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Differentiated thyroid cancers generally have favorable prognoses, though follicular thyroid cancer is overall associated with a worse prognosis due in part to increased incidence of distant metastasis. We report a case of a 51-year-old woman with a history of widely invasive follicular thyroid carcinoma treated with a total thyroidectomy, radioactive iodine and external beam radiation. Five and a half years following her surgery, she was found to have an axillary lymph node mass, multiple lung masses, and a hilar mass in the setting of declining thyroglobulin (Tg) antibodies. Her metastases were initially thought to be due to a primary lung adenocarcinoma given a neoplastic cell immunophenotype that included an absence of Tg expression and co-expression of TTF-1 and Napsin A. However, PAX8 expression demonstrated that the axillary and hilar metastases were actually thyroid in origin rather than lung. Axillary metastases in differentiated thyroid carcinoma are exceedingly rare and previous reports have typically involved widely disseminated disease with extensive neck lymphadenopathy. With a decline in Tg antibodies levels in high-risk patients, one should consider progression and loss of differentiation of thyroid carcinoma rather than a response to treatment. Learning points Axillary metastases in differentiated thyroid carcinoma are uncommon. In patients with high-risk thyroid carcinomas, a decline in thyroglobulin antibody may not signal disease improvement, but rather a progression to a poorly differentiated form of cancer. PAX8 staining can be used to differentiate thyroid carcinomas from lung adenocarcinomas. Patient Demographics: Adult, Female, Hispanic or Latino - other, United States Clinical Overview: Thyroid, Thyroid Related Disciplines: Surgery, Otolaryngology Publication Details: Unique/unexpected symptoms or presentations of a disease, February, 2021 Background Differentiated thyroid cancers, including follicular thyroid carcinoma (FTC) and papillary thyroid carcinoma (PTC), are generally associated with favorable prognoses (1). FTC is the second most common differentiated thyroid cancer, historically accounting for up to 10–15% of all thyroid malignancies (2). Distant metastases, most commonly lung and bone (3) are found at presentation in up to 27% of FTCs (4) and up to 46% of patients with extensive vascular invasion on histology (3). Compared to PTC, FTC is overall associated with a worse prognosis due in part to this increased presence of metastases. Cervical lymph node metastases are less common in FTC with an incidence of 2–8% increasing to 17% in invasive disease (2, 5). This is compared to an incidence of up to 50% for PTC (6). Axillary lymph node metastases have previously been described in only eight patients with PTC (7) and only one patient with FTC (8). Here, we report a second case of late axillary lymph node metastasis in a patient with invasive FTC that was initially misdiagnosed as metastatic pulmonary adenocarcinoma.

The COVID-19 pandemic has created opportunities for innovation in diabetes care that were not possible before. From the lens of this “new normal” state, we have an opportunity to rapidly implement, test, and iterate models of diabetes care to achieve the quadruple aim of improving medical outcomes, patient experience, provider satisfaction, and reducing costs. Two of the biggest threats to optimal diabetes care have been lack of access to specialty diabetes care and fractured care. In this perspective, we discuss several innovative diabetes models of care which promote collaborative care models and improve access to high-quality specialty diabetes care. We discuss ongoing challenges to diabetes care innovation, and offer practical solutions to foster innovation and sustain current strides made during the pandemic.

Aims Cyclophilin-D is a well-known regulator of the mitochondrial permeability transition pore (PTP), the main effector of cardiac ischaemia/reperfusion injury. However, the binding of CypD to the PTP is poorly understood. Cysteine 202 (C202) of CypD is highly conserved among species and can undergo redox-sensitive post-translational modifications. We investigated whether C202 regulates the opening of PTP. Methods and results We developed a knock-in mouse model using CRISPR where CypD-C202 was mutated to a serine (C202S). Infarct size is reduced in CypD-C202S Langendorff perfused hearts compared to wild type (WT). Cardiac mitochondria from CypD-C202S mice also have higher calcium retention capacity compared to WT. Therefore, we hypothesized that oxidation of C202 might target CypD to the PTP. Indeed, isolated cardiac mitochondria subjected to oxidative stress exhibit less binding of CypD-C202S to the proposed PTP component F1F0-ATP-synthase. We previously found C202 to be S-nitrosylated in ischaemic preconditioning. Cysteine residues can also undergo S-acylation, and C202 matched an S-acylation motif. S-acylation of CypD-C202 was assessed using a resin-assisted capture (Acyl-RAC). WT hearts are abundantly S-acylated on CypD C202 under baseline conditions indicating that S-acylation on C202 per se does not lead to PTP opening. CypD C202S knock-in hearts are protected from ischaemia/reperfusion injury suggesting further that lack of CypD S-acylation at C202 is not detrimental (when C is mutated to S) and does not induce PTP opening. However, we find that ischaemia leads to de-acylation of C202 and that calcium overload in isolated mitochondria promotes de-acylation of CypD. Furthermore, a high bolus of calcium in WT cardiac mitochondria displaces CypD from its physiological binding partners and possibly renders it available for interaction with the PTP. Conclusions Taken together the data suggest that with ischaemia CypD is de-acylated at C202 allowing the free cysteine residue to undergo oxidation during the first minutes of reperfusion which in turn targets it to the PTP.

