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Background: Excessive gestational weight gain (eGWG) increases risk for pregnancy complications and future obesity for pregnant persons and children. Yet, it is unclear whether eGWG leads to higher child adiposity at 2 years, independent of pregnant person's body mass index while considering important covariates. Moreover, understanding the characteristics of pregnant persons experiencing eGWG will help design future targeted interventions., Objective: The objectives of the analyses were to assess the association between eGWG and childhood adiposity at 2-years-old, while controlling for pregnant persons' body mass index (BMI) and other important covariates and to describe the characteristics of pregnant persons who experience eGWG during their second pregnancy., Design: This is a secondary analysis of 221 pregnant persons and their 2-year-old children who were enrolled in the Glowing longitudinal observational study., Participants/setting: Participants were recruited between 2011- 2014 in central Arkansas. Participants were secundigravida persons with BMIs 18.5-35kg/m2, >20 years old, and who conceived without assistance., Main Outcome Measures: The main outcome measure was 2-year-old fat mass index measured by quantitative nuclear magnetic resonance. Secondary outcomes included: first pregnancy gestational weight gain (GWG), dietary and physical activity characteristics in between pregnancies, second pregnancy nausea levels, and motivation level to adhere to the GWG guidelines., Statistical Analysis Performed: Multivariable regression analyses were used to examine the associations between GWG and childhood fat mass index at 2 years of age. Pearson correlations and Wilcoxon rank sum tests were used to identify the characteristics of pregnant persons who experienced eGWG., Results: Pregnant persons' eGWG (β = 0.503, P =0.03) was positively associated with child adiposity at age 2 years independent of maternal BMI (P = 0.3). Pregnant persons who experienced eGWG during their second pregnancy had greater odds of: eGWG in first pregnancies (OR = 7.5; P <0.001), dieting behavior (OR = 14.3; P =0.02), and low motivation to adhere to the GWG guidelines (OR = 11.2; P =0.009). Fewer participants had eGWG in their second pregnancy (52.5 %) compared to their first pregnancy (66.8%) which was different by BMI groups (BMI 18.5-24.9 kg/m2: 23.6% decrease in participants who gained eGWG, BMI 25-29.9 kg/m2: 20.0% decrease, and BMI ≥ 30 kg/m2: 37.9% decrease)., Conclusions: EGWG among pregnant persons is associated with child adiposity at age 2-years. Pregnant persons who experienced eGWG during their second pregnancy reported low motivation to gain weight within guidelines, eGWG in first pregnancy, and reported prior dieting behavior. Future research focusing on patients with these characteristics may increase success of interventions designed to limit eGWG., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Clustering of cardiometabolic risk factors in childhood significantly increases the risk of atherosclerotic cardiovascular disease later in life. Identification of modifiable parental factors that contribute to offspring cardiometabolic health is critical for the prevention of disease. The objective was to identify factors associated with child cardiometabolic risk factors at age 5 years., Methods: Triads from a longitudinal cohort were recalled at 5 years (n = 68). Dietary intake, anthropometrics, physical activity and serum-based risk factors were collected. Best subset selection, linear and logistic regressions were used to identify triad variables associated with increased risk of cardiometabolic risk factor clustering at age 5 years., Results: In this cohort, best subset modelling revealed that increased paternal fat mass, serum low-density lipoproteins and triglycerides, maternal dietary added sugar and being female were associated with increased odds of offspring having two or more cardiometabolic risk factors at age 5 years., Conclusions: Dietary and exercise interventions prior to conception targeting paternal adiposity and dyslipidaemia as well as maternal dietary habits could decrease children's cardiometabolic risk in later life., (© 2024 World Obesity Federation.)

