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The rapid dissemination of antibiotic resistance combined with the decline in the discovery of novel antibiotics represents a major challenge for infectious disease control that can only be mitigated by investments into novel treatment strategies. Alternative antimicrobials including silver have regained interest due to their diverse mechanisms of inhibiting microbial growth. One such example is AGXX, a broad-spectrum antimicrobial that produces highly cytotoxic reactive oxygen species (ROS) to inflict extensive macromolecular damage. Due to connections identified between ROS production and antibiotic lethality, we hypothesized that AGXX could potentially increase the activity of conventional antibiotics. Using the gram-negative pathogenPseudomonas aeruginosa, we screened possible synergistic effects of AGXX on several antibiotic classes. We found that the combination of AGXX and aminoglycosides tested at sublethal concentrations led to a rapid exponential decrease in bacterial survival and restored sensitivity of a kanamycin-resistantP. aeruginosastrain. We deciphered elevated ROS production as a significant contributor to the synergy and demonstrated that the addition of ROS scavengers resulted in reduced endogenous ROS levels and increased bacterial survival, whileP. aeruginosastrains deficient in ROS detoxifying/repair genes were more susceptible to AGXX/aminoglycoside treatment. We further demonstrate that this synergistic interaction was associated with a significant increase in outer and inner membrane permeability, resulting in increased antibiotic influx. Our study also revealed that AGXX/aminoglycoside-mediated killing requires an active proton motive force across the bacterial membrane. Overall, our findings provide an understanding of cellular targets that could be inhibited to increase the activity of conventional antimicrobials.IMPORTANCEThe emergence of drug-resistant bacteria coupled with the decline in antibiotic development highlights the need for novel alternatives. Thus, new strategies aimed at repurposing conventional antibiotics have gained significant interest. The necessity of these interventions is evident especially in gram-negative pathogens as they are particularly difficult to treat due to their outer membrane. This study highlights the effectiveness of the silver containing antimicrobial AGXX in potentiating aminoglycoside activities againstP. aeruginosa. The combination of AGXX and aminoglycosides not only reduces bacterial survival rapidly but also significantly re-sensitizes aminoglycoside-resistant strains. In combination with gentamicin, AGXX induces increased endogenous oxidative stress, membrane damage and iron sulfur cluster disruption. These findings emphasize AGXX’s potential as a route of antibiotic adjuvant development and shed light into potential targets to enhance aminoglycoside activity.

Cure rates in adult acute lymphoblastic leukemia (ALL) improved using pediatric-based chemotherapy and stem cell transplantation (SCT). However, limited data on health condition of cured adults are available whereas pediatric data cannot be transferred. The GMALL analyzed the health status in survivors of adult ALL retrospectively. Physicians answered a questionnaire on general condition (ECOG status) and comorbidity or syndrome occurrence observed after treatment. 538 patients with a median age of 29 (15-64) years at diagnosis were analyzed, median follow-up was seven (3-24) years. 31% had received SCT. ECOG status was 0-1 in 94%, 34% had not developed significant comorbidities. Most frequent comorbidities involved the neurologic system (27%), endocrine system (20%), skin (18%), Graft-versus-Host-Disease (15%), cardiac system (13%), fatigue (13%). SCT impacted ECOG status and comorbidity occurrence significantly. ECOG 0-1 was observed in 86% of SCT and 98% of non-SCT patients (p

PURPOSE In contrast to 5-azacytidine (5-aza), allogeneic stem-cell transplantation (HSCT) represents a curative treatment strategy for patients with myelodysplastic syndromes (MDS), but therapy-related mortality (TRM) limits its broader use in elderly patients with MDS. The present prospective multicenter study compared HSCT following 5-aza pretreatment with continuous 5-aza treatment in patients with higher-risk MDS age 55-70 years. METHODS One hundred ninety patients with a median age of 63 years were enrolled. Patients received 4-6 cycles of 5-aza followed by HLA-compatible HSCT after reduced-intensity conditioning or by continuous 5-aza if no donor was identified. RESULTS Twenty-eight patients did not fulfill inclusion criteria (n = 20), died (n = 2) withdrew informed consent (n = 5), or were excluded for an unknown reason (n = 1). 5-aza induction started in 162 patients, but only 108 (67%) were eligible for subsequent allocation to HSCT (n = 81) or continuation of 5-aza (n = 27) because of disease progression (n = 26), death (n = 12), or other reasons (n = 16). Seven percent died during 5-aza before treatment allocation. The cumulative incidence of TRM after HSCT at 1 year was 19%. The event-free survival and overall survival after 5-aza pretreatment and treatment allocation at 3 years were 34% (95% CI, 22 to 47) and 50% (95% CI, 39 to 61) after allograft and 0% and 32% (95% CI, 14 to 52) after continuous 5-aza treatment ( P < .0001 and P = .12), respectively. Fourteen patients progressing after continuous 5-aza received a salvage allograft from an alternative donor, and 43% were alive at last follow-up. CONCLUSION In older patients with MDS, reduced-intensity conditioning HSCT resulted in a significantly improved event-free survival in comparison with continuous 5-aza therapy. Bridging with 5-aza to HSCT before is associated with a considerable rate of dropouts because of progression, mortality, and adverse events.

Donor lymphocyte infusion (DLI) can (re-)induce durable remission in relapsing patients after allogeneic hematopoietic stem-cell transplantation (alloHSCT). However, DLI harbors the risk of increased non-relapse mortality due to the co-occurrence of graft-versus-host disease (GVHD). GVHD onset may be caused or accompanied by changes in the clonal T-cell receptor (TCR) repertoire. To investigate this, we analyzed T cells in a cohort of 21 patients receiving DLI after alloHSCT. We performed deep T-cell receptor β (TRB) sequencing of sorted CD4+CD25+CD127low regulatory T cells (Treg cells) and CD4+ conventional T cells (Tcon cells) in order to track longitudinal changes in the TCR repertoire. GVHD following DLI was associated with less diverse but clonally expanded CD4+CD25+CD127low Treg and CD4+ Tcon TCR repertoires, while patients without GVHD exhibited healthy-like repertoire properties. Moreover, the diversification of the repertoires upon GVHD treatment was linked to steroid-sensitive GVHD, whereas decreased diversity was observed in steroid-refractory GVHD. Finally, the unbiased sample analysis revealed that the healthy-like attributes of the CD4+CD25+CD127low Treg TCR repertoire were associated with reduced GVHD incidence. In conclusion, CD4+CD25+CD127low Treg and CD4+ Tcon TRB repertoire dynamics may provide a helpful real-time tool to improve the diagnosis and monitoring of treatment in GVHD following DLI.

