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From a forward mutagenetic screen to discover mutations associated with obesity, we identified mutations in the Spag7 gene linked to metabolic dysfunction in mice. Here, we show that SPAG7 KO mice are born smaller and develop obesity and glucose intolerance in adulthood. This obesity does not stem from hyperphagia, but a decrease in energy expenditure. The KO animals also display reduced exercise tolerance and muscle function due to impaired mitochondrial function. Furthermore, SPAG7-deficiency in developing embryos leads to intrauterine growth restriction, brought on by placental insufficiency, likely due to abnormal development of the placental junctional zone. This insufficiency leads to loss of SPAG7-deficient fetuses in utero and reduced birth weights of those that survive. We hypothesize that a ‘thrifty phenotype’ is ingrained in SPAG7 KO animals during development that leads to adult obesity. Collectively, these results indicate that SPAG7 is essential for embryonic development and energy homeostasis later in life.

Abstract Background Gestational diabetes mellitus (GDM) and type 2 diabetes mellitus (T2DM) share many pathophysiological factors including genetics, but whether epigenetic marks are shared is unknown. We aimed to test whether a DNA methylation risk score (MRS) for T2DM was associated with GDM across ancestry and GDM criteria. Methods In two independent pregnancy cohorts, EPIPREG (n = 480) and EPIDG (n = 32), DNA methylation in peripheral blood leukocytes was measured at a gestational age of 28 ± 2. We constructed an MRS in EPIPREG and EPIDG based on CpG hits from a published epigenome-wide association study (EWAS) of T2DM. Results With mixed models logistic regression of EPIPREG and EPIDG, MRS for T2DM was associated with GDM: odd ratio (OR)[95% CI]: 1.3 [1.1–1.8], P = 0.002 for the unadjusted model, and 1.4 [1.1–1.7], P = 0.00014 for a model adjusted by age, pre-pregnant BMI, family history of diabetes and smoking status. Also, we found 6 CpGs through a meta-analysis (cg14020176, cg22650271, cg14870271, cg27243685, cg06378491, cg25130381) associated with GDM, and some of their methylation quantitative loci (mQTLs) were related to T2DM and GDM. Conclusion For the first time, we show that DNA methylation marks for T2DM are also associated with GDM, suggesting shared epigenetic mechanisms between GDM and T2DM.

This study recognizes the diversity and heterogeneous nature of a migrant group that long has been portrayed and perceived in a limited way, for instance in Norwegian media, without considering the multifaceted nature of the group in question. Drawing on data from focus group interviews, we apply narrative analysis to shed light on the impact stereotypes surrounding Poles have on Polish adult migrants’ striving for social inclusion and professional success in Norway. Being the largest migrant group in Norway, speaking a first language (L1) structurally different from Norwegian, and representing a former Eastern Bloc country, Poles constitute an important case to gain better knowledge of the interplay between language, labour, and social inclusion. Through our study, we aim to gain emic insights into parts of the process of settling in Norway. Our analysis centres on a case study of two focus group participants’ reactions to stereotypical portrayals of Polish (professionals) in Norwegian media, experiences with language learning, and the advice they would give to newcomers, as well as the importance of a sense of community for gaining the “small talk” competence necessary to ease social inclusion. The analysis draws on the key concepts of agency, investment, and well‐being. We show how the tension that occurs when second language (L2) participants are confronted with stereotypes may create a discursive space for empowerment and agency through the opportunity to contest and re‐create (professional) expectancies. The study also demonstrates that there most likely are ways forward to more inclusive practices for Polish migrants in Norway.

