Multiomics Characterization of Preterm Birth in Low- and Middle-Income Countries.

Importance: Worldwide, preterm birth (PTB) is the single largest cause of deaths in the perinatal and neonatal period and is associated with increased morbidity in young children. The cause of PTB is multifactorial, and the development of generalizable biological models may enable early detection and guide therapeutic studies. Objective: To investigate the ability of transcriptomics and proteomics profiling of plasma and metabolomics analysis of urine to identify early biological measurements associated with PTB. Design, Setting, and Participants: This diagnostic/prognostic study analyzed plasma and urine samples collected from May 2014 to June 2017 from pregnant women in 5 biorepository cohorts in low- and middle-income countries (LMICs; ie, Matlab, Bangladesh; Lusaka, Zambia; Sylhet, Bangladesh; Karachi, Pakistan; and Pemba, Tanzania). These cohorts were established to study maternal and fetal outcomes and were supported by the Alliance for Maternal and Newborn Health Improvement and the Global Alliance to Prevent Prematurity and Stillbirth biorepositories. Data were analyzed from December 2018 to July 2019. Exposures: Blood and urine specimens that were collected early during pregnancy (median sampling time of 13.6 weeks of gestation, according to ultrasonography) were processed, stored, and shipped to the laboratories under uniform protocols. Plasma samples were assayed for targeted measurement of proteins and untargeted cell-free ribonucleic acid profiling; urine samples were assayed for metabolites. Main Outcomes and Measures: The PTB phenotype was defined as the delivery of a live infant before completing 37 weeks of gestation. Results: Of the 81 pregnant women included in this study, 39 had PTBs (48.1%) and 42 had term pregnancies (51.9%) (mean [SD] age of 24.8 [5.3] years). Univariate analysis demonstrated functional biological differences across the 5 cohorts. A cohort-adjusted machine learning algorithm was applied to each biological data set, and then a higher-level machine learning modeling combined the results into a final integrative model. The integrated model was more accurate, with an area under the receiver operating characteristic curve (AUROC) of 0.83 (95% CI, 0.72-0.91) compared with the models derived for each independent biological modality (transcriptomics AUROC, 0.73 [95% CI, 0.61-0.83]; metabolomics AUROC, 0.59 [95% CI, 0.47-0.72]; and proteomics AUROC, 0.75 [95% CI, 0.64-0.85]). Primary features associated with PTB included an inflammatory module as well as a metabolomic module measured in urine associated with the glutamine and glutamate metabolism and valine, leucine, and isoleucine biosynthesis pathways. Conclusions and Relevance: This study found that, in LMICs and high PTB settings, major biological adaptations during term pregnancy follow a generalizable model and the predictive accuracy for PTB was augmented by combining various omics data sets, suggesting that PTB is a condition that manifests within multiple biological systems. These data sets, with machine learning partnerships, may be a key step in developing valuable predictive tests and intervention candidates for preventing PTB

Prediction of gestational age using urinary metabolites in term and preterm pregnancies.

Assessment of gestational age (GA) is key to provide optimal care during pregnancy. However, its accurate determination remains challenging in low- and middle-income countries, where access to obstetric ultrasound is limited. Hence, there is an urgent need to develop clinical approaches that allow accurate and inexpensive estimations of GA. We investigated the ability of urinary metabolites to predict GA at time of collection in a diverse multi-site cohort of healthy and pathological pregnancies (n = 99) using a broad-spectrum liquid chromatography coupled with mass spectrometry (LC-MS) platform. Our approach detected a myriad of steroid hormones and their derivatives including estrogens, progesterones, corticosteroids, and androgens which were associated with pregnancy progression. We developed a restricted model that predicted GA with high accuracy using three metabolites (rho = 0.87, RMSE = 1.58 weeks) that was validated in an independent cohort (n = 20). The predictions were more robust in pregnancies that went to term in comparison to pregnancies that ended prematurely. Overall, we demonstrated the feasibility of implementing urine metabolomics analysis in large-scale multi-site studies and report a predictive model of GA with a potential clinical value

