Codesigning enhanced models of care for Northern Australian Aboriginal and Torres Strait Islander youth with type 2 diabetes: study protocol.

INTRODUCTION: Premature onset of type 2 diabetes and excess mortality are critical issues internationally, particularly in Indigenous populations. There is an urgent need for developmentally appropriate and culturally safe models of care. We describe the methods for the codesign, implementation and evaluation of enhanced models of care with Aboriginal and Torres Strait Islander youth living with type 2 diabetes across Northern Australia. METHODS AND ANALYSIS: Our mixed-methods approach is informed by the principles of codesign. Across eight sites in four regions, the project brings together the lived experience of Aboriginal and Torres Strait Islander young people (aged 10-25) with type 2 diabetes, their families and communities, and health professionals providing diabetes care through a structured yet flexible codesign process. Participants will help identify and collaborate in the development of a range of multifaceted improvements to current models of care. These may include addressing needs identified in our formative work such as the development of screening and management guidelines, referral pathways, peer support networks, diabetes information resources and training for health professionals in youth type 2 diabetes management. The codesign process will adopt a range of methods including qualitative interviews, focus group discussions, art-based methods and healthcare systems assessments. A developmental evaluation approach will be used to create and refine the components and principles of enhanced models of care. We anticipate that this codesign study will produce new theoretical insights and practice frameworks, resources and approaches for age-appropriate, culturally safe models of care. ETHICS AND DISSEMINATION: The study design was developed in collaboration with Aboriginal and Torres Strait Islander and non-Indigenous researchers, health professionals and health service managers and has received ethical approval across all sites. A range of outputs will be produced to disseminate findings to participants, other stakeholders and the scholarly community using creative and traditional formats.

Developing an integrated clinical decision support system for the early identification and management of kidney disease-building cross-sectoral partnerships.

BACKGROUND: The burden of chronic conditions is growing in Australia with people in remote areas experiencing high rates of disease, especially kidney disease. Health care in remote areas of the Northern Territory (NT) is complicated by a mobile population, high staff turnover, poor communication between health services and complex comorbid health conditions requiring multidisciplinary care. AIM: This paper aims to describe the collaborative process between research, government and non-government health services to develop an integrated clinical decision support system to improve patient care. METHODS: Building on established partnerships in the government and Aboriginal Community-Controlled Health Service (ACCHS) sectors, we developed a novel digital clinical decision support system for people at risk of developing kidney disease (due to hypertension, diabetes, cardiovascular disease) or with kidney disease. A cross-organisational and multidisciplinary Steering Committee has overseen the design, development and implementation stages. Further, the system's design and functionality were strongly informed by experts (Clinical Reference Group and Technical Working Group), health service providers, and end-user feedback through a formative evaluation. RESULTS: We established data sharing agreements with 11 ACCHS to link patient level data with 56 government primary health services and six hospitals. Electronic Health Record (EHR) data, based on agreed criteria, is automatically and securely transferred from 15 existing EHR platforms. Through clinician-determined algorithms, the system assists clinicians to diagnose, monitor and provide guideline-based care for individuals, as well as service-level risk stratification and alerts for clinically significant events. CONCLUSION: Disconnected health services and separate EHRs result in information gaps and a health and safety risk, particularly for patients who access multiple health services. However, barriers to clinical data sharing between health services still exist. In this first phase, we report how robust partnerships and effective governance processes can overcome these barriers to support clinical decision making and contribute to holistic care.

4D Flow Cardiac MR in Primary Mitral Regurgitation.

