AIMS:To study the associations of dietary intake of A and E vitamins, as well as plasma retinols, carotenoids, and tocopherols in relation to development of islet autoimmunity and progression to T1D. MATERIALS AND METHODS:The Environmental Determinants of Diabetes in the Young (TEDDY) Study followed 7659 newborns with genetic susceptibility to T1D for 6 years in the USA, Finland, Germany, and Sweden. Dietary vitamin intake was assessed repeatedly with 3-day food-records in full cohort at ages 6 months to 6 years. Plasma retinols, carotenoids, and tocopherols were analysed in a nested case-control setting with 359 children with islet autoimmunity and 1033 matched controls. RESULTS:In the full cohort analyses, dietary intake of retinol, β-carotene, and vitamin E was not associated with the risk of islet autoimmunity or progression to T1D. Further, none of the plasma retinol, carotenoid, and tocopherol biomarkers were associated with islet autoimmunity or T1D in the full nested case-control analyses. We observed effect modification by country, breastfeeding, sex, and follow-up time for both intake and biomarkers of vitamins on the risk of islet autoimmunity or T1D, and some subgroup associations. Finally, a plasma carotenoid metabolite (likely zeinoxanthin) (OR 0.61, 95% CI 0.39, 0.95, p = 0.03) and γ-carotene at 6 months (OR 0.65, 95% CI 0.45, 0.94, p = 0.02) were inversely associated with the odds of developing GADA-first. CONCLUSIONS:Retinol, carotenoids and tocopherols were not consistently associated with islet autoimmunity. This study adds to the understanding of factors and their interactions related to T1D development.

BACKGROUND:The role of nutrient intake in celiac disease pathogenesis is poorly understood. OBJECTIVES:This study aims to examine whether longitudinal childhood intake of selected vitamins and minerals is associated with celiac disease autoimmunity (CDA, primary outcome) and celiac disease (secondary outcome) in genetically at-risk children. METHODS:A total of 6520 human leukocyte antigens-conferred at-risk children in the observational The Environmental Determinants of Diabetes in the Young (TEDDY) study were prospectively screened for tissue transglutaminase autoantibodies (tTGA) annually from ages 2 to 13 y. CDA was defined as persistent tTGA positivity in 2 samples ≥3 mo apart. Celiac disease was defined by biopsy-confirmed Marsh score ≥2 or mean tTGA ≥100 U/mL in 2 consecutive samples. Micronutrient intake was assessed via repeated 3-d food records, and adjusted hazard ratios (HRs) were estimated using time-dependent Cox proportional hazards and Bayesian joint models. RESULTS:Out of 6520 children, 1268 (19%) developed CDA and 479 (7.8%) were diagnosed with celiac disease. Results from both models suggested heterogeneity in associations by country as nutrients such as folate showed sporadic associations in the same or opposite direction across ages. Higher vitamin D intake (every 5 μg/1000 kcal) at multiple ages was associated with increased risk of CDA and celiac disease in Sweden, with the strongest at age 5 y for CDA [HR: 1.23, 95% confidence interval (CI): 1.11, 1.37; P < 0.001] and at age 4 y for celiac disease (HR: 1.20; 95% CI: 1.03, 1.40; P = 0.021). Higher iron intake (every 5 mg/1000 kcal) was also associated with increased risks of CDA and celiac disease in Sweden, with the highest observed up to age 5 y (HR: 1.70; 95% CI: 1.39, 2.08; P < 0.001 for CDA and HR:1.80; 95% CI: 1.37, 2.36; P < 0.001 for celiac disease). CONCLUSIONS:Modest country-specific associations were found between childhood micronutrient intake with risk of CDA and celiac disease, potentially reflecting the influence from regional dietary practices, fortification policies, and host factors in disease pathogenesis.

