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The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are thought to be the main drivers of insulin secretion in individuals with sulfonylurea (SU)-treated KCNJ11 permanent neonatal diabetes. The aim of this study was to assess for the first time the incretin hormone response to carbohydrate and protein/fat in adults with sulfonylurea-treated KCNJ11 permanent neonatal diabetes compared with that of controls without diabetes. Participants were given a breakfast high in carbohydrate and an isocaloric breakfast high in protein/fat on two different mornings. Incremental area under the curve and total area under the curve (0-240 minutes) for total GLP-1 and GIP were compared between groups, using non-parametric statistical methods. Post-meal GLP-1 and GIP secretion were similar in cases and controls, suggesting this process is adenosine triphosphate-sensitive potassium channel-independent. Future research will investigate whether treatments targeting the incretin pathway are effective in individuals with KCNJ11 permanent neonatal diabetes who do not have good glycemic control on sulfonylurea alone., (© 2023 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: Cardiopulmonary exercise testing (CPET), and its primary outcome of peak oxygen uptake (VO 2peak ), are acknowledged as biomarkers in the diagnostic and prognostic management of interstitial lung disease (ILD). However, the validity and repeatability of CPET in those with ILD has yet to be fully characterised, and this study fills this evidence gap., Methods: Twenty-six people with ILD were recruited, and 21 successfully completed three CPETs. Of these, 17 completed two valid CPETs within a 3-month window, and 11 completed two valid CPETs within a 6-month window. Technical standards from the European Respiratory Society established validity, and repeatability was determined using mean change, intraclass correlation coefficient and typical error., Results: Every participant (100%) who successfully exercised to volitional exhaustion produced a maximal, and therefore valid, CPET. Approximately 20% of participants presented with a plateau in VO 2 , the primary criteria for establishing a maximal effort. The majority of participants otherwise presented with secondary criteria of respiratory exchange ratios in excess of 1.05, and maximal heart rates in excess of their predicted values. Repeatability analyses identified that the typical error (expressed as percent of coefficient of variation) was 20% over 3-months in those reaching volitional exhaustion., Conclusion: This work has, for the first time, fully characterised how patients with ILD respond to CPET in terms of primary and secondary verification criteria, and generated novel repeatability data that will prove useful in the assessment of disease progression, and future evaluation of therapeutic regimens where VO 2peak is used as an outcome measure., (© 2022. The Author(s).)

Objective: Recent joint American Diabetes Association and European Association for the Study of Diabetes guidelines recommend routine islet autoantibody testing in all adults newly diagnosed with type 1 diabetes. We aimed to assess the impact of routine islet autoantibody testing in this population., Research Design and Methods: We prospectively assessed the relationship between islet autoantibody status (GADA, IA-2A, and ZNT8A), clinical and genetic characteristics, and progression (annual change in urine C-peptide-to-creatinine ratio [UCPCR]) in 722 adults (≥18 years old at diagnosis) with clinically diagnosed type 1 diabetes and diabetes duration <12 months. We also evaluated changes in treatment and glycemia over 2 years after informing participants and their clinicians of autoantibody results., Results: Of 722 participants diagnosed with type 1 diabetes, 24.8% (179) were autoantibody negative. This group had genetic and C-peptide characteristics suggestive of a high prevalence of nonautoimmune diabetes: lower mean type 1 diabetes genetic risk score (islet autoantibody negative vs. positive: 10.85 vs. 13.09 [P < 0.001] [type 2 diabetes 10.12]) and lower annual change in C-peptide (UCPCR), -24% vs. -43% (P < 0.001).After median 24 months of follow-up, treatment change occurred in 36.6% (60 of 164) of autoantibody-negative participants: 22.6% (37 of 164) discontinued insulin, with HbA1c similar to that of participants continuing insulin (57.5 vs. 60.8 mmol/mol [7.4 vs. 7.7%], P = 0.4), and 14.0% (23 of 164) added adjuvant agents to insulin., Conclusions: In adult-onset clinically diagnosed type 1 diabetes, negative islet autoantibodies should prompt careful consideration of other diabetes subtypes. When routinely measured, negative antibodies are associated with successful insulin cessation. These findings support recent recommendations for routine islet autoantibody assessment in adult-onset type 1 diabetes., (© 2022 by the American Diabetes Association.)

Background: Human birthweight is a complex, multifactorial trait. Maternal characteristics contribute to birthweight variation by influencing the intrauterine environment. Variation explained by genetic effects is also important, but their contributions have not been assessed alongside other key determinants. We aimed to investigate variance in birthweight explained by genetic scores in addition to easily-measurable clinical and anthropometric variables., Methods: We analysed 549 European-ancestry parent-offspring trios from a UK community-based birth cohort. We investigated variance explained in birthweight (adjusted for sex and gestational age) in multivariable linear regression models including genetic scores, routinely-measured maternal characteristics, and parental anthropometric variables. We used R-Squared (R 2 ) to estimate variance explained, adjusted R-squared (Adj-R 2 ) to assess improvement in model fit from added predictors, and F-tests to compare nested models., Results: Maternal and fetal genetic scores together explained 6.0% variance in birthweight. A model containing maternal age, weight, smoking, parity and 28-week fasting glucose explained 21.7% variance. Maternal genetic score explained additional variance when added to maternal characteristics (Adj-R 2  = 0.233 vs Adj-R 2  = 0.210, p < 0.001). Fetal genetic score improved variance explained (Adj-R 2  = 0.264 vs 0.248, p < 0.001) when added to maternal characteristics and parental heights., Conclusions: Genetic scores account for variance explained in birthweight in addition to easily measurable clinical variables. Parental heights partially capture fetal genotype and its contribution to birthweight, but genetic scores explain additional variance. While the genetic contribution is modest, it is comparable to that of individual clinical characteristics such as parity, which suggests that genetics could be included in tools aiming to predict risk of high or low birthweights., (© 2022. The Author(s).)

