Cancer risk following onset of type 2 diabetes in New Zealanders with impaired glucose tolerance over 25 years: a matched prospective cohort study.

BACKGROUND: In people with prediabetes, the link between developing type 2 diabetes (T2D) and cancer risk among those with impaired glucose tolerance (IGT) remains uncertain. We examined this association in IGT individuals from primary care in South and West Auckland, New Zealand, spanning 1994-2019, assessing 5- and 10-year cancer risks. METHODS: Study cohorts were extracted from the Diabetes Care Support Service in Auckland, New Zealand, linking it with national registries for death, cancer, hospital admissions, pharmaceutical claims, and socioeconomic status. We compared cancer risks in individuals with IGT newly diagnosed with or without T2D within a 1-5-year exposure window. Employing tapered matching and landmark analysis to address potential confounding effects, we formed comparative IGT cohorts. Weighted Cox regression models were then employed to assess the association between T2D onset and 5- and 10-year cancer risks. RESULTS: The study included 26,794 patients with IGT, with 629 newly diagnosed with T2D within 5 years and 13,007 without such a diagnosis. Those progressing to T2D had similar 5-year cancer risk but significantly higher 10-year risk (HR 1.35; 95% CI 1.09-1.68). This association was stronger in older individuals, the socioeconomically deprived, current smokers, those with worse metabolic measures, and lower renal function. Patients with IGT of NZ European ethnicity had lower 10-year cancer risk. CONCLUSIONS: T2D diagnosis influences cancer risk in individuals with IGT. Developing risk scores for high-risk IGT individuals and implementing cancer screening and structured diabetes prevention, especially in deprived or minority ethnic populations, is essential.

All-cause, premature, and cardiovascular death attributable to socioeconomic and ethnic disparities among New Zealanders with type 1 diabetes 1994-2019: a multi-linked population-based cohort study.

BACKGROUND: New Zealand (NZ) research into type 1 diabetes mellitus (T1DM) mortality can inform policy and future research. In this study we aimed to quantify the magnitude to which ethnicity and socioeconomic disparities influenced mortality at the population level among people with Type 1 diabetes (T1DM) in Auckland, New Zealand (NZ). METHODS: The cohort data were derived from the primary care diabetes audit program the Diabetes Care Support Service (DCSS), and linked with national primary care, pharmaceutical claims, hospitalisation, and death registration databases. People with T1DM enrolled in DCSS between 1994-2018 were included. All-cause, premature, and cardiovascular mortalities were estimated by Poisson regression models with adjustment for population-level confounders. The mortality rates ratio (MRR) was standardized against the DCSS type 2 diabetes population. Mortality rates were compared by ethnic group (NZ European (NZE) and non-NZE) and socioeconomic deprivation quintile. The population attributable fraction (PAF) was estimated for ethnic and socioeconomic disparities by Cox regression adjusting for demographic, lifestyle, and clinical covariates. The adjusted slope index inequality (SII) and relative index of inequality (RII) were used to measure the socioeconomic disparity in mortalities. RESULTS: Overall, 2395 people with T1DM (median age 34.6 years; 45% female; 69% NZE) were enrolled, among whom the all-cause, premature and CVD mortalities were 6.69 (95% confidence interval: 5.93-7.53), 3.30 (2.77-3.90) and 1.77 (1.39-2.23) per 1,000 person-years over 25 years. The overall MRR was 0.39 (0.34-0.45), 0.65 (0.52-0.80), and 0.31 (0.24-0.41) for all-cause, premature and CVD mortality, respectively. PAF attributable to ethnicity disparity was not significantly different for mortality. The adjusted PAF indicated that 25.74 (0.84-44.39)% of all-cause mortality, 25.88 (0.69-44.69)% of premature mortality, 55.89 (1.20-80.31)% of CVD mortality could be attributed to socioeconomic inequality. The SII was 8.04 (6.30-9.78), 4.81 (3.60-6.02), 2.70 (1.82-3.59) per 1,000 person-years and RII was 2.20 (1.94-2.46), 2.46 (2.09-2.82), and 2.53 (2.03-3.03) for all-cause, premature and CVD mortality, respectively. CONCLUSIONS: Our results suggest that socioeconomic disparities were responsible for a substantial proportion of all-cause, premature and CVD mortality in people with T1DM in Auckland, NZ. Reducing socioeconomic barriers to management and self-management would likely improve clinical outcomes.

Long-term impact of type 2 diabetes onset on dementia incidence rate among New Zealanders with impaired glucose tolerance: A tapered-matched landmark analysis over 25 years.

