Distinct Reproductive Phenotypes Segregate With Differences in Body Weight in Adolescent Polycystic Ovary Syndrome.

Introduction: Polycystic ovary syndrome (PCOS) is a heterogenous clinical syndrome defined by hyperandrogenism and irregular menses. In adult women with PCOS, discrete metabolic and reproductive subgroups have been identified. We hypothesize that distinct phenotypes can be distinguished between adolescent girls who are lean (LN-G) and girls with obesity (OB-G) at the time of PCOS diagnosis. Methods: Data were extracted from the CALICO multisite PCOS database. Clinical data collected at the time of diagnosis were available in 354 patients (81% with obesity) from 7 academic centers. Patients with body mass index (BMI) < 85th percentile for age and sex were characterized as lean (LN-G) and those with BMI percentile ≥ 95th percentile as obese (OB-G). We compared metabolic and reproductive phenotypes in LN-G and OB-G. Results: Reproductive phenotypes differed between the groups, with LN-G having higher total testosterone, androstenedione, and LH levels, while OB-G had lower sex hormone binding globulin (SHBG) and higher free testosterone. Metabolic profiles differed as expected, with OB-G having higher hemoglobin A1c, alanine aminotransferase, and serum triglycerides and more severe acanthosis nigricans. Conclusion: LN-G with PCOS had a distinct reproductive phenotype characterized by increased LH, total testosterone, and androstenedione levels, suggesting neuroendocrine-mediated ovarian androgen production. In contrast, phenotypes in OB-G suggest hyperandrogenemia is primarily driven by insulin resistance with low SHBG levels. These observations support the existence of distinct metabolic and reproductive subtypes in adolescent PCOS characterized by unique mechanisms for hyperandrogenemia.

Two-part vowel modifications in Child Directed Speech in Warlpiri may enhance child attention to speech and scaffold noun acquisition.

Study 1 compared vowels in Child Directed Speech (CDS; child ages 25-46 months) to vowels in Adult Directed Speech (ADS) in natural conversation in the Australian Indigenous language Warlpiri, which has three vowels (/i/, /a/, /u). Study 2 compared the vowels of the child interlocutors from Study 1 to caregiver ADS and CDS. Study 1 indicates that Warlpiri CDS vowels are characterised by fronting, /a/-lowering, f o -raising, and increased duration, but not vowel space expansion. Vowels in CDS nouns, however, show increased between-contrast differentiation and reduced within-contrast variation, similar to what has been reported for other languages. We argue that this two-part CDS modification process serves a dual purpose: Vowel space shifting induces IDS/CDS that sounds more child-like, which may enhance child attention to speech, while increased between-contrast differentiation and reduced within-contrast variation in nouns may serve didactic purposes by providing high-quality information about lexical specifications. Study 2 indicates that Warlpiri CDS vowels are more like child vowels, providing indirect evidence that aspects of CDS may serve non-linguistic purposes simultaneously with other aspects serving linguistic-didactic purposes. The studies have novel implications for the way CDS vowel modifications are considered and highlight the necessity of naturalistic data collection, novel analyses, and typological diversity.

Relationship of Aboriginal family wellbeing to social and cultural determinants, Central Australia: 'Waltja tjutangku nyakunytjaku'.

