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Global warming impacts the hydrological cycle, affecting the seasonality and timing of extreme precipitation. Understanding historical changes in extreme precipitation occurrence is crucial for assessing their impacts. This study uses relative entropy to analyze historical changes in seasonality and timing of extreme daily precipitation occurrences on the global domain for 63 years of fifth generation of the European Reanalysis reanalysis data. Our analysis reveals distinct regional patterns of change. During the second half of the 20th century, Africa and Asia experienced high clustering of precipitation extremes. Over the past 60 years, clustering increased in Africa while becoming more spread out in Asia. North America and Australia had initially lower clustering and showed slight increases over time. Extreme events in extra‐tropical land regions mainly occurred in summer, with modest shifts in timing. These findings have implications for risk assessments of natural hazard like flash floods and landslides, emphasizing the necessity for region‐specific adaptation strategies. Plain Language Summary: Global warming is changing how and when heavy rain and extreme weather events happen. It is important to understand these changes for planning and preparing for floods and other water‐related problems. In this study, we looked at long records of rainstorms to see how they have changed over time. We found that different regions have experienced different changes. During the second half of the 20th century, Africa and Asia were regions with the strongest seasonality. Over the 60 years we analyzed, seasonal clustering overall increased in Africa, while in Asia they became more spread out throughout the year. In Europe, North America and Australia, rainstorms were more spread out throughout the year but became slightly more concentrated. Most of the heavy rainstorms outside the tropics happened in summer, with a small shift in timing. These findings show how various regions have experienced different changes, which is important to take into account when planning and preparing for floods. Key Points: Global assessment of changes (1959–2021) in seasonality and timing of extreme daily precipitation occurrences using relative entropyPrecipitation extremes became more clustered in Africa and less clustered in AsiaShifts in timing of extreme precipitation by only a few days for most regions [ABSTRACT FROM AUTHOR]

Sedimentation devices have been widely implemented to remove suspended solids and attached pollutants from stormwater before entering surface waters. The treatment performance of these best management practices (BMPs) on fine particles is rarely investigated in a standardized way. To overcome this information gap a reliable and standardized testing procedure is formulated. Four devices have been tested on their suspended sediments removal efficiency at different discharges and particle sizes, using the newly developed standardized full scale test method. The observed removal rates of the facilities with a storage volume in the order of 1.5 m3 and settling surface around 1 m2 drop to low removal efficiencies at flow rates of 10 l/s or more. For small sized sediments (up to 63 μm) the removal efficiency is below 50%. The results of the experiments can be used to improve both the design and the dimensions of stormwater treatment devices. [ABSTRACT FROM AUTHOR]

Many small-scale water development initiatives are accompanied by hydrological research to study either the shape of the intervention or its impacts. Humans influence both, and thus one needs to take human agency into account. This paper focuses on the effects of human actions in the intervention and its associated hydrological research, as these effects have not yet been discussed explicitly in a systematic way. In this paper, we propose a systematic planning, based on evaluating three hydrological research projects in small-scale water intervention projects in Vietnam, Kenya, and Indonesia. The main purpose of the three projects was to understand the functioning of interventions in their hydrological contexts. Aiming for better decision-making on hydrological research in small-scale water intervention projects, we propose two analysis steps: (1) being prepared for surprises and (2) cost-benefit analysis. By performing the two analyses continuously throughout a small-scale hydrological intervention based project, effective hydrological research can be achieved. [ABSTRACT FROM AUTHOR]

Objectives: Despite major advances in treatment options for multiple myeloma (MM), patients refractory to the main drug classes and those with aggressive, especially extramedullary disease, still face a dismal outcome. For these patients, effective therapeutic options are urgently warranted., Methods: In this retrospective study, we report on the safety and efficacy of the intensive combination regimen of pomalidomide plus cisplatin, doxorubicin, cyclophosphamide, and etoposide (Pom-PACE) in patients with relapsed refractory MM (RRMM) or plasma cell leukemia (PCL). A study population of 20 consecutive patients treated with Pom-PACE at two academic centers was included for analysis. All patients had to have a confirmed relapse according to International Myeloma Working Group criteria and adequate organ function prior to the start of therapy. Data were collected by reviewing medical charts. Exploratory analyses were performed with regard to efficacy and safety., Results: Patients were heavily pretreated with a median number of four prior therapies (range: 1-10). All patients were exposed to immunomodulators, proteasome inhibitors, and alkylating agents, 80% were double-class refractory, 40% were triple-class refractory. Extramedullary MM or PCL were present in 15 patients (75%). Overall response rate (ORR) was 68%, with 31% achieving at least a very good partial response. Responses were achieved rapidly with an ORR of 64% after one cycle. Median progression-free survival was 8.9 months (0.92-not reached [NR]) and median overall survival was 11.8 months (3-40.6). Pom-PACE was associated with significant toxicity. All evaluable patients experienced Grade 4 hematological toxicity. However, no treatment related mortality was observed., Conclusion: Pomalidomide-PACE was able to induce rapid responses in heavily pretreated, aggressive RRMM with a manageable toxicity profile and therefore offers an effective salvage regimen and a potential bridging strategy to further treatment options such as chimeric antigen receptor T-cell therapy., (© 2024 The Author(s). European Journal of Haematology published by John Wiley & Sons Ltd.)

