Effects of a highly intensive balance therapy camp in children with developmental coordination disorder - An intervention protocol.

BACKGROUND: Children with Developmental Coordination Disorder (DCD) often (<87 %) experience postural control problems, impacting all levels of the International Classification of Functioning, Disability and Health (ICF) including their daily participation, self-esteem and mental health. Due to the multisystemic nature of postural control, comprehensive therapy should target all systems which is currently not the case. Highly intensive therapy is effective and commonly used in pediatric populations, but has not been explored yet to train postural control in children with DCD. AIMS: To investigate the effects of a highly intensive functional balance therapy camp at all ICF levels in children with DCD. METHODS AND PROCEDURES: The effects on postural control, muscle activity, brain alterations, self-perceived competence, self-identified goals, gross motor activities and participation are evaluated. Participants are assessed pre- and post-intervention, including a 3 months follow-up. Forty-eight children with DCD, aged 6-12 years old, receive 40 h of comprehensive balance training. This intervention is fun, individually tailored, targets all postural control systems, implements different motor learning strategies and includes both individual and group activities. CONCLUSION: Novel insights into the effects of a highly intensive comprehensive balance therapy camp designed for children with DCD will be gained at all levels of the ICF.

MicroRNA-based therapeutics for inflammatory disorders of the microbiota-gut-brain axis.

An emerging but less explored shared pathophysiology across microbiota-gut-brain axis disorders is aberrant miRNA expression, which may represent novel therapeutic targets. miRNAs are small, endogenous non-coding RNAs that are important transcriptional repressors of gene expression. Most importantly, they regulate the integrity of the intestinal epithelial and blood-brain barriers and serve as an important communication channel between the gut microbiome and the host. A well-defined understanding of the mode of action, therapeutic strategies and delivery mechanisms of miRNAs is pivotal in translating the clinical applications of miRNA-based therapeutics. Accumulating evidence links disorders of the microbiota-gut-brain axis with a compromised gut-blood-brain-barrier, causing gut contents such as immune cells and microbiota to enter the bloodstream leading to low-grade systemic inflammation. This has the potential to affect all organs, including the brain, causing central inflammation and the development of neurodegenerative and neuropsychiatric diseases. In this review, we have examined in detail miRNA biogenesis, strategies for therapeutic application, delivery mechanisms, as well as their pathophysiology and clinical applications in inflammatory gut-brain disorders. The research data in this review was drawn from the following databases: PubMed, Google Scholar, and Clinicaltrials.gov. With increasing evidence of the pathophysiological importance for miRNAs in microbiota-gut-brain axis disorders, therapeutic targeting of cross-regulated miRNAs in these disorders displays potentially transformative and translational potential. Further preclinical research and human clinical trials are required to further advance this area of research.

Retrospective review of the efficacy for sublingual ketamine in the treatment of chronic low back pain defined by a cause and central functional pain symptom focused clinical model.

PURPOSE: Chronic low back pain is a leading cause of disability worldwide. A clinical model for its cause is lacking. Defining a cause based clinical model and a framework of understanding back pain in terms of peripheral structural and central functional pain is essential for optimal management. MATERIALS AND METHODS: We describe the results of the largest published audit of 41 chronic low back pain patients, receiving outpatient sublingual ketamine therapy for defined central functional pain along with conventional peripheral structural pain management. Our clinical model assigns Movement Dysfunction as the primary cause for low back pain symptoms and restores it with Movement Therapy focused rehabilitation which is also defined. Patients were derived from a tertiary single neurosurgical specialist practice in Brisbane Australia over a three year period. RESULTS: Severe pain and disability measurements more than halved and only 13% of patients ceased ketamine prematurely due to predominantly non-sinister side effects common to all pharmaceutical therapies. All other surveyed metrics of utility were highly favourable in this challenging cohort of chronic back pain patients biased to poor outcomes. CONCLUSIONS: Outpatient ketamine maintains high efficacy and safety used in conjunction with a unique clinical model that describes chronic low back pain.

This paper builds on our previous publications that describe the disease of movement dysfunction as an integral factor to the development of a cause based clinical model for the condition of chronic low back pain symptoms.Our clinical application of this model, applying the necessary dual approach of controlling symptoms arising from peripheral structural pain and central functional pain in conjunction with elimination of root causation has shown favourable outcomes in patients with high levels of pain and disability based on their tertiary referral origin and high Oswestry Disability Scores.Removing chronic low back pain from its position as one of the world's leading causes of pain and disability is more likely if the rehabilitation industry can replicate and test treatment algorithms based around established clinical models of disease which is the important subject of this paper.

Psychometric properties of functional postural control tests in children: A systematic review.

