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Experimental research has been focusing on developing new substrates for growing shiitake mushrooms as alternatives to the standard oak sawdust substrate. The selection of appropriate lignocellulosic materials is based on their availability in the production area and their compatibility with the requirements of the mushroom species being cultivated. In comparison to oak sawdust substrate (OS) as the control, this study evaluated the potential of oak acorns (OA), olive pruning (OLPR), and vineyard pruning (VIP), and various combinations: OA-OLPR:1-1, OA-VIP:1-1, OS-OLPR:1-1, and OS-VIP:1-1, prepared on a dry weight basis. In comparison to OS, complete mycelial development was hastened in OA, OA-VIP: 1-1, and OS-VIP:1-1 by 9.5, 7.9, and 4.2 days and delayed in OLPR and OS-OLPR:1-1 by 11.3 and 7.0 days, respectively. Also, harvest was earlier in OA, OA-VIP:1-1, and OS-VIP:1-1 by 9.3, 6.7, and 3.3 days, respectively, while it was significantly delayed in OLPR, VIP, and OS-OLPR:1-1 by 12.3, 3.7, and 8.0 days, respectively. While the total biological yield was significantly reduced in OLPR, OS-OLPR:1-1, VIP, and OS-VIP:1-1, it was comparable to OS in OA, OA-OLPR:1-1, and OA-VIP:1-1 (597.0, 552.0, 532.2, and 556.2 g/kg, respectively). Production was consistently high over two consecutive flushes in OS, OA, and OA-VIP: 1-1. Total biological yields were higher in OA-OLPR: 1-1 than OS-OLPR:1-1 and in OA-VIP:1-1 than OS-VIP:1-1. OA increased mushroom number and firmness, VIP and OLPR increased mushroom weight, and OA-VIP:1-1 increased pileus thickness. Mushrooms' protein and fiber contents were higher than OS in all substrates and the highest in OA-OLPR:1-1 (8.7 %) and OLPR (2.8 %), respectively. Conclusively, the substrates OA, OA-VIP: 1-1, and OA-OLPR:1-1 may alternate oak sawdust; however, the first two substrates have an advantage over the third due to earlier harvests. Also, it is more favorable to use VIP and OLPR in combination with OA than to use them alone., Competing Interests: All other authors declare that they have no known competing interests that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: Individuals who receive allogeneic hematopoietic cell transplant (allo-HCT) are immunocompromised and at high risk of pneumococcal infections, especially in the months following transplant. This study evaluated the safety and immunogenicity of V114 (VAXNEUVANCE; Merck, Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA), a 15-valent pneumococcal conjugate vaccine (PCV), when given to allo-HCT recipients., Methods: Participants received 3 doses of V114 or PCV13 (Prevnar 13; Wyeth LLC) in 1-month intervals starting 3-6 months after allo-HCT. Twelve months after HCT, participants received either PNEUMOVAX 23 or a fourth dose of PCV (if they experienced chronic graft vs host disease). Safety was evaluated as the proportion of participants with adverse events (AEs). Immunogenicity was evaluated by measuring serotype-specific immunoglobulin G (IgG) geometric mean concentrations (GMCs) and opsonophagocytic activity (OPA) geometric mean titers (GMTs) for all V114 serotypes in each vaccination group., Results: A total of 274 participants were enrolled and vaccinated in the study. The proportions of participants with AEs and serious AEs were generally comparable between intervention groups, and the majority of AEs in both groups were of short duration and mild-to-moderate intensity. For both IgG GMCs and OPA GMTs, V114 was generally comparable to PCV13 for the 13 shared serotypes, and higher for serotypes 22F and 33F at day 90., Conclusions: V114 was well tolerated in allo-HCT recipients, with a generally comparable safety profile to PCV13. V114 induced comparable immune responses to PCV13 for the 13 shared serotypes, and was higher for V114 serotypes 22F and 33F. Study results support the use of V114 in allo-HCT recipients. Clinical Trials Registration. clinicaltrials.gov (NCT03565900) and European Union at EudraCT 2018-000066-11., Competing Interests: Potential conflicts of interest. M. W., Q. C., C. D., K. G., G. T., T. Sterling, S. M. P., T. Shekar, and U. K. B. are employees of