Purpose: To identify pathogenic microorganisms and microbiological risk factors causing high morbidity and mortality in immunocompromised patients requiring invasive mechanical ventilation due to pneumonia., Methods: A retrospective single-center study was performed at the intensive care unit (ICU) of the Department of Internal Medicine at Heidelberg University Hospital (Germany) including 246 consecutive patients with hematological malignancies requiring invasive mechanical ventilation due to pneumonia from 08/2004 to 07/2016. Microbiological and radiological data were collected and statistically analyzed for risk factors for ICU and 1-year mortality., Results: ICU and 1-year mortality were 63.0% (155/246) and 81.0% (196/242), respectively. Pneumonia causing pathogens were identified in 143 (58.1%) patients, multimicrobial infections were present in 51 (20.7%) patients. Fungal, bacterial and viral pathogens were detected in 89 (36.2%), 55 (22.4%) and 41 (16.7%) patients, respectively. Human herpesviruses were concomitantly reactivated in 85 (34.6%) patients. As significant microbiological risk factors for ICU mortality probable invasive Aspergillus disease with positive serum-Galactomannan (odds ratio 3.1 (1.2-8.0), p = 0.021,) and pulmonary Cytomegalovirus reactivation at intubation (odds ratio 5.3 (1.1-26.8), p = 0.043,) were identified. 1-year mortality was not significantly associated with type of infection. Of interest, 19 patients had infections with various respiratory viruses and Aspergillus spp. superinfections and experienced high ICU and 1-year mortality of 78.9% (15/19) and 89.5% (17/19), respectively., Conclusions: Patients with hematological malignancies requiring invasive mechanical ventilation due to pneumonia showed high ICU and 1-year mortality. Pulmonary Aspergillosis and pulmonary reactivation of Cytomegalovirus at intubation were significantly associated with negative outcome., (© 2024. The Author(s).)

Aims: Endemic SARS-CoV-2 infections still burden the healthcare system and represent a considerable threat to vulnerable patient cohorts, in particular immunocompromised (IC) patients. This study aimed to analyze the in-hospital outcome of IC patients with severe SARS-CoV-2 infection in Germany., Methods: This retrospective, observational study, analyzed administrative data from inpatient cases ( n = 146,324) in 84 German Helios hospitals between 1 January 2022 and 31 December 2022 with regard to in-hospital outcome and health care burden in IC patients during the first 12 months of Omicron dominance. As the primary objective, in-hospital outcomes of patients with COVID-19-related severe acute respiratory infection (SARI) were analyzed by comparing patients with ( n = 2037) and without IC diagnoses ( n = 14,772). Secondary analyses were conducted on IC patients with ( n = 2037) and without COVID-19-related SARI ( n = 129,515). A severe in-hospital outcome as a composite endpoint was defined per the WHO definition if one of the following criteria were met: intensive care unit (ICU) treatment, mechanical ventilation (MV), or in-hospital death., Results: In total, 12% of COVID-related SARI cases were IC patients, accounting for 15% of ICU admissions, 15% of MV use, and 16% of deaths, resulting in a higher prevalence of severe in-hospital courses in IC patients developing COVID-19-related SARI compared to non-IC patients (Odds Ratio, OR = 1.4, p < 0.001), based on higher in-hospital mortality (OR = 1.4, p < 0.001), increased need for ICU treatment (OR = 1.3, p < 0.001) and mechanical ventilation (OR = 1.2, p < 0.001). Among IC patients, COVID-19-related SARI profoundly increased the risk for severe courses (OR = 4.0, p < 0.001)., Conclusions: Our findings highlight the vulnerability of IC patients to severe COVID-19. The persistently high prevalence of severe outcomes in these patients in the Omicron era emphasizes the necessity for continuous in-hospital risk assessment and monitoring of IC patients.

