An estimated one-quarter to one-half of people diagnosed with haematological malignancies experience anaemia. There are different strategies for red blood cell (RBC) transfusions to treat anaemia. A restrictive transfusion strategy permits a lower haemoglobin (Hb) level whereas a liberal transfusion strategy aims to maintain a higher Hb. The most effective and safest strategy is unknown.
To determine the efficacy and safety of restrictive versus liberal RBC transfusion strategies for people diagnosed with haematological malignancies treated with intensive chemotherapy or radiotherapy, or both, with or without a haematopoietic stem cell transplant (HSCT).
We searched for randomised controlled trials (RCTs) and non-randomised studies (NRS) in MEDLINE (from 1946), Embase (from 1974), CINAHL (from 1982), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2023, Issue 2), and eight other databases (including three trial registries) to 21 March 2023. We also searched grey literature and contacted experts in transfusion for additional trials. There were no language, date or publication status restrictions.
We included RCTs and prospective NRS that evaluated restrictive versus liberal RBC transfusion strategies in children or adults with malignant haematological disorders receiving intensive chemotherapy or radiotherapy, or both, with or without HSCT.
Two authors independently screened references, full-text reports of potentially relevant studies, extracted data from the studies, and assessed the risk of bias. Any disagreement was discussed and resolved with a third review author. Dichotomous outcomes were presented as a risk ratio (RR) with a 95% confidence interval (CI). Narrative syntheses were used for heterogeneous outcome measures. Review Manager Web was used to meta-analyse the data. Main outcomes of interest included: all-cause mortality at 31 to 100 days, quality of life, number of participants with any bleeding, number of participants with clinically significant bleeding, serious infections, length of hospital admission (days) and hospital readmission at 0 to 3 months. The certainty of the evidence was assessed using GRADE.
Nine studies met eligibility; eight RCTs and one NRS. Six hundred and forty-four participants were included from six completed RCTs (n = 560) and one completed NRS (n = 84), with two ongoing RCTs consisting of 294 participants (260 adult and 34 paediatric) pending inclusion. Only one completed RCT included children receiving HSCT (n = 6); the other five RCTs only included adults: 239 with acute leukaemia receiving chemotherapy and 315 receiving HSCT (166 allogeneic and 149 autologous). The transfusion threshold ranged from 70 g/L to 80 g/L for restrictive and from 80 g/L to 120 g/L for liberal strategies. Effects were reported in the summary of findings tables only for the trials that included adults to reduce indirectness due to the limited evidence contributed by the prematurely terminated paediatric trial. Evidence from RCTs Overall, there may be little to no difference in the number of participants who die within 31 to 100 days using a restrictive compared to a liberal transfusion strategy, but the evidence is very uncertain (three studies; 451 participants; RR 1.00, 95% CI 0.27 to 3.70, P=0.99; very low-certainty evidence). There may be little to no difference in quality of life at 0 to 3 months using a restrictive compared to a liberal transfusion strategy, but the evidence is very uncertain (three studies; 431 participants; analysis unable to be completed due to heterogeneity; very low-certainty evidence). There may be little to no difference in the number of participants who suffer from any bleeding at 0 to 3 months using a restrictive compared to a liberal transfusion strategy (three studies; 448 participants; RR 0.91, 95% CI 0.78 to 1.06, P = 0.22; low-certainty evidence). There may be little to no difference in the number of participants who suffer from clinically significant bleeding at 0 to 3 months using a restrictive compared to a liberal transfusion strategy (four studies; 511 participants; RR: 0.94, 95% CI 0.74 to 1.19, P = 0.60; low-certainty evidence). There may be little to no difference in the number of participants who experience serious infections at 0 to 3 months using a restrictive compared to a liberal transfusion strategy (three studies, 451 participants; RR: 1.20, 95% CI 0.93 to 1.55, P = 0.17; low-certainty evidence). A restrictive transfusion strategy likely results in little to no difference in the length of hospital admission at 0 to 3 months compared to a liberal strategy (two studies; 388 participants; analysis unable to be completed due to heterogeneity in reporting; moderate-certainty evidence). There may be little to no difference between hospital readmission using a restrictive transfusion strategy compared to a liberal transfusion strategy (one study, 299 participants; RR: 0.89, 95% CI 0.52 to 1.50; P = 0.65; low-certainty evidence). Evidence from NRS The evidence is very uncertain whether a restrictive RBC transfusion strategy: reduces the risk of death within 100 days (one study, 84 participants, restrictive 1 death; liberal 1 death; very low-certainty evidence); or decreases the risk of clinically significant bleeding (one study, 84 participants, restrictive 3; liberal 8; very low-certainty evidence). No NRS reported on the other eligible outcomes.
Findings from this review were based on seven studies and 644 participants. Definite conclusions are challenging given the relatively few included studies, low number of included participants, heterogeneity of intervention and outcome reporting, and overall certainty of evidence. To increase the certainty of the true effect of a restrictive RBC transfusion strategy on clinical outcomes, there is a need for rigorously designed and executed studies. The evidence is largely based on two populations: adults with acute leukaemia receiving intensive chemotherapy and adults with haematologic malignancy requiring HSCT. Despite the addition of 405 participants from three RCTs to the previous review\'s results, there is still insufficient evidence to answer this review\'s primary outcome. If we assume a mortality rate of 3% within 100 days, we would need a total of 1492 participants to have an 80% chance of detecting, at a 5% level of significance, an increase in all-cause mortality from 3% to 6%. Further RCTs are needed overall, particularly in children.

