Engaging a community to focus on upper limb function in people with multiple sclerosis: the ThinkHand campaign case study.

BACKGROUND: Solving complex research challenges requires innovative thinking and alternative approaches to traditional methods. One such example is the problem of arm and hand, or upper limb function in multiple sclerosis (MS), a neurological condition affecting approximately 2.9 million people worldwide and more than 150,000 in the United Kingdom. Historically, clinical trials and research have focused on mobility and walking ability. This excludes a large number of patients who are wheelchair users, limiting their quality of life and restricting access to possibly helpful medications. To address this issue, the ThinkHand campaign was launched in 2016, aiming to raise awareness about the importance of upper limb function in MS and develop alternative ways to measure, record, and account for hand and arm function changes. MAIN BODY: The campaign utilised innovative strategies at scientific conferences and online surveys to engage people affected by MS, healthcare professionals, charities, and researchers in discussing the importance of preserving upper limb function. Through co-design and interdisciplinary collaboration, the campaign developed new tools like the low-cost cardboard version of the Nine-Hole Peg Test, facilitating remote monitoring of hand function. Additionally, the campaign co-created the "Under & Over" rehabilitation tool, allowing individuals with advanced MS to participate in a remote rehabilitation program.The impact of the ThinkHand campaign has been significant, helping to shift the focus of both academic and industry-supported trials, including the O'HAND and ChariotMS trials, both using upper limb function as their primary end point. The campaign's patient-centred approach highlighted the importance of recognising patients' perspectives in research and challenged established assumptions and practices. It demonstrated the effectiveness of interdisciplinary collaboration, systems thinking, and co-creation with stakeholders in tackling complex problems. CONCLUSION: The ThinkHand campaign provides valuable insights for health research practices. By involving patients at all stages, researchers can gain a deeper understanding of the impact of disease on their lives, identify gaps and focus research on their needs. Experimentation and iteration can lead to innovative solutions, and openness to unconventional methods can drive widespread change. The ThinkHand campaign exemplifies the potential of patient-centred approaches to address complex research challenges and revolutionise the field of MS research and management. Embracing such approaches will contribute to more inclusive and impactful research in the future.

Solving complex research challenges requires creative thinking and new ways of doing things. One such challenge is understanding the problems with arm and hand function in multiple sclerosis (MS), a neurological condition that affects more than 150,000 in the United Kingdom. In the past, research focused mainly on walking ability, leaving out many people who use wheelchairs.To tackle this issue, we created the ThinkHand campaign in 2016. Its goal was to raise awareness about the importance of hand and arm function for people with MS (pwMS) and find better ways to measure changes in these functions such that they can become outcomes in clinical trials. This could provide a pathway to better treatments for pwMS who cannot walk.The campaign used various methods, including surveys, social media posts, exhibitions and music to involve pwMS, healthcare professionals, charities, and researchers in discussions about the issues. Working together, they created tools to support pwMS, particularly those at an advanced stage of the disease (pwAMS), to take part in research and measure their hand and arm function. Through our collaborative approach focusing on patients' perspectives, the campaign challenged old ideas and deeply embedded practices. It showed that collaboration between different areas of expertise involving pwMS at all stages of research can help solve complex problems. This campaign teaches us valuable lessons for health research. When researchers listen to patients and try new things, they can better understand how a disease affects people's lives and develop better solutions.In conclusion, we show how embracing a patient-centred approach can address complex research challenges and improve how we study and manage MS and other conditions in the future.

Social determinants of health in multiple sclerosis.

Social determinants of health are the conditions in which people are born, grow, live, work and age. These circumstances are the non-medical factors that influence health outcomes. Evidence indicates that health behaviours, comorbidities and disease-modifying therapies all contribute to multiple sclerosis (MS) outcomes; however, our knowledge of the effects of social determinants - that is, the 'risks of risks' - on health has not yet changed our approach to MS. Assessing and addressing social determinants of health could fundamentally improve health and health care in MS; this approach has already been successful in improving outcomes in other chronic diseases. In this narrative Review, we identify and discuss the body of evidence supporting an effect of many social determinants of health, including racial background, employment and social support, on MS outcomes. It must be noted that many of the published studies were subject to bias, and screening tools and/or practical interventions that address these social determinants are, for the most part, lacking. The existing work does not fully explore the potential bidirectional and complex relationships between social determinants of health and MS, and the interpretation of findings is complicated by the interactions and intersections among many of the identified determinants. On the basis of the reviewed literature, we consider that, if effective interventions targeting social determinants of health were available, they could have substantial effects on MS outcomes. Therefore, funding for and focused design of studies to evaluate and address social determinants of health are urgently needed.

Genomics-informed delineation of conservation units in a desert amphibian.

