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Background and Aims Scepticism about the efficacy of thiopurines for ulcerative colitis [UC] is rising. This study aimed to evaluate mercaptopurine treatment for UC. Methods In this prospective, randomized, double-blind, placebo-controlled trial, patients with active UC, despite treatment with 5-aminosalicylates [5-ASA], were randomized for therapeutic drug monitoring [TDM]-guided mercaptopurine treatment or placebo for 52 weeks. Corticosteroids were given in the first 8 weeks and 5-ASA was continued. Proactive metabolite-based mercaptopurine and placebo dose adjustments were applied from week 6 onwards by unblinded clinicians. The primary endpoint was corticosteroid-free clinical remission and endoscopic improvement [total Mayo score ≤2 points and no item >1] at week 52 in an intention-to-treat analysis. Results Between December 2016 and April 2021, 70 patients were screened and 59 were randomized at six centres. In the mercaptopurine group, 16/29 [55.2%] patients completed the 52-week study, compared to 13/30 [43.3%] on placebo. The primary endpoint was achieved by 14/29 [48.3%] patients on mercaptopurine and 3/30 [10%] receiving placebo (Δ = 38.3%, 95% confidence interval [CI] 17.1–59.4, p = 0.002). Adverse events occurred more frequently with mercaptopurine [808.8 per 100 patient-years] compared to placebo [501.4 per 100 patient-years]. Five serious adverse events occurred, four on mercaptopurine and one on placebo. TDM-based dose adjustments were executed in 22/29 [75.9%] patients, leading to lower mercaptopurine doses at week 52 compared to baseline. Conclusions Optimized mercaptopurine treatment was superior to placebo in achieving clinical, endoscopic and histological outcomes at 1 year following corticosteroid induction treatment in UC patients. More adverse events occurred in the mercaptopurine group.

A considerable proportion of Crohn's disease patients that undergo ileocecal resection (ICR) have failed anti-tumor necrosis factor (TNF) therapy preoperatively. This study aimed to assess the effectiveness of retreatment of anti-TNF therapy in patients with postoperative recurrence.A real-world cohort study was performed on Crohn's disease patients who underwent primary ICR after anti-TNF therapy failure, and who were retreated with anti-TNF therapy for postoperative symptomatic Crohn's disease. The primary outcome was treatment failure (the need for (re)introduction of corticosteroids, immunosuppressants, or biologicals or the need for re-resection). Sub-analyses were performed on the nature of preoperative anti-TNF failure (primary non-response, secondary loss of response, intolerance), indication for ICR (refractory, stricturing, penetrating disease), combination therapy with immunomodulators, retreatment with the same anti-TNF agent and preoperative exposure to 1 vs.1 anti-TNF agents.In total, 66 of 364 patients retreated with anti-TNF therapy following ICR. Cumulative rates of treatment failure at 1 and 2 years were 28% and 47%. Treatment failure rate at 2 years was significantly lower in patients receiving combination therapy as compared to anti-TNF monotherapy (30% vs. 49%, P = 0.02). No difference in treatment failure was found with regards to the nature of preoperative anti-TNF failure (P = 0.76), indication for ICR (P = 0.88) switch of anti-TNF agent (P = 0.55) agent, and preoperative exposure to 1 vs.1 anti-TNF agents (P = 0.88).Retreatment with anti-TNF therapy for postoperative Crohn's disease recurrence is a valid strategy after preoperative failure. Combination therapy is associated with a lower rate of treatment failure.

There is a growing body of research on the interplay between increasingly digitally informed political campaigning and citizen engagement in the political sphere both on and offline. While much of the existing scholarship concerns how digital technology impacts engagement, participation and the spread of information, there is limited research into the ways in which specific digital content modes and social media platforms intersect in ways that can lead to increased involvement of individuals in high-effort political activities. This research paper focuses on the personal action framing of campaign videos created in support of the Labour Party’s general election campaign in 2017. Videos created by both the central campaign and the grassroots political organization Momentum were designed to be shared widely over social media platforms to achieve visibility over a broad network of supporters and undecided voters over the course of the campaign. By analyzing the content of these videos, I will show how specific instances of digital media, such as videos, can invite instances of high-effort political participation through personalized political action framing. Drawing on connective action theory, and in particular, the discussion of personalized politics (Bennett, 2012; Bennett & Segerberg, 2013), this research uses thematic content analysis to identify which high-effort political activities are alluded to most often in the video content. By comparing the videos produced by Labour with those of Momentum, this contribution addresses a gap in the existing literature as it relates to how campaigns can benefit from loosely connected ties to organizations that use digital media to expend their networks of influence to develop their strategic capacity. The methods explored in this research can inform future study on the use of campaign videos in political movement building and election campaigns.

A sizable portion of youth (ages 13–24) living with HIV in the United States have unsuppressed viral load. The AIDS Interventions (ATN) 152 study [evaluating the Triggered Escalating Real-Time Adherence (TERA) intervention] baseline data were examined to identify correlates of high viremia (>5000 copies/mL) and self-reported adherence, which can help in planning of differentiated services for viremic youth. Depression, HIV-stigma, and cannabis use were common in this sample of 87 youth. Almost half (48%) had high viremia, which associated with enacted stigma, moderate- to high-risk alcohol use, mental health diagnosis, and age ≥21. Self-reported adherence was related to viral load and associated with mental and physical health functioning, depression, social support, self-confident decision-making, total and internalized stigma, adherence motivation, and report of a missed a care visit in the past 6 months. Mental health emerged as a common correlate of viral load and adherence. Clinical Trial Registration number: NCT03292432.

Single-cell RNA sequencing of cells from cultured human blastocysts has enabled us to define the transcriptomic landscape of placental trophoblast (TB) that surrounds the epiblast and associated embryonic tissues during the enigmatic day 8 (D8) to D12 peri-implantation period before the villous placenta forms. We analyzed the transcriptomes of 3 early placental cell types, cytoTB (CTB), syncytioTB (STB), and migratoryTB (MTB), picked manually from cultured embryos dissociated with trypsin and were able to follow sublineages that emerged from proliferating CTB at the periphery of the conceptus. A unique form of CTB with some features of STB was detectable at D8, while mature STB was at its zenith at D10. A form of MTB with a mixed MTB/CTB phenotype arose around D10. By D12, STB generation was in decline, CTB had entered a new phase of proliferation, and mature MTB cells had begun to move from the main body of the conceptus. Notably, the MTB transcriptome at D12 indicated enrichment of transcripts associated with IFN signaling, migration, and invasion and up-regulation of HLA-C, HLA-E, and HLA-G. The STB, which is distinct from the STB of later villous STB, had a phenotype consistent with intense protein export and placental hormone production, as well as migration and invasion. The studies show that TB associated with human embryos is in rapid developmental flux during peri-implantation period when it must invade, signal robustly to the mother to ensure that the pregnancy continues, and make first contact with the maternal immune system.