BACKGROUND: Four-dimensional-flow cardiac MR (4DF-MR) offers advantages in primary mitral regurgitation. The relationship between 4DF-MR-derived mitral regurgitant volume (MR-Rvol) and the post-operative left ventricular (LV) reverse remodeling has not yet been established. PURPOSE: To ascertain if the 4DF-MR-derived MR-Rvol correlates with the LV reverse remodeling in primary mitral regurgitation. STUDY TYPE: Prospective, single-center, two arm, interventional vs. nonintervention observational study. POPULATION: Forty-four patients (male N = 30; median age 68 [59-75]) with at least moderate primary mitral regurgitation; either awaiting mitral valve surgery (repair [MVr], replacement [MVR]) or undergoing "watchful waiting" (WW). FIELD STRENGTH/SEQUENCE: 5 T/Balanced steady-state free precession (bSSFP) sequence/Phase contrast imaging/Multishot echo-planar imaging pulse sequence (five shots). ASSESSMENT: Patients underwent transthoracic echocardiography (TTE), phase-contrast MR (PMRI), 4DF-MR and 6-minute walk test (6MWT) at baseline, and a follow-up PMRI and 6MWT at 6 months. MR-Rvol was quantified by PMRI, 4DF-MR, and TTE by one observer. The pre-operative MR-Rvol was correlated with the post-operative decrease in the LV end-diastolic volume index (LVEDVi). STATISTICAL TESTS: Included Student t-test/Mann-Whitney test/Fisher's exact test, Bland-Altman plots, linear regression analysis and receiver operating characteristic curves. Statistical significance was defined as P < 0.05. RESULTS: While Bland-Altman plots demonstrated similar bias between all the modalities, the limits of agreement were narrower between 4DF-MR and PMRI (bias 15; limits of agreement -36 mL to 65 mL), than between 4DF-MR and TTE (bias -8; limits of agreement -106 mL to 90 mL) and PMRI and TTE (bias -23; limits of agreement -105 mL to 59 mL). Linear regression analysis demonstrated a significant association between the MR-Rvol and the post-operative decrease in the LVEDVi, when the MR-Rvol was quantified by PMRI and 4DF-MR, but not by TTE (P = 0.73). 4DF-MR demonstrated the best diagnostic performance for reduction in the post-operative LVEDVi with the largest area under the curve (4DF-MR 0.83; vs. PMRI 0.78; and TTE 0.51; P = 0.89). DATA CONCLUSION: This study demonstrates the potential clinical utility of 4DF-MR in the assessment of primary mitral regurgitation. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 5.

The effect of aspirin and eicosapentaenoic acid on urinary biomarkers of prostaglandin E2 synthesis and platelet activation in participants of the seAFOod polyp prevention trial.

Urinary prostaglandin (PG) E metabolite (PGE-M) and 11-dehydro (d)-thromboxane (TX) B2 are biomarkers of cyclooxygenase-dependent prostanoid synthesis. We investigated (1) the effect of aspirin 300 mg daily and eicosapentaenoic acid (EPA) 2000 mg daily, alone and in combination, on urinary biomarker levels and, (2) whether urinary biomarker levels predicted colorectal polyp risk, during participation in the seAFOod polyp prevention trial. Urinary PGE-M and 11-d-TXB2 were measured by liquid chromatography-tandem mass spectrometry. The relationship between urinary biomarker levels and colorectal polyp outcomes was investigated using negative binomial (polyp number) and logistic (% with one or more polyps) regression models. Despite wide temporal variability in PGE-M and 11-d-TXB2 levels within individuals, both aspirin and, to a lesser extent, EPA decreased levels of both biomarkers (74% [P ≤ .001] and 8% [P ≤ .05] reduction in median 11-d-TXB2 values, respectively). In the placebo group, a high (quartile [Q] 2-4) baseline 11-d-TXB2 level predicted increased polyp number (incidence rate ratio [IRR] [95% CI] 2.26 [1.11,4.58]) and risk (odds ratio [95% CI] 3.56 [1.09,11.63]). A low (Q1) on-treatment 11-d-TXB2 level predicted reduced colorectal polyp number compared to placebo (IRR 0.34 [0.12,0.93] for combination aspirin and EPA treatment) compared to high on-treatment 11-d-TXB2 values (0.61 [0.34,1.11]). Aspirin and EPA both inhibit PGE-M and 11-d-TXB2 synthesis in keeping with shared in vivo cyclooxygenase inhibition. Colorectal polyp risk and treatment response prediction by 11-d-TXB2 is consistent with a role for platelet activation during early colorectal carcinogenesis. The use of urinary 11-d-TXB2 measurement for a precision approach to colorectal cancer risk prediction and chemoprevention requires prospective evaluation.

