Reversal of High Fat Diet-Induced Obesity, Systemic Inflammation, and Astrogliosis by the NLRP3 Inflammasome Inhibitors NT-0249 and NT-0796.

Systemic and cerebral inflammatory responses are implicated in the pathogenesis of obesity and associated metabolic impairment. While the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome has been linked to obesity-associated inflammation, whether it contributes to the development or maintenance of obesity is unknown. We provide support for a direct role of saturated fatty acids, such as palmitic acid, as NLRP3 activating stimuli in obese states.

Treatment of axial spondyloarthritis with biologic and targeted synthetic DMARDs: British Society for Rheumatology guideline scope.

Pharmacological management has advanced considerably since the 2015 British Society for Rheumatology axial spondyloarthritis (axSpA) guideline to incorporate new classes of biologic DMARDs (bDMARDs, including biosimilars), targeted synthetic DMARDs (tsDMARDs) and treatment strategies such as drug tapering. The aim of this guideline is to provide an evidence-based update on pharmacological management of adults with axSpA (including AS and non-radiographic axSpA) using b/tsDMARDs. This guideline is aimed at health-care professionals in the UK who care directly for people with axSpA, including rheumatologists, rheumatology specialist nurses, allied health professionals, rheumatology specialty trainees and pharmacists; people living with axSpA; and other stakeholders, such as patient organizations and charities.

Archiving the COVID-19 pandemic in Mass Observation and Middletown.

The COVID-19 pandemic generated debates about how pandemics should be known. There was much discussion of what role the human sciences could play in knowing - and governing - the pandemic. In this article, we focus on attempts to know the pandemic through diaries, other biographical writing, and related forms like mass photography.

Seeing like an epidemiologist? Mobilising people against COVID-19.

Diaries and other materials in the Mass Observation Archive have been characterised as intersubjective and dialogic. They have been used to study top-down and bottom-up processes, including how ordinary people respond to sociological constructs and, more broadly, the footprint of social science in the 20th century. In this article, we use the Archive's COVID-19 collections to study how attempts to govern the pandemic by mobilising ordinary people to see like an epidemiologist played out in the United Kingdom during 2020.

Beyond compliance: Good citizenship during the COVID-19 pandemic.

In the UK, discussion of good citizenship during the COVID-19 pandemic largely focused on compliance and non-compliance with government rules. In this paper, we offer an alternative point of focus. Pandemic governance proceeded not only through rules/morality, but also through freedom/ethics.

The Impact of Individualizing Sodium Bicarbonate Supplementation Strategies on World-Class Rowing Performance.

Contemporary meta-analyses have generally demonstrated a positive effect of sodium bicarbonate (NaHCO) supplementation on exercise performance. However, despite these claims, there is limited data on contrasting individualized and standardized of NaHCO ingestion prior to exercise to further enhance performance outcomes. To determine whether NaHCO ingestion timing impacts 2,000-m rowing time-trial (TT) performance in elite-level rowers (Senior National team including Olympic/World Championships level) adhering to their own individualized pre-race strategies (e.

Moving healthcare professionals - a whole system approach to embed physical activity in clinical practice.

Background: Healthcare professionals are key informants to support individual behaviour change, and although there has been some progress in empowering clinicians to promote physical activity and health at work, an effective strategy overarching the whole medical educational journey is still lacking. This report provides an overview from the Moving Healthcare Professionals programme (MHPP), a whole-system educational approach to embed prevention and physical activity promotion into clinical practice.

Methods: The MHPP model integrates educational resources into three core domains of medical education: undergraduate education, postgraduate education and continuing professional development.

Active 10 - A new approach to increase physical activity in inactive people in England.

Public health physical activity (PA) guidelines are failing to increase levels of population PA, requiring a new approach. A national integrated marketing campaign was developed based on published literature and ethnographic research to get inactive lower socioeconomic 40-60 year olds to walk briskly for bouts of 10 or more minutes per day and move towards recommended levels of PA. National and local communications campaigns and partnerships promoted key messages and directed people to a free mobile phone app that provided the user with time, intensity and periodicity of walking, and included goal setting and encouragement to support behaviour change.

The Decline in Diffuse Support for National Politics: The Long View on Political Discontent in Britain.

This research note considers how to track long-term trajectories of political discontent in Britain. Many accounts are confined to using either survey data drawn from recent decades or imperfect behavioral measures such as voting or party membership as indicators of political disengagement. We instead develop an approach that provides the long view on political disaffection.

Molecular hybridization yields triazole bronchodilators for the treatment of COPD.

A 1,2,4-triazole motif was employed as a bioisostere for the ester commonly used in muscarinic antagonists, and subsequent integrative conjugation to a β2 agonist quinolinone furnished a new class of bifunctional MABAs for the treatment of COPD. Medicinal chemistry optimization using the principles of 'inhalation by design' furnished a clinical candidate with desirable pharmacological, pharmacokinetic and biopharmaceutical properties.

Oral and inhaled p38 MAPK inhibitors: effects on inhaled LPS challenge in healthy subjects.

Background: Inhaled LPS causes neutrophilic airway inflammation in healthy subjects. We compared the effects of p38 MAPK inhibitors and fluticasone propionate on the LPS response.

