Desmoid Tumors: A Comprehensive Review.

Desmoid tumors (DT) are rare, locally aggressive, fibroblastic soft-tissue tumors that are characterized by infiltrative growth and can affect organs and adjacent structures, resulting in substantial clinical burden impacting patients' health-related quality of life. Searches of PubMed, Embase, Cochrane, and key conferences were conducted in November 2021 and updated periodically through March 2023 to identify articles describing the burden of DT. Of 651 publications identified, 96 relevant ones were retained. Diagnosis of DT is challenging because of its morphologic heterogeneity and variable clinical presentation. Patients visit multiple healthcare providers, often facing delays in correct diagnosis. The low incidence of DT (estimated 3-5 cases per million person-years) limits disease awareness. Patients with DT experience a high symptom burden: up to 63% of patients experience chronic pain, which leads to sleep disturbance (73% of cases), irritability (46% of cases), and anxiety/depression (15% of cases). Frequently mentioned symptoms are pain, limited function and mobility, fatigue, muscle weakness, and swelling around the tumor. Overall, quality of life in patients with DT is lower than in healthy controls. There is no treatment approved by the US Food and Drug Administration for DT; however, treatment guidelines reference available options, such as active surveillance, surgery, systemic therapy, and locoregional therapy. Choice of active treatment may depend on tumor location, symptoms, and risk of morbidity. The substantial burden of illness of DT is related to difficulties in timely and accurate diagnosis, high symptom burden (pain and functional limitations), and decreased quality of life. There is a high unmet need for treatments that specifically target DT and improve quality of life.

Geographic atrophy: Mechanism of disease, pathophysiology, and role of the complement system.

Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD), characterized by atrophic lesions that first start in the outer retina and progressively expand to cover the macula and the fovea, the center of the macula, leading to irreversible loss of vision over time. GA is distinct from wet or neovascular AMD (nAMD), the other form of advanced AMD. Neovascular AMD is characterized by new invading leaky blood vessels in the macula that can lead to acute vision loss. GA and nAMD may coexist in the same eye. The underlying pathophysiology of GA is complex and thought to involve chronic inflammation due to overactivation of the complement system that leads to the loss of photoreceptors, retinal pigment epithelium (RPE), and the underlying choriocapillaris. The disappearance of these structures appears as sharply demarcated atrophic lesions that are typical of GA. Researchers have reported about 1 million reported cases of GA in the United States, and about 160,000 cases occur per year. The most important risk factors for GA are increasing age and family history. Diagnosis of GA is usually made by using multimodal imaging techniques. Lesions associated with GA are highly heterogeneous, and the growth rate may differ from patient to patient. Despite the progressive nature of GA, the fovea may be spared until much later in the disease, thereby retaining central vision in patients. With time, atrophic lesions may progressively grow to involve the fovea, thereby severely impairing central vision. Vision loss can happen rapidly once the lesions reach the fovea. However, even without the involvement of the fovea, ongoing vision impairment impacting daily life may be present. Median time from GA not involving the center of the fovea (without subfoveal involvement) to GA with lesion boundary affecting the foveal center (subfoveal involvement) ranges from 1.4 to 2.5 years. GA can greatly impact patients' functioning and quality of life and limit their independence by interfering with activities of daily living, including difficulties with reading, driving, watching television, recognizing faces, and being unable to do household chores. No treatments have been available until intravitreal pegcetacoplan was recently approved by the US Food and Drug Administration for GA secondary to AMD. DISCLOSURES: Dr Bakri serves as a consultant to Apellis Pharmaceuticals, as well as AbbVie, Adverum, Eyepoint, iLumen, Iveric Bio, Genentech, Novartis, Outlook Therapeutics, Pixium, Regeneron, Roche, and Regenxbio. Drs Sharp, Luo, and Sarda are employees of Apellis Pharmaceuticals. Dr Bektas and Ms Khan are employees of RTI Health Solutions. Apellis developed and led the concept design of this publication, review and interpretation, approval, and decision to publish. This research was developed under a research contract between RTI Health Solutions and Apellis Pharmaceuticals and was funded by Apellis Pharmaceuticals. This supplement is to describe the disease of geographic atrophy and was funded by Apellis. Apellis Pharmaceuticals has developed Syfovre (pegcetacoplan), the first and only treatment for geographic atrophy.

