Mechanisms and physiological function of daily haemoglobin oxidation rhythms in red blood cells.

Cellular circadian rhythms confer temporal organisation upon physiology that is fundamental to human health. Rhythms are present in red blood cells (RBCs), the most abundant cell type in the body, but their physiological function is poorly understood. Here, we present a novel biochemical assay for haemoglobin (Hb) oxidation status which relies on a redox-sensitive covalent haem-Hb linkage that forms during SDS-mediated cell lysis. Formation of this linkage is lowest when ferrous Hb is oxidised, in the form of ferric metHb. Daily haemoglobin oxidation rhythms are observed in mouse and human RBCs cultured in vitro, or taken from humans in vivo, and are unaffected by mutations that affect circadian rhythms in nucleated cells. These rhythms correlate with daily rhythms in core body temperature, with temperature lowest when metHb levels are highest. Raising metHb levels with dietary sodium nitrite can further decrease daytime core body temperature in mice via nitric oxide (NO) signalling. These results extend our molecular understanding of RBC circadian rhythms and suggest they contribute to the regulation of body temperature.

The genetic dissection of fetal haemoglobin persistence in sickle cell disease in Nigeria.

The clinical severity of sickle cell disease (SCD) is strongly influenced by the level of fetal haemoglobin (HbF) persistent in each patient. Three major HbF loci (BCL11A, HBS1L-MYB, and Xmn1-HBG2) have been reported, but a considerable hidden heritability remains. We conducted a genome-wide association study for HbF levels in 1006 Nigerian patients with SCD (HbSS/HbSß0), followed by a replication and meta-analysis exercise in four independent SCD cohorts (3,582 patients). To dissect association signals at the major loci, we performed stepwise conditional and haplotype association analyses and included public functional annotation datasets. Association signals were detected for BCL11A (lead SNP rs6706648, ß = -0.39, P = 4.96 × 10-34) and HBS1L-MYB (lead SNP rs61028892, ß = 0.73, P = 1.18 × 10-9), whereas the variant allele for Xmn1-HBG2 was found to be very rare. In addition, we detected three putative new trait-associated regions. Genetically, dissecting the two major loci BCL11A and HBS1L-MYB, we defined trait-increasing haplotypes (P < 0.0001) containing so far unidentified causal variants. At BCL11A, in addition to a haplotype harbouring the putative functional variant rs1427407-'T', we identified a second haplotype, tagged by the rs7565301-'A' allele, where a yet-to-be-discovered causal DNA variant may reside. Similarly, at HBS1L-MYB, one HbF-increasing haplotype contains the likely functional small indel rs66650371, and a second tagged by rs61028892-'C' is likely to harbour a presently unknown functional allele. Together, variants at BCL11A and HBS1L-MYB SNPs explained 24.1% of the trait variance. Our findings provide a path for further investigation of the causes of variable fetal haemoglobin persistence in sickle cell disease.

Acculturation and glycaemic control in Arab immigrants with type 2 diabetes in Australia.

AIMS/HYPOTHESIS: This study aimed to investigate acculturation's direct and mediated effects on HbA1c levels in individuals with type 2 diabetes from Arabic-speaking countries that are members of the Arab League who have emigrated to Australia. METHODS: In this multicentre cross-sectional study, we recruited 382 Arabic-speaking immigrants who were born in any of the 22 countries of the Arab League and who had type 2 diabetes from different healthcare settings in Australia. HbA1c levels were retrieved from medical records. A validated self-report questionnaire was used to assess behavioural and psychosocial outcomes. Acculturation was measured using the General Acculturation Index and the Adherence to Traditional Values tool. We used structural equation modelling to test mediation hypotheses. RESULTS: Participants had a mean HbA1c value of 63.9 mmol/mol (8.0%), a low acculturation level (mean±SD: 1.9±0.6; range: 1-5) and highly adhered to traditional values (mean General Acculturation Index value: 3.7±0.7; range: 1-5). Higher HbA1c was associated with lower acculturation levels (Pearson correlation coefficient [r] = -0.32, p<0.01) and higher adherence to traditional values (r=0.35, p<0.01). Self-efficacy, health literacy and self-care activities partially mediated the relationship between acculturation and HbA1c. CONCLUSIONS/INTERPRETATION: Among Arab immigrants in Australia with type 2 diabetes, the degree of acculturation is related to glycaemic control, suggesting possible avenues for new interventions.

