Exploring the patient journey to diagnosis of Gaucher disease from the perspective of 212 patients with Gaucher disease and 16 Gaucher expert physicians

Gaucher disease (GD) is a rare hereditary disorder caused by a deficiency of the lysosomal enzyme β-glucocerebrosidase. Diagnosis is challenging owing to a wide variability in clinical manifestations and severity of symptoms. Many patients may experience marked delays in obtaining a definitive diagnosis. The two surveys reported herein aimed to explore the patient journey to diagnosis of GD from the perspectives of Gaucher expert physicians and patients. Findings from the surveys revealed that many patients experienced diagnostic delays and misdiagnoses, with nearly 1 in 6 patients stating that they were not diagnosed with GD for 7years or more after first consulting a doctor. Physicians and patients both reported multiple referrals to different specialties before a diagnosis of GD was obtained, with primary care, haematology/haematology-oncology and paediatrics the main specialties to which patients first presented. Splenomegaly, thrombocytopenia, anaemia and bone pain were reported as the most common medical problems at first presentation in both surveys. These findings support a clear need for straightforward and easy-to-follow guidance designed to assist non-specialists to identify earlier patients who are at risk of GD

Association between serum keptin concentrations and insulin resistance: A population-based study from China

BACKGROUND Insulin resistance contributes to the cardio-metabolic risk. The effect of leptin in obese and overweight population on insulin resistance was seldom reported. METHODS A total of 1234 subjects (572 men and 662 women) aged ≥18 y was sampled by the procedure. Adiposity measures included BMI, waist circumference, hip circumference, WHR, upper arm circumference, triceps skinfold and body fat percentage. Serum leptin concentrations were measured by an ELISA method. The homeostasis model (HOMA-IR) was applied to estimate insulin resistance. RESULTS In men, BMI was the variable which was most strongly correlated with leptin, whereas triceps skinfold was most sensitive for women. More importantly, serum leptin levels among insulin resistant subjects were almost double compared to the subjects who had normal insulin sensitivity at the same level of adiposity in both men and women, after controlling for potential confounders. In addition, HOMA-IR increased significantly across leptin quintiles after adjustment for age, BMI, total energy intake, physical activity and smoking status in both men and women (p for trend <0.0001). CONCLUSIONS There was a significant association between HOMA-IR and serum leptin concentrations in Chinese men and women, independently of adiposity levels. This may suggest that serum leptin concentration is an important predictor of insulin resistance and other metabolic risks irrespective of obesity levels. Furthermore, leptin levels may be used to identify the cardio-metabolic risk in obese and overweight population.Hui Zuo, Zumin Shi, Baojun Yuan, Yue Dai, Gaolin Wu, Akhtar Hussai

Role of genetic polymorphisms in tumour angiogenesis

Angiogenesis plays a crucial role in the development, growth and spread of solid tumours. Pro- and anti-angiogenic factors are abnormally expressed in tumours, influencing tumour angiogenesis, growth and progression. Polymorphisms in genes encoding angiogenic factors or their receptors may alter protein expression and/or activity. This article reviews the literature to determine the possible role of angiogenesis-related polymorphisms in cancer. Further research studies in this potentially crucial area of tumour biology are proposed

A Matched Cohort Study Evaluating the Risks of Infections in People with Type 1 Diabetes and their Associations with Glycated Haemoglobin.

