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The availability of Janus kinase (JAK) inhibitors has transformed the management of rheumatoid arthritis (RA), helping patients achieve clinical remission. However, the emergence of opportunistic infections (OIs) associated with the use of JAK inhibitors has been reported. This structured literature review was conducted to summarize reports of OIs associated with JAK inhibitor treatment for RA in clinical trials.Structured searches were performed in MEDLINE® and Embase® to identify relevant clinical trial data through March 2021. Bibliographic searches of recent reviews were also conducted, and gray literature searches were used to supplement key gap areas. Publications were screened, extracted, and quality assessed. Data were narratively synthesized.Following screening, 105 publications describing 62 unique clinical trials reporting the rates of OIs in RA patients treated with JAK inhibitors were included. Overall, the highest exposure-adjusted incidence rate was reported for herpes zoster (HZ) infection (any form), followed by OI (any) and tuberculosis based on limited data from clinical trials with approved doses of JAK inhibitors. Lack of head-to-head trials and differences in trial design preclude direct comparison across JAK inhibitors. Higher rates of OIs were noted in the Asian and Australian populations compared with the global population. Higher rates of OIs were also noted with increasing dose of JAK inhibitors in most clinical trial data.HZ was the most common OI reported among RA patients using all currently approved JAK inhibitors in clinical trials, although tuberculosis and other OIs were also reported. More long-term safety studies in the real-world setting are needed to compare the risk of OIs between various JAK inhibitors.

Background Many patients with rheumatoid arthritis (RA) do not attain remission/low disease activity, remaining in a moderate disease activity state (MDAS) with ongoing disability and impaired quality of life (QoL). If patients in persistent MDAS with poor future outcomes could be prospectively identified, they could arguably be treated more intensively. We evaluated baseline factors predicting function (Health Assessment Questionnaire-Disability Index [HAQ-DI] scores) and QoL (3-level EuroQol-5 dimensions questionnaire [EQ-5D-3L] index scores) at 12 months in patients with RA in persistent MDAS in a real-world setting. Methods Patients with persistent MDAS (Disease Activity Score for 28-joint count based on erythrocyte sedimentation rate [DAS28-ESR] 3.2–5.1 on at least two consecutive outpatient appointments over 12 months) were identified retrospectively from Guy’s Hospital RA Centre and analysed in two groups: (1) biologic naïve at baseline or (2) receiving/ever received biologics. The baseline timepoint was the second-visit MDAS DAS28-ESR score; the endpoint was the closest visit to 12 months. Linear regression analyses evaluated relationships between baseline variables and (1) 12-month HAQ-DI scores, (2) 12-month rank-transformed EQ-5D-3L index scores, (3) 12-month changes in HAQ-DI scores, and (4) 12-month changes in EQ-5D-3L index scores. Results The analysis included 207 biologic-naïve and 188 biologic-experienced patients. All patients had moderate disability (mean HAQ-DI 1.21 and 1.46) and impaired QoL (mean EQ-5D-3L index scores 0.52 and 0.50). Many reported moderate/severe pain (93 and 96%) and showed little change in HAQ-DI and EQ-5D-3L index scores over 12 months. In both biologic-naïve and biologic-experienced groups, multivariate analysis revealed a significant association between baseline HAQ-DI scores and endpoint HAQ-DI scores (β = 0.67, P P P P P = 0.004, respectively). Baseline EQ-5D-3L index scores were significantly associated with 12-month changes in EQ-5D-3L index scores in both groups (β = − 0.73, P P = 0.003, respectively). Conclusions Patients with RA in persistent MDAS experience substantial ongoing physical disability, poor QoL, and pain. HAQ-DI is an important predictor of future disability and reduced QoL, supporting current national recommendations to measure HAQ-DI in routine care.