Thrombosis risk with haemoglobin C trait and haemoglobin C disease: A systematic review.

The thrombotic risk with haemoglobin C trait (HbAC) or haemoglobin C disease (HbCC) is unclear. However, individuals with HbCC have demonstrated chronic haemolysis, higher blood viscosity and altered rheology when compared to individuals with wild-type haemoglobin (HbAA). These physiological alterations may theoretically translate to increased risk of thrombosis; therefore, a systematic literature review was performed to investigate the possible association between HbAC and/or HbCC and thrombosis. Twenty-two studies met inclusion criteria representing 782 individuals with HbAC (n = 694) or HbCC (n = 88). Fifteen studies described the presence/absence of venous thromboembolism (VTE) in patients with HbAC (n = 685) or HbCC (n = 79), while seven studies described patients with HbAC (n = 9) or HbCC (n = 9) and arterial thrombosis. Most (n = 20) studies were case reports or case series; however, two studies suggested a potential increased VTE risk with HbAC compared to HbAA in (i) all patients (OR 2.2, 95% CI: 0.9-5.5) and in (ii) pregnant individuals (RR 3.7, 95% CI 0.9-16). This review is the largest assessment of patients with HbC trait or disease and thrombosis to date; despite its limitations, the findings suggest HbC may be a predisposing risk factor to thrombosis. Prospective cohort studies are warranted to definitively elucidate the risk of thrombosis in this population.

Biallelic hypomorphic variants in CAD cause uridine-responsive macrocytic anaemia with elevated haemoglobin-A2.

Biallelic pathogenic variants in CAD, that encode the multienzymatic protein required for de-novo pyrimidine biosynthesis, cause early infantile epileptic encephalopathy-50. This rare disease, characterized by developmental delay, intractable seizures and anaemia, is amenable to treatment with uridine. We present a patient with macrocytic anaemia, elevated haemoglobin-A2 levels, anisocytosis, poikilocytosis and target cells in the blood smear, and mild developmental delay. A next-generation sequencing panel revealed biallelic variants in CAD. Functional studies did not support complete abrogation of protein function; however, the patient responded to uridine supplement. We conclude that biallelic hypomorphic CAD variants may cause a primarily haematological phenotype.

Determinants of the haemoglobin level in patients with sickle cell disease living in sub-Saharan Africa: Major impact of the country of residence and independent effects of leucocyte and platelet counts and haemolysis.

The degree of anaemia in sickle cell disease (SCD) is a well-known contributor to morbidity and mortality. We aimed to explore the factors affecting haemoglobin (Hb) level in African SCD patients, considering haemolysis biomarkers (LDH and bilirubin level, and reticulocyte count), leucocyte and platelet counts and socio-demographic characteristics (gender, age group, country of residence and BMI). The research was part of the CADRE multinational cohort and involved 3699 SCD patients living in Mali, Senegal, Ivory Coast, Democratic Republic of Congo, Gabon and Cameroon: 2936 SS/Sß0, 587 SC and 176 Sß + patients with median Hb level of 8, 11.3 and 11.2 g/dL respectively (p < 0.001). In multivariate analysis conducted in 1394 SS/Sß0 patients, living in Cameroon, female gender, lower BMI, higher haemolysis markers (especially LDH) and higher leucocyte and platelet counts were independently associated with lower Hb level (all p < 0.05). In 497 SC and 156 Sß + patients, female gender (p < 0.001), lower BMI (p < 0.05) and higher platelet counts (p < 0.001) were independently associated with lower Hb level. Anaemia in African SCD patients is not only associated with haemolysis but also with the country of residence, lower BMI and leucocyte or platelet counts which might reflect inflammation related to infectious burden in the region.

Screening for haemoglobin disorders: One size may not fit all.