AIMS: People with type 1 diabetes (T1D) have raised infection rates compared to those without, but how these risks vary by age, sex and ethnicity, or by glycated haemoglobin (HbA1c), remain uncertain. TWEET: People with type 1 diabetes have an increased risk of infections. Mean HbA1c and its variability are important predictors. METHODS: 33,829 patients with T1D in Clinical Practice Research Datalink on 01/01/2015 were age-sex-ethnicity matched to two non-diabetes patients. Infections were collated from primary care and linked hospitalisation records during 2015-2019, and incidence rate ratios (IRRs) were estimated versus non-diabetes. For 26,096 people with T1D, with ≥3 HbA1c measurements in 2012-2014, mean and coefficient of variation were estimated, and compared across percentiles. RESULTS: People with T1D had increased risk for infections presenting in primary care (IRR=1.81, 95%CI 1.77-1.85) and hospitalisations (IRR=3.37, 3.21-3.53) compared to non-diabetes, slightly attenuated after further adjustment. Younger ages and non-White ethnicities had greater relative risks, potentially explained by higher HbA1c mean and variability amongst people with T1D within these sub-groups. Both mean HbA1c and greater variability were strongly associated with infection risks, but the greatest associations were at the highest mean levels (hospitalisations IRR=4.09, 3.64-4.59) for >97 versus ≤53mmol/mol. CONCLUSIONS: Infections are a significant health burden in T1D. Improved glycaemic control may reduce infection risks, while prompter infection treatments may reduce hospital admissions

Effects of long-term HbA1c variability on serious infection risks in patients with type 2 diabetes and the influence of age, sex and ethnicity: A cohort study of primary care data.

AIMS: Long-term HbA1c (glycated haemoglobin) variability is associated with micro- and macrovascular complications in Type 2 diabetes (T2D). We explored prospective associations between HbA1c variability and serious infections, and how these vary by HbA1c level, age, sex and ethnicity. METHODS: 411,963 T2D patients in England, aged 18-90, alive on 01/01/2015 in the Clinical Practice Research Datalink with ≥ 4 HbA1c measurements during 2011-14. Poisson regression estimated incidence rate ratios (IRRs) for infections requiring hospitalisation during 2015-19 by HbA1c Variability Score (HVS) and average level, adjusting for confounders, and stratified by age, sex, ethnicity and average level. Attributable risk fractions (AF) were calculated using reference categories for variability (HVS  1.2) was seen with even modest variability (HVS ≥ 20, 73 % of T2D patients), but only at higher average levels (≥64 mmol/mol, 27 % patients). Estimated AFs were markedly greater for variability than average level (17.1 % vs. 4.1 %). Associations with variability were greater among older patients, and those with lower HbA1c levels, but not observed among Black ethnicities. CONCLUSIONS: HbA1c variability between T2D patients' primary care visits appears to be associated with more serious infections than average level overall. Well-designed trials could test whether these associations are causal

Contribution of infection to mortality in people with type 2 diabetes: a population-based cohort study using electronic records

Background While people with type 2 diabetes (T2D) are more susceptible to infections, studies potentially underestimate the true burden of infection-related mortality since they rely on clinical coding systems primarily structured by body system, and by only focusing on underlying cause. This study examined cause-specific mortality in people with T2D compared to the general population during 2015–2019, focusing on infections. Methods 509,403 people aged 41–90 years with T2D alive on 1/1/2015 in Clinical Practice Research Datalink were matched to 976,431 without diabetes on age, sex, and ethnicity. Recorded underlying cause of death was identified through national linked mortality data; infection-related deaths were counted across all ICD-10 (10th revision of the International Classification of Diseases) chapters, not just infection chapters A00-B99. All-cause and cause-specific hazard ratios (HR) for mortality during 2015–2019 compared people with T2D to people without diabetes and were estimated using Cox models adjusting for region. Additional analyses for sepsis related mortality considered the impact of including any mention of sepsis on the death certificate. Findings 85,367/509,403 (16.8%) people with T2D died during 2015–2019 compared to 106,824/976,431 (10.9%) of people without diabetes of the same sex, age and ethnicity. All infections (11,128/85,367 = 13.0%) represented the third highest underlying cause of death among people with T2D after cardiovascular disease and cancer; a much higher contribution than counting only from specific infection chapters (1046/85,367 = 1.2%). The HR for people with T2D vs non-diabetes for all infection mortality (1.82, 95% CI 1.78–1.86) was higher than that estimated for all-cause (HR = 1.65, 95% CI 1.64–1.66). The estimated mortality rate associated with sepsis among people with T2D was highly dependent on whether any mention was included (2.2 per 1000 person-years) or only underlying cause (0.2 per 1000 person-years); but the HR for people with T2D vs non-diabetes was similar (any mention HR = 2.26, 95% CI 2.19–2.34 vs underlying cause only HR = 2.52, 95% CI 2.27–2.80). Interpretation People with T2D die from infections at a higher rate than similar people without diabetes, and the overall burden is greater than previously reported. Routine statistics concentrating on underlying cause of death may somewhat under-estimate the importance of infections as causes of death among people with T2D. These findings emphasise the potential importance of awareness, earlier diagnosis and treatment of infections to prevent premature deaths. Funding National Institute for Health and Care Research