Background: Direct peritoneal resuscitation (DPR) is associated with improved outcomes in trauma. Animal models suggest DPR has favorable effects on the liver. We sought to evaluate its safety and assess for improved outcomes in liver transplantation (LT)., Methods: LT patients with renal dysfunction and/or obesity were enrolled in a phase-I clinical trial. DPR lasted 8-24 ​h depending on postoperative disposition. Primary outcome was percent of patients completing DPR. Secondary outcomes evaluated complications. Controls with either obesity (control-1) or both risk factors (obesity ​+ ​renal dysfunction, control-2) were analyzed., Results: Fifteen patients were enrolled (seven with both criteria and eight with obesity alone). DPR was completed in 87 ​% of patients, with one meeting stopping criteria. Controls included 45 (control-1) and 24 (control-2) patients. Return to operating room, graft loss, and late infections were lower with DPR., Conclusion: DPR appears to be safe in closed abdomens following LT, warranting a follow-up phase-II trial to assess efficacy., Competing Interests: Declaration of competing interest Hunter B. Moore has issued patent for the tPA-TEG that is licensed through the University of Colorado. All other authors have no conflicts to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Maternal obesity is associated with increased concentrations of human milk (HM) obesogenic hormones, pro-inflammatory cytokines, and oligosaccharides (HMOs) that have been associated with infant growth and adiposity. The objective of this pilot study was to determine if adherence to a Mediterranean meal plan during lactation modulates macronutrients and bioactive molecules in human milk from mothers with obesity., Methods: Sixteen healthy, exclusively breastfeeding women with obesity (body mass index ≥30 kg/m 2 ) enrolled between 4 and 5 months postpartum. The women followed a 4-week Mediterranean meal plan which was provided at no cost. Maternal and infant anthropometrics, HM composition, and infant intakes were measured at enrollment and at weeks 2 and 4 of the intervention. Thirteen mother-infant dyads completed the study. Additionally, participants from an adjacent, observational cohort who had obesity and who collected milk at 5 and 6 months postpartum were compared to this cohort., Results: Participants' healthy eating index scores improved (+27 units, p  < 0.001), fat mass index decreased (-4.7%, p  < 0.001), and daily energy and fat intake were lower (-423.5 kcal/day, p < 0.001 and-32.7 g/day, p  < 0.001, respectively) following the intervention. While HM macronutrient concentrations did not change, HM leptin, total human milk oligosaccharides (HMOs), HMO-bound fucose, Lacto-N-fucopentaose (LNFP)-II, LNFP-III, and difucosyllacto-N-tetrose (DFLNT) concentrations were lower following the intervention. Infant intakes of leptin, tumor necrosis factor (TNF)-α, total HMOs, HMO-bound fucose, LNFP-III and DFLNT were lower following the intervention. Specific components of the maternal diet (protein and fat) and specific measures of maternal diet quality (protein, dairy, greens and beans, fruit and vegetables) were associated with infant intakes and growth., Discussion: Adherence to a Mediterranean meal plan increases dietary quality while reducing total fat and caloric intake. In effect, body composition in women with obesity improved, HM composition and infants' intakes were modulated. These findings provide, for the first time, evidence-based data that enhancing maternal dietary quality during lactation may promote both maternal and child health. Longer intervention studies examining the impact of maternal diet quality on HM composition, infant growth, and infant development are warranted., Competing Interests: JLS is an editorial board member of Frontiers in Pediatrics – Pediatric Obesity. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Sims, Saben, Martinez, Sobik, Crimmins, Bulmanski, Turner, Furst, Jansen, Bode and Andres.)

Competing Interests: The authors declare no conflicts of interest.

Background: Pneumonia is associated with increased morbidity and costs in the intensive care unit (ICU). Its early identification is key for optimal outcomes, but early biomarkers are lacking. Studies suggest that fibrinolysis resistance (FR) after major abdominal surgery is linked to an increased risk of infection. Patients and Methods: Patients in a randomized controlled trial for hemorrhagic shock were evaluated for FR. Fibrinolysis resistance was quantified by thrombelastography with exogenous tissue plasminogen activator (tPA-TEG) at 24- and 48-hours post-injury and measuring LY30 (%). A receiver-operating characteristics (ROC) curve analysis was used to identify a cutoff for increased risk of pneumonia, which was then validated in ICU patients at risk for venous thromboembolism (VTE). Multivariable logistic regression was used to control for confounders. Results: Forty-nine patients in the hemorrhagic shock cohort had tPA-TEGs at 24- and 48-hours (median ISS, 27; 7% pneumonia). A composite tPA-TEG LY30 of less than 4% at 24 and 48 hours was found to be the optimal cutoff for increased risk of pneumonia. This cohort had a seven-fold increased rate of pneumonia (4% vs. 28%; p = 0.048). Eighty-eight patients in the VTE cohort had tPA-TEGs at 24 and 48 hours post-ICU admission (median ISS, 28; 6% pneumonia). The tPA-TEG LY30 of less than 4% was associated with a 10-fold increased rate of pneumonia (19% vs. 1.5%; p = 0.002). In patients with traumatic brain injury, the same association was found (33% vs. 3.2%; p = 0.006). Adjusting for confounders, the tPA-TEG persisted as a substantial risk factor for pneumonia (adjusted odds ratio [OR], 35.7; 95% confidence interval [CI], 1.9-682; p = 0.018). Conclusions: Fibrinolysis resistance quantified by tPA-TEG within 48 hours of ICU admission is associated with an increased risk of pneumonia in patients in hemorrhagic shock and those at risk for VTE. Prospective validation of the tPA-TEG LY30 optimal cutoff for pneumonia and further investigation into whether endogenous FR is a cause of an altered immunity is warranted.

Background: The number of simultaneous liver-kidney (SLK) transplants has significantly increased in the United States. There has also been an increase in kidney-after-liver transplants associated with 2017 policy revisions aimed to fairly allocate kidneys after livers. SLK and kidney-after-liver candidates are prioritized in allocation policy for kidney offers ahead of kidney-alone candidates., Methods: We compared kidney graft outcomes of kidney-alone transplant recipients with SLK and kidney-after-liver transplants using paired kidney models to mitigate differences among donor risk factors. We evaluated recipient characteristics between transplant types and calculated differential graft years using restricted mean survival estimates., Results: We evaluated 3053 paired donors to kidney-alone and SLK recipients and 516 paired donors to kidney-alone and kidney-after-liver recipients from August 2017 to August 2022. Kidney-alone recipients were younger, more likely on dialysis, and Black race. One-year and 3-year post-transplant kidney graft survival for kidney-alone recipients was 94% and 86% versus SLK recipients 89% and 80%, respectively, P < 0.001. One-year and 3-year kidney graft survival for kidney-alone recipients was 94% and 84% versus kidney-after-liver recipients 93% and 87%, respectively, P = 0.53. The additional kidney graft years for kidney-alone versus SLK transplants was 21 graft years/100 transplants (SEM=5.0) within 4 years post-transplantation, with no significant difference between kidney-after-liver and kidney-alone transplants., Conclusions: Over a 5-year period in the United States, SLK transplantation was associated with significantly lower kidney graft survival compared with paired kidney-alone transplants. Most differences in graft survival between SLK and kidney-alone transplants occurred within the first year post-transplantation. By contrast, kidney-after-liver transplants had comparable graft survival with paired kidney-alone transplants., (Copyright © 2023 by the American Society of Nephrology.)