Accurate laboratory screening for sickle cell disease and other haemoglobin disorders is expanding worldwide. Two new reports describe different methods and strategies for screening in Mali and Denmark, respectively, and their encouraging results suggest that countries should tailor their screening programmes according to local needs, resources and opportunities. Commentary on: Guindo et al. Potential for a large-scale newborn screening strategy for sickle cell disease in Mali: a comparative diagnostic performance study of two rapid diagnostic tests (SickleScan® and HemotypeSC®) on cord blood. Br J Haematol 2024;204:337-345 and Gravholt et al. The Danish national haemoglobinopathy screening programme: report from 16 years of screening in a low-prevalence, non-endemic region. Br J Haematol 2024;204:329-336.

EPAS1-mutated paragangliomas associated with haemoglobin disorders.

We report a large series of 40 patients presenting EPAS1-mutated paraganglioma (PGL) in whom we investigated a cause underlying chronic hypoxia. Four patients suffered from hypoxaemic heart disease. In patients with available haemoglobin electrophoresis results, 59% presented with a haemoglobin disorder, including six with sickle cell disease, five with sickle cell trait and two with heterozygous haemoglobin C disease. Histological and transcriptomic characterization of EPAS1 tumours revealed increased angiogenesis and high similarities with pseudohypoxic PGLs caused by VHL gene mutations. Sickle haemoglobinopathy carriers could thus be at increased risk for developing EPAS1-PGLs, which should be taken into account in their management and surveillance.

The clinical spectrum of HbSC sickle cell disease-not a benign condition.

Sickle cell disease (SCD) includes a group of heterogenous disorders that result in significant morbidities. HbSS is the most common type of SCD and HbSC is the second most common type of SCD. The prevalence of HbSC disease in the United States and United Kingdom is ~1 in 7174 births and 1 in 6174 births respectively. Despite its frequency, however, HbSC disease has been insufficiently studied and was historically categorized as a more 'mild' form of SCD. We conducted this study of HbSC disease as part of the NHLBI funded Sickle Cell Disease Implementation Consortium (SCDIC). The SCDIC registry included 2282 individuals with SCD, ages 15-45 years of whom 502 (22%) had HbSC disease. Compared with people with sickle cell anaemia (SCA), the study found that people with HbSC disease had a higher frequency of splenomegaly (n (%) = 169 (33.7) vs. 392 (22.1)) and retinopathy (n (%) = 116 (23.1) vs. 189 (10.6)). A Many people with HbSC also had avascular necrosis (n (%) = 112 (22.3)), pulmonary embolism (n (%) = 43 (8.6)) and acute chest syndrome (n (%) = 228 (45.4)) demonstrating significant disease severity. HbSC disease is more clinically severe than was previously recognized and deserves additional evaluation and targeted treatments.

Microbiome in sickle cell disease: Pathophysiology and therapeutic insights.

Sickle cell disease (SCD) is a complex genetic blood disorder characterized by abnormal haemoglobin, resulting in sickle-shaped red blood cells. While extensive research has concentrated on the genetic and physiological aspects of SCD, recent studies suggest a potential role of the human microbiome in SCD pathophysiology, adding new dimensions to its understanding. This review synthesizes current knowledge on the microbiome's involvement in SCD, focusing on alterations in the gut microbiome composition and diversity compared to healthy individuals, and their implications for disease pathogenesis. We explore how microbiome changes may contribute to vaso-occlusive crises and other complications, along with the possible associations of specific microbial taxa or markers with disease crises and clinical outcomes. Additionally, we discuss the potential of microbiome-targeted interventions, including probiotics, dietary modifications, and faecal microbiota transplantation, in managing SCD complications and improving patient outcomes. Understanding the intricate relationship between the microbiome and SCD could lead to innovative therapeutic strategies and personalized interventions for better managing the disease. This review underscores the importance of further microbiome research and its integration into holistic SCD care.

Analysis of Erythrocyte Parameters in Multiple and Long-Term Blood Donors from Northern Pomerania (Poland).

