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ObjectiveGeneral practitioners may not prescribe amitriptyline for irritable bowel syndrome (IBS) despite using it for other chronic conditions. The Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment (ATLANTIS) trial found low-dose titrated amitriptyline was a safe and clinically effective second-line treatment for IBS in primary care. We undertook a prespecified cost-effectiveness analysis of ATLANTIS trial data.Design/methodComplete case (CC) and a full population (FP) analysis using multiply imputed data with analyses at 6 (365 participants CC, 463 participants FP) and 12 (224 participants CC, 291 participants FP) months. As the trial was not fully randomised between 6 and 12 months, we adopted inverse probability weighting to mitigate potential impact of participants choosing to continue trial medication.ResultsAt a 6-month time horizon, CC analysis demonstrated low-dose amitriptyline was more likely to be cost-effective than not (incremental net health benefit (NHB) 0.0029 quality-adjusted life years (QALYs)/person, low-dose amitriptyline dominant, 67.3% probability cost-effective), but not FP analysis. At 12 months, all analyses demonstrated low-dose amitriptyline was more likely to be cost-effective than not (CC: incremental NHB 0.00757 QALYs/person, low-dose amitriptyline dominant, 81.7% probability cost-effective; FP: incremental NHB 0.00388 QALYs/person, low-dose amitriptyline dominant, 68.7% probability cost-effective).ConclusionIn addition to the clinical benefit, safety and acceptability of low-dose amitriptyline in patients with IBS found in the ATLANTIS trial, these results indicate this inexpensive medication is likely to be cost-effective as a second-line treatment for IBS in primary care over 12 months. This strengthens amitriptyline as a treatment option for people with ongoing IBS symptoms.Trial registration numberISRCTN48075063.

Tissue-thin parchment made it possible to produce the first pocket Bibles: Thousands were made in the 13th century. The source of this parchment, often called “uterine vellum,” has been a long-standing controversy in codicology. Use of the Latin termabortivumin many sources has led some scholars to suggest that the skin of fetal calves or sheep was used. Others have argued that it would not be possible to sustain herds if so many pocket Bibles were produced from fetal skins, arguing instead for unexpected alternatives, such as rabbit. Here, we report a simple and objective technique using standard conservation treatments to identify the animal origin of parchment. The noninvasive method is a variant on zooarchaeology by mass spectrometry (ZooMS) peptide mass fingerprinting but extracts protein from the parchment surface by using an electrostatic charge generated by gentle rubbing of a PVC eraser on the membrane surface. Using this method, we analyzed 72 pocket Bibles originating in France, England, and Italy and 293 additional parchment samples that bracket this period. We found no evidence for the use of unexpected animals; however, we did identify the use of more than one mammal species in a single manuscript, consistent with the local availability of hides. These results suggest that ultrafine vellum does not necessarily derive from the use of abortive or newborn animals with ultrathin hides, but could equally well reflect a production process that allowed the skins of maturing animals of several species to be rendered into vellum of equal quality and fineness.

Most patients with irritable bowel syndrome (IBS) are managed in primary care. When first-line therapies for IBS are ineffective, the UK National Institute for Health and Care Excellence guideline suggests considering low- dose tricyclic antidepressants as second-line treatment, but their effectiveness in primary care is unknown, and they are infrequently prescribed in this setting. This randomised, double-blind, placebo-controlled trial (Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment [ATLANTIS]) was conducted at 55 general practices in England. Eligible participants were aged 18 years or older, with Rome IV IBS of any subtype, and ongoing symptoms (IBS Severity Scoring System [IBS-SSS] score ≥75 points) despite dietary changes and first-line therapies, a normal full blood count and C-reactive protein, negative coeliac serology, and no evidence of suicidal ideation. Participants were randomly assigned (1:1) to low-dose oral amitriptyline (10 mg once daily) or placebo for 6 months, with dose titration over 3 weeks (up to 30 mg once daily), according to symptoms and tolerability. Participants, their general practitioners, investigators, and the analysis team were all masked to allocation throughout the trial. The primary outcome was the IBS-SSS score at 6 months. Effectiveness analyses were according to intention-to-treat; safety analyses were on all participants who took at least one dose of the trial medication. This trial is registered with the ISRCTN Registry (ISRCTN48075063) and is closed to new participants. Between Oct 18, 2019, and April 11, 2022, 463 participants (mean age 48·5 years [SD 16·1], 315 [68%] female to 148 [32%] male) were randomly allocated to receive low-dose amitriptyline (232) or placebo (231). Intention-to-treat analysis of the primary outcome showed a significant difference in favour of low-dose amitriptyline in IBS-SSS score between groups at 6 months (–27·0, 95% CI –46·9 to –7·10; p=0·0079). 46 (20%) participants discontinued low-dose amitriptyline (30 [13%] due to adverse events), and 59 (26%) discontinued placebo (20 [9%] due to adverse events) before 6 months. There were five serious adverse reactions (two in the amitriptyline group and three in the placebo group), and five serious adverse events unrelated to trial medication. To our knowledge, this is the largest trial of a tricyclic antidepressant in IBS ever conducted. Titrated low-dose amitriptyline was superior to placebo as a second-line treatment for IBS in primary care across multiple outcomes, and was safe and well tolerated. General practitioners should offer low-dose amitriptyline to patients with IBS whose symptoms do not improve with first-line therapies, with appropriate support to guide patient-led dose titration, such as the self-titration document developed for this trial. National Institute for Health and Care Research Health Technology Assessment Programme (grant reference 16/162/01).

