Detrital carbonate contamination is one of the principal problems with the integrity of stable isotope data from authigenic lake carbonates. Here we investigate the origin and climatic implications ...of stable isotope data from carbonate minerals deposited in two Mediterranean lakes: Gölhisar Gölü (SW Turkey) and Lake Pamvotis (NW Greece). In Gölhisar Gölü the bulk carbonate oxygen and carbon isotope composition has previously been interpreted in terms of significant climate variation related to the lake's hydrological balance. However, the origin of the carbonates was not investigated even though phases of high magnetic susceptibility suggest that there were several periods of increased soil erosion from the karstic catchment which could bring detrital limestone in to the lake. SEM evidence suggests that the carbonates in Gölhisar Gölü sediments of Holocene age are predominantly derived from forms of authigenic calcite (i.e. platelets, prismatic crystals), although periods of inwash clearly occurred which may have influenced parts of the isotope stratigraphy during the last two millennia. For comparison we also looked at data of Late Pleistocene to Holocene age from Lake Pamvotis. Here, there is an excellent correlation between the bulk carbonate oxygen isotope and magnetic susceptibility data, but no significant correlation between the bulk carbonate isotope data and ostracod isotope data from the same levels. SEM analyses confirmed the presence of detrital carbonates and the lack of significant authigenic carbonate. While the Gölhisar record records aspects of climate in most of its isotope data, in the Pamvotis record only the ostracod data are likely to contain meaningful information.
Lake Sonachi, Kenya, is a small alkaline-saline crater lake that over the past 175 years has experienced considerable fluctuations in lake depth (Zmax= 3-18 m) and an alternation of meromictic and ...holomictic episodes lasting from a few years to several decades. Paleolimnological methods were used to reconstruct the long-term dynamics of algal and invertebrate communities in Lake Sonachi in relation to the historical evolution of their physical and chemical environment. Multivariate statistical analysis revealed only weak correlation between the stratigraphic distributions of fossil algal pigments, diatoms, and chironomid larvae in210Pb-dated sediment cores and the documented or reconstructed variation in lake depth, mixing regime, and surface-water conductivity. The eventful biological history of Lake Sonachi exemplifies the complexity of long-term community dynamics in tropical African soda lakes and reveals how phytoplankton community structure can exert direct control on benthic and planktonic invertebrate communities. The modest phytoplankton abundance and photosynthetic activity of Lake Sonachi when compared with other tropical African soda lakes represent recent lake conditions, resulting from a dramatic decline of filamentous cyanobacteria (e.g., Spirulina platensis) between the 1930s and 1970s and incomplete replacement by the small coccoid cyanobacteria (e.g., Synechococcus bacillaris), which are dominant today. This reduction in algal biomass favored benthic and planktonic invertebrates by reducing the prevalence of complete water-column anoxia associated with intense nighttime respiration of cyanobacterial blooms. Anoxia-intolerant halobiont chironomids expanded during an episode of low lake level (Z$_{max} < $4 m), holomixis, and high conductivity ($>$9,000 μS cm-1) in the late 1940s and 1950s, whereas they had failed to do so under similar conditions in the late 19th century when algal abundance was high. Planktonic cladocerans developed high population densities only during two short meromictic phases in the 1970s when conductivity was modest (3,000-6,000 μS cm-1) and algal abundance was low. The decline of filamentous cyanobacteria also increased water-column transparency but apparently did not increase benthic diatom abundance.