LIN28B is an RNA-binding protein necessary for maintaining pluripotency in stem cells and plays an important role in trophoblast cell differentiation. LIN28B action on target gene function often involves the Let-7 miRNA family. Previous work in cancer cells revealed that LIN28 through Let-7 miRNA regulates expression of androgen receptor (AR). Considering the similarities between cancer and trophoblast cells, we hypothesize that LIN28B also is necessary for the presence of AR in human trophoblast cells. The human first-trimester trophoblast cell line, ACH-3P was used to evaluate the regulation of AR by LIN28B, and a LIN28B knockdown cell line was constructed using lentiviral-based vectors. LIN28B knockdown in ACH-3P cells resulted in significantly decreased levels of AR and increased levels of Let-7 miRNAs. Moreover, treatment of ACH-3P cells with Let-7c mimic, but not Let-7e or Let-7f, resulted in a significant reduction in LIN28B and AR. Finally, forskolin-induced syncytialization and Let-7c treatment both resulted in increased expression of syncytiotrophoblast marker ERVW-1 and a significant decrease in AR in ACH-3P. These data reveal that LIN28B regulates AR levels in trophoblast cells likely through its inhibitory actions on let-7c, which may be necessary for trophoblast cell differentiation into the syncytiotrophoblast.

Serology (antibody) tests to detect previous SARS-CoV-2 infection have been in high demand from the beginning of the COVID-19 pandemic. The initial shortage of diagnostic tests coupled with asymptomatic infections led to a significant demand for serology tests to identify past infections., Serology (antibody) tests to detect previous SARS-CoV-2 infection have been in high demand from the beginning of the COVID-19 pandemic. The initial shortage of diagnostic tests coupled with asymptomatic infections led to a significant demand for serology tests to identify past infections. Despite serious limitations on the interpretation of a positive antibody test in terms of immunity to SARS-CoV-2, antibody testing was initially considered for release from social distancing, return to employment, and “immunity passports.” The regulatory approach to antibody tests was limited; manufacturers were encouraged to develop and market antibody tests without submitting validation data to the FDA. FDA guidance grew more stringent, but many poor-quality tests were already on the market—potentially inappropriately used for individual decision-making. This is a case study describing COVID-19 serology tests and the U.S. market and describes lessons learned for a future health security crisis.

It is very difficult to gain a better understanding of the events in human pregnancy that occur during and just after implantation because such pregnancies are not yet clinically detectable. Animal models of human placentation are inadequate. In vitro models that utilize immortalized cell lines and cells derived from trophoblast cancers have multiple limitations. Primary cell and tissue cultures often have limited lifespans and cannot be obtained from the peri-implantation period. We present here two contemporary models of human peri-implantation placental development: extended blastocyst culture and stem-cell derived trophoblast culture. We discuss current research efforts that employ these models and how such models might be used in the future to study the “black box” stage of human pregnancy.

Research Question: In the early stages of the COVID-19 pandemic, IVF clinics stopped the majority of patient treatment cycles to minimize the risk of disease transmission. The risk of SARS-CoV-2 viral exposure and potential cross contamination within the IVF lab remains largely unclear. To that end, the objective of this study was to examine follicular fluid (FF), culture media (M) and vitrification solution (VS) for SARS-CoV-2 in an IVF lab. Design: Prospective clinical study. All females undergoing transvaginal oocyte retrieval (TVOR) were required to have a negative SARS-CoV-2 RNA test 3-4 days prior to the procedure. Male partners were not tested. All cases utilized intracytoplasmic sperm injection (ICSI). The first tube of FF aspirated during oocyte retrieval, M drops following removal of embryos on day 5, and VS after blastocyst cryopreservation were analyzed for SARS-CoV-2 RNA. Results: In total, M from 61 patients, VS from 200 patients, and FF from 300 patients were analyzed. All samples were negative for SARS-CoV-2 viral RNA. Conclusion(s): With stringent safety protocols in place, including female patient testing and symptom-based screening of men, the presence of SARS-CoV-2 RNA was not detected in FF, M or VS. This work demonstrates the possibility of implementing a rapid laboratory screening assay for SARS-CoV-2 and has implications for safe laboratory operations, including cryostorage recommendations.

Antibody tests for detecting past infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have many uses for public health decision making, but demand has largely come from individual consumers. This review focuses on the individual relevance of antibody tests: their accuracy in detecting prior infection, what past SARS-CoV-2 infection can currently infer about future immunity or possible medical sequelae, and the potential future importance of antibody tests for vaccine selection and medical screening. Given uncertainty about the antibody tests (quality, accuracy level, positive predictive value) and what those tests might indicate immunologically (durability of antibodies and necessity for protection from reinfection), seropositive test results should not be used to inform individual decision making, and antibody testing should remain a tool of public health at this time., Highlights There is high consumer demand for antibody tests to detect past infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but there is a great deal of uncertainty about what a positive test means immunologically. Uneven test accuracy and statistical challenges, especially in areas of low disease prevalence, further complicate use of antibody tests for individual decision making. Antibody tests are important for convalescent plasma donation and may have future utility to identify coronavirus disease 2019 medical sequelae and for vaccine selection and prioritization. At the population level, tests are needed to support serosurveillance studies, to determine the case fatality rate, and to track increases or decreases in incidence and prevalence, but currently they are of limited utility for individuals.

Background It is unclear whether newborns with mild thyrotropin elevation (mTSHe) are at risk of neurocognitive impairment. We assessed whether mTSHe at birth persists during childhood and compared neurocognitive functioning to siblings. Methods This study encompassed children born in the Auckland region (New Zealand) with a newborn screen TSH level of 8 to 14 mIU/L blood, age 6.9 to 12.6 years at assessment, and their siblings. Thyroid function tests (serum TSH and free thyroxine) and neurocognitive assessments were performed, including IQ via the Wechsler Intelligence Scale for Children, fourth edition. Results Ninety-six mTSHe individuals were studied, including 67 children recruited with 75 sibling controls. Mean mTSHe newborn TSH level was 10.1 mIU/L blood and 2.4 mIU/L at assessment (range, 0.8-7.0 mIU/L, serum). Although higher newborn TSH levels in the mTSHe group correlated with lower full-scale IQ scores (r = 0.25; P = .040), they were not associated with the magnitude of the IQ difference within sibling pairs (P = .56). Cognitive scores were similar for mTSHe and controls (full-scale IQ 107 vs 109; P = .36), with a minor isolated difference in motor coordination scores. Conclusions Our data do not suggest long-term negative effects of neonatal mild TSH elevation. TSH elevation below the screen threshold appears largely transient, and midchildhood neurocognitive performance of these children was similar to their siblings. We propose that associations between neonatal mild TSH elevation and IQ are due to familial confounders. We caution against the practice of reducing screening CH cutoffs to levels at which the diagnosis may not offer long-term benefit for those detected.