MSD, and may hold stock in Merck & Co, Inc., Rahway, NJ, USA. L. M. was an employee of MSD at the time of the study and may hold stock in Merck & Co, Inc., Rahway, NJ, USA. L. M. is a co-inventor of a dozen patents related to the development of several pneumococcal conjugate vaccines, including the one being evaluated in this study. O. A. C. reports grants or contracts from Amplyx, Basilea, BMBF, Cidara, DZIF, EU-DG RTD (101037867), F2G, Gilead, Matinas, MedPace, MSD, Mundipharma, Octapharma, Pfizer, and Scynexis (payments all made to the University Hospital of Cologne); consulting fees from Abbvie, Amplyx, Biocon, Biosys, Cidara, Da Volterra, Gilead, IQVIA, Janssen, Matinas, MedPace, Menarini, Molecular Partners, MSG-ERC, Noxxon, Octapharma, Pardes, Pfizer, PSI, Scynexis, and Seres (all payments to the author); honoraria for lectures from Abbott, Abbvie, Al-Jazeera Pharmaceuticals, Astellas, Gilead, Grupo Biotoscana/United Medical/Knight, Hikma, MedScape, MedUpdate, MSD, Mylan, Noscendo, Pfizer, and Shionogi (all payments to the author); payment for expert testimony from Cidara; participation on a Data Safety Monitoring Board or Advisory Board from Actelion, Allecra, Cidara, Entasis, IQVIA, Janssen, MedPace, Paratek, PSI, Pulmocide, Shionogi, and The Prime Meridian Group; a patent at the German Patent and Trade Mark Office (DE 10 2021 113 007.7: German patent [“Geschlossene Inkubationssysteme mit verbessertem Atemwegszugang für Untersuchungsvorrichtungen”] filed by the University of Cologne and the listing author as 1 of 3 inventors); and stocks from CoRe Consulting and stock or stock options from EasyRadiology. O. A. C. also reports other financial or nonfinancial interests with DGHO, DGI, ECMM, EHA, ISHAM, MSG-ERC, and Wiley (Chair Infectious Diseases Working Party [DGHO], Chair SWG Infections in Hematology [EHA], Advisory Committee Member [DGI], Educational Officer [ECMM], Treasurer [ISHAM], Board of Directors Member [MSG-ERC], Editor-in-Chief for Mycoses [Wiley]). R. D. has received grants/research support from Pfizer, MSD, and Medimmune (to Ben Gurion University); has been a scientific consultant for Pfizer, MeMed, MSD, and Biondvax (Pfizer and MSD fees to ISRAVAX); has served on advisory boards of Pfizer, MSD, and Biondvax; has been a speaker for Pfizer, MSD, Sanofi Pasteur, and GSK (payment or honoraria to ISRAVAX); and reports payment for expert testimony from Pfizer to ISRAVAX. P. R. has served on vaccine advisory boards for MSD (Pneumococcal Vaccine Scientific Advisory Board March 2020, ongoing; institutional payments; no personal remuneration and RSV Monoclonal Antibody Scientific Advisory Board May 2022–February 2023; institutional payments; no personal remuneration), Pfizer (Meningococcal Vaccine Advisory Board November 2020, ongoing; institutional payments; no personal remuneration; and RSV Vaccine Advisory Board December 2022; institutional payments; no personal remuneration), and GlaxoSmithKline (RSV Scientific Advisory Board May 2021; institutional payments, no personal remuneration; and Meningococcal Vaccines Advisory Boards March 2021 to May 2023; institutional payments, no personal remuneration); received institutional grant funding from GlaxoSmithKline and MSD outside the submitted work (MSD: investigator-initiated research grants to Institution 2021 on RSV and pneumococcal diseases, no personal remuneration); and reports payment or honoraria from GlaxoSmithKline for lectures on meningococcal disease and vaccines October 2021 to October 2022; institutional payments, no personal remuneration; support to attend the International Society for Pneumococci and Pneumococcal Diseases Conference, Toronto, Canada, June 2022, to present at the Pneumonia Symposium from GlaxoSmithKline and to attend the Meningococcal Advisory Board meeting, Madrid, Spain, November 2022, from Pfizer. U. K. B. reports support for attending meetings and/or travel as an employee of MSD. P. L. reports consulting fees paid to their institution from Moderna; payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from Moderna and MSD (payment to institution); and participation on a Data Safety Monitoring Board or Advisory Board for MSD for a