Objectives: In vitro fertilization (IVF) has the potential to give babies to millions more people globally, yet it continues to be underutilized. We established a globally applicable and locally adaptable IVF prognostics report and framework to support patient–provider counseling and enable validated, data-driven treatment decisions. This study investigates the IVF utilization rates associated with the usage of machine learning, center-specific (MLCS) prognostic reports (the Univfy® report) in provider-patient pre-treatment and IVF counseling. Methods: We used a retrospective cohort comprising 24,238 patients with new patient visits (NPV) from 2016 to 2022 across seven fertility centers in 17 locations in seven US states and Ontario, Canada. We tested the association of Univfy report usage and first intra-uterine insemination (IUI) and/or first IVF usage (a.k.a. conversion) within 180 days, 360 days, and “Ever” of NPV as primary outcomes. Results: Univfy report usage was associated with higher direct IVF conversion (without prior IUI), with odds ratios (OR) 3.13 (95% CI 2.83, 3.46), 2.89 (95% CI 2.63, 3.17), and 2.04 (95% CI 1.90, 2.20) and total IVF conversion (with or without prior IUI), OR 3.41 (95% CI 3.09, 3.75), 3.81 (95% CI 3.49, 4.16), and 2.78 (95% CI 2.59, 2.98) in 180-day, 360-day, and Ever analyses, respectively; p < 0.05. Among patients with Univfy report usage, after accounting for center as a factor, older age was a small yet independent predictor of IVF conversion. Conclusions: Usage of a patient-centric, MLCS-based prognostics report was associated with increased IVF conversion among new fertility patients. Further research to study factors influencing treatment decision making and real-world optimization of patient-centric workflows utilizing the MLCS reports is warranted.

Denne artikkelen presenterer en metodisk framgangsmåte som innlemmer humoristiske videoinnslag i fokusgruppesamtaler med talere av norsk som andrespråk. Framgangsmåten er testet ut i et prosjekt der vi blant annet har undersøkt hvordan stereotypier spiller inn på språklæring og kommunikasjon blant voksne polske innvandrere i Norge. Dette temaet kan være ganske sensibelt, og for å gjøre det mindre krevende har vi startet samtalene ved først å vise klipp fra tre ulike, forsøksvis humoristiske framstillinger av møter mellom polakker og nordmenn, som alle har vært sendt på norsk TV. Disse framstillingene er – som ofte ellers i norske medietekster – nokså ensidige og basert på stereotypiske forventninger både til kjønn, språkkompetanse, yrke og adferd. Klippene har vist seg å frembringe interessante data som kommer inn på forhold som det i utgangspunktet kan være krevende å dele med fremmede forskere. Å se stereotypier og emosjoner i sammenheng har vist seg å være fruktbart, og vi mener at bruken av videostimuli – og særlig de som er ment å være humoristiske – tilfører en ekstra dimensjon til fokusgruppemetodikken, ikke minst når deltakeres egne erfaringer står i sentrum. Studier av forestillinger om f.eks. dialektal variasjon, nasjonale minoritetsspråk og andre innvandrerspråk enn polsk kan trolig skos over samme lest som studien vår, for erfaringene våre er at humor og videostimuli kan utvide perspektivet og inspirere deltakere til å bidra med viktige innsikter i identitetskonstruksjoner, andrespråklæring og -bruk.

Abstract Karst aquifers are a vital groundwater resource globally, but features such as rapid recharge and conduit flow make them highly vulnerable to land‐surface contamination. We apply environmental age tracers to the south‐central Texas Edwards aquifer, a karst resource in a rapidly urbanizing and drought‐prone region, to assess vulnerability to land‐surface contamination and risks unique to karst aquifers. We show that vulnerability of Edwards aquifer groundwater follows similar spatial and depth patterns common to porous‐media type aquifers, despite complicated karst hydrogeologic features. Shallow and unconfined parts are more vulnerable to land‐surface contamination than the deeper and confined parts, although even the oldest groundwater is mixed with some recent recharge. When modeled age‐tracer results are coupled with other independent geochemical tracers of water‐rock interaction specific to karst settings, they can yield insight into residence time and associated vulnerability.

