Digital Twins in Agriculture: Orchestration and Applications.

Digital Twins have emerged as an outstanding opportunity for precision farming, digitally replicating in real-time the functionalities of objects and plants. A virtual replica of the crop, including key agronomic development aspects such as irrigation, optimal fertilization strategies, and pest management, can support decision-making and a step change in farm management, increasing overall sustainability and direct water, fertilizer, and pesticide savings. In this review, Digital Twin technology is critically reviewed and framed in the context of recent advances in precision agriculture and Agriculture 4.0. The review is organized for each step of agricultural lifecycle, edaphic, phytotechnologic, postharvest, and farm infrastructure, with supporting case studies demonstrating direct benefits for agriculture production and supply chain considering both benefits and limitations of such an approach. Challenges and limitations are disclosed regarding the complexity of managing such an amount of data and a multitude of (often) simultaneous operations and supports.

Magnetic resonance imaging of intracranial anomalies in pregnancies complicated by twin anemia-polycythemia sequence.

PURPOSE: To describe fetal brain Magnetic Resonance Imaging (MRI) findings in a large series of monochorionic (MC) pregnancies complicated by Twin Anemia-Polycythemia Sequence (TAPS) prenatally diagnosed, so to characterize the potential intracranial complications associated with this condition, their frequency and potential treatment options. METHODS: This is a retrospective study of MC twin pregnancies complicated by TAPS and undergone fetal MRI in a single institution from 2006 to 2023. MRI control was performed and post-natal ultrasound (US) or MRI were available. RESULTS: 1250 MC pregnancies were evaluated in our institution. 50 pregnancies (4%) were diagnosed with TAPS, 29 underwent a fetal brain MRI. 13/29 pregnancies (44.8%) demonstrated brain findings at MRI in at least a twin. Neuroradiological findings were detected in 14/57 twins (24.6%). We detected four main categories of findings: hemorrhagic lesions, T2-weighted white-matter hyperintensities (WMH), brain edema-swelling and venous congestion. Nineteen findings were present in the anemic and three in the polycythemic twins, with a statistically significant ratio between the two groups (p-value = 0.01). Intrauterine MRI follow-up demonstrated the sequalae of hemorrhagic lesions. A complete regression of brain swelling, veins prominence and T2-WMHs was demonstrated after treatment. Postnatal imaging confirmed prenatal features. CONCLUSIONS: Our work demonstrates that TAPS-related MRI anomalies consisted in edematous/hemorrhagic lesions that occur mostly in anemic rather than in polycythemic twins. Fetoscopic laser surgery could have a potential decongestant role. Therefore, prenatal MRI may help in counselling and management in TAPS pregnancies, especially for the planning of therapy and the monitoring of its efficacy.

Matthew-Wood Syndrome in Monochorionic, Diamnionic Twins.

Matthew-Wood syndrome represents a rare genetic disorder characterized by diaphragmatic defects, pulmonary hypoplasia, micro- or anophthalmia, and cardiac defects. Most cases are lethal with very few infants living beyond a few years of life. Siblings with this diagnosis have been reported but never twins. In this article, we provided a review and discussion of this syndrome following its presentation in monochorionic, diamnionic twin females.

Dynamic mirroring: unveiling the role of digital twins, artificial intelligence and synthetic data for personalized medicine in laboratory medicine.