Disease and economic burden of surgery in desmoid tumors: a review.

INTRODUCTION: Desmoid tumors (DT) are soft-tissue tumors that infiltrate into surrounding structures with ill-defined margins. Although surgery is a potential treatment option, complete excision with negative margins is not often possible, the postsurgery recurrence rate is high, and surgery can result in disfigurement and/or loss of function. AREAS COVERED: We conducted a literature review to assess the burden of surgery in patients with DT, focusing on recurrence rates and functional deficits resulting from surgeries. Since economic data related to DT surgery is lacking, reviews of surgery costs in soft-tissue sarcomas and of general costs of amputations were conducted. Risk factors for DT recurrence after surgery are young age (<30 years), tumor location (extremities), tumor size (>5 cm in greatest diameter), positive resection margins, and history of trauma in the area of the primary tumor. Tumors in the extremities have the highest risk of recurrence (30%-90%). Lower rates of recurrences have been reported when radiotherapy was used after surgery (14%-38%). EXPERT OPINION: Although effective in specific cases, surgery may be associated with poor long-term functional outcomes and higher economic costs. Therefore, it is imperative to find alternative treatments with acceptable efficacy and safety profiles that do not adversely affect functional aspects in patients.

Anti-Alzheimer and Antioxidant Effects of Nelumbo nucifera L. Alkaloids, Nuciferine and Norcoclaurine in Alloxan-Induced Diabetic Albino Rats.

The present study is aimed to determine the efficacy and dose response of the nuciferine (1), norcoclaurine (2) and crude extract of Nelumbo nucifera in managements of diabetes, Alzheimer disease and related allergies. Experimentally, alloxan (100 mg/kg body weight (b.w.))-induced diabetic rats (200−250 g) were divided into seven groups (n = 6). Group I: normal control, Group II: diabetic control, Group III: standard treated with glibenclamide and Group lV-VII: treated with methanolic crude extracts (100, 200 mg/kg), nuciferine and norcoclaurine (10 mg/kg b.w.) for 15 days. Different tests were performed, including blood glucose, body weights and antioxidant enzyme assays, i.e., superoxide dismutase (SOD), catalase test (CAT), lipid peroxidation assay (TBARS), glutathione assay (GSH) and acetylcholinesterase (AChE) assay. Nuciferine and norcoclaurine significantly reduced blood glucose (p < 0.05) and restored body weight in diabetic rats. Moreover, nuciferine and norcoclaurine (10 mg/kg) significantly recovered the antioxidant enzymes (SOD, CAT, GPx and GSH) which decreased during induced diabetes. Significant increase in TBARS was also observed in the diabetic group and nuciferine as well as norcoclaurine (10 mg/kg) inhibited the increase in TBARS in diabetic animals (p < 0.05), as compared to glibenclamide. AChE activity was significantly recovered by nuciferine and norcoclaurine (10 mg/kg) both in the blood and brain of the diabetic group (p < 0.05). Nuciferine and norcoclaurine showed potent inhibitory effects against α-glucosidase and α-amylase with IC50, 19.06 ± 0.03, 15.03 ± 0.09 µM and 24.07 ± 0.05, 18.04 ± 0.021 µM, as confirmed by molecular docking studies. This study concludes that nuciferine and norcoclaurine significantly improve memory and could be considered as an effective phytomedicine for diabetes, Alzheimer's disease (AD) and oxidative stress.

Clinical effectiveness of a Malaysian-manufactured CAPD product: A randomised trial.