completely different topic (CMV) (paid to the author). J. M. reports consulting fees from Gilead Sciences, Mundipharma, F2G, and Pfizer, Inc (paid to the author); payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events; and support for attending meetings and/or travel from Gilead Sciences, Mundipharma, and F2G (paid to the author). K. M. M. reports grants or contracts and payment for honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from MSD; and participation on a Data Safety Monitoring Board or Advisory Board for Micrologics (purchased by Ferring Pharmaceuticals). S. N. reports consulting fees from Abbvie, AstraZeneca, Kite, Janssen, Lilly, Roche; payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from Abbvie, AstraZeneca, Kite, Takeda, Janssen, Novartis, and MSD; support for attending meetings and/or travel from Abbvie, AstraZeneca, Kite, Janssen, and Novartis. M. W. reports support for attending meetings and/or travel as an employee of MSD. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Mutant isocitrate dehydrogenase 1/2 (mIDH1/2) proteins catalyze production of the oncometabolite D-2-hydroxyglutarate (2-HG). Ivosidenib and enasidenib are oral inhibitors of mIDH1 and mIDH2, respectively. An open-label phase 1 study is evaluating the safety and efficacy of ivosidenib or enasidenib combined with intensive induction and consolidation chemotherapy in adult patients with newly diagnosed mIDH1/2 acute myeloid leukemia (AML; NCT02632708). In this population, we characterized the pharmacokinetics (PK), pharmacodynamics (PD), and PK/PD relationships for ivosidenib and enasidenib. Patients received continuous oral ivosidenib 500 mg once daily or enasidenib 100 mg once daily combined with chemotherapy. Serial blood samples were collected for measurement of the concentrations of the mIDH inhibitors. 2-HG concentrations were measured in both plasma and bone marrow aspirates. Samples were collected from 60 patients receiving ivosidenib and 91 receiving enasidenib. For both drugs, exposures at steady state were higher than after single doses, with mean accumulation ratios (based on area under the plasma concentration-time curve from time 0 to 24 hours) of 2.35 and 8.25 for ivosidenib and enasidenib, respectively. Mean plasma 2-HG concentrations were elevated at baseline. After multiple ivosidenib or enasidenib doses, mean trough plasma 2-HG concentrations decreased to levels observed in healthy individuals and were maintained with continued dosing. There was a corresponding reduction in bone marrow 2-HG concentrations. When combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML, ivosidenib and enasidenib demonstrated PK/PD profiles similar to those when they are given as single agents. These findings support the dosing of ivosidenib or enasidenib in combination with intensive chemotherapy for the treatment of patients with newly diagnosed mIDH1/2 AML., (© 2022 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Organic microfossils in Meso- and Neoproterozoic rocks are of key importance to track the emergence and evolution of eukaryotic life. An increasing number of studies combine Raman spectroscopy with synchrotron-based methods to characterize these microfossils. A recurring observation is that Raman spectra of organic microfossils show negligible variation on a sample scale and that variation between different samples can be explained by differences in thermal maturation or in the biologic origin of organic precursor material. There is a paucity of work, however, that explores the extent to which the petrographic framework and diagenetic processes might influence the chemical structure of organic materials. We present a detailed Raman spectroscopy-based study of a complex organic microfossil assemblage in the ca. 1 Ga old Angmaat Formation, Baffin Island, Canada. This formation contains abundant early diagenetic chert that preserves silicified microbial mats with numerous, readily identifiable organic microfossils. Individual chert beds show petrographic differences with discrete episodes of cementation and recrystallization. Raman spectroscopy reveals measurable variation of organic maturity between