In recent years, the integration of technological advancements and digitalization into healthcare has brought about a remarkable transformation in care delivery and patient management. Among these advancements, the concept of digital twins (DTs) has recently gained attention as a tool with substantial transformative potential in different clinical contexts. DTs are virtual representations of a physical entity (e.g., a patient or an organ) or systems (e.g., hospital wards, including laboratories), continuously updated with real-time data to mirror its real-world counterpart. DTs can be utilized to monitor and customize health care by simulating an individual's health status based on information from wearables, medical devices, diagnostic tests, and electronic health records. In addition, DTs can be used to define personalized treatment plans. In this study, we focused on some possible applications of DTs in laboratory medicine when used with AI and synthetic data obtained by generative AI. The first point discussed how biological variation (BV) application could be tailored to individuals, considering population-derived BV data on laboratory parameters and circadian or ultradian variations. Another application could be enhancing the interpretation of tumor markers in advanced cancer therapy and treatments. Furthermore, DTs applications might derive personalized reference intervals, also considering BV data or they can be used to improve test results interpretation. DT's widespread adoption in healthcare is not imminent, but it is not far off. This technology will likely offer innovative and definitive solutions for dynamically evaluating treatments and more precise diagnoses for personalized medicine.

Outcomes of dichorionic twin pregnancies with fused versus separate placentas.

PURPOSE: In a certain proportion of dichorionic twin pregnancies, the two placentas are fused. The clinical significance of this finding remains unclear. Our objective was to compare outcomes of dichorionic twin pregnancies with fused versus separate placentas as determined on first-trimester ultrasound. METHODS: Retrospective study of patients with dichorionic twins followed at a tertiary center between 2014 and 2022. The co-primary outcomes were fetal growth restriction and preeclampsia. Associations between fused placentas and the study outcomes were estimated using multivariable Poisson regression and were reported as adjusted relative risk (aRR) with a 95%-confidence interval (CI). RESULTS: Of the 328 eligible patients, 175 (53.4%) and 153 (46.6%) had fused and separate placentas, respectively. Compared with pregnancies with separate placentas, patients with fused placentas had a lower risk of preeclampsia [aRR 0.48 (95%-CI 0.24-0.97)] but a higher risk of fetal growth restriction [aRR 1.23 (95%-CI 1.02-1.48)] and admission to the neonatal intensive care unit [aRR 1.31 (95%-CI 1.01-1.71)]. In addition, pregnancies with fused placentas were more likely to have a total placental weight below the 10th percentile than those with separate placentas [aRR 1.93 (95%-CI 1.16-3.21)]. DISCUSSION: Dichorionic twin pregnancies with fused placentas have a lower risk of preeclampsia but are more likely to be complicated by fetal growth restriction, observations that may be attributed to the lower total placentas mass in pregnancies with fused compared with separate placentas. Fused placentas can be used as a potential biomarker for the prediction of pregnancy complications in dichorionic twin pregnancies.

Computational fluid dynamics based digital twins of fixed bed bioreactors validate scaling principles for recombinant adeno-associated virus gene therapy manufacturing.

Gene therapy using recombinant adeno-associated virus (rAAV) as delivery vehicles has garnered much interest in recent years. There are still significant gaps in our fundamental understanding of the manufacturing processes to deliver sufficient products. Manufacturing efforts of rAAV using HEK293 cells have commonly relied on fixed bed falling film bioreactors like the iCELLis®. We used computational fluid dynamics (CFD) to validate the operating conditions required for a predictive iCELLis® 500 scale-down model. The small-scale and at-scale systems have different flow paths causing validation of the corresponding agitation rates required to achieve the same linear flow through the fixed bed across scales to be non-trivial. Therefore, we used CFD to predict the theoretical scaling relationship. In addition, CFD could predict kLa differences between the two systems and the operating conditions required to match kLa between scales. We also confirmed that the location of DO control must be the same in both systems to achieve proper scaling. Experimental runs confirming the validity of the novel scale-down model showed that based on the modifications to the iCELLis® Nano system, we achieved similar DO, key metabolite, pH, and GC titer trends in both systems.

Pregnancy outcomes of monochorionic diamniotic and dichorionic diamniotic twin pregnancies conceived by assisted reproductive technology and conceived naturally: a study based on chorionic comparison.