Context Autoantibodies to thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) define preclinical autoimmune thyroid disease (AITD), which can progress to either clinical hypothyroidism or hyperthyroidism.Objective We determined the age at seroconversion in children genetically at risk for type 1 diabetes.Methods TPOAb and TgAb seropositivity were determined in 5066 healthy children with human leukocyte antigen (HLA) DR3- or DR4-containing haplogenotypes from The Environmental Determinants of Diabetes in the Young (TEDDY) study. Children seropositive on the cross-sectional initial screen at age 8 to 13 years had longitudinally collected samples (from age 3.5 months) screened retrospectively and prospectively for thyroid autoantibodies to identify age at seroconversion. The first-appearing autoantibody was related to sex, HLA genotype, family history of AITD, and subsequent thyroid dysfunction and disease.Results The youngest appearance of TPOAb and TgAb was age 10 and 15 months, respectively. Girls had higher incidence rates of both autoantibodies. Family history of AITD was associated with a higher risk of TPOAb hazard ratio (HR) 1.90; 95% CI, 1.17-3.08; and TgAb HR 2.55; 95% CI, 1.91-3.41. The risk of progressing to hypothyroidism or hyperthyroidism was not different between TgAb and TPOAb, but children with both autoantibodies appearing at the same visit had a higher risk compared to TPOAb appearing first (HR 6.34; 95% CI, 2.72-14.76).Conclusion Thyroid autoantibodies may appear during the first years of life, especially in girls, and in children with a family history of AITD. Simultaneous appearance of both autoantibodies increases the risk for hypothyroidism or hyperthyroidism.

Objective: To design a dynamic prediction model for estimating the time of progression from a single glutamic acid decarboxylase autoantibody (GADA) to multiple islet autoantibodies and type 1 diabetes in children, exploring different longitudinally measured risk variables. Research Design and Methods: GADA-positive children (n = 379) participating in The Environmental Determinants of Diabetes in the Young (TEDDY) study were followed for the appearance of additional autoantibodies against either insulin autoantibody (IAA), insulinoma-like 2 autoantibody (IA-2A), or zinc transporter 8 antibody (ZnT8A) and type 1 diabetes. A dynamic prediction model was designed, including trajectories of longitudinal risk variables, autoantibody titers, and metabolic variables (C-peptide, glucose, and HbA1c) together with time-invariant variables (gender, age at GADA positivity, and high-risk HLA genotypes). Results: Transition risk from GADA to multiple autoantibodies was increased by lower age (p < 0.001) and by increased GADA titers during follow-up (p < 0.001), and was less likely in children with HLA DQ2/X but not DQ2/8 (p=0.004). The transition risk from multiple autoantibodies without IA-2A to IA-2A positivity was associated with increased levels of 2 h glucose following oral glucose tolerance test (OGTT) (p < 0.001) and increased ZnT8A titers (p < 0.001). Increasing HbA1c (p < 0.001) and GADA titers (p < 0.001) were associated with an increased risk of transition from GADA only to type 1 diabetes; while increasing HbA1c (p < 0.001) was associated with the transition from multiple autoantibodies to type 1 diabetes. Risk of transition from multiple autoantibodies, including IA-2A to type 1 diabetes was also associated with 2 h glucose level (p < 0.001). Conclusion: The dynamic prediction model presented an individual time-specific risk of transition from a single GADA to multiple autoantibodies and type 1 diabetes.

In 2020, the World Health Organization (WHO) reported 604,000 new diagnoses of cervical cancer (CC) worldwide, and over 300,000 CC-related fatalities. The vast majority of CC cases are caused by persistent human papillomavirus (HPV) infections. HPV-related CC incidence and mortality rates have declined worldwide because of increased HPV vaccination and CC screening with the Papanicolaou test (PAP test). Despite these significant improvements, developing countries face difficulty implementing these programs, while developed nations are challenged with identifying HPV-independent cases. Molecular and proteomic information obtained from blood or tumor samples have a strong potential to provide information on malignancy progression and response to therapy in CC. There is a large amount of published biomarker data related to CC available but the extensive validation required by the FDA approval for clinical use is lacking. The ability of researchers to use the big data obtained from clinical studies and to draw meaningful relationships from these data are two obstacles that must be overcome for implementation into clinical practice. We report on identified multimarker panels of serum proteomic studies in CC for the past 5 years, the potential for modern computational biology efforts, and the utilization of nationwide biobanks to bridge the gap between multivariate protein signature development and the prediction of clinically relevant CC patient outcomes.