samples and between neighboring organic microfossils of the same taxonomy and taphonomic state. Scanning transmission X-ray microscopy performed on taphonomically similar coccoidal microfossils from the same thin section shows distinct chemical compositions, with varying ratios of aromatic compounds to ketones and phenols. Such observations imply that geochemical variation of organic matter is not necessarily coupled to thermal alteration or organic precursor material. Variation of the Raman signal across single samples is most likely linked to the diagenetic state of analyzed materials and implies an association between organic preservation and access to diagenetic fluids. Variation in the maturity of individual microfossils may be a natural outcome of local diagenetic processes and potentially exceeds differences derived from precursor organic material. These observations stress the importance of detailed in situ characterization by Raman spectroscopy to identify target specimens for further chemical analysis., (© 2021 John Wiley & Sons Ltd.)

The treatment and evolution of B-cell non-Hodgkin lymphoma (B-NHL) has undergone important changes in the last years with the emergence of targeted therapies, such as monoclonal antibodies, small molecules, antibody-drug conjugates, and bispecific antibodies. Nevertheless, a significant portion of patients remains refractory or relapsed (R/R) to the new therapeutic modalities, representing thus an unmet medical need. The use of CAR-T cells for the treatment of B-NHL patients has shown to be a promising therapy with impressive results in patients with R/R disease. The expectations are as high as the imminent approval of CAR-T cell therapy in Brazil, which it is expected to impact the prognosis of R/R B-NHL. The aim of this manuscript is to offer a consensus of specialists in the field of onco-hematology and cellular therapy, working in Brazil and United States, in order to discuss and offer recommendations in the present setting of the use of CAR-T cells for patients with B-NHL., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2021. Published by Elsevier España, S.L.U.)

Chimeric antigen receptor T (CAR-T) cell therapy is a novel therapeutic modality for acute lymphoblastic leukemia (ALL) with robust outcomes in patients with refractory or relapsed disease. At the same time, CAR-T cell therapy is associated with unique and potentially fatal toxicities, such as cytokine release syndrome (CRS) and neurological toxicities (ICANS). This manuscript aims to provide a consensus of specialists in the fields of Hematology Oncology and Cellular Therapy to make recommendations on the current scenario of the use of CAR-T cells in patients with ALL., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2021. Published by Elsevier España, S.L.U.)

Oxygen concentration defines the chemical structure of Earth's ecosystems while it also fuels the metabolism of aerobic organisms. As different aerobes have different oxygen requirements, the evolution of oxygen levels through time has likely impacted both environmental chemistry and the history of life. Understanding the relationship between atmospheric oxygen levels, the chemical environment, and life, however, is hampered by uncertainties in the history of oxygen levels. We report over 5,700 Raman analyses of organic matter from nine geological formations spanning in time from 742 to 1,729 Ma. We find that organic matter was effectively oxidized during weathering and little was recycled into marine sediments. Indeed, during this time interval, organic matter was as efficiently oxidized during weathering as it is now. From these observations, we constrain minimum atmospheric oxygen levels to between 2 to 24% of present levels from the late Paleoproterozoic Era into the Neoproterozoic Era. Indeed, our results reveal that eukaryote evolution, including early animal evolution, was not likely hindered by oxygen through this time interval. Our results also show that due to efficient organic recycling during weathering, carbon cycle dynamics can be assessed directly from the sediment carbon record., Competing Interests: The authors declare no competing interest.