The urgent need for massively scaled clinical or surveillance testing for SARS-CoV-2 has necessitated a reconsideration of the methods by which respiratory samples are collected, transported, processed and tested. Conventional testing for SARS-CoV-2 involves collection of a clinical specimen with a nasopharyngeal swab, storage of the swab during transport in universal transport medium (UTM), extraction of RNA, and quantitative reverse transcription PCR (RT-qPCR). As testing has scaled across the world, supply chain challenges have emerged across this entire workflow. Here we sought to evaluate how eliminating the UTM storage and RNA extraction steps would impact the results of molecular testing. Using paired mid-turbinate swabs self-collected by 11 individuals with previously established SARS-CoV-2 positivity, we performed a comparison of conventional (swab → UTM → RNA extraction → RT-qPCR) vs. simplified (direct elution from dry swab → RT-qPCR) protocols. Our results suggest that dry swabs eluted directly into a simple buffered solution (TE) can support molecular detection of SARS-CoV-2 via endpoint RT-qPCR without substantially compromising sensitivity. Although further confirmation with a larger sample size and variation of other parameters is necessary, these results are encouraging for the possibility of a simplified workflow that could support massively scaled testing for COVID-19 control.

Referansene til Sankt Olavs lov i Landsloven av 1274 ble brukt om fundamentet for det norske kongedømmet. De var derfor mer enn et symbol og var viktige for etableringen av en mer abstrakt og mindre personavhengig kongemakt i denne tidlige oppbyggingsfasen for en norsk sentralmakt i høymiddelalderen, og ble mobilisert i politisk vanskelige eller kritiske situasjoner i seinmiddelalderen som noe mer enn en referanse til gammel rett. Dette kommer vi fram til ved først å ta utgangspunkt i Landsloven av 1274, og deretter skille klarere mellom rettslige kilder på ene siden, og religiøse og litterære kilder på den andre, fram til Landsloven. Deretter ser vi på hvordan ideen om Sankt Olavs lov kom til å prege den politiske dialogen mellom befolkning og styresmakter i seinmiddelalderen og slik ble det limet mellom styringsnivåene som Landsloven gjør Sankt Olavs lov til. Til slutt ser vi på hvordan referansene til Sankt Olavs lov ble benyttet i krisesituasjoner innenfor unionsmonarkiet i seinmiddelalderen. Vi viser hvordan bruken av Sankt Olav i Norge tilsvarer bruken av Sankt Erik i Sverige.

Abstract Introduction: Clinical trials provide the “gold standard” evidence for advancing the practice of medicine, even as they evolve to integrate real-world data sources. Modern clinical trials are increasingly incorporating real-world data sources – data not intended for research and often collected in free-living contexts. We refer to trials that incorporate real-world data sources as real-world trials. Such trials may have the potential to enhance the generalizability of findings, facilitate pragmatic study designs, and evaluate real-world effectiveness. However, key differences in the design, conduct, and implementation of real-world vs traditional trials have ramifications in data management that can threaten their desired rigor. Methods: Three examples of real-world trials that leverage different types of data sources – wearables, medical devices, and electronic health records are described. Key insights applicable to all three trials in their relationship to Data and Safety Monitoring Boards (DSMBs) are derived. Results: Insight and recommendations are given on four topic areas: A. Charge of the DSMB; B. Composition of the DSMB; C. Pre-launch Activities; and D. Post-launch Activities. We recommend stronger and additional focus on data integrity. Conclusions: Clinical trials can benefit from incorporating real-world data sources, potentially increasing the generalizability of findings and overall trial scale and efficiency. The data, however, present a level of informatic complexity that relies heavily on a robust data science infrastructure. The nature of monitoring the data and safety must evolve to adapt to new trial scenarios to protect the rigor of clinical trials.