BACKGROUND: Postural control deficits are one of the most common impairments treated in pediatric physiotherapeutic practice. Adequate evaluation of these deficits is imperative to identify postural control deficits, plan treatment and assess efficacy. Currently, there is no gold standard evaluation for postural control deficits. However, the number of studies investigating the psychometric properties of functional pediatric postural control tests has increased significantly. OBJECTIVE: To facilitate the selection of an appropriate pediatric functional postural control test in research and clinical practice. METHODS: Systematic review following the PRISMA guidelines. PubMed, Web of Science and Scopus were systematically searched (last update: June 2022; PROSPERO: CRD42021246995). Studies were selected using the PICOs-method (pediatric populations (P), functional assessment tools for postural control (I) and psychometric properties (O). The risk of bias was rated with the COSMIN checklist and the level of evidence was determined with GRADE. For each test, the postural control systems were mapped, and the psychometric properties were extracted. RESULTS: Seventy studies investigating 26 different postural control tests were included. Most children were healthy or had cerebral palsy. Overall, the evidence for all measurement properties was low to very low. Most tests (95%) showed good reliability (ICC>0.70), but inconsistent validity results. Structural validity, internal consistency and responsiveness were only available for 3 tests. Only the Kids-BESTest and FAB covered all postural control systems. CONCLUSION: Currently, 2 functional tests encompass the entire construct of postural control. Although reliability is overall good, validity results depend on task, age and pathology. Future research should focus on test batteries and should particularly explore structural validity and responsiveness in different populations with methodologically strong study designs.

The impact of COVID-19 lockdown on the general health status of people with chronic health conditions in Belgium: a cross-sectional survey study.

BACKGROUND: Patients with chronic health conditions risk aggravation of their health status due to reduced access to health services during the COVID-19 related lockdown. OBJECTIVES: To investigate the impact of Belgian COVID-19 measures on general health status (i.e. worse or stable/better) of patients, adult and pediatric, with chronic health conditions and how this change in health status relates to personal and health behavior-related factors. DESIGN: A cross-sectional study using an online survey was conducted during the first COVID-19 related lockdown in Belgium. METHODS: Associations between change in health status since the lockdown and (change in) personal and health behavior-related factors (including physical activity, access to health-care services and social activities) were investigated. RESULTS: In adults (n = 561), almost all personal factors, including feelings of distress, depression, anxiety, somatization, and low self-efficacy, were significantly worse in patients with a worse health status during the lockdown (n = 293, 52%) compared to patients reporting a stable/better health status (p < .001-0.002). Also, these patients reported lower physical activity levels, more tele-consultations and less social activities (p < .001-0.006). In children (n = 55), all surveys were completed by a proxy (parent(s)/guardian) who reported a worse health status in 38% of the children. Level of distress of the child (p = .005) since the lockdown and somatization of the parent(s) (p = .0018) were significantly worse in children with a worse versus a stable/better health status. CONCLUSION: Fifty-two percent of the adults and 38% of children with chronic health conditions reported worsening of their general health status during the lockdown in March-May 2020 in Belgium. Negative personal factors and unhelpful health behavior seems to be associated with a worse health status.

Creeping yeast: a simple, cheap and robust protocol for the identification of mating type in Saccharomyces cerevisiae.

Saccharomyces cerevisiae is an exceptional genetic system, with genetic crosses facilitated by its ability to be maintained in haploid and diploid forms. Such crosses are straightforward if the mating type/ploidy of the strains is known. Several techniques can determine mating type (or ploidy), but all have limitations. Here, we validate a simple, cheap and robust method to identify S. cerevisiae mating types. When cells of opposite mating type are mixed in liquid media, they 'creep' up the culture vessel sides, a phenotype that can be easily detected visually. In contrast, mixtures of the same mating type or with a diploid simply settle out. The phenotype is observable for several days under a range of routine growth conditions and with different media/strains. Microscopy suggests that cell aggregation during mating is responsible for the phenotype. Yeast knockout collection analysis identified 107 genes required for the creeping phenotype, with these being enriched for mating-specific genes. Surprisingly, the RIM101 signaling pathway was strongly represented. We propose that RIM101 signaling regulates aggregation as part of a wider, previously unrecognized role in mating. The simplicity and robustness of this method make it ideal for routine verification of S. cerevisiae mating type, with future studies required to verify its molecular basis.

Balance control in individuals with developmental coordination disorder: A systematic review and meta-analysis.

