Fresh or frozen grafts for allogeneic stem cell transplantation: conceptual considerations and a survey on the practice during the COVID-19 pandemic from the EBMT Infectious Diseases Working Party (IDWP) and Cellular Therapy & Immunobiology Working Party (CTIWP).

The COVID-19 pandemic has had a significant impact on medical practices, including the delivery of allogeneic hematopoietic cell transplantation (HCT). In response, transplant centers have made changes to their procedures, including an increased use of cryopreservation for allogeneic haematopoietic progenitor cell (HPC) grafts. The use of cryopreserved grafts for allogeneic HCT has been reviewed and analysed in terms of potential benefits and drawbacks based on existing data on impact on cell subsets, hematological recovery, and clinical outcomes of approximately 2000 patients from different studies. A survey of European Society for Blood and Marrow Transplantation centers was also conducted to assess changes in practice during the pandemic and any unnecessary burdens on HPC donors. Before the pandemic, only 7.4% of transplant centers were routinely cryopreserving HPC products, but this percentage increased to 90% during the pandemic. The results of this review and survey suggest that cryopreservation of HPC grafts is a viable option for allogeneic HCT in certain situations, but further research is needed to determine long-term effects and ethical discussions are required to balance the needs of donors and patients when using frozen allografts.

Periodic Bedrock Ridges at the ExoMars 2022 Landing Site: Evidence for a Changing Wind Regime.

Wind-formed features are abundant in Oxia Planum (Mars), the landing site of the 2022 ExoMars mission, which shows geological evidence for a past wet environment. Studies of aeolian bedforms at the landing site were focused on assessing the risk for rover trafficability, however their potential in recording climatic fluctuations has not been explored. Here we show that the landing site experienced multiple climatic changes in the Amazonian, which are recorded by an intriguing set of ridges that we interpret as Periodic Bedrock Ridges (PBRs). Clues for a PBR origin result from ridge regularity, defect terminations, and the presence of preserved megaripples detaching from the PBRs. PBR orientation differs from superimposed transverse aeolian ridges pointing toward a major change in wind regime. Our results provide constrains on PBR formation mechanisms and offer indications on paleo winds that will be crucial for understanding the landing site geology.

Development of adaptive immune effector therapies in solid tumors.

State-of-the-art treatment strategies have drastically ameliorated the outcome of patients affected by cancer. However, resistant and recurrent solid tumors are generally nonresponsive to conventional therapies. A central factor in the sequence of events that lead to cancer is an alteration in antitumor immune surveillance, which results in failure to recognize and eliminate the transformed tumor cell. A greater understanding of the dysregulation and evasion of the immune system in the evolution and progression of cancer provides the basis for improved therapies. Targeted strategies, such as T-cell therapy, not only generally spare normal tissues, but also use alternative antineoplastic mechanisms that synergize with other therapeutics. Despite encouraging success in hematologic malignancies, adaptive cellular therapies for solid tumors face unique challenges because of the immunosuppressive tumor microenvironment, and the hurdle of T-cell trafficking within scarcely accessible tumor sites. This review provides a brief overview of current cellular therapeutic strategies for solid tumors, research carried out to increase efficacy and safety, and results from ongoing clinical trials.

Determining the time of death by morphological and immunohistochemical evaluation of collagen fibers in postmortem gingival tissues.

The estimation of the post mortem interval (PMI) is still one of the most challenging variables to determine and the different approaches currently used in its estimation generally yield to large post mortem windows. In the present study we combined morphological and immunohistochemical analysis in order to reach a more detailed knowledge on tissue organization and degradation after death. Ultrastructural cellular changes and the extracellular matrix of gingival tissues, collected at different post mortem intervals, were observed by a Transmission Electron Microscopy (TEM), in combination with the immunohistochemical detection of extracellular matrix proteins (i.e. collagen type I and collagen type III) as potential post mortem biochemical markers. The final goal was to find a correlation between morphological modifications, biomarkers expression and the time of death. Samples of gingival tissues obtained from 10 cadavers at different post mortem intervals (short post mortem interval, 1-3 days; mid post mortem interval, 4-6 days; long post mortem interval, 7-9 days) were processed for light microscopy and TEM and they were also immunostained with anti-collagen type I and type III antibodies. Results showed gradual degradation of extracellular matrix in the suboral connective tissue in relation to the different time of death. Moreover PMI was related to an increase of nuclear chromatin condensation and cytoplasmic vacuolization both in epithelial and connective tissues. In conclusion, in addition to traditional forensic approaches to estimate PMI, the combined analyses of cellular morphology, ultrastructure and immunohistochemical expression of collagen proteins allow to better infer the PMI.

