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Dose optimization of sirolimus may further improve outcomes in allogeneic hematopoietic cell transplant (HCT) patients receiving post-transplantation cyclophosphamide (PTCy) to prevent graft-versus-host disease (GVHD). Sirolimus exposure-response association studies in HCT patients (i.e., the association of trough concentration with clinical outcomes) have been conflicting. Sirolimus has important effects on T-cells, including conventional (Tcons) and regulatory T-cells (Tregs), both of which have been implicated in the mechanisms by which PTCy prevents GVHD, but there is an absence of validated biomarkers of sirolimus effects on these cell subsets. Considering the paucity of existing biomarkers and the complexities of the immune system, we conducted a literature review to inform a quantitative systems pharmacology (QSP) model of GVHD. The published literature presented multiple challenges. The sirolimus pharmacokinetic models insufficiently describe sirolimus distribution to relevant physiological compartments. Despite multiple publications describing sirolimus effects on Tcons and Tregs in preclinical and human ex vivo models, consistent parameters relating sirolimus concentrations to circulating Tcons and Tregs could not be found. Each aspect presents a challenge in building a QSP model of sirolimus and its temporal effects on T-cell subsets and GVHD prevention. To optimize GVHD prevention regimens, phase I studies and systematic studies of immunosuppressant concentration-effect association are needed for QSP modeling.

We study thermal production of dark matter (DM) in a realization of the minimal models of Bonnefoy et al. [Phys. Rev. Lett. 131, 221802 (2023)PRLTAO0031-900710.1103/PhysRevLett.131.221802], where parity is used to solve the strong CP problem by transforming the entire Standard Model (SM) into a mirror copy. Although the mirror electron e′ is a good DM candidate, its viability is mired by the presence of the mirror up quark u′, whose abundance is intimately related to the e′ abundance and must be suppressed. This can be achieved through a sequential freeze-in mechanism, where mirror photons are first produced from SM gluons, and then the mirror photons produce e′. After computing the details of this double freeze-in, we discuss the allowed parameter space of the model, which lies at the threshold of experimental observations. We find that this origin of e′ DM requires a low reheating temperature after inflation and is consistent with the baryon asymmetry arising from leptogenesis, providing mirror neutrinos have a significant degeneracy. Finally, we show that this e′ DM is not compatible with Higgs parity, the simplest scheme with exact parity, unless SM parameters deviate significantly from their central values or the minimal model is extended.

This study investigates the nature of the social interaction profiles observed among youth with intellectual disabilities (ID), defined while considering their relationships with their parents, peers, and teachers, as well as the implication of these profiles for self-esteem, aggressive behaviors, and prosocial behaviors. A sample of 393 youth with mild (48.2%) to moderate (51.8%) levels of ID, aged between 11 and 22 (M = 15.70), was recruited in Canada (n = 141) and Australia (n = 253). Our results revealed four profiles, corresponding to Socially Isolated (23.24%), Socially Integrated (39.83%), Socially Rejected (28.37%) and Socially Connected (8.57%) youth with ID. The socially integrated and connected profiles both presented higher self-esteem, more prosocial behaviors, and less aggressive behaviors than the socially isolated and rejected profiles.

Policy makers increasingly call on higher education to prepare learners for challenges such as global health emergencies or ecological crises. These can be understood as 'wicked problems', which are unbounded, complex and resist simplistic definition. Wicked problems involve stakeholders with incompatible value positions and attempted solutions can result in unforeseen outcomes. How academics stay committed to teaching about such challenging topics -- despite the many difficulties of contemporary higher education -- is an under-researched area. In this study, we interviewed academics who were deeply engaged with teaching about wicked problems. We drew on the concepts of landscapes of practice, boundary work and academic identities to make sense of the teachers' persistence and practices in this space. We conclude with advice for policy makers on how to support academics in this work.

