bluuebunny/crossref_metadata_2025 huggingface dataset:
Engagement in a Multi-Feature Digital Health Lifestyle Change Program as a Predictor of Weight Loss
Authors: Dzubur Eldin , James Roberta , Shah Bimal , Kompala Tejaswi
Published: May 2021

Background: Modern digital health interventions targeting weight loss employ multiple evidence-based strategies, including nutrition tracking, coaching, and activity monitoring, providing users with choice as they set and achieve their own goals. Still, limited research exists on the partial effects of each component of such interventions, and whether participants choose to use all of the features of a program. The objective of this study was to test the individual components of a fully-featured digital health lifestyle intervention as predictors of weight loss in a single statistical model.

Methods: Participants in the study (N=25,273) were enrolled in the Livongo for Weight Loss program as part of their employee wellness benefit across 57 states/territories of the US from April, 2019 to January, 2021. Participants received a cellular-connected scale to use daily in the program; they were asked to track their eating via the app and physical activity via smartphones or wearables. Additionally, participants could engage with coaches voluntarily or by receiving feedback from coaches on their recorded food logs. A mixed-effects generalized linear model was used to test the effects of scale usage, physical activity, human telephonic coaching, and food logs without and without coaching feedback on the percent weight loss the following month. Predictors were disaggregated into between- and within-subject components to understand the impact of each component relative to one’s own mean. The month in the program and whether or not that month occurred during the COVID-19 pandemic were entered as time-varying covariates. Baseline age, gender, and BMI were entered as time-invariant covariates.

Results: Participants were 45% male and had average age of 54.3 years old (SD =11.4), with an average BMI of 33.10 kg/m2 (SD: 6.2). On average, participants were enrolled in the program for 10.4 months (SD: 5.1). Each additional use of the scale above one’s own average was associated with an overall 7.4% weight loss (z=21.06,p<0.001). Similarly, each additional minute of moderate-vigorous physical activity (MVPA) above one’s own average was associated with an overall 2.4% weight loss (z=3.14, p<0.01). Lastly, coaching and food logging with coaching feedback at a frequency above one’s own average were associated with approximately a 6% weight loss throughout the program (z=3.08 and 2.35, respectively; p<0.05 for both).

Conclusion: We found that frequency of use of a scale in a weight loss intervention was most predictive of weight loss, followed by human coaching interaction and physical activity. However, food logging without feedback did not significantly impact weight loss among participants. Additional work is needed to understand drivers associated with increased utilization of beneficial program features, including optimizing the use of coaching, which offers great benefit, but may be costly to scale.
Insulin Resistance Moderates the Association Between BMI and Metabolic Syndrome Severity in Women 4–10 Years After Pregnancy, Independent of Gestational Diabetes Status
Authors: Callahan Makenzie , Martin Samantha , Bahorski Jessica , Pavela Gregory , Garvey W Timothy , Chandler-Laney Paula C
Published: May 2021

Objective: Obesity and gestational diabetes mellitus (GDM) increase the risk for metabolic syndrome (MetS). Insulin resistance (IR) is associated with obesity, contributes to risk for GDM, and persists after pregnancy even when glucose tolerance returns. Further, IR may enhance the risk of MetS associated with obesity and GDM. The purpose of this study was to test the hypothesis that IR moderates the relationship between BMI and MetS severity 4–10 years after pregnancy, independent of prior GDM, such that the positive association between BMI and MetS severity is stronger among women with greater IR. Methods: This hypothesis was tested in a secondary analysis of data collected from women enrolled in a study of the intergenerational transmission of obesity, 4–10 years after the index pregnancy. Recruitment in the parent study was stratified to include women with normal weight without GDM (NW), overweight or obesity without GDM (OwOB), and women with GDM during the index pregnancy. Standard clinical procedures were used to measure height, weight, waist circumference and blood pressure, and a fasting blood draw was obtained with which to measure glucose, insulin, triglycerides, and HDL-cholesterol. MetS was evaluated as a continuous outcome, reflecting severity, using the method of Gurka and DeBoer.1 IR was calculated with the homeostatic model assessment (HOMA-IR) and modeled as a continuous variable. An OLS regression model predicting MetS as a function of HOMA-IR, BMI, and their interaction, along with key covariates was used to test whether HOMA-IR moderates the relationship between BMI and MetS severity, independent of GDM. Results: The association between BMI and MetS severity was significantly modified by HOMA-IR (b=0.008, p<0.001), independent of GDM status during pregnancy, such that the positive association between BMI and MetS severity was stronger among individuals with higher HOMA-IR. For example, among women with HOMA-IR values 1-standard deviation below the mean, the estimated association between BMI and MetS severity was (b=0.0394, p<0.001); however, among women with a HOMA-IR value 1-standard deviation above the mean, the association between BMI and MetS severity was (b=0.0745, p<0.001). Conclusion: IR after pregnancy was a significant moderator of the association between BMI and MetS severity. Future studies should explore whether interventions to improve IR can reduce MetS severity independent of BMI and prior GDM.

References: 1.Gurka MJ, Lilly CL, Oliver MN, DeBoer MD. An examination of sex and racial/ethnic differences in the metabolic syndrome among adults: a confirmatory factor analysis and a resulting continuous severity score. Metabolism. 2014;63(2):218–225.
L-Leucine Supplementation for Preserving Lean Mass During Low Calorie Diet in Sarcopenic Obese Women: A Pilot Study
Authors: Camajani Elisabetta , Persichetti Agnese , Contini Savina , Lubrano Carla , Caprio Massimiliano , Gnessi Lucio , Basciani Sabrina
Published: May 2021