INTRODUCTION: We aimed to investigate the association between the onset of type 2 diabetes (T2D) and dementia incidence rates (IR) in the population with impaired glucose tolerance (IGT) identified in primary care in New Zealand (NZ) over 25 years. METHODS: Tapered matching and landmark analysis (accounting for immortal bias) were used to control for potential effects of known confounders. The association between T2D onset and 5- and 10-year IR of dementia was estimated by weighted Cox models. RESULTS: The onset of T2D was significantly associated with the 10-year IR of dementia, especially in the socioeconomically deprived, those of non-NZ European ethnicity, those currently smoking, and patients with higher metabolic measures. DISCUSSION: Our findings suggest that the onset of T2D is a significant risk factor for dementia in individuals with IGT. Dementia screening and structured diabetes prevention are vital in the population with IGT, particularly those from deprived or ethnic minority backgrounds. HIGHLIGHTS: Increased dementia incidence rate links with T2D onset in people with IGT. Significant incidence varied by ethnicity, socioeconomic status, and health factors. Results emphasize the diabetes manage and socioeconomic factors on dementia risk. Secondary analysis highlights the key role of vascular health in dementia prevention.

Effect of onset of type 2 diabetes on risks of cardiovascular disease and heart failure among new Zealanders with impaired glucose tolerance over 25 years: tapered-matched landmark analysis.

BACKGROUND: This study aimed to examine the association between the incident onset of T2DM and 5- and 10-year risks of CVD and HF in people with IGT identified in primary care in South and West Auckland, New Zealand (NZ) between 1994 and 2019. METHODS: We compared CVD and HF risks in patients with IGT and with/without T2D newly diagnosed within the exposure window (1-5 years). Tapered matching and landmark analysis (to account for immortal bias) were used to control for potential effects of known confounders. RESULTS: Among 26,794 patients enrolled with IGT, 845 had T2D newly diagnosed within 5 years from enrolment (landmark date) and 15,452 did not have T2D diagnosed. Patients progressing to T2D (vs. those not progressing) had a similar 5-year risk for CVD (hazard ratio 1.19; 95% CI 0.61-2.32) but significantly higher 10-year risk of CVD (2.45(1.40-4.29)), 5-year risk of HF (1.94(1.20-3.12)) and 10-year risk of HF (2.84(1.83-4.39). The association between the onset of T2D and risk of 10-year risk of CVD, 5-year and 10-year risk of HF was more likely among men, the socioeconomically deprived, those currently smoking, patients with higher metabolic measures and/or those with lower renal function. Patients of NZ European ethnicity had a lower 10-year risk of CVD. CONCLUSIONS: The study suggests that the diagnosis of T2D mediates the risk of CVD and HF in people with IGT. The development of risk scores to identify and better manage individuals with IGT at high risk of T2D is warranted.

Systems level expression correlation of Ras GTPase regulators.

BACKGROUND: Proteins of the ubiquitously expressed core proteome are quantitatively correlated across multiple eukaryotic species. In addition, it was found that many protein paralogues exhibit expression anticorrelation, suggesting that the total level of protein with a given functionality must be kept constant. METHODS: We performed Spearman's rank correlation analyses of gene expression levels for the RAS GTPase subfamily and their regulatory GEF and GAP proteins across tissues and across individuals for each tissue. A large set of published data for normal tissues from a wide range of species, human cancer tissues and human cell lines was analysed. RESULTS: We show that although the multidomain regulatory proteins of Ras GTPases exhibit considerable tissue and individual gene expression variability, their total amounts are balanced in normal tissues. In a given tissue, the sum of activating (GEFs) and deactivating (GAPs) domains of Ras GTPases can vary considerably, but each person has balanced GEF and GAP levels. This balance is impaired in cell lines and in cancer tissues for some individuals. CONCLUSIONS: Our results are relevant for critical considerations of knock out experiments, where functionally related homologs may compensate for the down regulation of a protein.

Par3/Bazooka and phosphoinositides regulate actin protrusion formation during Drosophila dorsal closure and wound healing.

