Exploring joint hypermobility syndrome, developmental coordination disorder and pain

INTRODUCTION Floppy, clumsy, hypermobile children are increasingly referred to occupational and physical therapy under the label of dyspraxia. Motor impairments associated with the umbrella diagnosis of developmental coordination disorder (DCD) have been reported as persisting into adolescence and adulthood and subsequently affecting functional abilities (Cousins and Smyth 2003). Within this heterogeneous condition the underlying mechanisms causing the motor difficulties remains unclear. Ayers (1985) hypothesised that some individuals might have somatosensory processing issues contributing to their poor motor planning and coordination difficulties. Similarities in functional difficulties have been noted in children with a diagnosis of DCD and joint hypermobility syndrome (JHS) (Kirby and Davies 2006). There is limited understanding of the relationship between the two conditions. JHS is a multisystemic inherited connective tissue disorder, in which hypermobile joints, pain, clumsiness, poor proprioception and dislocations are familiar features (Grahame and Hakim 2006; Adib et al 2005). It has been suggested that adults with JHS show poor movement patterns which contribute to biomechanical dysfunction and continuing pain (Clark et al 2009). Pain and disability reported in adults with JHS often leads to anxiety, depression, work incapacity and social isolation (Grahame and Hakim 2006). The purpose of this study was to explore the association between adults with JHS and DCD and long term pain. METHODOLOGY/ METHODS A mixed methods design influenced by a pragmatic paradigm was utilised. Subjects: 90 patients with JHS (18-65 years) recruited from a hypermobility clinic were compared, using a questionnaire, with 113 healthy volunteers (18-65 years) with no pain recruited from a university. Analysis: Quantitative data were described and examined by regression, odds ratios were calculated. Qualitative data was analysed thematically FINDINGS The percentage of subjects who reported DCD in patients with JHS and healthy volunteers were 56% and 19% respectively. A significant association between patients with JHS and DCD was noted, chi square = 30.11, p < .001. Patients with JHS were 6 times [95% CI 2.9 – 10.3] more likely to report DCD than healthy volunteers. Pain was a significant feature with an average of 9.8 pain sites reported (out of a total of 17). Open ended questions revealed many patients recalling pain starting in early childhood and adolescence. DISCUSSION These results suggest a significant association between patients with JHS and DCD and the reporting of long term pain. Early recognition and understanding of the needs of children with DCD who present with somatosensory impairment, pain modulation and JHS is therefore essential. Sensory integration therapy as part of a comprehensive early intervention program has the potential to mitigate long term problems. A multidisciplinary approach which involves health professionals and teachers is also recommended. CONCLUSION This research may be considered an early step in the identification of an association of DCD and JHS. Further studies are required to explore somatosensory processing issues experienced by those with DCD and JHS as this might be an important underlying mechanism

An Exploration of Neurophysiological Symptoms in Patients with Joint Hypermobility Syndrome and their Impact on Quality of Life.

Purpose: The purpose of this study was to explore the prevalence of neurophysiological symptoms in patients with Joint Hypermobility Syndrome (JHS) and their impact on quality of life. Relevance: Clinical experience suggests patients with JHS suffer from neurophysiological symptoms contributing to skill and health impairments affecting quality of life. MethodsA sample of 90 JHS-patients (mean age 34.7 ± 9.9 years), diagnosed according to the Brighton Criteria were compared with 113 healthy volunteers (mean age 35.7 ± 12.9) with no musculoskeletal pain. Neurophysiological symptoms were collected in a self report questionnaire. The Functional Difficulties Questionnaire was used for the assessment of developmental coordination disorder (DCD). A pain chart was employed to collect data relating to musculoskeletal pain. The SF-12 medical outcomes questionnaire was used for assessing quality of life. Analysis: Chi-square was employed to compare group proportions. Continuous numerical data comparisons were analysed using independent sample t-tests. Regression analysis was employed to analyse multiple variables. Results: Patients with JHS were significantly more likely to report the following than healthy volunteers; autonomic symptoms (70%, 12%); gastrointestinal symptoms (71%, 9%); DCD (56%, 19%) and chronic fatigue syndrome (31%, 1%). The mean number of pain sites reported for patients with JHS were 9.83 ± 4.18. Patients with JHS reported significantly lower physical component summary scores (PCS) of the SF-12 than healthy volunteers (p < 0.001). Pain was a significant predictor of reduced PCS of the SF-12 (p < 0.001) in a model that explained 23% of the variance. Conclusions Neurophysiological symptoms were common. Pain was a significant contributor to the health burden of patients with JHS. Research is required to explore the connectivity and implications of these symptoms in relation to the central nervous system. Implications: There is a requirement to acknowledge and understand the multidimensional nature of JHS

