Respiratory syncytial virus and other vaccine-preventable infections in Multiple Myeloma. A population-based study on 8672 myeloma patients diagnosed 2008-2021 from the Swedish Myeloma Registry.

Not available.

Levels and distribution profiles of Per- and Polyfluoroalkyl Substances (PFAS) in a high Arctic Svalbard ice core.

Per- and polyfluoroalkyl substances (PFAS) are a group of persistent organic contaminants of which some are toxic and bioaccumulative. Several PFAS can be formed from the atmospheric degradation of precursors such as fluorotelomer alcohols (FTOHs) as well as hydrochlorofluorocarbons (HFCs) and other ozone-depleting chlorofluorocarbon (CFC) replacement compounds. Svalbard ice cores have been shown to provide a valuable record of long-range atmospheric transport of contaminants to the Arctic. This study uses a 12.3 m ice core from the remote Lomonosovfonna ice cap on Svalbard to understand the atmospheric deposition of PFAS in the Arctic. A total of 45 PFAS were targeted, of which 26 were detected, using supercritical fluid chromatography (SFC) tandem mass spectrometry (MS/MS) and ultra-performance liquid chromatography (UPLC) MS/MS. C2 to C11 perfluoroalkyl carboxylic acids (PFCAs) were detected continuously in the ice core and their fluxes ranged from 2.5 to 8200 ng m-2 yr-1 (9.51-16,500 pg L-1). Trifluoroacetic acid (TFA) represented 71 % of the total mass of C2 - C11 PFCAs in the ice core and had increasing temporal trends in deposition. The distribution profile of PFCAs suggested that FTOHs were likely the atmospheric precursor to C8 - C11 PFCAs, whereas C2 - C6 PFCAs had alternative sources, such as HFCs and other CFC replacement compounds. Perfluorooctanesulfonic acid (PFOS) was also widely detected in 82 % of ice core subsections, and its isomer profile (81 % linear) indicated an electrochemical fluorination manufacturing source. Comparisons of PFAS concentrations with a marine aerosol proxy showed that marine aerosols were insignificant for the deposition of PFAS on Lomonosovfonna. Comparisons with a melt proxy showed that TFA and PFOS were mobile during meltwater percolation. This indicates that seasonal snowmelt and runoff from post-industrial accumulation on glaciers could be a significant seasonal source of PFAS to ecosystems in Arctic fjords.

Level of Evidence for the Treatment of Chronic Noninsertional Achilles Tendinopathy.

BACKGROUND: Noninsertional Achilles tendinopathy affects both athletes and sedentary individuals, and its incidence is rising. Conservative management is the mainstay of treatment, but a variety of operative techniques have been described to treat recalcitrant cases. We seek to outline the current available evidence for surgical management of noninsertional Achilles tendinopathy. STUDY DESIGN AND METHODS: A systematic review was performed using the MEDLINE and EMBASE databases, and all articles were reviewed by at least 2 authors. Each article was assigned a level of evidence in accordance with the standards of Journal of Bone and Joint Surgery. The available data were reviewed and a level of evidence was assigned to each intervention of interest, based on the revised classifications of Wright. RESULTS AND CONCLUSION: A total of 46 articles met inclusion and exclusion criteria. There is fair evidence (grade B) in support of open debridement with 1 level II study, 1 level III study, and 8 level IV studies. There is fair evidence (grade B) in support of arthroscopic or minimally invasive surgical techniques. There is poor evidence (grade C) in support of flexor hallucis longus transfer, longitudinal tenotomy, peritenolysis, gastrocnemius recession, and plantaris excision. There is insufficient evidence (grade I) to provide a recommendation about other surgical treatment methods for noninsertional Achilles tendinopathy.Levels of Evidence: Level III: Systematic review.

The rainbow connection: Disrupting background affect, overcoming barriers and emergent emotional collectives at "Pride in London".

This article focuses on a large-scale parade in the UK that is often overlooked in research concerned with the sociology of political emotions and group dynamics; "Pride in London". This is an annual parade celebrating, and raising awareness about, the LGBTQ+ community and commemorating the Stonewall riots. Following a brief description of the study context, participants and methods, the article illustrates the use of reflexive thematic analysis of 23 interviewee accounts of the parade. Analysis of emotional habitus and affective practices preceding, and on the day of, the parade offer an insight into the manifestation of collective emotion. Three themes are developed exploring the use of recognizable and emotive symbols, physicality of embodied emotion and spatial arrangement and the encompassing nature of group emotion. Finally, the interplay between background and foreground emotion is explored as a way of understanding and demonstrating the fluidity and temporality of affective experience and expression when people are engaged in collective action at a social justice event.

