Anticancer Activity of Astaxanthin-Incorporated Chitosan Nanoparticles.

Astaxanthin (AST)-encapsulated nanoparticles were fabricated using glycol chitosan (Chito) through electrostatic interaction (abbreviated as ChitoAST) to solve the aqueous solubility of astaxanthin and improve its biological activity. AST was dissolved in organic solvents and then mixed with chitosan solution, followed by a dialysis procedure. All formulations of ChitoAST nanoparticles showed small diameters (less than 400 nm) with monomodal distributions. Analysis with Fourier transform infrared (FT-IR) spectroscopy confirmed the specific peaks of AST and Chito. Furthermore, ChitoAST nanoparticles were formed through electrostatic interactions between Chito and AST. In addition, ChitoAST nanoparticles showed superior antioxidant activity, as good as AST itself; the half maximal radical scavenging concentrations (RC50) of AST and ChitoAST nanoparticles were 11.8 and 29.3 µg/mL, respectively. In vitro, AST and ChitoAST nanoparticles at 10 and 20 µg/mL properly inhibited the production of intracellular reactive oxygen species (ROSs), nitric oxide (NO), and inducible nitric oxide synthase (iNOS). ChitoAST nanoparticles had no significant cytotoxicity against RAW264.7 cells or B16F10 melanoma cells, whereas AST and ChitoAST nanoparticles inhibited the growth of cancer cells. Furthermore, AST itself and ChitoAST nanoparticles (20 µg/mL) efficiently inhibited the migration of cancer cells in a wound healing assay. An in vivo study using mice and a pulmonary metastasis model showed that ChitoAST nanoparticles were efficiently delivered to a lung with B16F10 cell metastasis; i.e., fluorescence intensity in the lung was significantly higher than in other organs. We suggest that ChitoAST nanoparticles are promising candidates for antioxidative and anticancer therapies of B16F10 cells.

A cluster randomised controlled trial, process and economic evaluation of quality improvement collaboratives aligned to a national audit to improve the care for people with diabetes (EQUIPD): study protocol.

BACKGROUND: People with type 1 diabetes and raised glucose levels are at greater risk of retinopathy, nephropathy, neuropathy, cardiovascular disease, sexual health problems and foot disease. The UK National Institute for Health and Care Excellence (NICE) recommends continuous subcutaneous 'insulin pump' therapy for people with type 1 diabetes whose HbA1c is above 69 mmol/mol. Insulin pump use can improve quality of life, cut cardiovascular risk and increase treatment satisfaction. About 90,000 people in England and Wales meet NICE criteria for insulin pumps but do not use one. Insulin pump use also varies markedly by deprivation, ethnicity, sex and location. Increasing insulin pump use is a key improvement priority. Audit and feedback is a common but variably effective intervention. Limited capabilities of healthcare providers to mount effective responses to feedback from national audits, such as the National Diabetes Audit (NDA), undermines efforts to improve care. We have co-developed a theoretically and empirically informed quality improvement collaborative (QIC) to strengthen local responses to feedback with patients and carers, national audits and healthcare providers. We will evaluate whether the QIC improves the uptake of insulin pumps following NDA feedback. METHODS: We will undertake an efficient cluster randomised trial using routine data. The QIC will be delivered alongside the NDA to specialist diabetes teams in England and Wales. Our primary outcome will be the proportion of people with type 1 diabetes and an HbA1c above 69 mmol/mol who start and continue insulin pump use during the 18-month intervention period. Secondary outcomes will assess change in glucose control and duration of pump use. Subgroup analyses will explore impacts upon inequalities by ethnicity, sex, age and deprivation. A theory-informed process evaluation will explore diabetes specialist teams' engagement, implementation, fidelity and tailoring through observations, interviews, surveys and documentary analysis. An economic evaluation will micro-cost the QIC, estimate cost-effectiveness of NDA feedback with QIC and estimate the budget impact of NHS-wide QIC roll out. DISCUSSION: Our study responds to a need for more head-to-head trials of different ways of reinforcing feedback delivery. Our findings will have implications for other large-scale audit and feedback programmes. TRIAL REGISTRATION: ISRCTN82176651 Registered 18 October 2022.

National Trends in Hyperglycemia and Diabetic Ketoacidosis in Children, Adolescents, and Young Adults With Type 1 Diabetes: A Challenge Due to Age or Stage of Development, or Is New Thinking About Service Provision Needed?