Background: In sarcopenic obese subjects it is essential to reduce body weight and to preserve lean mass, in order to avoid a worsening of muscle function (1). Several studies have shown that leucine supplementation can be useful to improve skeletal muscle mass in sarcopenic patients (2). Aim: Evaluate the effectiveness of a short-term low calorie diet (LCD) combined with combined supplementation with whey protein, leucine and vitamin D on weight loss, lean mass and muscle strength in sarcopenic, obese, hyperinsulinemic and menopause women. Materials and methods: 16 female with mean age: 58.1 years (range: 47–69 years), BMI 37.6 Kg/m2 (range: 31,7 - 44,1 Kg/m2), HOMA-index ≥ 2.5, were assigned to an LCD regimen (1000 kcal/day) with supplementation of 18 g protein, 4 g leucine and 5 mcg vitamin D for 45 days. Anthropometric indexes, blood and urine chemistry, body composition by DEXA, muscle strength by handgrip test and Short Physical Performance Battery (SPPB) were assessed at baseline and at the end of the treatment. Results: A significant reduction of BMI (35,7 vs 37,6 Kg/m2), waist circumference (102,4 vs 107 cm), HOMA index (2,3 vs 4,8) and fasting insulin (10,4 vs 17,4 μIU/ml) was observed in all patients. Women preserved total lean body mass (57 vs 55 %) and improved significantly muscle strength, as measured by handgrip (22,2 vs 18,6 Kg) and SPPB (8,9 vs 7,5). Conclusion: We conclude that LCD with adequate protein intake and a supplementation with whey protein, leucine and vitamin D should be promoted to maintain muscle mass and improve muscle strength in menopause women with sarcopenic obesity. References: 1. Batsis JA, Villareal DT. Sarcopenic obesity in older adults: aetiology, epidemiology and treatment strategies. Nat Rev Endocrinol. 2018 Sep;14(9):513–5372. Bauer JM, Verlaan S, Bautmans I, Brandt K, Donini LM, Maggio M, McMurdo ME, Mets T, Seal C, Wijers SL, Ceda GP, De Vito G, Donders G, Drey M, Greig C, Holmbäck U, Narici M, McPhee J, Poggiogalle E, Power D, Scafoglieri A, Schultz R, Sieber CC, Cederholm T. Effects of a vitamin D and leucine-enriched whey protein nutritional supplement on measures of sarcopenia in older adults, the PROVIDE study: a randomized, double-blind, placebo-controlled trial. J Am Med Dir Assoc. 2015 Sep 1;16(9)
Metabolic and Endocrine Comorbidities in Hidradenitis Suppurativa: A Nationwide Study
Authors: Edigin Ehizogie , Eseaton Precious O , Shaka Hafeez , Asemota Iriagbonse , Akuna Emmanuel , Ojemolon Pius , Velazquez Genaro , Asotibe Jennifer Chiagoziem , Williams Dimeji
Published: May 2021

Introduction: Hidradenitis suppurativa (HS) or acne inversa is a chronic, inflammatory, recurrent, debilitating skin disease. There have been studies linking HS to metabolic syndrome [1]. However, there is a scarcity of studies on metabolic and endocrine co-morbidities of hospitalized HS patients. This study aims to compare the prevalence of metabolic and endocrine co-morbidities in hospitalized HS patients to hospitalized non-HS patients.

Methods: Data were abstracted from the National Inpatient Sample (NIS) 2016 and 2017 Database. NIS is the largest inpatient hospitalization database in the United States. The NIS was searched for hospitalizations for adult patients aged 18 years or above with a principal or secondary diagnosis of HS and those without any diagnosis of HS. Chi-square test was used to compare the prevalence of common metabolic and endocrine comorbidities between HS and non-HS hospitalized patients. Co-morbidities were obtained from secondary diagnoses. We used ICD-10 codes to obtain HS hospitalizations and co-morbidities. STATA, version 16 was used for analysis.

Results: There were over 71 million discharges in the combined 2016 and 2017 NIS database. Out of which, 40,275 hospitalizations had a diagnosis of HS. HS hospitalizations had higher prevalence of type 2 diabetes (33.1% vs 24.5%, p<0.0001), type 1 diabetes mellitus (1.9% vs 0.9%, p<0.0001), obesity (35.8% vs 14.3%, p<0.0001), lower prevalence of dyslipidemia (21.3% vs 31.8%, p<0.0001), hypothyroidism (6.3% vs 12.0%, p<0.0001) and similar prevalence of hyperthyroidism (0.4% vs 0.5%, p=0.2373) compared to non-HS hospitalizations

Conclusion: Hospitalized HS patients have a higher prevalence of type 1 & 2 diabetes mellitus and obesity compared to hospitalized non-HS patients. An interdisciplinary approach involving the endocrinologist, dermatologist, and hospitalist may be needed to optimally manage these co-morbidities in hospitalized HS patients.

References 1. Ergun T. Hidradenitis suppurativa and the metabolic syndrome. Clin Dermatol. 2018;36(1):41–47. doi:10.1016/j.clindermatol.2017.09.007
Morbid Obesity Is Associated With Worse Outcomes and Increased Inpatient Mortality in Patients With Alcohol Induced Acute Pancreatitis
Authors: Shaka Hafeez , Rashad Essam , Achebe Ikechukwu , Asotibe Jennifer Chiagoziem , Palomera Emmanuel , Pudasaini Garima , Warraich Muhammad-Sheharyar
Published: May 2021

Introduction: The prevalence of obesity in the United States is rising. Obesity is a known comorbidity with various health impacts. Alcohol is a common etiology for acute pancreatitis. Obesity is known to be associated with liver dysfunction. It is unclear to what extent the degree of obesity affects patients with alcohol induced acute pancreatitis (AAP), as nationally representative data are lacking. This study aimed to ascertain the impact of morbid obesity on outcomes of patients with alcohol induced pancreatitis.