Abstract Effective field theories (EFTs) of heavy particles coupled to the inflaton are rife with operator redundancies, frequently obscured by sensitivity to both boundary terms and field redefinitions. We initiate a systematic study of these redundancies by establishing a minimal operator basis for an archetypal example, the abelian gauge-Higgs-inflaton EFT. Working up to dimension 9, we show that certain low-dimensional operators are entirely redundant and identify new non-redundant operators with potentially interesting cosmological collider signals. Our methods generalize straightforwardly to other EFTs of heavy particles coupled to the inflaton.

ABSTRACT This study characterized and compared the fecal and oral microbiota from women with early-stage breast cancer (BC), women with ductal carcinoma in situ (DCIS), and healthy women. Fecal and oral samples were collected from newly diagnosed patients prior to any therapy and characterized using 16S rRNA sequencing. Measures of gut microbial alpha diversity were significantly lower in the BC vs healthy cohort. Beta diversity differed significantly between the BC or DCIS and healthy groups, and several differentially abundant taxa were identified. Clustering (non-negative matrix factorization) of the gut microbiota identified five bacterial guilds dominated by Prevotella, Enterobacteriaceae, Akkermansia, Clostridiales, or Bacteroides. The Bacteroides and Enterobacteriaceae guilds were significantly more abundant in the BC cohort compared to healthy controls, whereas the Clostridiales guild was more abundant in the healthy group. Finally, prediction of functional pathways identified 23 pathways that differed between the BC and healthy gut microbiota including lipopolysaccharide biosynthesis, glycan biosynthesis and metabolism, lipid metabolism, and sphingolipid metabolism. In contrast to the gut microbiomes, there were no significant differences in alpha or beta diversity in the oral microbiomes, and very few differentially abundant taxa were observed. Non-negative matrix factorization analysis of the oral microbiota samples identified seven guilds dominated by Veillonella, Prevotella, Gemellaceae, Haemophilus, Neisseria, Propionibacterium, and Streptococcus; however, none of these guilds were differentially associated with the different cohorts. Our results suggest that alterations in the gut microbiota may provide the basis for interventions targeting the gut microbiome to improve treatment outcomes and long-term prognosis.IMPORTANCEEmerging evidence suggests that the gut microbiota may play a role in breast cancer. Few studies have evaluated both the gut and oral microbiomes in women with breast cancer (BC), and none have characterized these microbiomes in women with ductal carcinoma in situ (DCIS). We surveyed the gut and oral microbiomes from women with BC or DCIS and healthy women and identified compositional and functional features of the gut microbiota that differed between these cohorts. In contrast, very few differential features were identified in the oral microbiota. Understanding the role of gut bacteria in BC and DCIS may open up new opportunities for the development of novel markers for early detection (or markers of susceptibility) as well as new strategies for prevention and/or treatment.

Therapeutic innovation to address sickle cell disease (SCD) is at a historical apex, characterized by a drug discovery, development, and commercialization landscape that includes potentially curative gene therapies. Given the wide geographic distribution of SCD, with a major presence in Africa, it is imperative that new medicines are designed to meet the specific needs of persons with SCD everywhere. Target product profiles (TPPs) detail the desired attributes of new medicines and serve as a guide for drug developers. To support research efforts for curative treatments for SCD, we mobilized a large multi-disciplinary expert group to generate consensus-driven TPPs for ex vivo and in vivo SCD gene therapies, utilizing a modified Delphi methodology supplemented with virtual workshops. The main findings are TPPs that describe 20 minimal and optimal criteria for novel gene therapy products in categories of scope (3 criteria), performance/safety (11 criteria), manufacturing (4 criteria), and administration (2 criteria). TPPs for ex vivo and in vivo products differed in some performance/safety criteria and all criteria pertaining to manufacturing and administration. These outputs will ideally support development of durable treatments that are safe, efficacious, and practical for persons with SCD in global settings.