Teacher expectations of pupil ability can influence pupil’s educational progression, impacting subsequent streaming and exam level entry. Systematic errors in the accuracy of teacher expectations of pupil achievement may therefore have a lasting detrimental effect on a child’s education and life prospects. Associations between socioeconomic and demographic factors with teacher expectation accuracy have been previously investigated, but it is not known how expectation accuracy may relate to genetic factors. We investigated these relationships using data on nationally standardized exam results at ages 11 and 14 from a UK longitudinal cohort study. We found that teacher expectation of achievement was strongly correlated with subsequent achievement, that teacher expectation accuracy was patterned by pupil socioeconomic background but not teacher characteristics, and that teacher expectation accuracy related to pupil’s genetic liability to education. We find no strong evidence for heritability in teacher reporting accuracy, suggesting that the majority of variation in teacher expectation accuracy can be attributed to non-genetic factors.

Background/Aims Filgotinib is an oral, preferential janus kinase 1 inhibitor. FINCH 1 (NCT02889796) was a phase III, double-blind, placebo- and active-controlled study evaluating filgotinib efficacy and safety in patients with rheumatoid arthritis (RA) after inadequate response to methotrexate (MTX; MTX-IR). Methods MTX-IR patients with moderately or severely active RA were randomised (3:3:2:3) to filgotinib 200 mg daily, filgotinib 100 mg daily, adalimumab 40 mg every 2 weeks, or placebo on a background of stable MTX for up to 52 weeks. An exploratory subgroup analysis of FINCH 1 was conducted in patients with moderately active RA based on Disease Activity Score in 28 joints with C-reactive protein (DAS28[CRP])>3.2-≤5.1 at baseline. Proportion of patients achieving 20%/50%/70% improvement from baseline in American College of Rheumatology core criteria (ACR20/50/70), DAS28(CRP)≤3.2, DAS28(CRP) Results Of 1,755 treated patients, 24% had moderate disease at baseline with similar proportions (21.9%-26.9%) across treatment groups. In each treatment arm, baseline characteristics were well balanced for the moderate disease activity subpopulation. The majority (77%) were female, mean (standard deviation [SD]) duration of RA was 7.8 (7.7) years; mean (SD) baseline DAS28(CRP) was 4.6 (0.42). At W12 and W24, proportions achieving ACR20/50/70, DAS28(CRP) Conclusion In a subgroup of patients from FINCH 1 with baseline moderately active RA, significantly greater improvements in disease activity were observed with both filgotinib doses over placebo and associated with lower radiographic progression and reduced functional deficit. Disclosure M.H. Buch: Consultancies; MHB reports serving as a consultant for AbbVie; Eli Lilly; Gilead Sciences, Inc.; Sandoz; Sanofi; and Serono. Grants/research support; MHB reports grants or research support from Pfizer, Roche, and UCB. D. Walker: Grants/research support; DW has received funding from Bristol-Myers Squibb; Eli Lilly; Gilead Sciences, Inc.; Novartis; and Pfizer, Inc. P.D.W. Kiely: Other; PK has attended advisory boards, been part of a speakers bureau, or received support to attend educational meetings from AbbVie, Gilead, Lilly, Novartis, and Sanofi. C.J. Edwards: Consultancies; CJE has provided consultancy for AbbVie; Biogen; Bristol-Myers Squibb; Celgene; Eli Lilly; Fresenius; Gilead Sciences, Inc.; GSK; Janssen; MSD; Mundipharma; Pfizer; Roche; Samsung; and Sanofi. Member of speakers’ bureau; CJE has served on speaker's bureaus for AbbVie; Biogen; Bristol-Myers Squibb; Celgene; Eli Lilly; Fresenius; Gilead Sciences, Inc.; GSK; Janssen; MSD; Mundipharma; Pfizer; Roche; Samsung; and Sanofi. Grants/research support; CJE reports grants from AbbVie; Biogen; Bristol-Myers Squibb; Celgene; Eli Lilly; Fresenius; Gilead Sciences, Inc.; GSK; Janssen; MSD; Mundipharma; Pfizer; Roche; Samsung; and Sanofi. J. Barry: Corporate appointments; JB is an employee of Gilead Sciences Ltd. G. McCaughey: Corporate appointments; GMcC is an employee of Gilead Sciences Ltd. L. Akroyd: Corporate appointments; LA is an employee of Gilead Sciences Ltd. I. Tiamiyu: Corporate appointments; IT is an employee of Gilead Sciences, Inc. L. Ye: Corporate appointments; LY is an employee of Gilead Sciences, Inc. K. Chen: Corporate appointments; KC is an employee of Gilead Sciences, Inc. P.C. Taylor: Consultancies; PCT has served as a consultant to AbbVie, Biogen, Galapagos, Gilead, GlaxoSmithKline, Janssen, Lilly, Pfizer, BMS, Roche, Sanofi, Nordic Pharma, Fresenius, and UCB. Grants/research support; PCT reports research grants from Gilead Sciences, Inc.; Galapagos, and Celgene.