IntroductionRespiratory pathogens associated with childhood pneumonia are often detected in the upper respiratory tract of healthy children, making their contribution to pneumonia difficult to determine. We aimed to determine the contribution of common pathogens to pneumonia adjusting for rates of asymptomatic detection to inform future diagnosis, treatment and preventive strategies.MethodsA case–control study was conducted among children ResultsFrom May 2015 to October 2017, 230 cases and 230 controls were enrolled. At least one respiratory virus was identified in 57% of cases and 29% of controls (aOR: 4.7; 95% CI: 2.8 to 7.8). At least one bacterial species was detected in 72% of cases and 80% of controls (aOR: 0.7; 95% CI: 0.4 to 1.2). Respiratory syncytial virus (RSV) detection was most strongly associated with pneumonia (aOR: 58.4; 95% CI: 15.6 to 217.5). Mycoplasma pneumoniae was the only bacteria associated with pneumonia (aOR: 14.5; 95% CI: 2.2 to 94.8). We estimated that RSV, human metapneumovirus (HMPV), influenza, adenovirus and Mycoplasma pneumoniae were responsible for 20.2% (95% CI: 14.6 to 25.5), 9.8% (5.6% to 13.7%), 6.2% (2.5% to 9.7%), 4% (1.1% to 7.1%) and 7.2% (3.5% to 10.8%) of hospitalisations for childhood pneumonia, respectively.ConclusionsRespiratory viruses, particularly RSV and HMPV, are major contributors to pneumonia in Australian children.

The chromatin associated transcription factor HMGA2 is a downstream target of let-7 miRNAs and binds to chromatin to regulate gene expression. Inhibition of let-7 miRNAs by RNA-binding proteins LIN28A and LIN28B is necessary during early embryogenesis to ensure stable expression of HMGA2. In addition to LIN28, HMGA2 is regulated by a BRCA1/ZNF350/CtIP repressor complex. In normal tissues, the BRCA1/ZNF350/CtIP complex binds to the HMGA2 promoter to prevent transcription. However, in many cancers the oncomiR miR-182 targets BRCA1, preventing BRCA1 translation and allowing for increased HMGA2. Little is known about the regulation of HMGA2 during early placental development; therefore, we hypothesized that both LIN28 and BRCA1 can regulate HMGA2 in placental cells. Using siRNA and CRISPR gene editing techniques, we found that knockdowns of both LIN28A and LIN28B increase HMGA2 levels in ACH-3P cells. These cells also demonstrated deficiencies in cell differentiation, seemingly differentiating solely towards the syncytiotrophoblast sublineage, secreting higher amounts of hCG, and displaying upregulated ERVW-1. Additionally, we found that a knockout of both LIN28A and LIN28B caused a significant increase of miR-182 and a decrease in BRCA1 allowing HMGA2 mRNA levels to increase and protein levels to remain the same. Using chromatin immunoprecipitation, we saw binding of the BRCA1 repressor complex to HMGA2. We also saw a decrease in binding to HMGA2's promoter in the LIN28A/B knockout cells. These findings suggest a novel role for BRCA1 during early human placental development.

Background With increasing incidence of Inflammatory Bowel Disease (IBD) in developing countries and increasing prescription rates for biologics globally, knowledge on the cost burden of IBD and cost drivers is essential for health policy makers worldwide. We conducted a systematic review to determine cost-of-illness of IBD and assess time trends and geographical differences. Methods A systematic review of population-based studies that estimated cost-of-illness of IBD and were published in Embase, Medline, Web of Science and Google Scholar. Studies on interventions and those reporting costs for a subset of patients defined by phenotype or treatment were excluded, as these do not give a representative estimate of the cost-of-illness of IBD. Only studies published in English were included. Methodology of all included studies was assessed and costs were adjusted to 2018 US dollars. Results In total, 4,837 unique studies were screened on title and abstract and 4,730 excluded. After full-text screening, 64 of the remaining 107 studies were included in the systematic review. The study methodologies differed considerably, with large differences in perspective, valuation method and source population. Mean annual healthcare costs for prevalent Crohn′s disease (CD) cases in the last 10 years were in Asia $4,463; Europe $12,396 and North America $17,508. Costs for prevalent ulcerative colitis (UC) patients in the same period were $1,654, $7,206 and $13,569 respectively. For CD, the cost drivers moved from inpatient (61% of total costs) in 1995 to medication costs (77%) in 2016. Similar trends were identified for UC (1998: 50% and 36% versus 2016: 9%, and 82% for inpatient and medication costs, respectively). This cost trend is primarily attributable to an increase in medication costs in all four geographical areas, while in- and outpatient costs were relatively stable during the same time period. The annual costs of absenteeism and presenteeism per prevalent case of CD were $5,638 in Asia and $6,485 in Europe. For UC these costs were $4,828 and $6,414 respectively. Annual costs of absenteeism and presenteeism in North America were $20,074 per patient for a combined cohort of UC and CD patients. Conclusion Per patient costs for IBD are increasing worldwide, with highest costs in North America and lowest in Asia. This is primarily due to an increase in medication costs. Productivity costs are substantial and might even exceed healthcare costs. Biologic therapy was expected to decrease inpatient costs by reducing hospitalisations and surgery, but this does not appear to be the case. Continuing growth of these costs can lead to an intolerable burden on healthcare systems worldwide.

Background Randomised controlled trials have reported improvement of work productivity and activity impairment (WPAI) as well as quality of life in biological-treated inflammatory bowel disease (IBD) patients. However, data beyond clinical trials are limited. Methods This multicentre prospective cohort study evaluated the effect of initiating biological or small molecule therapy on work impairment in IBD patients. Subjects completed the WPAI questionnaire and Short IBD questionnaire (SIBDQ) at biological therapy initiation and at week 26. Clinical disease activity was assessed using the Harvey Bradshaw Index and Simple Clinical Colitis Activity Index. Biochemical disease activity was assessed using C-reactive protein and faecal calprotectin. Data are presented as mean ± standard deviation. Results In total, 156 IBD patients were included for analysis (median age 40 years, 55% male, 55% Crohn’s disease). Of these patients, 28% started infliximab, 33% adalimumab, 19% vedolizumab, 18% ustekinumab, 1% tofacitinib and 1% golimumab. Concomitant medication use at baseline included 28% prednisone, 12% budesonide, 34% mesalamine, and 46% immunomodulator. At baseline, 58% had clinical disease activity and 58% had biochemical disease activity. In our cohort, 111 (71%) were employed and 17 (11%) patients reported partial or full occupational disability. The mean total work impairment at baseline was 52% ± 36%. During follow-up, 7 patients lost their job and 8 patients started employment. For the entire cohort, improvements in all WPAI domains were observed: mean 11%-points decrease in missed working hours, 4%-points decrease in impairment while working, 15%-points decrease in total work impairment and 15%-points decrease in total activity impairment. Parallel improvements were seen in SIBDQ scores (mean improvement 7.6 ± 11.3). At week 26, 66 (42%) patients achieved the minimal clinical important difference in total work impairment (improvement ≥7%-points). Patients with clinical disease activity at baseline and clinical response to the biological (n=32) showed a larger improvement in total work impairment compared with other subjects (n=86) (mean difference 29%-points versus 10%-points; p=0.036 (T-test)). Similarly, these patients showed greater improvement in SIBDQ scores compared to other subjects (mean 13.8 versus 5.4, respectively; p Conclusion IBD patients experienced substantial work impairment prior to initiating biological treatment. Improved work impairment scores were seen after initiation of biological therapy and patients with clinical response showed even greater improvements. These results underline the importance of IBD disease control to improve work productivity and participation.