"Klingon headache" - a case report of mimic new daily persistent headache associated to primary essential cutis verticis gyrata.

BACKGROUND: Primary essential cutis verticis gyrata is a condition that usually affects healthy subjects associated to convoluted folds and furrows formed from thickened skin of the scalp resembling cerebriform pattern. CASE: we describe a case of association between primary essential cutis verticis gyrata and new daily persistent headache. DISCUSSION/CONCLUSIONS: In our knowledge this is the first description of new daily persistent headache associated with primary essential cutis verticis gyrata. We think that primary essential cutis verticis gyrata could be considered as a possible trigger factor, never described before, for the development of new daily persistent headache.

Hong-Ou-Mandel interference between independent III-V on silicon waveguide integrated lasers.

The versatility of silicon photonic integrated circuits has led to a widespread usage of this platform for quantum information-based applications, including quantum key distribution (QKD). However, the integration of simple high-repetition-rate photon sources is yet to be achieved. The use of weak-coherent pulses (WCPs) could represent a viable solution. For example, measurement device independent QKD (MDI-QKD) envisions the use of WCPs to distill a secret key immune to detector side channel attacks at large distances. Thus, the integration of III-V lasers on silicon waveguides is an interesting prospect for quantum photonics. Here we report the experimental observation of Hong-Ou-Mandel interference with 46±2% visibility between WCPs generated by two independent III-V on silicon waveguide integrated lasers. This quantum interference effect is at the heart of many applications, including MDI-QKD. This Letter represents a substantial first step towards an implementation of MDI-QKD fully integrated in silicon and could be beneficial for other applications such as standard QKD and novel quantum communication protocols.

Cord blood transplantation is associated with good outcomes in secondary Acute Myeloid Leukaemia in first remission.

BACKGROUND: We conducted a retrospective survey within the European Society for Blood and Marrow Transplantation (EBMT) registry to assess the outcomes of cord blood transplantation (CBT) in secondary acute myeloid leukaemia (sAML). METHODS: Inclusion criteria consisted of ≥18 years of age, sAML, first CBT between 2002 and 2016, and either first complete remission (CR) or active disease at CBT. RESULTS: One hundred forty-six patients met the study inclusion criteria. Status at transplantation was first CR (n = 97), primary refractory sAML (n = 30) or relapsed (n = 19) sAML. Neutrophil engraftment was achieved in 118 patients while the remaining 25 patients (17%) failed to engraft. This includes 13% of patients transplanted in first CR versus 30% of those transplanted with active disease (P = 0.008). Two-year incidences of relapse were 25% in first CR patients versus 36% in those with advanced disease (P = 0.06) while 2-year incidences of nonrelapse mortality were 35% and 49% (P = 0.03), respectively. At 2-year overall survival, leukaemia-free survival and graft-versus-host disease (GVHD)-free relapse-free survival were 42% vs. 19% (P < 0.001), 40% vs. 16% (P < 0.001), and 26% vs. 12% (P = 0.002) in first CR patients versus those with advanced disease, respectively. CONCLUSIONS: We report here the first study of CBT in a large cohort of sAML patients. Main observation was that CBT rescued approximately 40% of patients with sAML in first CR.

Occurrence of graft-versus-host disease increases mortality after umbilical cord blood transplantation for acute myeloid leukaemia: a report from Eurocord and the ALWP of the EBMT.