BACKGROUND: We compared the clinical effectiveness of a new peritoneal dialysis (PD) product with polyvinyl chloride-containing tubing (Stay Safe Link®, SSL) with the plastic-free alternative (Stay Safe®, STS) in patients on continuous ambulatory peritoneal dialysis (CAPD). METHOD: A multicentre, parallel, randomised, controlled, open-label, non-inferiority trial was conducted. Adult patients receiving CAPD were randomised in a 1:1 ratio to SSL or STS. The primary outcome was the rate of peritonitis after 1 year of follow-up. RESULTS: A total of 472 subjects were randomised (SSL, n = 233; STS, n = 239). One subject in each group was excluded from the analysis as they withdrew consent before the first dialysis dose. Four hundred and seventy subjects (SSL, n = 232; STS, n = 238) were included in the modified intention-to-treat analysis. Non-inferiority between two groups was established as no significant difference was found in peritonitis rate (incident rate ratio: 0.91, 95% CI: 0.65-1.28). No significant difference was detected in weekly Kt/V (p = 0.58) and creatinine clearance (p = 0.55). However, the average ultrafiltration volume was significantly lower in SSL, with a mean difference of 93 ml (p < 0.01). SSL also demonstrated a 2.57-times higher risk of device defect than STS (95% CI: 1.77-3.75). CONCLUSION: SSL was non-inferior in peritonitis rate compared to plastic-free STS over 1 year in patients requiring CAPD. There was no difference in the delivered dialysis dose, but there was a higher rate of device defects with SSL.

Revisiting time to translation: implementation of evidence-based practices (EBPs) in cancer control.

PURPOSE: Previous studies estimate translation of research evidence into practice takes 17 years. However, this estimate is not specific to cancer control evidence-based practices (EBPs), nor do these studies evaluate variation in the translational process. We examined the translational pathway of cancer control EBPs. METHODS: We selected five cancer control EBPs where data on uptake were readily available. Years from landmark publication to clinical guideline issuance to implementation, defined as 50% uptake, were measured. The translational pathway for each EBP was mapped and an average total time across EBPs was calculated. RESULTS: Five cancer control EBPs were included: mammography, clinicians' advice to quit smoking, colorectal cancer screening, HPV co-testing, and HPV vaccination. Time from publication to implementation ranged from 13 to 21 years, averaging 15 years. Time from publication to guideline issuance ranged from 3 to 17 years, and from guideline issuance to implementation, - 4 to 12 years. Clinician's advice to quit smoking, HPV co-testing, and HPV vaccination were most rapidly implemented; colorectal cancer screening and mammography were slowest to implement. CONCLUSION: The average time to implementation was 15 years for the five EBPs we evaluated, a marginal improvement from prior findings. Although newer EBPs such as HPV vaccination and HPV co-testing were faster to implement than other EBPs, continued efforts in implementation science to speed research to practice are needed.

Paroxysmal nocturnal hemoglobinuria: patient journey and burden of disease.

Patients with paroxysmal nocturnal hemoglobinuria (PNH) often experience a lengthy path to diagnosis. Fewer than 40% of patients with PNH receive a diagnosis within 12 months of symptom onset, and 24% of all PNH diagnoses can take 5 years or longer. Diagnostic delay is a source of distress and can affect emotional well-being for patients with PNH. In PNH disease management, patients and care providers focus on risk of organ failure and mortality related to disease progression; nonetheless, patients' health-related quality of life (HRQOL) is largely affected by extensive treatment requirements and nonfatal complications of disease, such as fatigue. In particular, thrombosis is associated with significant impairments in physical and social functioning and global health status and significant fatigue. Among patients with anemia who are transfusion dependent, the burden of transfusion is considerable. Transfusion dependence has a negative effect on HRQOL; is associated with risks and complications, including iron overload; and results in lost productivity due to travel times to and time spent at infusion centers. DISCLOSURES: This research was developed under a research contract between RTI Health Solutions and Apellis Pharmaceuticals and was funded by Apellis Pharmaceuticals. Bektas, Copley-Merriman, and Khan are employees of RTI Health Solutions. Sarda is an employee of Apellis Pharmaceuticals. Shammo consults for Apellis Pharmaceuticals.

Paroxysmal nocturnal hemoglobinuria: role of the complement system, pathogenesis, and pathophysiology.