Ivosidenib (AG-120) and enasidenib (AG-221) are targeted oral inhibitors of the mutant isocitrate dehydrogenase (mIDH) 1 and 2 enzymes, respectively. Given their effectiveness as single agents in mIDH1/2 relapsed or refractory acute myeloid leukemia (AML), this phase 1 study evaluated the safety and efficacy of ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML. Ivosidenib 500 mg once daily and enasidenib 100 mg once daily were well tolerated in this setting, with safety profiles generally consistent with those of induction and consolidation chemotherapy alone. The frequency of IDH differentiation syndrome was low, as expected given the concurrent administration of cytotoxic chemotherapy. In patients receiving ivosidenib, the frequency and grades of QT interval prolongation were similar to those observed with ivosidenib monotherapy. Increases in total bilirubin were more frequently observed in patients treated with enasidenib, consistent with this inhibitor's known potential to inhibit UGT1A1, but did not appear to have significant clinical consequences. In patients receiving ivosidenib (n = 60) or enasidenib (n = 91), end-of-induction complete remission (CR) rates were 55% and 47%, respectively, and CR/CR with incomplete neutrophil or platelet recovery (CR/CRi/CRp) rates were 72% and 63%, respectively. In patients with a best overall response of CR/CRi/CRp, 16/41 (39%) receiving ivosidenib had IDH1 mutation clearance and 15/64 (23%) receiving enasidenib had IDH2 mutation clearance by digital polymerase chain reaction; furthermore, 16/20 (80%) and 10/16 (63%), respectively, became negative for measurable residual disease by multiparameter flow cytometry. This trial was registered at www.clinicaltrials.gov as #NCT02632708., (© 2021 by The American Society of Hematology.)

Sulfate minerals are rare in the Archean rock record and largely restricted to the occurrence of barite (BaSO 4 ). The origin of this barite remains controversially debated. The mass-independent fractionation of sulfur isotopes in these and other Archean sedimentary rocks suggests that photolysis of volcanic aerosols in an oxygen-poor atmosphere played an important role in their formation. Here, we report on the multiple sulfur isotopic composition of sedimentary anhydrite in the ca. 3.22 Ga Moodies Group of the Barberton Greenstone Belt, southern Africa. Anhydrite occurs, together with barite and pyrite, in regionally traceable beds that formed in fluvial settings. Variable abundances of barite versus anhydrite reflect changes in sulfate enrichment by evaporitic concentration across orders of magnitude in an arid, nearshore terrestrial environment, periodically replenished by influxes of seawater. The multiple S-isotope compositions of anhydrite and pyrite are consistent with microbial sulfate reduction. S-isotope signatures in barite suggest an additional oxidative sulfate source probably derived from continental weathering of sulfide possibly enhanced by microbial sulfur oxidation. Although depositional environments of Moodies sulfate minerals differ strongly from marine barite deposits, their sulfur isotopic composition is similar and most likely reflects a primary isotopic signature. The data indicate that a constant input of small portions of oxidized sulfur from the continents into the ocean may have contributed to the observed long-term increase in Δ 33 S sulfate values through the Paleoarchean., (© 2020 John Wiley & Sons Ltd.)