Delineating conservation units (CUs, e.g., evolutionarily significant units, ESUs, and management units, MUs) is critical to the recovery of declining species because CUs inform both listing status and management actions. Genomic data have strengths and limitations in informing CU delineation and related management questions in natural systems. We illustrate the value of using genomic data in combination with landscape, dispersal and occupancy data to inform CU delineation in Nevada populations of the Great Basin Distinct Population Segment of the Columbia spotted frog (Rana luteiventris). R. luteiventris occupies naturally fragmented aquatic habitats in this xeric region, but beaver removal, climate change and other factors have put many of these populations at high risk of extirpation without management intervention. We addressed three objectives: (i) assessing support for ESUs within Nevada; (ii) evaluating and revising, if warranted, the current delineation of MUs; and (iii) evaluating genetic diversity, effective population size, adaptive differentiation and functional connectivity to inform ongoing management actions. We found little support for ESUs within Nevada but did identify potential revisions to MUs based on unique landscape drivers of connectivity that distinguish these desert populations from those in the northern portion of the species range. Effective sizes were uniformly small, with low genetic diversity and weak signatures of adaptive differentiation. Our findings suggest that management actions, including translocations and genetic rescue, might be warranted. Our study illustrates how a carefully planned genetic study, designed to address priority management goals that include CU delineation, can provide multiple insights to inform conservation action.

Visibility and representation of women in multiple sclerosis research.

OBJECTIVE: To establish the gender distribution of multiple sclerosis (MS) researchers across high-impact neurologic publications, MS-specific journals, and the European Committee for Treatment and Research in MS (ECTRIMS). METHODS: Journal editorial boards and contents were retrieved online to assess first-named and senior authors. Published tables of contents for each journal from 2017 were reviewed. Congrex, the ECTRIMS organizers, were contacted and speaker names were obtained from online abstracts to assess visible opinion leaders. RESULTS: A total of 2,080 articles were analyzed across 4 general neurology journals, and 452 across 2 MS journals. Overall, 36% of general neurology articles had a female first name author and 25% had a female senior author. In MS-specific journals, 44% of first authors and 35% of senior authors were female, with similar proportions of unique authors. There is limited female representation on the ECTRIMS executive board, but reasonable balance on Council. Almost 50% of attendees in 2017 were female, but only 35% of invited speakers. CONCLUSIONS: There is substantial female drop-off between junior and senior research level across multiple areas. Strategies to support gender balance are urgently required, including developing mentorship schemes, ensuring gender balance in conferences, and thorough examination of the barriers facing female academics with direct challenges to address unconscious bias.

Acceptable noise levels in preschool children with normal hearing.

BACKGROUND: The acceptable noise level (ANL) measure is an indicator of hearing aid use. The majority of research in this area has focused primarily on adults. Research using school-aged listeners, specifically 8 and 12 yr old children, demonstrated that the average ANL values, standard deviations (SDs), and distribution of ANL values for these children were similar to those of adult listeners. Additionally, the ANL measure is reliable over time, even in school-aged listeners. Although ANL values from adult and school-aged listeners have been investigated, no research to date has been conducted using preschool children. PURPOSE: The purpose of the present study was to determine if ANLs could be obtained in preschool children, aged 4 and 5 yr, with normal hearing. This study also aimed to investigate the reliability and distribution of ANL measurements from preschool children, as well as any effect that background noise might present in the listening environment. RESEARCH DESIGN: Seated in a sound-treated test suite, listeners were tasked with adjusting speech stimuli to their most comfortable listening level; then, with speech present, listeners were tasked with adjusting the background noise to their most acceptable background noise level. Three trials of each measure were averaged and were used to calculate each listener's ANL. STUDY SAMPLE: ANLs were attempted on 23 children, ages 4 yr (N = 14) to 5 yr (N = 9), with normal hearing. RESULTS: Less than half of the 4 yr old listeners performed the ANL task, whereas all of the 5 yr old listeners completed the task successfully. Good test-retest reliability was found for those preschool children who were able to complete the task. Mean ANLs, SDs, ranges, and distributions demonstrated that these values agree with ANL data collected from older school-aged listeners. CONCLUSIONS: Although ANL values were reliably measured in all of the 5 yr old listeners, this was not the case for 4 yr old listeners. ANL values were not reliably obtained from 4 yr old listeners; however, the ANL procedure is appropriate for use for 5 yr old listeners. Furthermore, ANL means, SDs, ranges, and distributions were in agreement with those from older school-aged children and adults, and ANLs in preschool listeners were unaffected by the type of background noise stimuli.

Small molecule mesengenic induction of human induced pluripotent stem cells to generate mesenchymal stem/stromal cells.