Background/Aims It became apparent at a session at the BSR Annual Conference 2019 that some CCGs restrict the prescription of high cost drugs (HCDs) beyond three drugs for people with rheumatoid arthritis (RA). We were interested to explore the efficacy of HCDs beyond the third choice in our own service. Methods All patients in our service who are being considered for HCDs, are discussed at a multi-disciplinary team meeting comprising of seven consultants and eight nurses. The HCD decision is recorded in the minutes of the meeting which were scrutinised to identify patients who had received four or more HCDs. We began at March 2017, the launch of JAK inhibitors, in the expectation that few people would have had four HCDs before that time. The medical records were reviewed for the order of HCDs given and for evidence of efficacy and toxicity. The response to each drug choice was graded as: responder; partial responder and failure (primary non-responder or toxicity). Results From a database of 2,673 patients with RA, 542 patients were taking HCDs, thirty-two of those had received four or more of these drugs. Eleven of the thirty-two patients had tried four HCDs, seven had received five HCDs, ten patients had six, one patient had seven HCDs, two had tried eight and one patient had received nine HCDs. The response rates for each choice of drug are shown in table 1. Many patients responded to their fourth, fifth and sixth choice of HCD. If there was a restriction of three HCDs in our service, thirty-three prescriptions for drugs that patients have responded to, would not have been made. Conclusion Many patients responded to their fourth or subsequent HCD. Thus, there is no clinical justification in restricting the use of HCDs below at least six choices. Additionally, this data suggests that only small numbers of patients are prescribed more than four HCDs. Therefore lifting this limitation would have little cost implication. P141 Table 1:HCD Response RateHCD Choice*123456>6Responder12 (38%)10 (31%)10 (31%)12 (44%)14 (58%)6 (60%)1 (14%)Partial Responder5 (16%)1 (3%)7 (22%)5 (19%)4 (17%)1 (10%)1 (14%)Failure15 (47%)21 (66%)15 (47%)10 (37%)6 (25%)3 (30%)5 (71%)n =3232322724107*Switches to biosimilars were not regarded as a change. Disclosure D. Walker: Honoraria; Gilead Sciences Ltd, Ely Lilly Pharmaceuticals, Pfizer Pharmaceutical. Grants/research support; Gilead Sciences Ltd. S. Robinson: None. J. Barry: Corporate appointments; Gilead Sciences Ltd. P. Punter: Corporate appointments; Gilead Sciences Ltd. S. Kearns: Corporate appointments; Gilead Sciences Ltd. I. Goff: None.

Large numbers of women take prescription and over-the-counter medications during pregnancy. However, there is very little definitive evidence about the potential effects of these drugs on the mothers and offspring. We will investigate the risks and benefits of continuing prescriptive drug use for chronic pre-existing maternal conditions such as diabetes, hypertension and thyroid related conditions throughout pregnancy. If left untreated, these conditions are established risk factors for adverse neonatal and maternal outcomes. However, some treatments for these conditions are associated with adverse neonatal outcomes. Our primary aims are twofold. Firstly, we aim to estimate the beneficial effect on the mother of continuing treatment during pregnancy. Second, we aim to determine whether there is an associated detrimental impact on the neonate of continuation of maternal treatment during pregnancy. To establish this evidence, we will investigate the relationship between maternal drug prescriptions and adverse and beneficial offspring outcomes to provide evidence to guide clinical decisions. We will conduct a hypothesis testing observational intergenerational cohort study using data from the UK Clinical Practice Research Datalink (CPRD). We will apply four statistical methods: multivariable adjusted regression, propensity score regression, instrumental variables analysis and negative control analysis. These methods should account for potential confounding when estimating the association between the drug exposure and maternal or neonatal outcome. In this protocol we describe the aims, motivation, study design, cohort and statistical analyses of our study to aid reproducibility and transparency within research.