Methods: Three randomised, double-blind, placebo-controlled, single dose crossover studies were performed.

Direct and indirect measurement of neuromuscular fatigue in Canadian football players.

This study assessed the effects of a fatiguing game simulation (G-Sim) on the balance of collegiate Canadian football players. The purpose of the study was to evaluate postural control as a potential tool for monitoring neuromuscular fatigue (NMF) in collision-based team sports. Fifteen male Canadian football players were recruited (mean±SD: age 21.

Velocity-specific strength recovery after a second bout of eccentric exercise.

A bout of eccentric exercise (ECC) has the protective effect of reducing muscle damage during a subsequent bout of ECC known as the "repeated bout effect" (RBE). The purpose of this study was to determine if the RBE is greater when both bouts of ECC are performed using the same vs. different velocity of contraction.

Quantification of training load in Canadian football: application of session-RPE in collision-based team sports.

The session-rating of perceived exertion (Session-RPE) method for quantifying internal training load (TL) has proven to be a highly valuable and accurate monitoring tool in numerous team sports. However, the influence of frequent impact during Canadian football on the validity of this subjective rating tool remains unclear. The aim of this study was to validate Session-RPE application to a prolonged, intermittent, high-intensity collision-based team sport through correlation of internal TL data collected using 2 criterion heart rate-based measures known as Polar Training-Impulse (TRIMP) and Edwards' TL.

Efficient conversion of a nonselective norepinephrin reuptake inhibitor into a dual muscarinic antagonist-β₂-agonist for the treatment of chronic obstructive pulmonary disease.

Following interrogation of a wide-ligand profile database, a nonselective norepinephrin reuptake inhibitor was converted into a novel muscarinic antagonist using two medicinal chemistry transformations (M3/NRI selectivity of >1000). Conjugation to a β(2) agonist motif furnished a molecule with balanced dual pharmacology, as demonstrated in a guinea pig trachea tissue model of bronchoconstriction. This approach provides new starting points for the treatment of chronic obstructive pulmonary disease and illustrates the potential for building selectivity into GPCR modulators that possess intrinsic promiscuity or reverse selectivity.

Inhalation by design: dual pharmacology β-2 agonists/M3 antagonists for the treatment of COPD.

This paper describes the successful design and development of dual pharmacology β-2 agonists-M3 antagonists, for the treatment of chronic obstructive pulmonary disorder using the principles of 'inhalation by design'. A key feature of this work is the combination of balanced potency and pharmacodynamic duration with desirable pharmacokinetic and material properties, whilst keeping synthetic complexity to a minimum.

Gastric cancer-related information on the Internet: incomplete, poorly accessible, and overly commercial.

Background: Patients increasingly use the Internet for gastric cancer information. However, the quality of the information is questionable. We evaluated the accuracy, completeness, accessibility, reliability, and readability of gastric cancer websites.

Phenotypic modulation of human urinary tract stroma-derived fibroblasts by transforming growth factor beta3.

Objectives: Animal models have described critical roles for transforming growth factor beta (TGFbeta) isoforms in modulating urinary tract stroma phenotype. TGFbeta3 is of particular interest because it may regulate TGFbeta1 and TGFbeta2 expression, but its modulatory affect has not been so well characterized in human cells. In this study, we aim to determine whether TGFbeta3 treatment induced differentiation of human urinary tract stroma-derived fibroblasts to a smooth muscle-like phenotype.

Second generation N-(1,2-diphenylethyl)piperazines as dual serotonin and noradrenaline reuptake inhibitors: improving metabolic stability and reducing ion channel activity.

New N-(1,2-diphenylethyl)piperazines 6 are disclosed as dual serotonin and noradrenaline reuptake inhibitors (SNRI) which may have potential in treating stress urinary incontinence (SUI). In this Letter, we present new data for SNRI PF-526014 (4) including performance in a canine in vivo model of SUI, cardiovascular assessment, pharmacokinetics in dog and determination of the primary routes of metabolism in vitro. Starting from 4, detailed structure activity relationships established that potent dual SNRIs could be achieved by appropriate substitution of the phenyl rings (6: R; R(1)) combined with a preferred stereochemistry.

Primary multifocal osseous Hodgkin's lymphoma.

Background: Hodgkin's disease (HD) most commonly presents with progressive painless enlargement of peripheral lymph nodes, especially around the cervical region. A few children have systemic symptoms and weight loss. At the time of diagnosis, osseous involvement is uncommon

Case Presentation: A case is described of Primary Multifocal Osseous Hodgkin's Lymphoma in a seven-year-old boy.

Optimizing treatment of hypothyroidism.

Several thyroid hormone preparations are currently available, including levothyroxine sodium (thyroxine), liothyronine (triiodothyronine), and desiccated thyroid extract, as well as a combination of levothyroxine sodium and liothyronine. Levothyroxine sodium monotherapy at an appropriate daily dose provides uniform levels of both thyroxine and triiodothyronine in the circulation without diurnal variation. Therefore, it is the preparation of choice in most patients with hypothyroidism of both the primary and central types.