Objectives: Psoriatic arthritis (PsA) has a strong genetic component, and the identification of genetic risk factors could help identify the ~30% of psoriasis patients at high risk of developing PsA. Our objectives were to identify genetic risk factors and pathways that differentiate PsA from cutaneous-only psoriasis (PsC) and to evaluate the performance of PsA risk prediction models. Methods: Genome-wide meta-analyses were conducted separately for 5,065 patients with PsA and 21,286 healthy controls and separately for 4,340 patients with PsA and 6,431 patients with PsC. The heritability of PsA was calculated as a single-nucleotide polymorphism (SNP)–based heritability estimate (h2SNP) and biologic pathways that differentiate PsA from PsC were identified using Priority Index software. The generalizability of previously published PsA risk prediction pipelines was explored, and a risk prediction model was developed with external validation. Results: We identified a novel genome-wide significant susceptibility locus for the development of PsA on chromosome 22q11 (rs5754467; P = 1.61 × 10−9), and key pathways that differentiate PsA from PsC, including NF-κB signaling (adjusted P = 1.4 × 10−45) and Wnt signaling (adjusted P = 9.5 × 10−58). The heritability of PsA in this cohort was found to be moderate (h2SNP = 0.63), which was similar to the heritability of PsC (h2SNP = 0.61). We observed modest performance of published classification pipelines (maximum area under the curve 0.61), with similar performance of a risk model derived using the current data. Conclusion: Key biologic pathways associated with the development of PsA were identified, but the investigation of risk classification revealed modest utility in the available data sets, possibly because many of the PsC patients included in the present study were receiving treatments that are also effective in PsA. Future predictive models of PsA should be tested in PsC patients recruited from primary care.

Microgrids are an increasingly relevant technology for integrating renewable energy sources into electricity systems. Based on a microgrid implementation in California, we investigate microgrid operation under real-world conditions. These conditions have not yet been considered in combination and encompass energy charges, demand charges, export limits, as well as uncertainty about future electricity demand and generation in the microgrid. Under these conditions, we evaluate the performance of two frequently applied groups of strategies for microgrid operation. The first group is composed of proactive strategies that optimize decisions based on forecasts of future electricity generation and demand. The second group includes reactive strategies that make operational decisions based exclusively on the current state of the microgrid. We evaluate the performance of the strategies under varying operational parameters, forecast accuracies, and microgrid configurations—well beyond our Californian showcase. Our results confirm the expectation that proactive strategies outperform reactive ones in the majority of settings. Yet, reactive strategies can perform better under short control intervals or under moderate prediction errors of PV generation or demand. Furthermore, the interplay between real-world conditions and operational strategies reveals several additional insights for research on microgrid operation. First, we find that demand charges and export limits decisively affect microgrid performance. Second, the impact of forecast errors is highly non-linear and non-monotonous. Third, escalating negative interactions between forecast errors and demand charges make proactive strategies benefit from longer control intervals. This result is contrary to existing best practice, which promotes short control intervals to minimize the impact of uncertainty.

Donor lymphocyte infusion (DLI) can (re-)induce durable remission in relapsing patients after allogeneic hematopoietic stem-cell transplantation (alloHSCT). However, DLI harbors the risk of increased non-relapse mortality due to the co-occurrence of graft-versus-host disease (GVHD). GVHD onset may be caused or accompanied by changes in the clonal T-cell receptor (TCR) repertoire. To investigate this, we analyzed T cells in a cohort of 21 patients receiving DLI after alloHSCT. We performed deep T-cell receptor β (

Preemptive and therapeutic donor lymphocyte infusions (preDLI and tDLI) are widely used in relapsing and relapsed hematopoietic malignancies after allogeneic stem cell transplantation (alloSCT) to enhance the graft-versus-malignancy effect. However, in advanced myeloid malignancies, long-term survival after preDLI and tDLI remains low, reflecting our inability to master the double-edged sword of alloreactivity, balancing anti-neoplastic activity versus graft-versus-host disease (GvHD). We previously evaluated a quantitative PCR-based high-sensitivity chimerism (hs-chimerism) based on insertion/deletion polymorphisms instead of short tandem repeats, where increasing host chimerism in peripheral blood predicts relapse more than a month before clinical diagnosis, and declining host chimerism signals anti-host alloreactivity. Here we report 32 consecutive patients with advanced myeloid malignancies receiving preDLI or tDLI “navigated” by hs-chimerism (“navigated DLI”). We compared them to a historical cohort of 110 consecutive preDLI or tDLI recipients, prior to implementation of hs-chimerism at our institution (“controls”). Both groups were comparable regarding age, gender, conditioning, donor type, and time to DLI. With longer median follow-up of the navigated DLI group (8.5 versus 5 months), their landmark overall (64%) and disease-free survival (62%) at 2 years from first DLI compared favorably with controls (23% and 21%, respectively). Improved survival of navigated DLI was due to both reduced relapse incidence (38% versus 60%) and non-relapse mortality (17% versus 44%) at 2 years. Early relapse prediction by hs-chimerism allowed a preemptive approach in 28% of navigated DLI versus 7% in controls. Our results confirm hs-chimerism as a highly valuable tool for monitoring and steering immune interventions after alloSCT.

Identification of immune phenotypes linked to durable graft-versus-leukemia (GVL) response following donor lymphocyte infusions (DLI) is of high clinical relevance. In this prospective observational study of 13 AML relapse patients receiving therapeutic DLI, we longitudinally investigated changes in differentiation stages and exhaustion markers of T cell subsets using cluster analysis of 30-color spectral flow cytometry during 24 months follow-up. DLI cell products and patient samples after DLI were analyzed and correlated to the clinical outcome. Analysis of DLI cell products revealed heterogeneity in the proportions of naïve and antigen experienced T cells. Cell products containing lower levels of effector memory (eff/m) cells and higher amounts of naïve CD4+ and CD8+ T cells were associated with long-term remission. Furthermore, investigation of patient blood samples early after DLI showed that patients relapsing during the study period, had higher levels of CD4+ eff/m T cells and expressed a mosaic of surface molecules implying an exhausted functional state. Of note, this observation preceded the clinical diagnosis of relapse by five months. On the other hand, patients with continuous remission retained lower levels of exhausted CD4+ eff/m T cells more than four months post DLI. Moreover, lower frequencies of exhausted CD8+ eff/m T cells as well as higher amounts of CD4+temra CD45RO+ T cells were present in this group. These results imply the formation of functional long-term memory pool of T cells. Finally, unbiased sample analysis showed that DLI cell products with low levels of eff/m cells both in CD4+ and CD8+ T cell subpopulations associate with a lower relapse incidence. Additionally, competing risk analysis of patient samples taken early after DLI revealed that patients with high amounts of exhausted CD4+ eff/m T cells in their blood exhibited significantly higher rates of relapse. In conclusion, differentially activated T cell clusters, both in the DLI product and in patients post infusion, were associated with AML relapse after DLI. Our study suggests that differences in DLI cell product composition might influence GVL. In-depth monitoring of T cell dynamics post DLI might increase safety and efficacy of this immunotherapy, while further studies are needed to assess the functionality of T cells found in the DLI.