Current guidelines for the management of rheumatoid arthritis (RA) recommend early treatment and a treat-to-target goal of remission or low disease activity. Over the past decade, this approach has been extremely successful in reducing disease activity and joint damage in patients with RA. At the same time, however, overall patient perception of well-being appears to have decreased with respect to outcome measures considered important by patients themselves, such as pain, fatigue, physical function and quality of life. The timely and effective use of patient-reported outcomes (PROs) should encourage healthcare professionals (HCPs) to focus more on the impact of RA on patients and how patients are feeling. This would facilitate shared decision making between patients and HCPs, ultimately leading to a more patient-centered approach, improved patient care and optimal health outcomes. Importantly, PROs provide information about individual patients that complements information provided by physical assessment and composite scores, and can also be used to guide patient care, such as determining whether a clinic visit is needed or whether management modifications are necessary. This is particularly important for patients who do not achieve the target of remission or low disease activity with pharmacological treatment. A number of validated PRO questionnaires are available, but how and which PROs should be incorporated into rheumatology clinical practice as part of the decision-making process is still controversial. Combining PROs with digital technology, such as computer adaptive tests, electronic PRO systems, web-based platforms and patient dashboards, could further aid PRO integration into daily rheumatology clinical practice.

Objectives: Access to biologic DMARDs for RA is often restricted to those with severe disease. This systematic review aimed to identify prognostic factors in patients with moderate disease activity who may be at risk of disease progression and poor clinical outcomes. Methods: MEDLINE, Embase and Cochrane databases were searched (final search 22 September 2017), and data from patients with moderate disease [28-joint DAS (DAS28) >3.2–≤5.1] were included. Studies were evaluated according to the measure(s) of progression/poor outcome used: radiographic, disease activity or other indicators. Results: The searches identified 274 publications, of which 30 were selected for data extraction. Fourteen studies were prioritized, because they specifically analysed patients with moderate RA. Nine studies reported radiographic progression outcomes for 3241 patients, three studies reported disease activity progression for 1516 patients, and two studies reported other relevant outcomes for 2094 patients. Prognostic factors with consistent evidence for progression/poor outcome prediction were as follows: DAS28 ≥ 4.2, the presence of anti-CCP antibodies, and power Doppler ultrasound score ≥1. Some predictors were specific to either disease activity or radiographic progression. Conclusion: Several criteria used in standard clinical practice were identified that have the potential to inform the selection of patients with moderate RA who are at greater risk of a poor outcome. A combination of two or more of these factors might enhance their predictive potential. Further work is required to derive clinical decision rules incorporating these factors.

Introduction Various factors play a role in the development of erectile dysfunction (ED). Aim To provide a descriptive comparison of erectile function response for tadalafil on-demand (PRN) and once-daily (OAD) dosing regimens in patients with common comorbid conditions, treatments, or risk factors that can be considered when treating ED. Methods In total, 17 PRN and 4 OAD placebo-controlled studies were included in the integrated database in these pooled analyses. Data were analyzed from patients treated with placebo, tadalafil 10 mg (low dose), and 20 mg (high dose) for the PRN studies and placebo, tadalafil 2.5 mg (low dose), and 5 mg (high dose) for the OAD studies. Main Outcome Measures The effects of tadalafil were measured using the International Index of Erectile Function administered from baseline to week 12. A descriptive comparison of the efficacy of tadalafil PRN vs OAD was examined in the clinical populations. Results Baseline characteristics of 4,354 men were comparable between the PRN and OAD groups, with differences seen only in the variables of race, body mass index (BMI) of at least 30 kg/m2, and alcohol use. Tadalafil was efficacious at improving erectile function for all clinical populations, except for the low-dose OAD group, which demonstrated a weaker effect vs placebo than the high-dose OAD group, and the low- and high-dose PRN groups vs placebo for patients with BMI of at least 30 kg/m2 for patients without a cardiovascular disorder, smokers, patients with ED duration shorter than 1 year, and patients without previous phosphodiesterase type 5 inhibitor use. Tadalafil was efficacious for patients with or without diabetes mellitus, arterial hypertension, hyperlipidemia, and alcohol use at baseline. Conclusion Tadalafil OAD and PRN regimens showed efficacy in patients with ED. No clinical populations of patients with ED seemed to benefit overwhelmingly from one dose regimen over the other.