The identification of cellular life in the rock record is problematic, since microbial life forms, and particularly bacteria, lack sufficient morphologic complexity to be effectively distinguished from certain abiogenic features in rocks. Examples include organic pore-fillings, hydrocarbon-containing fluid inclusions, organic coatings on exfoliated crystals and biomimetic mineral aggregates (biomorphs). This has led to the interpretation and re-interpretation of individual microstructures in the rock record. The morphologic description of entire populations of microstructures, however, may provide support for distinguishing between preserved micro-organisms and abiogenic objects. Here, we present a statistical approach based on quantitative morphological description of populations of microstructures. Images of modern microbial populations were compared to images of two relevant types of abiogenic microstructures: interstitial spaces and silica-carbonate biomorphs. For the populations of these three systems, the size, circularity, and solidity of individual particles were calculated. Subsequently, the mean/SD, skewness, and kurtosis of the statistical distributions of these parameters were established. This allowed the qualitative and quantitative comparison of distributions in these three systems. In addition, the fractal dimension and lacunarity of the populations were determined. In total, 11 parameters, independent of absolute size or shape, were used to characterize each population of microstructures. Using discriminant analysis with parameter subsets, it was found that size and shape distributions are typically sufficient to discriminate populations of biologic and abiogenic microstructures. Analysis of ancient, yet unambiguously biologic, samples (1.0 Ga Angmaat Formation, Baffin Island, Canada) suggests that taphonomic effects can alter morphometric characteristics and complicate image analysis; therefore, a wider range of microfossil assemblages should be studied in the future before automated analyses can be developed. In general, however, it is clear from our results that there is great potential for morphometric descriptions of populations in the context of life recognition in rocks, either on Earth or on extraterrestrial bodies., (© 2019 The Authors. Geobiology published by John Wiley & Sons Ltd.)

Purpose: To assess the effect of ethnicity, food, and itraconazole (strong CYP3A4 inhibitor) on the pharmacokinetics of ivosidenib after single oral doses in healthy subjects., Methods: Three phase 1 open-label studies were performed. Study 1: Japanese and Caucasian subjects received single doses of 250, 500, or 1000 mg ivosidenib (NCT03071770). Part 1 of study 2 (a two-period crossover study): subjects received 500 mg ivosidenib after either an overnight fast or a high-fat meal. Subjects received 1000 mg ivosidenib after an overnight fast in the single period of part 2 (NCT02579707). Study 3: in period 1, subjects received 250 mg ivosidenib; then, in period 2, subjects received oral itraconazole (200 mg once daily) on days 1-18, plus 250 mg ivosidenib on day 5 (NCT02831972)., Results: Ivosidenib was well tolerated in all three studies. Study 1: pharmacokinetic profiles were generally comparable, although AUC and C max were slightly lower in Japanese subjects than in Caucasian subjects, by ~ 30 and 17%, respectively. Study 2: AUC increased by ~ 25% and C max by ~ 98%, when ivosidenib was administered with a high-fat meal compared with a fasted state. Study 3: co-administration of itraconazole increased ivosidenib AUC by 169% (90% CI 145-195) but had no effect on ivosidenib C max ., Conclusions: No ivosidenib dose adjustment is deemed necessary for Japanese subjects. High-fat meals should be avoided when ivosidenib is taken with food. When co-administered with strong CYP3A4 inhibitors, monitoring for QT interval prolongation (a previously defined adverse event of interest) is recommended and an ivosidenib dose interruption or reduction may be considered. CLINICALTRIALS.GOV : NCT03071770, NCT02579707, and NCT02831972.

To date, only 13 genomes of green sulfur bacteria (family Chlorobiaceae) have been sequenced. The sequenced strains do not cover the full phylogenetic diversity of the family. We determined the complete genome sequence of Prosthecochloris sp. strain CIB 2401, thereby increasing the genome information for the poorly represented marine Chlorobiaceae., (Copyright © 2016 Nabhan et al.)

Several pectolytic bacterial strains, mainly isolated from monocotyledonous plants and previously identified as Pectobacterium carotovorum, were thought to belong to a novel species after several taxonomic analyses including DNA-DNA hybridization. In 16S rRNA gene sequence analyses, these strains had a similarity of >97.9 % to the 16S rRNA gene sequence of strains representing six other pectobacterial species and subspecies. These strains, represented by strain SCRI 109(T), also showed some unique chemotaxonomic features and quantitative differences in polar lipids, lipoquinones and fatty acids. A specific feature of strain SCRI 109(T) was the presence of DMK-8 lipoquinone, while the dominant fatty acids were the summed feature 3 (iso-C15 : 0 2-OH/C16 : 1ω7c), the unsaturated fatty acid C18 : 1ω7c and straight chain fatty acids, mainly C16 : 0. The DNA G+C content of strain SCRI 109(T) was 50.2 mol%. The taxonomic status of strain SCRI 109(T) and related strains in 16S rRNA gene sequence, chemotaxonomic, and physiological analyses was corroborated by the distinct clustering of these strains in multi-locus sequence analyses. It is proposed that these strains represent a novel species for which the name Pectobacterium aroidearum sp. nov. is proposed; the type strain is SCRI 109(T) ( = NCPPB 929(T) = LMG 2417(T) = ICMP 1522(T)).

