To utilise Fremantle Diabetes Study Phase II (FDS2) data to examine the association between Type 2 diabetes and incident aortic valve replacement (AVR) and to investigate potential risk factors in Type 2 diabetes. We followed 1430 FDS2 participants (mean age 66 years, 53% males) and 5720 age-, sex-, and postcode-matched people without diabetes from entry (2008–2011) to end-2021 for AVR ascertained from validated linked databases. Incidence rate ratios (IRRs) were calculated. Cox proportional hazards and competing risk models generated cause-specific (cs) and subdistribution (sd) hazard ratios (HRs) for incident AVR. At baseline, 11 participants with Type 2 diabetes (0.8%) and 37 without diabetes (0.6%) had undergone AVR ( p  = 0.589). There were 24 (1.7%) and 40 (0.7%) first incident AVR hospitalisations, respectively, in the two groups during 73,498 person-years of follow-up (IRR 2.40 [95% confidence interval (CI) 1.38, 4.08], p  = 0.0007). In pooled analyses, Type 2 diabetes had similar csHR (2.38 [1.43, 3.96]) and sdHR (2.34 [1.41, 3.88]), with increasing age and male sex as other statistically significant covariates. In Type 2 diabetes, incident AVR was bivariably associated with baseline blood glucose-lowering treatment intensity ( p  = 0.003) and with distal symmetrical polyneuropathy (DSPN) after age and sex adjustment ( p  = 0.025). Type 2 diabetes more than doubles the risk of AVR after adjusting for the competing risk of death. People with Type 2 diabetes going on to require AVR were more intensively managed and were more likely to have DSPN at baseline.

AIMS:To investigate whether i) ultrasonographically-assessed carotid arterial disease (CAD) is associated with diabetic retinopathy (DR) progression and retinal microangiopathy measured by optical coherence tomography angiography (OCTA), and ii) baseline DR prevalence and/or OCTA parameters are associated with CAD progression in type 2 diabetes. METHODS:Participants in the Fremantle Diabetes Study Phase II (n = 164, mean age 69.7 years, 55.5% males) in whom carotid ultrasonography/OCTA was performed in 2018-2019 were restudied a mean 3.7 years later. Generalized estimating equations assessed associations between baseline CAD indices and new/worsening DR and OCTA parameter changes, and between baseline DR status/OCTA parameters and changes in CAD metrics. RESULTS:Carotid stenosis (focal wall thickening ≥50% or intima-media thickness (IMT) > 1.5 mm) and carotid bifurcation IMT ≥1 mm at baseline were independently associated with reductions in superficial capillary plexus parafoveal vessel density (regression coefficients (95% CI) 0.73 (0.02 to 1.43) and 0.88 (95% CI: 0.06 to 1.69); P = 0.043 and 0.035, respectively). There were no independent associations between CAD parameters and new/worsening DR. There were no significant associations between baseline DR/OCTA parameters and new/worsening carotid stenosis. CONCLUSIONS:CAD may contribute to early DR in type 2 diabetes but we found no evidence of a bidirectional relationship.

CONTEXT:It is uncertain whether subclinical hypothyroidism (SCH) contributes to intrinsic renal dysfunction in people with type 2 diabetes mellitus (T2DM). OBJECTIVE:To investigate whether SCH persisting over 4 years is associated with incident impairment of renal function in people with T2DM. DESIGN:Longitudinal observational study. SETTING:Urban population of people with type 2 diabetes living in the community and enrolled in a prospective observational study of diabetes. PARTICIPANTS:725 without known thyroid dysfunction at baseline and at follow-up. MAIN OUTCOME MEASURES:Changes in estimated glomerular filtration rate (eGFR) and urine albumin:creatinine ratio (ACR) in participants stratified by thyroid status at baseline and follow-up into those with euthyroidism or transient or persistent subclinical (SCH)/overt hypothyroidism. RESULTS:After a mean ± SD 4.3 ± 0.4 years, 683 participants had stable euthyroidism, 18 transient SCH/overt hypothyroidism, and 24 persistent SCH/overt hypothyroidism. No significant changes in eGFR were observed in any group. Those with persistent SCH/overt hypothyroidism demonstrated a significant increase in ACR, which was not seen in those with euthyroidism and transient SCH/overt hypothyroidism (ΔACR 22.0 ± 81.4 vs 0.4 ± 36.7 and -0.3 ± 5.7 mg/mmol, respectively, P = .027). Similar results were seen when those with baseline ACR > 30 mg/mmol were excluded. CONCLUSION:Persistent SCH/overt hypothyroidism was associated with incident increased albuminuria not observed in euthyroid participants. Assessment of thyroid function in all patients with T2DM may be indicated, as some previous studies provide evidence that thyroxine replacement may ameliorate albuminuria.