Introduction: Incidental irradiation of the heart during radiotherapy can have long-term consequences(1). Deep Inspiration Breath Hold (DIBH) is used for patients receiving radiotherapy for breast cancer to reduce heart doses(2). DIBH can reduce mean heart dose by between 29-67% compared with free breathing(3); differences in dose reduction may be due to patient anatomy or variability in chest expansion achieved at an individual level(4). A survey of a breast cancer special interest group (BRIG) identified patient compliance, ability to hold their breath for the required time, and reproducibility of breath hold as major challenges to implementing DIBH. Between 12-21% of patients are reported to find the technique challenging(5, 6). While coaching has been shown to reduce maximum heart dose compared with non-coached patients(7), formal coaching is not typical in most radiotherapy centres and no standard patient resource exists to support practice prior to radiotherapy planning. Aim: To develop a series of instructional videos to enhance the number of patients that can achieve breath hold, improve patient self-efficacy and patient satisfaction with care. Method: The Medical Research Council (MRC)(8) framework for complex interventions was adopted. A co-design methodology(9) involving patient representatives and health practitioners (HCP) was used to develop a series of instructional videos and podcasts. Co-design workshops were audio recorded and transcribed verbatim. Video scripts were based upon themes identified through framework analysis. To minimise bias member checking was adopted and patient representatives participated in video scripting; to maintain the outputs' authenticity they also appeared as patients in the videos. Results: Key themes from the PPI workshop included: information needs; positioning during radiotherapy; and pre-treatment readiness. Additional themes from the HCP workshop included DIBH service challenges and teaching the DIBH technique. Five videos and two podcasts were developed. Conclusion: This presentation will highlight how participatory co-design facilitated video development to support a more effective DIBH experience. Resource examples will be presented alongside initial feedback from patient representatives and HCPs on suitability and usability. The next stage will assess the resources' effectiveness in supporting breath hold capability.

Circulating insulin-like growth factor-I (IGF-I) levels have been shown to be related to risk of prostate cancer in epidemiologic studies. While specific genetic loci responsible for interindividual variation in circulating IGF-I levels in normal men have not been identified, candidate genes include those involved in the growth hormone (GH)–IGF-I axis such as the hypothalamic factors GH releasing hormone (GHRH) and somatostatin and their receptors. To investigate the role of the GH–IGF-I axis on in vivo prostate carcinogenesis and neoplastic progression, we generated mice genetically predisposed to prostate cancer (the TRAMP model) to be homozygous for lit, a mutation that inactivates the GHRH receptor (GHRH-R) and reduces circulating levels of GH and IGF-I. The lit mutation significantly reduced the percentage of the prostate gland showing neoplastic changes at 35 weeks of age (P=0.0005) and was also associated with improved survival (P

In July 2000 the first Emergency Duty Team was established within the Eastern Health & Social Services Board in Northern Ireland, fundamentally changing the way in which out of hours social work services are provided. The other three Boards are now also examining how they might provide for their statutory responsibilities out of hours and are looking to the model of the Emergency Duty Team. The concept of the Emergency Duty Team is now almost 30 years old. With services becoming more fragmented and specialist, has the generic out of hours role been redefined too generally or does it still remain a credible model for dealing with all social work emergencies out of hours? This paper is a personal reflection on the establishment and current position of the Emergency Duty Team and seeks to argue that Emergency Duty Social Work is a distinct and specialist form of practice and that its staff have developed a level of expertise in crisis resolution across the spectrum of emergency social work intervention provi...

The Climbie Report 2003 has suggested radical reforms in relation to how child protection services are organised out of hours. The impact of this will be felt in Emergency Duty Teams throughout the UK leading those involved in commissioning child protection services to ask whether the generic emergency duty team is the most appropriate model for dealing with all social services emergencies out of normal working hours.

