Pneumocystis jiroveci pneumonia (PJP) is associated with high morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Little is known about PJP infections after HSCT because of ...the rarity of disease given routine prophylaxis. We report the results of a Center for International Blood and Marrow Transplant Research study evaluating the incidence, timing, prophylaxis agents, risk factors and mortality of PJP after autologous (auto) and allogeneic (allo) HSCT. Between 1995 and 2005, 0.63% allo recipients and 0.28% auto recipients of first HSCT developed PJP. Cases occurred as early as 30 days to beyond a year after allo HSCT. A nested case cohort analysis with supplemental data (n=68 allo cases, n=111 allo controls) revealed that risk factors for PJP infection included lymphopenia and mismatch after HSCT. After allo or auto HSCT, overall survival was significantly poorer among cases vs controls (P=0.0004). After controlling for significant variables, the proportional hazards model revealed that PJP cases were 6.87 times more likely to die vs matched controls (P<0.0001). We conclude PJP infection is rare after HSCT but is associated with high mortality. Factors associated with GVHD and with poor immune reconstitution are among the risk factors for PJP and suggest that protracted prophylaxis for PJP in high-risk HSCT recipients may improve outcomes.
We studied adults with acute myeloid leukemia (AML) after haploidentical (n = 192) and 8/8 HLA-matched unrelated donor (n = 1982) transplantation. Haploidentical recipients received calcineurin ...inhibitor (CNI), mycophenolate, and posttransplant cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis; 104 patients received myeloablative and 88 received reduced intensity conditioning regimens. Matched unrelated donor transplant recipients received CNI with mycophenolate or methotrexate for GVHD prophylaxis; 1245 patients received myeloablative and 737 received reduced intensity conditioning regimens. In the myeloablative setting, day 30 neutrophil recovery was lower after haploidentical compared with matched unrelated donor transplants (90% vs 97%, P = .02). Corresponding rates after reduced intensity conditioning transplants were 93% and 96% (P = .25). In the myeloablative setting, 3-month acute grade 2-4 (16% vs 33%, P < .0001) and 3-year chronic GVHD (30% vs 53%, P < .0001) were lower after haploidentical compared with matched unrelated donor transplants. Similar differences were observed after reduced intensity conditioning transplants, 19% vs 28% (P = .05) and 34% vs 52% (P = .002). Among patients receiving myeloablative regimens, 3-year probabilities of overall survival were 45% (95% CI, 36-54) and 50% (95% CI, 47-53) after haploidentical and matched unrelated donor transplants (P = .38). Corresponding rates after reduced intensity conditioning transplants were 46% (95% CI, 35-56) and 44% (95% CI, 0.40-47) (P = .71). Although statistical power is limited, these data suggests that survival for patients with AML after haploidentical transplantation with posttransplant cyclophosphamide is comparable with matched unrelated donor transplantation.
•Lower GVHD after haploidentical transplant with posttransplant cyclophosphamide compared with HLA-matched unrelated donor transplant.•Comparable overall survival after haploidentical compared with matched unrelated donor transplant for AML.
In the event of alleged use of organophosphorus nerve agents, all kinds of environmental samples can be received for analysis. These might include decontaminated and charred matter collected from the ...site of a suspected chemical attack. In other scenarios, such matter might be sampled to confirm the site of a chemical weapon test or clandestine laboratory decontaminated and burned to prevent discovery. To provide an analytical capability for these contingencies, we present a preliminary investigation of the effect of accelerant-based fire and liquid decontamination on soil contaminated with the nerve agent
O
-ethyl
S
-2-diisopropylaminoethyl methylphosphonothiolate (VX). The objectives were (a) to determine if VX or its degradation products were detectable in soil after an accelerant-based fire promoted by aviation fuel, including following decontamination with Decontamination Solution 2 (DS2) or aqueous sodium hypochlorite, (b) to develop analytical methods to support forensic analysis of accelerant-soaked, decontaminated and charred soil and (c) to inform the design of future experiments of this type to improve analytical fidelity. Our results show for the first time that modern analytical techniques can be used to identify residual VX and its degradation products in contaminated soil after an accelerant-based fire and after chemical decontamination and then fire. Comparison of the gas chromatography–mass spectrometry (GC-MS) profiles of VX and its impurities/degradation products from contaminated burnt soil, and burnt soil spiked with VX, indicated that the fire resulted in the production of diethyl methylphosphonate and
O,S
-diethyl methylphosphonothiolate (by an unknown mechanism). Other products identified were indicative of chemical decontamination, and some of these provided evidence of the decontaminant used, for example, ethyl 2-methoxyethyl methylphosphonate and bis(2-methoxyethyl) methylphosphonate following decontamination with DS2. Sample preparation procedures and analytical methods suitable for investigating accelerant and decontaminant-soaked soil samples are presented. VX and its degradation products and/or impurities were detected under all the conditions studied, demonstrating that accelerant-based fire and liquid-based decontamination and then fire are unlikely to prevent the retrieval of evidence of chemical warfare agent (CWA) testing. This is the first published study of the effects of an accelerant-based fire on a CWA in environmental samples. The results will inform defence and security-based organisations worldwide and support the verification activities of the Organisation for the Prohibition of Chemical Weapons (OPCW), winner of the 2013 Nobel Peace Prize for its extensive efforts to eliminate chemical weapons.