The translational potential of mesenchymal stem/stromal cells (MSCs) is limited by their rarity in somatic organs, heterogeneity, and need for harvest by invasive procedures. Induced pluripotent stem cells (iPSCs) could be an advantageous source of MSCs, but attempts to derive MSCs from pluripotent cells have required cumbersome or untranslatable techniques, such as coculture, physical manipulation, sorting, or viral transduction. We devised a single-step method to direct mesengenic differentiation of human embryonic stem cells (ESCs) and iPSCs using a small molecule inhibitor. First, epithelial-like monolayer cells were generated by culturing ESCs/iPSCs in serum-free medium containing the transforming growth factor-ß pathway inhibitor SB431542. After 10 days, iPSCs showed upregulation of mesodermal genes (MSX2, NCAM, HOXA2) and downregulation of pluripotency genes (OCT4, LEFTY1/2). Differentiation was then completed by transferring cells into conventional MSC medium. The resultant development of MSC-like morphology was associated with increased expression of genes, reflecting epithelial-to-mesenchymal transition. Both ESC- and iPSC-derived MSCs exhibited a typical MSC immunophenotype, expressed high levels of vimentin and N-cadherin, and lacked expression of pluripotency markers at the protein level. Robust osteogenic and chondrogenic differentiation was induced in vitro in ES-MSCs and iPS-MSCs, whereas adipogenic differentiation was limited, as reported for primitive fetal MSCs and ES-MSCs derived by other methods. We conclude that treatment with SB431542 in two-dimensional cultures followed by culture-induced epithelial-to-mesenchymal transition leads to rapid and uniform MSC conversion of human pluripotent cells without the need for embryoid body formation or feeder cell coculture, providing a robust, clinically applicable, and efficient system for generating MSCs from human iPSCs.

Attachment and growth of human embryonic stem cells on microcarriers.

The use of human embryonic stem cells (hESCs) for cell-based therapies will require large quantities of genetically stable pluripotent cells and their differentiated progeny. Traditional hESC propagation entails adherent culture and is sensitive to enzymatic dissociation. These constraints hamper modifying method from 2-dimensional flat-bed culture, which is expensive and impractical for bulk cell production. Large-scale culture for clinical use will require innovations such as suspension culture for bioprocessing. Here we describe the attachment and growth kinetics of both murine embryonic stem cells (mESCs) and hESCs on trimethyl ammonium-coated polystyrene microcarriers for feeder-free, 3-dimensional suspension culture. mESCs adhered and expanded according to standard growth kinetics. For hESC studies, we tested aggregate (collagenase-dissociated) and single-cell (TrypLE-dissociated) culture. Cells attached rapidly to beads followed by proliferation. Single-cell cultures expanded 3-fold over approximately 5 days, slightly exceeding that of hESC aggregates. Importantly, single-cell cultures were maintained through 6 passages with a 14-fold increase in cell number while still expressing the undifferentiated markers Oct-4 and Tra 1-81. Finally, hESCs retained their capacity to differentiate towards pancreatic, neuronal, and cardiomyocyte lineages. Our studies provide proof-of-principle of suspension-based expansion of hESCs on microcarriers, as a novel, economical and practical feeder-free means of bulk hESC production.

Dose-dependent increase or decrease of somatic intrachromosomal recombination produced by etoposide.

Chromosomal inversions and deletions can occur via somatic intrachromosomal recombination (SICR), a mechanism known to be important in mutagenesis and carcinogenesis. Here, we demonstrate a dose-dependent increase or decrease in SICR inversion frequency both in vivo and in vitro after treatment with etoposide, using the pKZ1 mouse mutagenesis model. pKZ1 mice received a single intraperitoneal injection of etoposide dose ranging from 0.0005 to 50mg/kg. Animals were sacrificed 3 days after treatment and the spleen was analysed for SICR. A significant 1.4-3.1-fold induction of SICR inversion events was detected in pKZ1 mice after treatment with etoposide doses ranging from 0.05 to 50 mg/kg etoposide. However, inversion frequencies after treatment with 0.0005 and 0.005 mg/kg etoposide decreased significantly to 0.67 and 0.43 of the levels observed in control animals, respectively. A pKZ1 mouse hybridoma cell line was exposed to etoposide (1-1000 nM) and a similar pattern of SICR response to that detected in vivo was observed. A significant 2.3-4.6-fold induction of SICR inversions was observed in pKZ1 cells treated with 100 and 1000 nM etoposide. Inversion frequencies after treatment with 1 and 10nM etoposide decreased significantly to 0.31 and 0.5 of the level observed in control cell lines. Our in vitro studies complement our in vivo studies and exclude a kinetic phenomenon as the responsible mechanism of reduction in SICR in response to low dose etoposide. Determination of the exact mechanism and significance of recombination suppression at low doses of etoposide treatment requires further investigation.