Design, synthesis, and biological evaluation of aryl piperazines with potential as antidiabetic agents via the stimulation of glucose uptake and inhibition of NADH:ubiquinone oxidoreductase

The management of blood glucose levels and the avoidance of diabetic hyperglycemia are common objectives of many therapies in the treatment of diabetes. An aryl piperazine compound 3a (RTC1) has been described as a promoter of glucose uptake, in part through a cellular mechanism that involves inhibition of NADH:ubiquinone oxidoreductase. We report herein the synthesis of 41 derivatives of 3a (RTC1) and a systematic structure-activity-relationship study where a number of compounds were shown to effectively stimulate glucose uptake in vitro and inhibit NADH:ubiquinone oxidoreductase. The hit compound 3a (RTC1) remained the most efficacious with a 2.57 fold increase in glucose uptake compared to vehicle control and micromolar inhibition of NADH:ubiquinone oxidoreductase (IC50 = 27 μM). In vitro DMPK and in vivo PK studies are also described, where results suggest that 3a (RTC1) would not be expected to provoke adverse drug-drug interactions, yet be readily metabolised, avoid rapid excretion, with a short half-life, and have good tissue distribution. The overall results indicate that aryl piperazines, and 3a (RTC1) in particular, have potential as effective agents for the treatment of diabetes

Laboratory contamination over time during low-biomass sample analysis

Bacteria are not only ubiquitous on earth but can also be incredibly diverse within clean laboratories and reagents. The presence of both living and dead bacteria in laboratory environments and reagents is especially problematic when examining samples with low endogenous content (e.g., skin swabs, tissue biopsies, ice, water, degraded forensic samples or ancient material), where contaminants can outnumber endogenous microorganisms within samples. The contribution of contaminants within high-throughput studies remains poorly understood because of the relatively low number of contaminant surveys. Here, we examined 144 negative control samples (extraction blank and no-template amplification controls) collected in both typical molecular laboratories and an ultraclean ancient DNA laboratory over 5 years to characterize long-term contaminant diversity. We additionally compared the contaminant content within a home-made silica-based extraction method, commonly used to analyse low endogenous content samples, with a widely used commercial DNA extraction kit. The contaminant taxonomic profile of the ultraclean ancient DNA laboratory was unique compared to modern molecular biology laboratories, and changed over time according to researcher, month and season. The commercial kit also contained higher microbial diversity and several human-associated taxa in comparison to the home-made silica extraction protocol. We recommend a minimum of two strategies to reduce the impacts of laboratory contaminants within low-biomass metagenomic studies: (a) extraction blank controls should be included and sequenced with every batch of extractions and (b) the contributions of laboratory contamination should be assessed and reported in each high-throughput metagenomic study.Laura S. Weyrich, Andrew G. Farrer, Raphael Eisenhofer, Luis A. Arriola Jennifer Young, Caitlin A. Selway, Matilda Handsley‐Davis, Christina J. Adler James Breen, Alan Coope