Early mobilisation in critically ill COVID-19 patients: a subanalysis of the ESICM-initiated UNITE-COVID observational study

Background Early mobilisation (EM) is an intervention that may improve the outcome of critically ill patients. There is limited data on EM in COVID-19 patients and its use during the first pandemic wave. Methods This is a pre-planned subanalysis of the ESICM UNITE-COVID, an international multicenter observational study involving critically ill COVID-19 patients in the ICU between February 15th and May 15th, 2020. We analysed variables associated with the initiation of EM (within 72 h of ICU admission) and explored the impact of EM on mortality, ICU and hospital length of stay, as well as discharge location. Statistical analyses were done using (generalised) linear mixed-effect models and ANOVAs. Results Mobilisation data from 4190 patients from 280 ICUs in 45 countries were analysed. 1114 (26.6%) of these patients received mobilisation within 72 h after ICU admission; 3076 (73.4%) did not. In our analysis of factors associated with EM, mechanical ventilation at admission (OR 0.29; 95% CI 0.25, 0.35; p = 0.001), higher age (OR 0.99; 95% CI 0.98, 1.00; p ≤ 0.001), pre-existing asthma (OR 0.84; 95% CI 0.73, 0.98; p = 0.028), and pre-existing kidney disease (OR 0.84; 95% CI 0.71, 0.99; p = 0.036) were negatively associated with the initiation of EM. EM was associated with a higher chance of being discharged home (OR 1.31; 95% CI 1.08, 1.58; p = 0.007) but was not associated with length of stay in ICU (adj. difference 0.91 days; 95% CI − 0.47, 1.37, p = 0.34) and hospital (adj. difference 1.4 days; 95% CI − 0.62, 2.35, p = 0.24) or mortality (OR 0.88; 95% CI 0.7, 1.09, p = 0.24) when adjusted for covariates. Conclusions Our findings demonstrate that a quarter of COVID-19 patients received EM. There was no association found between EM in COVID-19 patients' ICU and hospital length of stay or mortality. However, EM in COVID-19 patients was associated with increased odds of being discharged home rather than to a care facility. Trial registration ClinicalTrials.gov: NCT04836065 (retrospectively registered April 8th 2021)

Metabolic profiling of follistatin overexpression: a novel therapeutic strategy for metabolic diseases

Rajan Singh,1,2 Shehla Pervin,1,2 Se-Jin Lee,3,4 Alan Kuo,5 Victor Grijalva,6 John David,7 Laurent Vergnes,8 Srinivasa T Reddy1,6 1Department of Obstetrics and Gynecology, UCLA School of Medicine, Los Angeles, CA, USA; 2Division of Endocrinology and Metabolism, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA; 3The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA; 4Department of Genetics and Genome Sciences, University of Connecticut School of Medicine, CT, USA; 5Department of Biology, California State University Dominguez Hills, CA, USA; 6Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, CA, USA; 7Department of Comparative Medicine, Pfizer Inc, San Diego, CA, USA; 8Department of Human Genetics, UCLA School of Medicine, Los Angeles, CA, USA Background: Follistatin (Fst) promotes brown adipocyte characteristics in adipose tissues.Methods: Abdominal fat volume (CT scan), glucose clearance (GTT test), and metabolomics analysis (mass spectrometry) of adipose tissues from Fst transgenic (Fst-Tg) and wild type (WT) control mice were analyzed. Oxygen consumption (Seahorse Analyzer) and lipidomics (gas chromatography) was analyzed in 3T3-L1 cells.Results: Fst-Tg mice show significant decrease in abdominal fat content, increased glucose clearance, improved plasma lipid profiles and significant changes in several conventional metabolites compared to the WT mice. Furthermore, overexpression of Fst in 3T3-L1 cells resulted in up regulation of key brown/beige markers and changes in lipidomics profiles. Conclusion: Fst modulates key factors involved in promoting metabolic syndrome and could be used for therapeutic intervention. Keywords: follistatin, transgenic, adipocyte, fibroblast growth factor 21, Adipo