Effective wound closure mechanisms are essential for maintenance of epithelial structure and function. The repair of wounded epithelia is primarily driven by the cells bordering the wound, which become motile after wounding, forming dynamic actin protrusions along the wound edge. The molecular mechanisms that trigger wound edge cells to become motile following tissue damage are not well understood. Using wound healing and dorsal closure in Drosophila, we identify a direct molecular link between changes in cell-cell adhesion at epithelial edges and induction of actin protrusion formation. We find that the scaffolding protein Par3/Bazooka and the lipid phosphatase Pten are specifically lost from cell-cell junctions at epithelial edges. This results in a localized accumulation of phosphatidylinositol 3,4,5-trisphosphate (PIP3), which promotes the formation of actin protrusions along the epithelial edge. Depleting PIP3 results in defective epithelial closure during both dorsal closure and wound healing. These data reveal a novel mechanism that directly couples loss of epithelial integrity to activation of epithelial closure.

Empagliflozin and dulaglutide: community awareness project promotes improved access to newly funded medications for Pacific patients with type 2 diabetes.

AIM: The aims of our awareness campaign were to increase the number of inquiries by patients to doctors for two new diabetes drugs funded by Pharmac on 1 February 2021 and 1 September 2021 respectively, to increase the number of applications for special authority, and to trial a "grass roots" community dissemination of information that appeals to explicit individual benefit from the new medicines. The campaign used an approach tailored primarily to the Pasifika community. METHODS: The campaign ran from April 2021 to July 2021 and targeted Counties Manukau communities using a talanoa approach by primarily by sharing key messages informally through social networks face-to-face by word-of-mouth. The key messages about the new medicines were shared orally with local organisations, family, friends, influential community leaders and colleagues such as justices of peace, kapa haka leaders, committee representatives from local schools, sports, cultural and hobby clubs. A printed pamphlet translated in Maori, Samoan, Tongan and English with the key messages was also distributed widely. The campaign notified 102 primary care practices, used Pacific equity teams to disseminate the information, promoted the message on Maori and Pasifika radio stations, and engaged a public relations company who contacted the South Auckland Community Trust, councillors, community boards and local churches. This approach was intended to spread the message through the community to reach people with type 2 diabetes and/or their families to prompt them to contact their doctor and see if they are eligible. To gauge how effective the campaign was, we gathered data from Pharmac that quantified new prescriptions for the new medicines by location and ethnicity. RESULTS: An estimated 45,000 people were exposed to our campaign materials or were told about the new medicines by people they knew. These estimations were conservatively based on the known membership, listenership, and reach of the various delivery arms by which this campaign was delivered. These data show Pacific patients, the focus of about 64% of our project work, were 40% more likely to apply and receive a prescription for empagliflozin in Counties Manukau than anywhere else in the country. CONCLUSION: Direct-to-consumer marketing is an effective way of increasing health awareness and uptake of newly funded diabetes medicine amongst Pacific patients with type 2 diabetes.

Association Between Onset of Type 2 Diabetes and Risk of Atrial Fibrillation in New Zealanders With Impaired Glucose Tolerance Over 25 Years.

Background The association between the onset of type 2 diabetes (T2D) and atrial fibrillation (AF) risk in individuals with impaired glucose tolerance (IGT) remains unclear. This study aimed to investigate the relationship between the incident onset of T2D and 5- and 10-year (after the landmark period) risks of AF in people with IGT identified in South and West Auckland primary care settings between 1994 and 2019. Methods and Results We compared AF risk in patients with IGT with and without newly diagnosed T2D within a 1- to 5-year exposure window. Tapered matching and landmark analysis (to address immortal bias) were used to control for confounding variables. The cohorts incorporated 785 patients who had T2D newly diagnosed within 5 years from enrollment (landmark date) and 15 079 patients without a T2D diagnosis. Patients progressing to T2D exhibited significantly higher 5-year (after the landmark period) AF risk (hazard ratio [HR], 1.34 [95% CI, 1.10-1.63]) and 10-year (after the landmark period) AF risk (HR, 1.28 [95% CI, 1.02-1.62]) compared with those without incident T2D. The association was more pronounced among men, older patients, socioeconomically deprived individuals, current smokers, those with higher metabolic measures, and lower renal function. New Zealand European ethnicity was associated with a lower 5- and 10-year risk of AF. Conclusions This study found a mediating effect of T2D on the risk of AF in a population with IGT in New Zealand. The development of risk scores and future replication studies can help identify and guide management of individuals with IGT at the highest risk of AF following incident T2D.

Health Inequality in Eight Adverse Outcomes Over a 25-Year Period in a Multi-Ethnic Population in New Zealand Population with Impaired Glucose Tolerance and/or Impaired Fasting Glucose: An Age-Period-Cohort Analysis.