Summary: Cancer cachexia is a disorder characterized by involuntary weight loss and impaired physical performance. Decline in physical performance of patients with cachexia is associated with poor quality of life, and currently there are no effective pharmacological interventions that restore physical performance. Here we examine the effect of GDF15 neutralization in a mouse model of cancer-induced cachexia (TOV21G) that manifests weight loss and muscle function impairments. With comprehensive assessments, our results demonstrate that cachectic mice treated with the anti-GDF15 antibody mAB2 exhibit body weight gain with near-complete restoration of muscle mass and markedly improved muscle function and physical performance. Mechanistically, the improvements induced by GDF15 neutralization are primarily attributed to increased caloric intake, while altered gene expression in cachectic muscles is restored in caloric-intake-dependent and -independent manners. The findings indicate potential of GDF15 neutralization as an effective therapy to enhance physical performance of patients with cachexia.

Background & Aims: Oncogenic Kirsten Rat Sarcoma virus (KRAS) is the hallmark mutation of human pancreatic cancer and a driver of tumorigenesis in genetically engineered mouse models of the disease. Although the tumor cell–intrinsic effects of oncogenic Kras expression have been widely studied, its role in regulating the extensive pancreatic tumor microenvironment is less understood. Methods: Using a genetically engineered mouse model of inducible and reversible oncogenic Kras expression and a combination of approaches that include mass cytometry and single-cell RNA sequencing we studied the effect of oncogenic KRAS in the tumor microenvironment. Results: We have discovered that non–cell autonomous (ie, extrinsic) oncogenic KRAS signaling reprograms pancreatic fibroblasts, activating an inflammatory gene expression program. As a result, fibroblasts become a hub of extracellular signaling, and the main source of cytokines mediating the polarization of protumorigenic macrophages while also preventing tissue repair. Conclusions: Our study provides fundamental knowledge on the mechanisms underlying the formation of the fibroinflammatory stroma in pancreatic cancer and highlights stromal pathways with the potential to be exploited therapeutically.

Background: Mitochondrial DNA copy number (mtDNAcn) in tissues and blood can be altered in conditions like diabetes and major depression and may play a role in aging and longevity. However, little is known about the association between mtDNAcn and personality traits linked to emotional states, metabolic health, and longevity. This study tests the hypothesis that blood mtDNAcn is related to personality traits and mediates the association between personality and mortality. Methods: We assessed the big five personality domains and facets using the Revised NEO Personality Inventory (NEO-PI-R), assessed depressive symptoms with the Center for Epidemiologic Studies Depression Scale (CES-D), estimated mtDNAcn levels from whole-genome sequencing, and tracked mortality in participants from the Baltimore Longitudinal Study of Aging. Results were replicated in the SardiNIA Project. Results: We found that mtDNAcn was negatively associated with the Neuroticism domain and its facets and positively associated with facets from the other four domains. The direction and size of the effects were replicated in the SardiNIA cohort and were robust to adjustment for potential confounders in both samples. Consistent with the Neuroticism finding, higher depressive symptoms were associated with lower mtDNAcn. Finally, mtDNAcn mediated the association between personality and mortality risk. Conclusions: To our knowledge, this is the first study to show a replicable association between mtDNAcn and personality. Furthermore, the results support our hypothesis that mtDNAcn is a biomarker of the biological process that explains part of the association between personality and mortality. Funding: Support for this work was provided by the Intramural Research Program of the National Institute on Aging (Z01-AG000693, Z01-AG000970, and Z01-AG000949) and the National Institute of Neurological Disorders and Stroke of the National Institutes of Health. AT was also supported by the National Institute on Aging of the National Institutes of Health Grant R01AG068093.

Abstract Despite intensive research, the aetiology of multiple sclerosis (MS) remains unknown. Cerebrospinal fluid proteomics has the potential to reveal mechanisms of MS pathogenesis, but analyses must account for disease heterogeneity. We previously reported explorative multivariate analysis by hierarchical clustering of proteomics data of MS patients and controls, which resulted in two groups of individuals. Grouping reflected increased levels of intrathecal inflammatory response proteins and decreased levels of proteins involved in neural development in one group relative to the other group. MS patients and controls were present in both groups. Here we reanalysed these data and we also reanalysed data from an independent cohort of patients diagnosed with clinically isolated syndrome (CIS), who have symptoms of MS without evidence of dissemination in space and/or time. Some, but not all, CIS patients had intrathecal inflammation. The analyses reported here identified a common protein signature of MS/CIS that was not linked to elevated intrathecal inflammation. The signature included low levels of complement proteins, semaphorin-7A, reelin, neural cell adhesion molecules, inter-alpha-trypsin inhibitor heavy chain H2, transforming growth factor beta 1, follistatin-related protein 1, malate dehydrogenase 1 cytoplasmic, plasma retinol-binding protein, biotinidase, and transferrin, all known to play roles in neural development. Low levels of these proteins suggest that MS/CIS patients suffer from abnormally low oxidative capacity that results in disrupted neural development from an early stage of the disease.