"They Don't Think Like Us": Exploring Attitudes of Non-Transgender Students Toward Transgender People Using Discourse Analysis.

Literature concerned with attitudes toward transgender (TG) individuals has been found to be lacking. Predominant research is quantitative and the few qualitative studies either investigated TG experience or attitudes of those with personal experience of TG people.This study investigated this topic using a qualitative approach employing semi-structured interviews exploring beliefs, understanding, and experience of TG people. Foucauldian Discourse Analysis was used to analyze the language used to construct a "transgender" discourse. Participants were cisgender, heterosexual, female participants from Black and ethnic minority backgrounds (n = 6).Prevalent discourses were; "Heteronormativity as a Benchmark," "The Ease of Disclosure'" and "Actualising the Other." Participants consistently drew on discourse that constructed TG as "other." Findings indicate a need to attend to context, as well as content, when exploring attitudes and that covert forms of prejudice need to be addressed and could inform anti-prejudice interventions and the creation of future transphobia measurements.

The European NAFLD Registry: A real-world longitudinal cohort study of nonalcoholic fatty liver disease.

Non-Alcoholic Fatty Liver Disease (NAFLD), a progressive liver disease that is closely associated with obesity, type 2 diabetes, hypertension and dyslipidaemia, represents an increasing global public health challenge. There is significant variability in the disease course: the majority exhibit only fat accumulation in the liver but a significant minority develop a necroinflammatory form of the disease (non-alcoholic steatohepatitis, NASH) that may progress to cirrhosis and hepatocellular carcinoma. At present our understanding of pathogenesis, disease natural history and long-term outcomes remain incomplete. There is a need for large, well characterised patient cohorts that may be used to address these knowledge gaps and to support the development of better biomarkers and novel therapies. The European NAFLD Registry is an international, prospectively recruited observational cohort study that aims to establish a large, highly-phenotyped patient cohort and linked bioresource. Here we describe the infrastructure, data management and monitoring plans, and the standard operating procedures implemented to ensure the timely and systematic collection of high-quality data and samples. Already recruiting subjects at secondary/tertiary care centres across Europe, the Registry is supporting the European Union IMI2-funded LITMUS 'Liver Investigation: Testing Marker Utility in Steatohepatitis' consortium, which is a major international effort to robustly validate biomarkers that diagnose, risk stratify and/or monitor NAFLD progression and liver fibrosis stage. The European NAFLD Registry has the demonstrable capacity to support research and biomarker development at scale and pace.

Nucleotide Sugar Transporter SLC35 Family Structure and Function.

The covalent attachment of sugars to growing glycan chains is heavily reliant on a specific family of solute transporters (SLC35), the nucleotide sugar transporters (NSTs) that connect the synthesis of activated sugars in the nucleus or cytosol, to glycosyltransferases that reside in the lumen of the endoplasmic reticulum (ER) and/or Golgi apparatus. This review provides a timely update on recent progress in the NST field, specifically we explore several NSTs of the SLC35 family whose substrate specificity and function have been poorly understood, but where recent significant progress has been made. This includes SLC35 A4, A5 and D3, as well as progress made towards understanding the association of SLC35A2 with SLC35A3 and how this relates to their potential regulation, and how the disruption to the dilysine motif in SLC35B4 causes mislocalisation, calling into question multisubstrate NSTs and their subcellular localisation and function. We also report on the recently described first crystal structure of an NST, the SLC35D2 homolog Vrg-4 from yeast. Using this crystal structure, we have generated a new model of SLC35A1, (CMP-sialic acid transporter, CST), with structural and mechanistic predictions based on all known CST-related data, and includes an overview of reported mutations that alter transport and/or substrate recognition (both de novo and site-directed). We also present a model of the CST-del177 isoform that potentially explains why the human CST isoform remains active while the hamster CST isoform is inactive, and we provide a possible alternate access mechanism that accounts for the CST being functional as either a monomer or a homodimer. Finally we provide an update on two NST crystal structures that were published subsequent to the submission and during review of this report.

Systems Genetics of Hepatic Metabolome Reveals Octopamine as a Target for Non-Alcoholic Fatty Liver Disease Treatment.