Methods: Data was obtained from the Nationwide Inpatient Sample database for 2016 and 2017. Hospital discharges of patients 18 years and over with a principal diagnosis of AAP were included. This cohort was divided based on presence of comorbid obesity into nonobese patients, mild-moderately obese patients (MMO) (BMI: 30.0 - 39.9) and morbidly obese patients (MO) (BMI >/=40.0). Primary outcome was inpatient mortality. Secondary outcomes included length of hospital stay (LOS), total hospital charges (THC), discharge diagnoses of hypocalcemia, sepsis, acute renal failure (AKI) and acute respiratory failure (ARF). Multivariate regression analysis was used to adjust for patients’ sociodemographic factors, Charlson comorbidity index as well as hospital characteristics as confounders.

Results: A total of 143650 hospitalizations were principally for AAP, with 5.5% and 2.7% of these patients classified as having MMO and MO, respectively.

In MO patients, there was increased odds of mortality (aOR=2.99, 95% CI: 1.509 - 5.917, p=0.002) when compared with patients who were nonobese. There was no difference in mortality in patients with MMO (aOR 0.88 95% CI: 0.383 - 2.026, p=0.765) when compared with the nonobese group. MO patients had increased mean LOS of 1.1 days (95% CI: 0.7 - 1.6, p<0.001) as well as THC of $14481 (95% CI: 7894 - 21068, p<0.001), increased odds of hypocalcemia (aOR=1.77, 95% CI: 1.302 - 2.392, p<0.001), sepsis (aOR=1.84, 95% CI: 1.183 - 2.873, p=0.007), AKI (aOR=1.55, 95% CI: 1.257 - 1.912, p<0.001).

Conclusion: Morbid obesity has a negative impact on outcomes of patients with AAP. Efforts should be channeled towards promoting alcohol cessation in at-risk patients as a preventative measure, as well as closer monitoring of hospitalized patients with morbid obesity to mitigated these adverse events.
The Relation Between Cortisol and Anthropometric Measurements Throughout Lifespan: A Systematic Review and Meta-Analysis
Authors: van der Valk Eline S , Abawi Ozair , Mohseni Mostafa , Abdelmoumen Amir , Wester Vincent L , van der Voorn Bibian , Iyer Anand M , van den Akker Erica L T , Hoeks Sanne E , de Rijke Yolanda B , Stalder Tobias , van Rossum Elisabeth F C
Published: May 2021

Introduction: Recently, cross-sectional studies report associations between long-term glucocorticoid levels in scalp hair (HairGC) and obesity. However, there is a wide variation in studied outcomes and associations, possibly caused by differences in population characteristics, e.g. age, sex, dispersion of adiposity, and used laboratory methods. The aim of this systematic review and meta-analysis was to investigate the relation between HairGC and anthropometrics and to explore possible moderators of this association. Methods: We searched the Medline, Embase, Cochrane, Web of Science, Scopus, Cinahl, PsycInfo, and Google Scholar databases for articles that relate HairGC to measures of adiposity (date 11-16-2020). Primary outcomes were correlations between hair cortisol (HairF) and cortisone (HairE), and anthropometrics: BMI, waist circumference (WC) and waist-hip-ratio (WHR). Authors were contacted to provide missing outcome information. Pooled correlation coefficients were calculated using random effects models. Assessment of heterogeneity was performed using the I2 statistic. Exploratory moderator analyses were performed with subgroup analyses and meta-regression. This systematic review was performed in accordance to the PRISMA guidelines. Results: Our systematic search identified 150 cohorts, comprising a total of 37,107 unique individuals, of which 15,033 sampled from population-based cohorts. For BMI, the pooled correlation for HairF was 0.121 (95% CI 0.083–0.158, n=26,941; I2 94.2%, p<0.001) and for HairE 0.108 (95% CI 0.047–0.167, n=7,250; I2 52%, p<0.01). For WC, the pooled correlation for HairF was 0.111 (95% CI 0.058–0.164, n=10,290; I2 63%, p<0.01) and for HairE 0.200 (95% CI 0.137–0.264, n=2,198; I2 0%, p=0.42). For WHR, the pooled correlation for HairF was 0.102 (95% CI 0.040–0.163, n=6,865; I2 27%, p=0.14) and for HairE 0.261 (95% CI 0.195–0.330, n=1,314; I2 0%, p=0.40). A higher percentage of male participants was related to stronger correlations with WC (p<0.001), but not with BMI and WHR. Mean age, mean BMI, and mean HairGC levels of the cohorts did not significantly moderate the pooled correlations, neither did the used laboratory techniques (immunoassays vs mass spectrometry-based assays).

Conclusion: This unique, large meta-analysis demonstrates that long-term endogenous glucocorticoids as assessed by HairGC show small but consistent correlations to measures of obesity, despite a large heterogeneity between the included cohorts. The strongest associations were found between HairE and WC and between HairE and WHR. This suggests that glucocorticoid levels in the high-normal range, especially cortisone, may contribute to or reflect the state of specifically central adiposity, even within the general population.
Effects of Glucagon-Like-Peptide-1 Analogue Treatment in Genetic Obesity
Authors: Welling Mila Sofie , de Groot Cornelis J , Kleinendorst Lotte , van der Voorn Bibian , Burgerhart Jan Steven , van der Valk Eline S , van Haelst Mieke M , van den Akker Erica L T , van Rossum Elisabeth F C
Published: May 2021

Introduction: Obesity is highly prevalent, comes with serious health burden and is difficult to treat. In a minority, there is a genetic cause for the obesity. In these patients, therapy-resistant obesity is often observed despite intensive lifestyle treatment. Moreover, it is still unclear whether bariatric surgery is less successful in genetic obesity. Liraglutide is a Glucagon-Like-Peptide-1 (GLP-1) receptor agonist or GLP-1 analogue, showing positive effects on metabolic parameters, satiety and weight loss in lifestyle-induced obesity. We present our experiences of GLP-1 analogue treatment in patients with genetic obesity disorders. Methods: Adults with overweight or severe obesity and a molecularly proven genetic cause were treated with liraglutide 3,0 mg daily, in addition to ongoing intensive supportive lifestyle treatment. Anthropometrics, metabolic parameters, resting energy expenditure (REE), side effects, and subjectively reported satiety and quality of life were assessed. Results: Two patients with a heterozygous pathogenic melanocortin 4 recepter variant and two patients with 16p11.2 deletion syndrome, ranging in age between 21 and 32 years and in BMI between 28.1 and 55.7 kg/m2 at baseline, were treated. At end of follow-up, ranging between 33 weeks and 12 years, a mean change in BMI and waist circumference was observed of -5.7 ± 3.8 kg/m2 and -15.2 ± 21.1 cm, respectively. All patients reported better quality of life, three of them also reported improved satiety. Moreover, improvement of metabolic parameters was seen. No clear effect on REE was observed. Two patients experienced mild side effects, e.g. nausea and stomach pain, for a brief period.