Der Wintertourismus stellte einen energieintensiven Industriezweig dar. Das Ziel des FFG-Forderprojekts Clean Energy for Tourism ist es, durch die Entwicklung von Technologien und Geschaftsmodellen Salzburgs Skigebiete am Weg zur Dekarbonisierung zu unterstutzen. In diesem Artikel werden die dafur entwickelte IKT-Infrastruktur, die Optimierungsalgorithmen sowie die Geschaftsmodelle vorgestellt.

This paper investigates the optimal planning of microgrids including the hydrogen energy system through mixed-integer linear programming model. A real case study is analyzed by extending the only microgrid lab facility in Austria. The case study considers the hydrogen production via electrolysis, seasonal storage and fueling station for meeting the hydrogen fuel demand of fuel cell vehicles, busses and trucks. The optimization is performed relative to two different reference cases which satisfy the mobility demand by diesel fuel and utility electricity based hydrogen fuel production respectively. The key results indicate that the low emission hydrogen mobility framework is achieved by high share of renewable energy sources and seasonal hydrogen storage in the microgrid. The investment optimization scenarios provide at least 66% and at most 99% carbon emission savings at increased costs of 30% and 100% respectively relative to the costs of the diesel reference case (current situation).

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a curative treatment for hematologic malignancies. Acute and chronic graft-versus-host disease (GvHD) are the major immune-mediated complications after alloHSCT. However, there is controversy whether neurologic complications after alloHSCT might represent manifestations of GvHD. We report three patients who acquired distinct, severe immune-mediated peripheral or central nervous system diseases after alloHSCT without other, concomitant GvHD manifestations. One patient had been diagnosed with B-cell chronic lymphocytic leukemia and two patients with high risk myelodysplastic syndrome. Patient #1 presented as LGI1- and GAD-IgG positive immune-mediated encephalitis, patient #2 was diagnosed with MOG-IgG positive encephalomyelitis, and patient #3 had chronic inflammatory polyneuropathy associated with SSA(Ro)-IgG positive Sjögren’s syndrome. 100% donor chimerism was detectable in the peripheral blood in all three. The specific antibodies were undetectable in donors’ and patients’ blood before alloHSCT suggesting that the antibodies had arisen from the transplanted donor immune system. Early intensive immunotherapy led to improvement of clinical symptoms and stability of the neurological disease, however, at the cost of losing the graft-versus-malignancy effect in one patient. In conclusion, we provide evidence of isolated, severe allo-immune diseases of the peripheral and central nervous system as complications of alloHSCT (“neuro-GvHD”). Interdisciplinary surveillance and thorough diagnostic work-up are needed for early diagnosis and treatment of neuro-immunologic complications after alloHSCT to improve the otherwise poor outcome.

BACKGROUND AND AIMS Acute kidney injury (AKI) is a common complication in allogeneic stem cell transplantation (SCT). Although short-lived, i.e. METHOD Over a 17-year period, 1394 allogeneic stem cell transplants were performed at our tertiary center. Of those, 42 were second transplants. For 1387, a detailed history of creatinine (n = 142 563) and eGFR (n = 96 689) could be extracted from the Enterprise Clinical Research Data Warehouse. The classification of the respective AKI stages was based on the current KDIGO classification relying solely on the changes in serum creatinine. For AKI, an increase in serum creatinine of ≥ 0.3 mg/dL (26.5 µmol/L) within 48 h or an increase in serum creatinine to ≥ 1.5× baseline within 7 days was used. Persistence of impaired renal function beyond day 90 was defined as CKD. For the analysis of big data and classification of the AKI/CKD an algorithm was programmed. Validation of the results was performed using a colour-coded visualization of renal function (Fig. 1). RESULTS Between 1 January 2003 and 31 December 2020, 239 252 values for creatinine and eGFR were enriched for 1387 transplantations for a period between day –28 before today + 118 after allogeneic stem cell transplantation. The overall incidence of AKI was 86% (n = 1199). A total of 993 patients (83%) have shown an AKIN 1, 173 (14%) an AKIN 2 and 33 (3%) an AKIN 3. Of those, 122 (13%) patients died before day + 90 after allogeneic stem cell transplantation and were therefore excluded from CKD analysis. For 271 of 833 patients (33%), the transition to chronic kidney disease has been observed. Further information on patient characteristics, underlying disease, transplant coordinates and related complications and relapse mortality are shown in Table 1. CONCLUSION AKI after SCT is the rule and not the exception. As the vast majority of patients show AKIN 1, it might be often clinically overlooked. However, early intervention might mitigate the development of long-term renal impairment. Automated detection (AKI alert systems) as well as identification and subsequent avoidance of factors contributing or aggravating injury (e.g. conditioning, immunosuppression, perfusion, tissue edema, inappropriate dosing of drugs) might minimize long-term renal complications in allogeneic SCT.

Background/Aims Patients with rheumatoid arthritis (RA) have a higher prevalence of coronary artery disease (CAD) than the general population which contributes to early mortality. Current screening tools for CAD, which are developed in the general population, are less effective for estimating CAD risk in patients with RA. This reduced performance is mainly due to the differing contribution from traditional risk factors and the contribution from disease-specific factors. Our understanding of the genetic basis of CAD has improved over recent years and shows promise for improving risk prediction in the form of polygenic risk scores (PRS). We hypothesise that PRS can help us improve CAD risk prediction in patients with RA by providing more accurate models of risk. Methods Patients were recruited from the Norfolk Arthritis Register (NOAR), a detailed community-based longitudinal observational study focused on the cause and outcome of inflammatory polyarthritis, between 1990 and 2017. Analysis was restricted to patients who satisfied the 2010 ACR criteria cumulatively over five years and had detailed clinical history at baseline and follow-up. We developed a prediction model based on traditional risk factors and explored the inclusion of a PRS (49K SNPs) in a subset of patients with available genetic data. Cox proportional hazards models were used to derive risk equations for evaluation of 10-year risk of CAD. We applied multiple imputations with chained equations using the Random Forest algorithm to replace missing values. Measures of calibration and discrimination were determined in the validation cohort of 423 individuals. Results A total of 2123 patients were included in the analysis with 136 incident cases of self-reported CAD. The model using only traditional risk factors achieved an AUC of 0.72 (95% CI 0.71, 0.73), with a calibration slope of 1.03, and explained approximately 50% (95% CI 47, 52%) of the variance of the outcome. We found that being male reduces the risk by a factor of 0.82 (95% CI 0.68, 1.00). The hazard ratio for age was found to be 1.00 (95% CI 0.99, 1.01) indicating risk remains the same across all age groups. Inclusion of a CAD PRS increased the performance with an AUC of 0.76 (95% CI 0.75, 0.77), explained variance of 53% (95% CI 49, 56%) but with a slightly worse calibration slope of 0.91. Conclusion An integrated risk score, that combines traditional risk factors with a PRS, improves CAD prediction in patients with RA. Further research is required to better understand the role of heritable components contributing to CAD risk in RA patients. By refining the underlying PRS, we hope to further improve CAD risk prediction in RA patients, through this integrated approach. Disclosure M. Soomro: None. M. Stadler: None. S. Viatte: None. A. MacGregor: None. S. Verstappen: None. A. Barton: None. J. Bowes: None.