The HO Southern Galactic Plane Survey (HOPS) - I. Techniques and HO maser data

The definitive version can be found at: http://onlinelibrary.wiley.com/ Copyright Royal Astronomical SocietyWe present first results of the HO Southern Galactic Plane Survey (HOPS), using the Mopra Radio Telescope with a broad-band backend and a beam size of about 2 arcmin. We have observed 100 deg of the southern Galactic plane at 12mm (19.5-27.5GHz), including spectral line emission from HO masers, multiple metastable transitions of ammonia, cyanoacetylene, methanol and radio recombination lines. In this paper, we report on the characteristics of the survey and HO maser emission. We find 540 HO masers, of which 334 are new detections. The strongest maser is 3933Jy and the weakest is 0.7Jy, with 62 masers over 100Jy. In 14 maser sites, the spread in the velocity of the HO maser emission exceeds 100kms. In one region, the HO maser velocities are separated by 351.3kms. The rms noise levels are typically between 1 and 2Jy, with 95 per cent of the survey under 2Jy. We estimate completeness limits of 98 per cent at around 8.4Jy and 50 per cent at around 5.5Jy. We estimate that there are between 800 and 1500 HO masers in the Galaxy that are detectable in a survey with similar completeness limits to HOPS. We report possible masers in NH (11,9) and (8,6) emission towards G19.61-0.23 and in the NH (3,3) line towards G23.33-0.30.Peer reviewe

Origins of the Ambient Solar Wind: Implications for Space Weather

The Sun's outer atmosphere is heated to temperatures of millions of degrees, and solar plasma flows out into interplanetary space at supersonic speeds. This paper reviews our current understanding of these interrelated problems: coronal heating and the acceleration of the ambient solar wind. We also discuss where the community stands in its ability to forecast how variations in the solar wind (i.e., fast and slow wind streams) impact the Earth. Although the last few decades have seen significant progress in observations and modeling, we still do not have a complete understanding of the relevant physical processes, nor do we have a quantitatively precise census of which coronal structures contribute to specific types of solar wind. Fast streams are known to be connected to the central regions of large coronal holes. Slow streams, however, appear to come from a wide range of sources, including streamers, pseudostreamers, coronal loops, active regions, and coronal hole boundaries. Complicating our understanding even more is the fact that processes such as turbulence, stream-stream interactions, and Coulomb collisions can make it difficult to unambiguously map a parcel measured at 1 AU back down to its coronal source. We also review recent progress -- in theoretical modeling, observational data analysis, and forecasting techniques that sit at the interface between data and theory -- that gives us hope that the above problems are indeed solvable.Comment: Accepted for publication in Space Science Reviews. Special issue connected with a 2016 ISSI workshop on "The Scientific Foundations of Space Weather." 44 pages, 9 figure

Lives versus Livelihoods? Perceived economic risk has a stronger association with support for COVID-19 preventive measures than perceived health risk

This paper examines whether compliance with COVID-19 mitigation measures is motivated by wanting to save lives or save the economy (or both), and which implications this carries to fight the pandemic. National representative samples were collected from 24 countries (N = 25,435). The main predictors were (1) perceived risk to contract coronavirus, (2) perceived risk to suffer economic losses due to coronavirus, and (3) their interaction effect. Individual and country-level variables were added as covariates in multilevel regression models. We examined compliance with various preventive health behaviors and support for strict containment policies. Results show that perceived economic risk consistently predicted mitigation behavior and policy support—and its effects were positive. Perceived health risk had mixed effects. Only two significant interactions between health and economic risk were identified—both positive

The Physics of Star Cluster Formation and Evolution

© 2020 Springer-Verlag. The final publication is available at Springer via https://doi.org/10.1007/s11214-020-00689-4.Star clusters form in dense, hierarchically collapsing gas clouds. Bulk kinetic energy is transformed to turbulence with stars forming from cores fed by filaments. In the most compact regions, stellar feedback is least effective in removing the gas and stars may form very efficiently. These are also the regions where, in high-mass clusters, ejecta from some kind of high-mass stars are effectively captured during the formation phase of some of the low mass stars and effectively channeled into the latter to form multiple populations. Star formation epochs in star clusters are generally set by gas flows that determine the abundance of gas in the cluster. We argue that there is likely only one star formation epoch after which clusters remain essentially clear of gas by cluster winds. Collisional dynamics is important in this phase leading to core collapse, expansion and eventual dispersion of every cluster. We review recent developments in the field with a focus on theoretical work.Peer reviewe

A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial

Background Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied. Methods This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants. Findings Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48–0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78–2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported. Interpretation This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation