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•Mismatch between field and laboratory studies in plastic types and end-points assessed.•Fibres are most prevalent in field studies while particles dominate laboratory studies.•There ...is a requirement to shift towards a harmonised approach to effects testing.•Sampling standards and parameter selection are suggested for field and laboratory studies.•Principal toxicity endpoints recommended for main trophic levels to aid data integration.
Current understanding of nano- and microplastic movement, propagation and potential effects on biota in freshwater environments is developing rapidly. Still, there are significant disconnects in the integration of knowledge derived from laboratory and field studies. This review synthesises the current understanding of nano- and microplastic impacts on freshwater biota from field studies and combines it with the more mechanistic insights derived from laboratory studies. Several discrepancies between the field and laboratory studies, impacting progress in process understanding, were identified including that the most prevalent plastic morphologies found in the field (fibres) are not those used in most of the laboratory studies (particles). Solutions to overcome these disparities are proposed to aid comparability of future studies. For example, environmental sampling and separation of biota into its constituents is encouraged when conducting field studies to map microplastic uptake preferences. In laboratory studies, recommendations include performing toxicity studies to systematically test possible factors affecting toxicity of nano- and microplastics, including morphology, chemical makeup (e.g., additives) and effects of plastic size. Consideration should be given to environmentally relevant exposure factors in laboratory studies, such as realistic exposure medium and effects of plastic ageing. Furthermore, based on this comprehensive review recommendations of principal toxicity endpoints for each of the main trophic levels (microbes, primary producers, primary consumers and secondary consumers) that should be reported to make toxicity studies more comparable in the future are given.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Combined-modality treatment (CMT) with 2× ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) and small-field radiotherapy is standard of care for patients with early-stage favorable Hodgkin ...lymphoma (HL). However, the role of radiotherapy has been challenged. Positron emission tomography (PET) after 2× ABVD (PET-2) might help to predict individual outcomes and guide treatment.
Between November 2009 and December 2015, we recruited patients age 18 to 75 years with newly diagnosed, early-stage favorable HL for this international randomized phase III trial. Patients were assigned to standard CMT of 2× ABVD and 20-Gy involved-field radiotherapy or PET-guided treatment, omitting involved-field radiotherapy after negative PET-2 (Deauville score < 3). Primary objectives were to exclude inferiority of 10% or more in 5-year progression-free survival (PFS) of ABVD alone compared with CMT in a per-protocol analysis among PET-2-negative patients (noninferiority margin for hazard ratio, 3.01) and to confirm PET-2 positivity (Deauville score ≥ 3) as a risk factor for PFS among CMT-treated patients.
We enrolled 1,150 patients. Median follow-up was 45 months. Among 628 PET-2-negative, per-protocol-treated patients, 5-year PFS was 93.4% (95% CI, 90.4% to 96.5%) with CMT and 86.1% (95% CI, 81.4% to 90.9%) with ABVD (difference 7.3% 95% CI, 1.6% to 13.0%; hazard ratio, 1.78 95% CI, 1.02 to 3.12). Five-year overall survival was 98.1% (95% CI, 96.5% to 99.8%) with CMT and 98.4% (95% CI, 96.5% to 100.0%) with ABVD. Among 693 patients who were assigned to CMT, 5-year PFS was 93.2% (95% CI, 90.2% to 96.2%) among PET-2-negative patients and 88.4% (95% CI, 84.2% to 92.6%) in PET-2-positive patients (
= .047). When using the more common liver cutoff (Deauville score, 4) for PET-2 positivity, the difference was more pronounced (5-year PFS, 93.1% 95% CI, 90.7% to 95.5%
80.9% 95% CI, 72.2% to 89.7%;
= .0011).
In early-stage favorable HL, a positive PET after two cycles ABVD indicates a high risk for treatment failure, particularly when a Deauville score of 4 is used as a cutoff for positivity. In PET-2-negative patients, radiotherapy cannot be omitted from CMT without clinically relevant loss of tumor control.
Given the persistence of microplastics in the environment and their potential toxicity to ecosystems, understanding of likely microplastic accumulation ‘hotspots’ in rivers is urgently needed. To ...contribute to this challenge, this paper reports results of a microplastic survey from a heavily urbanised catchment, the River Tame and four of its tributaries, which flows through the city of Birmingham, UK. All sediment sampled was found to contain microplastics with an average abundance of 165 particles kg−1. While urban areas generally have a greater abundance of microplastics as compared with rural, there is no simple relationship between microplastic numbers and population density or proximity to wastewater treatment sites. The greatest change in microplastic abundance was due to the presence of a lake along the course of the River Tame—i.e., flow velocities are reduced on entering the lake, which promotes the deposition of fine sediment and potentially microplastics. This suggests that the greatest concentrations of microplastics will not be found in-channel but rather on the floodplain and other low velocity environments such as meander cutoffs. We also identified a new mechanism of microplastic fixation in freshwater environments through ecological engineers, specifically caddisflies, that incorporated microplastics into their casing. These results highlight the need to explore further hydrodynamic and ecological impacts on microplastics fate and transport in rivers.
Deep molecular response (MR(4.5)) defines a subgroup of patients with chronic myeloid leukemia (CML) who may stay in unmaintained remission after treatment discontinuation. It is unclear how many ...patients achieve MR(4.5) under different treatment modalities and whether MR(4.5) predicts survival.
Patients from the randomized CML-Study IV were analyzed for confirmed MR(4.5) which was defined as ≥ 4.5 log reduction of BCR-ABL on the international scale (IS) and determined by reverse transcriptase polymerase chain reaction in two consecutive analyses. Landmark analyses were performed to assess the impact of MR(4.5) on survival.
Of 1,551 randomly assigned patients, 1,524 were assessable. After a median observation time of 67.5 months, 5-year overall survival (OS) was 90%, 5-year progression-free-survival was 87.5%, and 8-year OS was 86%. The cumulative incidence of MR(4.5) after 9 years was 70% (median, 4.9 years); confirmed MR(4.5) was 54%. MR(4.5) was reached more quickly with optimized high-dose imatinib than with imatinib 400 mg/day (P = .016). Independent of treatment approach, confirmed MR(4.5) at 4 years predicted significantly higher survival probabilities than 0.1% to 1% IS, which corresponds to complete cytogenetic remission (8-year OS, 92% v 83%; P = .047). High-dose imatinib and early major molecular remission predicted MR(4.5). No patient with confirmed MR(4.5) has experienced progression.
MR(4.5) is a new molecular predictor of long-term outcome, is reached by a majority of patients treated with imatinib, and is achieved more quickly with optimized high-dose imatinib, which may provide an improved therapeutic basis for treatment discontinuation in CML.
Reliable automated blood cell characterization and quantification remain challenging in pathologic samples, whereas slide reviews due to unnecessary flagging should be avoided. We compared 4 modern ...hematology analyzers-Abbott Sapphire, Siemens Advia 120, Sysmex XE-2100, and Beckman Coulter DxH 800-regarding complete blood cell count (CBC), leukocyte differential count, and flagging efficacy in a total of 202 samples from hematology patients and normal controls. Manual differential count was used as reference. The analyzers exhibited very good correlation for CBC parameters. Neutrophils and eosinophils also showed very good correlations, whereas lymphocytes and monocytes correlated fairly. The Advia 120 displayed notably lower measurements for both parameters, which is attributable to classification of some events as large unstained cells. Basophil counts were unreliable with all analyzers. Flagging for blasts and immature granulocytes showed moderate sensitivity and specificity. Operators must not rely on blast flagging alone to detect leukemic samples with any analyzer.
Summary
The blood count is one of the most common tests used for health assessment. In elderly individuals, selection of a ‘healthy’ reference population for laboratory assessment is difficult due to ...the high prevalence of chronic morbidities, leading to uncertainty regarding appropriate reference intervals. In particular, age‐specific lower haemoglobin reference limits to define anaemia are controversial. Here, we applied a data mining approach to a large dataset of 3 029 904 clinical routine samples to establish blood count reference intervals. We excluded samples from units/specialists with a high proportion of abnormal blood counts, samples from patients with an unknown or decreased estimated glomerular filtration rate, and samples with abnormal test results in selected other analytes. After sample exclusion, 566 775–572 060 samples from different individuals aged 20–100 years were available for analysis. We then used an established statistical algorithm to determine the distribution of physiological test results and calculated age‐ and sex‐specific reference intervals. Our results show substantial trends with age in haematology analytes' reference intervals. Most notably, haemoglobin and red cell counts decline in men with advanced age, accompanied by increases in red cell volume in both sexes. These findings were confirmed in an independent dataset, and suggest an at least partly physiologic cause.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Introduction
Standard protocols in flow cytometry (FCM) require lysis of erythrocytes, which may induce an unwanted loss of leukocytes as bystander effect.