OBJECTIVE: Adolescence is associated with high-risk hyperglycemia. This study examines the phenomenon in a life course context. RESEARCH DESIGN AND METHODS: A total of 93,125 people with type 1 diabetes aged 5 to 30 years were identified from the National Diabetes Audit and/or the National Paediatric Diabetes Audit for England and Wales for 2017/2018-2019/2020. For each audit year, the latest HbA1c and hospital admissions for diabetic ketoacidosis (DKA) were identified. Data were analyzed in sequential cohorts by year of age. RESULTS: In childhood, unreported HbA1c measurement is uncommon; however, for 19-year-olds, it increases to 22.3% for men and 17.3% for women, and then reduces to 17.9% and 13.1%, respectively, for 30-year-olds. Median HbA1c for 9-year-olds is 7.6% (60 mmol/mol) (interquartile range 7.1-8.4%, 54-68 mmol/mol) in boys and 7.7% (61 mmol/mol) (8.0-8.4%, 64-68 mmol/mol) in girls, increasing to 8.7% (72 mmol/mol) (7.5-10.3%, 59-89 mmol/mol) and 8.9% (74 mmol/mol) (7.7-10.6%, 61-92 mmol/mol), respectively, for 19-year-olds before falling to 8.4% (68 mmol/mol) (7.4-9.7%, 57-83 mmol/mol) and 8.2% (66 mmol/mol) (7.3-9.7%, 56-82 mmol/mol), respectively, for 30-year-olds. Annual hospitalization for DKA rose steadily in age from 6 years (2.0% for boys, 1.4% for girls) and peaked at 19 years for men (7.9%) and 18 years for women (12.7%), reducing to 4.3% for men and 5.4% for women at age 30 years. For all ages over 9 years, the prevalence of DKA was higher in female individuals. CONCLUSIONS: HbA1c and the prevalence of DKA increase through adolescence and then decline. Measurement of HbA1c, a marker of clinical review, falls abruptly in the late teenage years. Age-appropriate services are needed to overcome these issues.

Comparative Incidence of Diabetes Following Hospital Admission for COVID-19 and Pneumonia: A Cohort Study.

OBJECTIVE: The incidence of diabetes may be elevated following coronavirus disease 2019 (COVID-19), but it is unclear whether this is specific to severe acute respiratory syndrome coronavirus 2 infection, associated with shared risk factors for severe COVID-19 and diabetes, and/or a generic risk following illness. RESEARCH DESIGN AND METHODS: People admitted to the hospital for COVID-19 and/or pneumonia between 1 April 2020 and 31 August 2020 in England were linked with the National Diabetes Audit to identify incident diabetes after discharge up to 31 March 2021. Comparator cohorts admitted with pneumonia over the same dates in 2017, 2018, and 2019 were followed until 31 March 2018, 31 March 2019, and 31 March 2020, respectively. Poisson regression models were used to calculate adjusted diabetes incidence rates. RESULTS: Using the cohort of people discharged from the hospital following a diagnosis of COVID-19 without pneumonia in 2020 as the standard population (incidence rate 16.4 [95% CI 12.8-20.7] per 1,000 person-years), adjusting for age, sex, ethnicity, and deprivation, gave incidence rates of 19.0 (95% CI 13.8-25.6) and 16.6 (95% CI 13.3-20.4) per 1,000 person-years for those admitted for COVID-19 with pneumonia and pneumonia without COVID-19, respectively, in 2020. These rates are not significantly different from those found after hospital admission for pneumonia in 2019, 2018, and 2017, at 13.7 (95% CI 10.8-17.3), 13.8 (95% CI 10.9-17.4), and 14.2 (95% CI 10.9-18.3) per 1,000 person-years, respectively. CONCLUSIONS: Our data do not support a clear impact of COVID-19 on the incidence of diabetes compared with risks in several comparator groups, including contemporaneously assessed risks in people hospitalized with pneumonia.

Impact of case-mix adjustment on observed variation in the healing of diabetic foot ulcers at 12 weeks using data from the National Diabetes Foot Care Audit of England and Wales: A cohort study.

AIM: This cohort study investigates the extent to which variation in ulcer healing between services can be explained by demographic and clinical characteristics. METHODS: The National Diabetes Foot Care Audit collated data on people with diabetic foot ulcers presenting to specialist services in England and Wales between July 2014 and March 2018. Logistic regression models were created to describe associations between risk factors and a person being alive and ulcer-free 12 weeks from presentation, and to investigate whether variation between 120 participating services persisted after risk factor adjustment. RESULTS: Of 27,030 people with valid outcome data, 12,925 (47.8%) were alive and ulcer-free at 12 weeks, 13,745 (50.9%) had an unhealed ulcer and 360 had died (1.3%). Factors associated with worse outcome were male sex, more severe ulcers, history of cardiac or renal disease and a longer time between first presentation to a non-specialist healthcare professional and first expert assessment. After adjustment for these factors, four services (3.3%) were more than 3SD above and seven services (5.8%) were more than 3SD below the national mean for proportions that were alive and ulcer-free at follow-up. CONCLUSIONS/INTERPRETATIONS: Variation in the healing of diabetic foot ulcers between specialist services in England and Wales persisted after adjusting for demographic characteristics, ulcer severity, smoking, body mass index and co-morbidities. We conclude that other factors contribute to variation in healing of diabetic foot ulcers and include the time to specialist assessment.