Treatment for patients with cancer in the emergency department ranges from treating life-threatening emergencies to symptom management or issues unrelated to their cancer, but for which cancer and its treatment may be complicating factors. Nurses are expected to manage the care of this population and be aware of risk factors for complications that may be unique to cancer patients. To date, education for emergency nurses regarding oncologic emergencies and the care for patients with cancer has been limited. We conducted a cross-sectional needs assessment to establish emergency nurses' educational needs (knowledge, skills, and attitudes) related to the care of patients with cancer and to evaluate if there are different educational needs for emergency nurses associated with the care of the cancer patient by practice setting type. Of 237 nurses surveyed, only 28% of nurse respondents indicated receiving any cancer-specific education or training. Overall, scores on a knowledge assessment were relatively low (mean 53%; range 9.5-85.7%; SD 13%). Nurses reported variable confidence and skills, with the weakest areas being in the triage of complications and oncologic emergencies, assessment of complications related to cancer treatment, and end-of-life conversations. Nearly all of the respondents (97%) indicated a need for oncologic education for emergency nurses with moderate-high priority in relation to other educational needs. Our findings suggest that emergency nurses need a stronger foundation of the knowledge and skills required to care for patients with cancer. Results from this study can inform future curriculum development efforts. [ABSTRACT FROM AUTHOR]

Background & Aims: Disordered metabolism, steatosis, hepatic inflammation, and fibrosis contribute to the pathogenesis of nonalcoholic steatohepatitis (NASH). Acetyl-CoA carboxylase (ACC) catalyzes the first committed step in de novo lipogenesis (DNL) and modulates mitochondrial fatty acid oxidation. Increased hepatic DNL flux and reduced fatty acid oxidation are hypothesized to contribute to steatosis. Some proinflammatory cells also show increased dependency on DNL, suggesting that ACC may regulate aspects of the inflammatory response in NASH. PF-05221304 is an orally bioavailable, liver-directed ACC1/2 inhibitor. The present studies sought to evaluate the effects of PF-05221304 on NASH pathogenic factors in experimental model systems. Methods: The effects of PF-05221304 on lipid metabolism, steatosis, inflammation, and fibrogenesis were investigated in both primary human-derived in vitro systems and in vivo rodent models. Results: PF-05221304 inhibited DNL, stimulated fatty acid oxidation, and reduced triglyceride accumulation in primary human hepatocytes, and reduced DNL and steatosis in Western diet–fed rats in vivo, showing the potential to reduce hepatic lipid accumulation and potentially lipotoxicity. PF-05221304 blocked polarization of human T cells to proinflammatory but not anti-inflammatory T cells, and suppressed activation of primary human stellate cells to myofibroblasts in vitro, showing direct effects on inflammation and fibrogenesis. Consistent with these observations, PF-05221304 also reduced markers of inflammation and fibrosis in the diethylnitrosamine chemical–induced liver injury model and the choline-deficient, high-fat–fed rat model. Conclusions: The liver-directed dual ACC1/ACC2 inhibitor directly improved multiple nonalcoholic fatty liver disease/NASH pathogenic factors including steatosis, inflammation, and fibrosis in both human-derived in vitro systems and rat models.