Non-alcoholic fatty liver disease (NAFLD) is often associated with obesity and type 2 diabetes. To disentangle etiological relationships between these conditions and identify genetically-determined metabolites involved in NAFLD processes, we mapped 1H nuclear magnetic resonance (NMR) metabolomic and disease-related phenotypes in a mouse F2 cross derived from strains showing resistance (BALB/c) and increased susceptibility (129S6) to these diseases. Quantitative trait locus (QTL) analysis based on single nucleotide polymorphism (SNP) genotypes identified diet responsive QTLs in F2 mice fed control or high fat diet (HFD). In HFD fed F2 mice we mapped on chromosome 18 a QTL regulating liver micro- and macrovesicular steatosis and inflammation, independently from glucose intolerance and adiposity, which was linked to chromosome 4. Linkage analysis of liver metabolomic profiling data identified a QTL for octopamine, which co-localised with the QTL for liver histopathology in the cross. Functional relationship between these two QTLs was validated in vivo in mice chronically treated with octopamine, which exhibited reduction in liver histopathology and metabolic benefits, underlining its role as a mechanistic biomarker of fatty liver with potential therapeutic applications.

Thyroid dysfunction in preterm neonates exposed to iodine.

BACKGROUND: Infants <32 weeks' gestation should not be exposed to topical iodine and its avoidance is recommended during pregnancy and breast feeding. Exposure to contrast media and topical iodine is frequently used in many preterm neonates. AIM: To determine whether thyrotropin levels in preterm infants are affected by exposure to intrapartum/neonatal topical iodine and/or the use of iodinated contrast media. DESIGN: Infants <32 weeks' gestation were recruited. Maternal and neonatal exposures to iodinated contrast media and topical iodine were recorded; levels of thyrotropin and thyroxine were measured from blood-spot cards on postnatal days 7, 14, 28 and the equivalent of 36 weeks' gestation. RESULTS: One hundred and twenty-five infants were exposed to topical iodine/contrast media and 48 infants were unexposed. No infants were treated for hypothyroidism; three infants (exposed group) had transient hyperthyrotropinaemia. Mean thyrotropin levels were significantly higher on postnatal days 7, 14 and 28 in infants exposed to topical iodine prior to caesarean section compared to unexposed infants, a relationship which persisted after adjustment. CONCLUSIONS: In the context of this study, neonatal thyroid dysfunction was seen following exposure to iodine via caesarean section but not via exposure to contrast media.

Transcriptional regulation of PNPLA3 and its impact on susceptibility to nonalcoholic fatty liver Disease (NAFLD) in humans.

The increased expression of PNPLA3148M leads to hepatosteatosis in mice. This study aims to investigate the genetic control of hepatic PNPLA3 transcription and to explore its impact on NAFLD risk in humans. Through a locus-wide expression quantitative trait loci (eQTL) mapping in two human liver sample sets, a PNPLA3 intronic SNP, rs139051 A>G was identified as a significant eQTL (p = 6.6×10-8) influencing PNPLA3 transcription, with the A allele significantly associated with increased PNPLA3 mRNA. An electrophoresis mobility shift assay further demonstrated that the A allele has enhanced affinity to nuclear proteins than the G allele. The impact of this eQTL on NAFLD risk was further tested in three independent populations. We found that rs139051 did not independently affect the NAFLD risk, whilst rs738409 did not significantly modulate PNPLA3 transcription but was associated with NAFLD risk. The A-G haplotype associated with higher transcription of the disease-risk rs738409 G allele conferred similar risk for NAFLD compared to the G-G haplotype that possesses a lower transcription level. Our study suggests that the pathogenic role of PNPLA3148M in NAFLD is independent of the gene transcription in humans, which may be attributed to the high endogenous transcription level of PNPLA3 gene in human livers.

Establishment and molecular characterisation of seven novel soft-tissue sarcoma cell lines.

BACKGROUND: Soft-tissue sarcomas (STS) are a diverse group of malignancies that remain a diagnostic and therapeutic challenge. Relatively few reliable cell lines currently exist. Rapidly developing technology for genomic profiling with emerging insights into candidate functional (driver) aberrations raises the need for more models for in vitro functional validation of molecular targets. METHODS: Primary cell culture was performed on STS tumours utilising a differential attachment approach. Cell lines were characterised by morphology, immunocytochemistry, proliferation assays, short tandem repeat (STR) and microarray-based genomic copy number profiling. RESULTS: Of 47 STS cases of various subtypes, half formed adherent monolayers. Seven formed self-immortalised cell lines, including three undifferentiated pleomorphic sarcomas, two dedifferentiated liposarcomas (one of which had received radiotherapy), a leiomyosarcoma and a myxofibrosarcoma. Two morphologically distinct yet genetically identical variants were established in separate cultures for the latter two tumours. All cell lines demonstrated genomic and phenotypic features that not only confirm their malignant characteristics but also confirm retention of DNA copy number aberrations present in their parent tumours that likely include drivers. CONCLUSIONS: These primary cell lines are much-needed additions to the number of reliable cell lines of STS with complex genomics available for initial functional validation of candidate molecular targets.