Conclusion: We here show beneficial effects of GLP-1 analogues on weight, metabolic parameters, and quality of life in four patients with genetic obesity. Satiety improved in three of the four patients. All patient achieved at least the clinically relevant 5–10% weight loss. Our findings suggest that GLP-1 analogue treatment might be an effective treatment option, in addition to a healthy lifestyle, for patients with genetic obesity.
Prevalence of Non-Alcoholic Fatty Liver Disease (NAFLD) in Obese Type Two Diabetes Patients in an Endocrine Clinic
Authors: Shaghouli Amna Ali , Aranky Rola M
Published: May 2021

Introduction: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver diseases that is expected to become the main cause for liver transplantation by 2030.1 Its prevalence is increasing globally and regionally, and it is set to become the leading cause of chronic liver disease in many parts of the world. However, the epidemiology and demographic characteristics of NAFLD vary worldwide.2About 20% to 30% of the patients progress to develop nonalcoholic steatohepatitis (NASH), a subtype of NAFLD, with features of hepatocyte injury such as hepatocyte ballooning. NASH can develop to fibrosis, cirrhosis, and even hepatocellular carcinoma.3 NAFLD is correlated with obesity and insulin resistance in most cases in the Western world.2In Kuwait, obesity prevalence is estimated to be 39% for adult males and 52% for adult females.4 There is no pharmacotherapy approved for NAFLD treatment, and the main treatment is lifestyle modifications focusing on body fat loss.5

Methods: In 18 months duration, a total number of 306 patients who attended an endocrine clinic in Kuwait for general health checkups with an average BMI of 33.6 (Kg/m2) were requested to do an abdominal ultrasound for fatty liver screening. And out of 306 patients, 218 patients (71% of the patients) were diagnosed with NAFLD, the rest 29% of the patients either didn’t come back for a follow up or were not diagnosed with NAFLD.

Results: 218 patients have NAFLD, 153 of them are females and 65 are males with an average age and weight of 56.4 years and 87.9kg respectively. 78% of the patients were diabetic with an average HbA1c of 7.6%. The abdominal ultrasound showed the following result:83 patients had NAFLD grade 184 patients had NAFLD grade 2 21 patients had NAFLD grade 3While 30 patients had no grading, the results showed that they have a fatty liver with no grades mentioned. Also, reports showed that 27 patients had liver cirrhosis.

The 218 patients were requested to do blood test and average results of the following parameter were as shown at baseline:

Ferritin 98.3 ng/mLHemoglobin 13.5 g/dLPlatelets 274.5 x1000/cmmAST 23.8 U/LALT 27.9 U/LDirect Bilirubin 3.5 umol/LTotal Bilirubin 8.9 umol/LThe average calculated NAFLD, BARD and Fib-4 scores were -1.1, 3 and 1.1 respectively. All patients were unaware of NAFLD.

Conclusion: 78% of the study population had NAFLD and were unaware of that. More researches on NAFLD awareness and occurrence in the region are required.
The Effectiveness of Adding Pharmacotherapy to Dietary Counseling for Veterans in a Veterans Health Administration Move! Weight Management Program
Authors: Alvarez Diego Alcaraz , Salter Mary F , Gupta Namita , Thangavelu Thiyagarajan , Desouza Cyrus V
Published: May 2021

Background: Over 78% of veterans are overweight or obese. MOVE! is the VA’s national evidence-based self-management program. This program focuses on health and wellness through healthy eating, physical activity, and behavior change (1). We evaluated the effects of adding pharmacotherapy to dietitian coaching in a real-world MOVE! Program in the VA Nebraska-Western Iowa Health Care System.

Methods: A systematic retrospective and prospective chart review were completed of 66 patients who completed a minimum of 6 months of medication at our Weight Loss Medicine clinic from June 2017 to February 2020. Body composition was measured using SECA Bio Electrical Impedance Analyzer. Descriptive statistics were used to analyze weight changes, fat mass (FM), and fat-free mass (FFM) changes at 6 and 12 months after starting weight loss medications.

Results: The percentage of patients with a 5% decrease in weight from baseline after at least 6 months with pharmacotherapy was 47% and a 10% decrease was 36% after 12 months. In 6 months, a decrease of a minimum of 5% was seen with GLP-1 (semaglutide or liraglutide) 55 % (29/53), orlistat 11% (1/9), and bupropion-topiramate 25 % (1/4). An average of 3.4% FM decrease and a 3.47% FFM increase was seen from baseline to 6 months and 4.8% FM decrease and 4.7% FFM increase was seen from baseline to 12 months.

Conclusion: A clinically significant decrease in weight was seen at 6 and 12 months after starting weight loss medication in addition to monthly MOVE! Dietitian visits. A significant decrease was seen in FM and an increase in FFM. Veteran’s receiving a GLP-1 had a greater amount of weight loss compared with Orlistat and bupropion-topiramate. Weight loss medication is recommended as an adjunct to dietitian counseling for optimizing weight loss.