BACKGROUND: Although it is recognized that the majority of children with developmental coordination disorder (DCD) have balance deficits, comprehensive insights into which balance domains are affected, are still lacking in literature. RESEARCH QUESTION: To what extent is balance control deficient in individuals with DCD compared to controls? METHODS: Pubmed, Scopus and Web of Science were systematically searched. Risk of bias was assessed with the Scottish Intercollegiate Guidelines Network checklist for case-control studies. Mean and standard deviations characterizing balance control were extracted to calculate standardized mean differences (SMD) and pooled, if possible, using Review Manager. RESULTS: The results of 31 studies (1152 individuals with DCD, 1103 typically developing (TD) peers, mean age 10.4 years old) were extracted of which 17 were used for meta-analysis. The mean SMD for the balance subscale of the Movement Assessment Battery for Children was 1.63 (pooled 95 %CI =[1.30;1.97]), indicating children with DCD to perform significantly poorer than their TD peers. Force plate studies also revealed that children with DCD present with a larger sway path during bipedal stance with eyes closed (pooled mean SMD = 0.55; 95 %CI=[0.32;0.78]). Children with DCD tend to have direction-specific limited stability limits and task-independent delayed onset of anticipatory postural adjustments. INTERPRETATION: Children with DCD perform poorer on different domains of balance compared to TD peers. Future research should focus on comprehensive balance assessment in these children, preferably using a longitudinal design.

Aging and the Relationship between Balance Performance, Vestibular Function and Somatosensory Thresholds.

OBJECTIVES: The objective of this study was two-fold: (1) To evaluate the impact of the physiological aging process on somatosensory, vestibular, and balance functions, and (2) To examine the extent to which age and somatosensory and vestibular functions can predict balance performance. MATERIALS AND METHODS: In this cross-sectional study, 141 asymptomatic subjects were assessed for touch pressure thresholds (TPT) with Semmes-Weinstein monofilaments (SWF), vibration thresholds (VT) with a neurothesiometer (NT) and a Rydel-Seiffer tuning fork 128Hz (RSTF). Horizontal vestibulo-ocular reflexes (HVOR gain and asymmetry) were assessed using the video Head Impulse Test (vHIT). A modified version of the Romberg test was used to assess standing balance and the Timed Up and Go test (TUG) and tandem gait (TG) to evaluate dynamic balance. RESULTS: Significant age effects were found for TPT, VT, and balance but not for HVOR gain or asymmetry. Standing balance was explained for 47.2% by age, metatarsal 1 (MT1) (NT), and heel (SWF). The variance in TUG performance was explained for 47.0% by age, metatarsal 5 (MT5) (SWF), and medial malleolus (MM) (NT). Finally, the variance in TG performance was predicted for 43.1% by age, MT1 (NT), HVOR gain, and heel (SWF). CONCLUSION: Among asymptomatic adult population, both somatosensation and balance performance deteriorate with aging. In contrast, HVOR remains rather constant with age, which is possibly explained by the process of vestibular adaptation. Furthermore, this study provides evidence that the VT, TPT, HVOR gain, and age partly predict balance performance. Still, further research is needed, especially with bigger samples in decades 8 and 9.

Characterisation of microplastic contamination in sediment of England's inshore waters.

Plastic litter is an increasingly significant problem in the marine environment. Our study looks at a cost-effective method to quantify larger fractions of microplastics in marine sediments as an opportunistic addition to standard benthic infauna sampling. A subsample of microplastics (>1 mm) were enumerated and categorised from sediment samples collected as part of standard benthic habitat monitoring in twenty-two Marine Protected Areas across English inshore waters. Microplastic particles were found in 61.2% of the samples collected, with mean density per study site ranging from 0.2 in Dover to Deal MCZ to 42.7 in The Mersey Estuary Special Protection Area microplastic particles per 0.1 m2. High densities of plastic were found at remote sites, as well as those closer to urban or industrialised areas. Spatial protection measures such as MPAs are not themselves a suitable tool to tackle marine plastic pollution which should be addressed upstream at source.

Correction: Loss of tuberous sclerosis complex 2 sensitizes tumors to nelfinavir-bortezomib therapy to intensify endoplasmic reticulum stress-induced cell death.

This article was originally published under standard licence, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the paper have been modified accordingly.

Energy Stress-Mediated Cytotoxicity in Tuberous Sclerosis Complex 2-Deficient Cells with Nelfinavir and Mefloquine Treatment.