Background Ustekinumab is a monoclonal antibody that selectively targets p40, a shared subunit of the cytokines interleukin (IL)-12 and IL-23. It is registered for the treatment of Crohn’s disease (CD) and ulcerative colitis. We assessed the two-year efficacy and safety of ustekinumab in a real world, prospective cohort of CD patients. Methods CD patients who started ustekinumab in regular care were prospectively enrolled in the nationwide Initiative on Crohn and Colitis Registry. At week 0, 12, 24, 52 and 104, clinical remission (HBI ≤ 4 points), biochemical remission (fecal calprotectin (FC) ≤200 μg/g and/or CRP ≤5 mg/L), peri-anal fistula remission, extra-intestinal manifestations, ustekinumab dosage and safety outcomes were determined. Patients starting therapy less than two years ago were excluded for the current evaluation. The primary outcome was corticosteroid-free clinical remission at week 104. Results In total, 252 CD patient with at least two years of follow up were included. Of all included patients, the proportion of patients in corticosteroid-free clinical remission at week 12, 24, 52 and 104 was 32.3% (81/251), 41.4% (104/251), 39% (97/249) and 34.0% (84/247), respectively. Of the 97 patients in corticosteroid free clinical remission at week 52, 58 (59.8%) were still in corticosteroid-free clinical remission at week 104. In patients with combined clinical and biochemical disease activity at baseline (n=122), the corticosteroid-free clinical remission rates were 23.8% (29/122), 35.2% (43/122), 40.0% (48/120) and 32.8% (39/119) at week 12, 24, 52 and 104, respectively. The probability of remaining on ustekinumab treatment after 52 and 104 weeks was 64.3% and 54.8%, respectively. There were no predictive factors associated with corticosteroid-free clinical remission at week 104 on univariate and multivariate analysis. Most common adverse events were headache, skin reaction and musculoskeletal complaints. Two patients stopped ustekinumab due to an infection after 8 and 30 weeks of treatment (mild fever syndrome and moderate upper airway infection, respectively). The main reason for discontinuing treatment after 52 weeks was loss of response (66.7%). Conclusion Ustekinumab was effective and relatively safe in our real world, prospective cohort of CD patients. After 104 weeks of ustekinumab treatment, one third of patients were in corticosteroid-free clinical remission.

Background Prehabilitation strategies to improve the postoperative course after intestinal resections in Crohn’s disease (CD) are mostly non-evidence-based. Prehabilitation strategies may include preoperative nutritional, physical and psychological management and optimization of medical treatment prior to surgery. In this study, we explore whether and to what extent prehabilitation strategies are currently used in a real-world prospective cohort. Methods In this multicenter prospective cohort study, data were collected in three secondary and two tertiary Dutch hospitals. CD patients (pts) aged ≥ 18 years who underwent ileocecal or ileocolonic (re)resection were included between November 2017 and January 2021. Data were collected on disease severity, IBD medication at time of surgery, preoperative BMI, weight loss within a year prior to resection, assessment of sarcopenia and hand grip strength (HGS), laboratory assessment, including albumin and micronutrients, and preoperative visits to a dietician, physiotherapist and psychologist. In addition, the 30-day postoperative complication rate was recorded. Results To date, 90 pts were included (38% male, median age 35.6 years) (Table 1). The main indications for ileocolonic resection were stenosis (55 (61%)), therapy refractory inflammation (15 (17%)) and penetrating disease (14 (18.9%)). At time of surgery, 60 pts (67%) were on IBD medication (immunomodulator n=16; biological n=22; combination therapy n=11, corticosteroids n=19). Median preoperative BMI was 23.7 kg/m2 (IQR 20.9–27.2). Sarcopenia and HGS were not assessed. Preoperative weight within a year prior to resection was recorded in only 31/90 (34%) pts. During the preoperative period, 32/90 pts (36%) visited a dietician, of whom 25/32 (78%) received a nutritional intervention (enteral support 16 (64%), parenteral support 0, exclusive enteral nutrition (EEN) 7 (28%), total parenteral nutrition (TPN) 2 (8%)). 4/90 pts (4%) visited a physiotherapist and 6/90 (7%) a psychologist. Albumin was assessed in 52/90 (58%) pts (median 38 (IQR 32–45); ferritin, vitamin B12 and D in 9/90 (10%), 10/90 (11%), 6/90 (7%) patients. Postoperative complication occurred in 32/90 (36%) pts, most often infections (68%) (Table 2). Four pts underwent a re-intervention for abdominal infection (2/4), anastomotic leakage (1/4) or ileus (1/4). Five pts (16%) were readmitted for anastomotic leakage (2/5), ileus (1/5), abdominal pain (1/5) and infection (1/5). Conclusion Prehabilitation strategies are not routinely applied in CD patients scheduled for ileocolonic resection and, since postoperative complications occur in more than a third of patients, further research into the yield of implementing multimodal prehabilitation is indicated.

CRISPR, a powerful gene-editing technology, is revolutionizing the life sciences and medical research. The technology has also become democratized. Costs to use CRISPR are low and decreasing, kits are available to make the use of CRISPR straightforward, and there is a rapidly growing scientific literature describing CRISPR methodologies and novel applications. However, like other powerful advances in the life sciences, CRISPR raises biosecurity concerns: it could be misused for harm, and it lowers technical barriers to biological weapons development. This essay describes the history and dissemination of CRISPR as genome-editing techniques have become widespread, outlines potential biosecurity concerns, and recommends actions governments and scientists may take to reduce biosecurity risks. While it is not possible to eliminate biosecurity risks from the misuse of biotechnologies, including CRISPR, steps can be taken to increase security while allowing this powerful technology to remain widely available for beneficent purposes.