Intratumor heterogeneity as a clinical challenge becomes most evident after several treatment lines, when multidrug-resistant subclones accumulate. To address this challenge, the characterization of resistance mechanisms at the subclonal level is key to identify common vulnerabilities. In this study, we integrate whole-genome sequencing, single-cell (sc) transcriptomics (scRNA sequencing), and chromatin accessibility (scATAC sequencing) together with mitochondrial DNA mutations to define subclonal architecture and evolution for longitudinal samples from 15 patients with relapsed or refractory multiple myeloma. We assess transcriptomic and epigenomic changes to resolve the multifactorial nature of therapy resistance and relate it to the parallel occurrence of different mechanisms: (1) preexisting epigenetic profiles of subclones associated with survival advantages, (2) converging phenotypic adaptation of genetically distinct subclones, and (3) subclone-specific interactions of myeloma and bone marrow microenvironment cells. Our study showcases how an integrative multiomics analysis can be applied to track and characterize distinct multidrug-resistant subclones over time for the identification of molecular targets against them., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Influenza virus infection is a common cause of self-limiting respiratory tract infection (RTI), however immunocompromised patients are at an increased risk for a severe course of disease or fatal outcome. We therefore aimed to gain a better understanding of the molecular epidemiology of influenza viruses from patients with haematological disorders and their impact on the clinical course of disease. Molecular analysis using polymerase chain reaction (PCR) of nasopharyngeal swabs was performed for influenza virus in haematological patients at the Heidelberg University Hospital. Clinical data was evaluated to identify associated risk factors. For phylogenetic analysis, the hemagglutinin (HA) gene was sequenced. Out of 159 influenza positive patients, 117 patients developed upper RTI (influenza A: n = 73; influenza B: n = 44). Lower RTI was observed in n = 42 patients (26%), n = 22/42 patients developed severe disease and n = 16/159 (10.1%) patients died. Risk factors for lower RTI were nosocomial infection (p = 0.02), viral shedding for ≥14 days (p = 0.018), IgG levels <6 g/dL (p = 0.046), bacterial/fungal co-infections (p < 0.001). Risk factors for fatal outcome were age ≥65 years (p = 0.032), bacterial/fungal (p≤0.001) co-infections and high viral load (p = 0.026). Sequencing of the HA gene (n = 115) revealed subtype A(H3N2) (n = 46), A(H1N1)pdm09 (n = 24), B/Victoria (n = 34), B/Yamagata (n = 11). There was no correlation between influenza (sub)type and lower RTI. Influenza infection in haematological patients is associated with significant morbidity and mortality, the risk for aggravating co-infections, prolonged viral shedding and nosocomial transmission emphasizing the need for infection control., (© 2023 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Introduction: Infections are a leading cause of morbidity and mortality in patients with multiple myeloma (MM)., Methods: To examine the effects of modern second-generation novel agent therapy on immune cell subsets, in particular CD4+-T-cells, and infectious complications in patients with relapsed/refractory MM (RRMM), we conducted a prospective cohort study in 112 RRMM patients., Results: Substantially decreased CD4+-T-cells <200/µl before initiation of relapse therapy were detected in 27.7% of patients and were associated with a higher number of previous lines of therapy. Relapse therapy with carfilzomib or pomalidomide showed a significant further decrease of CD4+-T-cells. All novel agents led to a significant decrease of B-cell counts. Overall, infections were frequent with 21.3% of patients requiring antibacterial therapy within the first 3 months of relapse therapy, 5.6% requiring hospitalization. However, in the setting of standard antimicrobial prophylaxis in RRMM patients with very low CD4+-T-cells, no significant association of CD4+T-cell count and an increased risk of infection could be detected., Discussion: Our findings imply that reduced CD4+-T-cell numbers and infections are common in patients with RRMM. We also demonstrate an association with the number of previous therapies and certain substances suggesting an increased need for personalized prophylaxis strategies for opportunistic infections in this patient cohort., Competing Interests: LJ participated in an advisory board for Janssen. KM has nothing to declare. AB has nothing to declare. EKM reports consulting or advisory role, honoraria, research funding, and travel accommodations and expenses from Bristol Myers Squibb/Celgene, GlaxoSmithKline, Janssen-Cilag, Sanofi, Stemline and Takeda. DK has nothing to declare. KK received research funding from Sanofi. MH received research funding from Sanofi, BMS, Celgene and Novartis and participated in an advisory board for BeiGene. CM-T has a consulting role with Janssen and received research funding from Janssen. KJ participated in advisory boards and received honoraria from MSD, Amgen, Hexal, Riemser, Helsinn, Volontis, G1, Art-Tempi, Onkowissen, Roche, AstraZeneca, Takeda, Mundipharma, med update GmbH, Vifor and Karyopharma. H.G. received travel support from Amgen, BMS, GlaxoSmithKline GSK, Janssen, Novartis, Sanofi and Pfizer, research support from Amgen, BMS, Celgene, GlycoMimetics Inc., GSK, Heidelberg Pharma, Hoffmann-La Roche, Karyopharm, Janssen, Incyte Corporation, Millenium Pharmaceuticals Inc., Molecular Partners, Merck Sharp and Dohme MSD, MorphoSys AG, Pfizer, Sanofi, Takeda and Novartis, grants and/or provision of medicinal products from Amgen, Array Biopharma/Pfizer, BMS/Celgene, Chugai, Dietmar-Hopp-Foundation, Janssen, Johns Hopkins University, Mundipharma GmbH and Sanofi, honoraria from Amgen, BMS, Chugai, GlaxoSmithKline GSK, Janssen, Novartis, Sanofi and Pfizer and participated in advisory boards for Amgen, BMS, Janssen, Sanofi and Adaptive Biotechnology. MSR received travel grants from BMS, Amgen, Janssen, research funding from BMS, Janssen, Sanofi and Heidelberg Pharma and participated in advisory roles for BMS, Amgen, GSK, Janssen, Sanofi, Pfizer, AbbVie and Takeda. NG received honoraria from Abbvie, AstraZeneca, GSK, Hexal and MSD and has a consulting role for AstraZeneca and MSD. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2023 John, Miah, Benner, Mai, Kriegsmann, Hundemer, Kaudewitz, Müller-Tidow, Jordan, Goldschmidt, Raab and Giesen.)