Acute graft-versus-host disease (aGvHD) contributes to about 50% of transplant-related mortality (non-relapse mortality) after allogeneic hematopoietic stem cell transplantation (HSCT). Here the predictive value of a urinary proteomic profile (aGvHD_MS17) was tested together with preemptive prednisolone therapy. Two-hundred and fifty-nine of 267 patients were eligible for analysis. Ninety-two patients were randomized upon aGvHD_MS17 classification factor above 0.1 to receive either prednisolone (2–2.5 mg/kg, N = 44) or placebo (N = 47; N = 1 randomization failure) for 5 days followed by tapering. The remaining 167 patients formed the observation group. The primary endpoint of the randomized trial was incidence of aGvHD grade II between randomization and day +100 post HSCT. Analysis of the short-term preemptive prednisolone therapy in the randomized patients showed no significant difference in incidence or severity of acute GvHD (HR: 1.69, 95% CI: 0.66–4.32, P = 0.27). Prednisolone as preemptive treatment did not lead to an increase in relapse (20.2% in the placebo and 14.0% in the prednisolone group (P = 0.46)). The frequency of adverse events was slightly higher in the placebo group (64.4% versus 50%, respectively). Taken together, the results of the Pre-GvHD trial demonstrated the feasibility and safety of preemptive prednisolone treatment in the randomized patients.

Allogeneic hematopoietic stem cell transplantation (HCT) is standard treatment for adult high-risk (HR) acute lymphoblastic leukemia (ALL) and contributed to the overall improved outcome. We report a consecutive cohort of prospectively defined HR patients treated on German Multicenter Acute Lymphoblastic Leukemia trials 06/99-07/03 with similar induction/consolidation therapy and HCT in first remission. A total of 542 patients (15-55 years) with BCR-ABL-negative ALL were analyzed. Sixty-seven percent received HCT from matched unrelated donors (MUD) and 32% from matched sibling donors (MSD). The incidence of non-relapse mortality (NRM) was 20% at 5 years. NRM occurred after median 6.6 months; the leading cause (46%) was infection. NRM after MUD decreased from 39% in trial 06/99 to 16% in trial 07/03 (P.00001). Patient age was the strongest predictor of NRM. The 5-year relapse incidence was 23% using MSD and 25% using MUD. Minimal residual disease (MRD) was the strongest predictor of relapse (45% for molecular failure versus 6% for molecular CR; P.0001). The median follow-up was 67 months, and the 5-year survival rate was 58%. Age, subtype/high risk feature, MRD status, trial and acute GvHD were significant prognostic factors. We provide a large reference analysis with long follow-up confirming a similar outcome of MSD and MUD HCT and improved NRM for MUD HCT over years. MRD has a strong impact on relapse risk, whereas age was the strongest predictor of NRM. New adapted conditioning strategies should be considered for older patients combined with the goal to reduce the MRD level before stem cell transplantation.

140 Background: Prostate stem cell antigen (PSCA) is expressed in >80% of metastatic prostate cancers. BPX-601 is an autologous PSCA-directed chimeric antigen receptor (CAR)-T cell immunotherapy engineered to express a rimiducid-inducible MyD88/CD40 costimulation switch to enhance T cell potency and persistence. Safety and activity of BPX-601 with rimiducid in mCRPC and pancreatic cancer is being assessed in an ongoing, phase 1/2 clinical trial (NCT02744287). Results from the first two prostate cancer cohorts are reported. Methods: Eligible mCRPC patients (pts) had progressed on ≥ 2 prior therapies including an androgen receptor antagonist and taxane. Using a 3+3 design, pts received lymphodepleting chemotherapy followed by a single-dose of 5 x 106 BPX-601 cells/kg and single or weekly doses of 0.4 mg/kg rimiducid infused over 2 hours beginning 7 days following cell infusion. Primary objective of phase 1 is to determine safety, tolerability and MTD or RP2D. Secondary objectives include characterization of clinical efficacy, PK of rimiducid and long-term safety. Biomarkers indicative of GoCAR-T cell expansion in blood, immune cell activity, and infiltration to tumor are being monitored. Results: As of Sept 2022, 8 pts received BPX-601 5x106 cells/kg; 3 and 5 pts received a single or weekly (range: 1-30) doses of rimiducid. Most common ≥ grade 3 adverse events were myelosuppression, attributed to lymphodepletion. All patients developed cytokine release syndrome (6 G1, 2 G3). Immune-effector cell associated neurotoxicity syndrome occurred and resolved in 2 pts (1 G1, 1 G4). One pt experienced a DLT of neutropenic sepsis (G5) with possible hemophagocytic lymphohistiocytosis (eg, IL-18, ferritin, M-CSF, fractalkine, MIP-1β and IL-1RA levels were elevated). Of 7 evaluable pts, PSA50 response was observed in 3 pts at Day 28. Preliminary RECIST-based results demonstrated partial response in 1, stable disease in 3, 1 progressive disease; at data cut off 2 had not reached imaging timepoint. One patient continues on study with SD after >9 months, with persistent evidence of rimiducid responsiveness. Peripheral blood BPX-601 cells expanded to an average of 3466 vector copies / μg DNA +/- 3109 during the first week with continued re-expansion to an average of 30234 copies/ug DNA +/- 67031) following rimiducid treatment. Serum IFN-γ, GM-CSF and IL-6 rapidly increased over 24 hours following rimiducid treatment (mean IFN-γ increase 26.9-fold ± 14.2) and subsequently diminished over 2 days. Conclusions: BPX-601, a PSCA-directed GoCAR-T cell product, has preliminary evidence of biologic activity with toxicity characteristic of previously reported CAR-T studies. Markers of rimiducid-induced GoCAR-T cell activation and proliferation were observed. Exploration of escalating weekly rimiducid doses > 0.4 mg/kg and BPX-601 cell doses is planned. Clinical trial information: NCT02744287 .

The outbreak of the COVID-19 pandemic and associated measures to contain the SARS-CoV-2 coronavirus required a change in treatment format from face-to-face to remote psychotherapy. This study investigated the changes experienced by Austrian therapists when switching to psychotherapy at a distance. A total of 217 therapists participated in an online survey on changes experienced when switching settings. The survey was open from 26 June until 3 September 2020. Several open questions were evaluated using qualitative content analysis. The results show that the setting at a distance was appreciated by the therapists as a possibility to continue therapy even during an exceptional situation. Moreover, remote therapy offered the respondents more flexibility in terms of space and time. Nevertheless, the therapists also reported challenges of remote therapy, such as limited sensory perceptions, technical problems and signs of fatigue. They also described differences in terms of the therapeutic interventions used. There was a great deal of ambivalence in the data regarding the intensity of sessions and the establishment and/or maintenance of a psychotherapeutic relationship. Overall, the study shows that remote psychotherapy seems to have been well accepted by Austrian psychotherapists in many settings and can offer benefits. Clinical studies are also necessary to investigate in which contexts and for which patient groups the remote setting is suitable and where it is potentially contraindicated.