Islet autoantibodies (IA) that precede type 1 diabetes, tissue transglutaminase autoantibodies (tTGA) preceding celiac disease, and thyroid peroxidase (TPOA) or thyroglobulin (ThGA) autoantibodies preceding autoimmune thyroid disease may coincide. We aim to describe the order of first appearance of IA, tTGA, or thyroid autoimmunity in children, as well as the role of thyroid autoimmunity in risk of subsequent development of IA or tTGA. Children (n = 5437) with a genetically determined high risk for autoimmune disease from the USA, Finland, Germany, and Sweden were followed from birth to age 14 or type 1 diabetes diagnosis. Cox regression was used for survival analyses. IA, tTGA, and thyroid autoimmunity were the first or only type of autoantibody to develop in 10%, 20%, and 8% of the children, respectively, and 61% remained autoantibody negative (median follow-up 12.0 years). Among autoantibody positive children, a family history of autoimmune thyroid disease was associated with an increased risk of ThGA (OR 2.05, 95% CI 1.48, 2.85, p < 0.001), but not TPOA (OR 1.18, 95% CI 0.71, 1.95, p = 0.53), as the first or only autoantibody. TPOA as the first or only thyroid autoantibody was associated with increased risk of subsequent development of IA (HR 1.94, 95% CI 1.11, 3.41, p = 0.021) and tTGA (HR 1.69, 95% CI 1.04, 2.75, p = 0.036), while there was no association for ThGA-first thyroid autoimmunity with either IA or tTGA. Among children with IA, thyroid autoimmunity status at the time of IA seroconversion was not associated with risk of IAA versus GADA as the first appearing IA (TPOA-first p = 0.73, ThGA-first p = 0.20). The association between thyroid autoimmunity and either IA or tTGA depends on which thyroid autoantibody appears first. A better understanding of the co-occurrence and order of appearance of these three types of autoantibodies may aid in designing a more personalized approach to identifying individuals at highest risk for autoimmune comorbidity. Disclosure J.L. Clasen: None. H.E. Larsson: None. B. Jonsdottir: None. M.J. Haller: Consultant; Sanofi. Advisory Panel; SAB Biotherapeutics, Inc. Consultant; MannKind Corporation. D. Agardh: None. H.M. Parikh: None. K.F. Lynch: None. Å. Lernmark: Advisory Panel; DiaMyd Medical AB, Stockholm, Sweden. M. Rewers: Advisory Panel; Sanofi. Other Relationship; Sanofi. Consultant; Janssen Pharmaceuticals, Inc. Research Support; Juvenile Diabetes Research Foundation (JDRF). Consultant; Provention Bio, Inc. Research Support; Hemsley Charitable Trust, National Institute of Diabetes and Digestive and Kidney Diseases. R. McIndoe: None. J. Toppari: None. A. Ziegler: None. J. Krischer: None. B. Akolkar: None. W. Hagopian: Research Support; Janssen Pharmaceuticals, Inc., Provention Bio, Inc. Consultant; Sanofi-Aventis U.S., Randox R & D. K. Vehik: None. Funding NIH NIDDK (U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, UC4 DK100238, UC4 DK106955, UC4 DK112243, UC4 DK117483, U01 DK124166, U01 DK128847, and Contract No. HHSN267200700014C)

OBJECTIVES:To determine if nutritional status effects response to immunotherapy in women with gynecologic malignancies. METHODS:A retrospective chart review was conducted on gynecologic cancer patients who received immunotherapy at a single institution between 2015 and 2022. Immunotherapy included checkpoint inhibitors and tumor vaccines. The prognostic nutritional index (PNI) was calculated from serum albumin levels and total lymphocyte count. PNI values were determined at the beginning of treatment for each patient and assessed for their association with immunotherapy response. Disease control response (DCR) as an outcome of immunotherapy was defined as complete response, partial response, or stable disease. RESULTS:One hundred and ninety-eight patients received immunotherapy (IT) between 2015 and 2022. The gynecological cancers treated were uterine (38%), cervix (32%), ovarian (25%), and vulvar or vaginal (4%) cancers. The mean PNI for responders was higher than the non-responder group (p < 0.05). The AUC value for PNI as a predictor of response was 49. A PNI value of 49 was 43% sensitive and 85% specific for predicting a DCR. In Cox proportional hazards analysis, after adjusting for ECOG score and the number of prior chemotherapy lines, severe malnutrition was associated with progression-free survival (PFS) (HR = 1.85, p = 0.08) and overall survival (OS) (HR = 3.82, p < 0.001). Patients with PNI < 49 were at a higher risk of IT failure (HR = 2.24, p = 0.0001) and subsequent death (HR = 2.84, p = 9 × 10-5). CONCLUSIONS:PNI can be a prognostic marker to predict response rates of patients with gynecologic cancers treated with immunotherapy. Additional studies needed to understand the mechanistic role of malnutrition in immunotherapy response.