Background: Higher birthweight is associated with higher adult body mass index (BMI). Alleles that predispose to greater adult adiposity might act in fetal life to increase fetal growth and birthweight. Whether there are fetal effects of recently identified adult metabolically favorable adiposity alleles on birthweight is unknown., Aim: We aimed to test the effect on birthweight of fetal genetic predisposition to higher metabolically favorable adult adiposity and compare that with the effect of fetal genetic predisposition to higher adult BMI., Methods: We used published genome wide association study data (n = upto 406 063) to estimate fetal effects on birthweight (adjusting for maternal genotype) of alleles known to raise metabolically favorable adult adiposity or BMI. We combined summary data across single nucleotide polymorphisms (SNPs) with random effects meta-analyses. We performed weighted linear regression of SNP-birthweight effects against SNP-adult adiposity effects to test for a dose-dependent association., Results: Fetal genetic predisposition to higher metabolically favorable adult adiposity and higher adult BMI were both associated with higher birthweight (3 g per effect allele (95% CI: 1-5) averaged over 14 SNPs; P = 0.002; 0.5 g per effect allele (95% CI: 0-1) averaged over 76 SNPs; P = 0.042, respectively). SNPs with greater effects on metabolically favorable adiposity tended to have greater effects on birthweight (R2 = 0.2912, P = 0.027). There was no dose-dependent association for BMI (R2 = -0.0019, P = 0.602)., Conclusions: Fetal genetic predisposition to both higher adult metabolically favorable adiposity and BMI is associated with birthweight. Fetal effects of metabolically favorable adiposity-raising alleles on birthweight are modestly proportional to their effects on future adiposity, but those of BMI-raising alleles are not., (© The Author(s) 2021. Published by Oxford University Press.)

The rs2802292, rs2764264 and rs13217795 variants of FOXO3 have been associated with extreme longevity in multiple human populations, but the mechanisms underpinning this remain unclear. We aimed to characterise potential effects of longevity-associated variation on the expression and mRNA processing of the FOXO3 gene. We performed a comprehensive assessment of FOXO3 isoform usage across a wide variety of human tissues and carried out a bioinformatic analysis of the potential for longevity-associated variants to disrupt regulatory regions involved in isoform choice. We then related the expression of full length and 5' truncated FOXO3 isoforms to rs13217795 genotype in peripheral blood and skeletal muscle from individuals of different rs13217795 genotypes. FOXO3 isoforms displayed considerable tissue specificity. We determined that rs13231195 and its tightly aligned proxy variant rs9400239 may lie in regulatory regions involved in isoform choice. The longevity allele at rs13217795 was associated with increased levels of full length FOXO3 isoforms in peripheral blood and a decrease in truncated FOXO3 isoforms in skeletal muscle RNA. We suggest that the longevity effect of FOXO3 SNPs may in part derive from a shift in isoform usage in skeletal muscle away from the production of 5' truncated FOXO3 isoforms lacking a complete forkhead DNA binding domain, which may have compromised functionality., (© 2021. The Author(s).)

Size at birth is known to be influenced by various fetal and maternal factors, including genetic effects. South Asians have a high burden of low birth weight and cardiometabolic diseases, yet studies of common genetic variations underpinning these phenotypes are lacking. We generated independent, weighted fetal genetic scores (fGSs) and maternal genetic scores (mGSs) from 196 birth weight-associated variants identified in Europeans and conducted an association analysis with various fetal birth parameters and anthropometric and cardiometabolic traits measured at different follow-up stages (5-6-year intervals) from seven Indian and Bangladeshi cohorts of South Asian ancestry. The results from these cohorts were compared with South Asians in UK Biobank and the Exeter Family Study of Childhood Health, a European ancestry cohort. Birth weight increased by 50.7 g and 33.6 g per SD of fGS (P = 9.1 × 10-11) and mGS (P = 0.003), respectively, in South Asians. A relatively weaker mGS effect compared with Europeans indicates possible different intrauterine exposures between Europeans and South Asians. Birth weight was strongly associated with body size in both childhood and adolescence (P = 3 × 10-5 to 1.9 × 10-51); however, fGS was associated with body size in childhood only (P < 0.01) and with head circumference, fasting glucose, and triglycerides in adults (P < 0.01). The substantially smaller newborn size in South Asians with comparable fetal genetic effect to Europeans on birth weight suggests a significant role of factors related to fetal growth that were not captured by the present genetic scores. These factors may include different environmental exposures, maternal body size, health and nutritional status, etc. Persistent influence of genetic loci on size at birth and adult metabolic syndrome in our study supports a common genetic mechanism that partly explains associations between early development and later cardiometabolic health in various populations, despite marked differences in phenotypic and environmental factors in South Asians., (© 2022 by the American Diabetes Association.)

Aims/hypothesis: Higher maternal BMI during pregnancy is associated with higher offspring birthweight, but it is not known whether this is solely the result of adverse metabolic consequences of higher maternal adiposity, such as maternal insulin resistance and fetal exposure to higher glucose levels, or whether there is any effect of raised adiposity through non-metabolic (e.g. mechanical) factors. We aimed to use genetic variants known to predispose to higher adiposity, coupled with a favourable metabolic profile, in a Mendelian randomisation (MR) study comparing the effect of maternal 'metabolically favourable adiposity' on offspring birthweight with the effect of maternal general adiposity (as indexed by BMI)., Methods: To test the causal effects of maternal metabolically favourable adiposity or general adiposity on offspring birthweight, we performed two-sample MR. We used variants identified in large, published genetic-association studies as being associated with either higher adiposity and a favourable metabolic profile, or higher BMI (n = 442,278 and n = 322,154 for metabolically favourable adiposity and BMI, respectively). We then extracted data on the metabolically favourable adiposity and BMI variants from a large, published genetic-association study of maternal genotype and offspring birthweight controlling for fetal genetic effects (n = 406,063 with maternal and/or fetal genotype effect estimates). We used several sensitivity analyses to test the reliability of the results. As secondary analyses, we used data from four cohorts (total n = 9323 mother-child pairs) to test the effects of maternal metabolically favourable adiposity or BMI on maternal gestational glucose, anthropometric components of birthweight and cord-blood biomarkers., Results: Higher maternal adiposity with a favourable metabolic profile was associated with lower offspring birthweight (-94 [95% CI -150, -38] g per 1 SD [6.5%] higher maternal metabolically favourable adiposity, p = 0.001). By contrast, higher maternal BMI was associated with higher offspring birthweight (35 [95% CI 16, 53] g per 1 SD [4 kg/m 2 ] higher maternal BMI, p = 0.0002). Sensitivity analyses were broadly consistent with the main results. There was evidence of outlier SNPs for both exposures; their removal slightly strengthened the metabolically favourable adiposity estimate and made no difference to the BMI estimate. Our secondary analyses found evidence to suggest that a higher maternal metabolically favourable adiposity decreases pregnancy fasting glucose levels while a higher maternal BMI increases them. The effects on neonatal anthropometric traits were consistent with the overall effect on birthweight but the smaller sample sizes for these analyses meant that the effects were imprecisely estimated. We also found evidence to suggest that higher maternal metabolically favourable adiposity decreases cord-blood leptin while higher maternal BMI increases it., Conclusions/interpretation: Our results show that higher adiposity in mothers does not necessarily lead to higher offspring birthweight. Higher maternal adiposity can lead to lower offspring birthweight if accompanied by a favourable metabolic profile., Data Availability: The data for the genome-wide association studies (GWAS) of BMI are available at https://portals.broadinstitute.org/collaboration/giant/index.php/GIANT&#95;consortium&#95;data&#95;files . The data for the GWAS of body fat percentage are available at https://walker05.u.hpc.mssm.edu ., (© 2021. The Author(s).)