Competing Interests: The authors declare no funding or conflicts of interest.

Introduction: Currently in the United States, deceased donor liver transplant (DDLT) allocation priority is based on the model for end-stage liver disease including sodium (MELD-Na) score. The United Network for organ sharing's 'Share-15' policy states that candidates with MELD-Na scores of 15 or greater have priority to receive local organ offers compared to candidates with lower MELD-Na scores. Since the inception of this policy, major changes in the primary etiologies of end-stage liver disease have occurred and previous assumptions need to be recalibrated., Methods: The authors retrospectively analyzed the Scientific Registry of Transplant Recipients database between 2012 and 2021 to determine life years saved by DDLT at each interval of MELD-Na score and the time-to-equal risk and time-to-equal survival versus remaining on the waitlist. The authors stratified our analysis by MELD exception points, primary disease etiology, and MELD score., Results: On aggregate, compared to remaining on the waitlist, a significant 1-year survival advantage of DDLT at MELD-Na scores as low as 12 was found. The median life years saved at this score after a liver transplant was estimated to be greater than 9 years. While the total life years saved were comparable across all MELD-Na scores, the time-to-equal risk and time-to-equal survival decreased exponentially as MELD-Na scores increased., Conclusion: Herein, the authors challenge the perception as to the timing of DDLT and when that benefit occurs. The national liver allocation policy is transitioning to a continuous distribution framework and these data will be instrumental to defining the attributes of the continuos allocation score., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

On July 14, 2022, the Organ Procurement and Transplantation Network's (OPTN) Membership and Professional Standards Committee (MPSC) approved bylaws including two new post-transplant performance evaluation metrics, the 90-day (90D) and 1-year conditional on the 90-day (1YC90D) graft survival hazard ratio (HR). These metrics have replaced the previous 1-year (1Y) unconditional, post-transplant graft survival HR and are used to nationally rank and identify programs for MPSC review. The MPSC's policies have major implications for all transplant programs, providers, and patients across the United States. Herein we show two significant limitations with the new evaluation criteria, arbitrary censoring periods and interdependence in the new performance metrics. We have demonstrated a strong and consistent inverse correlation between the new evaluation metrics, thus proving a lack of independence. Moreover, these two evaluation criteria are interdependent even at nominal HRs. Thus, the 90D cohort can be used to accurately predict whether the 1YC90D is above or below a given HR threshold. This could alter practice behaviors and the timing of patient event reporting, which may result in many unintended consequences related to clinical practice. Here we provide the first evidence that this new evaluation system will lead to a significant increase in the number of programs flagged for MPSC review. When this occurs, the cost of operating a transplant program will increase without a clear demonstration of an increased accuracy in identifying problematic programs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Malamon, Ho, Jackson, Saben, Schold, Pomposelli, Pomfret and Kaplan.)