OBJECTIVE:To determine whether micronutrient intake and/or supplementation is associated with prevalent diabetes-related foot ulcer (DFU) and/or incident hospitalisation for DFU in type 2 diabetes. RESEARCH DESIGN AND METHODS:Participants with type 2 diabetes from the community-based Fremantle Diabetes Study Phase II (FDS2; 1499 participants, mean age 65.4 years, 51.8% males, recruited 2008-2011) were followed from entry to first hospitalization for/with DFU, death or 31 December 2016 (whichever came first). Cox proportional hazards modelling identified independent associates of prevalent DFU or first DFU hospitalization. RESULTS:Self-reported food frequency, including dietary intake of vitamin C, zinc and iron, taking vitamin supplements and B12 and iron levels were not independent associates of either prevalent DFU or incident DFU hospitalisation. Independent associates of prevalent DFU included younger age at diabetes diagnosis, being unmarried, retinopathy, distal symmetrical polyneuropathy (DSPN), previous diabetes-related amputation, peripheral revascularisation or bypass. Incident DFU hospitalisation was independently associated with male sex, marital status, age at diagnosis of diabetes, HbA1c, a history of DFU, a history of peripheral revascularisation/bypass, heart rate, and ln(NT-proBNP). CONCLUSIONS:Associates of prevalent and incident DFU included traditional risk factors such as DSPN and peripheral arterial disease. There was no association between nutritional status or taking vitamin supplements and prevalent DFU or incident DFU hospitalisation in people with type 2 diabetes.

Abstract Background Socio‐economic status (SES) is strongly linked to health outcomes but remains difficult to measure accurately. Conventional approaches based on large geographical units (e.g. postcodes) may obscure SES effects evident at smaller scales. Aims We aimed to address key limitations of postcode‐based socio‐economic analyses by developing and demonstrating a more geographically precise small‐area approach. Methods We developed an online platform ( https://onlinecalc.app/SEIFA_SA1/ ) that integrates small‐area SES data across multiple Australian Census periods and expresses SES as percentile rankings, preserving relative positionality over time and reducing inconsistencies introduced by Census method updates. To illustrate its utility, we analysed Australian participants from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, linking each participant's residential collection district (~200 households) to Index of Relative Socio‐economic Disadvantage (IRSD) and Index of Economic Resources (IER) percentiles 5‐yearly from 1986 to 2006. Results In 5147 participants, lower area‐level SES was consistently associated with prevalent cardiovascular disease (CVD) across all census years, while lower SES among participants who experienced new on‐trial CVD events was evident in census data from the decade before trial entry (1986–1996) and not in 2001 or later. Among participants randomised to placebo, lower SES tertiles (2001–2006 Census) were associated with higher rates of new on‐trial CVD (6.9% vs 9.8% and 7.0% vs 10.0% for upper vs lower IRSD and IER tertiles respectively; both P for trend = 0.027), whereas this association was not observed in fenofibrate‐treated participants, in whom total CVD events were reduced overall by 11% ( P = 0.035). Conclusion Assessing SES at smaller geographical scales provides a more sensitive measure of socio‐economic disparities influencing cardiovascular risk. This approach underscores the value of high‐resolution census data for improving equity‐focused health research and policy.

AIMS:To utilise Fremantle Diabetes Study Phase II (FDS2) data to examine the association between Type 2 diabetes and incident aortic valve replacement (AVR) and to investigate potential risk factors in Type 2 diabetes. METHODS:We followed 1430 FDS2 participants (mean age 66 years, 53% males) and 5720 age-, sex-, and postcode-matched people without diabetes from entry (2008-2011) to end-2021 for AVR ascertained from validated linked databases. Incidence rate ratios (IRRs) were calculated. Cox proportional hazards and competing risk models generated cause-specific (cs) and subdistribution (sd) hazard ratios (HRs) for incident AVR. RESULTS:At baseline, 11 participants with Type 2 diabetes (0.8%) and 37 without diabetes (0.6%) had undergone AVR (p = 0.589). There were 24 (1.7%) and 40 (0.7%) first incident AVR hospitalisations, respectively, in the two groups during 73,498 person-years of follow-up (IRR 2.40 [95% confidence interval (CI) 1.38, 4.08], p = 0.0007). In pooled analyses, Type 2 diabetes had similar csHR (2.38 [1.43, 3.96]) and sdHR (2.34 [1.41, 3.88]), with increasing age and male sex as other statistically significant covariates. In Type 2 diabetes, incident AVR was bivariably associated with baseline blood glucose-lowering treatment intensity (p = 0.003) and with distal symmetrical polyneuropathy (DSPN) after age and sex adjustment (p = 0.025). CONCLUSIONS:Type 2 diabetes more than doubles the risk of AVR after adjusting for the competing risk of death. People with Type 2 diabetes going on to require AVR were more intensively managed and were more likely to have DSPN at baseline.