Purpose The aim was to study the association between dietary intake of B vitamins in childhood and the risk of islet autoimmunity (IA) and progression to type 1 diabetes (T1D) by the age of 10 years. Methods We followed 8500 T1D-susceptible children born in the U.S., Finland, Sweden, and Germany in 2004 -2010 from the Environmental Determinants of Diabetes in the Young (TEDDY) study, which is a prospective observational birth cohort. Dietary intake of seven B vitamins was calculated from foods and dietary supplements based on 24-h recall at 3 months and 3-day food records collected regularly from 6 months to 10 years of age. Cox proportional hazard models were adjusted for energy, HLA-genotype, first-degree relative with T1D, sex, and country. Results A total of 778 (9.2) children developed at least one autoantibody (any IA), and 335 (3.9%) developed multiple autoantibodies. 280 (3.3%) children had IAA and 319 (3.8%) GADA as the first autoantibody. 344 (44%) children with IA progressed to T1D. We observed that higher intake of niacin was associated with a decreased risk of developing multiple autoantibodies (HR 0.95; 95% CI 0.92, 0.98) per 1 mg/1000 kcal in niacin intake. Higher intake of pyridoxine (HR 0.66; 95% CI 0.46, 0.96) and vitamin B12 (HR 0.87; 95% CI 0.77, 0.97) was associated with a decreased risk of IAA-first autoimmunity. Higher intake of riboflavin (HR 1.38; 95% CI 1.05, 1.80) was associated with an increased risk of GADA-first autoimmunity. There were no associations between any of the B vitamins and the outcomes “any IA” and progression from IA to T1D. Conclusion In this multinational, prospective birth cohort of children with genetic susceptibility to T1D, we observed some direct and inverse associations between different B vitamins and risk of IA.

Introduction & Objective: Stress is implicated as a factor in immune reactivity and autoimmune disorders. Adverse experiences and chronic stress may be associated with low morning cortisol levels. Here, we tested if morning saliva cortisol is associated with the development of islet autoimmunity (IA). Methods: Saliva was collected 30 minutes upon awakening and assayed for cortisol in 1049 children enrolled in The Environmental Determinants of Diabetes in the Young (TEDDY) study at 42 months. Using Cox proportional hazards models, we examined morning log2 cortisol at 42 months in relation to risk of IA between 4 and 15 years of age (any IA: n=89; GADA-first: n=53; IAA-first, n=23) in addition to TEDDY published factors associated with IA. Results: Morning saliva cortisol (median log2=3.34) at 42 months is inversely associated with the risk of IA from 4 years of age (HR (95%CI) per log2 increase (0.65 (0.51-0.83), p=0.0005) adjusting for HLA-DR-DQ, diabetes family history, sex, weight-z score at age 12 months, and country. Both high (HR=0.19) and low (HR=1.95) morning cortisol levels are significantly associated with risk of IA, independently, as compared to 79% of children with log2 cortisol levels between 2-3.99 (Figure). Conclusion: These findings suggest that morning saliva cortisol at 42 months of age is inversely associated with risk of IA in genetically at-risk children followed until 15 years of age. Disclosure K. Vehik: None. K.F. Lynch: None. H.M. Parikh: None. Å. Lernmark: Advisory Panel; DiaMyd Medical AB, Stockholm, Sweden. M. Rewers: Advisory Panel; Sanofi. Other Relationship; Sanofi. Consultant; Janssen Pharmaceuticals, Inc. Research Support; Juvenile Diabetes Research Foundation (JDRF). Consultant; Provention Bio, Inc. Research Support; Hemsley Charitable Trust, National Institute of Diabetes and Digestive and Kidney Diseases. R. McIndoe: None. J. Toppari: None. A. Ziegler: None. B. Akolkar: None. W. Hagopian: Research Support; Janssen Pharmaceuticals, Inc., Provention Bio, Inc. Consultant; Sanofi-Aventis U.S., Randox R & D. T.M. Brusko: None. J. Krischer: None. R.L. Roth: None. S.B. Johnson: None. Funding NIH NIDDK (U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, UC4 DK100238, UC4 DK106955, UC4 DK112243, UC4 DK117483, U01 DK124166, U01 DK128847, and Contract No. HHSN267200700014C)