Background: The estimated long-term survival (EPTS) score is used for kidney allocation. A comparable prognostic tool to accurately quantify EPTS benefit in deceased donor liver transplant (DDLT) candidates is nonexistent., Methods: Using the Scientific Registry of Transplant Recipients (SRTR) database, we developed, calibrated, and validated a nonlinear regression equation to calculate liver-EPTS (L-EPTS) for 5- and 10-year outcomes in adult DDLT recipients. The population was randomly split (70:30) into two discovery (N = 26,372 and N = 46,329) and validation cohorts (N = 11,288 and N = 19,859) for 5- and 10-year post-transplant outcomes, respectively. Discovery cohorts were used for variable selection, Cox proportional hazard regression modeling, and nonlinear curve fitting. Eight clinical variables were selected to construct the L-EPTS formula, and a five-tiered ranking system was created., Findings: Tier thresholds were defined and the L-EPTS model was calibrated (R 2  = 0.96 [5-year] and 0.99 [10-year]). Patients' median survival probabilities in the discovery cohorts for 5- and 10-year outcomes ranged from 27.94% to 89.22% and 16.27% to 87.97%, respectively. The L-EPTS model was validated via calculation of receiver operating characteristic (ROC) curves using validation cohorts. Area under the ROC curve was 82.4% (5-year) and 86.5% (10-year)., Interpretation: L-EPTS has high applicability and clinical utility because it uses easily obtained pre-transplant patients characteristics to accurately discriminate between those who are likely to receive a prolonged survival benefit and those who are not. It is important to evaluate medical urgency alongside survival benefit and placement efficiency when considering the allocation of a scarce resource., Funding: There are no funding sources related to this project., Competing Interests: Declaration of interests No funding was used to support this work. The authors of this manuscript have no conflicts of interest to disclose as described by eBioMedicine., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Solid organ transplantation (SOT) recipients are known to carry an increased risk of malignancy because of long-term immunosuppression. However, the progression of intraductal papillary mucinous neoplasm of the pancreas (IPMN) in this population remains unclear. We performed a systematic review by searching PubMed, Embase, Scopus, and Google Scholar. All studies containing IPMNs in solid organ transplantation recipients were screened. We included 11 studies in our final analysis, totaling 274 patients with IPMNs of the 8213 SOT recipients. The prevalence from 8 studies was 4.7% (95% CI 2.4%-7.7%) in a random-effects model with median study periods of 24 to 220 months. The median rate for all progressions from 10 studies was 20% (range, 0%-88%) within 13 to 41 months of the median follow-up time. By utilizing the results of 3 case-control studies, the relative risk from a random-effects model for progression (worrisome features and high-risk stigmata) of IPMNs was 0.39 (95% CI 0.12-1.31). No adenocarcinoma derived from IPMN was reported in the included studies. Overall, this study indicates that the progression of pretransplant IPMN does not increase drastically compared with the general nontransplant population. However, considering the limited literature, further studies are required for confirmation., (Copyright © 2022 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Living donor liver transplantation (LDLT) can help address the growing organ shortage in the United States, yet little is known about the current practice patterns in the medical evaluation of living liver donors. We conducted a 131-question survey of all 53 active LDLT transplant programs in the United States to assess current LDLT practices. The response rate was 100%. Donor acceptance rate was 0.33 with an interquartile range of 0.33-0.54 across all centers. Areas of high intercenter agreement included minimum age cutoff of 18 years (73.6%) and the exclusion of those with greater than Class 1 obesity (body mass index, 30.0-34.9 m/kg 2 ) (88.4%). Diabetes mellitus was not an absolute exclusion at most centers (61.5%). Selective liver biopsies were performed for steatosis or iron overload on imaging (67.9% and 62.3%, respectively) or for elevated liver enzymes (60.4%). Steatohepatitis is considered an exclusion at most centers (84.9%). The most common hypercoagulable tests performed were factor V Leiden (FVL) (88.5%), protein C (73.1%), protein S (71.2%), antithrombin III (71.2%) and prothrombin gene mutation (65.4%). At 41.5% of centers, donors were allowed to proceed with donation with FVL heterozygote status. Most programs discontinue oral contraceptive pills at least 28 days prior to surgery. At most centers, the need for cardiovascular ischemic risk testing is based on age (73.6%) and the presence of one or more cardiac risk factors (68.0%). Defining areas of practice consensus and variation underscores the need for data generation to develop evidence-based guidance for the evaluation and risk assessment of living liver donors., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Importance: Despite the acceptance of living-donor liver transplant (LDLT) as a lifesaving procedure for end-stage liver disease, it remains underused in the United States. Quantification of lifetime survival benefit and the Model for End-stage Liver Disease incorporating sodium levels (MELD-Na) score range at which benefit outweighs risk in LDLT is necessary to demonstrate its safety and effectiveness., Objective: To assess the survival benefit, life-years saved, and the MELD-Na score at which that survival benefit was obtained for individuals who received an LDLT compared with that for individuals who remained on the wait list., Design, Setting, and Participants: This case-control study was a retrospective, secondary analysis of the Scientific Registry of Transplant Recipients database of 119 275 US liver transplant candidates and recipients from January 1, 2012, to September 2, 2021. Liver transplant candidates aged 18 years or older who were assigned to the wait list (N = 116 455) or received LDLT (N = 2820) were included. Patients listed for retransplant or multiorgan transplant and those with prior kidney or liver transplants were excluded., Exposures: Living-donor liver transplant vs remaining on the wait list., Main Outcomes and Measures: The primary outcome of this study was life-years saved from receiving an LDLT. Secondary outcomes included 1-year relative mortality and risk, time to equal risk, time to equal survival, and the MELD-Na score at which that survival benefit was obtained for individuals who received an LDLT compared with that for individuals who remained on the wait list. MELD-Na score ranges from 6 to 40 and is well correlated with short-term survival. Higher MELD-Na scores (>20) are associated with an increased risk of death., Results: The mean (SD) age of the 119 275 study participants was 55.1 (11.2) years, 63% were male, 0.9% were American Indian or Alaska Native, 4.3% were Asian, 8.2% were Black or African American, 15.8% were Hispanic or Latino, 0.2% were Native Hawaiian or Other Pacific Islander, and 70.2% were White. Mortality risk and survival models confirmed a significant survival benefit for patients receiving an LDLT who had a MELD-Na score of 11 or higher (adjusted hazard ratio, 0.64 [95% CI, 0.47-0.88]; P = .006). Living-donor liver transplant recipients gained an additional 13 to 17 life-years compared with patients who never received an LDLT., Conclusions and Relevance: An LDLT is associated with a substantial survival benefit to patients with end-stage liver disease even at MELD-Na scores as low as 11. The findings of this study suggest that the life-years gained are comparable to or greater than those conferred by any other lifesaving procedure or by a deceased-donor liver transplant. This study's findings challenge current perceptions regarding when LDLT survival benefit occurs.