BACKGROUND: The efficacy of umbilical cord blood transplantation (UCBT) as treatment for acute myeloid leukaemia (AML) relies on immune-mediated graft-versus-leukaemia effects. Previous studies have suggested a strong association between graft-versus-host disease (GVHD) occurrence and graft-versus-leukaemia effects after allogeneic hematopoietic cell transplantation. METHODS: Here, we evaluated the kinetics of relapse rate in correlation with GVHD occurrence after UCBT. The kinetics of relapse rate over time in correlation to GVHD occurrence were assessed by calculating the relapse rate per patient-year within sequential 90-day intervals. The impact of GVHD on relapse and mortality was further studied in multivariate Cox models handling GVHD as a time-dependent covariate. RESULTS: The study included data from 1068 patients given single (n = 567) or double (n = 501) UCBT. The proportion of patients with grade II, III and IV acute GVHD was 20%, 7% and 4%, respectively. At 2 years, the cumulative incidence of chronic GVHD was 42%, the cumulative incidence of relapse was 32%, and overall survival was 32% as well. Relapse rates declined gradually over time during the first 30 months after transplantation. There was a possible suggestion that grade II-IV acute (HR = 0.8, P = 0.1) and chronic (HR = 0.65, P = 0.1) GVHD decreased relapse risk. However, grade II-IV acute GVHD significantly increased early (the first 18 months after UCBT) mortality (HR = 1.3, P = 0.02), whilst chronic GVHD increased each early (HR = 2.7, P < 0.001) and late (HR = 4.9, P < 0.001) mortality after UCBT. CONCLUSIONS: The occurrence of grade II-IV acute or chronic GVHD each increases overall mortality after UCBT for AML mitigating the possible graft-versus-leukemia effect of GVHD.

32-channel time-correlated-single-photon-counting system for high-throughput lifetime imaging.

Time-Correlated Single Photon Counting (TCSPC) is a very efficient technique for measuring weak and fast optical signals, but it is mainly limited by the relatively "long" measurement time. Multichannel systems have been developed in recent years aiming to overcome this limitation by managing several detectors or TCSPC devices in parallel. Nevertheless, if we look at state-of-the-art systems, there is still a strong trade-off between the parallelism level and performance: the higher the number of channels, the poorer the performance. In 2013, we presented a complete and compact 32 × 1 TCSPC system, composed of an array of 32 single-photon avalanche diodes connected to 32 time-to-amplitude converters, which showed that it was possible to overcome the existing trade-off. In this paper, we present an evolution of the previous work that is conceived for high-throughput fluorescence lifetime imaging microscopy. This application can be addressed by the new system thanks to a centralized logic, fast data management and an interface to a microscope. The new conceived hardware structure is presented, as well as the firmware developed to manage the operation of the module. Finally, preliminary results, obtained from the practical application of the technology, are shown to validate the developed system.

Risk of sinusoidal obstruction syndrome in allogeneic stem cell transplantation after prior gemtuzumab ozogamicin treatment: a retrospective study from the Acute Leukemia Working Party of the EBMT.

Gemtuzumab ozogamicin (GO) may increase the risk of sinusoidal obstruction syndrome (SOS) when used prior to allogeneic stem cell transplantation (HSCT). We assessed SOS incidence and outcomes after HSCT of 146 adults, with a median age of 50 years, previously receiving GO. SOS prophylaxis was used in 69 patients (heparin n=57, ursodeoxycholic acid n=8, defibrotide n=4). Cumulative incidence (CI) of SOS was 8% (n=11), with death in 3 patients. Median interval between last GO dose and HSCT was 130 days. Overall survival (OS) and SOS incidence did not differ for patients receiving GO ⩽3.5 months before HSCT and the others. CI of acute and chronic GVHD was 31% and 25%, respectively. Probability of OS and leukemia-free survival (LFS) at 5 years was 40% and 37%, respectively. Relapse incidence and non-relapse mortality were 42% and 21%, respectively. In multivariate analysis, active disease at HSCT was associated with relapse and worse LFS and OS (P<0.03). Liver abnormalities before HSCT correlated with worse OS (P<0.03). Use of low-dose GO prior to HSCT is associated with an acceptable SOS incidence. Prospective studies investigating the role and the utility of SOS prophylaxis are warranted.

Outcomes of UCB transplantation are comparable in FLT3+ AML: results of CIBMTR, EUROCORD and EBMT collaborative analysis.