Age at diagnosis and diagnostic delay across attention-deficit hyperactivity and autism spectrums.

BACKGROUND: Despite the known benefits of accurate and timely diagnosis for children with attention-deficit hyperactivity disorder and autism spectrum disorders (autism), for some children this goal is not always achieved. Existing research has explored diagnostic delay for autism and attention-deficit hyperactivity disorder only, and when attention-deficit hyperactivity disorder and autism co-occur, autism has been the focus. No study has directly compared age at diagnosis and diagnostic delay for males and females across attention-deficit hyperactivity disorder, autism and specifically, attention-deficit hyperactivity disorder + autism. METHODS: Australian caregivers (N = 677) of children with attention-deficit hyperactivity disorder, autism or attention-deficit hyperactivity disorder + autism were recruited via social media (n = 594) and the Monash Autism and ADHD Genetics and Neurodevelopment Project (n = 83). Caregivers reported on their child's diagnostic process. Diagnostic delay was the mean difference between general initial developmental concerns and the child's attention-deficit hyperactivity disorder and autism diagnosis. RESULTS: Children with autism were significantly younger at autism diagnosis than the attention-deficit hyperactivity disorder + autism group (ηp2 = 0.06), whereas children with attention-deficit hyperactivity disorder were significantly older at attention-deficit hyperactivity disorder diagnosis than the attention-deficit hyperactivity disorder + autism group (ηp2 = 0.01). Delay to attention-deficit hyperactivity disorder and autism diagnosis was significantly longer in the attention-deficit hyperactivity disorder + autism group compared to attention-deficit hyperactivity disorder (ηp2 = 0.02) and autism (η2 = 0.04) only. Delay to autism diagnosis for females with autism (η2 = 0.06) and attention-deficit hyperactivity disorder + autism (η2 = 0.04) was longer compared to males. CONCLUSIONS: Having attention-deficit hyperactivity disorder + autism and being female were associated with longer delays to diagnosis. The reasons for these delays and possible adverse effects on outcomes require further study.

Percutaneous Revascularization for Ischemic Left Ventricular Dysfunction: Cost-Effectiveness Analysis of the REVIVED-BCIS2 Trial.

BACKGROUND: Percutaneous coronary intervention (PCI) is frequently undertaken in patients with ischemic left ventricular systolic dysfunction. The REVIVED (Revascularization for Ischemic Ventricular Dysfunction)-BCIS2 (British Cardiovascular Society-2) trial concluded that PCI did not reduce the incidence of all-cause death or heart failure hospitalization; however, patients assigned to PCI reported better initial health-related quality of life than those assigned to optimal medical therapy (OMT) alone. The aim of this study was to assess the cost-effectiveness of PCI+OMT compared with OMT alone. METHODS: REVIVED-BCIS2 was a prospective, multicenter UK trial, which randomized patients with severe ischemic left ventricular systolic dysfunction to either PCI+OMT or OMT alone. Health care resource use (including planned and unplanned revascularizations, medication, device implantation, and heart failure hospitalizations) and health outcomes data (EuroQol 5-dimension 5-level questionnaire) on each patient were collected at baseline and up to 8 years post-randomization. Resource use was costed using publicly available national unit costs. Within the trial, mean total costs and quality-adjusted life-years (QALYs) were estimated from the perspective of the UK health system. Cost-effectiveness was evaluated using estimated mean costs and QALYs in both groups. Regression analysis was used to adjust for clinically relevant predictors. RESULTS: Between 2013 and 2020, 700 patients were recruited (mean age: PCI+OMT=70 years, OMT=68 years; male (%): PCI+OMT=87, OMT=88); median follow-up was 3.4 years. Over all follow-ups, patients undergoing PCI yielded similar health benefits at higher costs compared with OMT alone (PCI+OMT: 4.14 QALYs, £22 352; OMT alone: 4.16 QALYs, £15 569; difference: -0.015, £6782). For both groups, most health resource consumption occurred in the first 2 years post-randomization. Probabilistic results showed that the probability of PCI being cost-effective was 0. CONCLUSIONS: A minimal difference in total QALYs was identified between arms, and PCI+OMT was not cost-effective compared with OMT, given its additional cost. A strategy of routine PCI to treat ischemic left ventricular systolic dysfunction does not seem to be a justifiable use of health care resources in the United Kingdom. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920048.

