Assessment of movement coordination strategies to inform health of movement and guide retraining interventions.

Exploring characteristics of human movement has long been the focus of clinicians and researchers. Changes in movement coordination strategies have been identified in the presence of pain highlighting the need for assessment in clinical practice. A major development in the understanding of movement related disorders is recognition of individual differences in presentation and consequently the need to tailor interventions based on assessment. The purpose of this masterclass is to build a rationale for the clinical assessment of movement coordination strategies, exploring loss of movement choices, coordination variability, and to present a clinical framework for individualised management, including the use of cognitive movement control tests and retraining interventions. An approach for the qualitative rating of movement coordination strategies is presented. A compromised movement system may be one characterised by a lack of ability to access motor abundance and display choice in the use of movement coordination strategies. The identification of lost movement choices revealed during the assessment of movement coordination strategies is proposed as a marker of movement health. The health of the movement system may be informed by the ability to display choice in movement coordination strategies. There is evidence that restoring these choices has clinical utility and an influence on pain and improved function. This approach seeks to provide individuals with more flexible problem solving, enabled through a movement system that is robust to each unique challenge of function. This assessment framework sits within a bigger clinical reasoning picture for sustained quality of life. [Abstract copyright: Copyright © 2019 Elsevier Ltd. All rights reserved.

Movement control testing of older people in community settings: description of a screening tool and intra-rater reliability

Objective: To determine the intra-rater reliability of a newly developed movement screening tool; the ‘Movement control screen for older people in community settings’. The movement screening tool aims to identify movement control impairments which can potentially influence movement function. Method: Thirty one active female recreational golfers, aged 65-77 years,carried out three movement control tests included in the screening tool. Performance was videorecorded to enable repeated ratings. Each test was evaluated by criteria which were rated as pass or fail and ratings were carried out three weeks apart to examine intra-rater reliability. Reliability was assessed using percentage agreement and Cohen’s Kappa. Results: Percentage agreementfor each test ranged from 93.0-97.3%, with an overall mean agreement of 95.5%. Kappa values for test scores ranged from 0.35-0.90. Percentage agreement for individual criteria ranged from 83.0-100.0%, with kappa values ranging from 0.00-1.00. Discussion: Acceptable intra-rater reliability was established for overall tests scores of the screening tool but certain criteria wereidentified as being less reliable than others. Recommendations are made for refinement of some criteria to improve reliability of the screening tool.<br/

Motor control retraining exercises for shoulder impingement: effects on function, muscle activation, and biomechanics in young adults

Objective: Evidence for effective management of shoulder impingement is limited. The present study aimed to quantify the clinical, neurophysiological, and biomechanical effects of a scapular motor control retraining for young individuals with shoulder impingement signs.Method: Sixteen adults with shoulder impingement signs (mean age 22 ? 1.6 years) underwent the intervention and 16 healthy participants (24.8 ? 3.1years) provided reference data. Shoulder function and pain were assessed using the Shoulder Pain and Disability Index (SPADI) and other questionnaires. Electromyography (EMG) and 3 dimensional motion analysis was used to record muscle activation and kinematic data during arm elevation to 90? and lowering in 3 planes. Patients were assessed pre and post a 10-week motor control based intervention, utilizing scapular orientation retraining.Results: Pre-intervention, patients reported pain and reduced function compared to the healthy participants (SPADI in patients 20 ? 9.2; healthy 0 ? 0). Post intervention, the SPADI scores reduced significantly (P &lt; .001) by a mean of 10 points (?4). EMG showed delayed onset and early termination of serratus anterior and lower trapezius muscle activity pre-intervention, which improved significantly post-intervention (P &lt; .05). Pre intervention, patients exhibited on average 4.6-7.4? less posterior tilt, which was significantly lower in 2 arm elevation planes (P &lt; .05) than healthy participants. Postintervention, upward rotation and posterior tilt increased significantly (P &lt;.05) during 2 arm movements, approaching the healthy values.Conclusion: A 10-week motor control intervention for shoulder impingement increased function and reduced pain. Recovery mechanisms were indicated by changes in muscle recruitment andscapular kinematics. The efficacy of the intervention requires further examined in a randomizedcontrol trial

Tissue-specific transcriptomic changes associated with AmBisome® treatment of BALB/c mice with experimental visceral leishmaniasis.