OBJECTIVE: To evaluate monochorionic diamniotic (MCDA) and dichorionic diamniotic (DCDA) twin pregnancies conceived by assisted reproductive technology (ART) and conceived naturally. METHODS: We retrospectively analyzed the data on twin pregnancies conceived by ART from January 2015 to January 2022,and compared pregnancy outcomes of MCDA and DCDA twins conceived by ART with those of MCDA and DCDA twins conceived naturally, pregnancy outcomes between MCDA and DCDA twins conceived by ART, and pregnancy outcomes of DCT and TCT pregnancies reduced to DCDA pregnancies with those of DCDA pregnancies conceived naturally. RESULT: MCDA pregnancies conceived by ART accounted for 4.21% of the total pregnancies conceived by ART and 43.81% of the total MCDA pregnancies. DCDA pregnancies conceived by ART accounted for 95.79% of the total pregnancies conceived by ART and 93.26% of the total DCDA pregnancies. Women with MCDA pregnancies conceived by ART had a higher premature delivery rate, lower neonatal weights, a higher placenta previa rate, and a lower twin survival rate than those with MCDA pregnancies conceived naturally (all p < 0.05). Women with DCDA pregnancies conceived naturally had lower rates of preterm birth, higher neonatal weights, and higher twin survival rates than women with DCDA pregnancies conceived by ART and those with DCT and TCT pregnancies reduced to DCDA pregnancies (all p < 0.05). CONCLUSION: Our study confirms that the pregnancy outcomes of MCDA pregnancies conceived by ART are worse than those of MCDA pregnancies conceived naturally. Similarly, the pregnancy outcomes of naturally-conceived DCDA pregnancies are better than those of DCDA pregnancies conceived by ART and DCT and TCT pregnancies reduced to DCDA pregnancies.

Parasitic pygopagus conjoined twins' incidental findings in the obstructed labor of an intrapartum dead baby that had undergone emergency C-section: rare case report in South Papua.

BACKGROUND: Conjoined twins (CT), which used to be historically defined as "monstrous human" and previously so-called Siamese twins in the early eighteenth century, are one of the very rare congenital malformations with an uncertain etiology and complex yet remain inconclusively debatable regarding its pathophysiological mechanisms of fusion and fission theories. Among all types of CT, parasitic CT, especially the pygopagus sub-type, is exceedingly rarer. To the best of the authors' knowledge, no parasitic CT had been reported in Papua, and this is the first finding in South Papua. CASE REPORT: Herein, a 30-year-old multigravida female with 37th-week gestation, previous twice spontaneous miscarriage, and non-adequate antenatal care history is presented with a chief complaint of painful construction and greenish fluid leakage from the vagina, with an examination that showed a cephalic presentation with a "peculiar" big mass at the upper uterus and complete cervical dilation toward second-stage inpartu. Vaginal delivery was performed with a complication of obstructed labor due to uncommon dystocia with a suspected "big mass" below the fetal buttocks and intrapartum dead. Intrapartum transabdominal ultrasound demonstrates a gross anatomically like an organ inside a fluid-filled mass with unidentified parts, leading to a suspected type of congenital malformation at the baby's sacral region. Emergency C-section was done with findings of parasitic pygopagus CT, showing an attachment of a large irregular fluid-filled mass-like incomplete twin (parasite) with palpable soft tissue and bony structure inside to the buttocks of a male autosite twin, and an additional third leg which happened to be an under-developed lower extremity with a sacrum-like structure. CONCLUSIONS: An obstetrician's routine ANC and critical radiological evaluation will increase the odds of identifying CT or other congenital malformations to provide better delivery planning or further management. Increasing maternal health knowledge in society, improving medical skills and knowledge levels for health providers, and advancing supporting facilities and specialists are future strategies for managing and preventing such cases in low-middle-income countries.

TwinsMX: Exploring the Genetic and Environmental Influences on Health Traits in the Mexican Population.