BACKGROUND/AIMS: Assessment of the levels of vital blood parameters in donors is essential to evaluate their health status, ensure their suitability for donation, preserve the integrity of the circulatory system, and facilitate comprehensive health monitoring. The aim of our study was to analyse the levels of haemoglobin, haematocrit, erythrocyte count, MCV, MCH, and MCHC in 12 groups of first-time donors and experienced donors of both sexes at the John Paul II Regional Blood Donation and Treatment Centre in Slupsk, northern Poland. The donors were divided into three age groups (18-30 years, 31-45 years, and 46-65 years). METHODS: Using MANOVA multivariate significance tests, we examined the main effects of donor-related factors (age, sex, donor stage) on morphological blood parameters to evaluate different haematological parameters, such as Hb, Ht, RBC, MCV, MCH, and MCHC, and identified statistically significant relationships between all variables. RESULTS: The multivariate analysis of these three main factors showed that the variation in haemoglobin (Hb) levels accounted for 46% of the explained dependence in this statistical model. In particular, approximately half of the variability in the multivariate statistical analysis was attributed to the role of Hb and haematocrit (Ht). In addition, the ß-coefficient values for Hb and Ht were statistically higher in relation to donor sex and donor type (single versus repeat). These ß-coefficient values from our data represent the strength and direction of the relationship between the haematological parameters (Hb and Ht) and the specific donor characteristics. A higher ß-coefficient indicates a stronger influence of donor sex and donor type on these parameters, suggesting that these factors contribute significantly to the variation in the Hb and Ht levels. Based on our results, the comprehensive analysis of the entire statistical model of metabolic biomarkers revealed the following hierarchy: Hb > Ht > MCHC > MCV > RBC > MCH. The results obtained showed strong statistical relationships, as indicated by the high values of the key statistical indicators in our analysis. The coefficient of determination (R²) showed that the model explained a significant proportion of the variance in the data, while the F-test statistic confirmed the significance of the predictors. CONCLUSION: These strong statistical dependencies provided a clear justification for selecting this model over others, as it effectively represented the underlying relationships within the data. These statistics help to assess how well the model matches the actual data, thereby helping to reduce the risks associated with blood donation, optimise donor safety, and maintain the quality and efficiency of blood transfusion services.

Haemoglobin Gene Repertoire in Teleost and Cichlid Fishes Shaped by Gene Duplications and Genome Rearrangements.

Haemoglobin is a key molecule for oxygen transport in vertebrates. It exhibits remarkable gene diversity in teleost fishes, reflecting adaptation to various aquatic environments. In this study, we present the dynamic evolution of haemoglobin subunit genes based on a comparison of high-quality genome assemblies of 24 vertebrate species, including 17 teleosts (of which six are cichlids). Our findings indicate that teleost genomes contain a range of haemoglobin genes, from as few as five in fugu to as many as 43 in salmon, with the latter being the largest repertoire found in vertebrates. We find evidence that the teleost ancestor had at least four Hbα and three or four Hbß subunit genes, and that the current gene diversity emerged during teleost radiation, driven primarily by (tandem) gene duplications, genome compaction, and rearrangement dynamics. We provide insights into the genomic organisation of haemoglobin clusters in different teleost species. We further show that the evolution of paralogous rhbdf1 genes flanking both teleost clusters (LA and MN) supports the hypothesis for the origin of the LA cluster by rearrangement within teleosts, rather than by the teleost specific whole-genome duplication. We specifically focus on cichlid fishes, where adaptation to low oxygen environment plays role in species diversification. Our analysis of six cichlid genomes, including Pungu maclareni from the Barombi Mbo crater lake, for which we sequenced a representative genome, reveals 18-32 copies of the Hb genes, and elevated rates of non-synonymous substitutions compared to other teleosts. Overall, this work facilitates a deeper understanding of how haemoglobin genes contribute to the adaptive potential of teleosts.

Androgen Deficiency, Associations and Survival of Men With Stage 4 and 5 Chronic Kidney Disease: A Cohort Study.