Background: Branched-chain amino acids (BCAAs: isoleucine, leucine, and valine) and aromatic amino acids (AAAs: phenylalanine and tyrosine) are hypothesized to influence early-life obesity risk., Objective: To assess HM free amino acid (AA) concentrations and infant intakes of HM AAs from women with obesity (OB) compared to those with normal weight (NW) and determine the relationships between HM AA consumption and infant growth., Methods: HM samples were collected at 0.5 (n = 151), 2 (n = 129), and 6 (n = 93) months postpartum from mothers with NW (body mass index [BMI] = 18.5-24.9 kg/m 2 ) and OB (BMI > 30 kg/m 2 ). HM AAs were quantified via mass spectrometry. Infant HM intake, anthropometrics and body composition were assessed. Linear mixed-effects models (LMEM) examined the relationships between maternal BMI and HM AA intakes, and HM AA intake and infant growth over the first 6 months postpartum after adjusting for maternal and infant characteristics., Results: Maternal BMI was positively associated with infant intakes of isoleucine, leucine, and AAAs across timepoints. HM AA intakes were positively associated with weight-for-length z-score, fat mass index, and fat-free mass index in infants (p < 0.05)., Conclusions: Maternal BMI led to differences in HM AA composition, which was associated with infant body composition., (© 2021 World Obesity Federation.)

Objective: To identify single nucleotide variants (SNVs) associated with lisinopril effectiveness., Materials and Methods: This was an observational study using a candidate gene approach to examine SNVs associated with lisinopril effectiveness. Drug effectiveness was defined as 10% decrease in systolic blood pressure at 1 week follow-up. We used the Illumina GWAS MEGA chip to examine variants in the renin/angiotensin pathway that may be associated with drug effectiveness., Results: 61 subjects were enrolled, and 33 (54.1%) were responsive to lisinopril therapy. SNVs in AGT (p = 0.0141), REN (p = 0.0192), and ACE2 (p = 0.0002) were found to be associated with successful treatment on lisinopril. Conclusion and relevance: SNVs in the renin and angiotensin pathway are associated with lisinopril effectiveness in a pilot cohort of patients with uncontrolled hypertension.

Human milk oligosaccharides (HMOs) are bioactive molecules playing a critical role in infant health. We aimed to quantify the composition of HMOs of women with normal weight (18.5-24.9 kg/m 2 ), overweight (25.0-29.9 kg/m 2 ), or obesity (30.0-60.0 kg/m 2 ) and determine the effect of HMO intake on infant growth. Human milk (HM) samples collected at 2 months (2 M; n = 194) postpartum were analyzed for HMO concentrations via high-performance liquid chromatography. Infant HM intake, anthropometrics and body composition were assessed at 2 M and 6 M postpartum. Linear regressions and linear mixed-effects models were conducted examining the relationships between maternal BMI and HMO composition and HMO intake and infant growth over the first 6 M, respectively. Maternal obesity was associated with lower concentrations of several fucosylated and sialylated HMOs and infants born to women with obesity had lower intakes of these HMOs. Maternal BMI was positively associated with lacto-N-neotetraose, 3-fucosyllactose, 3-sialyllactose and 6-sialyllactose and negatively associated with disialyllacto-N-tetraose, disialyllacto-N-hexaose, fucodisialyllacto-N-hexaose and total acidic HMOs concentrations at 2 M. Infant intakes of 3-fucosyllactose, 3-sialyllactose, 6-sialyllactose, disialyllacto-N-tetraose, disialyllacto-N-hexaose, and total acidic HMOs were positively associated with infant growth over the first 6 M of life. Maternal obesity is associated with changes in HMO concentrations that are associated with infant adiposity.

Background: Human milk composition is altered by maternal obesity. The association between milk metabolites and infant outcomes has not been thoroughly investigated., Objectives: This study aimed to quantify maternal adiposity-related differences in the human milk metabolome and to identify metabolites associated with infant adiposity during the first 6 mo postpartum using untargeted metabolomics., Method: Maternal anthropometrics were assessed ≤14 weeks of gestation. Human milk samples were collected at 0.5 mo (n = 159), 2 mo (n = 131), and 6 mo (n = 94) postpartum from normal weight (NW, BMI = 18.5-24.9 kg/m2) and obese (OB, BMI >30 kg/m2) mothers. GC-time-of-flight-MS was used to identify metabolic signatures that discriminate NW and OB women. Partial least squared (PLS)-discriminant analysis, and PLS-regression models were assessed to examine relations between metabolites and maternal BMI and fat mass. Metabolites altered by maternal obesity were used in linear mixed effect models to predict infant adiposity., Results: Multivariate modeling identified 23, 17, and 10 metabolites that described maternal adiposity indices at 0.5 mo, 2 mo, and 6 mo postpartum, respectively. Monosaccharides and sugar alcohols were the most representative annotated metabolite classes that were increased in milk from OB women and included: mannose, ribose, lyxose, lyxitol (0.5 mo); mannose, ribitol, glycerol, isothreonic acid, lyxitol (2 mo); lyxitol and isothreonic acid (6 mo). Other discriminant metabolites included: 1-monostearin, xylonolactone, shikimic acid, pseudo uridine, and dodecanol (0.5 mo); N-acetyl-D-hexosamine and fumaric acid (2 mo); uric acid and tyrosine (6 mo). Mannose, lyxitol, and shikimic acid predicted higher infant adiposity over the first 6 mo of life., Conclusions: This study reports on 1 of the largest cohorts to date examining the metabolic profiles in human milk comparing NW and OB women. Maternal adiposity was associated with increased amounts of milk nonglucose monosaccharides. Human milk metabolomics may be useful in predicting infant adiposity. These trials were registered at www.clinicaltrials.gov as NCT01131117 and NCT02125149., (Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.)