Care processes in people in remission from type 2 diabetes: A cohort study using the National Diabetes Audit.

AIMS: People with type 2 diabetes can enter remission but may relapse or develop legacy complications. This analysis assesses whether people with remission from type 2 diabetes continue receiving annual care processes recommended in national guidelines and the potential impacts of formal recognition of remission. METHODS: People with type 2 diabetes with and without formal recognition (diagnostic code) of remission, and with and without evidence of remission (HbA1c < 48 mmol/mol without prescription for glucose-lowering drugs in preceding 26 weeks), included in the 2018/19 National Diabetes Audit (NDA) for England and Wales were followed up to identify care processes received between 1 January 2019 and 31 March 2020. RESULTS: Of the 2,822,145 people with type 2 diabetes in the cohort, 16,460 (0.58%) were coded with remission in the 2018/19 NDA. After adjustment for age, sex, socioeconomic deprivation and ethnicity, people coded with remission were less likely to receive each care process than those without such coding irrespective of HbA1c measurements (relative risk (RR) of receiving all 8 care processes 0.70 (95% CI 0.69-0.72)). For the 339,235 people with evidence of remission, irrespective of diagnostic coding compared to those without such evidence, the RR for receiving all 8 care processes was 0.94 (95% CI 0.93-0.94). CONCLUSIONS: People coded with remission of type 2 diabetes were less likely to receive diabetes care processes than those without such coding. People with evidence of remission had only a slightly reduced likelihood of receiving care processes. Formal recognition of remission may affect the provision or uptake of care processes.

Effectiveness of digital and remote provision of the Healthier You: NHS Diabetes Prevention Programme during the COVID-19 pandemic.

AIMS: To assess weight change in the Healthier You: NHS Diabetes Prevention Programme (NHS DPP) delivered via video conferencing (remote) sessions or delivered via specific digital interventions through apps or websites, during the COVID-19 pandemic compared to group-based face-to-face interventions, pre-pandemic. METHODS: Prospectively collected national service-level data relating to individuals with non-diabetic hyperglycaemia (HbA1c 42-47 mmol/mol (6.0%-6.4%) or fasting plasma glucose 5.5-6.9 mmol/L) referred to the NHS DPP from June 2016 to March 2022. RESULTS: Between March 2020 and March 2022, 335,961 people were referred to the programme and were offered a choice of remote or digital intervention. This was preceded by 556,793 people referred to the face-to-face programme between June 2016 and February 2022. Uptakes to intervention sessions were 47% for those offered a choice and 39% for face-to-face. Remote and digital participants were significantly younger (60 and 56 vs. 65 years) and heavier (86.1 kg and 91.0 kg vs. 84.1 kg) compared to face-to-face. Weight change was assessed for 42,407 remote, 7699 digital and 97,205 face-to-face participants with sufficient time to have finished the programme and no missing data. Mean weight losses for participants attending at least one intervention session were: 2.40 (2.36-2.44) kg, 2.59 (2.49-2.68) kg and 2.01 (1.98-2.04) kg for remote, digital and face-to-face participants respectively. Corresponding mean weight losses for those who completed the programme were: 3.24 (3.19-3.30) kg, 4.76 (4.60-4.92) kg and 3.04 (3.00-3.07) kg. There were no significant differences in weight change between interventions by ethnicity and deprivation. CONCLUSIONS: Weight losses achieved through remote and digital interventions were greater than those previously achieved through face-to-face interventions, without evidence of exacerbation of health inequalities.

Characteristics and care of young people with type 2 diabetes included in the national diabetes audit datasets for England.

INTRODUCTION: We report contemporary age-related prevalence, characteristics and care of children and young people with type 2 diabetes in England. METHODS: Individuals with a recorded diagnosis of type 2 diabetes between January 2019 and March 2020 were identified from a whole population register. Age, sex, ethnicity, deprivation quintile, weight, HbA1c and receipt of the nine National Institute for Health & Care Excellence (NICE) recommended annual care processes were extracted from electronic clinical records and analysed by pre-specified age bands. RESULTS: In total, 122,780 (4.6%) of 2,642,435 individuals in England with type 2 diabetes were aged under 40 years, comprising; 650 (0.5%) under 16 years, 910 (0.7%) aged 16-18 years, 8245 (6.7%) aged 19-25 and 112,975 (92%) aged 26-39 years. Compared to people with type 2 diabetes aged above 40 years, young people were significantly more likely to be from minority ethnic groups: 51% under 16 years, 41% 16-18 years, 38% 19-25 years, 38% 26-39 years, 27% 40-59 years and 15% 60-79 years were of Black or Asian ethnicity. In addition, those aged under 40 years were more likely to be obese, women, to live in the most-deprived socioeconomic areas and less likely to receive the NICE recommended annual care processes or achieve target HbA1c . INTERPRETATION: The substantial number of people under 40 years of age with type 2 diabetes, are more likely to have characteristics associated with inequalities and are less likely to achieve HbA1c targets and receive recommended care processes. These findings highlight the need to consider novel approaches to service provision for this high-risk group.