The complement system is part of the innate immune response system, which comprises more than 50 distinct plasma and serum proteins that interact to opsonize pathogens (i.e., mark pathogens for destruction) and induce inflammatory responses to fight infection. The role of the complement system is 2-fold: immune surveillance and host defense. Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, chronic, acquired, hematologic disease caused by somatic mutations in the gene PIGA in the hematopoietic stem cells. These stem cells produce abnormal clone blood cells that lack the complement regulatory proteins CD55 and CD59, causing the body to recognize these otherwise healthy red blood cells as damaged. The complement system destroys cells without these protective proteins, resulting in general hemolysis. PNH is characterized by fatigue; hemolytic anemia that can be severe and debilitating; increased lactic dehydrogenase level, reticulocyte count, and bilirubin level; propensity for thrombotic events; and renal dysfunction. Epidemiologic data, while sparse, suggest that an estimated 5,000-6,000 individuals in the United States are affected by PNH. If left untreated, PNH has a 10-year mortality rate of 29%, although the natural history of this disease has been recently altered by the introduction of complement inhibitors for the treatment of PNH. DISCLOSURES: This research was developed under a research contract between RTI Health Solutions and Apellis Pharmaceuticals and was funded by Apellis Pharmaceuticals. Bektas, Copley-Merriman, and Khan are employees of RTI Health Solutions. Sarda is an employee of Apellis Pharmaceuticals. Shammo consults for Apellis Pharmaceuticals.

Paroxysmal nocturnal hemoglobinuria: current treatments and unmet needs.

The current standard of care for paroxysmal nocturnal hemoglobinuria (PNH) are the C5 inhibitors eculizumab and ravulizumab, both monoclonal antibodies designed to target the complement protein C5, thereby preventing its cleavage and the formation of the terminal attack complex. C5 inhibitors have yielded substantial improvements in the treatment of PNH and changed the mortality and morbidity, as well as health-related quality of life of patients with the disease. These treatments target underlying intravascular hemolysis; however, they do not address extravascular hemolysis, resulting in incomplete response and remaining symptoms in some patients. Therefore, despite treatment with a C5 inhibitor, some patients still experience anemia with associated fatigue, transfusion needs, and impaired health-related quality of life. DISCLOSURES: This research was developed under a research contract between RTI Health Solutions and Apellis Pharmaceuticals and was funded by Apellis Pharmaceuticals. Bektas, Copley-Merriman, and Khan are employees of RTI Health Solutions. Sarda is an employee of Apellis Pharmaceuticals. Shammo consults for Apellis Pharmaceuticals.

Survival advantage of initiating dialysis in elderly and non-elderly incident end-stage kidney disease patients.

AIM: Many patients, especially the elderly, who require renal replacement therapies (RRT) have delayed or rejected dialysis for various reasons. Current dialysis guidelines may not be relevant for the elderly or frail patients. We aim to determine survival advantage of initiating dialysis in patients deemed to require RRT. METHODS: This was an observational cohort on incident end-stage kidney disease (ESKD) patients from January 1, 2007 to December 31, 2008. The primary outcome was all-cause mortality. Patients contributed person-time from the date of ESKD diagnosis until death, transplant or end of study on December 31, 2014, whichever occurred first. An extended Cox regression model with time-varying exposure to dialysis was used to account for immortal time bias. RESULTS: Of 3990 incident ESKD patients included, 70.2% patients initiated dialysis; 78.8% with haemodialysis (HD) while the remaining 21.2% with peritoneal dialysis (PD). Dialysis reduced hazard of death in both elderly and non-elderly patients even after controlling for comorbidities (hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.50, 0.68 and HR 0.76, 95% CI 0.69, 0.85, respectively). HD was protective in both the elderly and non-elderly (HR 0.53, 95% CI 0.45, 0.63 and HR 0.71, 95% CI 0.64, 0.80, respectively). PD significantly reduced risk of death compared to no dialysis in the elderly but not in the non-elderly. CONCLUSION: Dialysis improved survival in all incident ESKD patients. The findings suggested a larger protection offered by HD. Although improvement in survival from initiating dialysis was large, its true benefit should take overall quality of life into account. SUMMARY AT A GLANCE This observational study showed that initiation of dialysis improves the survival of end-stage kidney disease (ESKD) patients of all age groups, but the quality of life is an important aspect that has not been explored.