Since the inception of gene synthesis technologies, there have been concerns about possible misuse. Using gene synthesis, pathogens-particularly small viruses-may be assembled "from scratch" in the laboratory, evading the regulatory regimes many nations have in place to control unauthorized access to dangerous pathogens. Progress has been made to reduce these risks. In 2010, the US Department of Health and Human Services (HHS) published guidance for commercial gene synthesis providers that included sequence screening of the orders and customer screening. The industry-led International Gene Synthesis Consortium (IGSC) was formed in 2009 to share sequence and customer screening methods, and it now includes the major international gene synthesis providers among its members. Since the 2010 HHS Guidance was released, however, there have been changes in gene synthesis technologies and market conditions that have reduced the efficacy of these biosecurity protections, leading to questions about whether the 2010 HHS Guidance should be updated, what changes could make it more effective, and what other international governance efforts could be undertaken to reduce the risks of misuse of gene synthesis products. This article describes these conditions and recommends actions that governments should take to reduce these risks and engage other nations involved in gene synthesis research.

Background Differentiating bacterial from viral pneumonia is important for guiding targeted management and judicious use of antibiotics. We assessed if clinical characteristics and blood inflammatory biomarkers could be used to distinguish bacterial from viral pneumonia. Methods Western Australian children (≤17 years) hospitalized with radiologically-confirmed community-acquired pneumonia were recruited and clinical symptoms and management data were collected. C-reactive protein (CRP), white cell counts (WCC) and absolute neutrophil counts (ANC) were measured as part of routine care. Clinical characteristics and biomarker levels were compared between cases with definite bacterial pneumonia (clinical empyema and/or bacteria detected in blood or pleural fluid), presumed viral pneumonia (presence of ≥1 virus in nasopharyngeal swab without criteria for definite bacterial pneumonia), and other pneumonia cases (pneumonia in the absence of criteria for either definite bacterial or presumed viral pneumonia). The area-under-curve (AUC) of the receiver operating characteristic (ROC) curve for varying biomarker levels were used to characterise their utility for discriminating definite bacterial from presumed viral pneumonia. For biomarkers with AUC > 0.8 (fair discriminator), Youden index was measured to determine the optimal cut-off threshold, and sensitivity, specificity, predictive values (positive and negative) were calculated. We investigated whether better discrimination could be achieved by combining biomarker values with the presence/absence of symptoms. Results From May 2015 to October 2017, 230 pneumonia cases were enrolled: 30 with definite bacterial pneumonia, 118 with presumed viral pneumonia and 82 other pneumonia cases. Differences in clinical signs and symptoms across the groups were noted; more definite bacterial pneumonia cases required intravenous fluid and oxygen supplementation than presumed viral or other pneumonia cases. CRP, WCC and ANC were substantially higher in definite bacterial cases. For a CRP threshold of 72 mg/L, the AUC of ROC was 0.82 for discriminating definite bacterial pneumonia from presumed viral pneumonia. Combining the CRP with either the presence of fever (≥38οC) or the absence of rhinorrhea improved the discrimination. Conclusions Combining elevated CRP with the presence or absence of clinical signs/ symptoms differentiates definite bacterial from presumed viral pneumonia better than CRP alone. Further studies are required to explore combination of biomarkers and symptoms for use as definitive diagnostic tool. Electronic supplementary material The online version of this article (10.1186/s12890-019-0835-5) contains supplementary material, which is available to authorized users.

Background Chronic widespread pain (CWP) including fibromyalgia has a prevalence of up to 15% and is associated with substantial morbidity. Supporting psychosocial and behavioural self-management is increasingly important for CWP, as pharmacological interventions show limited benefit. We systematically reviewed the effectiveness of interventions applying self-management principles for CWP including fibromyalgia. Methods MEDLINE, Embase, PsycINFO, The Cochrane Central Register of Controlled Trials and the WHO International Clinical Trials Registry were searched for studies reporting randomised controlled trials of interventions adhering to self-management principles for CWP including fibromyalgia. Primary outcomes included physical function and pain intensity. Where data were sufficient, meta-analysis was conducted using a random effects model. Studies were narratively reviewed where meta-analysis could not be conducted Evidence quality was rated using GRADE (Grading of Recommendations, Assessment, Development and Evaluations) (PROSPERO-CRD42018099212). Results Thirty-nine completed studies were included. Despite some variability in studies narratively reviewed, in studies meta-analysed self-management interventions improved physical function in the short-term, post-treatment to 3 months (SMD 0.42, 95% CI 0.20, 0.64) and long-term, post 6 months (SMD 0.36, 95% CI 0.20, 0.53), compared to no treatment/usual care controls. Studies reporting on pain narratively had greater variability, however, those studies meta-analysed showed self-management interventions reduced pain in the short-term (SMD -0.49, 95% CI -0.70, -0.27) and long-term (SMD -0.38, 95% CI -0.58, -0.19) compared to no treatment/usual care. There were few differences in physical function and pain when self-management interventions were compared to active interventions. The quality of the evidence was rated as low. Conclusion Reviewed studies suggest self-management interventions can be effective in improving physical function and reducing pain in the short and long-term for CWP including fibromyalgia. However, the quality of evidence was low. Future research should address quality issues whilst making greater use of theory and patient involvement to understand reported variability.

Background There are limited data available on de-escalation of biological therapy after prior escalation in inflammatory bowel disease (IBD) patients. The aim of this study was to assess the frequency and success rate of de-escalation of biological therapy in IBD patients after prior dose escalation and evaluate which measures are used prior to de-escalation. Methods This multicentre, prospective, cohort study enrolled IBD patients treated with infliximab (IFX), adalimumab (ADA) or vedolizumab (VEDO) in whom therapy was de-escalated at least once after prior biological escalation. Objective disease measures for de-escalation were defined as faecal calprotectin ≤ 200 µg/g and/or therapeutic or supratherapeutic trough levels and/or radiologic or endoscopic remission. Successful de-escalation was defined as remaining on the same or lower biological dose for ≥6 months after de-escalation. Results In total, 206 IFX users, 85 ADA users and 55 VEDO users underwent therapy escalation. Of these, 34 (17%) patients on IFX, 18 (21%) patients on ADA and 8 (15%) patients on VEDO had received at least one subsequent de-escalation. De-escalation was successful in 91% of IFX patients, 89% of ADA patients and 100% of VEDO patients. The probability of remaining on the de-escalated regimen or further de-escalation after 1 year was 85% for IFX, 62% for ADA and 100% for VEDO. De-escalation based on objective disease measures was performed in 67% of all de-escalations. Objective de-escalations were successful in 98% versus 80% of subjective de-escalations. Conclusion De-escalation after biological escalation is successful in the majority of patients. Objective markers of remission increase the likelihood of successful de-escalation.