Developing services to support the delivery of care to people with early-onset type 2 diabetes.

Early-onset type 2 diabetes occurring in childhood or early adulthood carries a significant excess burden of microvascular diabetes complications, cardiovascular disease and premature death, compared to later onset type 2 diabetes along with adverse pregnancy outcomes in women of child-bearing age. National audit data in England reveal that 122,780 individuals under the age of 40 years are currently living with type 2 diabetes, with an over-representation of people from minority ethnicities and those in the most socioeconomically deprived quintiles. A diagnosis of type 2 diabetes earlier in life poses some unique challenges to healthcare providers that are not routinely encountered when type 2 diabetes presents later. These include; (1) the need to ensure correct diabetes classification in an age group that carries a higher probability of other types of diabetes, (2) overcoming difficulties in engaging with individuals who are of working age or in full-time education, (3) appreciating and addressing the lower attainment of diabetes treatment targets and (4) proactively supporting women of child-bearing age to optimise their future pregnancy outcomes through better preparation for pregnancy, including achieving optimum glycaemic control at the time of conception. Meanwhile, approaches to prevent type 2 diabetes in younger age groups are challenged by difficulties in identifying those at highest risk, by poorer attendance at lifestyle interventions to prevent or delay the onset of type 2 diabetes and by attenuation of associated weight loss in those that do attend. In this article, we discuss the importance of recognising and addressing the distinct challenges in delivering healthcare to those with early-onset type 2 diabetes, the greater challenges in preventing type 2 diabetes at younger ages, and key components of strategies that might address these challenges to drive improvements in pregnancy outcomes, microvascular and cardiovascular outcomes.

Associations between reductions in routine care delivery and non-COVID-19-related mortality in people with diabetes in England during the COVID-19 pandemic: a population-based parallel cohort study.

BACKGROUND: The Office for Health Improvement and Disparities, part of the UK Government Department of Health and Social Care, highlighted an emerging signal of increased non-COVID-19-related deaths in England between July and October, 2021, with a potentially disproportionate higher increase in people with diabetes. We aimed to substantiate and quantify this apparent excess mortality, and to investigate the association between diabetes routine care delivery and non-COVID-19-related-mortality in people with diabetes before and after the onset of the pandemic. METHODS: In this population-based parallel cohort study, we used the National Diabetes Audit (NDA) to identify people with diabetes in England. The primary outcome was non-COVID-19-related deaths between July 3, 2021, and Oct 15, 2021, in participants in the 2021 COVID-19 cohort (registered in the NDA in the periods Jan 1, 2019, to March 31, 2020, and Jan 1, 2020, to March 31, 2021) compared with deaths between June 29, 2019, and Oct 11, 2019 (the equivalent 15-week period in 2019) in the 2019 pre-COVID-19 comparator cohort (people registered in the NDA in the periods Jan 1, 2017, to March 31, 2018, and Jan 1, 2018 to March 31, 2019). In each cohort, multivariable logistic regression examined whether completion of eight diabetes care processes in each of the two years before the index mortality year was associated with non-COVID-19-related death, adjusting for diabetes type, age, sex, ethnicity, and socioeconomic deprivation. FINDINGS: There were 3 218 570 people in the 2021 cohort and 2 973 645 people in the 2019 comparator cohort. In the 2021 cohort, there were 30 118 non-COVID-19-related deaths in people with diabetes, compared with 27 132 in the comparator cohort, representing an 11% increase (95% CI 9-13). The unadjusted incidence rate ratio (IRR) for mortality in the 2021 cohort compared to the 2019 cohort was 1·026 (1·009-1·043; p=0·003), which was unchanged after adjustment for age, sex, ethnicity, socioeconomic deprivation, and diabetes type (IRR 1·023 (1·006-1·040); p=0·007). In the 2021 cohort, 853 660 (26·5%) people received all eight care processes in 2020-21 compared with 1 547 240 (48·1%) people in 2019-20; a 44·8% (95% CI 44·7-45·0) relative reduction. In the pre-COVID-19 comparator cohort, 1 370 315 (46·1%) people with diabetes received all eight care processes in 2018-19 compared with 1 437 740 (48·3%) in 2017-18; a 4·7% (95% CI 4·5-4·9) relative decrease. Non-COVID-19-related mortality in the 2021 cohort was highest in people who did not receive all eight care processes in either of the two previous years (OR 2·67 [95% CI 2·56-2·77]; p<0·001) compared with those who received all eight care processes in both previous years. Mortality was also significantly higher in those who received all eight care processes in 2019-20 but not in 2020-21 (OR 1·66 [95% CI 1·59-1·73]; p<0·001) or not in 2019-20 but in 2020-21 (OR 1·27 [1·20-1·35]; p<0·001). This pattern of association was similar in the 2019 pre-COVID-19 cohort. INTERPRETATION: Our results show an increased risk of mortality in those who did not receive all eight care processes in one or both of the previous two years. Our results provide evidence that the increased rate of non-COVID-19-related mortality in people with diabetes in England observed between July 3, and Oct 15 of 2021 is associated with a reduction in completion of routine diabetes care processes following the pandemic onset in 2020. FUNDING: None.

Incidence and Characteristics of Remission of Type 2 Diabetes in England: A Cohort Study Using the National Diabetes Audit.

OBJECTIVE: To assess the incidence of remission of type 2 diabetes in routine care settings. RESEARCH DESIGN AND METHODS: People with type 2 diabetes (HbA1c ≥48 mmol/mol [6.5%] or <48 mmol/mol [6.5%] with a prescription for glucose-lowering medications) alive on 1 April 2018 were identified from a national collation of health records in England and followed until 31 December 2019. Remission was defined as two HbA1c measurements of <48 mmol/mol (6.5%) at least 182 days apart, with no prescription for glucose-lowering medications 90 days before these measurements. RESULTS: In 2,297,700 people with type 2 diabetes, the overall incidence of remission per 1,000 person-years was 9.7 (95% CI 9.6-9.8) and 44.9 (95% CI 44.0-45.7) in 75,610 (3.3%) people who were diagnosed <1 year. In addition to shorter duration of diagnosis, baseline factors associated with higher odds of remission were no prescription for glucose-lowering medication, lower HbA1c and BMI, BMI reduction, White ethnicity, female sex, and lower socioeconomic deprivation. Among 8,940 (0.4%) with characteristics associated with remission (diagnosed <2 years, HbA1c <53 mmol/mol [7.0%], prescribed metformin alone or no glucose-lowering medications, BMI reduction of ≥10%), incidence of remission per 1,000 person-years was 83.2 (95% CI 78.7-87.9). CONCLUSIONS: Remission of type 2 diabetes was generally infrequent in routine care settings but may be a reasonable goal for a subset of people who lose a significant amount of weight shortly after diagnosis. Policies that encourage intentional remission of type 2 diabetes should seek to reduce the ethnic and socioeconomic inequalities identified.

Stimuli-Responsive Drug Delivery of Doxorubicin Using Magnetic Nanoparticle Conjugated Poly(ethylene glycol)-g-Chitosan Copolymer.

Stimuli-responsive nanoparticles are regarded as an ideal candidate for anticancer drug targeting. We synthesized glutathione (GSH) and magnetic-sensitive nanocomposites for a dual-targeting strategy. To achieve this goal, methoxy poly (ethylene glycol) (MePEG) was grafted to water-soluble chitosan (abbreviated as ChitoPEG). Then doxorubicin (DOX) was conjugated to the backbone of chitosan via disulfide linkage. Iron oxide (IO) magnetic nanoparticles were also conjugated to the backbone of chitosan to provide magnetic sensitivity. In morphological observation, images from a transmission electron microscope (TEM) showed that IO nanoparticles were embedded in the ChitoPEG/DOX/IO nanocomposites. In a drug release study, GSH addition accelerated DOX release rate from nanocomposites, indicating that nanocomposites have redox-responsiveness. Furthermore, external magnetic stimulus concentrated nanocomposites in the magnetic field and then provided efficient internalization of nanocomposites into cancer cells in cell culture experiments. In an animal study with CT26 cell-bearing mice, nanocomposites showed superior magnetic sensitivity and then preferentially targeted tumor tissues in the field of external magnetic stimulus. Nanocomposites composed of ChitoPEG/DOX/IO nanoparticle conjugates have excellent anticancer drug targeting properties.

Temporal trends in emergency admissions for diabetic ketoacidosis in people with diabetes in England before and during the COVID-19 pandemic: a population-based study.