Studiar av genusendring i norsk har jamt over brukt mykje plass på inventaret i kategorien «ubestemt artikkel», som fleire stader viser teikn til å skrøkke frå tre til to typar. I dei fleste samanhengar vert dei tre typane refererte til som ein (m.), ei (f.) og eit (n.). Faktiske realiseringar som er subsumerte under desse typane, kan vere avgjerande i jakta på endringsforklaringar. Denne artikkelen undersøkjer korleis hokjønnsartikkelen har vore realisert i Oslo gjennom dei siste par hundre åra. Kjeldematerialet er eit breitt utval av litterære framstillingar og vitskaplege skildringar av oslomålet, og korpusdata frå nyare tid. Variasjonen som vert avdekt, er sjeldan tematisert i nyare framstillingar av genustilhøva i Oslo. Den tilsløringa som ei slik subsumering inne­ber, treng ikkje å ha uheldige konsekvensar for analysane av genussystemet i Oslo, men artikkelen argumenterer likevel for at eit meir nyansert medvit om variasjon i dei språklege realiseringane av artiklane er viktig for vidare genusforsking i andre dialektområde.

Da vi i redaksjonen inviterte til å skrive artikkelbidrag til et temanummer om forskningsmetoder og -metodologi i andrespråksforskning, var responsen stor. Her foreligger resultatet, og vi kan stolt presentere et smekkfullt dobbeltnummer med hele 10 artikler skrevet av 20 forskere med tilknytning til 7 ulike institusjoner: Adam Mickiewicz Universitet i Poznań, Høgskolen i Innlandet, Høgskulen i Volda, OsloMet – storbyuniversitetet, Universitetet i Bergen, Universitetet i Oslo og Universitetet i Sørøst-Norge. Dette illustrerer bredden i det fagmiljøet som driver forskningsaktivitet på feltet i Norge eller om norske forhold. Artiklene i dette temaheftet demonstrerer også bredden og variasjonen i metodologiske tilnærminger på feltet; her er artikler om forskningsetikk, etnografiske tilnærminger, aksjonsforskning, studentinvolvering, flervalgsoppgaver, narrativ tilnærming, dybdeintervju, utvekslingsstrukturanalyse, dynamisk systemteori og innlærerkorpus.

In this article, we analyze the use of the term ‘morsmål’ (‘mother tongue’) in official Norwegian documents and in media texts to identify if and how its conceptualization has changed in the era of increasing globalization. Our point of view is explorative. When examining our data, we highlight the importance of reflecting openly about the instability of powerful concepts. We highlight two partly conflicting conceptualizations that we name the ‘traditional use’ and the ‘novel use’, respectively. Building on critical discourse analysis and conceptual metaphor theory we explore how the conceptualizations reveal certain aspects of ideologies and the potential management of multilingualism in society. A broader understanding of how conceptualizations of mother tongue(s) are played out in the Norwegian context may contribute to the dialogue about multilingualism as it is understood and recognized across diverse contexts.

Pregnancy is a valuable model to study the association between DNA methylation and several cardiometabolic traits, due to its direct potential to influence mother's and child's health. Epigenetics in Pregnancy (EPIPREG) is a population-based sample with the aim to study associations between DNA-methylation in pregnancy and cardiometabolic traits in South Asian and European pregnant women and their offspring. This cohort profile paper aims to present our sample with genetic and epigenetic data and invite researchers with similar cohorts to collaborative projects, such as replication of ours or their results and meta-analysis. In EPIPREG we have quantified epigenome-wide DNA methylation in maternal peripheral blood leukocytes in gestational week 28±1 in Europeans (n = 312) and South Asians (n = 168) that participated in the population-based cohort STORK Groruddalen, in Norway. DNA methylation was measured with Infinium MethylationEPIC BeadChip (850k sites), with technical validation of four CpG sites using bisulphite pyrosequencing in a subset (n = 30). The sample is well characterized with few missing data on e.g. genotype, universal screening for gestational diabetes, objectively measured physical activity, bioelectrical impedance, anthropometrics, biochemical measurements, and a biobank with maternal serum and plasma, urine, placenta tissue. In the offspring, we have repeated ultrasounds during pregnancy, cord blood, and anthropometrics up to 4 years of age. We have quantified DNA methylation in peripheral blood leukocytes in nearly all eligible women from the STORK Groruddalen study, to minimize the risk of selection bias. Genetic principal components distinctly separated Europeans and South Asian women, which fully corresponded with the self-reported ethnicity. Technical validation of 4 CpG sites from the methylation bead chip showed good agreement with bisulfite pyrosequencing. We plan to study associations between DNA methylation and cardiometabolic traits and outcomes.