The effectiveness of behaviour change interventions delivered by non-dental health workers in promoting children’s oral health: A systematic review and meta-analysis

Objectives: Dental caries is the most common preventable childhood condition. Non-dental professionals and health workers are often well placed to support parents in adopting positive oral health behaviours for their children. The aim of this study was to determine the effectiveness of behaviour change interventions and their individual component behaviour change techniques (BCTs), that were delivered by non-dental professionals and health workers. Methods: A systematic search of Ovid MEDLINE, PubMed, CINAHL, Cochrane Library, Web of Science, TRoPHI and PROQUEST from inception until March 2021 was conducted. Randomised controlled trials and quasi-experimental studies for improving oral health outcomes in children were included. Quality assessment was carried out using Cochrane Risk of Bias tool and ROBINS-I tool. Publication bias was assessed using funnel plots and Egger’s regression intercept. Effect sizes were estimated as standardised mean difference (SMD) and odds ratio/risk ratio for proportions. Meta-analyses were performed for studies reporting mean decayed, missing, filled surfaces (dmfs) and mean decayed, missing, filled, teeth (dmft) indices. Behaviour change technique coding was performed using behaviour change technique taxonomy v1 (BCTTv1). Results: Out of the 9,101 records retrieved, 36 studies were included with 28 showing a significant effect either in clinical and/or behavioural/knowledge outcomes. Most studies (n = 21) were of poor methodological quality. The pooled SMD for caries experience showed statistically significant result for caries prevention at surface level -0.15 (95% CI -0.25, -0.04) and at the tooth level -0.24 (95% CI -0.42, -0.07). In 28 effective interventions, 27 individual BCTs were identified and the most frequently used were: “Instructions on how to perform the behaviour” and “Information about health consequences”. Conclusion: There is low quality of evidence suggesting non-dental professionals and health workers may help improve oral health outcomes for children. To confirm these findings, further high-quality studies incorporating a variety of BCTs in their interventions for adoption of good oral health behaviours are needed

Jungle Fever : Kohderyhmätutkimuksen hyödyntäminen vaatemalliston suunnittelussa

Tämän opinnäytetyön aiheena on miesten malliston suunnittelu kohderyhmätutkimuksen pohjalta. Työ tehtiin yhteistyössä kotimaisen nuoriso/street/fashion-vaatemerkin, CTRL Clothing Oy:n kanssa. Työn tavoitteena oli luoda miesten mallisto, esitellä yritykselle uusi kohderyhmätutkimuksen pohjalta luotu tyyli ja tuoda mallistojen suunnitteluun täysin uusi näkökulma. Tutkimusmenetelmänä käytettiin internetkyselyä, joka julkaistiin CTRL:n Facebook-sivulla. Tutkimusmalli yhdistää määrällistä ja laadullista tutkimusta ja selvittää, mitä mieltä CTRL:n asiakkaat ovat yrityksestä ja heidän tuotteistaan. Tutkimustulosten avulla luotiin malliston visuaalinen ilme, jonka lisäksi tutkimustulokset luovutettiin yrityksen vapaaseen käyttöön. Malliston suunnittelussa otettiin tutkimustulosten lisäksi huomioon CTRL:n aikaisemmat mallistot sekä tulevat trendit. Mallistoon suunniteltiin tasokuvina 22 tuotetta kevät/kesä 2014 -kaudelle. Malliston suunnittelussa keskityttiin enemmän printteihin ja kuoseihin kuin varsinaisiin vaatemalleihin. Taiteellisen työn lähtökohtana toimi yksinomaan kyselytutkimuksesta saadut tulokset ja suunnittelijan näkemys. Toimeksiantajalle esiteltiin lopullinen mallisto jossa kyselytutkimuksen tulokset oli hyödynnetty.The subject for this thesis was designing a men's collection by applying a target audience research. The Thesis was made in collaboration with a Finnish youth/street/fashion -label CTRL Clothing. The goal was to build a collection, present a new style defined from the research and bring a completely new angle to the design process. The used research method was an Internet survey that was published on CTRL's Facebook page. The research model combining both quantitative and qualitative research methods examined how the customers felt about CTRL as a clothing label and their products. The results were used to create a new visual style for the collection. The research results were also handed over to the company for free use. In addition to the research results, previous CTRL collections and trends were also taken into attention in the design process. The collection consists of 22 products that were designed for the spring/summer 2014 season as flat technical drawings. Prints and patterns played a bigger role in the design process than the actual clothing models. The artistic part of the design process was based solely on the survey results and artist's view. The final collection that made use of the results was presented to the principal company