OBJECTIVE: The objective of this study was to apply a strength-based approach to examine the relation of cultural and social determinants to high family functioning for Aboriginal people in Central Australia. DESIGN: Cross-sectional study involving a quantitative analysis of survey data. Prevalence rate ratios (PRs) and 95% CIs were calculated from binomial regressions, adjusted for gender and age. Qualitative data from workshops with Aboriginal leaders in Central Australia supported the interpretation of the research findings. PARTICIPANTS: The study involved 639 Aboriginal people in Central Australia who participated in the Mayi Kuwayu Study. RESULT: Overall, 57.9% (370/639) of participants reported high/very high family functioning, 16.9% (108/639) reported moderate and 13.3% (85/639) reported low. The adjusted prevalence of family functioning was similar across gender, age groups and household sizes. Family functioning was associated with lower family financial status (aPR=0.74, 95% CI=0.60 to 0.91) and receiving welfare (0.88, 0.77 to 1.00). Family functioning was greater with high community cohesion (2.72, 1.68 to 4.39), high individual agency in community (2.15, 1.63 to 2.85); having an Aboriginal language as a first language (1.20, 1.04 to 1.37); speaking your Aboriginal language a lot (1.37, 1.12 to 1.68); high exposure to cultural practice and knowledge (1.45, 1.28 to 1.65); and multigenerational or extended family households (1.19, 1.02 to 1.38). CONCLUSION: High family functioning is a strength in Central Australia and is intrinsically connected with culture. Healthcare providers and programmes that build on the foundations of culture and family are an important approach to improving wellbeing.

DOCK4 Regulation of Rho GTPases Mediates Pulmonary Vascular Barrier Function.

BACKGROUND: The vascular endothelium maintains tissue-fluid homeostasis by controlling the passage of large molecules and fluid between the blood and interstitial space. The interaction of catenins and the actin cytoskeleton with VE-cadherin (vascular endothelial cadherin) is the primary mechanism for stabilizing AJs (adherens junctions), thereby preventing lung vascular barrier disruption. Members of the Rho (Ras homology) family of GTPases and conventional GEFs (guanine exchange factors) of these GTPases have been demonstrated to play important roles in regulating endothelial permeability. Here, we evaluated the role of DOCK4 (dedicator of cytokinesis 4)-an unconventional Rho family GTPase GEF in vascular function. METHODS: We generated mice deficient in DOCK4' used DOCK4 silencing and reconstitution approaches in human pulmonary artery endothelial cells' used assays to evaluate protein localization, endothelial cell permeability, and small GTPase activation. RESULTS: Our data show that DOCK4-deficient mice are viable. However, these mice have hemorrhage selectively in the lung, incomplete smooth muscle cell coverage in pulmonary vessels, increased basal microvascular permeability, and impaired response to S1P (sphingosine-1-phosphate)-induced reversal of thrombin-induced permeability. Consistent with this, DOCK4 rapidly translocates to the cell periphery and associates with the detergent-insoluble fraction following S1P treatment, and its absence prevents S1P-induced Rac-1 activation and enhancement of barrier function. Moreover, DOCK4-silenced pulmonary artery endothelial cells exhibit enhanced basal permeability in vitro that is associated with enhanced Rho GTPase activation. CONCLUSIONS: Our findings indicate that DOCK4 maintains AJs necessary for lung vascular barrier function by establishing the normal balance between RhoA (Ras homolog family member A) and Rac-1-mediated actin cytoskeleton remodeling, a previously unappreciated function for the atypical GEF family of molecules. Our studies also identify S1P as a potential upstream regulator of DOCK4 activity.

Vitamin D status in very low birth weight infants and response to vitamin D intake during their NICU stays: a prospective cohort study.

OBJECTIVE: To evaluate vitamin D status in very low birth weight (VLBW) infants and response to vitamin D intake. STUDY DESIGN: In this prospective cohort study of VLBW infants, 25-hydroxyvitamin D [25(OH)D] was measured regularly starting at birth. Daily vitamin D intake was estimated from parenteral and enteral sources. RESULTS: Of the included 83 infants born between November 2016 and March 2018, 44 (53%) had 25(OH)D < 30 ng/mL at birth but achieved vitamin D sufficiency (VDS) by 3 weeks while receiving 120-400 IU/day. Twenty-three (27.7%) infants had at least one 25(OH)D level >100 ng/mL during the study period. Infants whose intake was > 600 IU/day had higher prevalence of vitamin D excess (VDE). CONCLUSION: In our study, low 25(OH)D was common in VLBW infants at birth. Vitamin D intake of 120-260 IU/day from parenteral and 200-400 IU/day from enteral route was appropriate for VLBW infants to achieve VDS. Doses > 600 IU/day increased risk of VDE.