ObjectivesTo describe the development of Eczema Care Online (ECO), an online behaviour change intervention for young people with eczema (phase I); and explore and optimise the acceptability of ECO among this target group using think-aloud interviews (phase II).MethodsTheory-based, evidence-based and person-based approaches to intervention development were used. In phase I, a qualitative systematic review and qualitative interviews developed an in-depth understanding of the needs and challenges of young people with eczema. Guiding principles highlighted key intervention design objectives and features to address the needs of this target group to maximise user engagement. Behavioural analysis and logic modelling developed ECO’s hypothesised programme theory. In phase II, qualitative think-aloud interviews were carried out with 28 young people with eczema and the intervention was optimised based on their feedback.ResultsThe final intervention aimed to reduce eczema severity by supporting treatment use (emollients, topical corticosteroids/topical calcineurin inhibitors), management of irritants/triggers, emotional management and reducing scratching. Generally, young people expressed positive views of intervention content and design in think-aloud interviews. Quotes and stories from other young people with eczema and ECO’s focus on living with eczema (not just topical treatments) were valuable for normalising eczema. Young people believed ECO addressed knowledge gaps they had from childhood and the safety information about topical corticosteroids was reassuring. Negative feedback was used to modify ECO.ConclusionsA prototype of the ECO intervention was developed using rigorous and complementary intervention development approaches. Subsequent think-aloud interviews helped optimise the intervention, demonstrated ECO is likely to be acceptable to this target group, and provided support for our guiding principles including key design objectives and features to consider when developing interventions for this population. A randomised controlled trial and process evaluation of the intervention is underway to assess effectiveness and explore user engagement with the intervention’s behavioural goals.

IntroductionEffective communication can help optimise healthcare interactions and patient outcomes. However, few interventions have been tested clinically, subjected to cost-effectiveness analysis or are sufficiently brief and well-described for implementation in primary care. This paper presents the protocol for determining the effectiveness and cost-effectiveness of a rigorously developed brief eLearning tool, EMPathicO, among patients with and without musculoskeletal pain.Methods and analysisA cluster randomised controlled trial in general practitioner (GP) surgeries in England and Wales serving patients from diverse geographic, socioeconomic and ethnic backgrounds. GP surgeries are randomised (1:1) to receive EMPathicO e-learning immediately, or at trial end. Eligible practitioners (eg, GPs, physiotherapists and nurse practitioners) are involved in managing primary care patients with musculoskeletal pain. Patient recruitment is managed by practice staff and researchers. Target recruitment is 840 adults with and 840 without musculoskeletal pain consulting face-to-face, by telephone or video. Patients complete web-based questionnaires at preconsultation baseline, 1 week and 1, 3 and 6 months later. There are two patient-reported primary outcomes: pain intensity and patient enablement. Cost-effectiveness is considered from the National Health Service and societal perspectives. Secondary and process measures include practitioner patterns of use of EMPathicO, practitioner-reported self-efficacy and intentions, patient-reported symptom severity, quality of life, satisfaction, perceptions of practitioner empathy and optimism, treatment expectancies, anxiety, depression and continuity of care. Purposive subsamples of patients, practitioners and practice staff take part in up to two qualitative, semistructured interviews.Ethics approval and disseminationApproved by the South Central Hampshire B Research Ethics Committee on 1 July 2022 and the Health Research Authority and Health and Care Research Wales on 6 July 2022 (REC reference 22/SC/0145; IRAS project ID 312208). Results will be disseminated via peer-reviewed academic publications, conference presentations and patient and practitioner outlets. If successful, EMPathicO could quickly be made available at a low cost to primary care practices across the country.Trial registration number ISRCTN18010240.

