Is the Current Cut Point for Glycated Haemoglobin (HbA1c) Correct for Diagnosing Diabetes Mellitus in Premenopausal Women? Evidence to Inform Discussion.

INTRODUCTION: Women are on average diagnosed with diabetes mellitus at later age than men but have higher mortality. As the diagnosis of diabetes mellitus is primarily based on HbA1c, the use of a non-specific reference range and cut point for diabetes mellitus that does not account for gender differences in diabetes could potentially lead to underdiagnosis of diabetes mellitus in women and missed opportunities for intervention. We investigated whether a contributing factor to the later diagnosis in women may be a difference in distribution of HbA1c in premenopausal women versus men of the same age by comparing HbA1c values in men and women across multiple sites in the UK. METHODS: We analysed the HbA1c levels of 146,907 individuals who underwent single testing only and had HbA1c ≤ 50 mmol/mol between 2012 and 2019 in one laboratory (cohort 1). This was replicated in six laboratories with 938,678 individuals tested between 2019 and 2021 (cohort 2). RESULTS: In cohort 1, women < 50 years old had an HbA1c distribution markedly lower than that in men by a mean of 1.6 mmol/mol (p < 0.0001), while the difference in the distribution of HbA1c for individuals aged ≥ 50 years was less pronounced (mean difference 0.9 mmol/mol, p < 0.0001). For individuals under the age of 50, HbA1c in women lagged by up to 10 years compared to men. Similar findings were found in cohort 2. We estimated an additional 17% (n = 34,953) of undiagnosed women aged < 50 years in England and Wales could be reclassified to have diabetes mellitus, which may contribute to up to 64% of the difference in mortality rates between men/women with diabetes mellitus aged 16-50 years. CONCLUSION: The HbA1c cut point for diagnosis of diabetes mellitus may need to be re-evaluated in women under the age of 50 years. Early identification of diabetes mellitus in women has the potential to improve women's health outcomes in the longer term.

The Effect of the COVID-19 Pandemic on HbA1c Testing: Prioritization of High-Risk Cases and Impact of Social Deprivation.

INTRODUCTION: Studies show that the COVID-19 pandemic disproportionately affected people with diabetes and those from disadvantaged backgrounds. During the first 6 months of the UK lockdown, > 6.6 M glycated haemoglobin (HbA1c) tests were missed. We now report variability in the recovery of HbA1c testing, and its association with diabetes control and demographic characteristics. METHODS: In a service evaluation, we examined HbA1c testing across ten UK sites (representing 9.9% of England's population) from January 2019 to December 2021. We compared monthly requests from April 2020 to those in the equivalent 2019 months. We examined effects of (i) HbA1c level, (ii) between-practice variability, and (iii) practice demographics. RESULTS: In April 2020, monthly requests dropped to 7.9-18.1% of 2019 volumes. By July 2020, testing had recovered to 61.7-86.9% of 2019 levels. During April-June 2020, we observed a 5.1-fold variation in the reduction of HbA1c testing between general practices (12.4-63.8% of 2019 levels). There was evidence of limited prioritization of testing for patients with HbA1c > 86 mmol/mol during April-June 2020 (4.6% of total tests vs. 2.6% during 2019). Testing in areas with the highest social disadvantage was lower during the first lockdown (April-June 2020; trend test p < 0.001) and two subsequent periods (July-September and October-December 2020; both p < 0.001). By February 2021, testing in the highest deprivation group had a cumulative fall in testing of 34.9% of 2019 levels versus 24.6% in those in the lowest group. CONCLUSION: Our findings highlight that the pandemic response had a major impact on diabetes monitoring and screening. Despite limited test prioritization in the > 86 mmol/mol group, this failed to acknowledge that those in the 59-86 mmol/mol group require consistent monitoring to achieve the best outcomes. Our findings provide additional evidence that those from poorer backgrounds were disproportionately disadvantaged. Healthcare services should redress this health inequality.