Body mass index and infection risks in people with and without type 2 diabetes: A cohort study using electronic health records

Background Observational studies have found U-shaped associations between body mass index (BMI) and infections. While people with type 2 diabetes (T2D) are generally more likely to live with obesity and be at higher risk of infections, it is unknown whether BMI has the same impact on infection risk in people with and without diabetes, and whether this varies by type of infection. Methods 516,935 people with T2D and 751,909 people without diabetes, aged 18–90 and alive on 1/1/2015 with BMI measured during 2011–14 matched on age, sex and ethnicity in the Clinical Practice Research Datalink. Infections during 2015–19 were collated from primary care and linked hospitalisation records. Poisson regression estimated incidence rate ratios (IRR) for infection, across 12 BMI categories (from ≤19 kg/m2 to >48 kgm2) using a reference group of >24–≤26 kg/m2. Separate models for T2D and non-diabetes were used, adjusting for age, sex, ethnicity, deprivation, smoking and co-morbidity. Additional analyses explored associations by common infection types. \ud Results People with T2D were at higher infection risk than people without diabetes at all BMI levels, however the pattern observed at different BMI levels was similar in both groups (e.g. BMI >48 compared to BMI >24–≤26, T2D IRR = 2.35, 95%CI 2.26–2.44, non-diabetes IRR = 2.52, 95%CI 2.30–2.75 for hospitalisation-related infections). Hospitalisation-related infections showed a U-shaped association with BMI not explained by age, smoking or co-morbidity, whereas primary care infections were predominately associated with higher BMI levels only. Cellulitis showed the strongest trends in relation to high BMI levels, whilst lower respiratory tract infection and sepsis were related to both high and low BMI levels. Conclusions Infection risks are consistently higher for people with T2D but the association with increasing levels of BMI appears similar both in patients with and without diabetes. Additionally, being underweight is also associated with increased risk of infections requiring hospitalisation

Effects of long-term HbA1c variability on serious infection risks in patients with type 2 diabetes and the influence of age, sex and ethnicity: A cohort study of primary care data

Aims: Long-term HbA1c (glycated haemoglobin) variability is associated with micro- and macrovascular complications in Type 2 diabetes (T2D). We explored prospective associations between HbA1c variability and serious infections, and how these vary by HbA1c level, age, sex and ethnicity. Methods: 411,963 T2D patients in England, aged 18–90, alive on 01/01/2015 in the Clinical Practice Research Datalink with ≥ 4 HbA1c measurements during 2011–14. Poisson regression estimated incidence rate ratios (IRRs) for infections requiring hospitalisation during 2015–19 by HbA1c variability score (HVS) and average level, adjusting for confounders, and stratified by age, sex, ethnicity and average level. Attributable risk fractions (AF) were calculated using reference categories for variability (HVS &lt; 20) and average level (42–48 mmol/mol). Results: An increased infection risk (IRR &gt; 1.2) was seen with even modest variability (HVS ≥ 20, 73 % of T2D patients), but only at higher average levels (≥64 mmol/mol, 27 % patients). Estimated AFs were markedly greater for variability than average level (17.1 % vs. 4.1 %). Associations with variability were greater among older patients, and those with lower HbA1c levels, but not observed among Black ethnicities. Conclusions: HbA1c variability between T2D patients’ primary care visits appears to be associated with more serious infections than average level overall. Well-designed trials could test whether these associations are causal