Self-care is among the emerging types of mental health support which operate outside traditional services, although the meaning and practice of self-care for young people with mental health difficulties are currently unclear. This systematic review was pre-registered with PROSPERO (CRD42021282510) and investigated conceptualizations of self-care in academic publications which investigated or discussed self-care for young people's mental health or wellbeing. A Patient and Public Involvement (PPI) workshop facilitated young people with experience of mental health difficulties to respond to the identified concepts and co-develop a definition of self-care. Searches in PsycINFO, MEDLINE, Embase, CINAHL Plus, Scopus, Cochrane Library of Systematic Reviews, and gray literature sources resulted in 90 included publications. Content analysis indicated little conceptual consistency, with health and wellness promotion most commonly used to define self-care. The PPI workshop co-developed a definition of mental health self-care, which attendees felt should emphasize an individual process of self-awareness, self-compassion, and specific strategies to work toward emotional balance. This study highlights the gap between current academic understandings of young people's mental health self-care and young people's experience. The presented definition will enable future research to begin from an understanding of self-care which is relevant to young people with experience of mental health difficulties., Competing Interests: Declarations. Conflict of interest: On behalf of all authors, the corresponding author states that there are no conflicting or competing interests. Ethical information: Ethical approval was not required for systematic review research. As Patient and Public Involvement is not considered research, ethical approval was not required for this portion of the submission. Informed consent and consent for publication: Not applicable., (© 2023. The Author(s).)

Aims: Our study, employing a multi-omics approach, aimed to delineate the distinct gut microbiota and metabolic characteristics in individuals under 30 with unclassified diabetes, thus shedding light on the underlying pathophysiological mechanisms Methods: This age- and sex-matched case-control study involved 18 patients with unclassified diabetes, 18 patients with classic type 1 diabetes, 13 patients with type 2 diabetes, and 18 healthy individuals. Metagenomics facilitated the profiling of the gut microbiota, while untargeted liquid chromatography-mass spectrometry was used to quantify the serum lipids and metabolites. Results: Our findings revealed a unique gut microbiota composition in unclassified diabetes patients, marked by a depletion of Butyrivibrio proteoclasticus and Clostridium and an increase in Ruminococcus torques and Lachnospiraceae bacterium 8_1_57FAA. Comparative analysis identified the combined marker panel of five bacterial species, seven serum biomarkers, and three clinical parameters could differentiate patients with UDM from HCs with an AUC of 0.94 (95% CI 0.85–1). Notably, the gut microbiota structure of patients with unclassified diabetes resembled that of type 2 diabetes patients, especially regarding disrupted lipid and branched-chain amino acid metabolism. Conclusions: Despite sharing certain metabolic features with type 2 diabetes, unclassified diabetes presents unique features. The distinct microbiota and metabolites in unclassified diabetes patients suggest a significant role in modulating glucose, lipid, and amino acid metabolism, potentially influencing disease progression. Further longitudinal studies are essential to explore therapeutic strategies targeting the gut microbiota and metabolites to modify the disease trajectory. [ABSTRACT FROM AUTHOR]

Background: Although liraglutide has established advantages in treating patients with type 2 diabetes mellitus (T2DM) and metabolic syndrome (MS), there are still some patients with lower responsiveness to liraglutide. The objective of the study was to identify the predictors of response to liraglutide in patients with T2DM and MS. Methods: This retrospective cohort study included patients diagnosed with T2DM and MS who received liraglutide treatment as a part of their diabetes management for a minimum of six months. The participants were stratified into two groups: responders (HbA1c reduction≥1.0% and weight loss≥3%) and nonresponders. The discrepancies in baseline data between the two groups were analyzed, containing comedications, test parameters, and basic profiles. The affecting factors of response to liraglutide by Logistic regression analysis were performed, and the predictive ability of the identified factors was evaluated by plotting a receiver operating characteristic (ROC) curve. Results: A total of 417 patients with T2DM and MS were examined and followed up according to the inclusion criteria, and 206 patients completed the follow-up; 105 (50.97%) were responders and 101 (49.03%) were non-responders to liraglutide. The binary logistic regression analysis identified baseline HbA1c, baseline BMI, and the duration of T2DM as significant predictors of glycemic and weight responses to liraglutide (P <0.05). The area under the curve of the ROC for the three predictors of liraglutide response after 6 months of treatment was 0.851 (95% confidence interval: 0.793 - 0.910). Conclusion: The baseline HbA1c, baseline BMI, and duration of T2DM were shown to be predictive factors of glycemic and weight improvements in patients with T2DM and MS treated with liraglutide, and had good predictive power. [ABSTRACT FROM AUTHOR]

Introduction: Screening for islet-specific autoantibodies can identify individuals at risk for type 1 diabetes (T1D). Despite calls for increased nationwide autoantibody screening efforts, it is unclear how many individuals have participated in screening among people who may benefit from it. Moreover, knowledge and perceptions of autoantibody screening in real-world samples are not well understood. Methods: We surveyed a sample of individuals (aged 18+ years old) from T1D Exchange Registry with a personal or family history of T1D to assess their self-reported T1D autoantibody knowledge, experiences, and attitudes. Participants belonged to one of three groups: adults with T1D who had a biological child without T1D or future plans for a child (PWD); parents without T1D who had a biological child with T1D and one or more biological children without T1D (Caregivers); and first-degree adult children or siblings to a person with T1D (Relatives). Descriptive analyses (means, standard deviations, frequencies) are presented by participant groups. Results: A total of 510 participants enrolled in the study. Across groups, participants reported feeling a little to somewhat knowledgeable about autoantibody screening and positive perceptions of autoantibody screening in general. However, few participants had screened their child without T1D (PWDs, 21.94%; Caregivers, 46.30%) or themselves (Relatives, 19.23%). Among those who had screened, participants reported generally positive experiences. Among those who had not screened, many participants were "undecided" about autoantibody screening (PWD, 38.46%; Caregivers, 40.52%; Relatives, 44.44%). Influences reported for participants' decisions to screen, not screen, or their current indecision differed by group: PWDs (21.70%) and Caregivers (26.87%) most often reported self-initiated research as an influence and Relatives reported they had not previously considered screening (48.28%). Conclusion: Results highlight the need for more accessible information about screening, including real experiences from those who have screened. [ABSTRACT FROM AUTHOR]