TwinsMX registry is a national research initiative in Mexico that aims to understand the complex interplay between genetics and environment in shaping physical and mental health traits among the country's population. With a multidisciplinary approach, TwinsMX aims to advance our knowledge of the genetic and environmental mechanisms underlying ethnic variations in complex traits and diseases, including behavioral, psychometric, anthropometric, metabolic, cardiovascular and mental disorders. With information gathered from over 2800 twins, this article updates the prevalence of several complex traits; and describes the advances and novel ideas we have implemented such as magnetic resonance imaging. The future expansion of the TwinsMX registry will enhance our comprehension of the intricate interplay between genetics and environment in shaping health and disease in the Mexican population. Overall, this report describes the progress in the building of a solid database that will allow the study of complex traits in the Mexican population, valuable not only for our consortium, but also for the worldwide scientific community, by providing new insights of understudied genetically admixed populations.

Study on the Low Plastic Behavior of Expansion Deformation of Austenitic Stainless Steel.

The plastic deformation of TWIP steel is greatly inhibited during the expansion process. The stress-strain curves obtained through expansion experiments and observations of fracture morphology confirmed the low plastic behavior of TWIP steel during expansion deformation. Through an analysis of the mechanical expansion model, it was found that the expansion process has a lower stress coefficient and a faster strain rate than stretching, which inhibits the plasticity of TWIP steel during expansion deformation. Using metallographic microscopy, transmission electron microscopy, and EBSD to observe the twin morphology during expansion deformation and tensile deformation, it was found that expansion deformation has a higher twin density, which is manifested in a denser twin arrangement and a large number of twin deliveries in the microscopic morphology. During the expansion deformation process, dislocation slips are hindered by twins, the free path of the slips is reduced, and dislocations accumulate significantly. The accumulation area is the initial point of crack expansion. The results show that the significant dislocation accumulation caused by the delivery of a large number of twins under expansion deformation is the main reason for the decrease in the plasticity of TWIP steel.

Digital Twin Meets Knowledge Graph for Intelligent Manufacturing Processes.

In the highly competitive field of material manufacturing, stakeholders strive for the increased quality of the end products, reduced cost of operation, and the timely completion of their business processes. Digital twin (DT) technologies are considered major enablers that can be deployed to assist the development and effective provision of manufacturing processes. Additionally, knowledge graphs (KG) have emerged as efficient tools in the industrial domain and are able to efficiently represent data from various disciplines in a structured manner while also supporting advanced analytics. This paper proposes a solution that integrates a KG and DTs. Through this synergy, we aimed to develop highly autonomous and flexible DTs that utilize the semantic knowledge stored in the KG to better support advanced functionalities. The developed KG stores information about materials and their properties and details about the processes in which they are involved, following a flexible schema that is not domain specific. The DT comprises smaller Virtual Objects (VOs), each one acting as an abstraction of a single step of the Industrial Business Process (IBP), providing the necessary functionalities that simulate the corresponding real-world process. By executing appropriate queries to the KG, the DT can orchestrate the operation of the VOs and their physical counterparts and configure their parameters accordingly, in this way increasing its self-awareness. In this article, the architecture of such a solution is presented and its application in a real laser glass bending process is showcased.

Towards a Distributed Digital Twin Framework for Predictive Maintenance in Industrial Internet of Things (IIoT).

This study uses a wind turbine case study as a subdomain of Industrial Internet of Things (IIoT) to showcase an architecture for implementing a distributed digital twin in which all important aspects of a predictive maintenance solution in a DT use a fog computing paradigm, and the typical predictive maintenance DT is improved to offer better asset utilization and management through real-time condition monitoring, predictive analytics, and health management of selected components of wind turbines in a wind farm. Digital twin (DT) is a technology that sits at the intersection of Internet of Things, Cloud Computing, and Software Engineering to provide a suitable tool for replicating physical objects in the digital space. This can facilitate the implementation of asset management in manufacturing systems through predictive maintenance solutions leveraged by machine learning (ML). With DTs, a solution architecture can easily use data and software to implement asset management solutions such as condition monitoring and predictive maintenance using acquired sensor data from physical objects and computing capabilities in the digital space. While DT offers a good solution, it is an emerging technology that could be improved with better standards, architectural framework, and implementation methodologies. Researchers in both academia and industry have showcased DT implementations with different levels of success. However, DTs remain limited in standards and architectures that offer efficient predictive maintenance solutions with real-time sensor data and intelligent DT capabilities. An appropriate feedback mechanism is also needed to improve asset management operations.