Cost utility analysis of end stage renal disease treatment in Ministry of Health dialysis centres, Malaysia: Hemodialysis versus continuous ambulatory peritoneal dialysis.

OBJECTIVES: In Malaysia, there is exponential growth of patients on dialysis. Dialysis treatment consumes a considerable portion of healthcare expenditure. Comparative assessment of their cost effectiveness can assist in providing a rational basis for preference of dialysis modalities. METHODS: A cost utility study of hemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD) was conducted from a Ministry of Health (MOH) perspective. A Markov model was also developed to investigate the cost effectiveness of increasing uptake of incident CAPD to 55% and 60% versus current practice of 40% CAPD in a five-year temporal horizon. A scenario with 30% CAPD was also measured. The costs and utilities were sourced from published data which were collected as part of this study. The transitional probabilities and survival estimates were obtained from the Malaysia Dialysis and Transplant Registry (MDTR). The outcome measures were cost per life year (LY), cost per quality adjusted LY (QALY) and incremental cost effectiveness ratio (ICER) for the Markov model. Sensitivity analyses were performed. RESULTS: LYs saved for HD was 4.15 years and 3.70 years for CAPD. QALYs saved for HD was 3.544 years and 3.348 for CAPD. Cost per LY saved was RM39,791 for HD and RM37,576 for CAPD. The cost per QALY gained was RM46,595 for HD and RM41,527 for CAPD. The Markov model showed commencement of CAPD in 50% of ESRD patients as initial dialysis modality was very cost-effective versus current practice of 40% within MOH. Reduction in CAPD use was associated with higher costs and a small devaluation in QALYs. CONCLUSIONS: These findings suggest provision of both modalities is fiscally feasible; increasing CAPD as initial dialysis modality would be more cost-effective.

Health related quality of life of dialysis patients in Malaysia: Haemodialysis versus continuous ambulatory peritoneal dialysis.

BACKGROUND: Health related quality of life (HRQOL) is an important predictor of clinical outcomes for End Stage Renal Disease (ESRD) patients and to establish quality adjusted life years (QALYs) for economic evaluation studies. This study aims to measure the health utilities and to identify socio-demographic and clinical factors associated with HRQOL for haemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD) in Malaysia. METHODS: A total of 141 patients (77 HD and 64 CAPD) from 1 federal and four state hospitals participated in this cross-sectional study. Patients were randomly selected from the National Renal Registry (NRR) using a stratified random sampling. The EQ-5D-3 L questionnaire was used to measure HRQOL. Variables investigated include dialysis modalities, sociodemographic characteristics, co-morbidities and biochemical markers. Utilities are measured on an ordinal scale of 0-1, where 1 indicates full health and 0 indicates death. RESULTS: The mean utility scores were 0.854 ± 0.181 and 0.905 ± 0.124 (p > 0.05) and the mean Visual Analogue Scale (VAS) scores were 76.2 ± 12.90 and 77.1 ± 10.26 (p > 0.05) for HD and CAPD patients respectively. There was a significant difference in problems reported between HD (35.1%) and CAPD (15.6%) on usual activities dimension (p = 0.009). The proportion of patients having problems in the pain/discomfort domain in both modalities was high (34.0%). Haemoglobin (< 10 g/dL) (p = 0.003), number of co-morbidities ≥3 (p = 0.004) and wheelchair-bound status (p < 0.001) were significant predictors of poor HRQOL. CONCLUSIONS: The present cross-sectional study shows that CAPD patients have a higher utility index score than HD patients but this was not statistically significant. The utilities index score may be used to calculate QALYs.

Real-world evidence on adherence, persistence, switching and dose escalation with biologics in adult inflammatory bowel disease in the United States: A systematic review.

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.

A Simple Cloning-free Method to Efficiently Induce Gene Expression Using CRISPR/Cas9.