Training Pre-Service Teachers to Better Serve LGBTQ High School Students.

Pre-service teachers rarely receive training on how best to serve lesbian, gay, bisexual, transgender, and queer (LGBTQ) high school students. We tested whether participating in LGBTQ-focused service-based learning or LGBTQ-focused didactic training improved pre-service teachers' knowledge, attitudes, self-efficacy, and skills for serving LGBTQ high school students more than a control group. A non-randomised pre-test-post-test design with eighty-eight participants tested these differences. At post-test, the service-based learning group had significantly higher active-empathic listening and self-efficacy for working with LGBTQ high school students than the control group. There were no differences for didactic versus control groups. Overall, service-based learning may better prepare pre-service teachers to serve LGBTQ high school students.

Examining the Associations between Indigenous Rangers, Culture and Wellbeing in Australia, 2018-2020.

The centrality of culture to Indigenous peoples' health and wellbeing is becoming increasingly acknowledged in government policy. In Australia, the Indigenous Ranger program is a leading example of employment that supports increased cultural participation. In 2017, we demonstrated higher life satisfaction and family wellbeing among Indigenous Rangers compared to non-Rangers in Central Australia. Using an expanded national dataset, this present study aimed to: examine if associations between Ranger status and wellbeing continued to be observed in Central Australia; assess if these associations were observed among non-Central Australian Rangers; and, quantify the effect of mediating variables (Rangers status, cultural factors) on wellbeing outcomes. We analyzed Mayi Kuwayu baseline data (n = 9691 Aboriginal and Torres Strait Islander people) and compared participants who identified as past or currently employed Rangers compared to non-Rangers across two geographic locations (Central Australia, non-Central Australia). Ranger participation was significantly associated with very high life satisfaction and family wellbeing in Central Australia (high life satisfaction PR 1.31, 95% CI 1.09-1.57, and family wellbeing (PR 1.17, 95% CI 1.01-1.36) and non-Central Australia (high life satisfaction PR 1.29, 95% CI 1.06-1.57), family wellbeing (PR 1.37, 95% CI 1.14-1.65). These findings concord with those observed in the 2017 proof-of-concept study. Additionally, we found that Ranger status partially mediated the relationships between existing cultural practices (first language as your Indigenous language and living on your country) and the two wellbeing outcomes. Current cultural practices, spending time on country and speaking your Aboriginal language, also partially mediated the associations between Ranger status and high life satisfaction, and between Ranger status and high family wellbeing. This analysis supports evidence that both Ranger employment and cultural participation are contributors to wellbeing. Ranger work is not only good for land, but it is good for people. As such, determining policies that mutually acknowledge and enhance culture, health and wellbeing will likely have additional benefits for the broader Aboriginal and Torres Strait Islander population.

Parental Perception of the Factors that Affect Diabetes Management in Youth.

IN BRIEF Diabetes management is challenging for youth. We developed a theoretical framework for the facilitators and barriers to diabetes management in youth from the perspective of parents.

ADIPOR1 is essential for vision and its RPE expression is lost in the Mfrprd6 mouse.

The knockout (KO) of the adiponectin receptor 1 (AdipoR1) gene causes retinal degeneration. Here we report that ADIPOR1 protein is primarily found in the eye and brain with little expression in other tissues. Further analysis of AdipoR1 KO mice revealed that these animals exhibit early visual system abnormalities and are depleted of RHODOPSIN prior to pronounced photoreceptor death. A KO of AdipoR1 post-development either in photoreceptors or the retinal pigment epithelium (RPE) resulted in decreased expression of retinal proteins, establishing a role for ADIPOR1 in supporting vision in adulthood. Subsequent analysis of the Mfrprd6 mouse retina demonstrated that these mice are lacking ADIPOR1 in their RPE layer alone, suggesting that loss of ADIPOR1 drives retinal degeneration in this model. Moreover, we found elevated levels of IRBP in both the AdipoR1 KO and the Mfrprd6 models. The spatial distribution of IRBP was also abnormal. This dysregulation of IRBP hypothesizes a role for ADIPOR1 in retinoid metabolism.

