Results from the first English stool bank using faecal microbiota transplant as a medicinal product for the treatment of Clostridioides difficile infection.

BACKGROUND: Faecal Microbiota Transplant (FMT) has improved outcomes for the treatment of Clostridioides difficile infection (CDI) compared to antibiotic therapy. FMT is classified as a medicinal product in the United Kingdom, similar to the USA and Canada, limiting supply via stool banks without appropriate licencing. In the largest UK cohort to date, we describe the clinical outcomes for 124 patients receiving FMT for recurrent or refractory CDI and present a framework to produce FMT as a licenced medicinal product. METHODS: Anonymous unrelated healthy donors, screened via health assessment and microbiological testing donated stool. In aerobic conditions FMT aliquots were prepared for immediate use or frozen storage, following a production framework developed to comply with Good Manufacturing Practice. Outcome measures were clinical response to FMT defined as resolution of diarrhoea within seven days and clinical cure defined as response without diarrhoea recurrence at 90 days. FINDINGS: Clinical response was 83·9% (95% CI 76·0%-90·0%) after one treatment. Clinical cure was 78·2% (95% CI 67·4%-89·0%) across the cohort. Refractory cases appeared to have a lower initial clinical response rate compared to recurrent cases, however at day 90 there were no differences observed between these groups. INTERPRETATION: The methodology developed here enabled successful licencing of FMT by The Medicines and Healthcare products Regulatory Agency as a medicinal product. This has widened the availability of FMT in the National Health Service via a stool bank and can be applied in other centres across the world to improve access to safe and quality assured treatments

Experiences of HIV-positive postpartum women and health workers involved with community-based antiretroviral therapy adherence clubs in Cape Town, South Africa

Background The rollout of universal, lifelong treatment for all HIV-positive pregnant and breastfeeding women (“Option B+”) has rapidly increased the number of women initiating antiretroviral treatment (ART) and requiring ART care postpartum. In a pilot project in South Africa, eligible postpartum women were offered the choice of referral to the standard of care, a local primary health care clinic, or a community-based model of differentiated ART services, the adherence club (AC). ACs have typically enrolled only non-pregnant and non-postpartum adults; postpartum women had not previously been referred directly from antenatal care. There is little evidence regarding postpartum women’s preferences for and experiences of differentiated models of care, or the capacity of this particular model to cater to their specific needs. This qualitative paper reports on feedback from both postpartum women and health workers who care for them on their respective experiences of the AC. Methods One-on-one in-depth qualitative interviews were conducted with 19 (23%) of the 84 postpartum women who selected the AC and were retained at approximately 12 months postpartum, and 9 health workers who staff the AC. Data were transcribed and thematically analysed using NVivo 11. Results Postpartum women’s inclusion in the AC was acceptable for both participants and health workers. Health workers were welcoming of postpartum women but expressed concerns about prospects for longer term adherence and retention, and raised logistical issues they felt might compromise trust with AC members in general. Conclusions Enrolling postpartum women in mixed groups with the general adult population is feasible and acceptable. Preliminary recommendations are offered and may assist in supporting the specific needs of postpartum women transitioning from antenatal ART care. Trial registration Number NCT02417675 clinicaltrials.gov/ct2/show/record/NCT02417675 (retrospective reg.

Peptide location fingerprinting reveals tissue region-specific differences in protein structures in an ageing human organ

In ageing tissues, long-lived extracellular matrix (ECM) proteins are susceptible to the accumulation of structural damage due to diverse mechanisms including glycation, oxidation and protease cleavage. Peptide location fingerprinting (PLF) is a new mass spectrometry (MS) analysis technique capable of identifying proteins exhibiting structural differences in complex proteomes. PLF applied to published young and aged intervertebral disc (IVD) MS datasets (posterior, lateral and anterior regions of the annulus fibrosus) identified 268 proteins with age-associated structural differences. For several ECM assemblies (collagens I, II and V and aggrecan), these differences were markedly conserved between degeneration-prone (posterior and lateral) and -resistant (anterior) regions. Significant differences in peptide yields, observed within collagen I alpha 2, collagen II alpha 1 and collagen V alpha 1, were located within their triple-helical regions and/or cleaved C-terminal propeptides, indicating potential accumulation of damage and impaired maintenance. Several proteins (collagen V alpha 1, collagen II alpha 1 and aggrecan) also exhibited tissue region (lateral)-specific differences in structure between aged and young samples, suggesting that some ageing mechanisms may act locally within tissues. This study not only reveals possible age-associated differences in ECM protein structures which are tissue-region specific, but also highlights the ability of PLF as a proteomic tool to aid in biomarker discovery

A carbohydrate-binding protein, B-GRANULE CONTENT 1, influences starch granule size distribution in a dose-dependent manner in polyploid wheat

