Despite over 20 million unrelated donors being listed worldwide, donor attrition at the confirmatory typing (CT) stage of donor acquisition is a key source of delay. Anthony Nolan undertook a study ...of CT requests from 2010 to 2011 to identify factors associated with attrition. Of 7541 CT requests, 38.2% were cancelled for donor reasons. Of these, 19.4% were personal, 34.1% medical, 36% no contact, 7.9% emigrated and 2.6% others. African (odds ratio (OR) 2.78, P<0.001), African-Caribbean (OR 3.07, P<0.001), Asian (OR 2.65, P<0.001), Jewish (OR 1.54, P=0.009) and Mediterranean (OR=2.38, P<0.001) donors were more likely not to be available compared to Caucasian donors. Female donors were also more likely not to be available (OR=1.32, P<0.001): primarily due to pregnancy. Older donors were less likely to be available in univariate analysis, but this association was not significant after controlling for other factors. Blood donors and those recruited within the past five years had lower rates of attrition. Accumulation of additional attrition-associated characteristics for a given donor was associated with progressively greater odds of attrition (OR 1.99, 2.52, 3.4 and 5.53, respectively, for 1, 2, 3 and 4 risk factors, P<0.001). Donor registries must develop evidence-driven strategies to recruit and retain the most reliable donors.
The composition of the gut microbiome has been associated with clinical responses to immune checkpoint inhibitor (ICI) treatment, but there is limited consensus on the specific microbiome ...characteristics linked to the clinical benefits of ICIs. We performed shotgun metagenomic sequencing of stool samples collected before ICI initiation from five observational cohorts recruiting ICI-naive patients with advanced cutaneous melanoma (n = 165). Integrating the dataset with 147 metagenomic samples from previously published studies, we found that the gut microbiome has a relevant, but cohort-dependent, association with the response to ICIs. A machine learning analysis confirmed the link between the microbiome and overall response rates (ORRs) and progression-free survival (PFS) with ICIs but also revealed limited reproducibility of microbiome-based signatures across cohorts. Accordingly, a panel of species, including Bifidobacterium pseudocatenulatum, Roseburia spp. and Akkermansia muciniphila, associated with responders was identified, but no single species could be regarded as a fully consistent biomarker across studies. Overall, the role of the human gut microbiome in ICI response appears more complex than previously thought, extending beyond differing microbial species simply present or absent in responders and nonresponders. Future studies should adopt larger sample sizes and take into account the complex interplay of clinical factors with the gut microbiome over the treatment course.
Cyclooxygenase-2 (COX-2), a source of inflammatory mediators and a multifunctional neuronal modulator, is rapidly induced in select populations of cortical neurons after status epilepticus. The ...consequences of rapid activity-triggered induction of COX-2 in neurons have been the subject of much study and speculation. To address this issue directly, we created a mouse in which COX-2 is conditionally ablated in selected forebrain neurons. Results following pilocarpine-induced status epilepticus indicate that neuronal COX-2 promotes early neuroprotection and then delayed neurodegeneration of CA1 pyramidal neurons, promotes neurodegeneration of nearby somatostatin interneurons in the CA1 stratum oriens and dentate hilus (which themselves do not express COX-2), intensifies a broad inflammatory reaction involving numerous cytokines and other inflammatory mediators in the hippocampus, and is essential for development of a leaky blood-brain barrier after seizures. These findings point to a profound role of seizure-induced neuronal COX-2 expression in neuropathologies that accompany epileptogenesis.
Ultrahigh resolution (UHR) HLA matching is reported to result in better outcomes following unrelated donor hematopoietic cell transplantation, improving survival and reducing post-transplant ...complications. However, most studies included relatively small numbers of patients. Here we report the findings from a large, multicenter validation study.
UHR HLA typing was available on 5,140 conventionally 10 out of 10 HLA-matched patients with malignant disease transplanted between 2008 and 2017.
After UHR HLA typing, 82% of pairs remained 10 out of 10 UHR-matched; 12.3% of patients were 12 out of 12 UHR HLA-matched. Compared with 12 out of 12 UHR-matched patients, probabilities of grade 2-4 acute graft-versus-host disease (aGVHD) were significantly increased with UHR mismatches (overall
= .0019) and in those patients who were HLA-DPB1 T-cell epitope permissively mismatched or nonpermissively mismatched (overall
= .0011). In the T-cell-depleted subset, the degree of UHR HLA mismatch was only associated with increased transplant-related mortality (TRM) (overall
= .0068). In the T-cell-replete subset, UHR HLA matching was associated with a lower probability of aGVHD (overall
= .0020); 12 out of 12 UHR matching was associated with reduced TRM risk when compared with HLA-DPB1 T-cell epitope permissively mismatched patients, whereas nonpermissive mismatching resulted in a greater risk (overall
= .0003).
This study did not confirm that UHR 12 out of 12 HLA matching increases the probability of overall survival but does demonstrate that aGVHD risk, and in certain settings TRM, is lowest in UHR HLA-matched pairs and thus warrants consideration when multiple 10 out of 10 HLA-matched donors of equivalent age are available.