This narrative review provides a historical perspective on how observational research on type 2 diabetes has been developed and consolidated over the last 50 years and how well-designed cohort studies will provide us with knowledge for research and practice in the future and aid guideline development. We have included data from a large number of cohorts from every continent that have been used to study the development and/or progression of type 2 diabetes, including cohorts that are general population-based, disease-based, intervention-based and registry-based. We have structured the results from the past 50 years based on the following themes: diagnosis and screening, complications, risk factors and pathophysiology. We also discuss the strengths and weaknesses of observational research when compared with other research designs. Finally, we discuss the emerging and future directions for type 2 diabetes research using cohorts, which include novel developments, such as artificial intelligence, precision health and the exposome. We conclude that cohort research has significantly advanced our understanding of type 2 diabetes and aided guideline development, and complements experimental work, such as human randomised controlled trials and animal studies. Both approaches are essential and complementary in our pursuit to provide a more comprehensive understanding of the development and progression of type 2 diabetes, and to change dogma, practice and policies for better outcomes.

BACKGROUND:There are scant and variable data concerning the incidence of malaria in infants in endemic areas. This study evaluated the impact of maternal antimalarial treatment given postpartum on malaria incidence and growth/development in infants from coastal Papua New Guinea (PNG). METHODS:In an open-label, randomised controlled trial conducted in Madang Province, PNG, 183 mothers were randomised to no treatment (NT) or to artemisinin combination therapy (ACT) with further random allocation to artemether-lumefantrine or dihydroartemisinin-piperaquine. Their infants were assessed monthly over the next 6 months including for malaria identified by microscopy and/or polymerase chain reaction (PCR). RESULTS:Of 151 infants who completed study procedures, 2 developed slide-positive malaria (1 Plasmodium falciparum, 1 Plasmodium vivax; 1.3% [95% confidence interval {CI} 0.2 to 5.2]). Three others had PCR-detected infections (two P. falciparum, one P. vivax). The overall 6-month incidence of slide-/PCR-positive malaria was 3.3% (95% CI 1.2 to 8.0). Four of the five cases occurred in infants whose mothers were randomised to NT. There were no statistically significant between-group differences in infant growth and developmental milestones. CONCLUSIONS:The risk of malaria in early infancy in coastal PNG is low and infections are typically asymptomatic. Postpartum maternal ACT did not influence infant growth or development.

Estimated GFRs utilising creatinine- (eGFRcreat) or cystatin C-based (eGFRcyst) equations can generate discrepant results that are associated with clinical outcomes. A low eGFRcyst/eGFRcreat ratio (<0.60), reflecting a pathological glomerular state termed shrunken pore syndrome (SPS), has been associated with excess mortality in some clinical situations including diabetes. The aim of the present study was to explore this association in a longitudinal observational study of type 2 diabetes with special reference to participants with normal renal function. Of 1481 Fremantle Diabetes Study Phase II participants with type 2 diabetes, aged ≥17 years, 1466 had eGFRcreat and eGFRcyst assessed as part of the baseline assessment and were followed for 10 years or until death, whichever came first. Cox regression modelling was used to determine independent associates of death excluding eGFR; eGFRcyst/eGFRcreat ratio was then added to this model separately as a categorical or continuous variable. These analyses were also conducted in a subgroup (n=754) of participants with normal renal function (eGFRcreat ≥60 ml/min per 1.73 m2 and urinary albumin/creatinine ratio <3 mg/mmol) at baseline. At entry, the participants had a mean age of 65.9 years, 51.8