Background: Liposomal amphotericin B (AmBisome®) as a treatment modality for visceral leishmaniasis (VL) has had significant impact on patient care in some but not all regions where VL is endemic.  As the mode of action of AmBisome® in vivo is poorly understood, we compared the tissue-specific transcriptome in drug-treated vs untreated mice with experimental VL.    Methods:  BALB/c mice infected with L. donovani were treated with 8mg/kg AmBisome®, resulting in parasite elimination from liver and spleen over a 7-day period. At day 1 and day 7 post treatment (R x+1 and R x+7), transcriptomic profiling was performed on spleen and liver tissue from treated and untreated mice and uninfected mice.  BALB/c mice infected with M. bovis BCG (an organism resistant to amphotericin B) were analysed to distinguish between direct effects of AmBisome® and those secondary to parasite death.   Results: AmBisome® treatment lead to rapid parasitological clearance.  At R x+1, spleen and liver displayed only 46 and 88 differentially expressed (DE) genes (P<0.05; 2-fold change) respectively. In liver, significant enrichment was seen for pathways associated with TNF, fatty acids and sterol biosynthesis.  At R x+7, the number of DE genes was increased (spleen, 113; liver 400).  In spleen, these included many immune related genes known to be involved in anti-leishmanial immunity. In liver, changes in transcriptome were largely accounted for by loss of granulomas.   PCA analysis indicated that treatment only partially restored homeostasis.  Analysis of BCG-infected mice treated with AmBisome® revealed a pattern of immune modulation mainly targeting macrophage function.   Conclusions: Our data indicate that the tissue response to AmBisome® treatment varies between target organs and that full restoration of homeostasis is not achieved at parasitological cure.  The pathways required to restore homeostasis deserve fuller attention, to understand mechanisms associated with treatment failure and relapse and to promote more rapid restoration of immune competence

Candidates for Balancing Selection in Leishmania donovani Complex Parasites

The Leishmania donovani species complex is the causative agent of visceral leishmaniasis, which cause 20–40,000 fatalities a year. Here, we conduct a screen for balancing selection in this species complex. We used 384 publicly available L. donovani and L. infantum genomes, and sequence 93 isolates of L. infantum from Brazil to describe the global diversity of this species complex. We identify five genetically distinct populations that are sufficiently represented by genomic data to search for signatures of selection. We find that signals of balancing selection are generally not shared between populations, consistent with transient adaptive events, rather than long-term balancing selection. We then apply multiple diversity metrics to identify candidate genes with robust signatures of balancing selection, identifying a curated set of 24 genes with robust signatures. These include zetatoxin, nodulin-like, and flagellum attachment proteins. This study highlights the extent of genetic divergence between L. donovani complex parasites and provides genes for further stud

Decision regret in men living with and beyond nonmetastatic prostate cancer in the United Kingdom: A population‐based patient‐reported outcome study

Objective: Clinical options for managing nonmetastatic prostate cancer (PCa) vary. Each option has side effects associated with it, leading to difficulty in decision‐making. This study aimed to assess the relationship between patient involvement in treatment decision‐making and subsequent decision regret (DR), and quantify the impact of health‐related quality of life (HRQL) outcomes on DR. Methods: Men living in the United Kingdom, 18 to 42 months after diagnosis of PCa, were identified from cancer registration data and sent a questionnaire. Measures included the Decision Regret Scale (DRS), Expanded Prostate cancer Index Composite short form (EPIC‐26), EQ‐5D‐5L, and an item on involvement in treatment decision‐making. Multivariable ordinal regression was utilized, with DR categorized as none, mild, or moderate/severe regret. Results: A total of 17 193 men with stage I‐III PCa completed the DRS: 36.6% reported no regret, 43.3% mild regret, and 20.0% moderate/severe regret. The odds of reporting DR were greater if men indicated their views were not taken into account odds ratio ([OR] = 6.42, 95% CI: 5.39‐7.64) or were involved “to some extent” in decision‐making (OR = 4.63, 95% CI: 4.27‐5.02), compared with men who were “definitely” involved. After adjustment, including for involvement, men reporting moderate/big problems with urinary, bowel, or sexual function were more likely to experience regret compared with men with no/small problems. Better HRQL scores were associated with lower levels of DR. Conclusions: This large‐scale study demonstrates the benefit of patient involvement in treatment decision‐making for nonmetastatic PCa. However, men experiencing side effects and poorer HRQL report greater DR. Promoting engagement in clinical decision‐making represents good practice and may reduce the risk of subsequent regret

Obsessive Compulsive Treatment Efficacy Trial (OCTET) comparing the clinical and cost effectiveness of self-managed therapies: study protocol for a randomised controlled trial