BACKGROUND: Diabetic ketoacidosis (DKA) has been reported to be increasing in frequency during the COVID-19 pandemic. We aimed to examine the rates of DKA hospital admissions and the patient demographics associated with DKA during the pandemic compared with in prepandemic years. METHODS: Using a comprehensive, multiethnic, national dataset, the Secondary Uses Service repository, we extracted all emergency hospital admissions in England coded with DKA from March 1 to June 30, 2020 (first wave of the pandemic), July 1 to Oct 31, 2020 (post-first wave), and Nov 1, 2020, to Feb 28, 2021 (second wave), and compared these with DKA admissions in the equivalent periods in 2017-20. We also examined baseline characteristics, mortality, and trends in patients who were admitted with DKA. FINDINGS: There were 8553 admissions coded with DKA during the first wave, 8729 during the post-first wave, and 10 235 during the second wave. Compared with preceding years, DKA admissions were 6% (95% CI 4-9; p<0·0001) higher in the first wave of the pandemic (from n=8048), 6% (3-8; p<0·0001) higher in the post-first wave (from n=8260), and 7% (4-9; p<0·0001) higher in the second wave (from n=9610). In the first wave, DKA admissions reduced by 19% (95% CI 16-21) in those with pre-existing type 1 diabetes (from n=4965 to n=4041), increased by 41% (35-47) in those with pre-existing type 2 diabetes (from n=2010 to n=2831), and increased by 57% (48-66) in those with newly diagnosed diabetes (from n=1072 to n=1681). Compared with prepandemic, type 2 diabetes DKA admissions were similarly common in older individuals and men but were higher in those of non-White ethnicities during the first wave. The increase in newly diagnosed DKA admissions occurred across all age groups and these were significantly increased in men and people of non-White ethnicities. In the post-first wave, DKA admissions did not return to the baseline level of previous years; DKA admissions were 14% (11-17) lower in patients with type 1 diabetes (from n=5208 prepandemic to n=4491), 30% (24-36) higher in patients with type 2 diabetes (from n=2011 to n=2613), and 56% (47-66) higher in patients with newly diagnosed diabetes (from n=1041 to n=1625). During the second wave, DKA admissions were 25% (22-27) lower in patients with type 1 diabetes (from n=5769 prepandemic to n=4337), 50% (44-56) higher in patients with type 2 diabetes (from n=2608 to n=3912), and 61% (52-70) higher in patients with newly diagnosed diabetes (from n=1234 to n=1986). INTERPRETATION: Our results provide evidence for differences in the numbers and characteristics of people presenting with DKA during the COVID-19 pandemic compared with in the preceding 3 years. Greater awareness of risk factors for DKA in type 2 diabetes and vigilance for newly diagnosed diabetes presenting with DKA during the COVID-19 pandemic might help mitigate the increased impact of DKA. FUNDING: None.

Completion of annual diabetes care processes and mortality: A cohort study using the National Diabetes Audit for England and Wales.

AIM: To conduct an analysis to assess whether the completion of recommended diabetes care processes (glycated haemoglobin [HbA1c], creatinine, cholesterol, blood pressure, body mass index [BMI], smoking habit, urinary albumin, retinal and foot examinations) at least annually is associated with mortality. MATERIALS AND METHODS: A cohort from the National Diabetes Audit of England and Wales comprising 179 105 people with type 1 and 1 397 790 people with type 2 diabetes, aged 17 to 99 years on January 1, 2009, diagnosed before January 1, 2009 and alive on April 1, 2013 was followed to December 31, 2019. Cox proportional hazards models adjusting for demographic characteristics, smoking, HbA1c, blood pressure, serum cholesterol, BMI, duration of diagnosis, estimated glomerular filtration rate, prior myocardial infarction, stroke, heart failure, respiratory disease and cancer, were used to investigate whether care processes recorded January 1, 2009 to March 31, 2010 were associated with subsequent mortality. RESULTS: Over a mean follow-up of 7.5 and 7.0 years there were 26 915 and 388 093 deaths in people with type 1 and type 2 diabetes, respectively. Completion of five or fewer, compared to eight, care processes (retinal screening not included as data were not reliable) had a mortality hazard ratio (HR) of 1.37 (95% confidence interval [CI] 1.28-1.46) in people with type 1 and 1.32 (95% CI 1.30-1.35) in people with type 2 diabetes. The HR was higher for respiratory disease deaths and lower in South Asian ethnic groups. CONCLUSIONS: People with diabetes who have fewer routine care processes have higher mortality. Further research is required into whether different approaches to care might improve outcomes for this high-risk group.

Higher perceived stress and exacerbated motor symptoms in Parkinson's disease during the COVID-19 lockdown in New Zealand.

AIMS: Stress plays a key role in Parkinson's disease (PD) by acting on the dopaminergic system and worsening patients' motor function. The impact of New Zealand's strict lockdown measures to contain COVID-19 on perceived stress and PD motor symptoms remains unknown. Here we examined the relationship between perceived levels of stress, changes in physical activity levels and PD motor symptoms during lockdown. METHODS: During lockdown, 134 participants with PD and 49 controls completed a survey assessing perceived stress, self-reported changes in PD motor symptoms and physical activity duration and intensity prior to and during lockdown. RESULTS: Perceived stress was higher in PD than controls, and in those reporting a worsening of tremor, balance/gait, dyskinesia and bradykinesia compared to those indicating no change during the COVID-19 lockdown. These effects were not modulated by physical activity. CONCLUSIONS: Reducing stressors may be an important adjunct treatment strategy to improve motor function in PD.