Purpose The urinary albumin:creatinine ratio (uACR) can exhibit significant temporal changes but few studies have characterized transition patterns between uACR categories in type 2 diabetes. The study aim was to use group-based trajectory modelling (GBTM) to identify clusters of people with type 2 diabetes and distinct uACR trajectories. Participants and methods Of 1482 participants in the observational Fremantle Diabetes Study Phase II, 1145 (77.3%; mean age 65.4 years, 53.3% males) with ≥2 biennial uACR measurements over 6 years were included in GBTM. Independent baseline associates of uACR trajectory group membership were assessed using multinomial regression. Associations between group membership and changes in estimated glomerular filtration rate over four years were explored. Results The optimum GBTM model comprised six categories; normoalbuminuria (n=429, 37.5%), regression (n=82, 7.2%), progression (n=71, 6.2%), progression/regression (n=104, 9.1%), persistent microalbuminuria (n=401, 35.0%), persistent macroalbuminuria (n=58, 5.1%). The latter five groups had worse glycemic control than the normoalbuminuria group. The three groups starting from/returning to normoalbuminuria had heterogeneous baseline characteristics but a decline in renal function that was similar to the normoalbuminuric group. The persistent microalbuminuria group had adverse baseline cardiometabolic features and longitudinal renal outcomes relative to the normoalbuminuria/other microalbuminuria groups. The persistent macroalbuminuria group had, consistent with its baseline characteristics, the highest mortality (31.0% versus ≤18.5% in the other groups) and most rapid progression of renal dysfunction. Conclusions GBTM identified distinct uACR trajectory groups with clinical and prognostic implications, and could be used to stratify participants in clinical trials of new therapies for diabetic kidney disease.

The present study explores the potential of artificial intelligence as a substitute for trained clinician identification of a carotid bruit from multiple auditory recordings from an electronic stethoscope in 98 people with type 2 diabetes, 48 of whom had a bruit. We employed various deep networks, including ResNet and VGGish, alongside tailor-made deep learning models for this purpose. Our findings indicated that in scenarios such as this, where the data show high variability and yet are limited, the highest model accuracy achieved was 67.8%. This suggests the inadequacy of AI-driven systems in accurately detecting carotid bruits in the present participant sample. Detailed results for each deep learning and machine learning approach are presented separately, and the dataset has been established as a benchmark for future studies. Given the complexity observed with the current data volume, additional studies with larger sample sizes are warranted.

The PromarkerD test accurately predicts diabetic kidney disease. We aimed to determine whether PromarkerD and/or its constituent biomarkers would also identify an increased risk of distal sensory polyneuropathy (DSPN) complicating type 2 diabetes (T2D). We selected 160 community-based adults without baseline DSPN (mean age 69 years, 56% males), 80 of whom were free of DSPN after four years and 80 who developed DSN based on the vibration perception threshold. Baseline plasma apolipoprotein A-IV (ApoA4), CD5 antigen-like protein (CD5L) and insulin-like growth factor binding protein 3 (IBP3) concentrations were measured and PromarkerD risk scores were generated. Logistic regression modelling assessed associations between PromarkerD risk and its component proteins and incident DSPN. At Year 4, 77 of 151 with valid data (51%) had developed DSPN. The PromarkerD area under the receiver operating characteristic curve was 0.53 (95% CI 0.43-0.62). The odds ratio for the PromarkerD score for identifying incident DSPN was 0.97 (95% CI 0.82-1.16, P = 0.76), with similar non-significant results for plasma ApoA4, CD5L, and IBP3. PromarkerD and its constituent protein concentrations, each with some preclinical or epidemiological evidence of an association with DSPN, did not predict incident DSPN over 4 years of follow-up. These data support microangiopathy-specific pathophysiological mechanisms in T2D.

Purpose:People with resistance to thyroid hormone due to defective thyroid receptor β (RTHβ) exhibit adverse cardiovascular outcomes and premature mortality. Whether this reflects increased global cardiovascular disease (CVD) risk or hyperthyroxinemia-associated effects on cardiac rhythm and contractility is unknown. We determined CVD risk and plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations as a marker of reduced cardiac function in 99 individuals (mean age 41 years, 37% males) with RTHβ. Results:The mean (SD range) QRISK3 score for 82 participants was 2.0% (0.5-8.8%) vs 1.3% (0.3-5.0%) for age, sex, and ethnicity-matched healthy controls (P = .005). The QRISK3 heart age of RTHβ participants was 49.8 ± 14.5 years vs actual age 44.5 ± 12.4 years [difference 5.3 (95% confidence interval: 4.0, 6.5) years; P < .001]. The mean (SD range) plasma NT-proBNP in 79 RTHβ participants was 51 (18-142) pg/mL; 10.1% of values were above the age-specific 97.5th percentile of a large control sample. In multiple linear regression, age and female sex were significant independent predictors of NT-proBNP (P ≤ .001), but free T3, free T4, TSH, and QRISK3 10-year CVD risk were not. Conclusion:Elevated NT-proBNP concentrations, seen even in young people with RTHβ, suggest that myocardial dysfunction contributes to early adverse cardiovascular outcomes in this disorder, with increased atherosclerotic disease risk likely manifesting later in life. Measurement of NT-proBNP and assessment of cardiovascular risk should be considered at first presentation and periodically during follow-up of RTHβ.

