BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Functional aspects of the CD30 gene in Hodgkin’s lymphoma and anaplastic large cell lymphoma

Lymphomas are neoplasms of the human immune system and can be divided into two categories, Hodgkin’s lymphoma (HL) and non-Hodgkin’s lymphoma (NHL). Anaplastic large cell lymphoma (ALCL) is a form of NHL that shares a common distinctive feature with Hodgkin’s lymphoma, the overexpression of cytokine receptor, CD30. However, the responses in HL and ALCL differ. Activation of CD30 via its ligand, CD153 or antibodies triggers various cellular responses ranging from apoptosis to cell proliferation in ALCL but no response in HL. To further understand the role of these processes in the pathology, downstream signalling events arising from CD30 stimulation have been investigated; however, little is known about regulatory mechanisms that result in the characteristically high levels of CD30 in HL and ALCL. Here we review the studies that have focused on characterisation of the CD30 promoter as well as several factors that contribute to the transcriptional regulation of CD30 in these lymphomas

Dietary iron enhanced acute colonic inflammation.

<p>Body weight (A), endoscopic MEICS (B) and histological colitis (C) scores were measured in Iron and Control (Ctrl) mice treated with or without DSS for up to 7 days. In hematoxylin and eosin-stained distal colon sections (D), Iron/DSS mice exhibited extensive areas of mucosal erosion (arrowheads) with severe crypt damage (arrows) whilst crypt damage was moderate in Ctrl/DSS mice. There was no damage in Iron and Ctrl mice. Results are expressed as mean±SEM, n = 6–8. * <i>P</i><0.01 denotes significance between DSS treatment versus no treatment; # <i>P</i><0.05 denotes significance between Iron/DSS versus Ctrl/DSS or Iron versus Ctrl mice. Scale bar denotes 50 µm.</p

Cytokine gene expression in Iron and Control mice treated with or without DSS.

<p>Results are normalized against Hprt or Arbp expression and expressed relative to Control mice as mean±SEM; n = 3–6. * <i>P</i><0.05; denotes significance between DSS treatment versus no treatment and # <i>P</i><0.05; denotes significance between Iron/DSS versus Control/DSS or Iron versus Control mice.</p

Dietary iron enhanced cyclin D1 expression and promoted epithelial cell apoptosis during acute colonic inflammation.

<p>Colonic mRNA expression of cell cycle regulators, cyclin D1 (A), cyclin B1 (B) and c-myc (C) were measured in Iron and Control (Ctrl) mice treated with or without DSS for 7 days. PCNA protein expression (D) was determined by immunoblot in isolated colonic epithelial cells from Iron/DSS and Ctrl/DSS mice compared with non-DSS treated mice at day 3. Apoptotic colonic epithelial cells were quantified (E) from TUNEL staining (F; representative images shown) of whole colonic Swiss roll preparations from Iron and Ctrl mice treated with or without DSS for 3 days. Results are expressed as mean±SEM, n = 3–8. * <i>P</i><0.05 denotes significance between DSS treatment versus no treatment; # <i>P</i><0.05 denotes significance between Iron/DSS versus Ctrl/DSS or Iron versus Ctrl mice. @ <i>P</i><0.05 denotes significance between Iron/DSS versus Ctrl. Scale bar denotes 50 µm.</p

Iron accumulation in the colon increased F₂-isoprostane levels.

<p>3,3′-diaminobenzidine-enhanced Perls' Prussian blue (A) and ferritin and F4/80 double immunofluorescent (B) staining were performed on colon sections from Iron and Control (Ctrl) mice treated with or without DSS for 3 days. Colonic iron (A) accumulated in apical epithelial cells (black arrowheads) and macrophages of the lamina propria (black arrows). Immunofluorescent staining (B) of ferritin (red) was increased in colonic epithelial cells (white arrowheads) and in lamina propria F4/80⁺ (green) macrophages (white arrows) in iron-supplemented mice. Colon F₂-isoprostane concentration (C), plasma transferrin saturation (D), liver non-heme iron concentration (E) were measured in Iron and Ctrl mice treated with or without DSS for 7 days. Results are expressed as mean±SEM, n = 4–7. * <i>P</i><0.05 denotes significance between DSS treatment versus no treatment; # <i>P</i><0.05 denotes significance between Iron/DSS versus Ctrl/DSS or Iron versus Ctrl mice. Scale bar denotes 25 µm.</p

Iron transporter gene expression was modified in colonic tumors in inflammation-associated tumorigenesis.

<p>Iron importer, Dmt1 (A) and Tfr1 (B), as well as iron exporter, Fpn (C), mRNA expression were measured in colonic tumor (T) and non-tumor (nT) tissue from Iron/DSS and Control (Ctrl)/DSS mice at day 78. 3,3′-diaminobenzidine-enhanced Perls' Prussian blue staining (D) showed that no iron deposits were detected in the tumor epithelium from Iron/DSS or Ctrl/DSS mice. In surrounding non-tumor tissue, there was some stainable iron detected in colonic epithelial cells (arrowheads) of Iron/DSS mice compared with Ctrl/DSS mice and there was some evidence of distension and branching of glands in the mucosa (D; arrows). Results are expressed as mean±SEM, n = 3–6. * <i>P</i><0.05 denotes significance between T and nT tissue from Iron/DSS or Ctrl/DSS mice; # <i>P</i><0.05 denotes significance between Iron/DSS and Ctrl/DSS in T or nT tissue. Scale bar denotes 25 µm.</p

Dietary iron enhanced colonic inflammatory cytokine release and Stat3 signaling during acute colonic inflammation.

<p>Colonic IL-6 (A), IL-11 (B) and IL-1β (C) release from colonic tissue explants were measured after 24 hours in culture at 37°C. The tissue explants were harvested Iron and Control (Ctrl) mice treated with or without DSS for 7 days. Colonic Stat3 phosphorylation (D) was also determined in Iron/DSS and Ctrl/DSS mice compared with non-DSS treated mice at day 7. Immunofluorescent staining (E) of F4/80 (green) and IL-6 (red; left panels) or phosphorylated Stat3 (red; right panels) at day 3 of DSS treatment identified F4/80⁺ macrophages (arrows) as a main source of IL-6 production and epithelial crypt cells as active sites of nuclear pStat3 localization (white arrowheads) in Iron and Ctrl mice. Results are expressed as mean±SEM, n = 3–8. * <i>P</i><0.001 denotes significance between DSS treatment versus no treatment; # <i>P</i><0.05 denotes significance between Iron/DSS versus Ctrl/DSS or Iron versus Ctrl mice. Scale bar denotes 25 µm.</p