Malaria is a pervasive disease that affects millions of lives each year in equatorial regions of the world. During the erythrocytic phase of the parasite life cycle, Plasmodium falciparum invades red blood cells, where it catabolizes hemoglobin and sequesters the released toxic heme as innocuous hemozoin crystals. Artemisinin (ART)-class drugs are activated in vivo by newly released heme, which creates a carbon-centered radical that markedly reduces parasite density. Radical damage to parasite lipids and proteins is perceived to be ARTs’ dominant mechanism of action. By contrast, quinoline-class antimalarials inhibit the formation of hemozoin and in this way suppress heme detoxification. Here, we combine malaria parasite assays and scanning probe microscopy of growing β-hematin crystals to elucidate an unexpected mechanism employed by two widely administered antimalarials, ART, and artesunate to subdue the erythrocytic phase of the parasite life cycle. We demonstrate that heme–drug adducts, produced after the radical activation of ARTs and largely believed to be benign bystanders, potently kills P. falciparum at low exogenous concentrations. We show that these adducts inhibit β-hematin crystallization and heme detoxification, a pathway which complements the deleterious effect of radicals generated via parent drug activation. Our findings reveal an irreversible mechanism of heme–ART adduct inhibition of heme crystallization, unique among antimalarials and common crystal growth inhibitors, that opens new avenues for evaluating drug dosing regimens and understanding growing resistance of P. falciparum to ART.

Invitro culture (IVC) systems fail to completely recapitulate the invivo environment, resulting in metabolic stress during pre-implantation development and reduced blastocyst quality. We hypothesised that IVC-induced metabolic dysregulation in bovine embryos is mediated by changes in expression and/or activity of protein biomarkers associated with key metabolic pathways. Our objectives were to determine (1) expression of enzymes involved in glycolysis (HK-2, PKM2, LDHA, B and C isoforms), entry into the tricarboxylic acid (TCA) cycle (PDH), energy sensing/fatty acid oxidation (AMPK), and the metabolic signalling pathways (AKT, ERK, STAT3, 4EBP1) at the 1-cell (1C), 8- to 16-cell (8–16 C), and Day 7 blastocyst (d7BL) stage; and (2) evaluate the functional activity of these proteins both invivo (superovulated and flushed) and invitro (IVM/IVF/IVC) produced embryos using capillary Western blot (Protein-Simple, JESS; n=1 embryo/stage; n=3 replicates). For each protein, expression was normalized with total protein abundance in the same capillary and functional activity was determine based on the ratio of phosphorylated (p) to total (t) protein abundance in each sample. Data were analysed using a two-sample t-test. Results demonstrated significantly (P

During early placental development, tumor suppressors and oncogenes work synergistically to regulate cell proliferation and differentiation in a restrained manner compared with the uncontrollable growth in cancer. One example of this partnership is the regulation of the oncofetal protein HMGA2 by BRCA1. BRCA1 forms a repressor complex with ZNF350 and CtIP to bind to the promoter of HMGA2, preventing transcription. Chromatin immunoprecipitation determined BRCA1 forms this repressor complex in human trophoblast cells, suggesting a role in the placenta. Furthermore, miR-182 has been shown to target BRCA1 mRNA in ovarian cancer cells, blocking the formation of the BRCA1 repressor complex and allowing increased transcription of HMGA2. miR-182 was one of the first miRNAs described as elevated in the serum and placentas of preeclamptic women. Therefore, we hypothesized that BRCA1 is essential for normal trophoblast cell development. We used CRISPR-Cas9 genome editing and miR-182 overexpression to decrease BRCA1 protein in the Swan71 cell line. HMGA2 was significantly increased in the BRCA1 KO and miR-182 overexpressing cells compared to controls. We also determined that BRCA1 repressor complex binding to HMGA2 was significantly reduced in BRCA1 KO and miR-182 overexpressing cells compared with controls, leading us to conclude that increased HMGA2 was because of decreased binding of the BRCA1 repressor complex. Finally, we found that the caspase activity was significantly higher in BRCA1 KO and miR-182 overexpressing cells suggesting an increased amount of apoptosis. These data suggest that BRCA1 is an important regulator of the oncofetal protein HMGA2 and promotes cell survival in human placental cells.

Background Both thioguanine (TG) and low dose thiopurines and allopurinol (LDTA) can be considered for the treatment of inflammatory bowel disease (IBD) when conventional thiopurines fail due to intolerance or adverse events (AE). However, head-to-head trials are currently not available. The aim of this study was to compare the safety of TG and LDTA in IBD patients. Methods Adult IBD patients who failed conventional thiopurines and initiated LDTA in standard care were identified in the observational prospective multicentre ICC Registry. IBD patients who failed conventional thiopurines and initiated TG were retrospectively enrolled in three university hospitals. Patients with concomitant treatment with biologicals were excluded. The primary outcome was discontinuation of therapy due to AE. Secondary outcomes included: medication-related AE, infections (moderate: oral medication, severe: intravenously administrated medication), hospitalisations, and biological- and corticosteroid-free clinical remission (i.e. physician global assessment = 0) after 104 weeks of treatment. To adjust for confounding and selection bias, both multiple logistic regression and propensity score matching (PSM) were used to correct for baseline characteristics associated with disease severity or therapy refractoriness. Results In total, 182 IBD patients treated with TG (n = 94) or LDTA (n = 88) were included with a median follow-up of 104 weeks (IQR 91–104). The median dose of TG was 0.27 mg/kg (IQR 0.22–0.32), for LDTA: 100 mg allopurinol with either 0.67 mg/kg (IQR 0.54–0.75) azathioprine (n = 45) or 0.35 mg/kg (IQR 0.28–0.38) mercaptopurine (n = 41) (n = 2 unknown). By PSM, 64 TG patients were strictly matched with 64 LDTA patients with comparable baseline characteristics. In total, 19% (TG: 20%, LDTA: 18%) of patients discontinued therapy due AE. After adjusting for confounders, there were no significant differences in terms of discontinuation rate due to AE (TG: n = 19, LDTA = 16, OR 0.50 95% CI 0.15–1.68 p = 0.26), other AE (TG: n = 46, LDTA: n = 44, OR 0.89 95% CI 0.44–1.81 p = 0.75) (no cases of nodular regenerative hyperplasia of the liver were reported), infections (TG: n = 13, LDTA: n = 18, OR 1.05 95% CI 0.40–2.73 p = 0.93), hospitalisations (TG: n = 5, LDTA: n = 9, OR 2.00, 95% CI 0.64–6.23 p = 0.23), or biological- and corticosteroid-free clinical remission (OR 0.74 95% CI 0.33–1.68 p = 0.48). Escalation to biological treatment was comparable (TG 21% vs. LDTA 24% p = 0.68). All these results were in line with the PSM cohort. Conclusion A relative low percentage of patients with prior failure to conventional thiopurines discontinued therapy with TG or LDTA due to AE. Both maintenance therapies may be considered after failure of conventional thiopurines before escalating to biological therapy.