References

1 Kinsinger LS, Jones KR, Kahwati L et al. Design and dissemination of the MOVE! Weight-Management Program for Veterans. Prev Chronic Dis 2009; 6: A98
The Association of the Polychlorinated Biphenyl Class of Endocrine Disruptors With Polycystic Ovary Syndrome and Thyroid Dysfunction
Authors: Brennan Edwina , Cunningham Thomas Keith , Sathyapalan Thozhukat , Atkin Stephen Lawrence
Published: May 2021

Introduction:. Polychlorinated biphenyls (PCBs) are a class of endocrine disruptors with a long half-life in the body that are associated with irregular menses, growth and development delay, increased cancer risk, thyroid disorders and an increased risk of diabetes. Higher levels of PCBs have been related to polycystic ovary syndrome (PCOS). PCB toxicity depends on their structure, with coplanar PCBs being most toxic (akin to dioxins); therefore, PCB subtypes were determined to see if they differed in women with PCOS compared to normal controls. Methods:. PCB levels were compared in Caucasian women with (n=29) and without (n=30) PCOS and related to metabolic features. PCBs were fractionated then analysed by high-resolution gas chromatography-unit resolution mass spectrometry. Results:. The control and PCOS groups were age and BMI matched (p=ns); insulin resistance was not different (HOMA 1.7±1.0 v 2±1.6, p=ns) but free androgen index was increased in PCOS (p<0.004). PCB-118, 138, 153 and 180 were found in all subjects, whilst fewer subjects showed PCB-28(15/59), PCB-52(4/59) or PCB-101(26/59). There was no difference for PCB-188,138,153 and 180 between controls and PCOS, but all correlated with increasing age (p<0.01) and decreasing estimated glomerular filtration rate (p<0.05); no correlations with BMI, HOMA, testosterone, TSH or T3 were found; however, PCB-118 (the only coplanar PCB detected) associated with an increased T4/T3 ratio (p<0.01). Conclusion. Despite PCBs being banned over a decade ago, PCBs were detected, but did not differ between age and BMI matched women with and without PCOS. Thyroid dysfunction may be only associated with toxic coplanar PCBs, such as PCB-118 that was associated with a higher T4/T3 ratio.
In Utero Exposure to 17α-Hydroxyprogesterone Caproate May Contribute to Increasing Incidence Rates of Early-Onset Cancer
Authors: Murphy Caitlin C , Cirillo Piera M , Krigbaum Nickilou Y , Cohn Barbara
Published: May 2021

Background: 17α-hydroxyprogesterone caproate (17-OHPC) is a synthetic progestogen introduced in the 1950s to treat habitual and threatened abortion in pregnant women. Although 17-OHPC is still available (tradename Makena), little is known about its effects on health of adult offspring, and questions concerning safety and effectiveness remain. For example, progestogens have been implicated in cancer, and trends in the use of 17-OHPC in early pregnancy during the 1950s and 60s parallel increasing incidence rates of certain cancers in young adults, such as early-onset colorectal cancer, born during that time. Methods: We examined the effect of 17-OHPC exposure in utero on risk of cancer in adult offspring in the Child Health and Development Studies, a cohort of women receiving prenatal care between June 1959 and September 1966, with deliveries through June 1967 (n=18,751 live births excluding neonatal deaths among 14,507 mothers). Diagnosed conditions and prescribed medications were abstracted from mothers’ medical records beginning 6 months prior to pregnancy through delivery. We identified mothers who received 17-OHPC (tradenames Delalutin and Proluton) in early pregnancy, defined as day 1 - 140 of gestation. Incident cancers diagnosed in offspring through 2018 were ascertained by linkage with the California Cancer Registry. Results: Among 18,751 live births, 954 cancers were diagnosed at ages 18 - 58 years. The most frequent cancers were breast (20.9%), cervical (10.9%), colorectal (7.1%), and prostate (5.9%) cancer and melanoma (9.2%). Although few mothers (n=181, 1.0%) received 17-OHPC in early pregnancy, in utero exposure was more common in offspring diagnosed with cancer (n=18, 1.9%) compared to those without cancer (n=163, 0.9%). Conditions indicating 17-OHPC included threatened abortion (54.0%), amnionitis (9.4%), and incompetent cervix (3.0%). 17-OHPC increased risk of any cancer in offspring (OR 2.08, 95% CI 1.27, 3.40), with particularly striking associations for colorectal (OR 4.78, 95% CI 1.49, 15.41) and prostate (OR 3.83, 95% CI 0.93, 15.83) cancer. There was no association between conditions indicating 17-OHPC and risk of any cancer in offspring (threatened abortion: n=1,891 mothers, OR 1.07, 95% CI 0.87, 1.32), or with use of other progestogens within 6 months prior to pregnancy (medroxyprogesterone acetate: n=50 mothers, OR 0.38, 95% CI 0.05, 2.76). Conclusions: Findings support susceptibility of multiple organ systems to endocrine disruption during early development and risk of cancer decades later - and may partly explain increasing rates of early-onset colorectal cancer. Even before mechanisms of carcinogenesis are elucidated, caution using 17-OHPC and other endocrine-active pharmaceuticals in early pregnancy is warranted, especially in the absence of a clear short-term benefit, and given the possible effect on risk of cancer in adult offspring.
Favorable Prognostics of Post-Exercise Irisine Released as Prophylaxis of Serious Covid-19 in Obese Elderly
Authors: de Oliveira Arthu Línniker Lopes , Jales Césia Santos , de Queiroz Silva Igor Thiago Borges
Published: May 2021