The renal-outer-medullary-potassium (ROMK) channel, mutated in Bartter’s syndrome, regulates ion exchange in kidney, but its extra-renal functions remain unknown. Additionally, ROMK was postulated to be the pore-forming subunit of the mitochondrial ATP-sensitive K(+) channel (mitoK(ATP)), a mediator of cardioprotection. Using global and cardiomyocyte-specific knockout mice (ROMK-GKO and ROMK-CKO respectively), we characterize the effects of ROMK knockout on mitochondrial ion handling, the response to pharmacological K(ATP) channel modulators, and ischemia/reperfusion (I/R) injury. Mitochondria from ROMK-GKO hearts exhibited a lower threshold for Ca(2+)-triggered permeability transition pore (mPTP) opening but normal matrix volume changes during oxidative phosphorylation. Isolated perfused ROMK-GKO hearts exhibited impaired functional recovery and increased infarct size after I/R injury, particularly when I/R was preceded by an ischemic preconditioning (IPC) protocol. Because ROMK-GKO mice exhibited severe renal defects and cardiac remodeling, we further characterized ROMK-CKO hearts to avoid confounding systemic effects. Mitochondria from ROMK-CKO hearts had unchanged matrix volume responses during oxidative phosphorylation and still swelled upon addition of a mitoK(ATP) opener, but exhibited a lower threshold for mPTP opening, similar to GKO mitochondrial. Nevertheless, I/R induced damage was not exacerbated in ROMK-CKO hearts, either ex vivo or in vivo. Lastly, we examined the response of ROMK-CKO hearts to ex vivo I/R injury with or without IPC and found that IPC still protected these hearts, suggesting that cardiomyocyte ROMK does not participate significantly in the cardioprotective pathway elicited by IPC. Collectively, our findings from these novel strains of mice suggest that cardiomyocyte ROMK is not a central mediator of mitoK(ATP) function, although it can affect mPTP activation threshold.

Ensuring delivery of timely, coordinated, safe and cost-effective specialty care is one of the most pressing issues facing our healthcare systems worldwide.1 Poor access to specialty care is common across health delivery organisations, with wait times as high as 6–12 months in some communities.2–4 For many specialties this is rooted in a shortage of specialist physicians.5 A key question, therefore, is how to maximise the efficiency and effectiveness of specialist use and access. The traditional primary–specialty care interface consists of a primary care provider (PCP) faxing a referral request to a specialist’s office without much accompanying diagnostic information and waiting to hear from the patient when an appointment has been scheduled (often on a first-come, first-served basis). The process is inefficient as it often results in avoidable specialist visits, duplicate diagnostic testing and delayed diagnoses for those patients who need specialist evaluation sooner than others who were referred to the same specialist.6–8 Newer models for improving access to specialty care are thus urgently needed. Electronic consultation (eConsult), which provides a way for PCPs and their patients to obtain specialty expertise without an inperson patient visit to the specialist, has emerged as one potential solution for increasing access to specialty care through improved efficiency of consultation.1 eConsults are asynchronous virtual provider-to-provider consultations. They allow specialists to address consultative needs through chart review and communication with the referring provider, often without an inperson specialty care visit. They can be used to triage whether an inperson visit is needed, and when such a visit is needed, ensure adequate diagnostic work-up is completed before the visit. Ideally, this results in time saving for scarce specialists and improved wait times for patients. Studies of early adopters of eConsult programmes in …

The increased prevalence of obese, pregnant women who have a higher risk of glucose intolerance warrants the need for nutritional interventions to improve maternal glucose homeostasis. In this study, the effect of a low-glycemic load (GL) (n = 28) was compared to a high-GL (n = 34) dietary intervention during the second half of pregnancy in obese women (body mass index (BMI) &gt, 30 or a body fat &gt, 35%). Anthropometric and metabolic parameters were assessed at baseline (20 week) and at 28 and 34 weeks gestation. For the primary outcome 3h-glucose-iAUC (3h-incremental area under the curve), mean between-group differences were non-significant at every study timepoint (p = 0.6, 0.3, and 0.8 at 20, 28, and 34 weeks, respectively) and also assessing the mean change over the study period (p = 0.6). Furthermore, there was no statistically significant difference between the two intervention groups for any of the other examined outcomes (p ³ 0.07). In the pooled cohort, there was no significant effect of dietary GL on any metabolic or anthropometric outcome (p ³ 0.2). A post hoc analysis comparing the study women to a cohort of overweight or obese pregnant women who received only routine care showed that the non-study women were more likely to gain excess weight (p = 0.046) and to deliver large-for-gestational-age (LGA) (p = 0.01) or macrosomic (p = 0.006) infants. Thus, a low-GL diet consumed during the last half of pregnancy did not improve pregnancy outcomes in obese women, but in comparison to non-study women, dietary counseling reduced the risk of adverse outcomes.