This article provides an in-depth look at how K-12 students should be introduced to Machine Learning and the knowledge and skills they will develop as a result. We begin with an overview of the AI4K12 Initiative, which is developing national guidelines for teaching AI in K-12, and briefly discuss each of the "Five Big Ideas in AI" that serve as the organizing framework for the guidelines. We then discuss the general format and structure of the guidelines and grade band progression charts and provide a theoretical framework that highlights the developmental appropriateness of the knowledge and skills we want to impart to students and the learning experiences we expect them to engage in. Development of the guidelines is informed by best practices from Learning Sciences and CS Education research, and by the need for alignment with CSTA's K-12 Computer Science Standards, Common Core standards, and Next Generation Science Standards (NGSS). The remainder of the article provides an in-depth exploration of the AI4K12 Big Idea 3 (Learning) grade band progression chart to unpack the concepts we expect students to master at each grade band. We present examples to illustrate the progressions from two perspectives: horizontal (across grade bands) and vertical (across concepts for a given grade band). Finally, we discuss how these guidelines can be used to create learning experiences that make connections across the Five Big Ideas, and free online tools that facilitate these experiences.

Abstract Background Structured Problem Solving (SPS) is a patient-centered approach to promoting behavior change that relies on productive collaboration between coaches and participants and reinforces participant autonomy. We aimed to describe the design, implementation, and assessment of SPS in the multicenter Prevention of Urinary Stones with Hydration (PUSH) randomized trial. Methods In the PUSH trial, individuals with a history of urinary stone disease and low urine output were randomized to control versus a multicomponent intervention including SPS that was designed to promote fluid consumption and thereby prevent recurrent stones. We provide details specifically about training and fidelity assessment of the SPS coaches. We report on implementation experiences related to SPS during the initial conduct of the trial. Results With training and fidelity assessment, coaches in the PUSH trial applied SPS to help participants overcome barriers to fluid consumption. In some cases, coaches faced implementation barriers such as variable participant engagement that required tailoring their work with specific participants. The coaches also faced challenges including balancing rapport with problem solving, and role clarity for the coaches. Conclusions We adapted SPS to the setting of kidney stone prevention and overcame challenges in implementation, such as variable patient engagement. Tools from the PUSH trial may be useful to apply to other health behavior change settings in nephrology and other areas of clinical care. Trial registration ClinicalTrials.gov Identifier NCT03244189.

Persistence of HIV in people living with HIV (PWH) on suppressive antiretroviral therapy (ART) has been linked to physiological mechanisms of CD4+ T cells. Here, in the same 37 male PWH on ART we measure longitudinal kinetics of HIV DNA and cell turnover rates in five CD4 cell subsets: naïve (TN), stem-cell- (TSCM), central- (TCM), transitional- (TTM), and effector-memory (TEM). HIV decreases in TTM and TEM but not in less-differentiated subsets. Cell turnover is ~10 times faster than HIV clearance in memory subsets, implying that cellular proliferation consistently creates HIV DNA. The optimal mathematical model for these integrated data sets posits HIV DNA also passages between CD4 cell subsets via cellular differentiation. Estimates are heterogeneous, but in an average participant's year ~10 (in TN and TSCM) and ~104 (in TCM, TTM, TEM) proviruses are generated by proliferation while ~103 proviruses passage via cell differentiation (per million CD4). In simulations, therapies blocking proliferation and/or enhancing differentiation could reduce HIV DNA by 1-2 logs over 3 years. In summary, HIV exploits cellular proliferation and differentiation to persist during ART but clears faster in more proliferative/differentiated CD4 cell subsets and the same physiological mechanisms sustaining HIV might be temporarily modified to reduce it.

