Background: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterised by accumulation of activated (myo)fibroblasts and excessive extracellular matrix deposition. The enhanced accumulation of (myo)-fibroblasts may be attributed, in part, to the process of transforming growth factor b1 (TGFb1)-induced epithelial-mesenchymal transition (EMT), the phenotypic switching of epithelial to fibroblast-like cells. Although alveolar epithelial type II (ATII) cells have been shown to undergo EMT, the precise mediators and mechanisms remain to be resolved. The objective of this study is to investigate the role of SNAI transcription factors in the process of EMT and in IPF. Methods: Using quantitative reverse transcription-PCR (RT-PCR), immunofluorescence, immunohistochemistry, western blotting, as well as gain-and loss-of-function studies and functional assays, the role of SNAI1 and SNAI2 in TGFb1-induced EMT in ATII cells in vitro was assessed; and the expression of SNAI transcription factors was analysed in experimental and human IPF in vivo. Results: TGFb1 treatment increased the expression and nuclear accumulation of SNAI1 and SNAI2, in concert with induction of EMT in ATII cells. SNAI overexpression was sufficient to induce EMT, and small interfering RNA (siRNA)-mediated SNAI depletion attenuated TGFb1-induced ATII cell migration and EMT. SNAI expression was elevated in experimental and human IPF and localised to hyperplastic ATII cells in vivo.Conclusions: The results demonstrate that TGFb1-induced EMT in ATII cells is essentially controlled by the expression and nuclear translocation of SNAI transcription factors. Increased SNAI1 and SNAI2 expression in experimental and human IPF in vivo suggests that SNAImediated EMT may contribute to the fibroblast pool in idiopathic pulmonary fibrosis.

AIMTo systematically review the literature on epidemiology, disease burden, and treatment outcomes for Crohn’s disease (CD) patients with complex perianal fistulas.METHODSPubMed, Embase, and Cochrane were searched for relevant articles (published 2000-November 2016) and congress abstracts (published 2011-November 2016).RESULTSOf 535 records reviewed, 62 relevant sources were identified (mostly small observational studies). The cumulative incidence of complex perianal fistulas in CD from two referral-centre studies was 12%-14% (follow-up time, 12 years in one study; not reported in the second study). Complex perianal fistulas result in greatly diminished quality of life; up to 59% of patients are at risk of faecal incontinence. Treatments include combinations of medical and surgical interventions and expanded allogeneic adipose-derived stem cells. High proportions of patients experience lack of or inadequate response to treatment (failure and relapse rates, respectively: medical, 12%-73% and 0%-41%; surgical: 0%-100% and 11%-20%; combined medical/surgical: 0%-80% and 0%-50%; stem cells: 29%-47% and not reported). Few studies (1 of infliximab; 3 of surgical interventions) have been conducted in treatment-refractory patients, a population with high unmet needs. Limited data exist on the clinical value of anti-tumour necrosis factor-α dose escalation in patients with complex perianal fistulas in CD.CONCLUSIONComplex perianal fistulas in CD pose substantial clinical and humanistic burden. There is a need for effective treatments, especially for patients refractory to anti-tumour necrosis factor-α agents, as evidenced by high failure and relapse rates.

Summary What is known and objective The application of biologics to treat inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is well established. Our aim was to characterize the most recent five years of data on rates of adherence, persistence, switching and dose escalations with biologics used to treat IBD in the United States. Methods We systematically reviewed electronic databases MEDLINE, MEDLINE In‐Process, EMBASE and Cochrane Library for 2012‐2017 as well as conference proceedings for 2016‐2017 published in English. Results and discussion Of 449 records identified, 41 met all screening criteria. Published studies varied greatly in methodology, data sources, population studied, follow‐up time and endpoint definitions, preventing meaningful comparisons across studies. Based on studies using a medication possession rate threshold of <80% or <86%, 38%‐77% of patients were found non‐adherent to biologics. Discontinuation within the first 3 months occurred in 0%‐25% of patients in six studies; 7%‐65% discontinued by 12 months in 13 studies. Among all patients who initiated an index biologic, the switch rate to another biologic ranged from 4.5% to 20% in 6 studies. Dose escalations were reported in only four studies; 8%‐35% of patients had their dose escalated within the first year of therapy. What is new and conclusion This study demonstrates variability in study design and methodology to assess adherence, persistence, switching and dose escalation with biologics among adults with IBD in the United States. Our findings suggest that real‐world biologic use may be suboptimal and indicate new therapies and/or additional patient support may be needed.