Background: The thyroid function test (free triiodothyronine [FT3], free thyroxine [FT4], and thyroid-stimulating hormone [TSH]) is one of the key determinant of glucose homeostasis by regulating the balance of insulin. Thyroid dysfunction alters glucose metabolism, leading to insulin resistance (IR). This study aimed to assess the association between thyroid function and IR in pregnant Sudanese women. Method: A cross-sectional study was conducted in Saad Abuelela Hospital, Khartoum-Sudan, from January to April 2021. Obstetric/sociodemographic characteristics were gathered through questionnaires. Serum TSH, FT3, FT4, fasting plasma glucose (FPG), and fasting insulin levels were measured and evaluated, and IR was estimated using the homeostatic model assessment for insulin resistance (HOMA-IR) equation. Results: In total, the study included 127 pregnant women with a median age of 27.0 years (interquartile range [IQR] 23.0‒31.2) and a median gestational (IQR) age of 25.0 (IQR 25.0‒27.0) weeks. The medians (IQRs) of the TSH, FT3, and FT4 were 1.600 (1.162‒2.092) IU/ml, 2.020(1.772‒2.240) nmol/l, and 10.70 (9.60‒11.90) pmol/l, respectively. The median (IQR) of the FPG and fasting blood insulin level was [69.0 (62.00‒78.00) mg/dl] and [5.68(2.99‒11.66) IU/ml], respectively. The median (IQR) of the HOMA-IR level was 0.9407 (0.4356‒2.1410). There was a positive correlation between HOMA -IR and FT3 levels (r = 0.375; P < 0.001) and a negative correlation with FT4 levels (r= -0.312; P < 0.001). Also, a significant positive correlation was found between fasting insulin levels and FT3 levels (r = 0.438; P < 0.001) and a negative correlation with FT4 levels (r= -0.305; P < 0.001). Conclusions: This study indicated that FT3 has positive correlation with HOMA-IR, while FT4 has negative correlation among healthy pregnant women without a history of thyroid dysfunction. This may indicate screening of euthyroid pregnant women for thyroid dysfunction and IR. Further studies are needed. [ABSTRACT FROM AUTHOR]

Background: To establish the pathological diagnosis of UTUC before treatment is profitable. At present, the conventional pathological diagnostic methods have certain problems. Besides, the urine-based DNA methylation test have been already utilized to detect bladder cancer. Objective: To evaluate the sensitivity and specificity of DNA methylation plus 17 genes mutation test and compare the combined test with cytology. Materials and methods: We included 45 patients from April 2019 to May 2022, all of whom underwent radical nephroureterectomy (RNU), nephrectomy, diagnostic ureteroscopy or tissue biopsy. Before surgery, the urine samples were collected for DNA methylation plus 17 genes mutation test and cytology. The test performance was calculated, and comparative ROC curves were drawn. Results: The median age of the patients was 67 years. The Kappa value of the DNA methylation plus 17 genes mutation test and tissue pathology was 0.59 (p<0.001). The sensitivity/specificity/PPV/NPV of DNA methylation plus 17 genes mutation test was 86/80/94/62% compared with 29/100/100/29% for cytology. The AUC of DNA methylation plus 17 genes mutation test was 0.829 (p<0.001).The mutated gene proportion of UTUC patients was 51.43% for TERT and 25.71% for TP53. Conclusion: The test performance of DNA methylation plus 17 genes mutation test was satisfactory, which may replace cytology in the future. Further multicenter studies with larger samples are needed to confirm the clinical value of this promising method. Novelty & impact statements: We evaluated the diagnostic efficacy of a urine-based liquid biopsy for the detection of UTUC and compared the combined test with cytology. We found satisfactory results and concluded that the test could partly replace cytology. Further studies are needed. [ABSTRACT FROM AUTHOR]

Maintaining normal thyroid function is crucial in pregnancy, yet thyroid dysfunction and the presence of thyroid peroxidase antibodies (TPOAb) affect 0.5% to 18% of pregnant women. Here, we conducted a genome-wide association study (GWAS) of eight thyroid traits, including two thyroid-related hormones, four thyroid dysfunctions, and two thyroid autoimmunity measurements among 85,421 Chinese pregnant women to investigate the genetic basis of thyroid function during pregnancy. Our study identified 176 genetic loci, including 125 previously unknown genome-wide associations. Joint epidemiological and Mendelian randomization analyses revealed significant associations between the gestational thyroid phenotypes and gestational complications, birth outcomes, and later-age health outcomes. Specifically, genetically elevated thyroid-stimulating hormone (TSH) levels during pregnancy correlated with lower glycemic levels, reduced blood pressure, and longer gestational duration. Additionally, TPOAb and thyroid functions during pregnancy share genetic correlations with later-age thyroid and cardiac disorders. These findings provide insights into the genetic determinants of thyroid traits during pregnancy, which may lead to new therapeutics, early pre-diagnosis and preventive strategies starting from early adulthood. Normal maternal thyroid function holds significant relevance for pregnancy outcomes and long-term health. Here, the authors detect genetic associations with thyroid related traits in pregnant women. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a heterogeneous disease that encompasses a wide range of conditions, from mild cases to severe conditions where survival depends on insulin therapy. The Korean Diabetes Association Task Force Team for Diabetes with β-Cell Failure has established the term to classify severe refractory disease with β-cell failure. Individuals with β-cell failure are at high risk of diabetes-related complications. We propose that diabetes with β-cell failure can be diagnosed when individuals treated with multiple daily insulin injections or insulin pumps meet at least one of the following criteria: fasting C-peptide ≤ 0.6 ng/mL, non-fasting C-peptide ≤ 1.8 ng/mL, 24-hour urine C-peptide < 30 μg/day, or spot urine C-peptide/creatinine ratio ≤ 0.6 nmol/mmol. Among cases of diabetes with β-cell failure, β-cell failure with absolute insulin deficiency can be diagnosed when at least one of the following criteria is met: fasting C-peptide < 0.24 ng/mL, non-fasting C-peptide < 0.6 ng/mL, or spot urine C-peptide/creatinine ratio < 0.2 nmol/mmol. Multiple daily insulin injections with long-acting insulin analogs and rapid-acting insulin analogs or insulin pumps are required for treatment of diabetes with β-cell failure. Continuous glucose monitoring and an automated insulin delivery system, sensor-augmented pump, or smart insulin pen, along with structured education, are necessary. We call for improvements in the relevant systems to ensure that such treatments can be provided. [ABSTRACT FROM AUTHOR]