Evaluating temporal trends and the impact of surgical subspecialisation on patient outcomes following adhesional small bowel obstruction: a multicentre cohort study.

PURPOSE: Small bowel obstruction (SBO) is the most common indication for laparotomy in the UK. While general surgeons have become increasingly subspecialised in their elective practice, emergency admissions commonly remain undifferentiated. This study aimed to assess temporal trends in the management of adhesional SBO and explore the influence of subspecialisation on patient outcomes. METHODS: Data was collected for patients admitted acutely with adhesional SBO across acute NHS trusts in Northern England between 01/01/02 and 31/12/16, including demographics, co-morbidities and procedures performed. Patients were excluded if a potentially non-adhesional cause was identified and were grouped by the responsible consultant's subspecialty. The primary outcome of interest was 30-day inpatient mortality. RESULTS: Overall, 2818 patients were admitted with adhesional SBO during a 15-year period. There was a consistent female preponderance, but age and comorbidity increased significantly over time (both p < 0.001). In recent years, more patients were managed operatively with a trend away from delayed surgery also evident (2002-2006: 65.7% vs. 2012-2016: 42.7%, p < 0.001). Delayed surgery was associated with an increased mortality risk on multivariable regression analysis (OR: 2.46 (1.46-4.23, p = 0.001)). CT scanning was not associated with management strategy or timing of surgery (p = 0.369). There was an increased propensity for patients to be managed by gastrointestinal (colorectal and upper gastrointestinal) subspecialists over time. Length of stay (p < 0.001) and 30-day mortality (p < 0.001) both improved in recent years, with the best outcomes seen in colorectal (2.6%) and vascular subspecialists (2.4%). However, following adjustment for confounding variables, consultant subspecialty was not a predictor of mortality. CONCLUSION: Outcomes for patients presenting with adhesional SBO have improved despite the increasing burden of age and co-morbidity. While gastrointestinal subspecialists are increasingly responsible for their care, mortality is not influenced by consultant subspecialty.

Assessment of the effect of the COVID-19 pandemic on UK HbA1c testing: implications for diabetes management and diagnosis.

AIMS: The COVID-19 pandemic, and the focus on mitigating its effects, has disrupted diabetes healthcare services worldwide. We aimed to quantify the effect of the pandemic on diabetes diagnosis/management, using glycated haemoglobin (HbA1c) as surrogate, across six UK centres. METHODS: Using routinely collected laboratory data, we estimated the number of missed HbA1c tests for 'diagnostic'/'screening'/'management' purposes during the COVID-19 impact period (CIP; 23 March 2020 to 30 September 2020). We examined potential impact in terms of: (1) diabetes control in people with diabetes and (2) detection of new diabetes and prediabetes cases. RESULTS: In April 2020, HbA1c test numbers fell by ~80%. Overall, across six centres, 369 871 tests were missed during the 6.28 months of the CIP, equivalent to >6.6 million tests nationwide. We identified 79 131 missed 'monitoring' tests in people with diabetes. In those 28 564 people with suboptimal control, this delayed monitoring was associated with a 2-3 mmol/mol HbA1c increase. Overall, 149 455 'screening' and 141 285 'diagnostic' tests were also missed. Across the UK, our findings equate to 1.41 million missed/delayed diabetes monitoring tests (including 0.51 million in people with suboptimal control), 2.67 million screening tests in high-risk groups (0.48 million within the prediabetes range) and 2.52 million tests for diagnosis (0.21 million in the pre-diabetes range; ~70 000 in the diabetes range). CONCLUSIONS: Our findings illustrate the widespread collateral impact of implementing measures to mitigate the impact of COVID-19 in people with, or being investigated for, diabetes. For people with diabetes, missed tests will result in further deterioration in diabetes control, especially in those whose HbA1c levels are already high.

Variability in Test Interval Is Linked to Glycated Haemoglobin (HbA1c) Trajectory over Time.