Studies sought epidemiological profiles to establish risk groups for Covid-19’s evolution and discovered that the age group above 65 years old is one of the most severely affected, due to the presence of other comorbidities. In the USA approximately 55 million individuals are above that age range and more than 23 million are elderly obese individuals, alongside the high mortality rate in this population and lack of proven effective medicine against Covid-19, therapeutic alternatives against this disease are sought. With the occurrence of inflammatory pulmonary conditions increased by SARS-Cov-2 infection, irisin was indicated as having a potential preventive action. This peptide is secreted endogenously by striated skeletal muscles with fibronectin type III domain-containing protein 5 (FNDC5) proteolysis, when preceded by continued exercise of low to moderate intensity for more than 20 uninterrupted minutes. Regarding the weight variant, previous studies showed low levels of FNDC5 in people with excess fatty acids (in humans, adipose tissue divides into white, favoring the deposit of lipids, triglycerides and fat, more easily inflamed, and brown that stimulates thermogenesis). Among other functions, FNDC5 also stimulates the coactivator 1-alpha of PPAR gamma (PGC-1α) which corroborates with the uncoupling between the Uncoupling Protein 1 (UCP1) and the mitochondria. When UCP1 is disincorporated from this organelle, it becomes active and inhibits ATP synthesis, releasing heat, as well as favoring fatty acid oxidation and provides the mechanism of browning of white fat. After this conversion, irisin reduces ¼ of lipid accumulation present in the adipocyte by lipolysis, significantly increasing the levels of serum triglycerides and glycerols, as well as considerably reducing oxidative stress and DNA damage. Other genes expressed by irisin also assist in the fat browning process, such as TMEM26, ELOVL3, CIDEa and COX7a. Regarding the age variant, the SARS-CoV-2 Spike protein benefits from the high concentration of angiotensin-converting enzyme 2 (ACE2) receptors, present in elderly pulmonary alveoli, which bind to the airway and enable contagion. However, ACE2 is negatively regulated by Tribbles homolog 3 (TRIB3) protein from its connection to the nucleocapsid protein of the virus, generating some protection for the individual when TRIB3 is at satisfactory levels. In elderly men, this protein is below normal levels, making this population more vulnerable to SARS-CoV-2 infection. Moreover, it was verified that irisin’s weekly synthesis promoted by regular physical exercises triples TRIB3 levels in pulmonary alveoli. In short, this hormone was able to negatively modulate two important risk factors related to the inflammatory profile of this elderly population (weight and age), and thus irisin should be considered a potential molecule in the prevention against Covid-19.
Histone Lysine Demethylase 1A Is a Master Regulator of Genes Necessary for Trophoblast Cell Proliferation
Authors: Bouma Gerrit J , Ali Asghar , Hord Taylor K , Parsons Agata M , Anthony Russell Vernon , Bruemmer Jason E , Winger Quinton A
Published: May 2021

Histone lysine demethylase 1A is a master regulator of genes necessary for trophoblast cell proliferation.

A proper functioning placenta is critical for pregnancy, fetal growth and development and postnatal health. Trophoblast cell proliferation and differentiation is critical for placental development and function. Recently we demonstrated that the histone lysine demethylase KDM1A binds to androgen receptor (AR) in human and sheep trophoblast cells, and targets the same promoter region of vascular endothelial growth factor A (VEGFA), suggesting a role for KDM1A and AR in early placental angiogenesis. The goal of this study was to determine the function of KDM1A during early placental development. We hypothesized that KDM1A regulates genes that are necessary for trophoblast cell proliferation, and early placental development. To this end, both in vitro and in vivo approaches were used in this study. ACH-3P cells (human first trimester trophoblast cells (CT and EVT) fused with the choriocarcinoma cell line AC1-1) were used, and a KDM1A knock out (KO) cell line was generated using CRISPR-Cas 9 based genome editing. KDM1A KO in ACH-3P cells led to significant (P<0.05) reduction in AR and VEGFA. Furthermore, factors important for cell proliferation and trophoblast cell development high mobility group AT-hook 1 (HMGA1), LIN28, and MYC protooncogene (cMYC) were significantly (P<0.05) lower in KDM1A KO ACH-3P cells. Cell proliferation assays revealed a significant (P<0.05) reduction in KDM1A KO ACH-3P cells compared to scramble controls. An in vivo experiment was conducted to demonstrate a role for KDM1A in placental development, using the sheep as a model. Day 9 hatched blastocysts were flushed and infected with a Lenti-CRISPRv2 KDM1A target construct (n=4) to knockout KDM1A specifically in the trophectoderm, or with SC (n=5). Infected embryos were transferred to recipient ewes and embryos were collected at gestational day 16. Data suggests that KDM1A KO in trophoblast cells is necessary for conceptus elongation. Current experiments are ongoing to determine the effects of KDM1A and AR knockdown using shRNA lentiviral target vectors on conceptus elongation and pregnancy. Collectively these results indicate that KDM1A plays a central role in regulating genes necessary for trophoblast cell proliferation.

This project was supported by Agriculture and Food Research Initiative Competitive Grant no. 2019-67015-29000 from the USDA National Institute of Food and Agriculture.
Inherited Human XY Sex Reversal and Gonadal Neoplasia Due to Enhanced Formation of Non-Specific Enhanceosomes by an Architectural Transcription Factor
Authors: Chen Yen-Shan , Racca Joseph D , Belgorosky Alicia , Weiss Michael Aaron
Published: May 2021

The development of organisms is regulated by a fine-tuned gene-regulatory network, which is driven by transcription factors (TFs). In the embryogenesis, these TFs control diverse cell fates and final body plan. This is precisely regulated by a specific DNA-binding process and enhanceosome formation. A model is provided by testis determination in mammals, which is initiated by a Y-encoded architectural transcription factor, SRY. Mutations in SRY cause gonadal dysgenesis leading to various developmental defects. Such mutations cluster in SRY’s high mobility group (HMG) box, a sequence-specific DNA-binding domain shared by a conserved family of TFs. Here, we have characterized several mutations at the same position in HMG box, which are compatible with either male or female phenotypes as observed in an XY father and XY daughter, respectively. These mutations, at a function-unknown motif in the SRY HMG box, markedly disturb the specific DNA affinity. On transient transfection of human and rodent cell lines, the SRY variants exhibit decreased specific DNA-binding activity (relative to wild type) are associated with mis-formed enhanceosomes. The variants’ gene regulatory activities were reduced by 2-fold relative to wild-type SRY at similar levels of mRNA expression. When engineered mutations that functions to increase the DNA-binding specificity were deployed to SRY variants, the transcriptional activity was in association with restored occupancy of sex-specific enhancer elements in principal downstream gene Sox9. Our findings define a novel mechanism of impaired organogenesis, disturbed specific DNA-binding activity of a master transcription factor, leading to a developmental decision poised at the edge of ambiguity.
The Glucagon-Like Peptide 1 Receptor Agonist Liraglutide Stimulates Mechanistic Target of Rapamycin (mTOR) Signaling via PKA And Akt
Authors: Le Thao D V , Liu Dianxin , Collins Sheila , Ayala Julio E
Published: May 2021