Background Irritable bowel syndrome (IBS) is a common functional bowel disorder that has a considerable impact on patient quality of life and substantial societal and health care resource costs. Current treatments are often ineffective. Tricyclic antidepressants have shown promise in secondary care populations but their effectiveness in a primary care setting remains unclear. Methods ATLANTIS is a randomised, multi-centre, parallel-group, two-arm, double-blind, placebo-controlled trial of low-dose amitriptyline as a second-line treatment for IBS in primary care. Participants will be invited by letter, or recruited opportunistically, from general practices in three regions of England (West Yorkshire, Wessex, and West of England) and screened for eligibility. A total of 518 adult patients with IBS, who are symptomatic despite first-line therapies, will be randomised 1:1 to amitriptyline or identical placebo for 6 months. Treatment will commence at a dose of 10 mg (or one placebo tablet) daily at night, with dose titration up to a maximum of 30 mg at night, depending on side effects and response to treatment. Participant-reported assessments will be conducted at baseline and 3, 6, and 12 months post-randomisation. The primary objective is to determine the effectiveness of amitriptyline, compared with placebo, in improving participant-reported global symptoms of IBS at 6 months (using the IBS Severity Scoring System). Secondary outcomes include relief of IBS symptoms, effect on IBS-associated somatic symptoms (Patient Health Questionnaire-12), anxiety and depression (Hospital Anxiety and Depression Scale), ability to work and participate in other activities (Work and Social Adjustment Scale), acceptability and tolerability of treatment, self-reported health care use, health-related quality of life (EQ-5D-3L), and cost-effectiveness. A nested, qualitative study will explore patient and general practitioner experiences of treatments and trial participation, including acceptability, adherence, unanticipated effects, and implications for wider use of amitriptyline for IBS in primary care. Discussion Determining the clinical and cost-effectiveness of low-dose amitriptyline as a second-line treatment for IBS in primary care will provide robust evidence to inform management decisions. Trial registration ISRCTN ISRCTN48075063 . Registered on 7th June 2019.

Data on sepsis prevalence on the general wards is lacking on the UK and in the developed world. We conducted a multicentre, prospective, observational study of the prevalence of patients with sepsis or severe sepsis on the general wards and Emergency Departments (ED) in Wales. During the 24-hour study period all patients with NEWS≥3 were screened for presence of 2 or more SIRS criteria. To be eligible for inclusion, patients had to have a high clinical suspicion of an infection, together with a systemic inflammatory response (sepsis) and evidence of acute organ dysfunction and/or shock (severe sepsis). There were 5317 in-patients in the 24-hour study period. Data were returned on 1198 digital data collection forms on patients with NEWS≥3 of which 87 were removed, leaving 1111 for analysis. 146 patients had sepsis and 144 patients had severe sepsis. Combined prevalence of sepsis and severe sepsis was 5.5% amongst all in-patients. Patients with sepsis had significantly higher NEWS scores (3 IQR 3-4 for non-sepsis and 4 IQR 3-6 for sepsis patients, respectively). Common organ dysfunctions in severe sepsis were hypoxia (47%), hypoperfusion (40%) and acute kidney injury (25%). Mortality at 90 days was 31% with a median (IQR) hospital free stay of 78 (36-85) days. Screening for sepsis, referral to Critical Care and completion of Sepsis 6 bundle was low: 26%, 16% and 12% in the sepsis group. Multivariable logistic regression analysis identified higher National Early Warning Score, diabetes, COPD, heart failure, malignancy and current or previous smoking habits as independent variables suggesting the diagnosis of sepsis. We observed that sepsis is more prevalent in the general ward and ED than previously suggested before and that screening and effective treatment for sepsis and severe sepsis is far from being operationalized in this environment, leading to high 90 days mortality.

Current prostate organoid models rely on tissue-derived material or animal components and lack epithelial and stromal complexity. We defined a xeno-free system to generate human prostate organoids from induced pluripotent stem cells with consistent multilineage differentiation. Floating organoids self-organize into epithelial and stromal domains with basal, luminal, neuroendocrine, fibroblast, and smooth muscle markers. In an alternative modular co-culture system, engineered epithelial progenitors are aggregated with wild-type mesenchymal progenitors, enabling compartment-specific manipulation. Androgen receptor–overexpressing organoids showed increased epithelial AR and PSA expression and proliferation. Single-cell transcriptomics, together with qPCR and immunostaining, confirmed prostate lineage specification and tissue organization. This new xeno-free platform provides a reproducible, scalable, and genetically tractable model to study in-vitro prostate lineage programs, epithelial-stromal interactions, and disease biology. This study describes the generation of prostate organoids from human iPSCs. iPSCs, including those reprogrammed from patients carrying germline mutations, can be differentiated into prostate organoids either through monoculture or by co-culturing endodermal cells with mesenchymal progenitors. Genetic manipulation can be introduced before endoderm specification to model cancer drivers. The resulting multi-lineage organoids exhibit distinct epithelial (AR⁺, NKX3.1⁺, PSA⁺, CK8/18⁺) and stromal (VIM⁺, α-SMA⁺) compartments, providing a versatile platform for developmental studies, disease modelling, drug screening, and biomarker discovery.