Background: Allogeneic stem cell transplantation is the only curative option for patients with hereditary bone marrow failure syndromes. Umbilical cord blood is an alternative source of stem cells for allogeneic transplantation., Design and Methods: This multicenter, retrospective study is based on data reported to the Eurocord Registry about patients with hereditary bone marrow failure syndrome who underwent umbilical cord blood transplantation., Results: Sixty-four patients with hereditary bone marrow failure syndromes were transplanted from related (n = 20) or unrelated donors (n = 44). Diagnoses were Diamond-Blackfan anemia (21 patients), congenital amegakaryocytic thrombocytopenia (16 patients), dyskeratosis congenita (8 patients), Shwachman-Diamond syndrome (2 patients), severe congenital neutropenia (16 patients) and unclassified (1 patient). In the group of patients who received grafts from related donors, all patients but one received an HLA-matched sibling transplant. The median number of total nucleated cells infused was 5 × 10⁷/kg. The cumulative incidence of neutrophil recovery at 60 days was 95%. Two patients had grade II-IV acute graft-versus-host disease, while the 2-year cumulative incidence of chronic graft-versus-host disease was 11%. The 3-year overall survival rate was 95%. In the group of patients who received grafts from unrelated donors, 86% had HLA-mismatched grafts and three received two umbilical cord blood units. The median number of total nucleated cells infused was 6.1 × 10⁷/kg. The cumulative incidence of neutrophil recovery at day 60 in this group was 55%. The 100-day cumulative incidence of grade II-IV acute graft-versus-host disease was 24%, while the 2-year cumulative incidence of chronic graft-versus-host disease was 53%. The 3-year overall survival rate was 61%; better overall survival was associated with age less than 5 years (P = 0.01) and 6.1 × 10⁷/kg or more total nucleated cells infused (P = 0.05)., Conclusions: In patients with hereditary bone marrow failure syndromes, related umbilical cord blood transplantation is associated with excellent outcomes while increasing cell dose and better HLA matching might provide better results in unrelated umbilical cord blood transplantation.

Background: Umbilical-cord blood (UCB) is increasingly considered as an alternative to peripheral blood progenitor cells (PBPCs) or bone marrow, especially when an HLA-matched adult unrelated donor is not available. We aimed to determine the optimal role of UCB grafts in transplantation for adults with acute leukaemia, and to establish whether current graft-selection practices are appropriate., Methods: We used Cox regression to retrospectively compare leukaemia-free survival and other outcomes for UCB, PBPC, and bone marrow transplantation in patients aged 16 years or over who underwent a transplant for acute leukaemia. Data were available on 1525 patients transplanted between 2002 and 2006. 165 received UCB, 888 received PBPCs, and 472 received bone marrow. UCB units were matched at HLA-A and HLA-B at antigen level, and HLA-DRB1 at allele level (n=10), or mismatched at one (n=40) or two (n=115) antigens. PBPCs and bone-marrow grafts from unrelated adult donors were matched for allele-level HLA-A, HLA-B, HLA-C, and HLA-DRB1 (n=632 and n=332, respectively), or mismatched at one locus (n=256 and n=140, respectively)., Findings: Leukaemia-free survival in patients after UCB transplantation was comparable with that after 8/8 and 7/8 allele-matched PBPC or bone-marrow transplantation. However, transplant-related mortality was higher after UCB transplantation than after 8/8 allele-matched PBPC recipients (HR 1.62, 95% CI 1.18-2.23; p=0.003) or bone-marrow transplantation (HR 1.69, 95% CI 1.19-2.39; p=0.003). Grades 2-4 acute and chronic graft-versus-host disease (GvHD) were lower in UCB recipients compared with allele-matched PBPC (HR 0.57, 95% 0.42-0.77; p=0.002 and HR 0.38, 0.27-0.53; p=0.003, respectively), while the incidence of chronic, but not acute GvHD, was lower after UCB than after 8/8 allele-matched bone-marrow transplantation (HR 0.63, 0.44-0.90; p=0.01)., Interpretation: These data support the use of UCB for adults with acute leukaemia when there is no HLA-matched unrelated adult donor available, and when a transplant is needed urgently., (2010 Elsevier Ltd. All rights reserved.)