Purpose: We aimed to examine socioeconomic inequality (SI) in cause-specific outcomes among adults with impaired glucose tolerance (IGT) and/or Impaired fasting glucose (IFG) in New Zealand (NZ) over 25 years. Patients and Methods: A population-based open cohort was derived from Diabetes Care Support Service in NZ with national databases linkage. Patients aged ≥18 years with IGT and/or IFG were enrolled between 01/01/1994 and 31/07/2018 and followed up until death or 31/12/2018. Incident outcomes (all-cause, premature, cardiovascular, and cancer death; cardiovascular, myocardial infarction, stroke, heart failure, and end-stage kidney disease hospitalization) by demographic, anthropometric, socioeconomic status, clinical measurements, enrol-time-periods, and IGT/IFG were evaluated. Adjusted incidence rate ratios, absolute risk difference, and SI measurements (slope and relative index of inequality) were estimated using Age-Period-Cohort models. Results: 29,894 patients (58.5 (SD 14.3) years mean age; 52.2% female) were enrolled with 5.6 (IQR: 4.4-7.4) years of median follow-up. Mortality rates decreased, whereas hospitalization (except myocardial infarction) rates increased. SI was significant for each outcome. Higher mortality and hospitalization rates and worsened SI were common in men, older, the most deprived, and Maori patients, as well as patients with obesity, current smoking, with both IFG and IGT, and greater metabolic derangement (higher systolic blood pressure, lipids, and HbA1c, and lower level of mean arterial pressure). Conclusion: Enhanced management strategies are necessary for people with IGT and/or IFG to address persisting SI, especially for men, older people, current smokers, NZ European and Maori patients, patients with obesity, or with any abnormal metabolic measurements.

Adverse Clinical Outcomes Attributable to Socioeconomic and Ethnic Disparities Among People with Type 2 Diabetes in New Zealand Between 1994-2018: A Multiple Linked Cohort Study.

Purpose: The study aimed to examine the separate population-level contributions of the ethnic and socioeconomic disparities among people with type 2 diabetes mellitus (T2DM) and residence in New Zealand (NZ). Patients and Methods: A prospective cohort enrolled T2DM patients from 01/01/1994 into the Diabetes Care Support Service, a primary care audit program in Auckland, NZ. The cohort was linked to national registry databases (socioeconomic status, pharmaceutical claim, hospitalization, and death registration). Each cohort member was followed up till death or the study end time (31/12/2019), whichever came first. Incident clinical events (stroke, myocardial infarction (MI), heart failure (HF), end-stage renal disease (ESRD), and premature mortality (PM)) were used as outcomes. The attributable fractions (AFs) were estimated for the whole population and for specific population with NZ Europeans (NZE) and/or least deprived population as reference, both unadjusted and with adjustment for covariables by Cox Regression models. Results: Among 36,267 patients, adjusted population AFs indicated 6.6(-30.8-33.3)% of PM, 17.1(5.8-27.0)% of MI, 35.3(22.6-46.0)% of stroke, 14.3(3.2-24.2)% of HF, and 15.9(6.7-24.2)% of ESRD could be attributed to deprivation; while 14.3(3.3-25.4)% of PM, -3.3(-8.3-1.5)% of MI, -0.5(-6.7-5.3)% of stroke, 4.7(0.3-8.8)% of HF, 13.3(9.9-16.6)% of ESRD could be attributed to ethnicity. Deprivation contributed a significant AF to stroke, while ethnicity was important for ESRD. Gradient of AF for deprivation indicated NZE and Asians were most affected by deprivation across outcomes. Conversely, Maori, with the highest AFs for ethnicity of PM and ESRD, were unaffected by deprivation. At same deprivations, the AFs of MI and stroke were greatest among NZE compared with other ethnic groups; the AF of ESRD was greatest among Maori and Pasifika. Conclusion: Both socioeconomic deprivation and ethnicity are strongly associated with outcomes in patients with T2DM in NZ, although the extent of the deprivation gradient is greatest among NZE and Asians, and least among Maori.

Ethnic Differences in Cancer Rates Among Adults With Type 2 Diabetes in New Zealand From 1994 to 2018.