Associations between Participation in a Ranger Program and Health and Wellbeing Outcomes among Aboriginal and Torres Strait Islander People in Central Australia: A Proof of Concept Study.

Culture can be viewed as an integral part of Aboriginal and Torres Strait Islander health and wellbeing. This study explores the association between caring for country, through participation in a Ranger program, and wellbeing. We analyzed cross-sectional data collected in Central Australia in 2017, comparing health and wellbeing (life satisfaction, general health, psychological wellbeing and family wellbeing) among Aboriginal and Torres Strait Islander peoples employed as Rangers (n = 43) versus not employed as Rangers (n = 160). We tested if any differences in outcomes were explained by differences in key demographic or health factors. Ranger participation was significantly associated with very high life satisfaction (PR = 1.69, 95% CI: 1.29, 2.20) and high family wellbeing (PR = 1.47, 95% CI: 1.13, 1.90); associations remained significant after individual adjustment for education, income, employment, health risk factors and health conditions. The magnitude and direction of associations were similar for very good general health, but results were not significant. We did not identify an association between Ranger participation and psychological wellbeing. While based on a small sample, these findings support the assertion that participation in the Ranger program is associated with positive health and wellbeing outcomes. This supports the continuation of cultural participation and practice through the Ranger program and has implications for funding, program and policy development.

Impact of vaccine mandate on Tdap vaccination coverage among Illinois students 2014-15.

In response to recent pertussis resurgence, a multi-agency recommendation that students receive a one-time Tdap vaccine was introduced. Post mandate there was sequential increase in the Tdap vaccine uptake in the targeted population.

TMEM203 Is a Novel Regulator of Intracellular Calcium Homeostasis and Is Required for Spermatogenesis.

Intracellular calcium signaling is critical for initiating and sustaining diverse cellular functions including transcription, synaptic signaling, muscle contraction, apoptosis and fertilization. Trans-membrane 203 (TMEM203) was identified here in cDNA overexpression screens for proteins capable of modulating intracellular calcium levels using activation of a calcium/calcineurin regulated transcription factor as an indicator. Overexpression of TMEM203 resulted in a reduction of Endoplasmic Reticulum (ER) calcium stores and elevation in basal cytoplasmic calcium levels. TMEM203 protein was localized to the ER and found associated with a number of ER proteins which regulate ER calcium entry and efflux. Mouse Embryonic Fibroblasts (MEFs) derived from Tmem203 deficient mice had reduced ER calcium stores and altered calcium homeostasis. Tmem203 deficient mice were viable though male knockout mice were infertile and exhibited a severe block in spermiogenesis and spermiation. Expression profiling studies showed significant alternations in expression of calcium channels and pumps in testes and concurrently Tmem203 deficient spermatocytes demonstrated significantly altered calcium handling. Thus Tmem203 is an evolutionarily conserved regulator of cellular calcium homeostasis, is required for spermatogenesis and provides a causal link between intracellular calcium regulation and spermiogenesis.

Adrenocorticotropic hormone and cortisol levels in term infants born with meconium-stained amniotic fluid.