Gain-of-function studies often require the tedious cloning of transgene cDNA into vectors for overexpression beyond the physiological expression levels. The rapid development of CRISPR/Cas technology presents promising opportunities to address these issues. Here, we report a simple, cloning-free method to induce gene expression at an endogenous locus using CRISPR/Cas9 activators. Our strategy utilizes synthesized sgRNA expression cassettes to direct a nuclease-null Cas9 complex fused with transcriptional activators (VP64, p65, and Rta) for site-specific induction of endogenous genes. This strategy allows rapid initiation of gain-of-function studies in the same day. Using this approach, we tested two CRISPR activation systems, dSpCas9VPR and dSaCas9VPR, for induction of multiple genes in human and rat cells. Our results showed that both CRISPR activators allow efficient induction of six different neural development genes (CRX, RORB, RAX, OTX2, ASCL1, and NEUROD1) in human cells, whereas the rat cells exhibit more variable and less-efficient levels of gene induction, as observed in three different genes (Ascl1, Neurod1, Nrl). Altogether, this study provides a simple method to efficiently activate endogenous gene expression using CRISPR/Cas9 activators, which can be applied as a rapid workflow to initiate gain-of-function studies for a range of molecular- and cell-biology disciplines.

3D organoid-derived human glomeruli for personalised podocyte disease modelling and drug screening.

The podocytes within the glomeruli of the kidney maintain the filtration barrier by forming interdigitating foot processes with intervening slit diaphragms, disruption in which results in proteinuria. Studies into human podocytopathies to date have employed primary or immortalised podocyte cell lines cultured in 2D. Here we compare 3D human glomeruli sieved from induced pluripotent stem cell-derived kidney organoids with conditionally immortalised human podocyte cell lines, revealing improved podocyte-specific gene expression, maintenance in vitro of polarised protein localisation and an improved glomerular basement membrane matrisome compared to 2D cultures. Organoid-derived glomeruli retain marker expression in culture for 96 h, proving amenable to toxicity screening. In addition, 3D organoid glomeruli from a congenital nephrotic syndrome patient with compound heterozygous NPHS1 mutations reveal reduced protein levels of both NEPHRIN and PODOCIN. Hence, human iPSC-derived organoid glomeruli represent an accessible approach to the in vitro modelling of human podocytopathies and screening for podocyte toxicity.

Burden and outcomes for complex perianal fistulas in Crohn's disease: Systematic review.

AIM: To systematically review the literature on epidemiology, disease burden, and treatment outcomes for Crohn's disease (CD) patients with complex perianal fistulas. METHODS: PubMed, Embase, and Cochrane were searched for relevant articles (published 2000-November 2016) and congress abstracts (published 2011-November 2016). RESULTS: Of 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. CONCLUSION: Complex 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.

Nicotine preloading for smoking cessation: the Preloading RCT.