The point of departure is the Swedish rebellion against the regime of King John (Hans) in 1501. Sten Sture the Elder was the rebellion's most prominent leader. The article moves from a discussion of Sten's character and motives for his policy to a more general discussion of the motives of the late medieval Scandinavian aristocracy's political agitation and conduct. The principal question is whether the aristocrats were motived by economic profit and personal career alone, or if other motives, like political and ideological ones, also mattered. Several examples of aristocrats' political choices that cannot have been motivated by economic gains are examined. Thereafter, the article presents the main features of the late medieval aristocracy in Scandinavia as an elite, including its political position, and then especially the balance of power between the aristocracy and the monarch. The conclusion is that the late medieval Scandinavian aristocracy's political behaviour was motivated by a set of motives, that could differ from one situation to another.

Abstract Background Few early intervention programs aimed at maternal and child health have been developed to be integrated in the existing Child Health Service in a country where the service is free, voluntary and used by the majority of the eligible population. This study presents the process and the critical steps in developing the “New Mothers” program. Methods Formative research uses a mixed method, allowing us to obtain data from multiple sources. A scoping review provided information on early intervention programs and studies, clarifying key elements when framing a new program. Key informant and focus group interviews offered insight of existing challenges, perceptions, identified power structures and offered reflections germane to the identified framework, securing user involvement at all stages. Monthly meetings with the project group enabled feedback loops for the data, securing program advancement. Results The “New Mothers” program was formed based on a salutogenic theory, emphasizing resistance and strengths. Public health nurses in the existing Child Health Service were to offer universally all first-time mothers and children home visits from gestational week 28 until the child reached 2 years, with motivational interviewing and empathic communication as methods to mentor the mothers, help them identify their strengths and resources, and provide support and information. Conclusions Using formative research as mixed method ensures incorporation of detailed information from multiple resources when an early intervention program is developed. This method secured program appropriateness, both culturally and at system level, when integrating new elements in the existing service.

Dysregulation of hepatic lipid and cholesterol metabolism is a significant contributor to cardiometabolic health, resulting in excessive liver lipid accumulation and ultimately non-alcoholic steatohepatitis (NASH). Therapeutic activators of the AMP-Activated Protein Kinase (AMPK) have been proposed as a treatment for metabolic diseases; we show that the AMPK β1-biased activator PF-06409577 is capable of lowering hepatic and systemic lipid and cholesterol levels in both rodent and monkey preclinical models. PF-06409577 is able to inhibit de novo lipid and cholesterol synthesis pathways, and causes a reduction in hepatic lipids and mRNA expression of markers of hepatic fibrosis. These effects require AMPK activity in the hepatocytes. Treatment of hyperlipidemic rats or cynomolgus monkeys with PF-06409577 for 6 weeks resulted in a reduction in circulating cholesterol. Together these data suggest that activation of AMPK β1 complexes with PF-06409577 is capable of impacting multiple facets of liver disease and represents a promising strategy for the treatment of NAFLD and NASH in humans. Keywords: AMPK, NAFLD, Lipogenesis, ACC, Hyperlipidemia