Activating BRAF mutations are found in a small subset of patients with newly diagnosed multiple myeloma, but prevalence increases in late-stage, refractory disease, and the mutations are associated with adverse outcome. This prospective single-arm, open-label, multicenter phase 2 trial assessed the efficacy and safety of combined BRAF/MEK inhibition, using encorafenib and binimetinib, in patients with relapsed/refractory multiple myeloma (RRMM) carrying a BRAFV600E mutation. Patients received 450 mg encorafenib once daily and binimetinib 45 mg twice daily. The primary end point was the overall response rate achieved within the first year after start of treatment according to International Myeloma Working Group criteria. Twelve RRMM patients with a median of 5 prior lines of therapy were enrolled. The overall response rate was 83.3%, with 10 patients achieving at least a partial response. The median progression-free survival was 5.6 months, and overall survival was 55% at 24 months. Emerging resistance to therapy was driven by RAS mutations and structural variants involving the BRAF locus. This is the first prospective clinical trial to demonstrate that combined BRAF/MEK inhibition is highly effective in patients with BRAFV600E-mutated RRMM, and it represents a successful targeted precision medicine approach in this disease. This trial was registered at www.clinicaltrials.gov as #NCT02834364., (© 2023 by The American Society of Hematology.)

The novel coronavirus SARS-CoV-2 and the associated infectious disease COVID-19 pose a significant challenge to healthcare systems worldwide. Patients with cancer have been identified as a high-risk population for severe infections, rendering prophylaxis and treatment strategies for these patients particularly important. Rapidly evolving clinical research, resulting in the recent advent of various vaccines and therapeutic agents against COVID-19, offers new options to improve care and protection of cancer patients. However, ongoing epidemiological changes and rise of new virus variants require repeated revisions and adaptations of prophylaxis and treatment strategies to meet these new challenges. Therefore, this guideline provides an update on evidence-based recommendations with regard to vaccination, pharmacological prophylaxis and treatment of COVID-19 in cancer patients in light of the currently dominant omicron variants. It was developed by an expert panel of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO) based on a critical review of the most recent available data., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The outcomes of patients with multiple myeloma (MM) refractory to immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) remain poor. In this study, we performed whole genome and transcriptome sequencing of 39 heavily pretreated relapsed/refractory MM (RRMM) patients to identify mechanisms of resistance and potential therapeutic targets. We observed a high mutational load and indications of increased genomic instability. Recurrently mutated genes in RRMM, which had not been previously reported or only observed at a lower frequency in newly diagnosed MM, included NRAS, BRAF, TP53, SLC4A7, MLLT4, EWSR1, HCFC2, and COPS3. We found multiple genomic regions with bi-allelic events affecting tumor suppressor genes and demonstrated a significant adverse impact of bi-allelic TP53 alterations on survival. With regard to potentially resistance conferring mutations, recurrently mutated gene networks included genes with relevance for PI and IMiD activity; the latter particularly affecting members of the Cereblon and the COP9 signalosome complex. We observed a major impact of signatures associated with exposure to melphalan or impaired DNA double-strand break homologous recombination repair in RRMM. The latter coincided with mutations in genes associated with PARP inhibitor sensitivity in 49% of RRMM patients; a finding with potential therapeutic implications. In conclusion, this comprehensive genomic characterization revealed a complex mutational and structural landscape in RRMM and highlights potential implications for therapeutic strategies.