Importance: People with type 2 diabetes have greater risk for some site-specific cancers, and risks of cancers differ among racial and ethnic groups in the general population of Aotearoa New Zealand. The extent of ethnic disparities in cancer risks among people with type 2 diabetes in New Zealand is unclear. Objective: To compare the risks of 21 common adult cancers among Maori, Pasifika, and New Zealand European individuals with type 2 diabetes in New Zealand from 1994 to 2018. Design, Setting, and Participants: This population-based, matched cohort study used data from the primary care audit program in Auckland, New Zealand, linked with national cancer, death, and hospitalization registration databases, collected from January 1, 1994, to July 31, 2018, with follow-up data obtained through December 31, 2019. Using a tapered matching method to balance potential confounders (sociodemographic characteristics, lifestyle, anthropometric and clinical measurements, treatments [antidiabetes, antihypertensive, lipid-lowering, and anticoagulant], period effects, and recorded duration of diabetes), comparative cohorts were formed between New Zealand European and Maori and New Zealand European and Pasifika individuals aged 18 years or older with type 2 diabetes. Sex-specific matched cohorts were formed for sex-specific cancers. Exposures: Maori, Pasifika, and New Zealand European (reference group) ethnicity. Main Outcomes and Measures: The incidence rates of 21 common cancers recorded in nationally linked databases between 1994 and 2018 were the main outcomes. Weighted Cox proportional hazards regression was used to assess ethnic differences in risk of each cancer. Results: A total of 33 524 adults were included: 15 469 New Zealand European (mean [SD] age, 61.6 [13.2] years; 8522 [55.1%] male), 6656 Maori (mean [SD] age, 51.2 [12.4] years; 3345 [50.3%] female), and 11 399 Pasifika (mean [SD] age, 52.8 [12.7] years; 5994 [52.6%] female) individuals. In the matched New Zealand European and Maori cohort (New Zealand European: 8361 individuals; mean [SD] age, 58.9 [12.9] years; 4595 [55.0%] male; Maori: 5039 individuals; mean [SD] age, 51.4 [12.3] years; 2542 [50.5%] male), significant differences between New Zealand European and Maori individuals were identified in the risk for 7 cancers. Compared with New Zealand European individuals, the hazard ratios (HRs) among Maori individuals were 15.36 (95% CI, 4.50-52.34) for thyroid cancer, 7.94 (95% CI, 1.57-40.24) for gallbladder cancer, 4.81 (95% CI, 1.08-21.42) for cervical cancer (females only), 1.97 (95% CI, 1.30-2.99) for lung cancer, 1.81 (95% CI, 1.08-3.03) for liver cancer, 0.56 (95% CI, 0.35-0.90) for colon cancer, and 0.11 (95% CI, 0.04-0.27) for malignant melanoma. In the matched New Zealand European and Pasifika cohort (New Zealand European: 9340 individuals; mean [SD] age, 60.6 [13.1] years; 4885 [52.3%] male; Pasifika: 8828 individuals; mean [SD] age, 53.1 [12.6] years; 4612 [52.2%] female), significant differences between New Zealand European and Pasifika individuals were identified for 6 cancers. Compared with New Zealand European individuals, HRs among Pasifika individuals were 25.10 (95% CI, 3.14-200.63) for gallbladder cancer, 4.47 (95% CI, 1.25-16.03) for thyroid cancer, 0.48 (95% CI, 0.30-0.78) for colon cancer, 0.21 (95% CI, 0.09-0.48) for rectal cancer, 0.21 (95% CI, 0.07-0.65) for malignant melanoma, and 0.01 (95% CI, 0.01-0.10) for bladder cancer. Conclusions and Relevance: In this cohort study, differences in the risk of 21 common cancers were found between New Zealand European, Maori, and Pasifika groups of adults with type 2 diabetes in New Zealand from 1994 to 2018. Research into the mechanisms underlying these differences as well as additional screening strategies (eg, for thyroid and gallbladder cancers) appear to be warranted.

Ethnic differences in 25-year risk of incident chronic kidney disease among people with type 2 diabetes in New Zealand.