Introduction: Recent studies showed an association between personality traits and individual patterns of visual behaviour in laboratory and other settings. The current study extends previous research by measuring multiple personality traits in natural settings; and by comparing accuracy of prediction of multiple machine learning algorithms. Methods: Adolescent participants (N = 35) completed personality questionnaires (Big Five Inventory and Short Dark Triad Questionnaire) and visited an interactive museum while their eye movements were recorded with head-mounted eye tracking. To predict personality traits the eye-movement data was analysed using eight machine-learning methods: Random Forest, Adaboost, Naive Bayes, Support Vector Machine, Logistic Regression, k Nearest Neighbours, Decision Tree and a three-layer Perceptron. Results and discussion: Extracted eye movement features introduced to machine learning algorithms predicted personality traits with above 33% chance accuracy (34%–48%). This result is comparable to previous ecologically valid studies, but lower than in laboratory-based research. Better prediction was achieved for Machiavellianism and Extraversion compared to other traits (10 and 9 predictions above the chance level by different algorithms from different parts of the recording). Conscientiousness, Narcissism and Psychopathy were not reliably predicted from eye movements. These differences in predictability across traits might be explained by differential activation of different traits in different situations, such as new vs. familiar, exciting vs. boring, and complex vs. simple settings. In turn, different machine learning approaches seem to be better at capturing specific gaze patterns (e.g. saccades), associated with specific traits evoked by the situation. Further research is needed to gain better insights into trait-situation-algorithm interactions. [ABSTRACT FROM AUTHOR]

Background: Partial nephrectomy (PN) has become the dominant treatment modality for cT1 renal tumor lesions. Tumors suspected of malignant potential are indicated for surgery, but some are histologically classified as benign lesions after surgery. This study aims to analyze the number of benign findings after PN according to definitive histology and to evaluate whether there is an association between malignant tumor findings and individual factors. Methods: The retrospective study included 555 patients who underwent open or robotic-assisted PN for a tumor in our clinic from January 2013 to December 2020. The cohort was divided into groups according to definitive tumor histology (malignant tumors vs. benign lesions). The association of factors (age, sex, tumor size, R.E.N.A.L.) with the malignant potential of the tumor was further evaluated. Results: In total, 462 tumors were malignant (83%) and 93 benign (17%). Of the malignant tumors, 66% were clear-cell RCC (renal cell carcinoma), 12% papillary RCC, and 6% chromophobe RCC. The most common benign tumor was oncocytoma in 10% of patients, angiomyolipoma in 2%, and papillary adenoma in 1%. In univariate analysis, there was a higher risk of malignant tumor in males (OR 2.13, 95% CI 1.36–3.36, p = 0.001), a higher risk of malignancy in tumors larger than 20 mm (OR 2.32, 95% CI 1.43–3.74, p < 0.001), and a higher risk of malignancy in tumors evaluated by R.E.N.A.L. as tumors of intermediate or high complexity (OR 2.8, 95% CI 1.76–4.47, p < 0.001). In contrast, there was no association between older age and the risk of malignant renal tumor (p = 0.878). Conclusions: In this group, 17% of tumors had benign histology. Male sex, tumor size greater than 20 mm, and intermediate or high R.E.N.A.L. complexity were statistically significant predictors of malignant tumor findings. [ABSTRACT FROM AUTHOR]

Background: Oral semaglutide in older subjects with type 2 diabetes was as effective as in younger subjects, according to phase 3 clinical trials. However, its efficacy can be limited in very aged population, due to the presence of impaired cognitive function and the complex instructions for its use. Here, we investigated its efficacy and safety by further age bracket in older subjects in real-world. Methods: We retrospectively studied subjects > 65 years of age with type 2 diabetes who started oral semaglutide treatment. The primary outcome was the change in glycated hemoglobin (HbA1c) over 6 months. Adverse events and cognitive function were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) and the Hasegawa Dementia Rating Scale-revised (HDS-R). The achievement rate of glycemic targets was evaluated based on the age, health status of subjects and their use of anti-diabetic agents which can cause hypoglycemia, with additional analysis between two subgroups; early (65–74) versus late (≥ 75) older. Furthermore, we evaluated the relationships between their improvements in HbA1c and the baseline characteristics of the subjects, including their cognitive function and insulin secretory capacity. Results: We studied the efficacy of the drug in 24 subjects. Their HbA1c and body weight significantly decreased (− 13.1 ± 7.5 mmol/mol and − 3.0 ± 2.4 kg, respectively; P < 0.01). Although cognitive function was lower in the late older group (r = −0.57, P < 0.01), changes in HbA1c showed no difference between the two subgroups (P = 0.66) and it correlated with the insulin secretory capacity rather than cognitive function (r = −0.49, P < 0.05). Glycemic targets were more likely to be achieved (P < 0.01), but HbA1c excessively decreased in late older subjects who were also using insulin or an insulin secretagogue. The frequency of adverse events was similar to that in the clinical trial, whereas discontinuation of medication were more frequent among the late older subjects (Early; n = 2, Late; n = 4). Conclusions: Oral semaglutide improves the glycemic control of older subjects, but it might be a risk for potential hypoglycemia and discontinuation because of adverse events in subjects of ≥ 75 years. Attention should be paid to insulin secretory capacity and concomitant medications rather than concern about adherence. [ABSTRACT FROM AUTHOR]

Introduction: Postoperative urinary retention (POUR) is the inability to urinate after a surgical procedure despite having a full bladder. It is a common complication following lumbar spine surgery which has been extensively linked to increased patient morbidity and hospital costs. This study hopes to development and validate a predictive model for POUR following lumbar spine surgery using patient demographics, surgical and anesthesia variables. Methods: This is a retrospective observational cohort study of 903 patients who underwent lumbar spine surgery over the period of June 2017 to June 2019 in a tertiary academic medical center. Four hundred and nineteen variables were collected including patient demographics, ICD-10 codes, and intraoperative factors. Least absolute shrinkage and selection operation (LASSO) regression and logistic regression models were compared. A decision tree model was fitted to the optimal model to classify each patient’s risk of developing POUR as high, intermediate, or low risk. Predictive performance of POUR was assessed by area under the receiver operating characteristic curve (AUC-ROC). Results: 903 patients were included with average age 60 ± 15 years, body mass index of 30.5 ± 6.4 kg/m², 476 (53%) male, 785 (87%) white, 446 (49%) involving fusions, with average 2.1 ± 2.0 levels. The incidence of POUR was 235 (26%) with 63 (7%) requiring indwelling catheter placement. A decision tree was constructed with an accuracy of 87.8%. Conclusion: We present a highly accurate and easy to implement decision tree model which predicts POUR following lumbar spine surgery using preoperative and intraoperative variables. [ABSTRACT FROM AUTHOR]