Detailed chemical analysis of solutions used to decontaminate chemical warfare agents can be used to support verification and forensic attribution. Decontamination solutions are amongst the most ...difficult matrices for chemical analysis because of their corrosive and potentially emulsion-based nature. Consequently, there are relatively few publications that report their detailed chemical analysis. This paper describes the application of modern analytical techniques to the analysis of decontamination solutions following decontamination of the chemical warfare agent
O
-ethyl
S
-2-diisopropylaminoethyl methylphosphonothiolate (VX). We confirm the formation of
N
,
N
-diisopropylformamide and
N
,
N
-diisopropylamine following decontamination of VX with hypochlorite-based solution, whereas they were not detected in extracts of hydroxide-based decontamination solutions by nuclear magnetic resonance (NMR) spectroscopy or gas chromatography-mass spectrometry. We report the electron ionisation and chemical ionisation mass spectroscopic details, retention indices, and NMR spectra of
N
,
N
-diisopropylformamide and
N
,
N
-diisopropylamine, as well as analytical methods suitable for their analysis and identification in solvent extracts and decontamination residues.
•Microbiome alterations are associated with infection, GVHD, and other adverse transplant outcomes.•“Multiomic” technologies may better identify clinically actionable microbiome ...biomarkers.•Functional microbial characterization may improve diagnostic and therapeutic strategies.•Knowledge gaps persist in chronic GVHD and extraintestinal microbiome-host interactions.•Multi-institutional studies and data collection expansion will maximize microbiome research impact.
Infections with parasitic helminths such as Nippostronglyus brasiliensis induce dominant type 2 responses from antigen‐specific T helper cells. The potency of the Th2 bias can also drive Th2 ...responses to bystander antigens introduced at the same time as infection. We now report that the Th2‐promoting effect of infection can be reproduced with soluble N. brasiliensis excretory‐secretory proteins (NES) released by adult parasites in vitro. Immunization of BALB / c mice with NES results in the production of IL‐4 with elevated total serum IgE and specific IgG1 antibodies. NES is also able to stimulate IL‐4 and polyclonal IgE production in other mouse strains (C57BL / 6, B10.D2, CBA). These features are seen whether NES is administered without adjuvant as soluble protein in phosphate‐buffered saline or with complete Freund's adjuvant which normally favors Th1 responses. Thus, NES possesses intrinsic adjuvanticity. Moreover, co‐administration of hen egg lysozyme (HEL) with NES in the absence of other adjuvants results in generation of HEL‐specific lymphocyte proliferation, IL‐4 release and IgG1 antibody responses, documenting that NES can act as an adjuvant for third‐party antigens. Proteinase K digestion or heat treatment of NES before immunization abolished the IL‐4‐stimulating activity, indicating that the factors acting to promote Th2 induction are proteins secreted by the adult parasite.
Martian lava flows likely acquired S-rich material from the regolith during their emplacement on the planet’s surface. We investigated five of the twenty known nakhlites (Nakhla, Lafayette, Miller ...Range (MIL) 090032, Yamato 000593, and Yamato 000749) to determine whether these lavas show evidence of regolith assimilation, and to constrain the potential implications that this process has on chemical tracing of martian mantle source(s). To establish the proportionate influence of atmospheric, hydrothermal, and volcanic processes on nakhlite isotopic systematics we obtained in situ sulphur isotope data (Δ33S and δ34S) for sulphide grains (pyrrhotite and pyrite) in all five nakhlite samples. For Nakhla, Lafayette, and MIL 090032, these data are integrated with highly siderophile element (HSE) abundances and Os-isotope compositions, as well as textural information constrained prior to isotopic analysis. This work thereby provides the first Re-Os isotope systematics for two different nakhlites, and also the first Re-Os isotope data for martian sample for which detailed petrographic information was constrained prior to digestion.