INTRODUCTION: Insights into ethnic differences in the natural history of chronic kidney disease (CKD) among people with type 2 diabetes mellitus (T2DM) might inform clinical strategies to address disparities in hospitalization and mortality. Risks of CKD II-V stages over a 25-year period between New Zealand Europeans (NZEs), Maori and Pasifika, and with T2DM in Auckland, New Zealand (NZ) were compared. RESEARCH DESIGN AND METHODS: As a primary care audit program in Auckland, the Diabetes Care Support Service was linked with national registration databases. People with existing CKD II-V were ruled out. To balance potential confounders, we applied a tapered matching method . 'Quasi-trial'-matched cohorts were set up separately between Maori and NZE and between Pasifika and NZE. Ethnic population differences in risk of any and each stage of CKD over 1994-2018 were examined by weighted Cox regression model. RESULTS: The HRs for developing any CKD, CKD stages II-V for Maori (n=2215) versus NZE (n=2028) were 1.18 (95% CI 0.99 to 1.41), 1.10 (95% CI 0.91 to 1.32), 1.70 (95% CI 1.19 to 2.43), 3.93 (95% CI 2.16 to 7.14), and 3.74 (95% CI 1.74 to 8.05), respectively. Compared with NZE (n=2474), the HRs for developing any CKD, CKD stages II-V for Pasifika (n=3101) were 1.31 (95% CI 1.09 to 1.57), 1.26 (95% CI 1.05 to 1.52), 1.71 (95% CI 1.14 to 2.57), 3.75 (95% CI 1.40 to 10.05), and 4.96 (95% CI 1.56 to 15.75), respectively. CONCLUSIONS: Among people with T2DM in NZ, significant ethnic differences exist in the risk of progressing to each stage of CKD (stage V in particular). Mechanism studies underlying these differences, as well as the need for identification of biomarkers to predict the early onset renal lesion, are warranted.

Ethnic differences in metabolic achievement between Maori, Pacific, and European New Zealanders with type 2 diabetes.

AIMS: To compare variations in metabolic target achievement by ethnicity (Europeans, Maori and Pasifika) among patients with type 2 diabetes (T2DM) in Auckland, New Zealand (NZ) between 1994 and 2013. METHODS: 32,237 patients were enrolled. Adjusted marginal difference (European as reference) of systolic blood pressure (SBP), body mass index (BMI), HbA1c and total cholesterol, alongside the proportion achieving metabolic targets were estimated using multivariable mixed effect models at baseline, 1-, 2-, 3-, 4-, and 5-years, adjusted for covariates. RESULTS: Compared with Europeans, Maori and Pasifika had continuously, significantly higher HbA1c (by 0.3% (+3.5 mmol/mol) and 0.6% (+6.8 mmol/mol) respectively and BMI (+1.5 and +0.3 kg/m2 respectively) but lower SBP (-1.8 and -3.4 mmHg respectively) and TG (-0.03 and -0.34 mmol/L respectively), and insignificantly TC (+0.004 and +0.01 respectively), by 5-years of follow-up. While 49% Europeans were within target HbA1c, this was achieved by only 30% Maori and 27% Pasifika. Conversely, 41% Europeans, 46% Maori and 59% Pasifika achieved the SBP target (all P < 0.0001). CONCLUSIONS: Managing hyperglycemia appears to be more challenging than treating hypertension and dyslipidemia among Maori and Pasifika. New anti-hyperglycemia treatments, addressing health literacy, socioeconomic and any cultural barriers to management and self-management are urgently needed to reduce these disparities.

Aberrant Expression and Subcellular Localization of ECT2 Drives Colorectal Cancer Progression and Growth.

ECT2 is an activator of RHO GTPases that is essential for cytokinesis. In addition, ECT2 was identified as an oncoprotein when expressed ectopically in NIH/3T3 fibroblasts. However, oncogenic activation of ECT2 resulted from N-terminal truncation, and such truncated ECT2 proteins have not been found in patients with cancer. In this study, we observed elevated expression of full-length ECT2 protein in preneoplastic colon adenomas, driven by increased ECT2 mRNA abundance and associated with APC tumor-suppressor loss. Elevated ECT2 levels were detected in the cytoplasm and nucleus of colorectal cancer tissue, suggesting cytoplasmic mislocalization as one mechanism of early oncogenic ECT2 activation. Importantly, elevated nuclear ECT2 correlated with poorly differentiated tumors, and a low cytoplasmic:nuclear ratio of ECT2 protein correlated with poor patient survival, suggesting that nuclear and cytoplasmic ECT2 play distinct roles in colorectal cancer. Depletion of ECT2 reduced anchorage-independent cancer cell growth and invasion independent of its function in cytokinesis, and loss of Ect2 extended survival in a Kras G12D Apc-null colon cancer mouse model. Expression of ECT2 variants with impaired nuclear localization or guanine nucleotide exchange catalytic activity failed to restore cancer cell growth or invasion, indicating that active, nuclear ECT2 is required to support tumor progression. Nuclear ECT2 promoted ribosomal DNA transcription and ribosome biogenesis in colorectal cancer. These results support a driver role for both cytoplasmic and nuclear ECT2 overexpression in colorectal cancer and emphasize the critical role of precise subcellular localization in dictating ECT2 function in neoplastic cells. SIGNIFICANCE: ECT2 overexpression and mislocalization support its role as a driver in colon cancer that is independent from its function in normal cell cytokinesis.