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Digital fabrication laboratories (Fab Labs) are accessible to the public, including children and families. However, a variety of technical skills, tools, and expertise are needed in these spaces, and Fab Lab staff—instructors working there—are in a key role in helping Fab Lab users. There is, however, a lack of research on how these instructors can inspire children's genuine participation in Fab Labs. We analyze the challenges faced by four instructors during two months of Fab Lab workshops with 7–12-year-old children. The children worked in child-only or child-parent groups on informal digital design and fabrication activities. Based on genuine participation principles derived from the literature, we designed our workshops, which included the creation of instructor guideline. At the end, we developed a post-workshop framework in which the instructors provided feedback about their performance and experiences. We provide recommendations to help instructors support children's genuine participation in digital design and fabrication. [ABSTRACT FROM AUTHOR]

OBJECTIVE Little is known about the influence of residual islet function on glycemic control in type 1 diabetes (T1D). We investigated the associations between residual β-cell function and metrics of continuous glucose monitoring (CGM) in individuals with T1D. RESEARCH DESIGN AND METHODS In this cross-sectional cohort comprising 489 individuals (64% female, age 41.0 ± 14.0 years), T1D duration was 15.0 (interquartile range [IQR] 6.0-29.0) years. Individuals had a time in range (TIR) of 66% (IQR 52-80%) and a urinary C-peptide-to-creatinine ratio (UCPCR) of 0.01 (IQR 0.00-0.41) nmol/mmol. To assess β-cell function, we measured UCPCR (detectable >0.01 nmol/mmol), and to assess α-cell function, fasting plasma glucagon/glucose ratios were measured. CGM was used to record TIR (3.9-10 mmol/L), time below range (TBR) (<3.9 mmol/L), time above range (TAR) (>10 mmol/L), and glucose coefficient of variance (CV). For CGM, 74.7% used FreeStyle Libre 2, 13.8% Medtronic Guardian, and 11.5% Dexcom G6 as their device. RESULTS The percentage of patients with T1D who had a detectable UCPCR was 49.4%. A higher UCPCR correlated with higher TIR (r = 0.330, P < 0.05), lower TBR (r = -0.237, P < 0.05), lower TAR (r = -0.302, P < 0.05), and lower glucose CV (r = -0.356, P < 0.05). A higher UCPCR correlated negatively with HbA1c levels (r = -0.183, P < 0.05) and total daily insulin dose (r = -0.183, P < 0.05). Glucagon/glucose ratios correlated with longer TIR (r = 0.234, P < 0.05). CONCLUSIONS Significantly longer TIR, shorter TBR and TAR, and lower CV were observed in individuals with greater UCPCR-assessed β-cell function. Therefore, better CGM-derived metrics in individuals with preserved β-cell function may be a contributor to a lower risk of developing long-term complications. [ABSTRACT FROM AUTHOR]

Background: Type 1 diabetes mellitus (T1DM) management in children and adolescents requires intensive supervision and monitoring to prevent acute and late diabetes complications and to improve quality of life. Digital health interventions, in particular diabetes mobile health apps (mHealth apps) can facilitate specialized T1DM care in this population. This study evaluated the initial usability of and satisfaction with the m-Health intervention Diabetes: M app, and the ease of use of various app features in supporting T1DM care in rural and remote areas of Bosnia-Herzegovina with limited access to specialized diabetes care. Methods: This cross-sectional study, performed in February–March 2023, evaluated T1DM pediatric patients who used the Diabetes: M app in a 3-month mHealth-based T1DM management program, along with their parents and healthcare providers (HCPs). All participants completed selfadministered online questionnaires at the end of the 3-month period. Data were analyzed by descriptive statistics. Results: The study population included 50 T1DM patients (children/parents and adolescents) and nine HCPs. The mean ± SD age of the T1DM patients was 14 ± 4.54 years, with 26 (52%) being female. The mean ± SD age of the HCPs was 43.4 ± 7.76 years; all (100%) were women, with a mean ± SD professional experience of 17.8 ± 8.81 years. The app was reported usable in the domains of ease-of-use and satisfaction by the T1DM children/parents (5.82/7.0), T1DM adolescents/young adults (5.68/7.0), and HCPs (5.22/7.0). Various app features, as well as the overall app experience, were rated positively by the participants. Conclusion: The results strongly support the usability of mHealth-based interventions in T1DM care, especially in overcoming care shortage and improving diabetes management and communications between HCPs and patients. Further studies are needed to compare the effectiveness of apps used to support T1DM management with routine care. [ABSTRACT FROM AUTHOR]

Background: Advanced maternal age may affect the intrauterine environment and increase the risk of neurodevelopmental disorders in offspring. Thyroid hormones are critical for fetal neurological development but whether maternal age influences fetal thyroid hormone levels in euthyroid mothers is unknown. Objective: This study evaluated the association between cord blood thyroid hormones and maternal age, fetal sex, maternal thyroid function, and other perinatal factors. Methods: The study population consisted of 203 healthy women with term singleton pregnancies who underwent elective cesarean section. Maternal levels of free T3 (fT3), free T4 (fT4) and TSH before delivery, and cord levels of fT3, fT4 and TSH were measured. Spearman's correlation coefficient and multiple linear regression analyses were performed to determine the correlation between cord thyroid hormone parameters and maternal characteristics. Results: There were no significant differences in maternal serum or cord blood thyroid hormone levels between male and female births. In multivariate linear regression analysis, maternal age and maternal TSH values were negatively associated with the cord blood levels of fT3 in all births, after adjusting for confounding factors. Maternal age was more closely associated with the cord blood levels of fT3 in female than in male births. Conclusion: The inverse association between maternal age and cord blood levels of fT3 in euthyroid pregnant women suggested an impact of maternal aging on offspring thyroid function. [ABSTRACT FROM AUTHOR]