Abstract Background The phenotypic stability of mixed connective tissue disease (MCTD) is not clear, and knowledge about disease activity and remission is scarce. We aimed to establish the occurrence of evolution from MCTD to another defined rheumatic condition, and the prevalence and durability of remission after long-term observation. Methods In this large population-based prospective observational MCTD cohort study (N = 118), disease conversion was defined by the development of new auto-antibodies and clinical features compliant with another well-defined rheumatic condition. Remission was defined by a combination of systemic lupus erythematosus disease activity index 2000 (SLEDAI-2 K) of 0 and European League Against Rheumatism scleroderma trials and research (EUSTAR) activity index 90% of patients had EUSTAR activity index

Understanding the drivers and timescales over which groundwater quality changes informs groundwater management, use, and protection. To better understand timescales of water-quality change over short (daily to monthly) and long (seasonal to decadal) timescales, the U.S. Geological Survey’s National Water-Quality Assessment (NAWQA) Enhanced Trends Network (ETN) program instrumented and sampled three wells in the Edwards aquifer in south-central Texas. The wells were instrumented to provide high-frequency continuous (subhourly) water-quality data (temperature, pH, specific conductance, and dissolved oxygen), which were augmented by the collection of discrete samples (about 6 per year) for a range of geochemical constituents (including selected isotopes and age tracers). ETN data (2013–2017) are considered with data from additional sites for the same time period, and also historical records (over more than 80 years) of climatic and hydrologic conditions. During the four-year study, hydrologic conditions transitioned from very dry to very wet. Sites in the updip/unconfined part of the aquifer showed notable changes in water level and geochemistry (1) in response to rainfall/recharge events, and (2) over the multiyear dry/wet cycle. Sites in the downdip/confined part of the aquifer showed changes in water level/spring discharge over similar timescales, although the response is more muted. Geochemistry at the downdip/confined sites, however, varied slowly and minimally, indicating that the geochemical response of the deeper aquifer is decoupled from recent hydrologic responses. Changes at the updip/unconfined sites reflect mixing with recent recharge, whereas the downdip/confined sites were dominated by mineral-solution reactions resulting from longer (decadal) residence times. Mean groundwater ages interpreted from measured age tracers and lumped parameter models range from 7 to >700 years (where mixed with premodern downdip water) but were mostly modern. The aquifer is characterized by updip-to-downdip trends in geochemistry with respect to water-rock interaction and groundwater age. Fourier spectral analysis of historical records indicate hydrologic variability has occurred at dominant periods of 30 and 15 years; in conjunction with age tracers, these results provide insight into timescales at which the aquifer’s public supply is vulnerable to changes in the water quality of recharge. Keywords: Karst, Water quality, Groundwater age, Edwards aquifer, Trends

Myeloperoxidase (MPO) is a highly abundant protein within the neutrophil that is associated with lipoprotein oxidation, and increased plasma MPO levels are correlated with poor prognosis after myocardial infarct. Thus, MPO inhibitors have been developed for the treatment of heart failure and acute coronary syndrome in humans. 2-(6-(5-Chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide PF-06282999 is a recently described selective small molecule mechanism-based inactivator of MPO. Here, utilizing PF-06282999, we investigated the role of MPO to regulate atherosclerotic lesion formation and composition in the Ldlr-/- mouse model of atherosclerosis. Though MPO inhibition did not affect lesion area in Ldlr-/- mice fed a Western diet, reduced necrotic core area was observed in aortic root sections after MPO inhibitor treatment. MPO inhibition did not alter macrophage content in and leukocyte homing to atherosclerotic plaques. To assess non-invasive monitoring of plaque inflammation, [18F]-Fluoro-deoxy-glucose (FDG) was administered to Ldlr-/- mice with established atherosclerosis that had been treated with clinically relevant doses of PF-06282999, and reduced FDG signal was observed in animals treated with a dose of PF-06282999 that corresponded with reduced necrotic core area. These data suggest that MPO inhibition does not alter atherosclerotic plaque area or leukocyte homing, but rather alters the inflammatory tone of atherosclerotic lesions; thus, MPO inhibition could have utility to promote atherosclerotic lesion stabilization and prevent atherosclerotic plaque rupture.