3D matrix adhesion feedback controls nuclear force coupling to drive invasive cell migration.

Cell invasion is a multi-step process, initiated by the acquisition of a migratory phenotype and the ability to move through complex 3D extracellular environments. We determine the composition of cell-matrix adhesion complexes of invasive breast cancer cells in 3D matrices and identify an interaction complex required for invasive migration. ßPix and myosin18A (Myo18A) drive polarized recruitment of non-muscle myosin 2A (NM2A) to adhesion complexes at the tips of protrusions. Actomyosin force engagement then displaces the Git1-ßPix complex from paxillin, establishing a feedback loop for adhesion maturation. We observe active force transmission to the nucleus during invasive migration that is needed to pull the nucleus forward. The recruitment of NM2A to adhesions creates a non-muscle myosin isoform gradient, which extends from the protrusion to the nucleus. We postulate that this gradient facilitates coupling of cell-matrix interactions at the protrusive cell front with nuclear movement, enabling effective invasive migration and front-rear cell polarity.

PDIA6 and Maspin in Prostate Cancer.

BACKGROUND/AIM: PDIA6 is a disulphide isomerase of the PDI family, known to mediate disulphide bond formation in the endoplasmic reticulum. However, PDI-related proteins also function in other parts of the cell and PDIA6 has been shown to be involved in many types of cancers. We previously identified PDIA6 as a putative Maspin interactor. Maspin has itself been implicated in prostate cancer progression. Our aim was to further explore the roles of Maspin in prostate cancer and establish whether PDIA6 is also involved in prostate cancer. MATERIALS AND METHODS: RNA levels of PDIA6 and Maspin in prostate cell lines were measured using RT-PCR. Bioinformatics analysis of the TCGA database was used to find RNA levels of PDIA6 and Maspin in prostate cancer. siRNAs were used to knock-down PDIA6, and proliferation and migration assays were conducted on those cells. RESULTS: PDIA6 and Maspin RNA were shown to be expressed at varying levels in prostate cell lines. RNAseq data showed that PDIA6 expression was significantly increased in prostate adenocarcinoma samples, while Maspin RNA expression was decreased. When PDIA6 expression was knocked-down using siRNA in prostate cell lines, proliferation was decreased substantially in the two prostate cancer cell lines (DU145 and PC3) and also decreased in the normal prostate cell line (PNT1a), though less strongly. CONCLUSION: PDIA6 expression is higher in prostate cancer cells compared to normal prostate cells. Decreasing PDIA6 expression decreases proliferation. Thus, PDIA6 is a promising target for prostate cancer therapeutics.

Continuous Glucose Monitoring Metrics in High-Risk Pregnant Women with Type 2 Diabetes.