Research into animal cognitive abilities is increasing quickly and often uses methods where behavioral performance on a task is assumed to represent variation in the underlying cognitive trait. However, because these methods rely on behavioral responses as a proxy for cognitive ability, it is important to validate that the task structure does, in fact, target the cognitive trait of interest rather than non-target cognitive, personality, or motivational traits (construct validity). Although it can be difficult, or impossible, to definitively assign performance to one cognitive trait, one way to validate that task structure is more likely to elicit performance based on the target cognitive trait is to assess the temporal and contextual repeatability of performance. In other words, individual performance is likely to represent an inherent trait when it is consistent across time and across similar or different tasks that theoretically test the same trait. Here, we assessed the temporal and contextual repeatability of performance on tasks intended to test the cognitive trait behavioral flexibility in great-tailed grackles (Quiscalus mexicanus). For temporal repeatability, we quantified the number of trials to form a color preference after each of multiple color reversals on a serial reversal learning task. For contextual repeatability, we then compared performance on the serial color reversal task to the latency to switch among solutions on each of two different multi-access boxes. We found that the number of trials to form a preference in reversal learning was repeatable across serial color reversals and the latency to switch a preference was repeatable across color reversal learning and the multi-access box contexts. This supports the idea that the reversal learning task structure elicits performance reflective of an inherent trait, and that reversal learning and solution switching on multi-access boxes similarly reflect the inherent trait of behavioral flexibility.

As a highly regenerative organ, the intestine is a promising source for cellular reprogramming for replacing lost pancreatic β cells in diabetes. Gut enterochromaffin cells can be converted to insulin-producing cells by forkhead box O1 (FoxO1) ablation, but their numbers are limited. In this study, we report that insulin-immunoreactive cells with Paneth/goblet cell features are present in human fetal intestine. Accordingly, lineage-tracing experiments show that, upon genetic or pharmacologic FoxO1 ablation, the Paneth/goblet lineage can also undergo conversion to the insulin lineage. We designed a screening platform in gut organoids to accurately quantitate β-like cell reprogramming and fine-tune a combination treatment to increase the efficiency of the conversion process in mice and human adult intestinal organoids. We identified a triple blockade of FOXO1, Notch, and TGF-β that, when tested in insulin-deficient streptozotocin (STZ) or NOD diabetic animals, resulted in near normalization of glucose levels, associated with the generation of intestinal insulin-producing cells. The findings illustrate a therapeutic approach for replacing insulin treatment in diabetes.

Background Ulcerative colitis is an autoimmune reaction to imbalanced colonic microbiome in genetically predisposed patients. There have been four published randomised controlled trials of faecal microbiota transplant versus placebo in ulcerative colitis; three being positive. However, the methodology used varied and mechanistic data were sparse. Objective To identify an optimal faecal microbiota transplant delivery route to test in a future efficacy-powered randomised controlled trial. Design Prospective, multicentre, open-label, parallel-group, randomised pilot study. Participants were randomised in a 1 : 1 ratio to faecal microbiota transplant by nasogastric or by colonoscopy, minimised by partial Mayo score and current smoking status. Setting Three secondary care hospitals in the United Kingdom. Participants Thirty adult patients with mild to moderately active ulcerative colitis (partial Mayo score of ≥4 and ≤8). Interventions Faecal microbiota transplant samples were prepared at the University of Birmingham Microbiome Treatment Centre and administered to participants either via a nasogastric tube on 4 consecutive days repeated after a month (nasogastric) or by colonoscopy followed by 7 weekly enemas (COLON). Each treatment course was from a single matched donor. Participants and researchers underwent qualitative interviews regarding the faecal microbiota transplant experience. Main outcome measure Composite assessment of qualitative and quantitative data based on efficacy, acceptability and safety. Clinical response (primary measure of efficacy) was defined as a ≥3 point and ≥30% reduction in full Mayo score from randomisation to week 8 and a ≥1 point reduction in rectal bleeding subscore or absolute rectal bleeding