Brain functional connectivity correlates of anomalous interaction between sensorily isolated monozygotic twins.

This study examined brain functional connectivity (FC) changes associated with possible anomalous interactions between sensorily isolated monozygotic (MZ) twins. Brain FC was estimated using the Steady State Visual Evoked Potential-Event Related Partial Coherence (SSVEP-ERPC) methodology. Five twin pairs served twice as participants, with an average interval between sessions of 67 days. In each recording session, one twin, the Sender, viewed a randomized set of 50 general images and 50 personally relevant images, while the other twin, the Receiver, viewed a static personally relevant image for the entire duration of the session. Images appeared on the Sender screen for 1.0 s, with the interval between successive images varied randomly between 4.0 and 8.0 s. Receiver FC changes were calculated based on the appearance times of the images as viewed by the Sender. It was hypothesized that anomalous interactions would be indicated by statistically significant Receiver FC changes when those changes are determined using the Sender image appearance times. For each twin serving as Receiver, FC components were separately analyzed for the 50 general and the 50 personal images, yielding 38 observations (19 twin pairs by 2 conditions). The hypothesis was confirmed in that 11 of the 38 observations yielded statistically significant Receiver FC increases or decreases at the p < 0.01 level only when trials were synchronized to the Sender image appearance times. Overall, this effect was significant at the p = 4 × 10-8 Df = 175. To the best of our knowledge, this is the first study reporting statistically significant FC changes indicative of anomalous interactions between two sensorily isolated individuals.

Epigenome-wide association study identifies DNA methylation loci associated with handgrip strength in Chinese monozygotic twins.

Background: The decline in muscle strength and function with aging is well recognized, but remains poorly characterized at the molecular level. Here, we report the epigenetic relationship between genome-wide DNA methylation and handgrip strength (HGS) among Chinese monozygotic (MZ) twins. Methods: DNA methylation (DNAm) profiling was conducted in whole blood samples through Reduced Representation Bisulfite Sequencing method. Generalized estimating equation was applied to regress the DNAm of each CpG with HGS. The Genomic Regions Enrichment of Annotations Tool was used to perform enrichment analysis. Differentially methylated regions (DMRs) were detected using comb-p. Causal inference was performed using Inference about Causation through Examination of Familial Confounding method. Finally, we validated candidate CpGs in community residents. Results: We identified 25 CpGs reaching genome-wide significance level. These CpGs located in 9 genes, especially FBLN1, RXRA, and ABHD14B. Many enriched terms highlighted calcium channels, neuromuscular junctions, and skeletal muscle organ development. We identified 21 DMRs of HGS, with several DMRs within FBLN1, SLC30A8, CST3, and SOCS3. Causal inference indicated that the DNAm of 16 top CpGs within FBLN1, RXRA, ABHD14B, MFSD6, and TYW1B might influence HGS, while HGS influenced DNAm at two CpGs within FBLN1 and RXRA. In validation analysis, methylation levels of six CpGs mapped to FLBN1 and one CpG mapped to ABHD14B were negatively associated with HGS weakness in community population. Conclusion: Our study identified multiple DNAm variants potentially related to HGS, especially CpGs within FBLN1 and ABHD14B. These findings provide new clues to the epigenetic modification underlying muscle strength decline.

Reduced lung function during childhood in identical twins with discordant fetal growth: a cohort study.