Objectives: Polycystic ovary syndrome (PCOS) and thyroid disorders have both been linked to adverse pregnancy and neonatal outcomes. Even small variations in thyroid function within the normal range may influence fetal growth. Our aim was to investigate whether maternal thyroid function is associated with newborn anthropometrics in PCOS and explore the potential modifying effect of metformin.Methods: Post-hoc analyses of two RCTs in which pregnant women with PCOS were randomized to metformin or placebo, from first trimester to delivery. Maternal serum levels of thyroid stimulating hormone (TSH) and free thyroxine (fT4) were measured at gestational weeks (gw) 5–12, 19, 32 and 36 in 309 singleton pregnancies. The mean z-scores of birthweight, birth length, and head circumference were estimated in the offspring. Associations of maternal thyroid parameters with offspring anthropometrics and the outcomes large for gestational age (LGA) and small for gestational age (SGA) were studied using linear and logistic regression models, with adjustment for body mass index (BMI) when relevant.Results: Maternal fT4 at baseline was negatively associated with birth length (b= -0.09, p=0.048). Furthermore, ΔfT4 during pregnancy correlated positively to z-score of both birth weight and length (b=0.10, p=0.017 and b=0.10, p=0.047 respectively), independently of treatment group. TSH at baseline and gw19 was inversely associated with LGA (OR 0.47, p=0.012 and OR 0.58, p=0.042), while ΔTSH was positively associated with LGA (OR 1.99, p=0.023). There were inverse associations between TSH at baseline and SGA (OR 0.32, p=0.005) and between ΔfT4 and SGA (OR 0.59, p=0.005) in the metformin group only. There were no associations between maternal thyroid function and head circumference of the newborns.Conclusion: In women with PCOS, a higher maternal fT4 in early pregnancy and a greater decrease in fT4 during pregnancy was associated with a lower offspring birthweight and shorter birth length. Higher TSH by mid-gestation and smaller increase in TSH during pregnancy was associated with less risk of LGA. Subclinical variations in maternal thyroid function might play a role for birth anthropometrics of PCOS offspring. [ABSTRACT FROM AUTHOR]

Background: Clinical prediction models can help identify high-risk patients and facilitate timely interventions. However, developing such models for rare diseases presents challenges due to the scarcity of affected patients for developing and calibrating models. Methods that pool information from multiple sources can help with these challenges. Methods: We compared three approaches for developing clinical prediction models for population screening based on an example of discriminating a rare form of diabetes (Maturity-Onset Diabetes of the Young - MODY) in insulin-treated patients from the more common Type 1 diabetes (T1D). Two datasets were used: a case-control dataset (278 T1D, 177 MODY) and a population-representative dataset (1418 patients, 96 MODY tested with biomarker testing, 7 MODY positive). To build a population-level prediction model, we compared three methods for recalibrating models developed in case-control data. These were prevalence adjustment ("offset"), shrinkage recalibration in the population-level dataset ("recalibration"), and a refitting of the model to the population-level dataset ("re-estimation"). We then developed a Bayesian hierarchical mixture model combining shrinkage recalibration with additional informative biomarker information only available in the population-representative dataset. We developed a method for dealing with missing biomarker and outcome information using prior information from the literature and other data sources to ensure the clinical validity of predictions for certain biomarker combinations. Results: The offset, re-estimation, and recalibration methods showed good calibration in the population-representative dataset. The offset and recalibration methods displayed the lowest predictive uncertainty due to borrowing information from the fitted case-control model. We demonstrate the potential of a mixture model for incorporating informative biomarkers, which significantly enhanced the model's predictive accuracy, reduced uncertainty, and showed higher stability in all ranges of predictive outcome probabilities. Conclusion: We have compared several approaches that could be used to develop prediction models for rare diseases. Our findings highlight the recalibration mixture model as the optimal strategy if a population-level dataset is available. This approach offers the flexibility to incorporate additional predictors and informed prior probabilities, contributing to enhanced prediction accuracy for rare diseases. It also allows predictions without these additional tests, providing additional information on whether a patient should undergo further biomarker testing before genetic testing. [ABSTRACT FROM AUTHOR]

In this study, the role of social emotional learning and microsystem supports on the well-being of adolescents studying at the high school level was examined. It has been assumed that microsystem supports and social emotional learning created within the framework of the ecological approach have an important variance in explaining well-being in adolescents. A total of 1110 high school students, 560 male (50.5%) and 550 female (49.5%) participated in the study (Ageort = 15.52, sd = 0.85). A predictive relationship was found between peer relationships, parent engagement, self-regulation, social emotional learning and well-being. In addition to all these results, all these factors significantly explained the variance of well-being. Another important result is that SEL mediates between well being and ecological factors. This is proof that primarily supports social emotional learning is shaped by ecological factors. These findings are discussed in terms of the advantages of social emotional learning and microsystem support in order to increase the well-being of adolescents. [ABSTRACT FROM AUTHOR]

Objective: MODY (maturity onset diabetes of the young) is a rare, monogenic, autosomal dominant form of diabetes occurring in young (< 25 years) individuals. It has a wide phenotypic variability and can be misdiagnosed as type 1 diabetes mellitus (T1DM). Appropriate detection of MODY has therapeutic and genetic implications. This study aimed to detect MODY among long standing, clinically diagnosed T1DM patients with preserved C-peptide levels. Methods: This was a hospital-based cross-sectional study from central South India which included 100 clinically diagnosed T1DM patients (according to ADA criteria), with a duration of > 3 years. MODY probability score, urinary C-peptide to creatinine ratio (UCPCR), and relevant biochemical investigations were performed. Targeted next-generation sequencing (NGS) for MODY-related genes (13 genes) was done for individuals with UCPCR > 0.2. Results: A UCPCR value of > 0.2 (suggestive of preserved endogenous insulin secretion) was observed in eight individuals. The mean HbA1c values were lower, and the MODY probability score was higher in individuals with preserved endogenous insulin (8.07% vs 9.53% and 2.8% vs 1.5%; p-value: 0.005 and 0.004 respectively). One of the eight individuals (12.5%) had a non-pathogenic gene variant in KLF11. Conclusion: In a South Indian cohort of T1DM with preserved C-peptide, we could not find any case of MODY through targeted NGS. UCPCR can be used as a screening tool to identify cases needing genetic testing for MODY. Larger studies utilizing whole exome sequencing should be conducted to know the actual prevalence of MODY among T1DM. [ABSTRACT FROM AUTHOR]