OBJECTIVES: Anaemia is a key cause of morbidity in chronic kidney disease (CKD). Androgen deficiency (AD) in males can contribute to anaemia of all causes, including in CKD. We sought to examine the prevalence of AD in men with CKD, the extent to which it contributed to anaemia and whether it was independently associated with long-term survival. METHODS: This cross-sectional observational study was conducted among males aged 18 years and over with CKD stages 4 and 5. The study analysed morning blood samples with regard to their full blood count, urea and electrolytes, albumin, lipids, testosterone (T) and sex hormone binding globulin, with calculation of free testosterone by mass action equation. Mortality data were obtained 15 years later for survival analysis. RESULTS: Among 322 patients with a mean age of 63 years, the overall prevalence of AD was 68.9%. There was a statistically significant negative correlation between erythropoiesis stimulating agent (ESA) dose and testosterone concentrations (Pearson correlation -0.193, p = 0.05). There was a positive correlation between haemoglobin (Hb) and free testosterone level among patients not on ESA therapy (Pearson correlation 0.331, p < 0.001). Kaplan-Meier plots showed p < 0.001 on log-rank analysis, indicating that AD was significantly associated with worse survival. However, in Cox regression analysis, free testosterone was not associated with survival (95% CI for free testosterone 0.997-1.000). CONCLUSIONS: AD is highly prevalent among this population, and increases further with older age and more severe CKD warranting haemodialysis. Association of lower Hb and higher ESA dose with lower T concentration might be causative, which has important pharmaco-economic as well as clinical implications. Lower survival in men with low T, more likely reflects overall poor health rather than causation. A properly constituted randomised controlled study evaluating the effect of native T replacement is warranted in men with CKD and AD.

Nonpharmacological interventions on glycated haemoglobin in youth with type 1 diabetes: a Bayesian network meta-analysis.

The available evidence on the impact of specific non-pharmacological interventions on glycaemic control is currently limited. Consequently, there is a need to determine which interventions could provide the most significant benefits for the metabolic health of young individuals with type 1 diabetes mellitus. The aim of this study was to identify optimal nonpharmacological interventions on glycaemic control, measured by glycated haemoglobin (HbA1c), in children and adolescents with type 1 diabetes. Systematic searches were conducted in PubMed, Web of Science, Scopus, and SPORTDiscus from inception to July 1, 2023. Randomised clinical trials (RCT) investigating nonpharmacological interventions (e.g., physical activity, nutrition, and behavioural therapies) were included. Primary outcome was change in HbA1c levels. Secondary outcome was change in daily insulin dose requirement. Seventy-four RCT with 6,815 participants (49.43% girls) involving 20 interventions were analysed using a network meta-analysis. Most interventions showed greater efficacy than standard care. However, multicomponent exercise, which includes aerobic and strength training (n = 214, standardised mean difference [SMD] =- 0.63, 95% credible interval [95% CrI] - 1.09 to - 0.16) and nutritional supplements (n = 146, SMD =- 0.49, - 0 .92 to - 0.07) demonstrated the greatest HbA1c reductions. These interventions also led to the larger decreases in daily insulin needs (n = 119, SMD =- 0.79, 95% CrI -  1.19 to - 0.34) and (n = 57, SMD =- 0.62, 95% CrI -  1.18 to - 0.12, respectively). The current study underscores non-pharmacological options such as multicomponent exercise and nutritional supplements, showcasing their potential to significantly improve HbA1c in youth with type 1 diabetes. Although additional research to confirm their efficacy is required, these approaches could be considered as potential adjuvant therapeutic options in the management of type 1 diabetes among children and adolescents.

Protoporphyrin IX iron(II) revisited. An overview of the Mössbauer spectroscopic parameters of low-spin porphyrin iron(II) complexes.

Mössbauer parameters of low-spin six-coordinate [Fe(II)(Por)L2] complexes (where Por is a synthetic porphyrin; L is a nitrogenous aliphatic, an aromatic base or a heterocyclic ligand, a P-bonding ligand, CO or CN) and low-spin [Fe(Por)LX] complexes (where L and X are different ligands) are reported. A known point charge calculation approach was extended to investigate how the axial ligands and the four porphyrinato-N atoms generate the observed quadrupole splittings (ΔEQ) for the complexes. Partial quadrupole splitting (p.q.s.) and partial chemical shifts (p.c.s.) values were derived for all the axial ligands, and porphyrins reported in the literature. The values for each porphyrin are different emphasising the importance/uniqueness of the [Fe(PPIX)] moiety, (which is ubiquitous in nature). This new analysis enabled the construction of figures relating p.c.s and p.q.s values. The relationships presented in the figures indicates that strong field ligands such as CO can, and do change the sign of the electric field gradient in the [Fe(II)(Por)L2] complexes. The limiting p.q.s. value a ligand can have and still form a six-coordinate low-spin [Fe(II)(Por)L2] complex is established. It is shown that the control the porphyrin ligands exert on the low-spin Fe(II) atom limits its bonding to a defined range of axial ligands; outside this range the spin state of the iron is unstable and five-coordinate high-spin complexes are favoured. Amongst many conclusions, it was found that oxygen cannot form a stable low-spin [Fe(II)(Por)L(O2)] complex and that oxy-haemoglobin is best described as an [Fe(III)(Por)L(O2-)] complex, the iron is ferric bound to the superoxide molecule.