In Triticeae endosperm (e.g. wheat and barley), starch granules have a bimodal size distribution (with A- and B-type granules) whereas in other grasses the endosperm contains starch granules with a unimodal size distribution. Here, we identify the gene, BGC1 (B-GRANULE CONTENT 1), responsible for B-type starch granule content in Aegilops and wheat. Orthologues of this gene are known to influence starch synthesis in diploids such as rice, Arabidopsis, and barley. However, using polyploid Triticeae species, we uncovered a more complex biological role for BGC1 in starch granule initiation: BGC1 represses the initiation of A-granules in early grain development but promotes the initiation of B-granules in mid grain development. We provide evidence that the influence of BGC1 on starch synthesis is dose dependent and show that three very different starch phenotypes are conditioned by the gene dose of BGC1 in polyploid wheat: normal bimodal starch granule morphology; A-granules with few or no B-granules; or polymorphous starch with few normal A- or B-granules. We conclude from this work that BGC1 participates in controlling B-type starch granule initiation in Triticeae endosperm and that its precise effect on granule size and number varies with gene dose and stage of development

Subcellular heterogeneity of ryanodine receptor properties in ventricular myocytes with low T-tubule density

Rationale: In ventricular myocytes of large mammals, not all ryanodine receptor (RyR) clusters are associated with T-tubules (TTs); this fraction increases with cellular remodeling after myocardial infarction (MI). Objective: To characterize RyR functional properties in relation to TT proximity, at baseline and after MI. Methods: Myocytes were isolated from left ventricle of healthy pigs (CTRL) or from the area adjacent to a myocardial infarction (MI). Ca2+ transients were measured under whole-cell voltage clamp during confocal linescan imaging (fluo-3) and segmented according to proximity of TTs (sites of early Ca2+ release, F>F50 within 20 ms) or their absence (delayed areas). Spontaneous Ca2+ release events during diastole, Ca2+ sparks, reflecting RyR activity and properties, were subsequently assigned to either category. Results: In CTRL, spark frequency was higher in proximity of TTs, but spark duration was significantly shorter. Block of Na+/Ca2+ exchanger (NCX) prolonged spark duration selectively near TTs, while block of Ca2+ influx via Ca2+ channels did not affect sparks properties. In MI, total spark mass was increased in line with higher SR Ca2+ content. Extremely long sparks (>47.6 ms) occurred more frequently. The fraction of near-TT sparks was reduced; frequency increased mainly in delayed sites. Increased duration was seen in near-TT sparks only; Ca2+ removal by NCX at the membrane was significantly lower in MI. Conclusion: TT proximity modulates RyR cluster properties resulting in intracellular heterogeneity of diastolic spark activity. Remodeling in the area adjacent to MI differentially affects these RyR subpopulations. Reduction of the number of sparks near TTs and reduced local NCX removal limit cellular Ca2+ loss and raise SR Ca2+ content, but may promote Ca2+ waves

Learning at the Interstices; Locating Practical Philosophies for Understanding Physical/virtual Inter-spaces

Virtual worlds are relatively recent developments, and so it is tempting to believe that they need to be understood through newly developed theories and philosophies. However, humans have long thought about the nature of reality and what it means to be “real.” This paper examines the three persistent philosophical concepts of Metaxis, Liminality and Space that have evolved across more than 2000 years of meditation, contemplation and reflection. Our particular focus here is on the nature of the interface between the virtual and the physical: at the interstices, and how the nature of transactions and transitions across those interfaces may impact upon learning. This may, at first, appear to be an esoteric pursuit, but we ground our arguments in primary and secondary data from research studies in higher education

K201 (JTV-519) alters the spatiotemporal properties of diastolic Ca2+ release and the associated diastolic contraction during β-adrenergic stimulation in rat ventricular cardiomyocytes

K201 has previously been shown to reduce diastolic contractions in vivo during β-adrenergic stimulation and elevated extracellular calcium concentration ([Ca2+]o). The present study characterised the effect of K201 on electrically stimulated and spontaneous diastolic sarcoplasmic reticulum (SR)-mediated Ca2+ release and contractile events in isolated rat cardiomyocytes during β-adrenergic stimulation and elevated [Ca2+]o. Parallel experiments using confocal microscopy examined spontaneous diastolic Ca2+ release events at an enhanced spatiotemporal resolution. 1.0 μmol/L K201 in the presence of 150 nmol/L isoproterenol (ISO) and 4.75 mmol/L [Ca2+]o significantly decreased the amplitude of diastolic contractions to ~16% of control levels. The stimulated free Ca2+ transient amplitude was significantly reduced, but stimulated cell shortening was not significantly altered. When intracellular buffering was taken into account, K201 led to an increase in action potential-induced SR Ca2+ release. Myofilament sensitivity to Ca2+ was not changed by K201. Confocal microscopy revealed diastolic events composed of multiple Ca2+ waves (2–3) originating at various points along the cardiomyocyte length during each diastolic period. 1.0 μmol/L K201 significantly reduced the (a) frequency of diastolic events and (b) initiation points/diastolic interval in the remaining diastolic events to 61% and 71% of control levels respectively. 1.0 μmol/L K201 can reduce the probability of spontaneous diastolic Ca2+ release and their associated contractions which may limit the propensity for the contractile dysfunction observed in vivo