Type 1 diabetes is a chronic autoimmune disease in which destruction of pancreatic β-cells causes life-threatening metabolic dysregulation. Numerous approaches are envisioned for new therapies, but limitations of current clinical outcome measures are significant disincentives to development efforts. C-peptide, a direct byproduct of proinsulin processing, is a quantitative biomarker of β-cell function that is not cleared by the liver and can be measured in the peripheral blood. Studies of quantitative measures of β-cell function have established a predictive relationship between stimulated C-peptide as a measure of β-cell function and clinical benefits. C-peptide levels at diagnosis are often high enough to afford glycemic control benefits associated with protection from end-organ complications of diabetes, and even lower levels offer protection from severe hypoglycemia in type 1 diabetes, as observed in large prospective cohort studies and interventional trials of islet transplantation. These observations support consideration of C-peptide not just as a biomarker of β-cell function but also as a specific, sensitive, feasible, and clinically meaningful outcome defining β-cell preservation or restoration for clinical trials of disease-modifying therapies. Regulatory acceptance of C-peptide as a validated surrogate for demonstration of efficacy would greatly facilitate development of disease-modifying therapies for type 1 diabetes. Article Highlights: Mixed-meal stimulated C-peptide level has been established as a biomarker of endogenous β-cell function and is used clinically to monitor disease progression in type 1 diabetes. Large prospective cohort studies and interventional trials of islet transplantation demonstrate the relationship between stimulated C-peptide levels and clinical benefits. A recent meta-analysis of interventional clinical trials aimed at preserving β-cell function in those recently diagnosed further supports stimulated C-peptide level as a validated surrogate end point for clinical trials of disease-modifying therapies in type 1 diabetes. [ABSTRACT FROM AUTHOR]

Objective: Maturity-onset diabetes of the young (MODY) is the most common type of monogenic diabetes. To date, mutations have been identified in 14 different genes of patients with a clinical diagnosis of MODY. This study screened mutations in 14 MODY-related genes and the regulator factor X6 (RFX6) gene in children Methods: The presence of clinical features of MODY and negative results for three autoantibody markers of type 1 diabetes mellitus (T1DM) in children and adolescents were used as inclusion criteria for genetic testing. The screening panel for next-generation sequencing included 14 MODY-related genes (GCK, HNF4A, HNF1A, HNF1B, PDX1, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8, KCNJ11, and APPL1) and the RFX6 gene. Results: Twenty-four different variants in MODY-related genes were identified in 49 children diagnosed with autoantibody-negative T1DM. Twelve variants were classified as pathogenic/likely pathogenic (P/LP) while 12 were interpreted as variant of unknown significance. Nine of the P/LP variants were found in GCK, two in HNF1B, and one in ABCC8. Three variants were novel, and one was a de novo variant. All but one of the variants exhibited heterozygotic inheritance. Conclusion: The frequencies of the MODY subtypes differed from previous reports. Although GCK-MODY was the most frequent mutation in Turkish children, similar to previous studies, the second most prevalent MODY subtype was HNF1B-MODY. This study also established three additional novel mutations in different MODY genes. [ABSTRACT FROM AUTHOR]

Background: Mesenchymal stem cell infusion and vitamin D supplementation may have immunomodulatory actions that could prolong the preservation of residual insulin secretion in patients with type 1 diabetes (T1D). Intervention with these agents after onset of T1D could favor the development of a remission phase, with potential clinical impact. We aimed to compare the presence of clinical remission (CR), glycemic control and daily insulin requirement at 6, 12, 18, 24 and 36 months after the diagnosis of T1D using IDAA1c in patients who received therapy with adipose tissue-derived mesenchymal stem cell (ASC) infusion and vitamin D supplementation and a control group. Methods: This retrospective cohort study analyzed data from the medical records of patients with T1D diagnosed between 15 and 40 years. Partial CR was defined as an IDAA1c index < 9. Patients in the intervention group received an infusion of adipose tissued-derived mesenchymal stem cells (ASCs) within 3 months after diagnosis and supplementation with 2000 IU of cholecalciferol for 1 year, started on the day following the infusion. Partial CR was also determined using the ISPAD criteria, to assess its agreement with IDAA1c. Results: A total of 28 patients were evaluated: 7 in the intervention group (group 1) and 21 in the control group (group 2). All patients in group 1 evolved with partial CR while only 46.7% of patients in group 2 had this outcome. Group 1 had a higher frequency of CR when evaluated with IDAA1c and ISPAD criteria. The mean duration of CR varied between the two criteria. Although HbA1c was similar between groups during follow-up, group 1 had a lower total daily insulin requirement (p < 0.005) at all time points. At 36 months, group 1 used 49% of the total daily insulin dose used by group 2 with similar glycemic control. Conclusion: The intervention with infusion of ASC + vitamin D supplementation was associated with partial CR at 6 months. Although there were no differences in CR established by the IDAA1c and ISPAD criteria after three years of follow-up, patients who underwent intervention had nearly the half insulin requirement of controls with conventional treatment, with similar glycemic control. Trial Registration: 37001514.0.0000.5257. [ABSTRACT FROM AUTHOR]

Adverse neonatal outcomes are a prevailing risk factor for both short- and long-term mortality and morbidity in infants. Given the importance of these outcomes, refining their assessment is paramount for improving prevention and care. Here we aim to enhance the assessment of these often correlated and multifaceted neonatal outcomes. To achieve this, we employ factor analysis to identify common and unique effects and further confirm these effects using criterion-related validity testing. This validation leverages methylome-wide profiles from neonatal blood. Specifically, we investigate nine neonatal health risk variables, including gestational age, Apgar score, three indicators of body size, jaundice, birth diagnosis, maternal preeclampsia, and maternal age. The methylomic profiles used for this research capture data from nearly all 28 million methylation sites in human blood, derived from the blood spot collected from 333 neonates, within 72 h post-birth. Our factor analysis revealed two common factors, size factor, that captured the shared effects of weight, head size, height, and gestational age and disease factor capturing the orthogonal shared effects of gestational age, combined with jaundice and birth diagnosis. To minimize false positives in the validation studies, validation was limited to variables with significant cumulative association as estimated through an in-sample replication procedure. This screening resulted in that the two common factors and the unique effects for gestational age, jaundice and Apgar were further investigated with full-scale cell-type specific methylome-wide association analyses. Highly significant, cell-type specific, associations were detected for both common effect factors and for Apgar. Gene Ontology analyses revealed multiple significant biologically relevant terms for the five fully investigated neonatal health risk variables. Given the established links between adverse neonatal outcomes and both immediate and long-term health, the distinct factor effects (representing the common and unique effects of the risk variables) and their biological profiles confirmed in our work, suggest their potential role as clinical biomarkers for assessing health risks and enhancing personalized care. [ABSTRACT FROM AUTHOR]