Co-Created Solutions for Perinatal Professionals and Childbearing Needs for People with Hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorders.

Individuals living with hypermobile Ehlers-Danlos syndrome (hEDS) and Hypermobility Spectrum Disorders (HSD) have reported feeling discredited and unsupported by healthcare professionals. However, the level of knowledge about hEDS/HSD among maternity staff remains unknown. Informed by patient and public involvement, this research aimed to investigate maternity staff's knowledge and confidence in supporting people with hEDS/HSD, examine people with hEDS/HSD's experiences of perinatal care, and co-create tools to help maternity staff support people childbearing with hEDS/HSD. Two online mixed-methods international surveys were completed by childbearing people with hEDS/HSD (N = 955) and maternity staff (N = 307). This was followed by the co-creation of three tools with 17 co-creators and a design team. Two main qualitative themes were identified through thematic analysis: (1) a need for recognition of hEDS/HSD in perinatal care and (2) the delivery of appropriate individualised perinatal care. Quantitatively, people with hEDS/HSD perceived maternity professionals to have a low level of knowledge about the conditions. Respectively, maternity staff reported low levels of confidence in supporting people with hEDS/HSD. The co-created tools provide applicable outputs for both education and practice and include an i-learn module hosted by the Royal College of Midwives, a tool for perinatal records, and infomercials.

Co-creation of a complex, multicomponent rehabilitation intervention and feasibility trial protocol for the PostUraL tachycardia Syndrome Exercise (PULSE) study.

BACKGROUND: There is a dearth of research to support the treatment of people with postural tachycardia syndrome (PoTS). Despite expert consensus suggesting exercise is recommended for this patient group, there are no randomised control trials examining this rigorously. The aim was to co-create a feasibility trial protocol and a rehabilitation intervention for people living with PoTS. METHODS: The intervention and feasibility trial design were co-created as part of the PostUraL tachycardia Syndrome Exercise (PULSE) study. We used the 'three co's framework' of co-define, co-design and co-refine. Recruitment included key national charities and National Health Service Trusts treating people living with PoTS in the UK. Eighteen patient and public involvement members attended the co-define session, and 16 co-creators with a mix of expertise attended the subsequent co-design and co-refine sessions. Seven intervention practitioners were trained in the rehabilitation intervention, providing feedback for further co-refinement. RESULTS: The final co-created intervention comprises online physical activity, and lifestyle and behaviour change support sessions. It is based on functional movement activities using a patient-centred approach tailored to individual needs. Physical activity intensity is guided by individuals' perception of effort rather than by objective measures. Recumbent bikes are provided for home use. Patients deemed randomisation to be acceptable because research in this area was considered important. CONCLUSIONS: An innovative approach was used to co-create the PULSE intervention and feasibility trial protocol to meet the evidence-based and logistical needs of people living with PoTS, clinicians, service deliverers, third-sector organisations, academics and funders. This can be used as a successful example and template for future research internationally. People living with PoTS were recognised as experts and involved in every aspect of conceptualisation, design and refinement. This complex rehabilitation intervention is currently being tested in a randomised feasibility trial comparing the PULSE intervention with best-practice usual care for people living with PoTS. TRIAL REGISTRATION: ISRCTN45323485 was registered on April 7, 2020.

Inclusive Smartphone Interface Design in Context: Co(Re)designing the PIS.

User-context optimises smartphone interface-design. Neglect of user-context during development, delays or prevents marginalised-consumer benefit. Working with People with Learning Disability (PWLD) to develop interfaces refined by communication-need will improve User-Experience (UX). In research, a Participant Information Sheet (PIS) discloses planned study-activity. This paper explains co-creation of a PIS based on communication-need of PWLD.

Establishing user needs for a stability assessment tool to guide wheelchair prescription.

PURPOSE: The WheelSense project aims to develop a system for assessing the stability and performance of wheelchairs through a user-centred design process. This study sought to capture user needs and define the specification for the system. METHOD: A mixed methods approach was adopted. An online survey was completed by 98 participants working in wheelchair provision. The results were built upon through 10 semi-structured interviews and one focus group (n = 5) with professionals working in wheelchair provision in three NHS Trusts in the UK. RESULTS: The results provided a picture of the current UK practice in stability testing. Issues with the reliability and usefulness of the existing methods used to assess the stability and performance of wheelchairs were highlighted. Requirements for a new system were ascertained. These included improved accuracy of tipping angles, features to support record keeping, improved client/carer education support and ability to model or predict client-wheelchair system performance in different configurations. CONCLUSIONS: The paper concludes that there is a need for improved tools to determine the stability of the client-wheelchair system and support the prescription process, to ensure client safety and optimum equipment performance. A list of requirements has been produced to guide the future development of WheelSense. Implications for Rehabilitation The results of this survey and interview-based study present a picture of wheelchair stability testing practices in the UK, and highlight the need for new, more informative methods for guiding wheelchair prescription. The requirements for the design of a new system, or further development of existing tools to support the stability testing and prescription of wheelchairs have been established.