To assess morbidity and mortality of parainfluenza virus (PIV) infections in immunocompromised patients, we analysed PIV infections in a hematology and stem cell transplantation (SCT) unit over the course of three years. Isolated PIV strains were characterized by sequence analysis and nosocomial transmission was assessed including phylogenetic analysis of viral strains. 109 cases of PIV infection were identified, 75 in the setting of SCT. PIV type 3 (n = 68) was the most frequent subtype. PIV lower respiratory tract infection (LRTI) was observed in 47 patients (43%) with a mortality of 19%. Severe leukopenia, prior steroid therapy and presence of co-infections were significant risk factors for development of PIV-LRTI in multivariate analysis. Prolonged viral shedding was frequently observed with a median duration of 14 days and up to 79 days, especially in patients after allogeneic SCT and with LRTI. Nosocomial transmission occurred in 47 patients. Phylogenetic analysis of isolated PIV strains and combination with clinical data enabled the identification of seven separate clusters of nosocomial transmission. In conclusion, we observed significant morbidity and mortality of PIV infection in hematology and transplant patients. The clinical impact of co-infections, the possibility of long-term viral shedding and frequent nosocomial transmission should be taken into account when designing infection control strategies., Competing Interests: NG: honoraria from MSD and Roche, advisory board from Pfizer, and travel grants from BMS and Karyopharm; DT – honoraria and travel grants from Gilead, IQone, MSD, and Pfizer, and travel grants from Abbvie, Astellas, Celgene, Jazz; CMT – grants and/or provision of investigational medicinal product from Pfizer, Daiichi Sankyo, and BiolineRx, research support by Deutsche Forschungsgemeinschaft DFG, Deutsche Krebshilfe, BMBF, Wilhelm Sander Stiftung, José Carreras Stiftung, and Bayer AG, and advisory boards from Pfizer, and Janssen-Cilag GmbH. This does not alter our adherence to PLOS ONE policies on sharing data and materials

A newly developed Boron-based Large-scale Observation of Soil Moisture (or BLOSM) system is currently being tested and implemented. The stationary system provides a cost-effective way to measure fast and thermalized neutrons by using low-cost, non-hazardous and accessible materials and equipment. BLOSM operates by measuring cosmic-ray induced neutrons and by comparing the amount of fast neutrons with the amount of thermal neutrons. Fast neutrons are moderated by hydrogen atoms in the air, organic materials, and especially and primarily by water in the soil, causing the ratio between fast and thermal to be a strong indicator of soil moisture content. The fast/thermal ratio is representative for soil moisture a scale of about 30 hectares, while standard soil moisture measurements are representative for less than a square meter. This is a well-established fact but present neutron detectors are very costly. Thanks to the low-cost of the probe, BLOSM can eventually be applied at a large scale and significantly increase the number of soil-water data points thereby enabling improvement of existing hydrology models as well as new applications such as monitoring fire hazards and agricultural droughts. Here, we present the build and first tests in the laboratory. We show that BLOSM can indeed measure fast and thermal neutrons, which opens the way to applications outside the laboratory., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Low-cost dual-frequency receivers and antennas have created opportunities for a wide range of new applications, in regions and disciplines where traditional GNSS equipment is unaffordable. However, the major drawback of using low-cost antenna equipment is that antenna phase patterns are typically poorly defined. Therefore, the noise in tropospheric zenith delay and coordinate time series is increased and systematic errors may occur. Here, we present a field calibration method that fully relies on low-cost solutions. It does not require costly software, uses low-cost equipment (~500 Euros), requires limited specialist expertise, and takes complex processing steps into the cloud. The application is more than just a relative antenna calibration: it is also a means to assess the quality and performance of the antenna, whether this is at a calibration site or directly in the field. We cover PCV calibrations, important for deformation monitoring, GNSS meteorology and positioning, and the computation of PCOs when the absolute position is of interest. The method is made available as an online web service. The performance of the calibration method is presented for a range of antennas of different quality and price in combination with a low-cost dual-frequency receiver. Carrier phase residuals of the low-cost antennas are reduced by 11-34% on L1 and 19-39% on L2, depending on the antenna type and ground plane used. For the cheapest antenna, when using a circular ground plane, the L1 residual is reduced from 3.85 mm before to 3.41 mm after calibration, and for L2 from 5.34 mm to 4.3 mm. The calibration reduces the Median Absolute Deviations (MADs) of the low-cost antennas in the vertical direction using Post Processed Kinematic (PPK) by 20-24%. For the cheapest antenna, the MAD is reduced from 5.6 to 3.8 mm, comparable to a geodetic-grade antenna (3.5 mm MAD). The calibration also has a positive impact on the Precise Point Positioning (PPP) results, delivering more precise results and reducing height biases.