To find new anti-cancer drug therapies, we wanted to exploit homeostatic vulnerabilities within Tuberous Sclerosis Complex 2 (TSC2)-deficient cells with mechanistic target of rapamycin complex 1 (mTORC1) hyperactivity. We show that nelfinavir and mefloquine synergize to selectively evoke a cytotoxic response in TSC2-deficient cell lines with mTORC1 hyperactivity. We optimize the concentrations of nelfinavir and mefloquine to a clinically viable range that kill cells that lack TSC2, while wild-type cells tolerate treatment. This new clinically viable drug combination causes a significant level of cell death in TSC2-deficient tumor spheroids. Furthermore, no cell recovery was apparent after drug withdrawal, revealing potent cytotoxicity. Transcriptional profiling by RNA sequencing of drug treated TSC2-deficient cells compared to wild-type cells suggested the cytotoxic mechanism of action, involving initial ER stress and an imbalance in energy homeostatic pathways. Further characterization revealed that supplementation with methyl pyruvate alleviated energy stress and reduced the cytotoxic effect, implicating energy deprivation as the trigger of cell death. This work underpins a critical vulnerability with cancer cells with aberrant signaling through the TSC2-mTORC1 pathway that lack flexibility in homeostatic pathways, which could be exploited with combined nelfinavir and mefloquine treatment.

Loss of tuberous sclerosis complex 2 sensitizes tumors to nelfinavir-bortezomib therapy to intensify endoplasmic reticulum stress-induced cell death.

Cancer cells lose homeostatic flexibility because of mutations and dysregulated signaling pathways involved in maintaining homeostasis. Tuberous Sclerosis Complex 1 (TSC1) and TSC2 play a fundamental role in cell homeostasis, where signal transduction through TSC1/TSC2 is often compromised in cancer, leading to aberrant activation of mechanistic target of rapamycin complex 1 (mTORC1). mTORC1 hyperactivation increases the basal level of endoplasmic reticulum (ER) stress via an accumulation of unfolded protein, due to heightened de novo protein translation and repression of autophagy. We exploit this intrinsic vulnerability of tumor cells lacking TSC2, by treating with nelvinavir to further enhance ER stress while inhibiting the proteasome with bortezomib to prevent effective protein removal. We show that TSC2-deficient cells are highly dependent on the proteosomal degradation pathway for survival. Combined treatment with nelfinavir and bortezomib at clinically relevant drug concentrations show synergy in selectively killing TSC2-deficient cells with limited toxicity in control cells. This drug combination inhibited tumor formation in xenograft mouse models and patient-derived cell models of TSC and caused tumor spheroid death in 3D culture. Importantly, 3D culture assays differentiated between the cytostatic effects of the mTORC1 inhibitor, rapamycin, and the cytotoxic effects of the nelfinavir/bortezomib combination. Through RNA sequencing, we determined that nelfinavir and bortezomib tip the balance of ER protein homeostasis of the already ER-stressed TSC2-deficient cells in favor of cell death. These findings have clinical relevance in stratified medicine to treat tumors that have compromised signaling through TSC and are inflexible in their capacity to restore ER homeostasis.

Exploiting cancer vulnerabilities: mTOR, autophagy, and homeostatic imbalance.

Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) at lysosomes plays a pivotal role in cell growth control where an array of large multiprotein complexes relay nutrient, energy, and growth signal inputs through mTORC1. In cancer cells, such regulation often becomes disconnected, leading to uncontrolled cell growth and an elevation in cellular stress. Consequently, cancer cells often lose homeostatic balance as they grow in unfavorable conditions, i.e. when nutrients and energy are limited yet mTORC1 is still aberrantly activated. Cancer cells lose signaling flexibility because of hyperactive mTORC1 that leads to heightened cellular stress and loss of nutrient and energy homeostasis, all of which are potential avenues for cancer therapy. Cancer cells often enhance mTORC1 to drive cell growth and proliferation, while also maintaining their survival. Autophagy regulation by mTORC1 is critically involved in nutrient and energy homeostasis, cell growth control, and survival. Studying mTORC1 and autophagy as a potential therapeutic target for cancer treatment has been the focus of a wide range of research over the past few decades. This review will explore the signaling pathways central to mTORC1 and autophagy regulation, and cancer vulnerabilities while considering anticancer therapies.

Targeting protein homeostasis with nelfinavir/salinomycin dual therapy effectively induces death of mTORC1 hyperactive cells.