The protein product of the immediate-early gene c-fos is expressed rhythmically in the shell region of the suprachiasmatic nucleus (SCN), the mammalian circadian clock. Recently, we found that exposure to an entraining light pulse caused a suppression of Fos expression in the SCN shell in rats. To study the hypothesis that suppression of Fos in the shell is a correlate of photic entrainment, we used rats that were treated with the retinal neurotoxin monosodium glutamate (MSG) during the neonatal period. In spite of retinal degeneration, MSG-treated rats entrained normally and displayed light-induced suppression of Fos within the SCN shell. These results support the view that light-induced suppression of Fos within the SCN shell is a cellular correlate of photic entrainment.

Introduction. Irukandji syndrome is because of envenoming by a number of small jellyfish. It results in a delayed onset of generalized pain, sweating hypertension, and tachycardia. There is no antivenom. Case report. A 44-year-old healthy male was stung while swimming in NE Australia. He rapidly developed Irukandji syndrome. He had a rapid deterioration in conscious level because of an intracerebral hemorrhage. He developed left ventricular failure with an elevated troponin (34 mcg/L, N < 0.4) requiring inotropic support. He progressed to brain death and died on day 13 poststing. Nematocysts recovered from the patient skin were consistent with a large Carukia barnesi. Discussion. This is the first case of a death because of Irukandji syndrome where the jellyfish Carukia barnesi has been demonstrated to the causative creature.

A 24-year-old woman presented with a 5-year history of painless, nonpruritic swelling of her lips (Figure 1). The swelling was initially intermittent but became progressive and persistent. It began on her upper lip and gradually extended to the lower lip and right inner cheek. She was otherwise well and reported no gastrointestinal or respiratory symptoms. Physical examination showed a rubbery, infiltrated, erythematous swelling of both lips; an erythematous plaque on the right cheek; and a cobblestonelike appearance on the right buccal mucosa. The findings of a routine blood workup, including the serum angiotensin-converting enzyme level, were normal. The results of a Mantoux test were negative. A chest x-ray film did not show any signs of lymphadenopathy. Patch tests, including standard, metal, bakery, and dental batteries, revealed no abnormalities. The findings of colonoscopy were unremarkable. A punch biopsy specimen of the buccal mucosa showed noncaseating granulomatous inflammation, confirming the clinical impression of granulomatous cheilitis (Figure 2). THERAPEUTIC CHALLENGE

There has been a recent explosion in knowledge regarding the central role of the immune system in the pathogenesis of psoriasis. Originally felt to be primarily a disorder of keratinocyte hyperproliferation, it has recently been classified as a T cell-mediated, autoimmune disease. Type 1 cytokines released predominantly from activated T lymphocytes are now considered to cause the psoriatic phenotype, including the epidermal and vascular changes. Armed with this new knowledge, pharmaceutical and biotechnology companies have developed more specific, immunologically directed interventions. These newer agents aim to be both more effective in clearing a condition that is associated with much morbidity and to be more selective, resulting in fewer toxic side effects than current therapies. This article gives an overview of the newer immunotherapeutic approaches from the points of view of safety, efficacy and mechanisms of action. The review also outlines the steps involved in the immune response leading to psoriasis and considers how each step could offer a target for therapeutic intervention. Infliximab, etanercept, alefacept and efalizumab are considered in detail.

Identification tests have been presented for 23 compounds containing either one or two quaternary anmonium functional groups. The reactions of these compounds with ammonium reineckate, picric acid, and chloroplatinic acid have been studied and 54 adducts have been isolated and their melting ranges presented. In addition, microcrystal tests showed that many adducts possessed distinctive crystalline morphology. Photomicrographs are presented as a supplemental and additional parameter for characterication purposes.

Background This multicenter, randomized, double-blind, double-dummy, placebo-controlled trial primarily evaluated the efficacy of tadalafil once-daily (OaD) or on-demand (“pro-re-nata”; PRN) treatment, started early post-nsRP. Secondary outcome-measures on quality-of-life (QoL) and treatment satisfaction are reported. Methods Patients, aged