OBJECTIVE: To evaluate cord blood concentrations of adrenocorticotropic hormone (ACTH) and cortisol in well term infants born with and without meconium-stained amniotic fluid (MSAF) and term infants born with MSAF who experienced respiratory distress (RD). STUDY DESIGN: This was a prospective observational study. Fifty-four term infants were enrolled in the study in three groups: group 1 consisted of 18 well infants who were born with clear amniotic fluid, group 2 had 18 well infants born with MSAF, and group 3 had 18 infants born with MSAF who experienced RD in the first 24 h of age. Cord blood ACTH and cortisol concentrations were measured in infants born in all three groups. Groups 2 and 3 had serum ACTH and cortisol levels re-measured at 22-26 h of age. RESULT: The mean ACTH and cortisol levels at birth in group 3 infants were 18.3 pg/mL and 12.6 mg/dL, respectively. These were significantly lower than those in group 2 infants. CONCLUSION: Term infants born with MSAF and who experienced respiratory distress had significantly lower levels of ACTH and cortisol at birth compared with well term infants born with MSAF or clear amniotic fluid. This study suggests that inadequate response of ACTH and cortisol hormones may play a role in the development of respiratory distress in term infants with MSAF.

Pancreatic ductal adenocarcinoma is associated with a distinct urinary metabolomic signature.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with poor prognosis in part due to the lack of early detection and screening methods. Metabolomics provides a means for noninvasive screening of tumor-associated perturbations in cellular metabolism. METHODS: Urine samples of PDAC patients (n = 32), healthy age and gender-matched controls (n = 32), and patients with benign pancreatic conditions (n = 25) were examined using (1)H-NMR spectroscopy. Targeted profiling of spectra permitted quantification of 66 metabolites. Unsupervised (principal component analysis, PCA) and supervised (orthogonal partial-least squares discriminant analysis, OPLS-DA) multivariate pattern recognition techniques were applied to discriminate between sample spectra using SIMCA-P(+) (version 12, Umetrics, Sweden). RESULTS: Clear distinction between PDAC and controls was noted when using OPLS-DA. Significant differences in metabolite concentrations between cancers and controls (p < 0.001) were noted. Model parameters for both goodness of fit, and predictive capability were high (R (2) = 0.85; Q (2) = 0.59, respectively). Internal validation methods were used to confirm model validity. Sensitivity and specificity of the multivariate OPLS-DA model were summarized using a receiver operating characteristics (ROC) curve, with an area under the curve (AUROC) = 0.988, indicating strong predictive power. Preliminary analysis revealed an AUROC = 0.958 for the model of benign pancreatic disease compared with PDAC, and suggest that the cancer-associated metabolomic signature dissipates following RO resection. CONCLUSIONS: Urinary metabolomics detected distinct differences in the metabolic profiles of pancreatic cancer compared with healthy controls and benign pancreatic disease. These preliminary results suggest that metabolomic approaches may facilitate discovery of novel pancreatic cancer biomarkers.

Urinary metabolomic signature of esophageal cancer and Barrett's esophagus.

BACKGROUND: Esophageal adenocarcinoma (EAC) often presents at a late, incurable stage, and mortality has increased substantially, due to an increase in incidence of EAC arising out of Barrett's esophagus. When diagnosed early, however, the combination of surgery and adjuvant therapies is associated with high cure rates. Metabolomics provides a means for non- invasive screening of early tumor-associated perturbations in cellular metabolism. METHODS: Urine samples from patients with esophageal carcinoma (n = 44), Barrett's esophagus (n = 31), and healthy controls (n = 75) were examined using (1)H-NMR spectroscopy. Targeted profiling of spectra using Chenomx software permitted quantification of 66 distinct metabolites. Unsupervised (principal component analysis) and supervised (orthogonal partial least-squares discriminant analysis OPLS-DA) multivariate pattern recognition techniques were applied to discriminate between samples using SIMCA-P(+) software. Model specificity was also confirmed through comparison with a pancreatic cancer cohort (n = 32). RESULTS: Clear distinctions between esophageal cancer, Barrett's esophagus and healthy controls were noted when OPLS-DA was applied. Model validity was confirmed using two established methods of internal validation, cross-validation and response permutation. Sensitivity and specificity of the multivariate OPLS-DA models were summarized using a receiver operating characteristic curve analysis and revealed excellent predictive power (area under the curve = 0.9810 and 0.9627 for esophageal cancer and Barrett's esophagus, respectively). The metabolite expression profiles of esophageal cancer and pancreatic cancer were also clearly distinguishable with an area under the receiver operating characteristics curve (AUROC) = 0.8954. CONCLUSIONS: Urinary metabolomics identified discrete metabolic signatures that clearly distinguished both Barrett's esophagus and esophageal cancer from controls. The metabolite expression profile of esophageal cancer was also discrete from its precursor lesion, Barrett's esophagus. The cancer-specific nature of this profile was confirmed through comparison with pancreatic cancer. These preliminary results suggest that urinary metabolomics may have a future potential role in non-invasive screening in these conditions.