Background: Fetal growth restriction (FGR) can negatively affect lung development, leading to increased respiratory morbidity and reduced lung function later in life. Studies regarding the impact of FGR on lung function in singletons are influenced by genetic, obstetric, and maternal factors. To overcome these confounding factors, we aim to investigate lung function in identical twins with selective FGR (sFGR). Methods: Lung function assessments were performed in identical twins with sFGR born in our centre between March 1, 2002, and December 31, 2017, aged between 5 and 17 years. sFGR was defined as birthweight discordance ≥20%. Outcome measures consisted of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and transfer factor for carbon monoxide (DLCO) and were compared between the smaller and larger twin. Findings: Thirty-nine twin pairs performed spirometry of sufficient quality. Median gestational age at birth was 34.3 (interquartile range (IQR) 32.1-36.0) weeks with median birthweights of 1500 (IQR 1160-1880) grams and 2178 (IQR 1675-2720) grams for the smaller and larger twin, respectively. Smaller twins had significantly lower z-scores for FEV1 (-0.94 versus -0.41, p = 0.0015), FVC (-0.56 versus -0.06, p < 0.0001) and DLCO (-0.50 versus 0.00, p < 0.0001) compared to larger co-twins. Interpretation: Although being genetically identical, sFGR in identical twins is associated with a reduction in static and dynamic lung volume and a reduction in lung diffusion, even when taking the reduced lung volume into account. This indicates that adverse growth conditions in utero negatively affect lung development and function, potentially contributing to an increase in respiratory morbidities later in life. Funding: The Dutch Heart Foundation and The Bontius Foundation.

A 20-year follow-up study of identical twin sisters with immunoglobulin A nephropathy.

Immunoglobulin A nephropathy (IgAN) is characterized by diverse clinicopathological phenotypes. Herein we present a follow-up study of previously reported identical twin sisters with IgAN. The older sister exhibited more severe kidney histopathology and proteinuria and a lower birthweight than did her younger sister, and only the older sister experienced two childbirths. These raised concerns regarding her kidney outcomes. However, with timely multidisciplinary treatments, the older sister's kidney function remained preserved after 20 years of IgAN history. Our findings indicate the significant contribution of environmental/epigenetic factors to IgAN progression and the need for tailored medical care corresponding to life events.

Risk of intrapartum cesarean delivery in twin pregnancies: A retrospective cohort study.

OBJECTIVE: To compare the risk of intrapartum cesarean delivery (CD) between patients with twin and singleton pregnancies undergoing a trial of labor and identify risk factors for intrapartum CD in twin pregnancies. METHODS: The present study was a retrospective cohort study of patients with a twin or singleton pregnancy who underwent a trial of labor at ≥340/7 weeks in a single center (2015-2022). The primary outcome was the rate of intrapartum CD. In twin pregnancies, this outcome was limited to CD of both twins. The association of plurality with intrapartum CD was estimated using multivariable Poisson regression. RESULTS: A total of 20 754 patients met the study criteria, 669 of whom had a twin pregnancy. Patients with twins had a greater risk of intrapartum CD (of both twins) than those with singleton pregnancies (22.1% vs 15.9%, respectively; aRR 1.38 [95% CI: 1.15-1.66]), primarily due to a greater risk of failure to progress. In addition, 4.1% of the twin pregnancies had a CD for the second twin, resulting in an overall CD rate in twin pregnancies of 26.2%. Variables associated with intrapartum CD in twin pregnancies included nulliparity (aOR 3.50, 95% CI: 2.34-5.25), birthweight discordance >20% (aOR 2.47, 95% CI: 1.27-4.78), and labor induction (aOR 1.64, 95% CI: 1.07-2.53). The rate of intrapartum CD was highest when all three risk factors were present (67% [95% CI: 41%-87%]). CONCLUSION: Twin pregnancies are associated with a greater risk of intrapartum CD than singleton pregnancies. Information on the individualized risk of intrapartum CD may be valuable when counseling patients with twins regarding mode of delivery.

Emergency Cesarean Section in a Dichorionic Diamniotic Twin Pregnancy With Hydrops Fetalis: A Report of a Critical Case.