subscore of 0 or 1. Results Thirty ulcerative colitis patients were randomised: 16 to nasogastric; 14 to COLON. Seven participants in the nasogastric arm and two in the COLON arm withdrew from treatment and clinical follow-up. Eight of 16 (50%) nasogastric participants were adherent compared to 12/14 (86%) COLON participants. Clinical response data were available for 20 of 30 randomised participants. Clinical response was seen in 2/8 (25%) nasogastric participants versus 9/12 (75%) COLON participants: adjusted risk ratio 2.94 (95% CI 0.84 to 10.30). Adverse events were reported in 11/16 (69%) nasogastric participants versus 11/14 (79%) COLON participants. There were three serious adverse events in two nasogastric participants. Faecal microbiota transplant was deemed an acceptable treatment for ulcerative colitis, with greater participant and clinician acceptability for the COLON route. Faecal microbiota transplant responders had a greater reduction in faecal calprotectin compared to non-responders (t-test p = 0.03) and increase in faecal microbiome diversity (Shannon diversity p < 0.01). In the whole cohort, a negative association between faecal calprotectin and diversity was seen (Kendall’s tau z = −2.8231, p = 0.004757). There were increases in faecal acetate (p = 0.05) and butyrate (p = 0.03) after faecal microbiota transplant intervention, but these were not associated with clinical response. A limitation was that this was an open-label pilot study, which was not powered to assess for efficacy of faecal microbiota transplant. Conclusions Faecal microbiota transplant delivered by the colonic route was considered safe and better tolerated than the nasogastric route. The colonic route was preferred by both participants and clinicians. Mechanistic signals indicated reduction in colonic inflammation and increased microbiome diversity in faecal microbiota transplant responders. Future work An efficacy-powered randomised controlled trial. Trial registration This trial is registered as ISRCTN74072945 and EudraCT 2015-005753-12. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 13/179/01) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 14. See the NIHR Funding and Awards website for further award information. Plain language summary Ulcerative colitis, a chronic inflammatory condition affecting the colon, results from the body’s immune response to imbalance in colonic microbes (microbiota). Faecal microbiota transplantation involves transferring processed donated stool samples from carefully screened healthy donors to ulcerative colitis patients aiming to correct the imbalance and reduce inflammation. There have been four trials comparing faecal microbiota transplant with placebo (dummy no treatment) to treat ulcerative colitis, and one which investigated faecal microbiota transplant with dietary intervention. Three of these studies showed encouraging benefit for faecal microbiota transplant. However, these studies varied in the methods used, with faecal microbiota transplant delivered either to the stomach or colon, or both. The aim of this study was to identify the best route of faecal microbiota transplant administration before undertaking a large-scale trial comparing faecal microbiota transplant with placebo. Between March 2018 and 30 April 2019 ulcerative colitis patients from three hospitals were randomly allocated to receive faecal microbiota transplant via either a tube inserted through the nose into the stomach on 4 consecutive days repeated after a month (nasogastric group; 16 participants) or by colonoscopy followed by 7 weekly enemas (COLON group; 14 participants). Faecal microbiota transplant was well accepted, with both patients with ulcerative colitis and healthcare staff stating a preference for the colonic route. Only 8 of 16 in the nasogastric group completed the study compared to 12 of 14 in the COLON group. Altogether, 9/12 (75%) in the COLON group improved compared with 2/8 (25%) in the nasogastric group. The majority of participants [11/14 (79%) COLON vs. 11/16 (69%) nasogastric] had mild, short-lived side effects following faecal microbiota transplant. There were three serious adverse events. Faecal calprotectin (indicating colonic inflammation) fell in responders and stool samples showed an increase in the number of microbial species after faecal microbiota transplant. At the end of the study, a recommendation was made by the Independent Oversight Committee to proceed to a large placebo-controlled randomised trial using the colonic route. Scientific summary Background Ulcerative colitis (UC) results from an exaggerated immune response to an imbalanced (dysbiotic) colonic microbiome in genetically predisposed patients. At the inception of this study, there had been four published randomised controlled trials (RCTs) comparing faecal microbiota transplantation (FMT) with placebo to treat UC in adults. Of these