Trend analyses were performed on several indicators of Arctic haze using data from sites located in the North American, Norwegian, Finnish and Russian Arctic for the spring months of March and April. ...Concentrations of nonseasalt (nss) SO
4
=
in the Canadian, Norwegian and Finnish Arctic were found to have decreased by 30-70% from the early 1990s to present. The magnitude of the decrease depended on location. The trend in nss SO
4
=
at Barrow, Alaska from 1997 to present, is unclear. Measurements at Barrow of light scattering by aerosols show a decrease of about 50% between the early 1980s and the mid-1990s for both March and April. Restricting the analysis to the more recent period of 1997 to present indicates an increase in scattering of about 50% during March. Aerosol NO
3
-
measured at Alert, Canada has increased by about 50% between the early 1990s and 2003. Nss K
+
and light absorption, indicators of forest fires, have a seasonal maximum during the winter and spring and minimum during the summer and fall at both Alert and Barrow. Based on these data, the impact of summertime forest fire emissions on low-altitude surface sites within the Arctic is relatively small compared to winter/spring emissions. Key uncertainties about the impact of long range transport of pollution to the Arctic remain including the certainty of the recent detected trends; sources, transport and trends of soot; and radiative effects due to complex interactions between aerosols, clouds and radiation in the Arctic.
Hematopoietic cell transplantation from HLA-haploidentical related donors is increasingly used to treat hematologic cancers; however, characteristics of the optimal haploidentical donor have not been ...established. We studied the role of donor HLA mismatching in graft-versus-host disease (GVHD), disease recurrence, and survival after haploidentical donor transplantation with posttransplantation cyclophosphamide (PTCy) for 1434 acute leukemia or myelodysplastic syndrome patients reported to the Center for International Blood and Marrow Transplant Research. The impact of mismatching in the graft-versus-host vector for HLA-A, -B, -C, -DRB1, and -DQB1 alleles, the HLA-B leader, and HLA-DPB1 T-cell epitope (TCE) were studied using multivariable regression methods. Outcome was associated with HLA (mis)matches at individual loci rather than the total number of HLA mismatches. HLA-DRB1 mismatches were associated with lower risk of disease recurrence. HLA-DRB1 mismatching with HLA-DQB1 matching correlated with improved disease-free survival. HLA-B leader matching and HLA-DPB1 TCE-nonpermissive mismatching were each associated with improved overall survival. HLA-C matching lowered chronic GVHD risk, and the level of HLA-C expression correlated with transplant-related mortality. Matching status at the HLA-B leader and HLA-DRB1, -DQB1, and -DPB1 predicted disease-free survival, as did patient and donor cytomegalovirus serostatus, patient age, and comorbidity index. A web-based tool was developed to facilitate selection of the best haploidentical-related donor by calculating disease-free survival based on these characteristics. In conclusion, HLA factors influence the success of haploidentical transplantation with PTCy. HLA-DRB1 and -DPB1 mismatching and HLA-C, -B leader, and -DQB1 matching are favorable. Consideration of HLA factors may help to optimize the selection of haploidentical related donors.
We report on radio and X-ray monitoring observations of the BHC Swift J1753.5−0127 taken over a ∼10 yr period. Presented are daily radio observations at 15 GHz with the Arcminute Microkelvin Imager ...Large Array (AMI-LA) and X-ray data from Swift X-ray Telescope and Burst Alert Telescope. Also presented is a deep 2 h JVLA observation taken in an unusually low-luminosity soft-state (with a low disc temperature). We show that although the source has remained relatively radio-quiet compared to XRBs with a similar X-ray luminosity in the hard-state, the power-law relationship scales as ζ = 0.96 ± 0.06, i.e. slightly closer to what has been considered for radiatively inefficient accretion discs. We also place the most stringent limit to date on the radio-jet quenching in an XRB soft-state, showing the connection of the jet quenching to the X-ray power-law component; the radio flux in the soft-state was found to be < 21 μJy, which is a quenching factor of ≳ 25.
Every year, from December to April, anthropogenic haze spreads over most of the North Indian Ocean, and South and Southeast Asia. The Indian Ocean Experiment (INDOEX) documented this Indo‐Asian haze ...at scales ranging from individual particles to its contribution to the regional climate forcing. This study integrates the multiplatform observations (satellites, aircraft, ships, surface stations, and balloons) with one‐ and four‐dimensional models to derive the regional aerosol forcing resulting from the direct, the semidirect and the two indirect effects. The haze particles consisted of several inorganic and carbonaceous species, including absorbing black carbon clusters, fly ash, and mineral dust. The most striking result was the large loading of aerosols over most of the South Asian region and the North Indian Ocean. The January to March 1999 visible optical depths were about 0.5 over most of the continent and reached values as large as 0.2 over the equatorial Indian ocean due to long‐range transport. The aerosol layer extended as high as 3 km. Black carbon contributed about 14% to the fine particle mass and 11% to the visible optical depth. The single‐scattering albedo estimated by several independent methods was consistently around 0.9 both inland and over the open ocean. Anthropogenic sources contributed as much as 80% (±10%) to the aerosol loading and the optical depth. The in situ data, which clearly support the existence of the first indirect effect (increased aerosol concentration producing more cloud drops with smaller effective radii), are used to develop a composite indirect effect scheme. The Indo‐Asian aerosols impact the radiative forcing through a complex set of heating (positive forcing) and cooling (negative forcing) processes. Clouds and black carbon emerge as the major players. The dominant factor, however, is the large negative forcing (‐20±4 W m−2) at the surface and the comparably large atmospheric heating. Regionally, the absorbing haze decreased the surface solar radiation by an amount comparable to 50% of the total ocean heat flux and nearly doubled the lower tropospheric solar heating. We demonstrate with a general circulation model how this additional heating significantly perturbs the tropical rainfall patterns and the hydrological cycle with implications to global climate.
PDF