Last hope for the doomed? Thoughts on the importance of a parasexual cycle for the yeast Candida albicans.

The yeast Candida albicans, a commensal colonizer and occasional pathogen of humans, has a rudimentary mating ability. However, mating is a cumbersome process that has never been observed outside the laboratory, and the population structure of the species is predominantly clonal. Here we discuss recent findings that indicate that mating ability is under selection in C. albicans, i.e. that it is a biologically relevant process. C. albicans strains can only mate after they have sustained genetic damage. We propose that the rescue of such damaged strains by mating may be the primary reason why mating ability is under selection.

The development and testing of a system for wheelchair stability measurement.

Wheelchair stability has an impact on safety as well as wheelchair performance, propulsion and manoeuvrability. Wheelchair stability is affected by the addition of life-supporting heavy equipment, e.g. ventilators and oxygen cylinders, as well as the characteristics of the user e.g. limb amputations, obesity. The aim of the research described here was to develop and test a stability assessment system that would guide and support the adjustment of wheelchairs to individual needs, characteristics and lifestyles. The resulting system provides assessment of centre of gravity and wheelchair stability and calculates the wheelchair tipping angles. The system consists of a force platform that senses the weight distribution of the wheelchair and calculates the centres of the contact points of the wheels and the distances between them. The measurement data are transferred via a WiFi connection to a portable tablet computer where wheelchair stability parameters are calculated. A touchscreen GUI provides visualization of the stability results and navigation through the measurement modes. The developed new concept has been evaluated through technical laboratory-based testing to determine the validity of the data collected. Initial testing has been undertaken within the clinical setting in 3 large hospitals in the UK. Initial results suggest that Wheelsense® provides a valuable tool to support clinical judgement.

Selective Advantages of a Parasexual Cycle for the Yeast Candida albicans.

The yeast Candida albicans can mate. However, in the natural environment mating may generate progeny (fusants) fitter than clonal lineages too rarely to render mating biologically significant: C. albicans has never been observed to mate in its natural environment, the human host, and the population structure of the species is largely clonal. It seems incapable of meiosis, and most isolates are diploid and carry both mating-type-like (MTL) locus alleles, preventing mating. Only chromosome loss or localized loss of heterozygosity can generate mating-competent cells, and recombination of parental alleles is limited. To determine if mating is a biologically significant process, we investigated if mating is under selection. The ratio of nonsynonymous to synonymous mutations in mating genes and the frequency of mutations abolishing mating indicated that mating is under selection. The MTL locus is located on chromosome 5, and when we induced chromosome 5 loss in 10 clinical isolates, most of the resulting MTL-homozygotes could mate with each other, producing fusants. In laboratory culture, a novel environment favoring novel genotypes, some fusants grew faster than their parents, in which loss of heterozygosity had reduced growth rates, and also faster than their MTL-heterozygous ancestors-albeit often only after serial propagation. In a small number of experiments in which co-inoculation of an oral colonization model with MTL-homozygotes yielded small numbers of fusants, their numbers declined over time relative to those of the parents. Overall, our results indicate that mating generates genotypes superior to existing MTL-heterozygotes often enough to be under selection.

The enigma of the major repeat sequence of Candida albicans.

The major repeat sequence, discovered in the yeast Candida albicans, is a stretch of repeated DNA that occurs nine times in the haploid genome of this opportunistic fungal pathogen and probably a similar number of times in the genome of Candida dubliniensis. In C. albicans it constitutes 1-2% of the genome. Its occurrence is limited to those two species. Despite its major role as a genomic feature, its function, mode of expansion in size due to duplication of internal subunits, and its origin and mechanism of distribution throughout the genome are not understood, although it is associated with chromosome translocations, chromosome length polymorphisms and regulation of the yeast-hypha dimorphic transition. The polymorphism of the major repeat sequence has been exploited in epidemiology and taxonomic studies. This review describes its sequence, occurrence, use in epidemiology and examines the evidence for its role in chromosome dynamics.

Effect of the major repeat sequence on mitotic recombination in Candida albicans.