Human milk oligosaccharides (HMOs) are bioactive molecules in human milk that play a critical role in infant health. Obesity and associated metabolic aberrations can negatively impact lactation and alter milk composition. Here, the relationship between maternal glucose homeostasis and HMO composition from 136 healthy women was examined. Maternal glucose homeostasis (fasting plasma glucose and insulin, homeostatic model assessment for insulin resistance, and insulin sensitivity index) was evaluated at 30 weeks of gestation in healthy women (body mass index = 18.5-35 kg/m 2 ). Human milk samples were collected at two months postpartum. HMO concentrations were measured via high performance liquid chromatography. Women were categorized into "secretor" and "non-secretor" groups based on 2'-Fucosyllactose concentrations (<100 nmol/mL, non-secretor). Pearson's correlation analysis and linear models were used to assess the relationships between maternal glucose homeostasis and HMO concentrations. In non-secretors, third trimester fasting plasma glucose and insulin were negatively associated with total HMO-bound sialic acid and concentrations of the sialylated HMOs 3'-sialyllactose and disialylacto-N-tetraose. In secretors, difucosyllactose and lacto-N-fucopentaose-II concentrations increased and sialyllacto-N-tetraose c and sialyllacto-N-tetraose b decreased as insulin sensitivity increased. This study is the first to demonstrate a relationship between obesity-associated maternal factors and HMO composition in both secretor and non-secretor populations.

Background: Cannabis (MJ) policy liberalization in a majority of US states has impacted emergency department (ED) visits. It is important to understand why people come to the ED after using MJ because the drug is now available to experienced and naïve people across the country. The objectives of this study were to (1) improve upon administrative dataset methodology by performing additional chart review to describe ED visits related to cannabis, (2) understand why patients come to the ED after using cannabis, and (3) begin to inform our understanding of cannabis-attributable ED visits to start to educate patients and providers about cannabis' safety. Methods: We performed a retrospective chart review of ED visits identified by cannabis ICD-9 and 10-CM codes between 2012 and 2016. Visits were reviewed and determined if the visit was partially attributable to cannabis based upon a pre-specified definition, then categorized into clinical complaint categories. Descriptive statistics, Chi-Square, and T-tests were used to elucidate the data. Results: About one-fourth (25.74%) of visits with cannabis ICD-CM codes were found to be at least partially attributable to cannabis. These patients are more often young, Caucasian males when compared to the overall ED population ( p  < .0001). Patients with a cannabis-attributable visit were more often admitted to the hospital ( p  < .0001). The most common complaints in cannabis-attributable visits were gastrointestinal and psychiatric complaints, as well as intoxication. The number of cannabis-attributable visits rose with time ( p =.012). Conclusions: Based on a pre-specified definition, with good inter-rater reliability, we found that 25% of visits with a cannabis ICD-CM code were partially attributable to cannabis. These findings represent areas to target in cannabis user education as public perceptions change across time.

Bone mass and quality in humans are controlled by numerous genetic and environmental factors that are not fully understood. Increasing evidence has indicated that maternal metabolic dysregulation impairs multiple physiological processes in the adult offspring, but a similar effect on bone health is yet to be established. Here, we have analyzed the bones of first-generation offspring from murine dams that present metabolic syndrome due to a high-fat and high-sugar (HF/HS) diet. Micro-CT analyses show that the long bones of HF/HS offspring possess lower cortical bone mass and weaker mechanical strength than normal, even though the trabecular bone is not affected. Histomorphometry and serum biochemistry indicate that both bone formation and resorption are diminished in the HF/HS offspring. In vitro, both osteoblast and osteoclast progenitors from the HF/HS offspring are deficient in differentiation, likely due to impairment of mitochondrial respiration. The study, therefore, identifies maternal metabolic health as an important environmental factor influencing bone volume and strength., (© Endocrine Society 2020.)

Introduction: Only ~ 50% of hypertensive patients will respond to treatment., Objective: This pilot study aims to identify clinical and metabolite markers that predict response to lisinopril., Methods: Hypertensive patients (n = 45) received lisinopril (10 mg) at their baseline visit. Blood pressures were reevaluated one week later. Responders to lisinopril (n = 19) were defined by a 10% decline in systolic blood pressure. Plasma metabolites were evaluated with mass spectrometry., Results: BMI (p = 0.009), GFR (p = 0.015) and 2-oxoglutarate were included in a logistic regression model to predict response to lisinopril., Conclusions: Further validation cohorts are needed to confirm the predictive values of these clinical and metabolic markers.

The Emergency Medicine Specimen Bank (EMSB) was developed to facilitate precision medicine in acute care. The EMSB is a biorepository of clinical health data and biospecimens collected from all adult English- or Spanish-speaking individuals who are able and willing to provide consent and are treated at the UCHealth-University of Colorado Hospital Emergency Department. The EMSB is the first acute care biobank that seeks to enroll all patients, with all conditions who present to the ED. Acute care biobanking presents many challenges that are unique to acute care settings such as providing informed consent in a uniquely stressful and fast-paced environment and collecting, processing, and storing samples for tens of thousands of patients per year. Here, we describe the process by which the EMSB overcame these challenges and was integrated into clinical workflow allowing for operation 24 hours a day, 7 days a week at a reasonable cost. Other institutions can implement this template, further increasing the power of biobanking research to inform treatment strategies and interventions for common and uncommon phenotypes in acute care settings., (© 2018 by the Society for Academic Emergency Medicine.)

