, supporting their association with bacteria. In addition to small cccRNAs in the viroid size range, a broad variety of ribozyviruses and novel viruses with cccRNAs genomes, with genomes reaching nearly 5 kilobases, were discovered. Thus, metatranscriptome mining shows that the diversity of viroid-like cccRNAs genomes is far greater than previously suspected, prompting reassessment of the relevance of these replicators for understanding the primordial RNA world.

The role of eculizumab in treating Shiga-toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) patients with neurological involvement remains unclear. We describe two distinctly different STEC-HUS patients with neurologic involvement successfully managed with eculizumab, and perform a literature review of all published cases. Both patients had complete resolution of neurological symptoms after initiation of eculizumab. Eighty patients with STEC-HUS treated with eculizumab were identified in the literature, 68.7% had complete resolution of neurological symptoms. Based on our experience and literature review, three prevailing themes were noted: 1) Early eculizumab administration optimized neurological outcomes, 2) Symptom resolution may not be immediate, neurological symptoms may initially worsen before improvement, and 3) Plasma exchange yielded no benefit. Early administration of eculizumab may reverse neurotoxicity in patients with STEC-HUS.