Aims: We previously showed that the glycated haemoglobin (HbA1c) testing frequency links to diabetes control. Here, we examine the effect of variability in test interval, adjusted for the frequency, on change in HbA1c (ΔHbA1c). Materials & Methods. HbA1c results were collected on 83,872 people with HbA1c results at baseline and 5 years (±3 months) later and ≥6 tests during this period. We calculated the standard deviation (SD) of test interval for each individual and examined the link between deciles of SD of the test interval and ΔHbA1c level, stratified by baseline HbA1c. Results: In general, less variability in testing frequency (more consistent monitoring) was associated with better diabetes control. This was most evident with moderately raised baseline HbA1c levels (7.0-9.0% (54-75 mmol/mol)). For example, in those with a starting HbA1c of 7.0-7.5% (54-58 mmol/mol), the lowest SD decile was associated with little change in HbA1c over 5 years, while for those with the highest decile, HbA1c rose by 0.4-0.6% (4-6 mmol/mol; p < 0.0001). Multivariate analysis showed that the association was independent of the age/sex/hospital site. Subanalysis suggested that the effect was most pronounced in those aged <65 years with baseline HbA1c of 7.0-7.5% (54-58 mmol/mol). We observed a 6.7-fold variation in the proportion of people in the top-three SD deciles across general practices. Conclusions: These findings indicate that the consistency of testing interval, not the just number of tests/year, is important in maintaining diabetes control, especially in those with moderately raised HbA1c levels. Systems to improve regularity of HbA1c testing are therefore needed, especially given the impact of COVID-19 on diabetes monitoring.

Synthetic Strategy Towards Heterodimetallic Half-Sandwich Complexes Based on a Symmetric Ditopic Ligand.

Multimetallic complexes have been shown in several examples to possess greater anticancer activity than their monometallic counterparts. The increased activity has been attributed to altered modes of action. We herein report the synthesis of a series of heterodimetallic compounds based on a ditopic ligand featuring 2-pyridylimine chelating motifs and organometallic half-sandwich moieties. The complexes were characterized by a combination of 1H NMR spectroscopy, electrospray ionization mass spectrometry, elemental analysis and single crystal X-ray diffraction. Investigations into the stability of representative complexes in DMSO-d 6 and 10% DMSO-d 6 /D2O revealed the occurrence of solvent-chlorido ligand exchange. Proliferation assays in four human cancer cell lines showed that the Os-Rh complex possessed minimal activity, while all other complexes were inactive.

Can we check serum lithium levels less often without compromising patient safety?

BACKGROUND: Lithium is viewed as the first-line long-term treatment for prevention of relapse in people with bipolar disorder. AIMS: This study examined factors associated with the likelihood of maintaining serum lithium levels within the recommended range and explored whether the monitoring interval could be extended in some cases. METHOD: We included 46 555 lithium rest requests in 3371 individuals over 7 years from three UK centres. Using lithium results in four categories (<0.4 mmol/L; 0.40-0.79 mmol/L; 0.80-0.99 mmol/L; ≥1.0 mmol/L), we determined the proportion of instances where lithium results remained stable or switched category on subsequent testing, considering the effects of age, duration of lithium therapy and testing history. RESULTS: For tests within the recommended range (0.40-0.99 mmol/L categories), 84.5% of subsequent tests remained within this range. Overall, 3 monthly testing was associated with 90% of lithium results remaining within range, compared with 85% at 6 monthly intervals. In cases where the lithium level in the previous 12 months was on target (0.40-0.79 mmol/L; British National Formulary/National Institute for Health and Care Excellence criteria), 90% remained within the target range at 6 months. Neither age nor duration of lithium therapy had any significant effect on lithium level stability. Levels within the 0.80-0.99 mmol/L category were linked to a higher probability of moving to the ≥1.0 mmol/L category (10%) compared with those in the 0.4-0.79 mmol/L group (2%), irrespective of testing frequency. CONCLUSION: We propose that for those who achieve 12 months of lithium tests within the 0.40-0.79 mmol/L range, the interval between tests could increase to 6 months, irrespective of age. Where lithium levels are 0.80-0.99 mmol/L, the test interval should remain at 3 months. This could reduce lithium test numbers by 15% and costs by ~$0.4 m p.a.