Allogeneic hematopoietic cell transplantation (HCT) from siblings or unrelated donors (URD) during complete remission (CR) may improve leukemia-free survival (LFS) in FMS-like tyrosine kinase 3+ (FLT3+) acute myeloid leukemia (AML), which has poor prognosis because of high relapse rates. Umbilical cord blood (UCB) HCT outcomes are largely unknown in this population. We found that compared with sibling HCT, relapse risks were similar after UCB (n=126) (hazard ratio (HR) 0.86, P=0.54) and URD (n=91) (HR 0.81, P=0.43). UCB HCT was associated with statistically higher non-relapse mortality compared with sibling HCT (HR 2.32, P=0.02), but not vs URD (HR 1.72, P=0.07). All three cohorts had statistically nonsignificant 3-year LFS: 39% (95% confidence interval (CI): 30-47) after UCB, 43% (95% CI: 30-54) after sibling and 50% (95% CI: 40-60) after URD. Chronic graft-versus-host disease rates were significantly lower after UCB compared with either sibling (HR 0.59, P=0.03) or URD (HR 0.49, P=0.001). Adverse factors for LFS included high leukocyte count at diagnosis and HCT during CR2 (second CR). UCB is a suitable option for adults with FLT3+ AML in the absence of an human leukocyte antigen-matched sibling and its immediate availability may be particularly important for FLT3+ AML where early relapse is common, thus allowing HCT in CR1 (first CR) when outcomes are best.

Current practices for screening, consent and care of related donors in France: Haematopoietic stem cell transplantation coordinator nurses' perceptions.

Haematopoietic stem cell transplantation-coordinating nurses (HSCT-CNs) play an important role in informing related donors (RDs) and in organising human leucocyte antigen (HLA) tests, pre-donation workup and stem cells collection. Our pilot study aimed to explore French HSCT-CNs' perceptions of RD care issues. Twenty-nine French HSCT adult units were sent a questionnaire on the subject of donation procedures, HSCT-CNs' data and their professional experience of related donation issues. Twenty-two HSCT-CNs returned a completed questionnaire, and 90% of HSCT units were involved to some degree in both patient and donor care. Responses indicated that the provision of information to potential donors prior to HLA tests was insufficient, while donors were given a medical consultation only during the pre-donation workup. Questions were raised about the consent and voluntary status of RDs. None of the HSCT teams organised a post-donation consultation, while 57% provided follow-up by phone or via a questionnaire. Our results draw attention to the conflict of interest experienced by HSCT-CNs when caring simultaneously for patients and donors. The specific psychosocial difficulties associated with becoming an RD are also highlighted. French HSCT-CNs' perceptions of related donation reveal many ethical and clinical problems that have yet to be fully explored. Data on this topic remain scarce, and our pilot study may contribute to the current debate on the organisation of RD care.

Randomized noninferiority field trial comparing 2 first-generation cephalosporin products at dry off in quarters receiving an internal teat sealant in dairy cows.

The study objective was to compare 2 commercial dry cow mastitis products at the quarter level, with concurrent internal teat sealant application, evaluating the cure risk difference, odds of a cure, odds of a new intramammary infection (NIMI) during the dry period, and risk for a clinical mastitis (CM) case between calving and 60d in milk (DIM). A total of 590 cows (2,360 quarters) from 8 commercial dairy herds in Italy were enrolled and randomized to 1 of the 2 treatments at dry off: Cefovet A (CF; 250mg of cephazoline; Merial Italia SpA, Milan, Italy), and Cepravin (CP; 250mg of cephalonium dehydrate MSD Animal Health Srl, Segrate, Italy). Quarter milk samples were collected before dry cow therapy treatment at dry off, 2 to 9 DIM, and 10 to 17 DIM. Quarter milk samples from CM cases were collected during the first 60 DIM. Noninferiority analysis was used to evaluate the effect of treatment on the risk difference of a bacteriological cure during the dry period, the primary outcome. The odds of cure, developing a NIMI during the dry period, and the risk of a CM event within 60 DIM were evaluated with multivariable logistic regression and hazard analysis, respectively. The overall crude quarter-level prevalence of NIMI at dry off was 15.3%. The most common pathogen isolated from milk samples at dry-off was coagulase-negative staphylococci. Noninferiority analysis showed no effect of treatment on the risk difference for a cure between dry off and both postpartum samples, difference was 0.013. The least squares means from the multivariable model evaluating the odds of cure was 94% for CF and 95%for CP. We observed no effect of treatment on the odds for the presence of a NIMI at 2 to 9 DIM (least squares means: CF=0.09 and CP=0.07), nor did we note a difference in risk of experiencing a CM event between calving and 60 DIM (hazard ratio=0.8). In conclusion, no difference was observed between the 2 products evaluated when assessing the aforementioned outcomes in quarters also receiving an internal teat sealant.

Impact of HLA in cord blood transplantation outcomes.

Umbilical cord blood (UCB) emerged in the last 20 years as a valid alternative source of hematopoietic stem cell (HSC) in allogeneic transplantation setting, mainly in the absence of a fully human leucocyte antigen (HLA)-matched sibling. The probability of finding a matched unrelated donor through the registries varies from 20 to 70%, depending on the ethnicity of the patients. Therefore, patients in need may benefit of an HLA-mismatched hematopoietic stem cell transplantation from haploidentical donors or from UCB. One of the advantages of using UCB is the lower incidence of acute graft-versus-host-disease and allowance of greater HLA mismatch. Conversely, the low number of HSCs and lymphocytes and specific immunological features of T cells are associated with delayed engraftment and immune reconstitution and consequently, increased opportunistic infections. Nevertheless, retrospective studies showed similar results comparing UCB with other stem cell sources, both in pediatric and adult setting. The ability to use partially HLA-matched UCB units allows expanding the donor pool. Many UCB banks have strategies to increase their inventory including UCB grafts that have rare haplotypes. HLA and cell dose are very important factors associated with outcomes after umbilical cord blood transplantation (UCBT) that interact with each other. Increasing cell dose counterbalances the number of HLA disparities. Understanding those interactions, the role of HLA mismatches and other immunogenic factors, are important to allow clinicians to choose the best cord blood graft for patients. This review will describe the role of HLA in UCBT setting.

Microbiological Quality of the Water used in Agriculture in Sardinia.

BACKGROUND: The microbiological quality of the water used in irrigation is crucial for the safety of products, such as fruit and vegetables, especially when destined to be consumed raw. However, the microbiological quality of this water is not defined at a community regulatory level or at a national level. METHODS: With our present work, we wanted to investigate the microbiological quality of the water used for crop irrigation in various Sardinian provinces. Since in most fields the irrigation water is filtered to remove any impurities, the sample was processed twice - both before and after the filtering process. Furthermore, with the purpose of hypothesising the potential health risks attributable to the consumption of crops from the tested fields, samples of horticultural product were collect. Any eventual seasonal differences in the values of microbial concentration were assessed. Microorganism faecal contamination indicators (Escherichia coli, total coliform and faecal streptococci), but even the presence of the opportunistic pathogen such as Pseudomonas aeruginosa were researched in irrigation water. Total mesophilic counts (TMC) were assessed at 36°C and 22°C. On horticultural products we researched both the indicators of process parameters, such as Escherichia coli, Total mesophilic counts at 30°C, Enterobacteriaceae, Total Psychrophilic counts and Pseudomonas aeruginosa, and pathogens, such as Salmonella spp, Listeria monocytogenes and Yersinia enterocolitica. RESULTS: The number of target microorganisms, when present in irrigation water, was very limited: Escherichia coli, total coliform and faecal streptococci, were detected respectively in 48% and 67% of the water samples tested with average concentration values of 0.9, 1.2 and 1.4 log respectively. In fresh vegetable products, the total mesophilic counts (TMC) were found to have average values of 6.6x107 CFU/g. The average values of Enterobacteriaceae totalled 6.1x105 CFU/g; Escherichia coli was detected in only one sample (curly endive) with a value of 180 CFU/g. CONCLUSION: The data highlights the high quality of the water and how this contributed to achieving satisfactory quality on prime material. However the use of filters, to eliminate impurities, and reservoirs, may represent a crucial issue, if not managed correctly.