407 Background: It has been hypothesized that the rarity of molecular inclusion criteria hampers trial accrual. In this study, we attempted to address this challenge in the context of a SETD2-mutation targeted trial. Methods: Patients who received molecular sequencing services from Tempus were analyzed for the presence of SETD2 molecular variants that matched trial enrollment criteria, and resided within 50 miles from the treatment center or were receiving treatment at clinical sites with strong referral histories. A written notification was issued to the ordering physician whenever a likely match was identified, and additional phone and email outreach follow up, including reasons for not pursuing the clinical trial, was conducted. Results: Over one year, 38 eligible patients were identified, none of which were enrolled. The most common reason for not being enrolled was cohort closure following initial identification and outreach. More specifically, cohort closure occurred < 2 months, 2-4 months, 4-6 months and > 6 months following identification of the mutation in 5, 8, 2 and 7 patients, respectively. Physicians for additional potential patients cited trial consideration as a future option, presence of prohibitive comorbidities, lack of interest, and patient death in 6, 3, 2 and 1 patients, respectively. Physicians for 4 patients did not respond to multiple follow up attempts. In regards to individual follow up, physicians received 0-1, 2-3, and 4 or more follow up outreach notifications regarding trial availability for 14, 19, and 5 patients respectively. Conclusions: Despite identification of a large number of potential trial candidates for a molecular targeted therapeutic trial through use of matching algorithms and extensive treating physician follow up, no patients were enrolled. This raises the hypothesis that the biggest barrier to enrollment, as in other settings, is treating physician motivation and that AI algorithms for identifying potential subjects are insufficient. Larger target populations than anticipated, better coordination between outreach efforts and enrollment status, and directed patient outreach may be necessary.

Our current understanding of the regulation of gene expression in the earlyDrosophila melanogasterembryo comes from observations of a few genes at a time, as within situhybridizations, or observation of gene expression levels without regards to patterning, as with RNA-sequencing. Single-nucleus RNA-sequencing however, has the potential to provide new insights into the regulation of gene expression for many genes at once while simultaneously retaining information regarding the position of each nucleus prior to dissociation based on patterned gene expression. In order to establish the practicality of single-nucleus RNA sequencing in the context of a real biological question, here we look at the difference in gene expression between control and an insulator protein, dCTCF, maternal null embryos during zygotic genome activation at nuclear cycle 14. We find that early embryonic nuclei can be grouped into distinct clusters according to gene expression. From both virtual and publishedin situhybridizations, we also find that these clusters correspond to spatial regions of the embryo. Lastly, we present multiple examples of differential gene expression between control and maternal CTCF null nuclei in one or more clusters, but not in bulk when grouping expression across all nuclei. These results highlight the potential for single-nucleus RNA-sequencing to reveal new insights into the regulation of gene expression in the earlyDrosophila melanogasterembryo.

Purpose: Relapse after allogeneic hematopoietic cell transplantation (allo-HCT) remains the first cause of transplant failure in patients with Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL). In other hematologic malignancies, therapeutic advances resulted in significant improvement over time in survival of patients relapsing after transplant. Experimental Design: We compared outcomes at European Society for Blood and Marrow Transplantation (EBMT) participating centers of 899 adult patients with Ph+ ALL who relapsed between 2000 and 2019 after allo-HCT performed in first complete remission. Median follow-up for alive patients was 56 months. Results: Overall, 116 patients relapsed between 2000 and 2004, 225 between 2005 and 2009, 294 between 2010 and 2014, and 264 between 2015 and 2019. Patient and transplant characteristics were similar over the four time periods except for a progressive increase in unrelated donors, peripheral blood stem cells, reduced intensity conditioning, and in vivo T-cell depletion and a progressive decrease in total body irradiation. The 2-year overall survival (OS) after relapse increased from 27.8% for patients relapsing between 2000 and 2004 to 54.8% for 2015 and 2019 (P = 0.001). A second allo-HCT within 2 years after relapse was performed in 13.9% of patients resulting in a 2-year OS of 35.9%. In multivariate analysis, OS from relapse was positively affected by a longer time from transplant to relapse and the year of relapse. Conclusions: We observed a major progressive improvement in OS from posttransplant relapse for patients with Ph+ ALL over the years, likely multifactorial including transplant-related factors, posttransplant salvage, and improvement in supportive care. These large-scale real-world data can serve as a benchmark for future studies in this setting. See related commentary by Gale, p. 813

Currently, many Microgrid projects remain financially uncertain and not bankable for institutional investors due to major challenges in existing planning and design methods that require multiple, complex steps and software tools. Existing techniques treat every Microgrid project as a unique system, resulting in expensive, non-standardized approaches and implementations which cannot be compared. That is, it is not possible to correlate the results from different planning methods performed by different project developers and/or engineering companies. This very expensive individual process cannot guarantee financial revenue streams, cannot be reliably audited, impedes pooling of multiple Microgrid projects into a financial asset class, nor does it allow for wide-spread and attractive Microgrid and Distributed Energy Resource projects deployment. Thus, a reliable, integrated, and streamlined process is needed that guides the Microgrid developer and engineer through conceptual design, engineering, detailed electrical design, implementation, and operation in a standardized and data driven approach, creating reliable results and financial indicators that can be audited and repeated by investors and financers. This article describes the steps and methods involved in creating bankable Microgrids by relying on an integrated Microgrid planning software approach that unifies proven technologies and tested planning methods, researched and developed by the United States National Laboratory System as well as the US Department of Energy, to reduce design times.

Purpose Clonal hematopoiesis of indeterminate potential (CHIP) occurs in the blood of approximately 20% of older persons. CHIP is linked to an increased risk of hematologic malignancies and of all-cause mortality; thus, the eligibility of stem-cell donors with CHIP is questionable. We comprehensively investigated how donor CHIP affects outcome of allogeneic hematopoietic stem-cell transplantation (HSCT). Methods We collected blood samples from 500 healthy, related HSCT donors (age ≥ 55 years) at the time of stem-cell donation for targeted sequencing with a 66-gene panel. The effect of donor CHIP was assessed on recipient outcomes, including graft-versus-host disease (GVHD), cumulative incidence of relapse/progression (CIR/P), and overall survival (OS). Results A total of 92 clonal mutations with a median variant allele frequency of 5.9% were identified in 80 (16.0%) of 500 donors. CHIP prevalence was higher in donors related to patients with myeloid compared with lymphoid malignancies (19.2% v 6.3%; P ≤ .001). In recipients allografted with donor CHIP, we found a high cumulative incidence of chronic GVHD (cGVHD; hazard ratio [HR], 1.73; 95% CI, 1.21 to 2.49; P = .003) and lower CIR/P (univariate: HR, 0.62; 95% CI, 0.40 to 0.97; P = .027; multivariate: HR, 0.63; 95% CI, 0.41 to 0.98; P = .042) but no effect on nonrelapse mortality. Serial quantification of 25 mutations showed engraftment of 24 of 25 clones and disproportionate expansion in half of them. Donor-cell leukemia was observed in two recipients. OS was not affected by donor CHIP status (HR, 0.88; 95% CI, 0.65 to 1.321; P = .434). Conclusion Allogeneic HSCT from donors with CHIP seems safe and results in similar survival in the setting of older, related donors. Future studies in younger and unrelated donors are warranted to extend these results. Confirmatory studies and mechanistic experiments are warranted to challenge the hypothesis that donor CHIP might foster cGVHD development and reduce relapse/progression risk.