four seminal studies, three involved delivery of FMT via the colonic route and one a combination of delivery to the foregut and colon. This latter study was the only one of the four not to show a difference in efficacy compared to placebo. Foregut-delivered FMT is extensively and successfully used in clinical practice to treat Clostridioides difficile infection (CDI). From the results of the UC trials, FMT appeared to have therapeutic potential for UC. However, the methodology employed in these studies was varied and, taking into account the efficacy of FMT delivered to the foregut to treat CDI, there was uncertainty regarding the best route of delivery in the context of UC. Objectives The aims of this pilot study were as follows: to determine which FMT administration route [nasogastric (NG) or colonic (COLON)] should be investigated in a randomised double-blind, placebo-controlled trial to determine whether a full-scale RCT was feasible. In order to achieve these aims, the pilot study had the following clinical objectives. To assess the following: whether FMT by the NG route induces clinical response in patients with active UC whether FMT by the COLON route induces clinical response in patients with active UC tolerability and safety which route of FMT delivery (if any) was suitable to investigate in a full-scale RCT. The aims of the qualitative research were to assess the following: patient and clinician acceptability of FMT (NG route) patient and clinician acceptability of FMT (COLON route). The aims of the nested-mechanistic substudy were to assess the following: whether FMT by either route is associated with a change in faecal calprotectin as a surrogate marker of colonic inflammation changes in the colonic microbiome induced by FMT via each route changes in the metabolome [short-chain fatty acids (SCFAs)] induced by FMT via each route effect of diet (donors) time from stool donation to treatment. Methods In this prospective, multicentre, open-label, parallel group, randomised pilot study, adult patients with mild to moderate active UC (partial Mayo score of ≥4 and ≤8) were recruited from three centres in the UK (Birmingham, Glasgow and St Mark’s, London). Patients were randomised to receive FMT delivered either via a NG tube for delivery to the stomach (foregut-NG) on 4 consecutive days repeated after a month or by a combination of delivery through a colonoscope followed by 7 weekly enemas (hindgut-COLON). All participants underwent a treatment schedule using FMT derived, in each case, from a single donor. The primary outcome was a composite assessment of both qualitative and quantitative data based on efficacy, acceptability and safety. Clinical response (primary measure of efficacy) was defined as a ≥3 point and a ≥30% reduction in full Mayo score from randomisation to week 8 and a ≥1 point reduction in the rectal bleeding subscore or an absolute rectal bleeding subscore of 0 or 1. Patient and clinician acceptability of FMT and preference of treatment route was assessed through semi-structured qualitative research interviews. Interviews also explored reasons for adherence to treatment allocation and patients’ perspectives on FMT and trial experience. Participants were interviewed face to face or by telephone at two time points, first following the screening visit and prior to randomisation, and second after the 12-week follow-up period. Safety was assessed by the number of participants experiencing adverse events (AEs) and serious adverse events (SAEs). For the translational research, stool samples were taken from participants at baseline and then at 2 weekly intervals throughout the study to assess microbiome diversity (by 16S rRNA sequencing) and to examine the effect of FMT on faecal calprotectin. Donor stool samples were also analysed by 16S rRNA sequencing. Biopsy samples were taken from the colon at the time of endoscopy (baseline and week 8) to analyse mucosa-associated microbiome by 16S rRNA sequencing. SCFA levels in stool samples were also measured throughout the study and blood was taken from participants to look for changes in C-reactive protein (CRP) in response to FMT. Donors were asked to fill in a dietary questionnaire in order to look for associations between dietary components in their habitual diet and the efficacy of their donated FMT samples. Results Thirty patients with UC were randomised between March 2018 and April 2019; 16 to NG; 14 to COLON route. Seven participants in the NG arm and two participants in the colonic arm withdrew from the study. Clinical response was achieved in a higher proportion of participants in the colonic arm [9/12 (75%)] compared with the NG arm [2/8 (25%)]; [adjusted risk ratio 2.94 (95% confidence interval, 0.84 to 10.30)]. In the colonic arm, 12/14 (86%) participants were considered adherent compared with 8/16 (50%) in the NG arm. AEs were reported in 11/14 (79%) participants in the