Reformulation initiative for partial replacement of saturated with unsaturated fats in dairy foods attenuates the increase in LDL cholesterol and improves flow-mediated dilatation compared with conventional dairy: the randomized, controlled REplacement of SaturatEd fat in dairy on Total cholesterol (RESET) study

Background Modifying dairy fat composition by increasing the MUFA content is a potential strategy to reduce dietary SFA intake for cardiovascular disease (CVD) prevention in the population. Objectives To determine the effects of consuming SFA-reduced, MUFA-enriched (modified) dairy products, compared with conventional dairy products (control), on the fasting cholesterol profile (primary outcome), endothelial function assessed by flow-mediated dilatation (FMD; key secondary outcome), and other cardiometabolic risk markers. Methods A double-blind, randomized, controlled crossover 12-wk intervention was conducted. Participants with a 1.5-fold higher (moderate) CVD risk than the population mean replaced habitual dairy products with study products (milk, cheese, and butter) to achieve a high-fat, high-dairy isoenergetic daily dietary exchange [38% of total energy intake (%TE) from fat: control (dietary target: 19%TE SFA; 11%TE MUFA) and modified (16%TE SFA; 14%TE MUFA) diet]. Results Fifty-four participants (57.4% men; mean ± SEM age: 52 ± 3 y; BMI: 25.8 ± 0.5 kg/m2) completed the study. The modified diet attenuated the rise in fasting LDL cholesterol observed with the control diet (0.03 ± 0.06 mmol/L and 0.19 ± 0.05 mmol/L, respectively; P = 0.03). Relative to baseline, the %FMD response increased after the modified diet (0.35% ± 0.15%), whereas a decrease was observed after the control diet (−0.51% ± 0.15%; P< 0.0001). In addition, fasting plasma nitrite concentrations increased after the modified diet, yet decreased after the control diet (0.02 ± 0.01 μmol/L and −0.03 ± 0.02 μmol/L, respectively; P = 0.01). Conclusions In adults at moderate CVD risk, consumption of a high-fat diet containing SFA-reduced, MUFA-enriched dairy products for 12 wk showed beneficial effects on fasting LDL cholesterol and endothelial function compared with conventional dairy products. Our findings indicate that fatty acid modification of dairy products may have potential as a public health strategy aimed at CVD risk reduction. This trial was registered at clinicaltrials.gov as NCT02089035

Supplemental Online Learning Tools (SOLTs) to Support Deaf and Hard of Hearing Students in Introductory Statistics Courses

Research in most Science, Technology, Engineering, and Mathematics (STEM) disciplines uses statistical methods. Thus as students develop into research scientists, introductory statistics serves as a gateway course. If students struggle to incorporate statistics into their knowledge base, they may be effectively kept from careers that rely on statistics. DHH students learn differently and thus may lag behind their hearing counterparts in mainstream classrooms. In part, a gap in language knowledge can impede the understanding of statistics topics. What is a variable? What does it mean to have a distribution? With sign language interpreters and other support services, many mainstream instructors believe that DHH students have equal access to learning in their classrooms. Yet variations of instructional skill, interpreter knowledge of the discipline, and the lack of alternative representations of content often result in access that falls short of equal . This paper describes the work of a team of faculty and student researchers seeking best practices for creating supplemental online learning tools. Starting from a list of prioritized challenging topics in statistics, the team developed a number of strategies and produced a pilot set of instructional videos. Formative feedback led to revised videos, which provided a significant gain in knowledge for DHH students when shown in an experimental setting

Faking like a woman? Towards an interpretative theorization of sexual pleasure.

This article explores the possibility of developing a feminist approach to gendered and sexual embodiment which is rooted in the pragmatist/interactionist tradition derived from G.H. Mead, but which in turn develops this perspective by inflecting it through more recent feminist thinking. In so doing we seek to rebalance some of the rather abstract work on gender and embodiment by focusing on an instance of 'heterosexual' everyday/night life - the production of the female orgasm. Through engaging with feminist and interactionist work, we develop an approach to embodied sexual pleasure that emphasizes the sociality of sexual practices and of reflexive sexual selves. We argue that sexual practices and experiences must be understood in social context, taking account of the situatedness of sex as well as wider socio-cultural processes the production of sexual desire and sexual pleasure (or their non-production) always entails interpretive, interactional processes

Optimising outcomes of exercise and corticosteroid injection in patients with subacromial pain (impingement) syndrome: a factorial randomised trial