The Mouse Metabolic Phenotyping Center (MMPC)Live Program was established in 2023 by the National Institute for Diabetes, Digestive and Kidney Diseases (NIDDK) at the National Institutes of Health (NIH) to advance biomedical research by providing the scientific community with standardized, high quality phenotyping services for mouse models of diabetes and obesity. Emerging as the next iteration of the MMPC Program which served the biomedical research community for 20 years (2001-2021), MMPCLive is designed as an outwardly-facing consortium of service cores that collaborate to provide reduced-cost consultation and metabolic, physiologic, and behavioral phenotyping tests on live mice for U.S. biomedical researchers. Four MMPCLive Centers located at universities around the country perform complex and often unique procedures in vivo on a fee for service basis, typically on mice shipped from the client or directly from a repository or vendor. Current areas of expertise include energy balance and body composition, insulin action and secretion, whole body carbohydrate and lipid metabolism, cardiovascular and renal function, food intake and behavior, microbiome and xenometabolism, and metabolic pathway kinetics. Additionally, an opportunity arose to reduce barriers to access and expand the diversity of the biomedical research workforce by establishing the VIBRANT Program. Directed at researchers historically underrepresented in the biomedical sciences, VIBRANT-eligible investigators have access to testing services, travel and career development awards, expert advice and experimental design consultation, and short internships to learn test technologies. Data derived from experiments run by the Centers belongs to the researchers submitting mice for testing which can be made publicly available and accessible from the MMPCLive database following publication. In addition to services, MMPCLive staff provide expertise and advice to researchers, develop and refine test protocols, engage in outreach activities, publish scientific and technical papers, and conduct educational workshops and training sessions to aid researchers in unraveling the heterogeneity of diabetes and obesity.

Context The 2 peaks of type 1 diabetes incidence occur during early childhood and puberty. Objective We sought to better understand the relationship between puberty, islet autoimmunity, and type 1 diabetes. Methods The relationships between puberty, islet autoimmunity, and progression to type 1 diabetes were investigated prospectively in children followed in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Onset of puberty was determined by subject self-assessment of Tanner stages. Associations between speed of pubertal progression, pubertal growth, weight gain, homeostasis model assessment of insulin resistance (HOMA-IR), islet autoimmunity, and progression to type 1 diabetes were assessed. The influence of individual factors was analyzed using Cox proportional hazard ratios. Results Out of 5677 children who were still in the study at age 8 years, 95% reported at least 1 Tanner Stage score and were included in the study. Children at puberty (Tanner Stage ≥2) had a lower risk (HR 0.65, 95% CI 0.45-0.93; P = .019) for incident autoimmunity than prepubertal children (Tanner Stage 1). An increase of body mass index Z-score was associated with a higher risk (HR 2.88, 95% CI 1.61-5.15; P < .001) of incident insulin autoantibodies. In children with multiple autoantibodies, neither HOMA-IR nor rate of progression to Tanner Stage 4 were associated with progression to type 1 diabetes. Conclusion Rapid weight gain during puberty is associated with development of islet autoimmunity. Puberty itself had no significant influence on the appearance of autoantibodies or type 1 diabetes. Further studies are needed to better understand the underlying mechanisms.