Background Tools for patient identification to safely cease anti-TNF therapy in Crohn’s disease (CD) patients are urgently needed. After an individual participant data meta-analysis (IPD-MA) a predictive diagnostic tool has been developed for cessation of anti-TNF therapy in CD. This study aims to validate this tool. Methods A retrospective study was conducted, in 16 Dutch Hospitals, of CD patients in whom anti-TNF therapy was ceased. Inclusion criteria were anti-TNF therapy use >6 months, start of anti-TNF therapy due to luminal CD and remission as an indication for cessation. Collected baseline demographic, clinical, biochemical, treatment and imaging data were included; age, gender, smoking, Montreal classification, disease- and remission duration, history of surgery, type of anti-TNF medication, previous or concomitant immunosuppressant, thiopurines level, previous anti-TNF therapy, anti-TNF therapy duration, haemoglobin, leukocytes, thrombocytes, albumin, C-reactive protein, anti-TNF serum concentration, anti-infliximab/adalimumab antibodies, remission at MRI/endoscopy, additional stop reason other than remission. The primary outcome was documented relapse of CD that necessitated (re)introduction of biologicals, corticosteroids or immune-suppressants or surgery. Results A total of 523 CD patients (333 females (63%), median age 40 years (IQR 32 – 53)) were included. 293 (56%) patients experienced a relapse after anti-TNF cessation after a median follow-up of 30.2 months (IQR 15–51). The relapse rate was 33% (95% CI 31–34) and 53% (95% CI 52–53) after 1 and 2 years, respectively. The discriminative ability of the prediction model in this external validation cohort (Table 1) equalled that of a previous IPD-MA with a C-statistic of 0.59. An update of the model with faecal calprotectin resulted in a C-statistic of 0.60 [0.55–0.63] and a reported calibration slope of 0.69. Conclusion A previously developed predictive diagnostic tool to safely cease anti-TNF therapy in CD has been validated, however, showed moderate performance in this external cohort. A further update of the model with biochemical and histological data is necessary to improve our ability to adequately select patients for cessation of anti-TNF therapy and is currently being performed.

BACKGROUND Youth living with HIV (YLWH) are confronted with many self-care challenges that can be experienced as overwhelming in the context of normal developmental processes that characterize adolescence and young adulthood. A sizable minority of YLWH have unsuppressed viral loads in the United States attributable to antiretroviral therapy (ART) nonadherence. Interventions to promote sustained viral suppression in YLWH are needed. OBJECTIVE The aim of this study is to evaluate the efficacy of the Triggered Escalating Real-Time Adherence (TERA) intervention in comparison with standard of care (SOC) in YLWH (aged 13-24 years) failing ART on (1) primary outcome measures—HIV viral suppression (VLS), defined as both METHODS The TERA study is a phase 2, multisite clinical trial conducted with 120 YLWH failing ART (randomized 1:1 to TERA or SOC) at participating clinical sites within the Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN). Participants are followed for a total of 48 weeks. For TERA arm participants, the first 12 weeks involve delivery of the intervention. For all participants, clinical outcomes are collected throughout follow-up, and adherence is assessed using EDM over the full 48 weeks. During the 12-week intervention period, TERA arm participants receive 3 remote coaching sessions delivered in clinic via videoconferencing timed to coincide with baseline and follow-up clinical visits, text message reminders when the EDM has not been opened at dose time (which escalate to 2-way theory-informed short message service coaching interactions in response to real-time nonadherence), and review of dosing graphs produced by EDM at follow-up visits. RESULTS Launch dates for enrollment varied by site. Enrollment began in April 2018 and is expected to be completed by August 2019, with results presented by the second quarter of 2021. CONCLUSIONS Effective, generalizable, and scalable approaches to rapidly assist YLWH failing to achieve and sustain VLS may have a substantial impact on individual health and efforts to curb transmission. Coaching for a brief but intensive period from remote coaches and using communication channels common to youth may offer multiple unique advantages in promoting self-care. CLINICALTRIAL ClinicalTrials.gov NCT03292432; https://clinicaltrials.gov/ct2/show/NCT03292432 (Archived by WebCite at http://www.webcitation.org/768J8ijjp). INTERNATIONAL REGISTERED REPOR DERR1-10.2196/11416

Background: Youth living with HIV (YLWH) are confronted with many self-care challenges that can be experienced as overwhelming in the context of normal developmental processes that characterize adolescence and young adulthood. A sizable minority of YLWH have unsuppressed viral loads in the United States attributable to antiretroviral therapy (ART) nonadherence. Interventions to promote sustained viral suppression in YLWH are needed. Objective: The aim of this study is to evaluate the efficacy of the Triggered Escalating Real-Time Adherence (TERA) intervention in comparison with standard of care (SOC) in YLWH (aged 13-24 years) failing ART on (1) primary outcome measures—HIV viral suppression (VLS), defined as both

Respiratory pathogens associated with childhood pneumonia are often detected in the upper respiratory tract of healthy children, making their contribution to pneumonia difficult to determine. We aimed to determine the contribution of common pathogens to pneumonia adjusting for rates of asymptomatic detection to inform future diagnosis, treatment and preventive strategies.A case-control study was conducted among children18 years in Perth, Western Australia. Cases were children hospitalised with radiologically confirmed pneumonia; controls were healthy children identified from outpatient and local immunisation clinics. Nasopharyngeal swabs were collected and tested for 14 respiratory viruses and 6 bacterial species by Polymerase chain reaction (PCR). For each pathogen, adjusted odds ratio (aOR; 95% CI) was calculated using multivariate logistic regression and population-attributable fraction (95% CI) for pneumonia was estimated.From May 2015 to October 2017, 230 cases and 230 controls were enrolled. At least one respiratory virus was identified in 57% of cases and 29% of controls (aOR: 4.7; 95% CI: 2.8 to 7.8). At least one bacterial species was detected in 72% of cases and 80% of controls (aOR: 0.7; 95% CI: 0.4 to 1.2). Respiratory syncytial virus (RSV) detection was most strongly associated with pneumonia (aOR: 58.4; 95% CI: 15.6 to 217.5).Respiratory viruses, particularly RSV and HMPV, are major contributors to pneumonia in Australian children.

IntroductionPneumonia is the leading cause of childhood morbidity and mortality globally. Introduction of the conjugateHaemophilus influenzaeB and multivalent pneumococcal vaccines in developed countries including Australia has significantly reduced the overall burden of bacterial pneumonia. With the availability of molecular diagnostics, viruses are frequently detected in children with pneumonia either as primary pathogens or predispose to secondary bacterial infection. Many respiratory pathogens that are known to cause pneumonia are also identified in asymptomatic children, so the true contribution of these pathogens to childhood community-acquired pneumonia (CAP) remains unclear. Since the introduction of pneumococcal vaccines, very few comprehensive studies from developed countries have attempted to determine the bacterial and viral aetiology of pneumonia. We aim to determine the contribution of bacteria and viruses to childhood CAP to inform further development of effective diagnosis, treatment and preventive strategies.Methods and analysisWe are conducting a prospective case–control study (PneumoWA) where cases are children with radiologically confirmed pneumonia admitted to Princess Margaret Hospital for Children (PMH) and controls are healthy children identified from PMH outpatient clinics and from local community immunisation clinics. The case–control ratio is 1:1 with 250 children to be recruited in each arm. Nasopharyngeal swabs are collected from both cases and controls to detect the presence of viruses and bacteria by PCR; pathogen load will be assessed by quantitative PCR. The prevalence of pathogens detected in cases and controls will be compared, the OR of detection and population attributable fraction to CAP for each pathogen will be determined; relationships between pathogen load and disease status and severity will be explored.Ethics and disseminationThis study has been approved by the human research ethics committees of PMH, Perth, Australia (PMH HREC REF 2014117EP). Findings will be disseminated at research conferences and in peer-reviewed journals.