G-CSF mobilized peripheral blood has emerged as the dominant source of stem cells for allogeneic stem cell transplantation. G-CSF modulates T cell function and Suppressor of Cytokine Signaling-3 ...(SOCS3) is the major regulator of signaling by this cytokine, although the downstream effects in vivo remain unclear. We have therefore examined the effect of SOCS3 in the well established B6 → B6D2F1 murine model of acute GVHD directed to major histocompatibility antigens. Using SOCS3−/Δvav mice in which SOCS3 deficiency is restricted to the haematopoietic compartment we transplanted splenocytes from G-CSF mobilized wild-type (WT) or SOCS3−/Δvav donors and demonstrated that the absence of SOCS3 within the graft accelerated GVHD (median survival 23 vs. 39 days, P=0.04). By using SOCS3−/ΔLysM and SOCS3−/Δlck donors in which SOCS3 deficiency was restricted to the myeloid or T cell lineage respectively we confirmed SOCS3 deficiency enhanced GVHD via effects only within the donor T cell (median survival 19 vs. 35 and 39 days in SOCS3−/Δlck vs. WT and SOCS3−/ΔLysM, P<0.0001). This protective effect of SOCS3 was also seen in the absence of G-CSF mobilization since bone marrow and purified donor T cells from SOCS3−/Δvav donor mice significantly accelerated GVHD mortality (median survival 29 vs. 44 days, P=0.04). In mixing experiments this acceleration of GVHD was again seen only when the donor T cell was SOCS-3 deficient.
SOCS3−/Δlck donor T cells underwent enhanced alloantigen dependent proliferation after transplantation as determined by CFSE dilution and demonstrated increased IL-10, IL-17 and IFNγ generation but reduced IL-4 secretion. In contrast no effects were seen in IL-6 and TNF secretion, or CD8 cytotoxicity against host-type targets. Consistent with the increased mortality, SOCS3−/Δlck donor T cells induced significantly more severe gastrointestinal GVHD as determined by semi-quantitative histopathology (GI tract scores 18 ± 1.7 vs. 10.2 ± 1.1, P=0.008). Blockade of the IL-10 receptor or IL-17 neutralization from the day of transplant or after the initiation of GVHD failed to attenuate the enhanced GVHD mortality induced by SOCS3−/Δlck donor T cells. The suppression of acute GVHD by SOCS3 is thus consistent with its ability to suppress IFNγ generation by the donor T cell, a cytokine which we have shown to be a key and direct mediator of GVHD within the GI tract (Burman A et al, Blood 2007: 110:1064).
These studies highlight the previously unrecognized role of the SOCS3 molecule in regulating alloreactive T cell responses and suggest that the delivery of small molecule SOCS3 agonists may prove to be useful for the inhibition of Th1 dependent acute GVHD.
Carbapenem-resistant
(CRE) represent a health threat, but effective control interventions remain unclear. Hospital wastewater sites are increasingly being highlighted as important potential ...reservoirs. We investigated a large
carbapenemase (KPC)-producing
outbreak and wider CRE incidence trends in the Central Manchester University Hospital NHS Foundation Trust (CMFT) (United Kingdom) over 8 years, to determine the impact of infection prevention and control measures. Bacteriology and patient administration data (2009 to 2017) were linked, and a subset of CMFT or regional hospital KPC-producing
isolates (
= 268) were sequenced. Control interventions followed international guidelines and included cohorting, rectal screening (
= 184,539 screens), environmental sampling, enhanced cleaning, and ward closure and plumbing replacement. Segmented regression of time trends for CRE detections was used to evaluate the impact of interventions on CRE incidence. Genomic analysis (
= 268 isolates) identified the spread of a KPC-producing
outbreak clone (strain A, sequence type 216 ST216;
= 125) among patients and in the environment, particularly on 2 cardiac wards (wards 3 and 4), despite control measures. ST216 strain A had caused an antecedent outbreak and shared its KPC plasmids with other
lineages and
species. CRE acquisition incidence declined after closure of wards 3 and 4 and plumbing replacement, suggesting an environmental contribution. However, ward 3/ward 4 wastewater sites were rapidly recolonized with CRE and patient CRE acquisitions recurred, albeit at lower rates. Patient relocation and plumbing replacement were associated with control of a clonal KPC-producing
outbreak; however, environmental contamination with CRE and patient CRE acquisitions recurred rapidly following this intervention. The large numbers of cases and the persistence of
in
, including pathogenic lineages, are of concern.
In response to a national call for re-evaluation of the use of race in clinical algorithms, the National Kidney Foundation (NKF) and the American Society of Nephrology (ASN) established a Task Force ...to reassess inclusion of race in the estimation of glomerular filtration rate (GFR) in the United States and its implications for diagnosis and management of patients with, or at risk for, kidney diseases.
The Task Force organized its activities over 10 months in phases to (1) clarify the problem and evidence regarding GFR estimating equations in the United States (described previously in an interim report), and, in this final report, (2) evaluate approaches to address use of race in GFR estimation, and (3) provide recommendations. We identified 26 approaches for the estimation of GFR that did or did not consider race and narrowed our focus, by consensus, to 5 of those approaches. We holistically evaluated each approach considering 6 attributes: assay availability and standardization; implementation; population diversity in equation development; performance compared with measured GFR; consequences to clinical care, population tracking, and research; and patient centeredness. To arrive at a unifying approach to estimate GFR, we integrated information and evidence from many sources in assessing strengths and weaknesses in attributes for each approach, recognizing the number of Black and non-Black adults affected.
(1) For US adults (>85% of whom have normal kidney function), we recommend immediate implementation of the CKD-EPI creatinine equation refit without the race variable in all laboratories in the United States because it does not include race in the calculation and reporting, included diversity in its development, is immediately available to all laboratories in the United States, and has acceptable performance characteristics and potential consequences that do not disproportionately affect any one group of individuals. (2) We recommend national efforts to facilitate increased, routine, and timely use of cystatin C, especially to confirm estimated GFR in adults who are at risk for or have chronic kidney disease, because combining filtration markers (creatinine and cystatin C) is more accurate and would support better clinical decisions than either marker alone. If ongoing evidence supports acceptable performance, the CKD-EPI eGFR–cystatin C (eGFRcys) and eGFR creatinine–cystatin C (eGFRcr-cys_R) refit without the race variables should be adopted to provide another first-line test, in addition to confirmatory testing. (3) Research on GFR estimation with new endogenous filtration markers and on interventions to eliminate race and ethnic disparities should be encouraged and funded. An investment in science is needed for newer approaches that generate accurate, unbiased, and precise GFR measurement and estimation without the inclusion of race, and that promote health equity and do not generate disparate care.
This unified approach, without specification of race, should be adopted across the United States. High-priority and multistakeholder efforts should implement this solution.
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There is a limited access to liver transplantation, however, many organs are discarded based on subjective assessment only. Here we report the VITTAL clinical trial (ClinicalTrials.gov number ...NCT02740608) outcomes, using normothermic machine perfusion (NMP) to objectively assess livers discarded by all UK centres meeting specific high-risk criteria. Thirty-one livers were enroled and assessed by viability criteria based on the lactate clearance to levels ≤2.5 mmol/L within 4 h. The viability was achieved by 22 (71%) organs, that were transplanted after a median preservation time of 18 h, with 100% 90-day survival. During the median follow up of 542 days, 4 (18%) patients developed biliary strictures requiring re-transplantation. This trial demonstrates that viability testing with NMP is feasible and in this study enabled successful transplantation of 71% of discarded livers, with 100% 90-day patient and graft survival; it does not seem to prevent non-anastomotic biliary strictures in livers donated after circulatory death with prolonged warm ischaemia.
IMPORTANCE: There are potential benefits and harms of hyperoxemia and hypoxemia for extremely preterm infants receiving more vs less supplemental oxygen. OBJECTIVE: To compare the effects of ...different target ranges for oxygen saturation as measured by pulse oximetry (Spo2) on death or major morbidity. DESIGN, SETTING, AND PARTICIPANTS: Prospectively planned meta-analysis of individual participant data from 5 randomized clinical trials (conducted from 2005-2014) enrolling infants born before 28 weeks’ gestation. EXPOSURES: Spo2 target range that was lower (85%-89%) vs higher (91%-95%). MAIN OUTCOMES AND MEASURES: The primary outcome was a composite of death or major disability (bilateral blindness, deafness, cerebral palsy diagnosed as ≥2 level on the Gross Motor Function Classification System, or Bayley-III cognitive or language score <85) at a corrected age of 18 to 24 months. There were 16 secondary outcomes including the components of the primary outcome and other major morbidities. RESULTS: A total of 4965 infants were randomized (2480 to the lower Spo2 target range and 2485 to the higher Spo2 range) and had a median gestational age of 26 weeks (interquartile range, 25-27 weeks) and a mean birth weight of 832 g (SD, 190 g). The primary outcome occurred in 1191 of 2228 infants (53.5%) in the lower Spo2 target group and 1150 of 2229 infants (51.6%) in the higher Spo2 target group (risk difference, 1.7% 95% CI, −1.3% to 4.6%; relative risk RR, 1.04 95% CI, 0.98 to 1.09, P = .21). Of the 16 secondary outcomes, 11 were null, 2 significantly favored the lower Spo2 target group, and 3 significantly favored the higher Spo2 target group. Death occurred in 484 of 2433 infants (19.9%) in the lower Spo2 target group and 418 of 2440 infants (17.1%) in the higher Spo2 target group (risk difference, 2.8% 95% CI, 0.6% to 5.0%; RR, 1.17 95% CI, 1.04 to 1.31, P = .01). Treatment for retinopathy of prematurity was administered to 220 of 2020 infants (10.9%) in the lower Spo2 target group and 308 of 2065 infants (14.9%) in the higher Spo2 target group (risk difference, −4.0% 95% CI, −6.1% to −2.0%; RR, 0.74 95% CI, 0.63 to 0.86, P < .001). Severe necrotizing enterocolitis occurred in 227 of 2464 infants (9.2%) in the lower Spo2 target group and 170 of 2465 infants (6.9%) in the higher Spo2 target group (risk difference, 2.3% 95% CI, 0.8% to 3.8%; RR, 1.33 95% CI, 1.10 to 1.61, P = .003). CONCLUSIONS AND RELEVANCE: In this prospectively planned meta-analysis of individual participant data from extremely preterm infants, there was no significant difference between a lower Spo2 target range compared with a higher Spo2 target range on the primary composite outcome of death or major disability at a corrected age of 18 to 24 months. The lower Spo2 target range was associated with a higher risk of death and necrotizing enterocolitis, but a lower risk of retinopathy of prematurity treatment.
Socioeconomic position (SEP) is a multi-dimensional construct reflecting (and influencing) multiple socio-cultural, physical, and environmental factors. In a sample of 286,301 participants from UK ...Biobank, we identify 30 (29 previously unreported) independent-loci associated with income. Using a method to meta-analyze data from genetically-correlated traits, we identify an additional 120 income-associated loci. These loci show clear evidence of functionality, with transcriptional differences identified across multiple cortical tissues, and links to GABAergic and serotonergic neurotransmission. By combining our genome wide association study on income with data from eQTL studies and chromatin interactions, 24 genes are prioritized for follow up, 18 of which were previously associated with intelligence. We identify intelligence as one of the likely causal, partly-heritable phenotypes that might bridge the gap between molecular genetic inheritance and phenotypic consequence in terms of income differences. These results indicate that, in modern era Great Britain, genetic effects contribute towards some of the observed socioeconomic inequalities.
Serial measurements of symptoms, peak flow rates, methacholine bronchial responsiveness, and ragweed-specific IgE antibodies were made before and during the ragweed pollen season in 13 sensitized ...subjects. Allergen inhalation tests were carried out with aerosols of pollen extract out of season in nine subjects; isolated early asthmatic responses were provoked in four, and dual responses (early followed by late) were provoked in five. During the pollen season all subjects developed hay fever and eight had symptoms of asthma. There was a real increase in methacholine responsiveness during the ragweed season. This increase appeared before or after the occurrence of asthma symptoms and changes in flow rates and was greater in subjects with symptoms in the pollen season, dual responses after allergen inhalation tests, and higher levels of ragweed-specific IgE antibodies. The results confirm the occurrence of seasonal asthma and increases in nonallergic (nonspecific) bronchial responsiveness to methacholine from seasonal pollen exposure. They suggest that the occurrence of symptoms is closely linked to the allergic inflammatory reaction and the induction of increased nonallergic responsiveness.
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