Physical Activity Is Prospectively Associated With Adolescent Nonalcoholic Fatty Liver Disease.

OBJECTIVES: The aim of the present study was to assess whether objectively measured physical activity at mean ages 12 and 14 years are prospectively associated with ultrasound scan liver fat and stiffness (alanine aminotransferase, aspartate aminotransferase [AST], and γ-glutamyl transferase [GGT]) assessed at mean age 17.8 years. METHODS: Participants were from the Avon Longitudinal Study of Parents and Children. Total physical activity (counts per minute) and minutes of moderate to vigorous physical activity (MVPA) were measured using ActiGraph accelerometers at mean ages 12 and 14 years. RESULTS: Greater total physical activity and MVPA at ages 12 and 14 years were associated with lower odds of liver fat and lower GGT levels at mean age 17.8 years, such as per 15-minute increase in daily MVPA at age 12 years, the confounder adjusted odds ratio of liver fat was 0.47 (95% confidence interval [CI] 0.27-0.84). Associations attenuated after additional adjustment for fat mass as a potential confounder (eg, per 15-minute increase in daily MVPA at age 12 years, the odds ratio of liver fat attenuated to 0.65 [95% CI 0.35-1.21]) or a potential mediator (eg, per 15-minute increase in daily MVPA at age 12 years the odds ratio of liver fat attenuated to 0.59 [95% CI 0.32-1.09]). Results did not further attenuate after additional adjustment for insulin resistance. There was some evidence that greater total physical activity and MVPA at age 12 years were associated with the higher AST levels. CONCLUSIONS: Adolescents who were more active in childhood have lower odds of fatty liver and lower GGT levels. These findings are likely to be, at least in part, explained by adiposity.

Childhood energy intake is associated with nonalcoholic fatty liver disease in adolescents.

BACKGROUND: Greater adiposity is an important risk factor for nonalcoholic fatty liver disease (NAFLD). Thus, it is likely that dietary intake is involved in the development of the disease. Prospective studies assessing the relation between childhood dietary intake and risk of NAFLD are lacking. OBJECTIVE: This study was designed to explore associations between energy, carbohydrate, sugar, starch, protein, monounsaturated fat, polyunsaturated fat, saturated fat, and total fat intake by youth at ages 3, 7, and 13 y and subsequent (mean age: 17.8 y) ultrasound scan (USS)-measured liver fat and stiffness and serum alanine aminotransferase, aspartate aminotransferase, and γ-glutamyltransferase. We assessed whether observed associations were mediated through fat mass at the time of outcome assessment. METHODS: Participants were from the Avon Longitudinal Study of Parents and Children. Trajectories of energy and macronutrient intake from ages 3-13 y were obtained with linear-spline multilevel models. Linear and logistic regression models examined whether energy intake and absolute and energy-adjusted macronutrient intake at ages 3, 7, and 13 y were associated with liver outcomes. RESULTS: Energy intake at all ages was positively associated with liver outcomes; for example, the odds of having a USS-measured liver fat per 100 kcal increase in energy intake at age 3 y were 1.79 (95% CI: 1.14, 2.79). Associations between absolute macronutrient intake and liver outcomes were inconsistent and attenuated to the null after adjustment for total energy intake. The majority of associations attenuated to the null after adjustment for fat mass at the time liver outcomes were assessed. CONCLUSION: Higher childhood and early adolescent energy intake is associated with greater NAFLD risk, and the macronutrients from which energy intake is derived are less important. These associations appear to be mediated, at least in part, by fat mass at the time of outcome assessment.

Pharmacological induction of CCL5 in vivo prevents gp120-mediated neuronal injury.

The human immunodeficiency virus (HIV) envelope protein gp120 promotes neuronal injury which is believed to cause HIV-associated neurocognitive disorders. Therefore, blocking the neurotoxic effect of gp120 may lead to alternative strategies to reduce the neurotoxic effect of HIV. In vitro, the neurotoxic effect of M-tropic gp120BaL is reduced by the chemokine CCL5, the natural ligand of CCR5 receptors. To determine whether CCL5 reduces the toxic effect of gp120BaL in vivo, animals were intrastriatally injected with lentiviral vectors overexpressing CCL5 prior to an intrastriatal injection of gp120BaL (400 ng). Neuronal injury was determined by silver staining, cleaved caspase-3 and TUNEL. Overexpression of CCL5 decreased gp120-mediated neuronal injury. CCL5 expression can be up-regulated by chronic morphine. Therefore, we examined whether morphine reduces the neurotoxic effect of gp120BaL. Rats stereotaxically injected with gp120BaL into the striatum received saline or chronic morphine for five days (10 mg/kg escalating to 30 mg/kg twice a day). Morphine-treated rats showed a decrease in all markers used to determine neuronal degeneration compared to saline-treated rats. The neuroprotective effect of morphine was significantly attenuated by expressing CCL5 shRNA. Our results suggest that compounds that increase the endogenous production of CCL5 may be used to reduce the pathogenesis of HIV-associated neurocognitive disorders.