Background: UK National Institute of Health and Clinical Excellence guidelines for obsessive compulsive disorder (OCD) specify recommendations for the treatment and management of OCD using a stepped care approach. Steps three to six of this model recommend treatment options for people with OCD that range from low-intensity guided self-help (GSH) to more intensive psychological and pharmacological interventions. Cognitive behavioural therapy (CBT), including exposure and response prevention, is the recommended psychological treatment. However, whilst there is some preliminary evidence that self-managed therapy packages for OCD can be effective, a more robust evidence base of their clinical and cost effectiveness and acceptability is required. Methods/Design: Our proposed study will test two different self-help treatments for OCD: 1) computerised CBT (cCBT) using OCFighter, an internet-delivered OCD treatment package; and 2) GSH using a book. Both treatments will be accompanied by email or telephone support from a mental health professional. We will evaluate the effectiveness, cost and patient and health professional acceptability of the treatments. Discussion: This study will provide more robust evidence of efficacy, cost effectiveness and acceptability of self-help treatments for OCD. If cCBT and/or GSH prove effective, it will provide additional, more accessible treatment options for people with OCD

Chromosomal assembly of the nuclear genome of the endosymbiontbearing trypanosomatid Angomonas deanei

Abstract Angomonas deaneiA. deane

Tissue and host species-specific transcriptional changes in models of experimental visceral leishmaniasis [version 1; referees: 3 approved, 1 approved with reservations]

Background: Human visceral leishmaniasis, caused by infection with Leishmania donovani or L. infantum, is a potentially fatal disease affecting 50,000-90,000 people yearly in 75 disease endemic countries, with more than 20,000 deaths reported. Experimental models of infection play a major role in understanding parasite biology, host-pathogen interaction, disease pathogenesis, and parasite transmission. In addition, they have an essential role in the identification and pre-clinical evaluation of new drugs and vaccines. However, our understanding of these models remains fragmentary. Although the immune response to Leishmania donovani infection in mice has been extensively characterized, transcriptomic analysis capturing the tissue-specific evolution of disease has yet to be reported. Methods: We provide an analysis of the transcriptome of spleen, liver and peripheral blood of BALB/c mice infected with L. donovani. Where possible, we compare our data in murine experimental visceral leishmaniasis with transcriptomic data in the public domain obtained from the study of L. donovani-infected hamsters and patients with human visceral leishmaniasis. Digitised whole slide images showing the histopathology in spleen and liver are made available via a dedicated website, www.leishpathnet.org. Results: Our analysis confirms marked tissue-specific alterations in the transcriptome of infected mice over time and identifies previously unrecognized parallels and differences between murine, hamster and human responses to infection. We show commonality of interferon-regulated genes whilst confirming a greater activation of type 2 immune pathways in infected hamsters compared to mice. Cytokine genes and genes encoding immune checkpoints were markedly tissue specific and dynamic in their expression, and pathways focused on non-immune cells reflected tissue specific immunopathology. Our data also addresses the value of measuring peripheral blood transcriptomics as a potential window into underlying systemic disease.  Conclusions: Our transcriptomic data, coupled with histopathologic analysis of the tissue response, provide an additional resource to underpin future mechanistic studies and to guide clinical research

3’Nucleotidase/nuclease is required for Leishmania infantum clinical isolate susceptibility to miltefosine

Summary Background Miltefosine treatment failure in visceral leishmaniasis in Brazil has been associated with deletion of the miltefosine susceptibility locus (MSL) in Leishmania infantum. The MSL comprises four genes, 3′ -nucleotidase/nucleases (NUC1 and NUC2); helicase-like protein (HLP); and 3,2-trans-enoyl-CoA isomerase (TEI). Methods In this study CRISPR-Cas9 was used to either epitope tag or delete NUC1, NUC2, HLP and TEI, to investigate their role in miltefosine resistance mechanisms. Additionally, miltefosine transporter genes and miltefosine-mediated reactive oxygen species homeostasis were assessed in 26 L. infantum clinical isolates. A comparative lipidomic analysis was also performed to investigate the molecular basis of miltefosine resistance. Findings Deletion of both NUC1, NUC2 from the MSL was associated with a significant decrease in miltefosine susceptibility, which was restored after re-expression. Metabolomic analysis of parasites lacking the MSL or NUC1 and NUC2 identified an increase in the parasite lipid content, including ergosterol; these lipids may contribute to miltefosine resistance by binding the drug in the membrane. Parasites lacking the MSL are more resistant to lipid metabolism perturbation caused by miltefosine and NUC1 and NUC2 are involved in this pathway. Additionally, L. infantum parasites lacking the MSL isolated from patients who relapsed after miltefosine treatment were found to modulate nitric oxide accumulation in host macrophages. Interpretation Altogether, these data indicate that multifactorial mechanisms are involved in natural resistance to miltefosine in L. infantum and that the absence of the 3’nucleotidase/nuclease genes NUC1 and NUC2 contributes to the phenotype.publishersversionpublishe