Methods
In the present study, we ...investigated the influence of 6 laboratory protocols using 4 different lysing reagents, FACS® Lysing Solution (FacsL), QUICKLYSIS® (QuickL), IOTest® 3 Lysing Solution (NH4Cl), VersaLyse® (VersaL), and VersaLyse® with added fixative (VersaFix) on the relative quantity of leukocyte subsets identified by CD3, CD4, CD8, CD19, CD14, CD16, CD56, and CD45, applying a no‐lyse‐no‐wash (NoL) protocol as reference. In addition, we compared the efficiency of red blood cell (RBC) lysis.
Results
Peripheral blood samples from 52 individuals were analyzed. NoL was suitable as reference method, but led to less clear‐cut gating of lymphocyte and monocyte populations due to a wider distribution of light scatter. Best completeness of RBC lysis with remaining erythrocytes below 10% was achieved using NH4Cl and VersaL. We observed a loss of 11% of monocytes after QuickL. Lymphocyte counts were 19% lower after FacsL. Cell subsets within the lymphocyte compartment were rather similar between the different methods with the exception of lower B‐cell counts (−8%) and higher NK‐cell counts (+11%) after FacsL. NH4Cl and VersaL were in good accordance with the NoL method and also with the mean values of all methods.
Conclusion
Our data show that the lysing reagents tested lead to specific deviations in the quantitation of leukocyte subsets and show different efficiency of erythrocyte lysis.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Biallelic mutations of the CEBPA gene (CEBPAbi) define a distinct entity associated with favorable prognosis; however, the role of monoallelic mutations (CEBPAsm) is poorly understood. We ...retrospectively analyzed 4708 adults with acute myeloid leukemia (AML) who had been recruited into the Study Alliance Leukemia trials, to investigate the prognostic impact of CEBPAsm. CEBPA mutations were identified in 240 patients (5.1%): 131 CEBPAbi and 109 CEBPAsm (60 affecting the N-terminal transactivation domains CEBPAsmTAD and 49 the C-terminal DNA-binding or basic leucine zipper region CEBPAsmbZIP). Interestingly, patients carrying CEBPAbi or CEBPAsmbZIP shared several clinical factors: they were significantly younger (median, 46 and 50 years, respectively) and had higher white blood cell (WBC) counts at diagnosis (median, 23.7 × 109/L and 35.7 × 109/L) than patients with CEBPAsmTAD (median age, 63 years, median WBC 13.1 × 109/L; P < .001). Co-mutations were similar in both groups: GATA2 mutations (35.1% CEBPAbi; 36.7% CEBPAsmbZIP vs 6.7% CEBPAsmTAD; P < .001) or NPM1 mutations (3.1% CEBPAbi; 8.2% CEBPAsmbZIP vs 38.3% CEBPAsmTAD; P < .001). CEBPAbi and CEBPAsmbZIP, but not CEBPAsmTAD were associated with significantly improved overall (OS; median 103 and 63 vs 13 months) and event-free survival (EFS; median, 20.7 and 17.1 months vs 5.7 months), in univariate and multivariable analyses. Additional analyses revealed that the clinical and molecular features as well as the favorable survival were confined to patients with in-frame mutations in bZIP (CEBPAbZIP-inf). When patients were classified according to CEBPAbZIP-inf and CEBPAother (including CEBPAsmTAD and non-CEBPAbZIP-inf), only patients bearing CEBPAbZIP-inf showed superior complete remission rates and the longest median OS and EFS, arguing for a previously undefined prognostic role of this type of mutation.
•CEBPAsmbZIP- and CEBPAbi-mutant AML share clinical and mutational characteristics and are distinct from CEBPAsmTAD-mutant AML.•Only in-frame mutations in CEBPA-bZIP are associated with favorable clinical response in monoallelic and biallelic constellations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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