Patients with cancer are at particular risk for infection but also have diminished vaccine responses, usually quantified by the level of specific antibodies. Nonetheless, vaccines are specifically recommended in this vulnerable patient group. Here, we discuss the cellular part of the vaccine response in patients with cancer. We summarize the experience with vaccines prior to and during the SARS-CoV-2 pandemic in different subgroups, and we discuss why, especially in patients with cancer, T cells may be the more reliable correlate of protection. Finally, we provide a brief outlook on options to improve the cellular response to vaccines.

Virtually all patients with multiple myeloma become unresponsive to treatment over time. Relapsed/refractory multiple myeloma (RRMM) is accompanied by the clonal evolution of myeloma cells with heterogeneous genomic aberrations and profound changes of the bone marrow microenvironment (BME). However, the molecular mechanisms that drive drug resistance remain elusive. Here, we analyze the heterogeneous tumor cell population and its complex interaction network with the BME of 20 RRMM patients by single cell RNA-sequencing before/after treatment. Subclones with chromosome 1q-gain express a specific transcriptomic signature and frequently expand during treatment. Furthermore, RRMM cells shape an immune suppressive BME by upregulation of inflammatory cytokines and close interaction with the myeloid compartment. It is characterized by the accumulation of PD1 + γδ T-cells and tumor-associated macrophages as well as the depletion of hematopoietic progenitors. Thus, our study resolves transcriptional features of subclones in RRMM and mechanisms of microenvironmental reprogramming with implications for clinical decision-making., (© 2021. The Author(s).)

Since of the first sex pheromone and the adoption of pheromone in pest management, the global pheromone market size has grown to reach USD 2.4 billion per year in 2019. This has enabled the development of environmentally friendly approaches that significantly reduce the application of pesticides. Recently, there have been reports of the failure of various commercial codlemone: (E,E)-8,10-dodecadien-1-ol formulations used for monitoring the apple pest codling moth, Cydia pomonella (L.). This work was initiated to investigate factors behind the lack of efficacy of codlemone lure in the Northern Hemisphere (Germany) and Southern Hemisphere (New Zealand). We hypothesised that the observed failure could be due to two main factors: (a) a shift in the response of male codling moth to codlemone and (b) degradation of codlemone under field conditions that renders the lure less attractive. Field trial tests of various doses and blends containing minor pheromone compounds suggested no change in response of male codling moth. The addition of an antioxidant and a UV stabiliser to codlemone resulted in a significant increase in the number of males caught in Germany, but not in New Zealand. Mean maximum temperatures during the growing season since 2004 indicate a 3 °C increase to 35 °C in Germany, but just a 1.5 °C rise to 30 °C in New Zealand. Chemical analysis of the lures used in the field trials in Germany and New Zealand indicated more degradation products and reduced half-life of the lures in Germany compared with those in New Zealand. Heating codlemone lures to 32 °C significantly reduced the number of males caught in traps and increased the isomeric and chemical impurities of codlemone compared with unheated lures. Our data provide the first evidence that climate change affects pheromone molecule stability, thus reducing its biological efficacy. Our finding suggests that climate change could be a general problem for chemical communication and, therefore, could affect the integrity of natural ecosystems., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Salvage high-dose chemotherapy and autologous stem cell transplantation (HDCT/ASCT) is a treatment option for relapsed and/or refractory multiple myeloma (RRMM). No data are available on salvage HDCT/ASCT following re-induction treatment with state-of-the-art triplet regimens. We retrospectively report on 44 patients receiving salvage HDCT/ASCT following re-induction with carfilzomib/lenalidomide/dexamethasone (KRd). All patients received frontline HDCT/ASCT with median time to progression (TTP1) of 2.9 (1.2-13.5) years, enabling paired comparison of frontline and salvage HDCT/ASCT. After re-induction and before salvage transplant, 25/44 patients (57%) attained ≥ very good partial response (VGPR), which increased to 34/44 (77%) at best response after salvage HDCT/ASCT. Median progression-free survival (PFS) was 23.3 months from salvage HDCT/ASCT. Patients with ≥ VGPR at the time of salvage HDCT/ASCT and those receiving maintenance treatment post salvage HDCT/ASCT had significantly superior PFS (hazard ratio (HR) 0.19, p = 0.001 and HR 0.20, p = 0.009). In patients achieving at least an equal depth of response before salvage HDCT/ASCT as before frontline HDCT/ASCT, PFS after salvage HDCT/ASCT was comparable to the frontline situation ( p = 0.3). This is the first report of state-of-the-art triplet re-induction and salvage HDCT/ASCT for RRMM after frontline transplantation. Deep remissions achieved with KRd translate into prolonged PFS following salvage HDCT/ASCT and are enhanced by maintenance treatment.