The prognosis of patients with blast crisis (BC) chronic myeloid leukemia (CML) is still dismal. Allogeneic stem cell transplantation represents the only curative treatment option, but data on transplant outcomes are scarce. We therefore conducted a retrospective, registry-based study of adult patients allografted for BC CML, focusing on patients with active disease at transplant and pretransplant prognostic factors. One hundred seventy patients allografted for BC CML after tyrosine kinase inhibitor pretreatment between 2004 and 2016 were analyzed. Before transplant, 95 patients were in remission, whereas 75 patients had active BC. In multivariable analysis of the entire cohort, active BC at transplant was the strongest factor associated with decreased overall survival (hazrd ratio, 1.87; P = .010) and shorter leukemia-free survival (LFS; hazard ratio, 1.69; P = .017). For patients with BC in remission at transplant, advanced age (≥45 years), lower performance status (≤80%), longer interval from diagnosis BC to transplant (>12 months), myeloablative conditioning, and unrelated donor (UD) transplant were risk factors for inferior survival. In patients with active BC, only UD transplant was significantly associated with prolonged LFS and trended toward improved overall survival. In summary, survival of patients allografted for BC CML was strongly dependent on pretransplant remission status. In patients with remission of BC, conventional prognostic factors remained the major determinants of outcome, whereas in those with active BC at transplant, UD transplant was associated with prolonged LFS in our study. ispartof: BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION vol:25 issue:10 pages:2008-2016 ispartof: location:United States status: published

Head and neck cancer (HNC) surgery remains an important component of management but is associated with a high rate of surgical site infection (SSI). We aimed to assess the safety and efficacy of a topical mucosal antiseptic bundle in preventing SSI and evaluate microbial predictors of infection through a genomic sequencing approach.This study was an open-label, single-arm, single-center, phase 2 trial of a topical mucosal antiseptic bundle in patients with HNC undergoing aerodigestive tract resection and reconstruction. Patients underwent topical preparation of the oral mucosa with povidone-iodine (PI) and chlorhexidine gluconate (CHG) pre- and intra-operatively followed by oral tetracycline ointment every 6 hours for 2 days post-operatively. The primary outcome was change in bacterial bioburden at the oral surgical site. Secondary outcomes included safety, SSI, and microbial predictors of infection.Of 27 patients screened between January 8, 2021, and May 14, 2021, 26 were enrolled and 25 completed the study. There were no antiseptic-related adverse events. The topical mucosal antiseptic bundle significantly decreased oral bacterial colony-forming units from pre-operative levels (logThe bacterial strains which subsequently caused SSI were frequently identified in the pre-operative oral cavity. Accordingly, a topical antiseptic bundle decreased oral bacterial bioburden throughout the peri-operative period and was associated with a low rate of SSI, supporting further study of topical antisepsis in HNC surgery.Alliance Oncology.

Next-generation sequencing (NGS)-based measurable residual disease (MRD) monitoring in patients with acute myeloid leukemia (AML) is widely applicable and prognostic prior to allogeneic hematopoietic cell transplantation (alloHCT). We evaluated the prognostic role of clonal hematopoiesis–associated DNMT3A, TET2, and ASXL1 (DTA) and non-DTA mutations for MRD monitoring post-alloHCT to refine MRD marker selection. Of 154 patients with AML, 138 (90%) had at least one mutation at diagnosis, which were retrospectively monitored by amplicon-based error-corrected NGS on day 90 and/or day 180 post-alloHCT. MRD was detected in 34 patients on day 90 and/or day 180 (25%). The rate of MRD positivity was similar when DTA and non-DTA mutations were considered separately (17.6% vs 19.8%). DTA mutations had no prognostic impact on cumulative incidence of relapse, relapse-free survival, or overall survival in our study and were removed from further analysis. In the remaining 131 patients with at least 1 non-DTA mutation, clinical and transplantation-associated characteristics were similarly distributed between MRD-positive and MRD-negative patients. In multivariate analysis, MRD positivity was an independent adverse predictor of cumulative incidence of relapse, relapse-free survival, and overall survival but not of nonrelapse mortality. The prognostic effect was independent of different cutoffs (above limit of detection, 0.1% and 1% variant allele frequency). MRD log-reduction between diagnosis and post-alloHCT assessment had no prognostic value. MRD status post-alloHCT had the strongest impact in patients who were MRD positive prior to alloHCT. In conclusion, non-DTA mutations are prognostic NGS-MRD markers post-alloHCT, whereas the prognostic role of DTA mutations in the posttransplant setting remains open.

Human cytomegalovirus (HCMV) reactivation remains a relevant complication after hematopoietic stem cell transplantation (HSCT) despite the great progress made in prophylaxis and treatment. Adaptive Natural Killer (NK) cells undergo a persistent reconfiguration in response to HCMV reactivation however, the exact role of adaptive NK cells in HCMV surveillance is currently unknown. We studied the relationship between HCMV reactivation and adaptive NK cells in 70 patients monitored weekly until day +100 after HSCT. Absolute cell counts of adaptive NK cells increased significantly after resolution of HCMV-reactivation compared to patients without reactivation. Patients with HCMV-reactivation had an early reconstitution of adaptive NK cells (“Responders”) and had mainly a single reactivation (75% Responders vs 48% Non-Responders). Adaptive NK cells eliminated HCMV-infected human foreskin fibroblasts (HFF) in vitro and recruited T cells in an in vitro transwell migration assay. An extensive cytokine/chemokine panel demonstrated strongly increased secretion of CXCL10/IP-10, IFN-α, IL-1α, IL-1β, IL-5, IL-7 and CCL4. Thus, adaptive NK cells may control viral spread and T cell expansion and survival during HCMV-reactivation. Taken together, we have demonstrated the potential of adaptive NK cells in the control of HCMV reactivation both by direct cytotoxicity and by recruitment of other immune cells.