Metabolomics and surgical oncology: Potential role for small molecule biomarkers.

Metabolomics, the newest of the "omics" sciences, has brought much excitement to the field of oncology as a potential new translational tool capable of bringing the molecular world of cancer care to the bedside. While still early in its development, metabolomics could alter the scope and role of surgery in the multidisciplinary treatment of cancer. This review examines potential roles of metabolomics in areas of early cancer detection, personalized therapeutics and tumorigenesis.

Change in human social behavior in response to a common vaccine.

PURPOSE: The purpose of this study was to test the hypothesis that exposure to a directly transmitted human pathogen-flu virus-increases human social behavior presymptomatically. This hypothesis is grounded in empirical evidence that animals infected with pathogens rarely behave like uninfected animals, and in evolutionary theory as applied to infectious disease. Such behavioral changes have the potential to increase parasite transmission and/or host solicitation of care. METHODS: We carried out a prospective, longitudinal study that followed participants across a known point-source exposure to a form of influenza virus (immunizations), and compared social behavior before and after exposure using each participant as his/her own control. RESULTS: Human social behavior does, indeed, change with exposure. Compared to the 48 hours pre-exposure, participants interacted with significantly more people, and in significantly larger groups, during the 48 hours immediately post-exposure. CONCLUSIONS: These results show that there is an immediate active behavioral response to infection before the expected onset of symptoms or sickness behavior. Although the adaptive significance of this finding awaits further investigation, we anticipate it will advance ecological and evolutionary understanding of human-pathogen interactions, and will have implications for infectious disease epidemiology and prevention.

Trypanosome trans-sialidase mediates neuroprotection against oxidative stress, serum/glucose deprivation, and hypoxia-induced neurite retraction in Trk-expressing PC12 cells.

Trypanosome trans-sialidase (TS) is a sialic acid-transferring enzyme and a novel ligand of tyrosine kinase (TrkA) receptors but not of neurotrophin receptor p75NTR. Here, we show that TS targets TrkB receptors on TrkB-expressing pheochromocytoma PC12 cells and colocalizes with TrkB receptor internalization and phosphorylation (pTrkB). Wild-type TS but not the catalytically inactive mutant TSDeltaAsp98-Glu induces pTrkB and mediates cell survival responses against death caused by oxidative stress in TrkA- and TrkB-expressing cells like those seen with nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). These same effects are not observed in Trk deficient PC12(nnr5) cells, but are re-established in PC12(nnr5) cells stably transfected with TrkA or TrkB, are partially blocked by inhibitors of tyrosine kinase (K-252a), mitogen-activated protein/mitogen-activated kinase (PD98059) and completely blocked by LY294002, an inhibitor of phosphatidylinositol 3-kinase (PI3K). Both TrkA- and TrkB-expressing cells pretreated with TS or their natural ligands are protected against cell death caused by serum/glucose deprivation or from hypoxia-induced neurite retraction. The cell survival effects of NGF and BDNF against oxidative stress are significantly inhibited by the neuraminidase inhibitor, Tamiflu. Together, these observations suggest that trypanosome TS mimics neurotrophic factors in cell survival responses against oxidative stress, hypoxia-induced neurite retraction and serum/glucose deprivation.