We compare, in this manuscript, antibiotic prophylaxis versus granulocyte-colony stimulating factor (G-CSF) support as anti-infective strategies, in patients with multiple myeloma (MM), undergoing high-dose therapy followed by autologous stem cell transplantation (HDT/ASCT). At our institution, antibiotic prophylaxis after HDT/ASCT in MM was stopped in January 2017 and replaced by G-CSF support in March 2017. Consecutive MM patients who received HDT/ASCT between March 2016 and July 2018 were included in this single-center retrospective analysis. In total, 298 patients and 353 individual cases of HDT/ASCT were evaluated. In multivariate analyses, G-CSF support was associated with a significantly shortened duration of severe leukopenia < 1/nL ( p < 0.001, hazard ratio (HR) = 16.22), and hospitalization (estimate = -0.19, p < 0.001) compared to antibiotic prophylaxis. Rates of febrile neutropenia, need of antimicrobial therapy, transfer to intensive care unit, and death, were similar between the two groups. Furthermore, antibiotic prophylaxis was associated with a significantly increased risk for the development of multidrug resistant bacteria especially vancomycin-resistant Enterococcus faecium compared to G-CSF support (odds ratio (OR) = 17.38, p = 0.01). Stop of antibiotic prophylaxis as an anti-infective strategy was associated with a reduction in overall resistance rates of bacterial isolates. These results indicate that G-CSF support should be the preferred option in MM patients undergoing HDT/ASCT.

The worldwide spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the associated infectious coronavirus disease (COVID-19) has posed a unique challenge to medical staff, patients and their families. Patients with cancer, particularly those with haematologic malignancies, have been identified to be at high risk to develop severe COVID-19. Since publication of our previous guideline on evidence-based management of COVID-19 in patients with cancer, research efforts have continued and new relevant data has come to light, maybe most importantly in the field of vaccination studies. Therefore, an update of our guideline on several clinically important topics is warranted. Here, we provide a concise update of evidence-based recommendations for rapid diagnostics, viral shedding, vaccination and therapy of COVID-19 in patients with cancer. This guideline update was prepared by the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology by critically reviewing the currently available data on these topics applying evidence-based medicine criteria., Competing Interests: Conflict of Interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: N.G. reports receiving personal fees from MSD, Roche, Pfizer; grants from BMS, Karyopharm, outside the submitted work. SCM reports grants from University of Cologne (KoelnFortune), DMyKG, DZIF, personal fees from Octapharma, outside the submitted work. YK reports personal fees from GILEAD Sciences, grants, personal fees and other from MSD SHARP & DOHME, outside the submitted work. GB reports grants from The German Federal Ministry of Research and Education, The German Federal Ministry of Health, personal fees from Jazz Pharmaceuticals, MSD, NewConceptOncology, outside the submitted work. CL reports non-financial support from Jazz Pharmaceuticals, Neovii, outside the submitted work. MH reports personal fees from Amgen, Janssen, Celgene, Sanofi, Takeda, outside the submitted work. MBB is the PI of the COVACTA Trial at LMU. OAC is supported by the German Federal Ministry of Research and Education, is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy - CECAD, EXC 2030 - 390661388 and has received research grants from Actelion, Amplyx, Astellas, Basilea, Cidara, Da Volterra, F2G, Gilead, Janssen, Medicines Company, Melinta, Merck/MSD, Octapharma, Pfizer, Scynexis, is a consultant to Actelion, Allecra, Amplyx, Astellas, Basilea, Biosys, Cidara, Da Volterra, Entasis, F2G, Gilead, IQVIA, Matinas, MedPace, Menarini, Merck/MSD, Mylan, Nabriva, Noxxon, Octapharma, Paratek, Pfizer, PSI, Roche Diagnostics, Scynexis, and Shionogi, and received lecture honoraria from Astellas, Basilea, Gilead, Grupo Biotoscana, Merck/MSD and Pfizer. PK has received non-financial scientific grants from Miltenyi Biotec GmbH, Bergisch Gladbach, Germany, and the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany, and received lecture honoraria from or has been advisor to Akademie für Infektionsmedizin e.V., Ambu GmbH, Astellas Pharma, Gilead Sciences GPR Academy Ruesselsheim, MSD Sharp & Dohme GmbH, Noxxon N.V., and University Hospital, LMU Munich, outside the submitted work. ES reports lecture honoraria from Gilead, outside the submitted work. M.v.L.T. reports personal fees from Celgene, Gilead, Chugai, Janssen, Novartis, Amgen, Takeda, BMS, Medac, Oncopeptides, Merck, CDDF, Pfizer, 4DPharma, Shionogi; grants from BMBF, Deutsche Jose Carreras Leukämie-Stiftung, IZKF Jena, DFG, Novartis, Gilead, Deutsche Krebshilfe, Celgene, outside the submitted work. RS, MR, MK, MS, HW, HHH, BW have nothing to disclose., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Despite major treatment advances in recent years, patients with multiple myeloma inevitably relapse. The RNA polymerase II complex has been identified as a promising therapeutic target in both proliferating and dormant cancer cells. Alpha-amanitin, a toxin so far without clinical application due to high liver toxicity, specifically inhibits this complex. Here, we describe the development of HDP-101, an anti-B-cell maturation antigen (BCMA) antibody conjugated with an amanitin derivative. HDP-101 displayed high efficacy against both proliferating and resting myeloma cells in vitro , sparing BCMA-negative cells. In subcutaneous and disseminated murine xenograft models, HDP-101 induced tumor regression at low doses, including durable complete remissions after a single intravenous dose. In cynomolgus monkeys, HDP-101 was well tolerated with a promising therapeutic index. In conclusion, HDP-101 safely and selectively delivers amanitin to myeloma cells and provides a novel therapeutic approach to overcome drug resistance in this disease., (©2020 American Association for Cancer Research.)