Probiotics, prebiotics, and synbiotics in type 1 diabetes mellitus: A systematic review and meta-analysis of clinical trials.

Dysbiosis or imbalance of microbes in the gut has been associated with susceptibility and progression of type 1 diabetes mellitus (T1DM). The present systematic review and meta-analysis examined the effects of probiotics, prebiotics, and synbiotics on fasting blood glucose (FBG), haemoglobin A1c (HbA1c), C-peptide, and insulin requirements in T1DM patients. A systematic search for trials published up to October 2022 was conducted in PubMed, EMBASE, Scopus, Google Scholar, ScienceDirect, Web of Science, and the Central Cochrane Library. Random effect models were used to synthesise quantitative data by STATA14 . After the evaluation of 258 identified entries, five randomised controlled trials (n = 356; mean age = 11.7 years old) were included. The pooled effect size showed that FBG decreased following probiotic supplementation (weighted mean difference = -31.24 mg/dL; 95% confidence interval = -45.65, -16.83; p < 0.001), however, there was no significant improvement in serum HbA1c, C-peptide, and insulin requirements. Probiotic supplementation could be a complementary therapeutic strategy in T1DM. The evidence is limited; therefore, it is crucial to conduct more trials.

Effectiveness of educational interventions for diabetes-related foot disease: A systematic review and meta-analysis.

This systematic review and meta-analysis pooled evidence from randomised controlled trials (RCTs) on the effectiveness of educational programs for people with or at risk of diabetes-related foot disease (DFD). A systematic search identified RCTs evaluating the effectiveness of educational programs in preventing or managing DFD. The primary outcome was risk of developing a foot ulcer. Secondary outcomes included any amputation, mortality, changes in cardiovascular risk factors, foot-care knowledge and self-care behaviours. Meta-analyses were performed using random effects models. Risk of bias was assessed using Cochrane's ROB-2 tool. Education programs were tested in 29 RCTs (n = 3891) and reduced risk of a foot ulcer by approximately half although the upper 95% confidence interval (CI) reached 1.00 (odds ratio [OR], OR 0.54; 95% CI 0.29, 1.00, I2  = 65%). Education programs reduced risk of any amputation (OR 0.34; 95% CI 0.13, 0.88, I2  = 38%) and HbA1c levels (standardized mean difference -0.73; 95% CI -1.26, -0.20, I2  = 93%) without affecting all-cause mortality (OR 1.09; 95% CI 0.57, 2.07, I2  = 0%). Education programs mostly significantly improved DFD knowledge (13 of 16 trials) and self-care behaviour scores (19 of 20 trials). Only one trial was deemed at low risk of bias. Previously tested education programs have mostly effectively improved participants' knowledge and self-care behaviours and reduced risk of foot ulceration and amputation. Larger high quality trials with longer follow-up are needed.

Interaction effects of MTHFR C677T and A1298C polymorphisms with maternal glycated haemoglobin levels on adverse birth outcomes.