Cohort profile: National Diabetes Audit for England and Wales.

The National Diabetes Audit (NDA) collates and analyses data on the quality and variation in clinical care and outcomes for people with diabetes. It also provides opportunities to assess trends, determinants, and outcomes of diabetes to help guide clinical and public health priorities. COHORT: Between 1 January 2003 and 31 March 2020, a total of 5,280,885 people diagnosed with diabetes were included in at least one NDA data collection. To this date, median follow-up was 12 and 8 years for people with type 1 diabetes and type 2 diabetes respectively. Comparisons with the 2019/20 Quality and Outcomes Framework show it included 98% of adults in England and Wales with diagnosed type 1 and type 2 diabetes. Data include demographic characteristics (age, sex, ethnicity, age at diagnosis, deprivation), risk factors (HbA1c , blood pressure, cholesterol, body mass index, smoking status) diabetic and cardiovascular complications and deaths. SECONDARY ANALYSIS: Secondary analyses have included comparisons of HbA1c and blood pressure measurements in cohorts with similar characteristics to the Epidemiology of Diabetes Interventions and Complications study and the UK Prospective Diabetes Study; COVID-19 related mortality in people with type 1 and type 2 diabetes and incidence of type 2 diabetes following admission to intensive care units. FUTURE PLANS: Commissioned NDA reports will continue to inform service development in England and Wales. The same data, with or without linkages to other external datasets, are also a rich resource for clinically orientated research.

Neuropsychiatric Symptoms Are Associated with Dementia in Parkinson's Disease but Not Predictive of it.

BACKGROUND: Neuropsychiatric symptoms in Parkinson's disease (PD) may increase dementia (PDD) risk. The predictive value of these symptoms, however, has not been compared to clinical and demographic predictors of future PDD. OBJECTIVES: Determine if neuropsychiatric symptoms are useful markers of PDD risk. METHODS: 328 PD participants completed baseline neuropsychiatric and MDS-Task Force-Level II assessments. Of these, 202 non-demented individuals were followed-up over a four-years period to detect conversion to PDD; 51 developed PDD. ROC analysis tested associations between baseline neuropsychiatric symptoms and future PDD. The probability of developing PDD was also modeled as a function of neuropsychiatric inventory (NPI)-total score, PD Questionnaire (PDQ)-hallucinations, PDQ-anxiety, and contrasted to cognitive ability, age, and motor function. Leave-one-out information criterion was used to evaluate which models provided useful information when predicting future PDD. RESULTS: The PDD group experienced greater levels of neuropsychiatric symptoms compared to the non-PDD groups at baseline. Few differences were found between the PD-MCI and PD-N groups. Six neuropsychiatric measures were significantly, but weakly, associated with future PDD. The strongest was NPI-total score: AUC = 0.66 [0.57-0.75]. There was, however, no evidence it contained useful out-of-sample predictive information of future PDD (delta ELPD = 1.8 (SD 2.5)); Similar results held for PDQ-hallucinations and PDQ-anxiety. In contrast, cognitive ability (delta ELPD = 36 (SD 8)) and age (delta ELPD = 11 (SD 5)) provided useful predictive information of future PDD. CONCLUSIONS: Cognitive ability and age strongly out-performed neuropsychiatric measures as markers of developing PDD within 4 years. Therefore, neuropsychiatric symptoms do not appear to be useful markers of PDD risk.

Prescription of glucose-lowering therapies and risk of COVID-19 mortality in people with type 2 diabetes: a nationwide observational study in England.

BACKGROUND: In patients with type 2 diabetes, hyperglycaemia is an independent risk factor for COVID-19-related mortality. Associations between pre-infection prescription for glucose-lowering drugs and COVID-19-related mortality in people with type 2 diabetes have been postulated but only investigated in small studies and limited to a few agents. We investigated whether there are associations between prescription of different classes of glucose-lowering drugs and risk of COVID-19-related mortality in people with type 2 diabetes. METHODS: This was a nationwide observational cohort study done with data from the National Diabetes Audit for people with type 2 diabetes and registered with a general practice in England since 2003. Cox regression was used to estimate the hazard ratio (HR) of COVID-19-related mortality in people prescribed each class of glucose-lowering drug, with covariate adjustment with a propensity score to address confounding by demographic, socioeconomic, and clinical factors. FINDINGS: Among the 2 851 465 people with type 2 diabetes included in our analyses, 13 479 (0·5%) COVID-19-related deaths occurred during the study period (Feb 16 to Aug 31, 2020), corresponding to a rate of 8·9 per 1000 person-years (95% CI 8·7-9·0). The adjusted HR associated with recorded versus no recorded prescription was 0·77 (95% CI 0·73-0·81) for metformin and 1·42 (1·35-1·49) for insulin. Adjusted HRs for prescription of other individual classes of glucose-lowering treatment were as follows: 0·75 (0·48-1·17) for meglitinides, 0·82 (0·74-0·91) for SGLT2 inhibitors, 0·94 (0·82-1·07) for thiazolidinediones, 0·94 (0·89-0·99) for sulfonylureas, 0·94 (0·83-1·07) for GLP-1 receptor agonists, 1·07 (1·01-1·13) for DPP-4 inhibitors, and 1·26 (0·76-2·09) for α-glucosidase inhibitors. INTERPRETATION: Our results provide evidence of associations between prescription of some glucose-lowering drugs and COVID-19-related mortality, although the differences in risk are small and these findings are likely to be due to confounding by indication, in view of the use of different drug classes at different stages of type 2 diabetes disease progression. In the context of the COVID-19 pandemic, there is no clear indication to change prescribing of glucose-lowering drugs in people with type 2 diabetes. FUNDING: None.