Objective: To describe glucose metrics in a high-risk population of women with type 2 diabetes (T2DM) in pregnancy and to explore the associations with neonatal outcomes. Research Design and Methods: Prospective observational study of 57 women. Continuous glucose monitoring (CGM) trajectories were determined from metrics collected in early and late gestation using the first and last two (mean 16 and 35) weeks of Freestyle Libre data. Logistic regression was used to examine associations of CGM metrics with neonatal hypoglycemia (glucose <2.6 mmol/L requiring intravenous dextrose) and large for gestational age (LGA) (>90th percentile for gestational age and sex). Pregnancy-specific target glucose range was 3.5-7.8 mmol/L (63-140 mg/dL). Results: Forty-one women used CGM for 15 weeks (mean age 33 years, 73% Aboriginal or Torres Strait Islander, 32% living remotely). There was limited change in average metrics from early to late pregnancy. For the subgroup with sensor use >50% (n = 29), mean time in range (TIR) increased by 9%, time above range reduced by 12%, average glucose reduced by 1 mmol/L, and time below range increased by 3%. Neonatal hypoglycemia was associated with most CGM metrics, HbA1c and CGM targets, particularly those from late pregnancy. LGA was associated with hyperglycemic metrics from early pregnancy. Each 1% increase TIR was associated with a 4%-5% reduction in risk of neonatal complications. Conclusion: In this high-risk group of women with T2DM, CGM metrics only improved during pregnancy in those with greater sensor use and were associated with LGA in early pregnancy and neonatal hypoglycemia throughout. Culturally appropriate health care strategies are critical for successful use of CGM technology.

Circulating epigenomic biomarkers correspond with kidney disease susceptibility in high-risk populations with type 2 diabetes mellitus.

AIMS: To investigate epigenomic indices of diabetic kidney disease (DKD) susceptibility among high-risk populations with type 2 diabetes mellitus. METHODS: KDIGO (Kidney Disease: Improving Global Outcomes) clinical guidelines were used to classify people living with or without DKD. Differential gene methylation of DKD was then assessed in a discovery Aboriginal Diabetes Study cohort (PROPHECY, 89 people) and an external independent study from Thailand (THEPTARIN, 128 people). Corresponding mRNA levels were also measured and linked to levels of albuminuria and eGFR. RESULTS: Increased DKD risk was associated with reduced methylation and elevated gene expression in the PROPHECY discovery cohort of Aboriginal Australians and these findings were externally validated in the THEPTARIN diabetes registry of Thai people living with type 2 diabetes mellitus. CONCLUSIONS: Novel epigenomic scores can improve diagnostic performance over clinical modelling using albuminuria and GFR alone and can distinguish DKD susceptibility.

Polymorphisms in Cyclooxygenase, Lipoxygenase, and TP53 Genes Predict Colorectal Polyp Risk Reduction by Aspirin in the seAFOod Polyp Prevention Trial.

Aspirin and eicosapentaenoic acid (EPA) reduce colorectal adenomatous polyp risk and affect synthesis of oxylipins including prostaglandin E2. We investigated whether 35 SNPs in oxylipin metabolism genes such as cyclooxygenase (PTGS) and lipoxygenase (ALOX), as well as 7 SNPs already associated with colorectal cancer risk reduction by aspirin (e.g., TP53; rs104522), modified the effects of aspirin and EPA on colorectal polyp recurrence in the randomized 2 × 2 factorial seAFOod trial. Treatment effects were reported as the incidence rate ratio (IRR) and 95% confidence interval (CI) by stratifying negative binomial and Poisson regression analyses of colorectal polyp risk on SNP genotype. Statistical significance was reported with adjustment for the false discovery rate as the P and q value. 542 (of 707) trial participants had both genotype and colonoscopy outcome data. Reduction in colorectal polyp risk in aspirin users compared with nonaspirin users was restricted to rs4837960 (PTGS1) common homozygotes [IRR, 0.69; 95% confidence interval (CI), 0.53-0.90); q = 0.06], rs2745557 (PTGS2) compound heterozygote-rare homozygotes [IRR, 0.60 (0.41-0.88); q = 0.06], rs7090328 (ALOX5) rare homozygotes [IRR 0.27 (0.11-0.64); q = 0.05], rs2073438 (ALOX12) common homozygotes [IRR, 0.57 (0.41-0.80); q = 0.05], and rs104522 (TP53) rare homozygotes [IRR, 0.37 (0.17-0.79); q = 0.06]. No modification of colorectal polyp risk in EPA users was observed. In conclusion, genetic variants relevant to the proposed mechanism of action on oxylipins are associated with differential colorectal polyp risk reduction by aspirin in individuals who develop multiple colorectal polyps. SNP genotypes should be considered during development of personalized, predictive models of colorectal cancer chemoprevention by aspirin. PREVENTION RELEVANCE: Single-nucleotide polymorphisms in genes controlling lipid mediator signaling may modify the colorectal polyp prevention activity of aspirin. Further investigation is required to determine whether testing for genetic variants can be used to target cancer chemoprevention by aspirin to those who will benefit most.