We report the largest variation in δ34S yet found in martian meteorites (−13.20‰ to +15.16‰). The relatively positive Δ33S and δ34S values of MIL 090032 (δ34S = +10.54 ± 0.09‰; Δ33S = −0.67 ± 0.10‰) indicate this meteorite assimilated sulphur affected by UV-photochemistry. In contrast, the strongly negative values of Lafayette (δ34S = −10.76 ± 0.14‰; Δ33S = −0.09 ± 0.12‰) are indicative of hydrothermal processes on Mars. Nakhla, Yamato 000593, and Yamato 000749 sulphides have a narrower range of sulphur isotope compositions (Δ33S and δ34S ∼ 0) that is consistent with no assimilation of martian surface materials during lava flow emplacement. Consequently we used this second group of Δ33S values to approximate the Δ33S of the nakhlite source, yielding a Δ33S value of −0.1‰.
Nakhlite HSE patterns result from a sulphide-saturated melt where Ru-Os-Ir alloys/sulphide were likely crystallized during earlier phases of magmatic processing in Mars to result in the fractionated HSE patterns of the nakhlites. Our data, alongside a synthesis of previously published data, suggest assimilation of an enriched component to the primary nakhlite melt, potentially a late-stage crystallization cumulate from the martian magma ocean stage. In the context of this model, and within large uncertainties, our data hint at perturbation and potential decoupling of nakhlite Re-Os isotope systematics from other isotopic systems as a result of small degrees of assimilation of a regolith component with highly radiogenic 187Os/188Os.
Understanding the cause of differences among general circulation model projections of carbon dioxide-induced climatic change is a necessary step toward improving the models. An intercomparison of 14 ...atmospheric general circulation models, for which sea surface temperature perturbations were used as a surrogate climate change, showed that there was a roughly threefold variation in global climate sensitivity. Most of this variation is attributable to differences in the models' depictions of cloud-climate feedback, a result that emphasizes the need for improvements in the treatment of clouds in these models if they are ultimately to be used as climatic predictors.
The in vivo depletion of recipient and donor T lymphocytes using antithymocyte globulin (ATG; Thymoglobulin) is widely adopted in allogeneic hematopoietic stem cell transplantation (HCT) to reduce ...the incidence of both graft failure and graft-versus-host disease (GVHD). However, excess toxicity to donor lymphocytes may hamper immune reconstitution, compromising antitumor effects and increasing infection. Granulocyte-colony stimulating factor (G-CSF) administered early after HCT may increase ATG-mediated lymphotoxicity. This study aimed to investigate the effect of an interaction between ATG and post-transplantation granulocyte colony-stimulating factor (G-CSF) on allogeneic HCT outcomes, using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry. We studied patients age ≥18 years with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) who received Thymoglobulin-containing preparative regimens for HLA-matched sibling/unrelated or mismatched unrelated donor HCT between 2010 and 2018. The effect of planned G-CSF that was started between pretransplantation day 3 and post-transplantation day 12 was studied in comparison with transplantations that did not include G-CSF. Cox regression models were built to identify risk factors associated with outcomes at 1 year after transplantation. A total of 874 patients met the study eligibility criteria, of whom 459 (53%) received planned G-CSF. HCT with planned G-CSF was associated with a significantly increased risk for nonrelapse mortality (NRM) (hazard ratio HR 2.03; P <.0001; 21% versus 12%) compared to HCT without G-CSF. The 6-month incidence of viral infection was higher with G-CSF (56% versus 47%; P = .007), with a particular increase in Epstein-Barr virus infections (19% versus 11%; P = .002). The observed higher NRM with planned G-CSF led to lower overall survival (HR, 1.52; P = .0005; 61% versus 72%). There was no difference in GVHD risk between the treatment groups. We performed 2 subgroup analyses showing that our findings held true in patients age ≥50 years and in centers where G-CSF was used in some, but not all, patients. In allogeneic peripheral blood HCT performed with Thymoglobulin for AML and MDS, G-CSF administered early post-transplantation resulted in a 2-fold increase in NRM and a 10% absolute decrement in survival. The use of planned G-CSF in the early post-transplantation period should be carefully considered on an individual patient basis, weighing any perceived benefits against these risks.
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