Uncontrolled cell growth in Tuberous Sclerosis Complex occurs due to inappropriate activation of mechanistic (mammalian) target of rapamycin complex 1 (mTORC1). The current therapy, rapamycin, produced promising clinical trial results, but patient tumours regrow if treatment is discontinued, revealing rapamycin has cytostatic properties rather than a cytotoxic effect. Taking advantage of the enhanced levels of endoplasmic reticulum (ER) stress present in TSC2-null cells, we investigated drug combinations producing a cytotoxic response. We found a nelfinavir and salinomycin combination specifically killed TSC2-deficient, mTORC1 hyperactive cells. Cytotoxicity was rescued by reducing protein synthesis, either through mTORC1 inhibition or cycloheximide treatment. This indicates that the drug combination targets the cells by tipping the protein homeostasis balance of the already metabolically stressed TSC2-deficient cells in favour of cell death. Furthermore, this drug combination also inhibited tumour formation in TSC2-deficient cell models and caused tumour spheroid death in 3D culture. Importantly, the 3D assay could differentiate the cytostatic agent, rapamycin, from the cytotoxic nelfinavir/salinomycin combination. Sporadic cancer cell lines with hyperactive mTORC1 signalling were also susceptible to this nelfinavir/salinomycin drug combination. This work indicates that the protein homeostasis pathway is an attractive therapeutic target in both Tuberous Sclerosis Complex and mTORC1-driven sporadic cancers.

Correction: Beyond Academia - Interrogating Research Impact in the Research Excellence Framework.

[This corrects the article DOI: 10.1371/journal.pone.0168533.].

Beyond Academia - Interrogating Research Impact in the Research Excellence Framework.

Big changes to the way in which research funding is allocated to UK universities were brought about in the Research Excellence Framework (REF), overseen by the Higher Education Funding Council, England. Replacing the earlier Research Assessment Exercise, the purpose of the REF was to assess the quality and reach of research in UK universities-and allocate funding accordingly. For the first time, this included an assessment of research 'impact', accounting for 20% of the funding allocation. In this article we use a text mining technique to investigate the interpretations of impact put forward via impact case studies in the REF process. We find that institutions have developed a diverse interpretation of impact, ranging from commercial applications to public and cultural engagement activities. These interpretations of impact vary from discipline to discipline and between institutions, with more broad-based institutions depicting a greater variety of impacts. Comparing the interpretations with the score given by REF, we found no evidence of one particular interpretation being more highly rewarded than another. Importantly, we also found a positive correlation between impact score and [overall research] quality score, suggesting that impact is not being achieved at the expense of research excellence.

Endoplasmic reticulum stress and cell death in mTORC1-overactive cells is induced by nelfinavir and enhanced by chloroquine.

Inappropriate activation of mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is common in cancer and has many cellular consequences including elevated endoplasmic reticulum (ER) stress. Cells employ autophagy as a critical compensatory survival mechanism during ER stress. This study utilised drug-induced ER stress through nelfinavir in order to examine ER stress tolerance in cell lines with hyper-active mTORC1 signalling. Our initial findings in wild type cells showed nelfinavir inhibited mTORC1 signalling and upregulated autophagy, as determined by decreased rpS6 and S6K1 phosphorylation, and SQTSM1 protein expression, respectively. Contrastingly, cells with hyper-active mTORC1 displayed basally elevated levels of ER stress which was greatly exaggerated following nelfinavir treatment, seen through increased CHOP mRNA and XBP1 splicing. To further enhance the effects of nelfinavir, we introduced chloroquine as an autophagy inhibitor. Combination of nelfinavir and chloroquine significantly increased ER stress and caused selective cell death in multiple cell line models with hyper-active mTORC1, whilst control cells with normalised mTORC1 signalling tolerated treatment. By comparing chloroquine to other autophagy inhibitors, we uncovered that selective toxicity invoked by chloroquine was independent of autophagy inhibition yet entrapment of chloroquine to acidified lysosomal/endosomal compartments was necessary for cytotoxicity. Our research demonstrates that combination of nelfinavir and chloroquine has therapeutic potential for treatment of mTORC1-driven tumours.

Six children with pyruvate kinase deficiency from one small town: molecular characterization of the PK-LR gene.

We identified the pyruvate kinase liver/red cell enzyme gene mutation of 8 children previously diagnosed with pyruvate kinase deficiency who were living in a remote town in the western United States. Six were found to be homozygous for the mutation 1529G-A (510 Arg-Gln). Two previously thought to have pyruvate kinase deficiency did not, because they were heterozygous.

Gender, sexuality, body image and eating behaviours.

One hundred and twenty one participants reported sexual orientation, body mass index, body shape concerns, eating motives and eating styles. Measures of body dissatisfaction were greater in heterosexual women and homosexual men (ps <.05), while heterosexual women had smaller (ps <.001) ideal body shapes. Eating weight control motive was lower in heterosexual men compared to women (ps <.05). Restrained eating was lower in heterosexual men compared to heterosexual women or homosexual men (ps <.001). The findings support the role of socially prescribed body shapes on body shape concerns, eating motivations, and eating styles in men and women and suggest impacts are greater for heterosexual women and homosexual men.