Objective: We studied if vitamin D intake was associated with risk of IA or progression to T1D and whether single nucleotide polymorphisms (SNP) in vitamin D metabolism genes modify the effect of intake on risk. Methods: We followed 7,520 high risk children from birth until development of IA, defined as persistent GAD65 (GADA), insulin (IAA) and/or IA-2 autoantibodies, and until progression to T1D. Vitamin D intake from foods and supplements was estimated with 3 day food records collected quarterly in the first year and then semi-annually to age 10. We analyzed vitamin D per energy intake in time-dependent Cox proportional hazards models, adjusting for country, sex, T1D family history, HLA, energy, ancestry and seroconversion age (for progression analysis). We tested interactions between intake and 18 SNPs in GC, CYP2R1, CYP24A1, DHCR7 and VDR on risk of IA and progression to T1D using a false discovery rate of <0.05 for significance. Results: Higher vitamin D intake was associated with increased risk of GADA-first, only in those with 2 minor alleles in a SNP in CYP24A1 (which inactivates vitamin D) (Figure). Higher vitamin D intake at seroconversion was associated with decreased risk of progression from IA to T1D, only in those with no minor alleles in SNPs in GC (vitamin D binding protein gene) and VDR (vitamin D receptor gene). Conclusion: Vitamin D intake may have differing effects on risk of IA and T1D, depending on variants in vitamin D genes. Disclosure J.M. Norris: None. J.L. Clasen: None. X. Liu: None. U. Uusitalo: None. C. Andrén Aronsson: None. S. Hummel: None. J. Yang: None. M. Rewers: Advisory Panel; Sanofi. Other Relationship; Sanofi. Consultant; Janssen Pharmaceuticals, Inc. Research Support; Juvenile Diabetes Research Foundation (JDRF). Consultant; Provention Bio, Inc. Research Support; Hemsley Charitable Trust, National Institute of Diabetes and Digestive and Kidney Diseases. R. McIndoe: None. W. Hagopian: Research Support; Janssen Pharmaceuticals, Inc., Provention Bio, Inc. Consultant; Sanofi-Aventis U.S., Randox R & D. A. Ziegler: None. Å. Lernmark: Advisory Panel; DiaMyd Medical AB, Stockholm, Sweden. J. Toppari: None. S.S. Rich: None. S. Onengut-Gumuscu: None. H.M. Parikh: None. I.A.M. Erlund: None. B. Akolkar: None. J. Krischer: None. S. Virtanen: None. Funding NIH NIDDK (U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, UC4 DK100238, UC4 DK106955, UC4 DK112243, UC4 DK117483, U01 DK124166, U01 DK128847, and Contract No. HHSN267200700014C)

The goal of the TEDDY (The Environmental Determinants of Diabetes in the Young) study is to elucidate factors leading to the initiation of islet autoimmunity (first primary outcome) and those related to progression to type 1 diabetes mellitus (T1DM; second primary outcome). This Review outlines the key findings so far, particularly related to the first primary outcome. The background, history and organization of the study are discussed. Recruitment and follow-up (from age 4 months to 15 years) of 8,667 children showed high retention and compliance. End points of the presence of autoantibodies against insulin, GAD65, IA-2 and ZnT8 revealed the HLA-associated early appearance of insulin autoantibodies (1-3 years of age) and the later appearance of GAD65 autoantibodies. Competing autoantibodies against tissue transglutaminase (marking coeliac disease autoimmunity) also appeared early (2-4 years). Genetic and environmental factors, including enterovirus infection and gastroenteritis, support mechanistic differences underlying one phenotype of autoimmunity against insulin and another against GAD65. Infant growth and both probiotics and high protein intake affect the two phenotypes differently, as do serious life events during pregnancy. As the end of the TEDDY sampling phase is approaching, major omics approaches are in progress to further dissect the mechanisms that might explain the two possible endotypes of T1DM.

Objective To study the interaction between HLA genotype, early probiotic exposure, and timing of complementary foods in relation to risk of islet autoimmunity (IA). Research design and methods The TEDDY study prospectively follows 8,676 children with increased genetic risk of type 1 diabetes. We used Cox regression model adjusting for potential confounders to study early feeding and the risk of IA in a sample of 7,770 children Results Any solid food introduced early (<6 months) was associated with increased risk of IA if the child had the HLA DR3/4 genotype and no probiotic exposure during the first year of life. Rice introduced at 4-5.9 months compared to later in the U.S. was associated with increased risk of IA. Conclusions Timing of solid food introduction, including rice, may be associated with IA in HLA DR3/4 children not exposed to probiotics. The microbiome composition under these exposure combinations requires further study.