Concordance and timing in recording cancer events in primary care, hospital and mortality records for patients with and without psoriasis: A population-based cohort study

From PLOS via Jisc Publications RouterHistory: collection 2021, received 2021-02-05, accepted 2021-06-30, epub 2021-07-19Publication status: PublishedFunder: THE INTERNATIONAL LEAGUE OF DERMATOLOGICAL SOCIETIESFunder: national institute for health researchBackground: The association between psoriasis and the risk of cancer has been investigated in numerous studies utilising electronic health records (EHRs), with conflicting results in the extent of the association. Objectives: To assess concordance and timing of cancer recording between primary care, hospital and death registration data for people with and without psoriasis. Methods: Cohort studies delineated using primary care EHRs from the Clinical Practice Research Datalink (CPRD) GOLD and Aurum databases, with linkage to hospital episode statistics (HES), Office for National Statistics (ONS) mortality data and indices of multiple deprivation (IMD). People with psoriasis were matched to those without psoriasis by age, sex and general practice. Cancer recording between databases was investigated by proportion concordant, that being the presence of cancer record in both source and comparator datasets. Delay in recording cancer diagnoses between CPRD and HES records and predictors of discordance were also assessed. Results: 58,904 people with psoriasis and 350,592 comparison patients were included using CPRD GOLD; whereas 213,400 people with psoriasis and 1,268,998 comparison patients were included in CPRD Aurum. For all cancer records (excluding keratinocyte), concordance between CPRD and HES was greater than 80%. Concordance for same-site cancer records was markedly lower (<68% GOLD-linked data; <72% Aurum-linked data). Concordance of non-Hodgkin lymphoma and liver cancer recording between CPRD and HES was lower for people with psoriasis compared to those without. Conclusions: Concordance between CPRD and HES is poor when restricted to cancers of the same site, with greater discordance in people with psoriasis for some cancers of specific sites. The use of linked patient-level data is an important step in reducing misclassification of cancer outcomes in epidemiological studies using routinely collected electronic health records

Responsible management: Engaging moral reflexive practice through threshold concepts

YesIn this conceptual paper we argue that, to date, principles of responsible management have not impacted practice as anticipated because of a disconnect between knowledge and practice. This disconnect means that an awareness of ethical concerns, by itself, does not help students take personal responsibility for their actions. We suggest that an abstract knowledge of principles has to be supplemented by an engaged understanding of the responsibility of managers and leaders to actively challenge irresponsible practices. We argue that a form of moral reflexive practice drawing on an understanding of threshold concepts is central to responsible management, and provides a gateway to transformative learning. Our conceptual argument leads to implications for management and professional education

Barley grain (1,3;1,4)-β-glucan content:effects of transcript and sequence variation in genes encoding the corresponding synthase and endohydrolase enzymes

The composition of plant cell walls is important in determining cereal end uses. Unlike other widely consumed cereal grains barley is comparatively rich in (1,3;1,4)-β-glucan, a source of dietary fibre. Previous work showed Cellulose synthase-like genes synthesise (1,3;1,4)-β-glucan in several tissues. HvCslF6 encodes a grain (1,3;1,4)-β-glucan synthase, whereas the function of HvCslF9 is unknown. Here, the relationship between mRNA levels of HvCslF6, HvCslF9, HvGlbI (1,3;1,4)-β-glucan endohydrolase, and (1,3;1,4)-β-glucan content was studied in developing grains of four barley cultivars. HvCslF6 was differentially expressed during mid (8-15 DPA) and late (38 DPA) grain development stages while HvCslF9 transcript was only clearly detected at 8-10 DPA. A peak of HvGlbI expression was detected at 15 DPA. Differences in transcript abundance across the three genes could partially explain variation in grain (1,3;1,4)-β-glucan content in these genotypes. Remarkably narrow sequence variation was found within the HvCslF6 promoter and coding sequence and does not explain variation in (1,3;1,4)-β-glucan content. Our data emphasise the genotype-dependent accumulation of (1,3;1,4)-β-glucan during barley grain development and a role for the balance between hydrolysis and synthesis in determining (1,3;1,4)-β-glucan content, and suggests that other regulatory sequences or proteins are likely to be involved in this trait in developing grain.Guillermo Garcia-Gimenez, Joanne Russell, Matthew K. Aubert, Geoffrey B. Fincher, Rachel A. Burton, Robbie Waugh, Matthew R. Tucker, Kelly Housto