The association of nonalcoholic fatty liver disease with central and peripheral blood pressure in adolescence: findings from a cross-sectional study.

OBJECTIVES: We aimed to determine the association of nonalcoholic fatty liver disease (NAFLD) with central and peripheral blood pressure (BP), in a general adolescent population and to examine whether associations are independent of adiposity. METHODS: Using cross-sectional data from a subsample (N = 1904) of a UK birth cohort, we assessed markers of NAFLD including ultrasound scan (USS) determined fatty liver, shear velocity (marker of liver fibrosis), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyltransferase (GGT) at a mean age of 17.8 years. These were related to BP [central and peripheral SBP and DBP and mean arterial pressure (MAP)]. RESULTS: Fatty liver was positively associated with central and peripheral SBP, DBP and MAP in models adjusting for age, sex, social class, puberty and alcohol intake. These positive associations were attenuated to the null when fat mass was included. For example, in confounder-adjusted models, not including fat mass, mean central SBP was 3.74 mmHg [95% confidence interval (CI) 1.12 to 6.36] higher in adolescents with USS fatty liver than in those without; with additional adjustment for fat mass, the association attenuated to the null value (-0.37 mmHg; 95% CI -3.09 to 2.36). Similar patterns were found for associations of ALT and GGT with central and peripheral BP. There was no consistent evidence of associations of shear velocity or AST with BP measurements. Fatty liver was not consistently associated with central pulse pressure (PP), peripheral PP and Aix@75. CONCLUSION: NAFLD is not associated with higher central or peripheral BP in adolescents once confounding by adiposity is taken into account.

Treatment of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is now the commonest cause of chronic liver disease in developed countries. Treatment depends on the stage of disease, and non-invasive methods for risk stratification are urgently needed. Lifestyle modification (aimed at weight loss and increasing physical activity) and management of the features of metabolic syndrome are vital for all patients with NAFLD. Metformin is the first-line therapy for diabetic patients with NAFLD and also reduces the risk of hepatocellular carcinoma. Clinicians should have a low threshold for introducing a statin for the management of dyslipidaemia. Antihypertensive agents that target the renin-angiotensin system should be first-line in NAFLD for the management of hypertension. For patients with progressive disease, liver-directed pharmacotherapy with vitamin E should be considered. Non-alcoholic steatohepatitis cirrhosis is an increasingly common indication for liver transplantation.

Weight trajectories through infancy and childhood and risk of non-alcoholic fatty liver disease in adolescence: the ALSPAC study.

BACKGROUND & AIMS: Adiposity is a key risk factor for NAFLD. Few studies have examined prospective associations of infant and childhood adiposity with subsequent NAFLD risk. We examined associations of weight-for-height trajectories from birth to age 10 with liver outcomes in adolescence, and assessed the extent to which associations are mediated through fat mass at the time of outcome assessment. METHODS: Individual trajectories of weight and height were estimated for participants in the Avon Longitudinal Study of Parents and Children using random-effects linear-spline models. Associations of birthweight (adjusted for birth length) and weight change (adjusted for length/height change) from 0-3 months, 3 months-1 y, 1-3 y, 3-7 y, and 7-10 y with ultrasound scan (USS) determined liver fat and stiffness, and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) at mean age 17.8 y were assessed with linear and logistic regressions. Mediation by concurrent fat mass was assessed with adjustment for fat mass at mean age 17.8 y. RESULTS: Birth weight was positively associated with liver stiffness and negatively with ALT and AST. Weight change from birth to 1 y was not associated with outcomes. Weight change from 1-3 y, 3-7 y, and 7-10 y was consistently positively associated with USS and blood-based liver outcomes. Adjusting for fat mass at mean age 17.8 y attenuated associations toward the null, suggesting associations are largely mediated by concurrent body fatness. CONCLUSIONS: Greater rates of weight-for-height change between 1 y and 10 y are consistently associated with adverse liver outcomes in adolescence. These associations are largely mediated through concurrent fatness.