The optimal dosing strategy for perioperative beta-blockers to safely achieve recommended target heart rates (HRs) by current guidelines is not well defined. An HR-titrated perioperative beta-blocker dosing regimen versus a fixed-dose regimen was assessed by clinical outcomes, postoperative heart rate, and beta-blocker-related complications. Patients (n = 64) scheduled to undergo moderate- to high-risk vascular surgery and without contraindications to beta-blockade were randomized to either a fixed-dose or HR-titrated beta-blocker dosing schedule. Clinical outcomes and HRs were followed immediately preoperatively to 24 hr postoperatively. A difference in mean HR between the two dosing arms was significant immediately postoperatively (70.1 vs. 58.2 bpm for fixed dose and HR-titrated arms, respectively; p = 0.012) but at no other time points. However, the HR-titrated strategy led to a significant reduction in the percentage of HR measurements >80 bpm (34.5% vs. 16.1%, p < 0.001) and to a significant reduction in absolute HR change (17.5 vs. 22.5 bpm, p = 0.034). There were no significant differences in the occurrence of asymptomatic hypotension between the two study arms, and no beta-blocker-related adverse events occurred in either study arm. An aggressive, HR-titrated perioperative beta-blocker dosing strategy was associated with more consistent maintenance of postoperative HRs within the range recommended by current guidelines and did not result in increased drug-related adverse events. The question of what is the best perioperative beta-blocker dosing regimen warrants further evaluation in a large-scale clinical trial.

The purpose of this study is to assess the effect of an apparent alteration in intracellular pH and the effect of amiloride on the activity of the Na+/H+ antiporter in perfused rat kidney. Rat kidney-Na+ retention was determined using tracer 22Na in perfusate composed of HCl-glycine buffer (pH 3.80 to pH 5.92) or NH4OH-glycine buffer (pH 6.22-7.95) containing Na+ to match physiologic concentrations. Plotting renal Na+ retention for 10 min versus pH in absence of amiloride showed two classical uncompetitive activator curves for H+, one curve from pH 4.19 to 5.10 and another from pH 6.22 to 7.95. H+ acts as an uncompetitive reversible binding substrate with the receptor triggering activation of the exchanger already sequestered with Na+, thus yielding two Ka values for the exchanger suggesting non-first order kinetics. Using an equation derived for uncompetitive-activation binding of Nao+ and Hi+, plotting [mM Na+ mg protein-1 10 min-1]-1 versus [H+], two linear plots are observed on Cartesian coordinates with abscissa intersecting at 47 +/- 1 microM, pKa = 4.32 +/- 0.02 (pH 4.19-5.10) and 4.21 +/- 0.02 microM, pKa = 5.38 +/- 0.01 (pH 6.22-7.95), respectively. Perfusing buffer containing 2 mM amiloride, completely inactivated the antiporter showing stronger inhibition between pH 3.80 and 5.92. Results suggest the presence of two uncompetitive binding sites for H+ with the Na+/H+ exchanger. One is a high affinity binding site at physiological intracellular apparent pH, and another is a low affinity binding site at ischaemic apparent pH, implying the existence of two titration sites for intracellular pH regulation.