For diseases of the brain, the pig (Sus scrofa) is increasingly being used as a model organism that shares many anatomical and biological similarities with humans. We report that pig induced pluripotent stem cells (iPSC) can recapitulate events in early mammalian neural development. Pig iPSC line (POU5F1(high)/SSEA4(low)) had a higher potential to form neural rosettes (NR) containing neuroepithelial cells than either POU5F1(low)/SSEA4(low) or POU5F1(low)/SSEA4(high) lines. Thus, POU5F1 and SSEA4 pluripotency marker profiles in starting porcine iPSC populations can predict their propensity to form more robust NR populations in culture. The NR were isolated and expanded in vitro, retaining their NR morphology and neuroepithelial molecular properties. These cells expressed anterior central nervous system fate markers OTX2 and GBX2 through at least seven passages, and responded to retinoic acid, promoting a more posterior fate (HOXB4+, OTX2-, and GBX2-). These findings offer insight into pig iPSC development, which parallels the human iPSC in both anterior and posterior neural cell fates. These in vitro similarities in early neural differentiation processes support the use of pig iPSC and differentiated neural cells as a cell therapy in allogeneic porcine neural injury and degeneration models, providing relevant translational data for eventual human neural cell therapies.

Incontinence is associated with mental illness and neuroleptic medications but diagnosis and treatment is often poor or non-existent. Problems of incontinence are compounded in secure psychiatric services for women by poor health, obesity, and a sedentary lifestyle. Addressing the physical health of this group necessitates a more accurate picture of the nature, incidence, and management of incontinence. A point-in-time survey of 108 women who agreed to be interviewed (93%) covered presence, frequency, and nature of incontinence, and information on management case note data was used to gather demographic and previous medical history, comparisons were made between patients with and without problems of incontinence. Findings indicate a problem of incontinence in 48% of women with a dominance of problems of stress and urge enuresis. Of modifiable factors that contribute to enuresis, the current study highlighted the contribution of obesity, smoking and clozapine medication. A further finding was the preference for managing rather than treating problems of incontinence. Actions to improve the detection and treatment of this problem are described.

Background The use of biologicals has improved the treatment of IBD but the understanding of adverse drug reactions (ADRs) and the knowledge of patients’ perception on ADRs is poor. Patient-reporting may provide more insight in the extent and burden of ADRs in daily practice which in turn can lead to treatment optimisation. This study aimed to assess systematic patient-reported ADRs during biological therapy in IBD patients. Methods This multicentre, prospective, event monitoring study enrolled adult Crohn’s disease (CD) and ulcerative colitis (UC) patients treated with a biological between 1 January 2017 and 31 December 2018. Patients completed bimonthly comprehensive web-based questionnaires regarding indication and use of, description of biological induced ADRs, follow-up of previous ADRs, experienced burden of the ADR using a 5-point Likert scale, contact with a healthcare provider and therapeutic consequences due to the ADR. Patient-reported ADRs were MedDRA coded by trained pharmacovigilance assessors. MedDRA is a multi-hierarchical dictionary used to code reported ADRs into specific unambiguous terms (preferred terms). Preferred terms are subsequently grouped into high-level terms, high-level group terms and system organ classes. In total there are 26 system organ classes. Results In total, 182 patients in 4 centres (female 51%, mean (standard deviation) age 42.2 (14.2) years, CD 77%) were included and completed 750 questionnaires. At baseline, 49% used an immunomodulator (43% thiopurines, 6% methotrexate), while biologicals were documented as follows: 59% infliximab, 30% adalimumab, 9% vedolizumab, 1% ustekinumab. At least one ADR was reported by 50% of the participants, and 233 ADRs were reported in total with a median reported ADRs per participant of 2 (interquartile range, 1–3). Fatigue (n = 26), headache (n = 20), injection site reactions (n = 16) and arthralgia (n = 12) were most commonly reported, with a mean burden of 3.31, 1.63, 2.55 and 3.33, and a correlation in time with the administration of the biologic was described in 58%, 85%, 81% and 8% in these ADRs, respectively. Participants contacted a healthcare provider in 62% of all ADRs. In two out of 90 patients who reported an ADR, the biological was discontinued. Conclusion We established a patient-reported pharmacovigilance monitoring system and participants in this study frequently reported ADRs due to biologicals. Fatigue and arthralgia resulted in the highest burden. This reporting system may provide more understanding of patient-experienced ADRs which may ultimately lead to increased adherence of therapy and improved quality of life.

Reducing the use of seclusion to deal with challenging behaviour is a priority in secure services for women. This study describes the concurrent introduction of a series of initiatives based on recovery principles and the full involvement of patients in their risk management plans.Following change implementation, the first 19 patients who had completed one year of treatment were matched with 19 patients who had completed their first year of treatment before change.A significant decline in both the number of seclusions and risk behaviour post-change was complemented by improved staff ratings of institutional behaviour, increased treatment engagement and a reduction in time spent in medium security. Staff and patients differed in terms of their ratings of the most effective strategies introduced. Patients favoured the Relational Security item of increased individual engagement and timetabled Behaviour Chain Analysis sessions. Staff viewed on ward training and use of de-escalation techniques as most effective.Findings confirm results from mixed gender forensic mental health samples that seclusion can be successfully reduced without an increase in patient violence or alternative coercive strategies. Limitations of the study are discussed along with the need for future evaluations to address issues of fidelity and utilise vigorously designed case studies.

Germ cells (GCs) are critically important as the vehicle that passes genetic information from one generation to the next. Correct development of these cells is essential and perturbation in their development often leads to reproductive failure and disease. Despite the importance of GCs, little is known about the mechanisms underlying the acquisition and maintenance of the GC character. Using a reprogramming strategy, we demonstrate that overexpression of ectopic transcription factors in embryonic fibroblasts can lead to the generation of chicken induced primordial germ cells (ciPGCs). These ciPGCs express pluripotent markers POU5F1, SSEA1, and the GC defining proteins, CVH and DAZL, closely resembling in vivo sourced PGCs instead of embryonic stem cells. Moreover, CXCR4 expressing ciPGCs were capable of migrating to the embryonic gonad after injection into the vasculature of stage 15 embryos, indicating the acquisition of a GC fate in these cells. Direct availability of ciPGCs in vitro would facilitate the study of GC development as well as provide a potential strategy for the conservation of important genetics of agricultural and endangered birds using somatic cells.