Sickle cell disease (SCD) affects millions worldwide, yet there are few therapeutic options. To develop effective treatments, preclinical models that recapitulate human physiology and SCD pathophysiology are needed. SCD arises from a single Glu-to-Val substitution at position 6 in the β subunit of hemoglobin (Hb), promoting Hb polymerization and subsequent disease. Sheep share important physiological and developmental characteristics with humans, including the same developmental pattern of fetal to adult Hb switching. Herein, we investigated whether introducing the SCD mutation into the sheep β-globin locus would recapitulate SCD\'s complex pathophysiology by generating high quality SWISS-MODEL sheep Hb structures and performing MD simulations of normal/sickle human (huHbA/huHbS) and sheep (shHbB/shHbS) Hb, establishing how accurately shHbS mimics huHbS behavior. shHbS, like huHbS, remained stable with low RMSD, while huHbA and shHbB had higher and fluctuating RMSD. shHbB and shHbS also behaved identically to huHbA and huHbS with respect to β2-Glu6 and β1-Asp73 (β1-Asn72 in sheep) solvent interactions. These data demonstrate that introducing the single SCD-causing Glu-to-Val substitution into sheep β-globin causes alterations consistent with the Hb polymerization that drives RBC sickling, supporting the development of a SCD sheep model to pave the way for alternative cures for this debilitating, globally impactful disease.

The management of life-threatening complications in patients with sickle cell disease (SCD) requires an accurate and reproducible quantification of haemoglobin A (HbA) and S (HbS) with a short turnaround time and 24-7 availability. We propose a novel method for quantifying HbA and HbS using the glycated haemoglobin (HbA1c) assay on a Tosoh HLC-723G8 (G8) analyser in variant mode. HbA and HbS results obtained using our method highly correlated with results obtained using a reference method (r > 0.99 for 124 samples of patients with SCD or sickle cell trait). Our method met laboratory requirements for linearity (coefficient of variation [CV] and bias <5%), between-run and within-run reproducibility (CV <10%) and carryover (<0.5%) over the range of HbS and HbA values expected in a therapeutic context. Using the G8 analyser in variant mode is viable for monitoring HbA and HbS concentrations in dire situations. This method is easy to use, quick (1.6 min per sample), and automatable and produces highly reproducible results without significant bias. Finally, it does not require modifications to the analytical pipeline recommended by the supplier, enabling a 24-7 availability without disrupting routine monitoring of HbA1c in the laboratory.

Meleagris gallopavo (turkey) coexpresses distinct hemoglobin (Hb) isoforms, Hb α2Aβ2 (HbA) and α2Dβ2 (HbD), at a ratio of ∼3:1 (HbA:HbD). Herein, the reactivities of HbA and HbD were investigated in their native and free fatty acid (FFA)-modified states. Results indicated that HbD displays elevated autoxidation (kox) and an increased propensity to oxidize lipids in its reduced (oxy) and oxidized (met) forms. Interestingly, metHbD displayed less heme-globin cross-linking compared to HbA. Regarding FFA-modified Hb, we found that an FFA mixture and linoleic acid (LA) produced a bis-histidyl ferric (Bis-His) Hb species, decreasing the ability of Hb to oxidize lipids. Using molecular docking, we found LA to hydrogen bond with β Arg C6, found at the α1β2 interface, but the extent of Bis-His formation differs between HbA and HbD. Our findings suggest HbA displays elevated oxidative stability compared to HbD and that FFA may act as allosteric effectors of metHb.

暂无摘要。

OBJECTIVE: The escalating prevalence of diabetes worldwide has resulted in a dramatic increase in the number of people who need testing, which in turn necessitates faster HbA1c measurement. The Tosoh GR01 addresses the need for fast turnaround times of whilst offering pragmatic steps to maintain result accuracy in a single instrument by offering two distinct operating modes: Short Mode (SM) and Long Mode (LM). The aim of this study was to evaluate all relevant aspects of the performance of the Tosoh GR01 with a view to accepting the instrument as a future Secondary Reference Measurement Procedure (SRMP) for the IFCC.
METHODS: Certified Clinical & Laboratory Standards Institute (CLSI) Evaluation Protocols (EP) were used to evaluate precision (EP-5), accuracy (EP-9), linearity (EP-6), carry-over (EP-10) and the effect of hemoglobin variants and other potential interferences.
RESULTS: Both modes demonstrated CVs <0.6 % in SI units and <0.4 % in NGSP units at 46 mmol/mol (6.4 %) and 75 mmol/mol (9.0 %) and passed both National Glycohemoglobin Standardization Program (NGSP) and International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) certification procedures when compared with 7 IFCC Certified Secondary Reference Measurement Procedures (SRMP). Sigma for both modes was >6 when using the results of EP-5 and EP-9 at an HbA1c concentration of 50 mmol/mol (6.7 %). Neither mode showed any interference with common Hb-variants except for HbAE when HbA1c was >65 mmol/mol. In the SM HbAS, HbAD and HbAC were recognized but no result was reported.
CONCLUSIONS: There is a good balance between speed and accuracy for determining HbA1c with the Tosoh GR01 in both analytical modes and the device is suitable for use as an IFCC SRMP.