Financial health and obesity.

We use individual-level panel data from the English Longitudinal Survey of Ageing over the period 2004-2013 to investigate the links between financial health and obesity. We find that having no debt (high savings) is associated with a 3.6 (1.6) percentage point lower probability of having a Body Mass Index in excess of 30. Our results are robust to using different estimation methods, to measuring financial health with a subjective indicator, and adiposity with waist circumference. A lower rate of time preference and lower stress levels may be mechanisms which help to explain the association between good financial health and obesity.

Ethnic differences in mortality and hospital admission rates between Maori, Pacific, and European New Zealanders with type 2 diabetes between 1994 and 2018: a retrospective, population-based, longitudinal cohort study.

BACKGROUND: Type 2 diabetes affects Indigenous and non-European populations disproportionately, including in New Zealand, where long-term temporal trends in cause-specific clinical outcomes between Maori, Pacific, and European people remain unclear. We aimed to compare the rates of mortality and hospital admission between Maori, Pacific, and European patients with type 2 diabetes in Auckland, New Zealand, over a period of 24 years. METHODS: In this retrospective, population-based, longitudinal cohort study, we identified a cohort of patients (aged 35-84 years) with type 2 diabetes enrolled between Jan 1, 1994, and July 31, 2018, to the primary care audit programme, the Diabetes Care Support Service (DCSS) in Auckland, New Zealand. Patients with type 1 diabetes, prediabetes, and gestational diabetes were excluded. We linked data from the DCSS with national death registration, hospital admission, pharmaceutical claim, and socioeconomic status databases. Patients were followed up until death or July 31, 2018 (date of last enrolment to the DCSS). Incident clinical events (all-cause mortality, cardiovascular mortality, cancer mortality, cardiovascular hospital admission, cancer hospital admission, and end-stage renal disease hospital admission) were identified. Event rates were stratified by ethnic group, age group, sex, socioeconomic status, and time period (<1998, 1999-2013, 2004-08, 2009-13, and 2014-18). Incidence rate ratios (IRRs) and absolute risk differences were adjusted for sex, age, smoking status, obesity, socioeconomic status, and time period by use of age-period-cohort modelling. FINDINGS: Between Jan 1, 1994, and July 31, 2018, 45 072 patients with type 2 diabetes (21 936 [48·7%] female; mean age 56·7 years [SD 13·8]) were enrolled in the DCSS and followed up for a median of 9·7 years (IQR 5·8-13·6). 16 755 (37·2%) were European, 7093 (15·7%) were Maori, and 12 044 (26·7%) were Pacific patients. Despite a similar temporal trend (decreasing mortality and increasing hospital admissions) across the three ethnic groups, Maori and Pacific patients had consistently higher hospital admission rates than European patients. Maori but not Pacific patients had higher adjusted IRRs for all-cause mortality (1·96 [95% CI 1·80-2·14]), cardiovascular mortality (1·93 [1·63-2·29]) and cancer mortality (1·64 [1·40-1·93]) rates compared with European patients. INTERPRETATION: Compared with European patients, poorer health outcomes have persisted among Maori and Pacific people with type 2 diabetes for more than 20 years. New policies supporting prevention and more intensive management of type 2 diabetes are urgently needed. Research into the biological and societal mechanisms underlying these disparities, and the associated differences between Maori and Pacific patients is also needed. FUNDING: Counties Manukau Health and Middlemore Foundation.

Environment Influences Tumor Progression and Transcriptional Subtype in a New Model of Pancreatic Cancer.

In this issue, Miyabayashi and colleagues describe a novel intraductal model of pancreatic cancer that allows modeling of the transcriptional subtypes of pancreatic cancer. Using this model, they are able to observe subtype switching driven by the microenvironment, a process at least partially mediated by RAS signaling.See related article by Miyabayashi et al., p. 1566.

Accelerated partner therapy (APT) partner notification for people with Chlamydia trachomatis: protocol for the Limiting Undetected Sexually Transmitted infections to RedUce Morbidity (LUSTRUM) APT cross-over cluster randomised controlled trial.