Recent human and animal studies investigating the roles of the genome, epigenome, and environmental cues have identified associations between offspring predisposition to life-long obesity/metabolic disease and epigenetic modifications such as DNA methylation. This review explores the mechanisms by which maternal exposures impair the health of not only the next generation but also potentially future generations of offspring., (©2017 Int. Union Physiol. Sci./Am. Physiol. Soc.)

Maternal obesity impairs offspring health, but the responsible mechanisms are not fully established. To address this question, we fed female mice a high-fat/high-sugar diet from before conception until weaning and then followed the outcomes in the next three generations of offspring, all fed a control diet. We observed that female offspring born to obese mothers had impaired peripheral insulin signaling that was associated with mitochondrial dysfunction and altered mitochondrial dynamic and complex proteins in skeletal muscle. This mitochondrial phenotype persisted through the female germline and was passed down to the second and third generations. Our results indicate that maternal programming of metabolic disease can be passed through the female germline and that the transfer of aberrant oocyte mitochondria to subsequent generations may contribute to the increased risk for developing insulin resistance., (Copyright © 2016. Published by Elsevier Inc.)

Study Question: What effect does diet-induced obesity have on endometrial stromal cell (ESC) decidualization?, Summary Answer: Diet-induced obesity impairs ESC decidualization., What Is Known Already: Decidualization is important for successful implantation and subsequent health of the pregnancy. Compared with normal-weight women, obese women have lower pregnancy rates (both spontaneous and by assisted reproductive technology), higher rates of early pregnancy loss and poorer oocyte quality., Study Design, Size, Duration: Beginning at 6 weeks of age, female C57Bl/6J mice were fed either a high-fat/high-sugar diet (HF/HS; 58% Fat Energy/Sucrose) or a diet of standard mouse chow (CON; 13% Fat) for 12 weeks. At this point, metabolic parameters were measured. Some of the mice (n = 9 HF/HS and 9 CON) were mated with reproductively competent males, and implantation sites were assessed. Other mice (n = 11 HF/HS and 10 CON) were mated with vasectomized males, and artificial decidualization was induced. For in vitro human studies of primary ESCs, endometrial tissue was obtained via biopsy from normo-ovulatory patients without history of infertility (obese = BMI > 30 kg/m(2), n = 11 and lean = BMI < 25 kg/m(2), n = 7) and from patients consented for hysterectomies for a benign indication (n = 4). In vitro studies were also performed with immortalized human ESCs. ESCs were decidualized in culture for nine 9 days in the presence or absence of palmitic acid (PA), and the degree of decidualization was assessed by measuring expression of decidualization markers., Participants/materials, Setting, Methods: The sizes of implantation sites and fetuses were analyzed in mice mated with reproductively competent males. In mice mated with vasectomized males, decidualization was induced, and uterine tissues were analyzed via hematoxylin and eosin staining, quantitative RT-PCR (RT-qPCR), and western blots. Human ESCs were cultured in vitro and induced to decidualize by treatment with cAMP and medroxyprogesterone. The level of expression of decidualization markers was assessed by RT-qPCR (mRNA) and western blotting (protein). ATP content of ESCs was measured, and levels of autophagy were assessed by western blotting of the autophagy regulators acetyl coa carboxylase (ACC) and ULK1 (Ser 317). Autophagic flux was measured by western blot of the marker LC3b-II., Main Results and the Role of Chance: Mice exposed to an HF/HS diet became obese and metabolically impaired. HF/HS-exposed mice mated to reproductively competent males had smaller implantation sites in early pregnancy (P <0.001) and larger fetuses at term (P <0.05) than CON-exposed mice. In the artificial decidualization experiments, mice exposed to the HF/HS diet developed 50% smaller deciduomas than mice exposed to CON diet (P< 0.001). Human ESCs cultured in the presence of PA had markedly decreased mRNA expression of the decidualization markers, decidual prolactin (PRL) (P< 0.0001) and insulin-like growth factor binding protein 1 (IGFBP1) (P< 0.0001). Expression of PRL and IGFBP1 by mRNA were also significantly lower in early follicular phase ESCs of obese women than in those of normal-weight women (P< 0.05). Protein expression of phosphorylated ACC and phosphorylated ULK1, both activated forms, were lower in deciduomas of HF/HS mice than in those of control mice (P < 0.01). In immortalized human ESCs, LC3b-II levels were higher in decidualized cells than in controls, indicating increased autophagy. PA treatment abrogated this increase., Limitations, Reasons for Caution: Many aspects of obesity and metabolic impairment could contribute to the decidualization defects observed in the HF/HS-exposed mice. Although our findings suggest that both autophagy and decidualization are impaired by exposure to PA, the underlying mechanisms should be elucidated. Finally, our human patient sample size was small., Wider Implications of the Findings: Although many factors contribute to poor reproductive outcome and early pregnancy loss in obese women, our study suggests the importance of decidualization defects. Such defects may contribute to compromised endometrial receptivity and poor implantation. If defects in autophagy contribute to impaired decidualization, therapeutics could be developed to improve this process and thus improve implantation and pregnancy outcomes in obese women., Study Funding/competing Interests: Grants include NIH 5T32HD040135-12 (J.S.R.), R01 HD065435 (K.H.M.), NIH T32 HD049305 (J.L.S.) and ACOG Research Grant (M.B.S.). The authors report no conflicts of interest., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Maternal metabolic diseases increase offspring risk for low birth weight and cardiometabolic diseases in adulthood. Excess fructose consumption may confer metabolic risks for both women and their offspring. However, the direct consequences of fructose intake per se are unknown. We assessed the impact of a maternal high-fructose diet on the fetal-placental unit in mice in the absence of metabolic syndrome and determined the association between maternal serum fructose and placental uric acid levels in humans. In mice, maternal fructose consumption led to placental inefficiency, fetal growth restriction, elevated fetal serum glucose and triglyceride levels. In the placenta, fructose induced de novo uric acid synthesis by activating the activities of the enzymes AMP deaminase and xanthine oxidase. Moreover, the placentas had increased lipids and altered expression of genes that control oxidative stress. Treatment of mothers with the xanthine oxidase inhibitor allopurinol reduced placental uric acid levels, prevented placental inefficiency, and improved fetal weights and serum triglycerides. Finally, in 18 women delivering at term, maternal serum fructose levels significantly correlated with placental uric acid levels. These findings suggest that in mice, excess maternal fructose consumption impairs placental function via a xanthine oxidase/uric acid-dependent mechanism, and similar effects may occur in humans.