BACKGROUND: Nicotine preloading means using nicotine replacement therapy prior to a quit date while smoking normally. The aim is to reduce the drive to smoke, thereby reducing cravings for smoking after quit day, which are the main cause of early relapse. A prior systematic review showed inconclusive and heterogeneous evidence that preloading was effective and little evidence of the mechanism of action, with no cost-effectiveness data. OBJECTIVES: To assess (1) the effectiveness, safety and tolerability of nicotine preloading in a routine NHS setting relative to usual care, (2) the mechanisms of the action of preloading and (3) the cost-effectiveness of preloading. DESIGN: Open-label randomised controlled trial with examination of mediation and a cost-effectiveness analysis. SETTING: NHS smoking cessation clinics. PARTICIPANTS: People seeking help to stop smoking. INTERVENTIONS: Nicotine preloading comprised wearing a 21 mg/24 hour nicotine patch for 4 weeks prior to quit date. In addition, minimal behavioural support was provided to explain the intervention rationale and to support adherence. In the comparator group, participants received equivalent behavioural support. Randomisation was stratified by centre and concealed from investigators. MAIN OUTCOME MEASURES: The primary outcome was 6-month prolonged abstinence assessed using the Russell Standard. The secondary outcomes were 4-week and 12-month abstinence. Adverse events (AEs) were assessed from baseline to 1 week after quit day. In a planned analysis, we adjusted for the use of varenicline (Champix®; Pfizer Inc., New York, NY, USA) as post-cessation medication. Cost-effectiveness analysis took a health-service perspective. The within-trial analysis assessed health-service costs during the 13 months of trial enrolment relative to the previous 6 months comparing trial arms. The base case was based on multiple imputation for missing cost data. We modelled long-term health outcomes of smoking-related diseases using the European-study on Quantifying Utility of Investment in Protection from Tobacco (EQUIPT) model. RESULTS: In total, 1792 people were eligible and were enrolled in the study, with 893 randomised to the control group and 899 randomised to the intervention group. In the intervention group, 49 (5.5%) people discontinued preloading prematurely and most others used it daily. The primary outcome, biochemically validated 6-month abstinence, was achieved by 157 (17.5%) people in the intervention group and 129 (14.4%) people in the control group, a difference of 3.02 percentage points [95% confidence interval (CI) -0.37 to 6.41 percentage points; odds ratio (OR) 1.25, 95% CI 0.97 to 1.62; p = 0.081]. Adjusted for use of post-quit day varenicline, the OR was 1.34 (95% CI 1.03 to 1.73; p = 0.028). Secondary abstinence outcomes were similar. The OR for the occurrence of serious AEs was 1.12 (95% CI 0.42 to 3.03). Moderate-severity nausea occurred in an additional 4% of the preloading group compared with the control group. There was evidence that reduced urges to smoke and reduced smoke inhalation mediated the effect of preloading on abstinence. The incremental cost-effectiveness ratio at the 6-month follow-up for preloading relative to control was £710 (95% CI -£13,674 to £23,205), but preloading was dominant at 12 months and in the long term, with an 80% probability that it is cost saving. LIMITATIONS: The open-label design could partially account for the mediation results. Outcome assessment could not be blinded but was biochemically verified. CONCLUSIONS: Use of nicotine-patch preloading for 4 weeks prior to attempting to stop smoking can increase the proportion of people who stop successfully, but its benefit is undermined because it reduces the use of varenicline after preloading. If this latter effect could be overcome, then nicotine preloading appears to improve health and reduce health-service costs in the long term. Future work should determine how to ensure that people using nicotine preloading opt to use varenicline as cessation medication. TRIAL REGISTRATION: Current Controlled Trials ISRCTN33031001. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 41. See the NIHR Journals Library website for further project information.

Generation of a human induced pluripotent stem cell line CERAi001-A-6 using episomal vectors.

We report the generation of the hiPSC line CERAi001-A-6 from primary human dermal fibroblasts. Reprogramming was performed using episomal vector delivery of OCT4, SOX2, KLF4, L-MYC, LIN28 and shRNA for p53.

Patient-completed or symptom-based screening tools for endometriosis: a scoping review.

PURPOSE: The objective of this review was to evaluate existing patient-completed screening questionnaires and/or symptom-based predictive models with respect to their potential for use as screening tools for endometriosis in adult women. Validated instruments were of particular interest. METHODS: We conducted structured searches of PubMed and targeted searches of the gray literature to identify studies reporting on screening instruments used in endometriosis. Studies were screened according to inclusion and exclusion criteria that followed the PICOS (population, intervention, comparison, outcomes, study design) framework. RESULTS: A total of 16 studies were identified, of which 10 described measures for endometriosis in general, 2 described measures for endometriosis at specific sites, and 4 described measures for deep-infiltrating endometriosis. Only 1 study evaluated a questionnaire that was solely patient-completed. Most measures required physician, imaging, or laboratory assessments in addition to patient-completed questionnaires, and several measures relied on complex scoring. Validation for use as a screening tool in adult women with potential endometriosis was lacking in all studies, as most studies focused on diagnosis versus screening. CONCLUSIONS: This literature review did not identify any fully validated, symptom-based, patient-reported questionnaires for endometriosis screening in adult women.

Mitochondrial replacement in an iPSC model of Leber's hereditary optic neuropathy.

Cybrid technology was used to replace Leber hereditary optic neuropathy (LHON) causing mitochondrial DNA (mtDNA) mutations from patient-specific fibroblasts with wildtype mtDNA, and mutation-free induced pluripotent stem cells (iPSCs) were generated subsequently. Retinal ganglion cell (RGC) differentiation demonstrates increased cell death in LHON-RGCs and can be rescued in cybrid corrected RGCs.