Very low doses of ionizing radiation and redox associated modifiers affect survivin-associated changes in radiation sensitivity

Exposure of cells to a dose of ionizing radiation as low as 5mGy can induce changes in radiation sensitivity expressed by cells exposed to subsequent higher doses at later times. This is referred to as an adaptive effect. We describe a unique survivin-associated adaptive response in which increased radiation resistance or sensitization of cells can be induced by exposure to 5mGy or to the reactive oxygen species (ROS) generating drug Emodin (1,3,8-trihydroxy-6-methylanthraquinone), a naturally occurring anthraquinone. The purpose of this study was to determine the role of ROS generating processes in affecting both the intracellular localization of the inhibitor of apoptosis protein survivin and its subsequent effect on radiation response in the presence or absence of the anti-oxidant N-acetyl-L-cysteine (NAC). Experiments were performed using two well characterized murine sarcomas: SA-NH p53 wild-type (WT) and FSa p53 mutant (Mut), grown either in culture or as solid tumors in the right hind legs of C3H mice. Doses of 5mGy or 50μM Emodin were used to induce changes in the response of these tumor cells to higher radiation exposures using a multi-dosing paradigm. Effects on radiation sensitivity were determined for SA-NH and FSa cells as a function of survivin translocation either to the cytoplasm or nucleus in the presence or absence of 10mM NAC treatment. In vitro survival assays (2Gy per fraction, two once daily fractions) and tumor growth delay (TGD) (5Gy per fraction, five once daily fractions) studies were performed. Intracellular localization of survivin was determined by enzyme-linked immunosorbent assay (ELISA) and correlated to survival response and treatment conditions. 2Gy alone had no effect on intracellular translocation of survivin. When preceded 15min earlier by 5mGy or Emodin exposures, survivin became elevated in the cytoplasm of p53 WT SA-NH as compared to the nuclei of p53 Mut FSa cells. SA-NH cells transfected with p53 small interfering RNA (siRNA), in contrast, responded similarly to p53 Mut FSa cells by becoming more radiation sensitive if exposed to 5mGy prior to each 2Gy irradiation. In contrast to their respective responses to five once daily 5Gy fractions, SA-NH tumors were protected by 5mGy exposures administered 15min prior to each daily 5Gy dose as evidenced by a more rapid growth (1.9 day decrease in TGD, P=0.032), while FSa tumors were sensitized, growing at a much slower rate (4.5 day increase in TGD, P<0.001). Exposure of SA-NH and FSa tumor cells to 10mM NAC inhibited the ability of 5mGy and Emodin to induce intracellular translocation of survivin and the corresponding altered adaptive survival response. The survivin-associated adaptive response can be induced following a multi-dosing scheme in which very low radiation doses are followed shortly thereafter by higher doses consistent with a standard image guided radiotherapy protocol that is currently widely used in the treatment of cancer. While induced by exposure to ROS generating stresses, the ultimate expression of changes in radiation response is dependent upon the bi-functionality of the tumor associated protein survivin and its intracellular translocation