Characteristics and outcomes of pregnant women with type 1 or type 2 diabetes: a 5-year national population-based cohort study.

BACKGROUND: Diabetes in pregnancy is associated with preterm delivery, birthweight extremes, and increased rates of congenital anomaly, stillbirth, and neonatal death. We aimed to identify and compare modifiable risk factors associated with adverse pregnancy outcomes in women with type 1 diabetes and those with type 2 diabetes and to identify effective maternity clinics. METHODS: In this national population-based cohort study, we used data for pregnancies among women with type 1 or type 2 diabetes collected in the first 5 years of the National Pregnancy in Diabetes audit across 172 maternity clinics in England, Wales, and the Isle of Man, UK. Data for obstetric complications (eg, preterm delivery [<37 weeks' gestation], large for gestational age [LGA] birthweight [>90th percentile]) and adverse pregnancy outcomes (congenital anomaly, stillbirth, neonatal death) were obtained for pregnancies completed between Jan 1, 2014, and Dec 31, 2018. We assessed associations between modifiable (eg, HbA1c, BMI, pre-pregnancy care, maternity clinic) and non-modifiable risk factors (eg, age, ethnicity, deprivation, duration of type 1 diabetes) with pregnancy outcomes in women with type 1 diabetes compared with those with type 2 diabetes. We calculated associations between maternal factors and perinatal deaths using a regression model, including diabetes type and duration, maternal age, BMI, deprivation quintile, first trimester HbA1c, preconception folic acid, potentially harmful medications, and third trimester HbA1c. FINDINGS: Our dataset included 17 375 pregnancy outcomes in 15 290 pregnant women. 8690 (50·0%) of 17 375 pregnancies were in women with type 1 diabetes (median age at delivery 30 years [10-90th percentile 22-37], median duration of diabetes 13 years [3-25]) and 8685 (50·0%) were in women with type 2 diabetes (median age at delivery 34 years [27-41], median duration of diabetes 3 years [0-10]). The rates of preterm delivery (3325 [42·5%] of 7825 pregnancies among women with type 1 diabetes, 1825 [23·4%] of 7815 with type 2 diabetes; p<0·0001), and LGA birthweight (4095 [52·2%] of 7845 with type 1 diabetes, 2065 [26·2%] of 7885 with type 2 diabetes; p<0·0001) were higher in type 1 diabetes. The prevalence of congenital anomaly (among women with type 1 diabetes: 44·8 per 1000 livebirths, terminations, and fetal losses; among women with type 2 diabetes: 40·5 per 1000 livebirths, terminations, and fetal losses; p=0·17) and stillbirth (type 1 diabetes: 10·4 per 1000 livebirths and stillbirths; type 2 diabetes: 13·5 per 1000 livebirths and stillbirths; p=0·072) did not significantly differ between diabetes types, but rates of neonatal death were higher in mothers with type 2 diabetes than in those with type 1 diabetes (type 1 diabetes: 7·4 per 1000 livebirths; type 2 diabetes 11·2 per 1000 livebirths; p=0·013). Across the whole study population, independent risk factors for perinatal death (ie, stillbirth or neonatal death) were third trimester HbA1c of 6·5% (48 mmol/mol) or higher (odds ratio 3·06 [95% CI 2·16-4·33] vs HbA1c <6·5%), being in the highest deprivation quintile (2·29 [1·16-4·52] vs the lowest quintile), and having type 2 diabetes (1·65 [1·18-2·31] vs type 1 diabetes). Variations in HbA1c and LGA birthweight were associated with maternal characteristics (age, diabetes duration, deprivation, BMI) without substantial differences between maternity clinics. INTERPRETATION: Our data highlight persistent adverse pregnancy outcomes in women with type 1 or type 2 diabetes. Maternal glycaemia and BMI are the key modifiable risk factors. No maternity clinics were had appreciably better outcomes than any others, suggesting that health-care system changes are needed across all clinics. FUNDING: None.