Background: Current diagnosis of Transthyretin-related Amyloidosis (ATTR) using bone scintigraphy is primarily based on visual scoring and semi-quantitative indices. With the introduction of new potential life-prolonging drugs for ATTR, a more precise quantification of myocardial amyloid burden is desirable for improved response prediction and therapy monitoring. Methods: At first, quantification experiments using an anthropomorphic thorax phantom were performed. Second, 32 patients underwent both planar whole body [99mTc]- 3,3-Diphosphono-1,2-Propanodicarboxylic Acid (DPD)-scintigraphy and quantitative Single-Photon Emission Computed Tomography/Computed Tomography (SPECT/CT) of the thorax. SPECT/CT standardized myocardial uptake values SUVpeak and SUVpeak normalized to bone uptake (nSUVpeak) were determined. Results: Phantom measurements showed a strong linear relationship between the activity in the myocardial insert and the measured activity (r = 0.9998, p = 0.01), but the measured activity was systematically underestimated by approximately 30%. Receiver operating characteristics (ROC) analysis revealed a 100% sensitivity and specificity at a cut-off of 3.1 for SUVpeak for the differentiation of both patient groups. Conclusion: SUV quantification of ATTR amyloid burden is feasible using novel SPECT/CT technology. With a SUVpeak cut-off of 3.1, patients with Perugini grade 2 and 3 could be clearly separated from those with Perugini grade 0 and 1. Besides ATTR diagnostics, quantification of amyloid deposits could potentially be used for therapy monitoring and prognostication in patients with cardiac ATTR.

Because of the long history of the Finn Dinghy sailing class, the difference between a gold medal and a mediocre result often comes down to personal mistakes of the sailor, or to who has the most optimised equipment. Regarding the latter, the Finn class rules permit certain design variations of the hull, mast, sail and rudder. In the current contribution, we describe a method for developing a customised rudder system aimed at optimal performance during the Tokyo 2020 Olympics. Based on hydrodynamic analysis of existing rudder designs, an improved rudder geometry was developed. Based on the concept geometry, the rudder and tiller were structurally designed and manufactured to achieve high stiffness and sufficient strength, while respecting the minimum mass requirements as specified by the rules.

TPS191 Background: Recent updates to genetic testing recommendations and approved treatment options for prostate cancer (PCa) patients (pts) have clarified the need for comprehensive genetic registries. Germline DNA damage repair (DDR) defects are present in over 10% of pts who develop metastatic castration-resistant prostate cancer (mCRPC) while 5-10% of pts with localized PCa have germline pathogenic variants in DDR genes. NCCN guidelines have recently expanded to address genetic testing to include high risk localized, node positive and metastatic disease, in addition to family cancer history criteria. In May 2020, the FDA approved 2 PARP inhibitors for mCRPC treatment. Genetic registries can address the critical need to identify pts for recently approved targeted treatments, understand real-world effects of targeted therapies, and expand clinical trials examining less common mutations. PROMISE is a prospective genetic registry equipped to meet these needs. Methods: 5,000 PCa pts will be screened via the online study portal and at-home germline testing to identify and enroll 500 eligible pts with germline pathogenic variants, likely pathogenic variants, and variants of uncertain significance (VUS) in the genes of interest: ATM, ATR, BRCA1, BRCA2, BRIP1, CHEK2, FAM175A, GEN1, HOXB13, MRE11A, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, TP53 and XRCC2. Additional genes may be added as evidence emerges. Eligible pts must be assigned male at birth and have documented PCa through tissue biopsy, and/or PSA >100ng/dL, and/or radiographic evidence of disease. Pts with or without prior genetic testing, including those with known pathogenic variants, are encouraged to enroll. Exclusion criteria are: inability or unwillingness to provide information for eligibility and incomplete inclusion criteria. Following germline testing, all pts will be offered genetic counseling and periodic newsletters with updates on treatments and clinical trials. Every 6 months, eligible pts will complete a patient-reported outcome (PRO) survey (EORTC QLQ-C30) and updated medical records will be obtained for clinical data abstraction. Eligible pts will enter long-term follow-up. The primary endpoint is the creation of a prospective genetic registry of PCa pts. Additional endpoints include: frequency of pathogenic or likely pathogenic germline variants of interest, recruitment of a control group with a VUS in the genes of interest, association between disease characteristics and germline testing results, comparison of PROs between disease subpopulations, longitudinal outcomes, and overall survival. Study duration will be 20 years (active recruitment: 5 years, follow-up: 15 years). PROMISE is recruiting at 10 US sites and has 282 subjects enrolled in the screening phase to date. PROMISE is sponsored and managed by the Prostate Cancer Clinical Trials Consortium. Clinical trial information: NCT04995198.

84 Background: Ephrin receptors and their membrane-localized ligands induce bidirectional signaling and facilitate tumor-stroma interactions. Expression of EphB4 is increased in prostate cancer tissue and cell lines and retained in castration resistant states, and can promote cell migration, invasion, and metastases. Blocking the EphB4-EphrinB2 pathway, which can be accomplished by soluble EphB4 conjugated to human serum albumin (sEphB4-HSA), has efficacy in preclinical models of aggressive prostate cancer. A phase I clinical trial of sEphB4-HSA led to response or stable disease in 56% of patients, with no grade 4 or 5 related adverse events, and combination pembrolizumab sEphB4-HSA led to a 52% response rate in EphrinB2 expressing urothelial cancer. We hypothesized that targeting the EphB4-EphrinB2 pathway may serve as a therapeutic target in the treatment of metastatic castration resistant prostate cancer (mCRPC). Methods: We conducted a single arm, phase II trial in patients with progressive mCRPC and treatment with at least one second generation androgen receptor (AR)-targeted therapy but no more than three prior therapies for mCRPC. On Day 1 of each cycle patients received sEphB4-HSA 1000 mg IV, with cycle length 14 days cycles 1-6 and cycle length 21 days for cycle 7 and beyond. The primary endpoint was confirmed prostate specific antigen (PSA) response rate (confirmed decrease in PSA by > 50%). We employed a Simon two stage Minimax design, requiring two or more responses among the first 15 patients to enroll an additional ten patients. Results: Fourteen eligible patients enrolled in the study. Median age was 73.5 years (range 52-83), patients had a median baseline PSA value of 65.11 ng/mL (range 7.77-2850 ng/mL) and received a median of three prior therapies (range 1-3) for mCRPC. Ten patients received prior taxane for mCRPC or hormone sensitive prostate cancer. The median length of treatment with sEphB4-HSA was 6.5 weeks (range 2-35 weeks). The potentially treatment-related adverse events (AEs) that occurred in more than 25% of patients were hypertension (10 patients) and fatigue (7 patients). Three patients experienced a serious adverse event potentially related to therapy, including one patient with a grade 5 event (cerebral vascular accident) possibly related to study drug. No patient had a confirmed PSA response, and the study was stopped for futility. Thirteen patients had PSA progression ( > 25% increase in PSA), and one patient withdrew due to toxicity prior to having an evaluable PSA response. The median time to PSA progression was 28 days (95% CI 28-64 days), and median time to radiologic progression was 55 days (95% CI 55 days-NR). Of three patients with measurable disease, two had stable disease and one had progressive disease. Conclusions: In patients with mCRPC who progressed on prior second generation AR-targeted therapy, sEphB4-HSA monotherapy had no discernable anti-tumor activity. Clinical trial information: NCT04033432.