The major repeat sequence (MRS) is known to play a role in karyotypic variation in Candida albicans. The MRS affects karyotypic variation by expanding and contracting internal repeats, by altering the frequency of chromosome loss, and by serving as a hotspot for chromosome translocation. We proposed that the effects of the MRS on translocation could be better understood by examination of the effect of the MRS on a similar event, mitotic recombination between two chromosome homologs. We examined the frequency of mitotic recombination across an MRS of average size (approximately 50 kb) as well as the rate of recombination in a 325-kb stretch of DNA adjacent to the MRS. Our results indicate that mitotic recombination frequencies across the MRS were not enhanced compared to the frequencies measured across the 325-kb region adjacent to the MRS. Mitotic recombination events were found to occur throughout the 325-kb region analyzed as well as within the MRS itself. This analysis of mitotic recombination frequencies across a large portion of chromosome 5 is the first large-scale analysis of mitotic recombination done in C. albicans and indicates that mitotic recombination frequencies are similar to the rates found in Saccharomyces cerevisiae.

Effect of the major repeat sequence on chromosome loss in Candida albicans.

The major repeat sequence (MRS) is found at least once on all but one chromosome in Candida albicans, but as yet it has no known relation to the phenotype. The MRS affects karyotypic variation by serving as a hot spot for chromosome translocation and by expanding and contracting internal repeats, thereby changing chromosome length. Thus, MRSs on different chromosomes and those on chromosome homologues can differ in size. We proposed that the MRS's unique repeat structure and, more specifically, the size of the MRS could also affect karyotypic variation by altering the frequency of mitotic nondisjunction. Subsequent analysis shows that both natural and artificially induced differences in the size of the chromosome 5 MRS can affect chromosome segregation. Strains with chromosome 5 homologues that differ in the size of the naturally occurring MRSs show a preferential loss of the homologue with the larger MRS on sorbose, indicating that a larger MRS leads to a higher risk of mitotic nondisjunction for that homologue. While deletion of an MRS has no deleterious effect on the deletion chromosome under normal growth conditions and leads to no obvious phenotype, strains that have the MRS deleted from one chromosome 5 homologue preferentially lose the homologue with the MRS remaining. This effect on chromosome segregation is the first demonstration of a phenotype associated with the MRS.

Recent advances in the genomic analysis of Candida albicans.

The release of the diploid genomic sequence of Candida albicans and its recent community-based annotation have permitted a number of studies which have significantly advanced our understanding of the biology of this important human pathogen. These advances range from analysis of genomic changes to differential gene expression under a variety of conditions. A few general conclusions can be drawn from the data presently in hand; one can expect more and more new insights as the number and kind of experiments grows.

Chromosome translocation induced by the insertion of the URA blaster into the major repeat sequence (MRS) in Candida albicans.

Electrophoretic karyotype studies have shown that clinical isolates of Candida albicans have extensive chromosome length polymorphisms. Chromosome translocation is one of the causes of karyotypic variation. Chromosome translocation events have been shown to occur very frequently at or near the major repeat sequence (MRS) on chromosomes. The MRS consists of the repeated sequences RB2, RPS and HOK, and the repeated sequences are considered to be the template for recombination. To investigate which element of the MRS is important for chromosome translocation, we constructed three cassettes, each containing a URA blaster and sequences homologous to one of the repeats, for insertion into the MRS region on the chromosomes. The ura3 strain STN22u2, which shows a stable, standard karyotype, was transformed with each construct. Insertion events with each cassette occurred at almost all chromosomes. Insertion into the RB2 repeat, but not into the RPS repeat, was accompanied by chromosome translocation in some transformants: chromosome translocations between chromosomes R and 7 and chromosomes 1 and 7 were found, as well as deletions of 7A and 7C from chromosome 7. We conclude that the insertion at the RB2 region may initiate chromosome translocation in C. albicans.

MFalpha1, the gene encoding the alpha mating pheromone of Candida albicans.

Candida albicans, the single most frequently isolated human fungal pathogen, was thought to be asexual until the recent discovery of the mating-type-like locus (MTL). Homozygous MTL strains were constructed and shown to mate. Furthermore, it has been demonstrated that opaque-phase cells are more efficient in mating than white-phase cells. The similarity of the genes involved in the mating pathway in Saccharomyces cerevisiae and C. albicans includes at least one gene (KEX2) that is involved in the processing of the alpha mating pheromone in the two yeasts. Taking into account this similarity, we searched the C. albicans genome for sequences that would encode the alpha pheromone gene. Here we report the isolation and characterization of the gene MFalpha1, which codes for the precursor of the alpha mating pheromone in C. albicans. Two active alpha-peptides, 13 and 14 amino acids long, would be generated after the precursor molecule is processed in C. albicans. To examine the role of this gene in mating, we constructed an mfalpha1 null mutant of C. albicans. The mfalpha1 null mutant fails to mate as MTLalpha, while MTLa mfalpha1 cells are still mating competent. Experiments performed with the synthetic alpha-peptides show that they are capable of inducing growth arrest, as demonstrated by halo tests, and also induce shmooing in MTLa cells of C. albicans. These peptides are also able to complement the mating defect of an MTLalpha kex2 mutant strain when added exogenously, thereby confirming their roles as alpha mating pheromones.