This case report describes the emergent scenario of a 41-year-old primipara at 31.2 weeks of gestation, presenting with abdominal and back pain in the context of a dichorionic diamniotic twin pregnancy complicated by hydrops fetalis. The patient, with a history of hypertension, hyperthyroidism, and a cervical stitch in place, underwent an emergency lower segment cesarean section. The ultrasound revealed an intrauterine left footling in one twin, contributing to the suspected hydrops fetalis. Neonatal complications arose, particularly with Baby B, necessitating immediate resuscitation and intensive care. Successful outcomes were achieved through a well-coordinated multidisciplinary approach involving obstetricians, neonatologists, and anesthesiologists. This case underscores the importance of prompt recognition, timely interventions, and collaborative care in managing complex pregnancies, shedding light on the challenges associated with dichorionic diamniotic twin pregnancies and emphasizing the need for ongoing research to refine perinatal strategies.

Association between epigenetic age and type 2 diabetes mellitus or glycemic traits: A longitudinal twin study.

Epigenetic clocks based on DNA methylation have been known as biomarkers of aging, including principal component (PC) clocks representing the degree of aging and DunedinPACE representing the pace of aging. Prior studies have shown the associations between epigenetic aging and T2DM, but the results vary by epigenetic age metrics and people. This study explored the associations between epigenetic age metrics and T2DM or glycemic traits, based on 1070 twins (535 twin pairs) from the Chinese National Twin Registry. It also explored the temporal relationships of epigenetic age metrics and glycemic traits in 314 twins (157 twin pairs) who participated in baseline and follow-up visits after a mean of 4.6 years. DNA methylation data were used to calculate epigenetic age metrics, including PCGrimAge acceleration (PCGrimAA), PCPhenoAge acceleration (PCPhenoAA), DunedinPACE, and the longitudinal change rate of PCGrimAge/PCPhenoAge. Mixed-effects and cross-lagged modelling assessed the cross-sectional and temporal relationships between epigenetic age metrics and T2DM or glycemic traits, respectively. In the cross-sectional analysis, positive associations were identified between DunedinPACE and glycemic traits, as well as between PCPhenoAA and fasting plasma glucose, which may be not confounded by shared genetic factors. Cross-lagged models revealed that glycemic traits (fasting plasma glucose, HbA1c, and TyG index) preceded DunedinPACE increases, and TyG index preceded PCGrimAA increases. Glycemic traits are positively associated with epigenetic age metrics, especially DunedinPACE. Glycemic traits preceded the increases in DunedinPACE and PCGrimAA. Lowering the levels of glycemic traits may reduce DunedinPACE and PCGrimAA, thereby mitigating age-related comorbidities.

Enhanced resolution profiling in twins reveals differential methylation signatures of type 2 diabetes with links to its complications.

BACKGROUND: Type 2 diabetes (T2D) susceptibility is influenced by genetic and environmental factors. Previous findings suggest DNA methylation as a potential mechanism in T2D pathogenesis and progression. METHODS: We profiled DNA methylation in 248 blood samples from participants of European ancestry from 7 twin cohorts using a methylation sequencing platform targeting regulatory genomic regions encompassing 2,048,698 CpG sites. FINDINGS: We find and replicate 3 previously unreported T2D differentially methylated CpG positions (T2D-DMPs) at FDR 5% in RGL3, NGB and OTX2, and 20 signals at FDR 25%, of which 14 replicated. Integrating genetic variation and T2D-discordant monozygotic twin analyses, we identify both genetic-based and genetic-independent T2D-DMPs. The signals annotate to genes with established GWAS and EWAS links to T2D and its complications, including blood pressure (RGL3) and eye disease (OTX2). INTERPRETATION: The results help to improve our understanding of T2D disease pathogenesis and progression and may provide biomarkers for its complications. FUNDING: Funding acknowledgements for each cohort can be found in the Supplementary Note.