colonic arm and 11/16 (69%) in the NG arm. There were three SAEs in two participants in the NG arm, and none in the colonic arm. Qualitative research found a high level of enthusiasm for the trial among both patients and staff. Patients were more positive about the colonic treatment route than the NG route, both before randomisation and after the patients had been through the study. Lower calprotectin levels, implying reduced colonic inflammation, averaged over the last half of the treatment course (weeks 4, 6 and 8), were seen in the responders (N = 11, mean 508.6 mg/kg) versus the non-responders (N = 9, mean 853.6 mg/kg) (p = 0.03). Furthermore, there was a negative association between faecal microbiome alpha diversity [rarefied total operational taxonomic unit (OTU) richness] and calprotectin levels (p < 0.01). This is the first time that change in faecal calprotectin, a widely used clinical inflammatory biomarker in UC, has been reported in response to FMT in inflammatory bowel disease (IBD). With respect to SCFAs, there were significant and large increases observed in the concentration of acetate (45% increase, p = 0.05) and butyrate (57% increase, p = 0.03) across all participants (N = 19) from baseline to week 2 following FMT treatment. This effect was also observed over the course of the entire FMT treatment period from baseline to 8 weeks (N = 16, acetate 21% increase, p = 0.02; butyrate 39% increase, p = 0.08). Significant changes were not observed for the other SCFAs measured, notably propionate (2 weeks p = 0.46, 8 weeks p = 0.36). The observed increase in acetate and butyrate was not associated with clinical response, and in fact when restricted to the responder group (N = 9) changes at both 2 and 8 weeks were no longer significant, although increases were still observed. Across all participants that completed FMT to day 56, and for whom baseline and week 8 DNA was available (N = 13), there was no significant change in faecal microbiome alpha diversity, as measured by rarefied Shannon diversity of 3% OTUs (p = 0.43). However, when restricted to the colonic arm only (N = 8), there was a significant increase in alpha diversity (p = 0.01) observed after FMT. Again, for those participants in the colonic arm that responded to FMT, there was a significant increase in alpha diversity (rarefied Shannon diversity, p < 0.01) compared to those who did not. No differences were seen in alpha diversity of mucosa-associated bacteria pre and post treatment. Donor microbiome diversity, as measured by rarefied 16S rRNA gene Shannon diversity, varied substantially between donors. There was a non-significant positive association between clinical response and donor diversity (p = 0.19) with the treatment arm taken into account. In this pilot study, CRP values were lower at baseline in the colonic arm (4.2 mg/l) compared with the NG arm (11.3 mg/l). Similarly, CRP values at weeks 4, 6 and 8 were also lower in the colonic arm than in the NG arm. With regard to data derived from diet questionnaires administered to donors, higher milk and milk product intakes were associated with higher alpha diversity, but this was not statistically significant. The mean number of days from stool donation to FMT treatment was similar in participants who achieved a clinical response compared with those who did not achieve a clinical response. There was no association between time from stool donation and treatment, and clinical response when added to the primary intention-to-treat analysis model. Conclusion This pilot study suggests that in patients with active UC, FMT delivered via the colonic route appears to be safe and better tolerated with signals suggesting greater efficacy compared to the NG route. The pilot study was welcomed by patients and clinicians, and FMT appears, at least in the short term, to be safe and well tolerated. On review of these data, the Independent Oversight Committee recommended progressing to the planned placebo-controlled randomised trial, which would be powered to assess efficacy, and would have enabled more detailed mechanistic studies to assess for strains engrafting from donors to recipients, which are associated with clinical response. Patients remain very interested in FMT as a potential treatment for UC as this microbiome manipulation affords an alternative therapy to immune system suppression as a means to treat UC. The trial management group involved in this pilot believe that further studies to assess the efficacy of FMT in UC with a focus on understanding mechanisms are warranted as the first step towards developing precision live biotherapeutics for IBD. Trial registration This trial is registered as ISRCTN74072945 and EudraCT 2015-005753-12. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 13/179/01) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 14. See the NIHR Funding and Awards website for further award information.