Over the past century the electric power industry has evolved to support the delivery of power over long distances with highly interconnected transmission systems. Despite this evolution, some remote communities are not connected to these systems. These communities rely on small, disconnected distribution systems, i.e., microgrids to deliver power. However, as microgrids often are not held to the same reliability standards as transmission grids, remote communities can be at risk for extended blackouts. To address this issue, we develop an optimization model and an algorithm for capacity planning and operations of microgrids that include ${N}$ -1 security and other practical modeling features like ac power flow physics, component efficiencies, and thermal limits. We demonstrate the computational effectiveness of our approach on two test systems; a modified version of the IEEE 13 node test feeder and a model of a distribution system in a remote community in Alaska.

Conventional analysis of host chimerism (HC) frequently fails to detect relapse before its clinical manifestation in patients with hematological malignancies after allogeneic stem cell transplantation (allo-SCT). Quantitative PCR (qPCR)-based highly-sensitive chimerism analysis extends the detection limit of conventional (short tandem repeats-based) chimerism analysis from 1 to 0.01% host cells in whole blood. To date, the diagnostic value of highly-sensitive chimerism analysis is hardly defined. Here, we applied qPCR-based chimerism analysis to 901 blood samples of 71 out-patients with hematological malignancies after allo-SCT. Receiver operating characteristics (ROC) curves were calculated for absolute HC values and for the increments of HC before relapse. Using the best cut-offs, relapse was detected with sensitivities of 74 or 85% and specificities of 69 or 75%, respectively. Positive predictive values (PPVs) were only 12 or 18%, but the respective negative predictive values were 98 or 99%. Relapse was detected median 38 or 45 days prior to clinical diagnosis, respectively. Considering also durations of steadily increasing HC of more than 28 days improved PPVs to more than 28 or 59%, respectively. Overall, highly-sensitive chimerism analysis excludes relapses with high certainty and predicts relapses with high sensitivity and specificity more than a month prior to clinical diagnosis.

This paper proposes a new methodology to capture the impact of fast moving clouds on utility power demand charges observed in microgrids with photovoltaic (PV) arrays, generators, and electrochemical energy storage. It consists of a statistical approach to introduce sub-hourly events in the hourly economic accounting process. The methodology is implemented in the Distributed Energy Resources Customer Adoption Model (DER-CAM), a state of the art mixed integer linear model used to optimally size DER in decentralized energy systems. Results suggest that previous iterations of DER-CAM could undersize battery capacities. The improved model depicts more accurately the economic value of PV as well as the synergistic benefits of pairing PV with storage.

Summary Background The impact of the intensity of conditioning before allogeneic haemopoietic cell transplantation (HCT) has been studied in a randomised phase 3 trial comparing reduced-intensity conditioning with myeloablative conditioning in patients with acute myeloid leukaemia in first complete remission. Because of the short follow-up of the original trial, whether reduced-intensity conditioning increases the risk of late relapse compared with myeloablative conditioning remained unclear. To address this question, we present retrospective 10-year follow-up data of this trial and focus on late relapse. Methods The original randomised phase 3 trial included patients aged 18–60 years, with intermediate-risk or high-risk acute myeloid leukaemia, an adequate organ function, and an available HLA-matched sibling donor or an unrelated donor with at least nine out of ten HLA alleles matched. Patients were randomly assigned (1:1) to 120 mg/m 2 fludarabine combined with four 2 Gy doses of total-body irradiation (reduced-intensity conditioning) or six 2 Gy doses of total-body irradiation and 120 mg/kg cyclophosphamide (myeloablative conditioning). The primary and secondary efficacy endpoints of this trial have been published previously. In this retrospective, long-term follow-up analysis, data were collected from medical reports from individual participating study centres, and from physician and patient interviews. Endpoints included in this analysis were cumulative relapse incidence, overall survival, disease-free survival, and non-relapse mortality in the original study population and in patients alive and relapse-free at 12 months after HCT (landmark analysis). 10-year time to event rates were calculated in the intention-to-treat population and were compared with the Gray test. The trial is registered with ClinicalTrials.gov, number NCT00150878. Findings In the original trial, 195 patients were randomly assigned to receive reduced-intensity conditioning (n=99) or myeloablative conditioning (n=96). For this retrospective analysis, data were collected with a nearly complete follow-up (completeness index 99%). Median follow-up time for surviving patients was 9·9 years (IQR 8·5–11·4), during which the cumulative incidence of relapse in the complete study population was identical in both groups (30% [95% CI 20–39] in the reduced-intensity conditioning group vs 30% [21–40] in the myeloablative conditioning group; Gray test p=0·99). Relapse occurred at a median of 5·0 months (IQR 3·0–8·8) in the reduced-intensity conditioning group versus 9·5 months (4·5–20·5) in the myeloablative conditioning group. 10-year disease-free survival was 55% (95% CI 45–66) in the reduced-intensity conditioning group and 43% (34–55) in the myeloablative conditioning group (hazard ratio [HR] 0·76 [0·51–1·14]; p=0·19). 10-year non-relapse mortality was 16% (95% CI 8–24) in the reduced-intensity conditioning group and 26% (17–36) in the myeloablative conditioning group (subdistribution HR 0·60 [95% CI 0·32–1·11]; Gray test p=0·10). The incidence of long-term toxicities associated with total-body irradiation was comparable; secondary malignancies occurred in six (6%) of 94 patients in the reduced-intensity conditioning group and five (6%) of 90 in the myeloablative conditioning group (p=1·00). Interpretation There is no evidence that reduced-intensity conditioning increases the risk of late relapse compared with myeloablative conditioning. Given that the reduced-intensity conditioning group in the original trial was associated with lower early morbidity and toxicity, reduced-intensity conditioning with moderately reduced total-body irradiation doses could be the preferred conditioning strategy for patients with acute myeloid leukaemia who are younger than 60 years and transplanted in first complete remission. Funding None.

The intra-hour intermittency of solar energy and demand introduce significant design challenges for microgrids. To avoid costly energy shortfalls and mitigate outage probability, islanded microgrids must be designed with sufficient distributed energy resources (DER) to meet demand and fulfill the energy and power balance. To avoid excessive runtime, current design tools typically only utilize hourly data. As such, the variable nature of solar and demand is often overlooked. Thus, DER designed based on hourly data may result in significant energy shortfalls when deployed in real-world conditions. This research introduces a new, fast method for optimizing DER investments and performing dispatch planning to consider intra-hour variability. A novel set of constraints which operate on intra-hour data are implemented in a mixed-integer-linear-program microgrid investment optimization. Variability is represented by the single worst-case intra-hour fluctuation. This allows for fast optimization times compared to other approaches tested. Applied to a residential microgrid case study with 5-minute intra-hour resolution, this new method is shown to maintain optimality within 2% and reduce runtime by 98.2% compared to full-scale-optimizations which consider every time-step explicitly. Applicable to a variety of technologies and demand types, this method provides a general framework for incorporating intra-hour variability into microgrid design.