暂无摘要。

Metformin, a first-line medication for type 2 diabetes, might also have a protective effect against ageing-related diseases, but so far little experimental evidence is available. We sought to assess the target-specific effect of metformin on biomarkers of ageing in the UK Biobank.
In this drug target mendelian randomisation study, we assessed the target-specific effect of four putative targets of metformin (AMPK, ETFDH, GPD1, and PEN2), involving ten genes. Genetic variants with evidence of causation of gene expression, glycated haemoglobin A1c (HbA1c), and colocalisation were used as instruments mimicking the target-specific effect of metformin via HbA1c lowering. The biomarkers of ageing considered were phenotypic age (PhenoAge) and leukocyte telomere length. To triangulate the evidence, we also assessed the effect of HbA1c on the outcomes using a polygenic mendelian randomisation design and assessed the effect of metformin use on these outcomes using a cross-sectional observational design.
GPD1-induced HbA1c lowering was associated with younger PhenoAge (β -5·26, 95% CI -6·69 to -3·83) and longer leukocyte telomere length (β 0·28, 0·03 to 0·53), and AMPKγ2 (PRKAG2)-induced HbA1c lowering was associated with younger PhenoAge (β -4·88, -7·14 to -2·62) but not with longer leukocyte telomere length. Genetically predicted HbA1c lowering was associated with younger PhenoAge (β -0·96 per SD lowering of HbA1c, 95% CI -1·19 to -0·74) but not associated with leukocyte telomere length. In the propensity score matched analysis, metformin use was associated with younger PhenoAge (β -0·36, 95% CI -0·59 to -0·13) but not with leukocyte telomere length.
This study provides genetic validation evidence that metformin might promote healthy ageing via targets GPD1 and AMPKγ2 (PRKAG2), and the effect could be in part due to its glycaemic property. Our findings support further clinical research into metformin and longevity.
Healthy Longevity Catalyst Award, National Academy of Medicine, and Seed Fund for Basic Research, The University of Hong Kong.

UNASSIGNED: Neonatal screening is the first action necessary to identify children with sickle cell disease (SCD) and thus ensure their care. Using rapid tests to give an immediate result to families is a new resilient approach of great interest. These two aspects are essential for establishing an adequate health policy for this disease. This study was undertaken in Kisangani to update the current incidence of neonatal SCD.
UNASSIGNED: Heel prick blood samples of 1432 babies born from different racial groups of parents living in Kisangani were collected at birth and screened using a point of care test, i.e. the HemoTypeSCTM.
UNASSIGNED: The incidence at birth was 2.2% (n = 31; 95% CI: [1.5%-3.1%]) for HbSS homozygosity and 21% (n = 303; 95% CI: [19%-23%]) for HbAS heterozygosity. Compared to a previous study in 2010; the incidence at the birth of the HbSS form has doubled, while that of the heterozygous form HbAS remained almost unchanged. The inter-ethnic incidence of HbSS among the five top-represented ethnic groups was significant (<0.001).
UNASSIGNED: The prevalence of homozygote form has doubled compared to the 0.96% reported in 2010. Setting up a neonatal screening program and an awareness unit is necessary to assess the need for care services correctly.

Malaria affects a significant portion of the global population, with 247 million cases in 2021, primarily in Africa. However, certain hemoglobinopathies, such as sickle cell trait (SCT), have been linked to lower mortality rates in malaria patients. Hemoglobin (Hb) mutations, including HbS and HbC, can cause sickle cell disease (SCD) when both alleles are inherited (HbSS and HbSC). In SCT, one allele is inherited and paired with a normal allele (HbAS, HbAC). The high prevalence of these alleles in Africa may be attributed to their protective effect against malaria. Biomarkers are crucial for SCD and malaria diagnosis and prognosis. Studies indicate that miRNAs, specifically miR-451a and let-7i-5p, are differentially expressed in HbSS and HbAS compared to controls. Our research examined the levels of exosomal miR-451a and let-7i-5p in red blood cells (RBCs) and infected red blood cells (iRBCs) from multiple sickle Hb genotypes and their impact on parasite growth. We assessed exosomal miR-451a and let-7i-5p levels in vitro in RBC and iRBC supernatants. Exosomal miRNAs exhibited distinct expression patterns in iRBCs from individuals with different sickle Hb genotypes. Additionally, we discovered a correlation between let-7i-5p levels and trophozoite count. Exosomal miR-451a and let-7i-5p could modulate SCD and malaria severity and serve as potential biomarkers for malaria vaccines and therapies.