The most significant increase in metabolic syndrome over the previous decade occurred in women of reproductive age, which is alarming given that metabolic syndrome is associated with reproductive problems including subfertility and early pregnancy loss. Individuals with metabolic syndrome often consume excess fructose, and several studies have concluded that excess fructose intake contributes to metabolic syndrome development. Here, we examined the effects of increased fructose consumption on pregnancy outcomes in mice. Female mice fed a high-fructose diet (HFrD) for 6 weeks developed glucose intolerance and mild fatty liver but did not develop other prominent features of metabolic syndrome such as weight gain, hyperglycemia, and hyperinsulinemia. Upon mating, HFrD-exposed mice had lower pregnancy rates and smaller litters at midgestation than chow-fed controls. To explain this phenomenon, we performed artificial decidualization experiments and found that HFrD consumption impaired decidualization. This appeared to be due to decreased circulating progesterone as exogenous progesterone administration rescued decidualization. Furthermore, HFrD intake was associated with decreased bone morphogenetic protein 2 expression and signaling, both of which were restored by exogenous progesterone. Finally, expression of forkhead box O1 and superoxide dismutase 2 [Mn] proteins were decreased in the uteri of HFrD-fed mice, suggesting that HFrD consumption promotes a prooxidative environment in the endometrium. In summary, these data suggest that excess fructose consumption impairs murine fertility by decreasing steroid hormone synthesis and promoting an adverse uterine environment.

Maternal metabolic and nutrient trafficking adaptations to lactation differ among lean and obese mice fed a high fat (HF) diet. Obesity is thought to impair milk lipid production, in part, by decreasing trafficking of dietary and de novo synthesized lipids to the mammary gland. Here, we report that de novo lipogenesis regulatory mechanisms are disrupted in mammary glands of lactating HF-fed obese (HF-Ob) mice. HF feeding decreased the total levels of acetyl-CoA carboxylase-1 (ACC), and this effect was exacerbated in obese mice. The relative levels of phosphorylated (inactive) ACC, were elevated in the epithelium, and decreased in the adipose stroma, of mammary tissue from HF-Ob mice compared to those of HF-fed lean (HF-Ln) mice. Mammary gland levels of AMP-activated protein kinase (AMPK), which catalyzes formation of inactive ACC, were also selectively elevated in mammary glands of HF-Ob relative to HF-Ln dams or to low fat fed dams. These responses correlated with evidence of increased lipid retention in mammary adipose, and decreased lipid levels in mammary epithelial cells, of HF-Ob dams. Collectively, our data suggests that maternal obesity impairs milk lipid production, in part, by disrupting the balance of de novo lipid synthesis in the epithelial and adipose stromal compartments of mammary tissue through processes that appear to be related to increased mammary gland AMPK activity, ACC inhibition, and decreased fatty acid synthesis.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world, and it is thought to be the hepatic manifestation of the metabolic syndrome. Excess dietary fructose causes both metabolic syndrome and NAFLD in rodents and humans, but the pathogenic mechanisms of fructose-induced metabolic syndrome and NAFLD are poorly understood. GLUT8 (Slc2A8) is a facilitative glucose and fructose transporter that is highly expressed in liver, heart, and other oxidative tissues. We previously demonstrated that female mice lacking GLUT8 exhibit impaired first-pass hepatic fructose metabolism, suggesting that fructose transport into the hepatocyte, the primary site of fructose metabolism, is in part mediated by GLUT8. Here, we tested the hypothesis that GLUT8 is required for hepatocyte fructose uptake and for the development of fructose-induced NAFLD. We demonstrate that GLUT8 is a cell surface-localized transporter and that GLUT8 overexpression or GLUT8 shRNA-mediated gene silencing significantly induces and blocks radiolabeled fructose uptake in cultured hepatocytes. We further show diminished fructose uptake and de novo lipogenesis in fructose-challenged GLUT8-deficient hepatocytes. Finally, livers from long term high-fructose diet-fed GLUT8-deficient mice exhibited attenuated fructose-induced hepatic triglyceride and cholesterol accumulation without changes in hepatocyte insulin-stimulated Akt phosphorylation. GLUT8 is thus essential for hepatocyte fructose transport and fructose-induced macrosteatosis. Fructose delivery across the hepatocyte membrane is thus a proximal, modifiable disease mechanism that may be exploited to prevent NAFLD.