Serum lithium test requesting across three UK regions: an evaluation of adherence to monitoring guidelines.

BACKGROUND: Bipolar disorder is the fourth most common mental health condition, affecting ~ 1% of UK adults. Lithium is an effective treatment for prevention of relapse and hospital admission, and is widely recommended as a first-line treatment. We previously showed in other areas that laboratory testing patterns are variable with sub-optimal conformity to guidance. We therefore examined lithium results and requesting patterns relative to monitoring recommendations. METHODS: Data on serum lithium levels and intervals between requests were extracted from Clinical Biochemistry laboratory information systems at the University Hospitals of North Midlands, Salford Royal Foundation Trust and Pennine Acute Hospitals from 2012 to 2018 (46,555 requests; 3371 individuals). Data were examined with respect to region/source of request, age and sex. RESULTS: Across all sites, lithium levels on many requests were outside the recommended UK therapeutic range (0.4-0.99 mmol/L); 19.2% below the range and 6.1% above the range (median [Li]: 0.60 mmol/L). A small percentage were found at the extremes (3.2% at < 0.1 mmol/L, 1.0% at ≥1.4 mmol/L). Most requests were from general practice (56.3%) or mental health units (34.4%), though those in the toxic range (≥1.4 mmol/L) were more likely to be from secondary care (63.9%). For requesting intervals, there was a distinct peak at 12 weeks, consistent with guidance for those stabilised on lithium therapy. There was no peak at 6 months, as recommended for those aged < 65 years on unchanging therapy, though re-test intervals in this age group were more likely to be longer. There was a peak at 0-7 days, reflecting those requiring closer monitoring (e.g. treatment initiation, toxicity). However, for those with initial lithium concentrations within the BNF range (0.4-0.99 mmol/L), 69.4% of tests were requested outside expected testing frequencies. CONCLUSIONS: Our data showed: (a) lithium levels are often maintained at the lower end of the recommended therapeutic range, (b) patterns of lithium results and testing frequency were comparable across three UK sites with differing models of care and, (c) re-test intervals demonstrate a noticeable peak at the recommended 3-monthly, but not at 6-monthly intervals. Many tests were repeated outside expected frequencies, indicating the need for measures to minimise inappropriate testing.

Structural characterization of twisted gastrulation provides insights into opposing functions on the BMP signalling pathway.

Twisted gastrulation (Tsg) and chordin are secreted glycoproteins that function together as BMP (bone morphogenetic protein) antagonists to regulate BMP growth factor signalling. Chordin binds to BMPs, preventing them from interacting with their receptors and Tsg is known to strengthen this inhibitory complex. Tsg also acts as a BMP agonist by promoting cleavage of chordin by tolloid-family proteinases. Here we explore the structural mechanism through which Tsg exerts this dual activity. We have characterized the nanoscale structure of human Tsg using in-solution biomolecular analysis and show that Tsg is a globular monomer with a flattened cross shape. Tsg has a high proportion of N-linked glycans, in relation to its molecular weight, which supports a role in solubilising BMPs. Tsg binds with high affinity to the C-terminal region of chordin and was also able to inhibit BMP-7 signalling directly but did not have an effect on BMP-4 signalling. Although both Tsg and mammalian tolloid are involved in chordin cleavage, no interaction could be detected between them using surface plasmon resonance. Together these data suggest that Tsg functions as a BMP-agonist by inducing conformational change in chordin making it more susceptible to tolloid cleavage and as a BMP-antagonist either independently or via a chordin-mediated mechanism. Following single cleavage of chordin by tolloids, Tsg continues to strengthen the inhibitory complex, supporting a role for partially cleaved chordin in BMP regulation.