Objectives: To compare the clinical effectiveness of (1) physiotherapist-led exercise versus an exercise leaflet, and (2) ultrasound-guided subacromial corticosteroid injection versus unguided injection for pain and function in subacromial pain (formerly impingement) syndrome (SAPS).Methods: This was a single-blind 2×2 factorial randomised trial. Adults with SAPS were randomised equally to one of four treatment groups: (1) ultrasound-guided corticosteroid injection and physiotherapist-led exercise, (2) ultrasound-guided corticosteroid injection and an exercise leaflet, (3) unguided corticosteroid injection and physiotherapist-led exercise and (4) unguided corticosteroid injection and an exercise leaflet. The primary outcome was the Shoulder Pain and Disability Index (SPADI), collected at 6 weeks, 6 and 12 months and compared at 6 weeks for the injection interventions and 6 months for the exercise interventions by intention to treat.Results: We recruited 256 participants (64 treatment per group). Response rates for the primary outcome were 94% at 6 weeks, 88% at 6 months and 80% at 12 months. Greater improvement in total SPADI score was seen with physiotherapist-led exercise than with the exercise leaflet at 6 months (adjusted mean difference -8.23; 95% CI -14.14 to -2.32). There were no significant differences between the injection groups at 6 weeks (-2.04; -7.29 to 3.22), 6 months (-2.36; -8.16 to 3.44) or 12 months (1.59; -5.54 to 8.72).Conclusions: In patients with SAPS, physiotherapist-led exercise leads to greater improvements in pain and function than an exercise leaflet. Ultrasound guidance confers no additional benefit over unguided corticosteroid injection

Learning through social spaces: migrant women and lifelong learning in post-colonial London

This article shows how migrant women engage in learning through social spaces. It argues that such spaces are little recognised, and that there are multiple ways in which migrant women construct and negotiate their informal learning through socialising with other women in different informal modes. Additionally, the article shows how learning is shaped by the socio-political, geographical and multicultural context of living in London, outlining ways in which gendered and racialised identities shape, construct and constrain participation in lifelong learning. The article shows that one way in which migrant women resist (post)colonial constructions of difference is by engaging in informal and non-formal lifelong learning, arguing that the benefits are (at least) two-fold. The women develop skills (including language skills) but also use their informal learning to develop what is referred to in this article as 'relational capital'. The article concludes that informal lifelong learning developed through social spaces can enhance a sense of belonging for migrant women

Development and external validation of a clinical prediction model to aid coeliac disease diagnosis in primary care:an observational study

BACKGROUND: Coeliac disease (CD) affects approximately 1% of the population, although only a fraction of patients are diagnosed. Our objective was to develop diagnostic prediction models to help decide who should be offered testing for CD in primary care. METHODS: Logistic regression models were developed in Clinical Practice Research Datalink (CPRD) GOLD (between Sep 9, 1987 and Apr 4, 2021, n=107,075) and externally validated in CPRD Aurum (between Jan 1, 1995 and Jan 15, 2021, n=227,915), two UK primary care databases, using (and controlling for) 1:4 nested case-control designs. Candidate predictors included symptoms and chronic conditions identified in current guidelines and using a systematic review of the literature. We used elastic-net regression to further refine the models. FINDINGS: The prediction model included 24, 24, and 21 predictors for children, women, and men, respectively. For children, the strongest predictors were type 1 diabetes, Turner syndrome, IgA deficiency, or first-degree relatives with CD. For women and men, these were anaemia and first-degree relatives. In the development dataset, the models showed good discrimination with a c-statistic of 0·84 (95% CI 0·83–0·84) in children, 0·77 (0·77–0·78) in women, and 0·81 (0·81–0·82) in men. External validation discrimination was lower, potentially because ‘first-degree relative’ was not recorded in the dataset used for validation. Model calibration was poor, tending to overestimate CD risk in all three groups in both datasets. INTERPRETATION: These prediction models could help identify individuals with an increased risk of CD in relatively low prevalence populations such as primary care. Offering a serological test to these patients could increase case finding for CD. However, this involves offering tests to more people than is currently done. Further work is needed in prospective cohorts to refine and confirm the models and assess clinical and cost effectiveness. FUNDING: National Institute for Health Research Health Technology Assessment Programme (grant number NIHR129020

Improving a Natural Enzyme Activity through Incorporation of Unnatural Amino Acids