Background/Objective. Growth and obesity have been associated with increased risk of islet autoimmunity (IA) and progression to type 1 diabetes. We aimed to estimate the effect of energy-yielding macronutrient intake on the development of IA through BMI. Research Design and Methods. Genetically at-risk children (n = 5,084) in Finland, Germany, Sweden, and the USA, who were autoantibody negative at 2 years of age, were followed to the age of 8 years, with anthropometric measurements and 3-day food records collected biannually. Of these, 495 (9.7%) children developed IA. Mediation analysis for time-varying covariates (BMI z-score) and exposure (energy intake) was conducted. Cox proportional hazard method was used in sensitivity analysis. Results. We found an indirect effect of total energy intake (estimates: indirect effect 0.13 [0.05, 0.21]) and energy from protein (estimates: indirect effect 0.06 [0.02, 0.11]), fat (estimates: indirect effect 0.03 [0.01, 0.05]), and carbohydrates (estimates: indirect effect 0.02 [0.00, 0.04]) (kcal/day) on the development of IA. A direct effect was found for protein, expressed both as kcal/day (estimates: direct effect 1.09 [0.35, 1.56]) and energy percentage (estimates: direct effect 72.8 [3.0, 98.0]) and the development of GAD autoantibodies (GADA). In the sensitivity analysis, energy from protein (kcal/day) was associated with increased risk for GADA, hazard ratio 1.24 (95% CI: 1.09, 1.53), p = 0.042 . Conclusions. This study confirms that higher total energy intake is associated with higher BMI, which leads to higher risk of the development of IA. A diet with larger proportion of energy from protein has a direct effect on the development of GADA.

To investigate if inflammatory biomarkers can predict the prognosis of patients in remission with platinum-sensitive high-grade serous ovarian cancer.

Objective: This study investigated physical activity and its association with the development of islet autoimmunity (IA) and type 1 diabetes in genetically at-risk 5-15 year old children. Research Design and Methods: As part of the longitudinal Environmental Determinants of Diabetes in the Young (TEDDY) study, annual assessment of activity using accelerometry was conducted from age 5. Time-to-event analyses using Cox proportional hazard models were used to assess the association between time spent in moderate-to-vigorous physical activity per day and the appearance of one or several autoantibodies and progression to type 1 diabetes in three risk groups: 1) 3869 IA negative children of whom 157 became single IA positive; 2) 302 single IA positive children of whom 73 became multiple IA positive; 3) 294 multiple IA positive children of whom 148 developed type 1 diabetes. Results: No significant association was found in risk group 1 or risk group 2. A significant association was seen in risk group 3 (HR = 0.920, 95% CI 0.856, 0.988 per 10 minutes, p = 0.021), particularly when GADA was the first autoantibody (HR = 0.883, 95% CI 0.783, 0.996 per 10 minutes, p=0.043). Conclusions: More daily minutes spent in moderate-to-vigorous physical activity was associated with a reduced risk of progression to type 1 diabetes in 5-15 year old children who had developed multiple islet autoantibodies.

OBJECTIVE:To determine if inflammatory biomarkers can predict the long-term outcome of platinum therapy in patients with high-grade serous ovarian cancer. METHODS:Women diagnosed with high-grade serous epithelial ovarian cancer (n = 70) at a single institution were enrolled in a prospective serum collection study between 2005 and 2020. Seventeen markers of inflammation and oxidative stress were measured in serum samples on a chemistry analyzer. Association was tested for serum levels with progression-free survival (PFS), time to recurrence (TTR), overall survival (OS), and time to death (TTD) using Cox proportional hazards and Kaplan-Meier curves. Patient survival was censored at 10 years. RESULTS:Higher serum levels of LDH were associated with worse PFS (HR 2.57, p = 0.028). High serum levels of BAP (HR 0.38, p = 0.025), GSP (HR 0.40, p = 0.040), HDL-c (HR 0.27, p = 0.002), and MG (HR 0.36, p = 0.017) were associated with improved PFS. Higher expression of LDH was associated with worse OS (HR 2.16, p = 0.023). Higher levels of CK.nac (HR 0.39, p = 0.033) and HDL-c (HR 0.35, p = 0.029) were associated with improved OS. Similar outcomes were found with TTR and TTD analyses. CONCLUSION:General inflammatory biomarkers may serve as a guide for prognosis and treatment benefit. Future studies needed to further define their role in predicting prognosis or how these markers may affect response to therapy.