Glucagon-like peptide 1 receptor (GLP-1R) agonists enhance glucose-stimulated insulin secretion and act on several regions of the brain to reduce food intake and body weight, making the GLP-1R a major therapeutic target for the treatment of type 2 diabetes and obesity. Surprisingly, little is known about the signaling mechanisms mediating the food intake-lowering effects of GLP-1R agonists. We have previously shown that inhibiting the mechanistic Target of Rapamycin (mTOR) in the ventromedial hypothalamus blocks anorexia induced by GLP-1R activation in this brain nucleus (1). Therefore, the goal of the present studies is to elucidate the mechanisms by which GLP-1R activation stimulates mTOR signaling. To accomplish this, we treated Chinese Hamster Ovary cells stably expressing the human GLP-1R with the GLP-1R agonist liraglutide (Lira) in combination with inhibitors of various signaling molecules. Since PKA is a canonical target of GLP-1R signaling, and PKA phosphorylates mTOR and its regulating protein Raptor following β-adrenergic stimulation (2), we used the PKA inhibitors H89 and KT 5720 to examine whether PKA is required for the stimulation of mTOR activity by Lira. We expressed myc-tagged mTOR or Raptor in GLP-1R stably expressing CHO cells, treated them with Lira, immunoprecipitated myc-mTOR or myc-Raptor, and immunoblotted for the PKA substrate RRXS/T motif. We found that Lira significantly increased PKA-substrate motif phosphorylation of myc-Raptor but not myc-mTOR, and this was blocked by pre-treatment with H89. Lira also failed to stimulate phosphorylation of a Ser791Ala Raptor mutant that cannot be phosphorylated by PKA (2). To test whether Akt, a well-known regulator of mTOR activity, contributes to the activation of mTOR signaling by Lira, we pre-treated GLP-1R stably expressing CHO cells with either of the Akt inhibitors Akt-i 1/2 and MK-2206 followed by treatment with Lira or forskolin (Fsk), a cAMP inducer and PKA activator. Pre-treatment with either Akt-i 1/2 or MK-2206 blocked mTOR activation by both Lira and Fsk. This suggests that the contribution of Akt to Lira-induced mTOR activation is likely downstream of cAMP production. Taken together, our results suggest a novel two-pronged, PKA-dependent mechanism for the stimulation of mTOR signaling following GLP-1R activation – directly via phosphorylation of Raptor and indirectly via stimulation of Akt. Future studies will assess the respective contributions and temporal dynamics of each of these pathways. Reference: (1) Burmeister et al., Am J Physiol Endocrinol Metab. 2017 Aug;313: E651–E662. (2) Liu et al., J Clin Invest. 2016;126(5):1704-1716.
The Worldwide Landscape of Variants in the Androgen Receptor Gene Related to Androgen Insensitivity Syndrome: An Integrative Analysis
Authors: Batista Rafael Loch , Mendonca Berenice Bilharinho
Published: May 2021

Androgen Insensitivity Syndrome (AIS) is an X-linked genetic disease and it is the most common cause of 46,XY DSD. It is divided into 3 phenotypes: complete (CAIS), partial (PAIS), and mild (MAIS). To analyse the landscape of AR variants in AIS we collected all AR variants reported among AIS in the literature (Pubmed, EMBASE, Medline) and websites (ensemble, HGMD, ClinVar). They were analyzed according to phenotype, exon location, domain, amino acid (aa) conservation, sex assignment, external genitalia virilization (EMS score), molecular and functional studies. Conservation analysis of the AR were performed using CONSURF plataform. To test our hypothesis that non-synonymous AR variants could also impact on splicing, we used both ESEfinder and Human Splicing Finder 3.1. We founded 901 individuals with AIS: CAIS = 565 (62.7%); PAIS = 282 (31.3%); and MAIS = 54 (6%). They had 465 different AR variants: CAIS = 290 (62.3%); PAIS = 135 (29.1%); and MAIS = 40 (8.6%). Among MAIS and PAIS, most variants were at LDB domain (22 out 40 = 55% and 84 out 135 = 62.2%, respectively) whereas they were at NTD domain among CAIS (129 out 290 = 44.5%). Most were missense (81%). However, small indels (11%), nonsense (3%), splicing sites (4%) and large deletions (1%) were all reported. Non-synonymous AR variants accounting for 60%, 96%, and 100% of CAIS, PAIS, and MAIS, respectively. Synonymous AR variants were rarely found (n=3). In 81% only the AR sequencing was performed. The remaining was detected by WES (18%) or WGS (1%). Deep intronic variant was detected in PAIS (n=1) while variants in the 5’UTR of the AR gene in both PAIS and CAIS (n=2). Most AR variants were located at conserved aa (78%), but AR variants at non-conserved aa were more frequently indels (p<.01). Functional studies were found in 38%, mostly showing reduced AR expression. Among PAIS, 48% (n=134) were assigned as male at birth. The median EMS was 5 (95% CI, 5-7) in those assigned as male while it was 3.2 (95% CI, 2-6) in those assigned as female (p<.01). The median of EMS score was lower in variants at NTD domain (2.8, 95% CI, 0-7). We identified 34 AR variants causing more than one AIS phenotype (mostly CAIS and PAIS) and 6 AR variants causing all of three AIS phenotypes. In silico analysis suggests potential to disrupt normal AR splicing in 18 (53%) by creating new acceptor or donor splicing sites (n=11) or exonic splicing signals (n=7). More severe AR variants are related to CAIS. Most AR variants were reported only based on AR sequencing. Therefore, the functional pathogenicity of these variants remains unclear. Further studies including WGS could help to expand the molecular diagnosis of AIS. There is phenotype variability in AIS. So, sex assignment of patients with PAIS cannot be based on a specific identified AR gene mutation. There is potential to alter splicing among non-synonymous AR variants, which could be an explanation for phenotype variability in AIS.
Improved Acromegaly Patient Satisfaction With Oral Octreotide Capsules Compared With Injectable Somatostatin Receptor Ligands in the MPOWERED Trial
Authors: Gordon Murray B , Fleseriu Maria , Dreval Akexander V , Pokramovich Yulia , Bondar Irina , Isaeva Elena , Molitch Mark E , Macut Djuro P , Leonova Nina , Raverot Gerald , Kirschner Lawrence S , Chanson Philippe , Gilgun-Sherki Yossi , Ludlam William H , Patou Gary , Haviv Asi , Biermasz Nienke , Melmed Shlomo , Strasburger Christian J
Published: May 2021