INTRODUCTION: Partner notification (PN) is a process aiming to identify, test and treat the sex partners of people (index patients) with sexually transmitted infections (STIs). Accelerated partner therapy (APT) is a PN method whereby healthcare professionals assess sex partners, by telephone consultation, before giving the index patient antibiotics and STI self-sampling kits to deliver to their sex partner(s). The Limiting Undetected Sexually Transmitted infections to RedUce Morbidity programme aims to determine the effectiveness of APT in heterosexual women and men with chlamydia and determine whether APT could affect Chlamydia trachomatis transmission at population level. METHODS AND ANALYSIS: This protocol describes a cross-over cluster randomised controlled trial of APT, offered as an additional PN method, compared with standard PN. The trial is accompanied by an economic evaluation, transmission dynamic modelling and a qualitative process evaluation involving patients, partners and healthcare professionals. Clusters are 17 sexual health clinics in areas of England and Scotland with contrasting patient demographics. We will recruit 5440 heterosexual women and men with chlamydia, aged ≥16 years.The primary outcome is the proportion of index patients testing positive for C. trachomatis 12-16 weeks after the PN consultation. Secondary outcomes include: proportion of sex partners treated; cost effectiveness; model-predicted chlamydia prevalence; experiences of APT.The primary outcome analysis will be by intention-to-treat, fitting random effects logistic regression models that account for clustering of index patients within clinics and trial periods. The transmission dynamic model will be used to predict change in chlamydia prevalence following APT. The economic evaluation will use mathematical modelling outputs, taking a health service perspective. Qualitative data will be analysed using interpretative phenomenological analysis and framework analysis. ETHICS AND DISSEMINATION: This protocol received ethical approval from London-Chelsea Research Ethics Committee (18/LO/0773). Findings will be published with open access licences. TRIAL REGISTRATION NUMBER: ISRCTN15996256.

Uterotonic Drugs for the Prevention of Postpartum Haemorrhage: A Cost-Effectiveness Analysis.

OBJECTIVE: The objective of this study was to estimate the relative cost effectiveness for the full range of uterotonic drugs available for preventing postpartum haemorrhage (PPH). METHODS: A model-based economic evaluation was constructed using effectiveness data from a network meta-analysis, and supplemented by the literature. A UK National Health Service (NHS) perspective was adopted for the analysis, which is based on UK costs from published sources. The primary outcome measure is cost per case of PPH avoided (≥ 500 mL blood loss), with secondary outcome measures of cost per case of severe PPH avoided (≥ 1000 mL) and cost per major outcome (surgery) averted also being analysed. RESULTS: Carbetocin is shown to be the most effective strategy. Excluding adverse events, 'ergometrine plus oxytocin' was shown to be the least costly strategy. The incremental cost-effectiveness ratio for prevention of PPH with carbetocin compared with prevention with 'ergometrine plus oxytocin' was £1889 per case of PPH ≥ 500 mL avoided; £30,013 per case of PPH ≥ 1000 mL avoided; and £1,172,378 per major outcome averted. Including adverse events in the analysis showed oxytocin to be the least costly strategy. The incremental cost-effectiveness ratio for prevention of PPH with carbetocin compared with prevention with oxytocin was £928 per case of PPH ≥ 500 mL avoided; £22,900 per case of PPH ≥ 1000 mL avoided; and £894,514 per major outcome averted. CONCLUSION: The results suggest carbetocin, oxytocin and 'ergometrine plus oxytocin' could all be favourable options for being the most cost-effective strategy for preventing PPH. Carbetocin could be the preferred choice, especially if the price of carbetocin decreased. Mixed findings mean a clear-cut conclusion cannot be made as to which uterotonic is the most cost effective. Future research should focus on collecting more robust evidence on the probability of having adverse events from the uterotonic drugs, and on adapting the model for low- and middle-income countries.

RAL GTPases Drive Intestinal Stem Cell Function and Regeneration through Internalization of WNT Signalosomes.

Ral GTPases are RAS effector molecules and by implication a potential therapeutic target for RAS mutant cancer. However, very little is known about their roles in stem cells and tissue homeostasis. Using Drosophila, we identified expression of RalA in intestinal stem cells (ISCs) and progenitor cells of the fly midgut. RalA was required within ISCs for efficient regeneration downstream of Wnt signaling. Within the murine intestine, genetic deletion of either mammalian ortholog, Rala or Ralb, reduced ISC function and Lgr5 positivity, drove hypersensitivity to Wnt inhibition, and impaired tissue regeneration following damage. Ablation of both genes resulted in rapid crypt death. Mechanistically, RALA and RALB were required for efficient internalization of the Wnt receptor Frizzled-7. Together, we identify a conserved role for RAL GTPases in the promotion of optimal Wnt signaling, which defines ISC number and regenerative potential.