Surface-Induced Hydrophobin Assemblies with Versatile Properties and Distinct Underlying Structures.

Hydrophobins are remarkable proteins due to their ability to self-assemble into amphipathic coatings that reverse surface wettability. Here, the versatility of the Class I hydrophobins EASΔ15 and DewY in diverse nanosuspension and coating applications is demonstrated. The hydrophobins are shown to coat or emulsify a range of substrates including oil, hydrophobic drugs, and nanodiamonds and alter their solution and surface behavior. Surprisingly, while the coatings confer new properties, only a subset is found to be resistant to hot detergent treatment, a feature previously thought to be characteristic of the functional amyloid form of Class I hydrophobins. These results demonstrate that substrate surface properties can influence the molecular structures and physiochemical properties of hydrophobin and possibly other functional amyloids. Functional amyloid assembly with different substrates and conditions may be analogous to the propagation of different polymorphs of disease-associated amyloid fibrils with distinct structures, stability, and clinical phenotypes. Given that amyloid formation is not required for Class I hydrophobins to serve diverse applications, our findings open up new opportunities for their use in applications requiring a range of chemical and physical properties. In hydrophobin nanotechnological applications where high stability of assemblies is required, simultaneous structural and functional characterization should be carried out. Finally, while results in this study pertain to synthetic substrates, they raise the possibility that at least some members of the pseudo-Class I and Class III hydrophobins, reported to form assemblies with noncanonical properties, may be Class I hydrophobins adopting alternative structures in response to environmental cues.

Identification of non-ischaemic fibrosis in male veteran endurance athletes, mechanisms and association with premature ventricular beats.

Left ventricular fibrosis can be identified by late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) in some veteran athletes. We aimed to investigate prevalence of ventricular fibrosis in veteran athletes and associations with cardiac arrhythmia. 50 asymptomatic male endurance athletes were recruited. They underwent CMR imaging including volumetric analysis, bright blood (BB) and dark blood (DB) LGE, motion corrected (MOCO) quantitative stress and rest perfusion and T1/T2/extracellular volume mapping. Athletes underwent 12-lead electrocardiogram (ECG) and 24-h ECG. Myocardial fibrosis was identified in 24/50 (48%) athletes. All fibrosis was mid-myocardial in the basal-lateral left ventricular wall. Blood pressure was reduced in athletes without fibrosis compared to controls, but not athletes with fibrosis. Fibrotic areas had longer T2 time (44 ± 4 vs. 40 ± 2 ms, p < 0.0001) and lower rest myocardial blood flow (MBF, 0.5 ± 0.1 vs. 0.6 ± 0.1 ml/g/min, p < 0.0001). On 24-h ECG, athletes with fibrosis had greater burden of premature ventricular beats (0.3 ± 0.6 vs. 0.05 ± 0.2%, p = 0.03), with higher prevalence of ventricular couplets and triplets (33 vs. 8%, p = 0.02). In veteran endurance athletes, myocardial fibrosis is common and associated with an increased burden of ventricular ectopy. Possible mechanisms include inflammation and blood pressure. Further studies are needed to establish whether fibrosis increases risk of malignant arrhythmic events.

Association between maternal hyperglycemia in pregnancy and offspring anthropometry in early childhood: the pandora wave 1 study.