Background: Improved patient-reported outcomes (PROs) are increasingly becoming a key treatment objective in acromegaly. Validated PROs were used to assess disease and treatment burden in the MPOWERED phase 3 trial in acromegaly, which also assessed safety and efficacy of oral octreotide capsules (OOC; MYCAPSSA®) compared to injectable SRLs (iSRLs).

Methods: Eligible patients had acromegaly diagnosis, biochemical control of acromegaly (insulin-like growth factor I <1.3 × upper limit of normal; mean integrated growth hormone, <2.5 ng/mL) and ≥6 months’ iSRL treatment (octreotide or lanreotide). Eligible patients entered a 26-week Run-in phase to determine the effective OOC dose; responders at week 24 then entered a 36-week randomized controlled treatment (RCT) phase receiving OOC or iSRLs in a 3:2 ratio. The Acromegaly Treatment Satisfaction Questionnaire (Acro-TSQ) is a recently validated tool that includes 27 items in 6 domain scores for PROs in acromegaly.1 Acro-TSQ data were collected at baseline (reflecting outcomes on iSRLs), end of Run-in (reflecting outcomes on OOC), and end of RCT (OOC or iSRLs).

Results: Of 146 enrolled patients, 92 entered RCT (OOC, N=55; iSRLs, N=37). Acro-TSQ scores at the end of Run-in (26 weeks’ OOC treatment) were compared to baseline (iSRLs). In the 92 patients randomized, 3 of 5 Acro-TSQ domains (emotional reaction, treatment convenience, and treatment satisfaction) showed significant improvement at end of Run-in compared to baseline. Injection site interference was not assessed as no injection site reactions were observed with OOC. Other domains showed a nonstatistically significant pattern of improvement at end of Run-in when compared to baseline. Patients randomized to iSRLs in the RCT after receiving OOC in the Run-in (N=37) reported more anxiety (RCT end, 53%; Run-in end, 29%) and frustration (RCT end, 45%; Run-in end, 34%) with iSRLs compared to OOC. Overall treatment satisfaction was higher while receiving OOC (Run-in end, 92%; after receiving iSRLs in RCT, 75%). Breakthrough symptoms were reported more frequently with iSRLs (31%) than OOC (15%) at the end of RCT.

Conclusion: Higher patient satisfaction, convenience and emotional well-being, and improved symptom control based on the newly validated Acro-TSQ PRO reporting tool were observed with OOC compared to iSRLs in patients enrolled in the MPOWERED trial.

1Fleseriu M, et al. Pituitary. 2020 Aug;23(4):347-358.
Effects of Diet-Induced Obesity on Hypothalamic Kisspeptin-Neurokinin-Dynorphin (KNDy) Neurons and Luteinizing Hormone Secretion in Sex Hormone-Primed Male and Female Rats
Authors: Minabe Shiori , Iwata Kinuyo , Ozawa Hitoshi
Published: May 2021

Metabolic stress resulting from a nutrient excess causes infertility in both sexes. Kisspeptin-neurokinin B-dynorphin (KNDy) neurons in the arcuate nucleus (ARC) have been suggested to be key players in reproduction via direct stimulation of gonadotropin-releasing hormone (GnRH) and subsequent gonadotropin release in mammalian species. In this study, we investigated the sex differences in the effects of a high-fat diet (HFD) on KNDy-associated gene expression in the ARC to determine the pathogenic mechanism underlying obesity-induced infertility. Wistar-Imamichi strain male and female rats (7 weeks of age) were fed either a standard diet (10% calories from fat) or high-fat diet (45% calories from fat) for 4 months. In male rats, the HFD caused a significant suppression of Kiss1(encoding kisspeptin), Tac3(encoding neurokinin B), and Pdyn(encoding dynorphin A) gene expression in the ARC, resulting in a decrease in plasma luteinizing hormone (LH) levels. In female rats, 58% of the HFD-fed female rats exhibited irregular estrous cycles, while the other rats showed regular cycles. LH pulses were found, and the numbers of ARC Kiss1-,Tac3-, and Pdyn-expressing cells were high in control animals and almost allHFD-fed female rats, but two out of 10 rats showed profound HFD-induced suppression of LH pulse frequency and reduction in these cells. No statistical differences in LH secretion or ARC KNDy gene expression were observed between HFD-fed and control female rats. Additionally, the number of Gnrh1-expressing cells in the preoptic area was comparable between the groups in both sexes. Our findings revealed that HFD-fed male rats showed KNDy-dependent infertility, while irregular menstruation was mainly induced by KNDy-independent pathways during the incipient stage of obese infertility in female rats. Taken together, hypothalamic kisspeptin neurons in male rats may be susceptible to HFD-induced obesity compared with those in female rats.