AIMS: The role of maternal genetic factors in the association between high glycated haemoglobin (HbA1c) levels and adverse birth outcomes remains unclear. MATERIALS AND METHODS: In this study, the maternal HbA1c levels of 5108 normoglycemic pregnant women in China were measured, and A1298C and C677T polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene were genotyped. RESULTS: Elevated HbA1c levels during the second trimester were associated with increased risks of macrosomia, large-for-gestational age (LGA), preterm birth (PTB), and reduced gestational age (p < 0.05). Pregnant women with MTHFR A1298C AA or C677T CT + TT genotypes were susceptible to adverse pregnancy outcomes related to HbA1c levels. Among pregnant women with the A1298C AA genotype, each standard deviation (SD) increase in HbA1c levels increased the risk of PTB by 1.32-times and reduced the gestational age by 0.11 weeks (p < 0.05). For MTHFR C677T CC + TT genotype carriers, higher HbA1c levels were associated with 1.49-, 1.24-, and 1.23-times increased risks of macrosomia, LGA, and PTB, respectively (p < 0.05). A U-shaped curve for PTB risk in relation to HbA1c levels was observed among the C677T CC + TT participants, with a cut-off value of 4.58%. Among subjects with the A1298C AA genotype combined with the C677T CT + TT genotype, each SD increase in HbA1c levels was associated with 1.40 and 1.37-times increased risks of LGA and PTB, respectively. CONCLUSIONS: Our findings highlight the importance of glycaemic control during pregnancy and the potential impact of genetic factors on birth outcomes. However, further large-scale studies are required to confirm these findings.

Impact of preoperative haemoglobin A1c levels on postoperative outcomes in adults undergoing major noncardiac surgery: A systematic review.

AIMS: Diabetes is known to increase morbidity and mortality after major surgery. However, literature is conflicting on whether elevated preoperative haemoglobin A1c (HbA1c) levels are associated with worse outcomes following major noncardiac surgery. We aimed to investigate the effect of incremental preoperative HbA1c levels on postoperative outcomes in adults who had undergone major noncardiac surgery. METHODS: We systematically searched PubMed, EMBASE and the Cochrane Library databases for eligible studies published between January 2012 and July 2023. Randomised controlled trials and observational studies (cohort and case-control studies) which measured HbA1c within 6 months before surgery and compared outcomes between at least three incremental subgroups or analysed HbA1c as a continuous variable were included. The systematic review protocol was registered with PROSPERO (CRD42023391946). RESULTS: Twenty observational studies investigating outcomes across multiple surgical types were included. Higher preoperative HbA1c levels were associated with increased odds of overall postoperative complications, postoperative acute kidney injury, anastomotic leak, surgical site infections and increased length of stay. Each 1% increase in preoperative HbA1c was associated with increased odds of these complications. No association with reoperations and 30-day mortality was identified. The literature was highly variable with respect to composite major complications, perioperative cardiovascular events, hospital readmissions, postoperative pneumonia and systemic thromboembolism. CONCLUSIONS: Current evidence suggested that higher preoperative HbA1c levels were associated with increased odds of postoperative complications and extended length of stay in adults undergoing major noncardiac surgery. Further high-quality studies would be needed to quantify the risks posed and determine whether early intervention improves outcomes.

A comparison of the safety and effectiveness of insulin aspart with other bolus insulins in women with pre-existing Type 1 diabetes during pregnancy: A post hoc analysis of a prospective cohort study.

AIMS: The safety and efficacy of insulin analogue insulin aspart (IAsp) have been demonstrated in a randomised clinical trial in pregnant women with Type 1 diabetes (T1D), and IAsp is widely used during pregnancy. The aim of this study was to assess glycaemic control and safety of IAsp versus other bolus insulins in Type 1 diabetic pregnancy in a real-world setting. METHODS: This was a post hoc analysis of a prospective cohort study of 1840 pregnant women with T1D, treated with IAsp (n = 1434) or other bolus insulins (n = 406) in the Diabetes Pregnancy Registry. The primary (composite) outcome was the proportion of pregnancies resulting in major congenital malformations or perinatal or neonatal death. Secondary outcomes included all HbA1c values measured immediately before and during pregnancy and major hypoglycaemia, as well as abortion, pre-eclampsia, pre-term delivery, large for gestational age at birth, stillbirth and fetal malformations. RESULTS: There were no significant differences found in any of the pregnancy outcomes between treatment with IAsp and other bolus insulins in either the crude or propensity score-adjusted analyses. However, maternal HbA1c was lower in the IAsp group at the end of the third trimester (adjusted difference, -0.16% point [95% CI -0.28;-0.05]; -1.8 mmol/mol [95% CI -3.1;-0.6]; p = 0.0046). CONCLUSIONS: No significant differences in safety or pregnancy outcomes were demonstrated when comparing treatment with IAsp versus other bolus insulins in women with T1D during pregnancy. The observed improvement in HbA1c with IAsp in late pregnancy should be confirmed in other studies.