Lung cancer is the main cancer killer in both men and women, mostly due to the rapid development of drug resistant metastatic disease. Here, we evaluate the potential involvement of SRC family kinases (SFK) in lung cancer biology and assess the possible benefits of their inhibition as a therapeutic approach. We demonstrated that various SRC family members, including LYN and LCK, normally expressed solely in hematopoietic cells and neural tissues, are overexpressed and activated in a panel of SCLC and NSCLC cell lines. This was clinically relevant as LYN and FYN are also overexpressed in lung cancer clinical specimens. Moreover, LYN overexpression correlated with decreased patient survival on univariate and multivariate analysis. Dasatinib (BMS-354825), a SRC/ABL inhibitor, effectively blocked SFK activation at nanomolar concentrations which correlated with a significant decrease in cell numbers of multiple lung cancer cell lines. This effect was matched by a decrease in DNA synthesis, but only moderate induction of apoptosis. Indeed, dasatinib as well as PP2, another SFK inhibitor, strongly induced autophagy that likely prevented apoptosis. However, inhibition of this autophagic response induced robust apoptosis and sensitised lung cancer cells to dasatinib in vitro and in vivo. Our results provide an explanation for why dasatinib failed in NSCLC clinical trials. Furthermore, our data suggest that combining SFK inhibitors with autophagy inhibitors could provide a novel therapeutic approach in this disease.

In July 2019, the National Institute for Health and Care Excellence (NICE) initiated a major review of its health technology evaluation methods to update its methods guide. This update has recently concluded with the publication of its health technology evaluation manual in January 2022. This paper reports the methods and findings of the review in relation to the recommended approach to use for the measurement and valuation of health-related quality of life (HRQoL) in submissions to NICE. Issues related to (i) the methods to use when NICE’s preferred measure (EQ-5D) is not appropriate or not available; (ii) adjusting health state utility values over time to account for age; (iii) measuring and valuing HRQoL in children and young people; and (iv) including carers’ QoL in economic evaluations were included in this review. This commentary summarises the methods used to undertake the review, its findings, and the changes to NICE methods that were proposed based on these findings. It also outlines topics where further research is needed before definitive methods guidance can be issued. The broad proposals described here were subject to a public consultation in 2020 and a further consultation on the updated methods guidance was completed in October 2021 before the publication of the manual in January 2022.

No abstract

S87 10th Revision, Clinical Modification (ICD-9/10-CM) diagnosis codes (ICD-9-CM: 555, 556; ICD-10-CM: K50, K51). The first diagnosis date was designated as the index date. A comparison cohort of patients without IBD diagnosis was created for patients of the same age, sex, race, index year, and similar Charlson comorbidity index (CCI) score. A random index date was chosen for the comparison cohort to reduce selection bias. Patients were required to have continuous medical and pharmacy benefits for 12 months pre-and post-index date. A generalized linear model (GLM) was performed to compare follow-up HRU and costs between the cohorts, adjusting for demographic and clinical characteristics. ReSultS: A total of 12,418 patients were included in each cohort (IBD and comparator cohorts). The mean age was 42 years, and 54% were female. IBD patients had higher CCI scores (0.54 vs 0.49; p< 0.001). After balancing for clinical characteristics in the GLM, IBD patients had more inpatient (0.34 vs 0.08; p< 0.001), emergency room (ER; 1.03 vs 0.40; p< 0.001), ambulatory (30.32 vs 15.23, p< 0.001), and pharmacy visits (16.73 vs 8.28, p< 0.001), as well as longer hospital length of stay (2.29 vs 0.48 days; p< 0.

S8710th Revision, Clinical Modification (ICD-9/10-CM) diagnosis codes (ICD-9-CM: 555, 556; ICD-10-CM: K50, K51). The first diagnosis date was designated as the index date. A comparison cohort of patients without IBD diagnosis was created for patients of the same age, sex, race, index year, and similar Charlson comorbidity index (CCI) score. A random index date was chosen for the comparison cohort to reduce selection bias. Patients were required to have continuous medical and pharmacy benefits for 12 months pre-and post-index date. A generalized linear model (GLM) was performed to compare follow-up HRU and costs between the cohorts, adjusting for demographic and clinical characteristics. ReSultS: A total of 12,418 patients were included in each cohort (IBD and comparator cohorts). The mean age was 42 years, and 54% were female. IBD patients had higher CCI scores (0.54 vs 0.49; p< 0.001). After balancing for clinical characteristics in the GLM, IBD patients had more inpatient (0.34 vs 0.08; p< 0.001), emergency room (ER; 1.03 vs 0.40; p< 0.001), ambulatory (30.32 vs 15.23, p< 0.001), and pharmacy visits (16.73 vs 8.28, p< 0.001), as well as longer hospital length of stay (2.29 vs 0.48 days; p< 0.