The prevalence of autoimmune diabetes was assessed in 113 indigenous and 1555 non-indigenous participants in the Fremantle Diabetes Study Phase II. Both type 1 diabetes (3.5% vs. 8.2%) and latent autoimmune diabetes of adults diagnosed based on glutamic acid decarboxylase antibody (GADA) positivity (1.0% vs. 5.7%) were lower in Aboriginal participants (P = 0.101 and 0.039 respectively). Six Aboriginals with GADA-negative type 2 diabetes were positive for tyrosine phosphatase-related islet antigen 2 antibodies but did not exhibit relative insulin deficiency.

Background/Objectives: The current standard of care for assessing chronic kidney disease complicating diabetes (DKD) includes measurement of estimated glomerular filtration rate (eGFR) and urinary albumin:creatinine ratio (uACR) but both tests have limitations. The present study compared the biomarker-based Promarker®D test with conventional biochemical measures for predicting future kidney function decline in adults with type 2 diabetes (T2D). Methods: Baseline concentrations of apolipoprotein A-IV, CD5 antigen-like protein and insulin-like growth factor binding protein 3 were combined with age, serum HDL cholesterol and eGFR to generate PromarkerD risk scores for incident DKD/eGFR decline ≥ 30% (the primary endpoint) in 857 adults with T2D (mean age 65.4 years, 54% males). Logistic regression modelling was used to compare the association of (i) PromarkerD, (ii) eGFR, (iii) uACR, and (iv) eGFR plus uACR with this outcome during 4 years of follow-up. Results: Study participants were classified by PromarkerD as low (63%), moderate (13%), or high risk (24%) for kidney function decline at baseline. Over a mean 4.2 years, 12.5% developed the primary endpoint. PromarkerD scores showed significantly higher predictive performance (area under the receiver operating characteristic curve (AUC) 0.88 (95% confidence interval (CI) 0.85–0.91)) compared to conventional biochemical measures (AUC = 0.63–0.82). There was a progressive increase in risk with moderate and high risk by PromarkerD exhibiting greater odds of the primary endpoint compared to those at low risk (odds ratios (OR) (95% CI) 8.11 (3.99–16.94) and 21.34 (12.03–40.54), respectively, both p < 0.001). Conclusions: PromarkerD more accurately identifies adults with T2D at risk of kidney function decline than current usual care biochemical tests.

Relative telomere length (rTL), a biomarker of biological ageing, has been implicated in type 2 diabetes and its complications. We aimed to identify the associates of rTL change over 4 years (∆rTL), and to investigate whether rTL and ∆rTL are associated with complications and mortality in adults with type 2 diabetes from the Australian observational community-based Fremantle Diabetes Study Phase II (FDS2). Participants (n = 819) from the FDS2 cohort had baseline and Year-4 (mean ± SD 4.2 ± 0.4 years) rTL measured by qPCR (intra- and inter-assay

Amoxicillin plus gentamicin is the recommended first-line empiric therapy for neonates with infection. Guidelines vary widely in dose (mg/kg), dose frequency, and adjustments according to post-menstrual age (PMA) and post-natal age (PNA). We aimed to develop a population pharmacokinetic (PK) model for amoxicillin in neonates with clinical evidence of sepsis and design optimal dosing regimens. One hundred seventy-seven neonates receiving intravenous amoxicillin for infection were enrolled in a prospective, observational PK study in Papua New Guinea (PNG). The probability of PK-pharmacodynamic target attainment (PK-PD PTA) was determined based on minimum inhibitory concentrations (MIC) and the proportion of time concentrations that remained above these values (%T > MIC). Neonates with concentrations > 140 mg/L were considered to be at increased risk of amoxicillin neurotoxicity. A population PK model was developed. Simulations tested existing guidelines and proposed simplified regimens. The median PMA and PNA were 38 (37-40) weeks and 0 (0-2) days, respectively. From simulations, existing regimens with 50 or 100 mg/kg doses were associated with higher potential neurotoxic concentrations (24.9% and 84.5%, respectively). With the existing 30 mg/kg PNG regimen, neonates receiving twice-daily dosing between 3 and 7 days were systematically underdosed. A proposed 30 mg/kg regimen, with twice-daily dosing for the first 2 days PNA and three times daily from day 3, provides an optimal balance between the probability of PK-PD target attainment while minimizing toxicity. For fixed volume dosing, using 52 mg (0.25 mL of 250 mg in 1.2 mL) for those <3 kg and 104 mg (0.5 mL) for those ≥3 kg is proposed.