BACKGROUND: In-utero hyperglycemia exposure influences later cardiometabolic risk, although few studies include women with pre-existing type 2 diabetes (T2D) or assess maternal body mass index (BMI) as a potential confounder. OBJECTIVE: To explore the association of maternal T2D and gestational diabetes mellitus (GDM) with childhood anthropometry, and the influence of maternal BMI on these associations. METHODS: The PANDORA cohort comprises women (n = 1138) and children (n = 1163). Women with GDM and T2D were recruited from a hyperglycemia in pregnancy register, and women with normoglycemia from the community. Wave 1 follow-up included 423 children, aged 1.5-5 years (median follow-up age 2.5 years). Multivariable linear regression assessed associations between maternal antenatal variables, including BMI and glycemic status, with offspring anthropometry (weight, height, BMI, skinfold thicknesses, waist, arm and head circumferences). RESULTS: Greater maternal antenatal BMI was associated with increased anthropometric measures in offspring independent of maternal glycemic status. After adjustment, including for maternal BMI, children exposed to maternal GDM had lower mean weight (-0.54 kg, 95% CI: -0.99, -0.11), BMI (-0.55 kg/m2, 95% CI: -0.91, -0.20), head (-0.52 cm, 95% CI: -0.88, -0.16) and mid-upper arm (-0.32 cm, 95% CI: -0.63, -0.01) circumferences, and greater mean suprailiac skinfold (0.78 mm, 95% CI: 0.13, 1.43), compared to children exposed to normoglycemia. Adjustment for maternal BMI strengthened the negative association between GDM and child weight, BMI and circumferences. Children exposed to maternal T2D had smaller mean head circumference (-0.82 cm, 95% CI: -1.33, -0.31) than children exposed to normoglycemia. Maternal T2D was no longer associated with greater child mean skinfolds (p = 0.14) or waist circumference (p = 0.18) after adjustment for maternal BMI. CONCLUSIONS: Children exposed to GDM had greater suprailiac skinfold thickness than unexposed children, despite having lower mean weight, BMI and mid-upper arm circumference, and both GDM and T2D were associated with smaller mean head circumference. Future research should assess whether childhood anthropometric differences influence lifetime cardiometabolic and neurodevelopmental risk.

Colorectal polyp outcomes after participation in the seAFOod polyp prevention trial: Evidence of rebound elevated colorectal polyp risk after short-term aspirin use.

BACKGROUND: The seAFOod polyp prevention trial was a randomised, placebo-controlled, 2 × 2 factorial trial of aspirin 300 mg and eicosapentaenoic acid (EPA) 2000 mg daily in individuals who had a screening colonoscopy in the English Bowel Cancer Screening Programme (BCSP). Aspirin treatment was associated with a 20% reduction in colorectal polyp number at BCSP surveillance colonoscopy 12 months later. It is unclear what happens to colorectal polyp risk after short-term aspirin use. AIM: To investigate colorectal polyp risk according to the original trial treatment allocation, up to 6 years after trial participation. METHODS: All seAFOod trial participants were scheduled for further BCSP surveillance and provided informed consent for the collection of colonoscopy outcomes. We linked BCSP colonoscopy data to trial outcomes data. RESULTS: In total, 507 individuals underwent one or more colonoscopies after trial participation. Individuals grouped by treatment allocation were well matched for clinical characteristics, follow-up duration and number of surveillance colonoscopies. The polyp detection rate (PDR; the number of individuals who had ≥1 colorectal polyp detected) after randomization to placebo aspirin was 71.1%. The PDR was 80.1% for individuals who had received aspirin (odds ratio [OR] 1.13 [95% confidence interval 1.02, 1.24]; p = 0.02). There was no difference in colorectal polyp outcomes between individuals who had been allocated to EPA compared with its placebo (OR for PDR 1.00 [0.91, 1.10]; p = 0.92). CONCLUSION: Individuals who received aspirin in the seAFOod trial demonstrated increased colorectal polyp risk during post-trial surveillance. Rebound elevated neoplastic risk after short-term aspirin use has important implications for aspirin cessation driven by age-related bleeding risk. ISRCTN05926847.