Patients with cancer are at an increased risk to suffer severe coronavirus disease 2019 (COVID-19). Therefore, specific preventative measures including COVID-19 vaccines are especially important. Both anticancer therapies and the underlying malignancy itself can lead to significant immunosuppression posing a particular challenge for vaccination strategies in these patients. At the moment, four COVID-19 vaccines are European Medicines Agency (EMA) approved in Germany: two mRNA and two viral vector-based vaccines. All four vaccines show excellent protection against severe COVID-19. Their mechanism of action relies on the induction of the production of virus-specific proteins by human cells and the following activation of a specific adaptive immune response. Vaccination against COVID-19 has been prioritized for cancer patients and medical personnel in Germany. Regarding timing of vaccination, vaccination prior to initiation of anticancer therapy seems ideal in newly diagnosed disease. However, due to the significant risk of severe COVID-19 in cancer patients, vaccination is also strongly recommended for patients already undergoing anticancer therapy. In these patients, immune response might be reduced. In two particular patient cohorts, namely stem cell transplant recipients and patients treated with B‑cell depleting agents, an interval of several months following therapy is recommended because otherwise the response to vaccination will most likely be severely reduced. Preliminary data suggest only low rates of seroconversion following a single shot of vaccine in cancer patients. Therefore, on the long run, repeat vaccination regimens might be preferable in cancer patients., (© The Author(s) 2021.)

Background: Chronic graft-versus-host disease (cGVHD) represents a double-edged sword. In its nonsevere form, cGVHD associates with better control of the malignant disease, thus highlighting graft-versus-leukemia effects. However, severe cGVHD leads to debilitating morbidity and increased nonrelapse mortality. The prediction of severe cGVHD, in particular at disease onset, is therefore of high importance for ensuing clinical decisions and overall success of allogeneic stem cell transplantations. CXC-chemokine ligand 9 (CXCL9) is an interferon-inducible chemokine of the CXC family and is increased in cGVHD. Endothelial activation and stress index (EASIX) was shown to predict death after acute graft-versus-host disease. We explored CXCL9 and EASIX as predictors of severe cGVHD., Methods: Sera and clinical data of 480 patients were available who survived at least 6 months following allogeneic stem cell transplantation without steroid-refractory acute graft-versus-host disease and without early relapse. CXCL9 and EASIX were measured on day +100 and onset of cGVHD., Results: Development of nonsevere cGVHD was significantly associated with improved overall survival (hazard ratio 0.53, P < 0.001). CXCL9 serum levels at the onset of cGVHD predicted the development of severe cGVHD later on (hazard ratio 1.33, P = 0.02). In contrast, EASIX at the onset of cGVHD was not associated with cGVHD severity but was a significant independent risk factor for overall mortality and nonrelapse mortality., Conclusions: CXCL9 levels at the onset of cGVHD can help to predict severe courses of the disease and have potential for optimizing tailored administration of immunosuppressive therapy.