The bacterial phosphotriesterases catalyze hydrolysis of the pesticide paraoxon with very fast turnover rates and are thought to be near to their evolutionary limit for this activity. To test whether the naturally evolved turnover rate could be improved through the incorporation of unnatural amino acids and to probe the role of peripheral active site residues in nonchemical steps of the catalytic cycle (substrate binding and product release), we replaced the naturally occurring tyrosine amino acid at position 309 with unnatural L-(7-hydroxycoumarin-4-yl)ethylglycine (Hco) and L-(7-methylcoumarin-4-yl)ethylglycine amino acids, as well as leucine, phenylalanine, and tryptophan. Kinetic analysis suggests that the 7-hydroxyl group of Hco, particularly in its deprotonated state, contributes to an increase in the rate-limiting product release step of substrate turnover as a result of its electrostatic repulsion of the negatively charged 4-nitrophenolate product of paraoxon hydrolysis. The 8-11-fold improvement of this already highly efficient catalyst through a single rationally designed mutation using an unnatural amino acid stands in contrast to the difficulty in improving this native activity through screening hundreds of thousands of mutants with natural amino acids. These results demonstrate that designer amino acids provide easy access to new and valuable sequence and functional space for the engineering and evolution of existing enzyme functions

Rosiglitazone Induces Mitochondrial Biogenesis in Differentiated Murine 3T3-L1 and C3H/10T1/2 Adipocytes

Growing evidence indicates that PPARγ agonists, including rosiglitazone (RSG), induce adipose mitochondrial biogenesis. By systematically analyzing mitochondrial gene expression in two common murine adipocyte models, the current study aimed to further establish the direct role of RSG and capture temporal changes in gene transcription. Microarray profiling revealed that in fully differentiated 3T3-L1 and C3H/10T1/2 adipocytes treated with RSG or DMSO vehicle for 1, 2, 4, 7, 24, and 48 hrs, RSG overwhelmingly increased mitochondrial gene transcripts time dependently. The timing of the increases was consistent with the cascade of organelle biogenesis, that is, initiated by induction of transcription factor(s), followed by increases in the biosynthesis machinery, and then by increases in functional components. The transcriptional increases were further validated by increased mitochondrial staining, citrate synthase activity, and O2 consumption, and were found to be associated with increased adiponectin secretion. The work provided further insight on the mechanism of PPARγ-induced mitochondrial biogenesis in differentiated adipocytes

Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia.

Thiazide diuretics are among the most widely used treatments for hypertension, but thiazide-induced hyponatremia (TIH), a clinically significant adverse effect, is poorly understood. Here, we have studied the phenotypic and genetic characteristics of patients hospitalized with TIH. In a cohort of 109 TIH patients, those with severe TIH displayed an extended phenotype of intravascular volume expansion, increased free water reabsorption, urinary prostaglandin E2 excretion, and reduced excretion of serum chloride, magnesium, zinc, and antidiuretic hormone. GWAS in a separate cohort of 48 TIH patients and 2,922 controls from the 1958 British birth cohort identified an additional 14 regions associated with TIH. We identified a suggestive association with a variant in SLCO2A1, which encodes a prostaglandin transporter in the distal nephron. Resequencing of SLCO2A1 revealed a nonsynonymous variant, rs34550074 (p.A396T), and association with this SNP was replicated in a second cohort of TIH cases. TIH patients with the p.A396T variant demonstrated increased urinary excretion of prostaglandin E2 and metabolites. Moreover, the SLCO2A1 phospho-mimic p.A396E showed loss of transporter function in vitro. These findings indicate that the phenotype of TIH involves a more extensive metabolic derangement than previously recognized. We propose one mechanism underlying TIH development in a subgroup of patients in which SLCO2A1 regulation is altered.This work was supported by an Academy of Medical Sciences grant for clinical lecturers (to JSW and MG), British Heart Foundation grant PG/09/089 (to KMO), the National Institute for Health Research (NIHR) Royal Brompton Cardiovascular Biomedical Research Unit (to JSW and SC), the Fondation Leducq (to JSW and SC), and the British Heart Foundation (to JSW and SC). MDT holds a Medical Research Council Senior Clinical Fellowship (G0902313). This work was supported by the Medical Research Council (grant numbers G510364 and G1000861). This research used the ALICE and SPECTRE High Performance Computing Facilities at the University of Leicester