Cardiac reverse remodeling in primary mitral regurgitation: mitral valve replacement vs. mitral valve repair.

BACKGROUND: When feasible, guidelines recommend mitral valve repair (MVr) over mitral valve replacement (MVR) to treat primary mitral regurgitation (MR), based upon historic outcome studies and transthoracic echocardiography (TTE) reverse remodeling studies. Cardiovascular magnetic resonance (CMR) offers reference standard biventricular assessment with superior MR quantification compared to TTE. Using serial CMR in primary MR patients, we aimed to investigate cardiac reverse remodeling and residual MR post-MVr vs MVR with chordal preservation. METHODS: 83 patients with ≥ moderate-severe MR on TTE were prospectively recruited. 6-min walk tests (6MWT) and CMR imaging including cine imaging, aortic/pulmonary through-plane phase contrast imaging, T1 maps and late-gadolinium-enhanced (LGE) imaging were performed at baseline and 6 months after mitral surgery or watchful waiting (control group). RESULTS: 72 patients completed follow-up (Controls = 20, MVr = 30 and MVR = 22). Surgical groups demonstrated comparable baseline cardiac indices and co-morbidities. At 6-months, MVr and MVR groups demonstrated comparable improvements in 6MWT distances (+ 57 ± 54 m vs + 64 ± 76 m respectively, p = 1), reduced indexed left ventricular end-diastolic volumes (LVEDVi; - 29 ± 21 ml/m2 vs - 37 ± 22 ml/m2 respectively, p = 0.584) and left atrial volumes (- 23 ± 30 ml/m2 and - 39 ± 26 ml/m2 respectively, p = 0.545). At 6-months, compared with controls, right ventricular ejection fraction was poorer post-MVr (47 ± 6.1% vs 53 ± 8.0% respectively, p = 0.01) compared to post-MVR (50 ± 5.7% vs 53 ± 8.0% respectively, p = 0.698). MVR resulted in lower residual MR-regurgitant fraction (RF) than MVr (12 ± 8.0% vs 21 ± 11% respectively, p = 0.022). Baseline and follow-up indices of diffuse and focal myocardial fibrosis (Native T1 relaxation times, extra-cellular volume and quantified LGE respectively) were comparable between groups. Stepwise multiple linear regression of indexed variables in the surgical groups demonstrated baseline indexed mitral regurgitant volume as the sole multivariate predictor of left ventricular (LV) end-diastolic reverse remodelling, baseline LVEDVi as the most significant independent multivariate predictor of follow-up LVEDVi, baseline indexed LV end-systolic volume as the sole multivariate predictor of follow-up LV ejection fraction and undergoing MVR (vs MVr) as the most significant (p < 0.001) baseline multivariate predictor of lower residual MR. CONCLUSION: In primary MR, MVR with chordal preservation may offer comparable cardiac reverse remodeling and functional benefits at 6-months when compared to MVr. Larger, multicenter CMR studies are required, which if the findings are confirmed could impact future surgical practice.

The role of structural racism and geographical inequity in diabetes outcomes.

Diabetes is pervasive, exponentially growing in prevalence, and outpacing most diseases globally. In this Series paper, we use new theoretical frameworks and a narrative review of existing literature to show how structural inequity (structural racism and geographical inequity) has accelerated rates of diabetes disease, morbidity, and mortality globally. We discuss how structural inequity leads to large, fixed differences in key, upstream social determinants of health, which influence downstream social determinants of health and resultant diabetes outcomes in a cascade of widening inequity. We review categories of social determinants of health with known effects on diabetes outcomes, including public awareness and policy, economic development, access to high-quality care, innovations in diabetes management, and sociocultural norms. We also provide regional perspectives, grounded in our theoretical framework, to highlight prominent, real-world challenges.