This is a pre-copyedited, author-produced version of an article accepted for publication in Cardiovascular Research (CVR) following peer review. The version of record Perrino, Ferdinandy, Bøtker, Brundel, Collins, Davidson, Den Ruijter, Engel, Gerdts, Girao, Gyöngyösi, Hausenloy, Lecour, Madonna, Marber, Murphy, Pesce, Regitz-Zagrosek, Sluijter, Steffens, Gollmann-Tepeköylü, Van Laake, Van Linthout, Schulz, Ytrehus. Improving translational research in sex-specific effects of comorbidities and risk factors in ischaemic heart disease and cardioprotection: Position paper and recommendations of the ESC Working Group on Cellular Biology of the Heart. Cardiovascular Research (CVR). 2021;117(2):367-385, is available online at: https://doi.org/10.1093/cvr/cvaa155. Ischaemic heart disease (IHD) is a complex disorder and a leading cause of death and morbidity in both men and women. Sex, however, affects several aspects of IHD, including pathophysiology, incidence, clinical presentation, diagnosis as well as treatment and outcome. Several diseases or risk factors frequently associated with IHD can modify cellular signalling cascades, thus affecting ischaemia/reperfusion injury as well as responses to cardioprotective interventions. Importantly, the prevalence and impact of risk factors and several comorbidities differ between males and females, and their effects on IHD development and prognosis might differ according to sex. The cellular and molecular mechanisms underlying these differences are still poorly understood, and their identification might have important translational implications in the prediction or prevention of risk of IHD in men and women. Despite this, most experimental studies on IHD are still undertaken in animal models in the absence of risk factors and comorbidities, and assessment of potential sex-specific differences are largely missing. This ESC WG Position Paper will discuss: (i) the importance of sex as a biological variable in cardiovascular research, (ii) major biological mechanisms underlying sex-related differences relevant to IHD risk factors and comorbidities, (iii) prospects and pitfalls of preclinical models to investigate these associations, and finally (iv) will provide recommendations to guide future research. Although gender differences also affect IHD risk in the clinical setting, they will not be discussed in detail here.

Background Cryptococcal meningoencephalitis (CM) is a major cause of mortality in immunosuppressed patients and previously healthy individuals. In the latter, a post-infectious inflammatory response syndrome (PIIRS) is associated with poor clinical response despite antifungal therapy and negative cerebrospinal fluid (CSF) cultures. Data on effective treatment are limited. Methods Between March 2015 and March 2020, 15 consecutive previously healthy patients with CM and PIIRS were treated with adjunctive pulse corticosteroid taper therapy (PCT) consisting of intravenous methylprednisolone 1 gm daily for 1 week followed by oral prednisone 1 mg/kg/day, tapered based on clinical and radiological response plus oral fluconazole. Montreal cognitive assessments (MOCA), Karnofsky performance scores, magnetic resonance imaging (MRI) brain scanning, ophthalmic and audiologic exams, and CSF parameters including cellular and soluble immune responses were compared at PIIRS diagnosis and after methylprednisolone completion. Results The median time from antifungal treatment to steroid initiation was 6 weeks. The most common symptoms at PIIRS diagnosis were altered mental status and vision changes. All patients demonstrated significant improvements in MOCA and Karnofsky scores at 1 month (P Conclusions PCT in this small cohort of PIIRS was associated with improvements in CM-related complications with minimal toxicity in the acute setting.

Insulinomas are rare, and even rarer in patients with end-stage renal disease (ESRD). Clear criteria for the biochemical diagnosis of insulinomas in patients with renal failure have not been established, and hypoglycemia is often attributed to the renal disease itself, frequently leading to a delay in diagnosis. We describe a case of a patient who presented with asymptomatic recurrent hypoglycemia during hemodialysis. Disease progression and biochemical testing strongly suggested an insulinoma. Computed tomography (CT) of the abdomen and pelvis, 111In-pentetreotide scintigraphy and endoscopic ultrasound did not localize a pancreatic tumor. A calcium stimulation test was performed while the patient was taking diazoxide due to severe hypoglycemia with fasting for a couple of hours without treatment. The test showed a marked increase in insulin after calcium infusion in the dorsal pancreatic artery, localizing the tumor to the body and tail of the gland. Exploratory surgery easily identified a tumor at the body of the pancreas and pathology confirmed an insulin-secreting pancreatic neuroendocrine tumor. On follow-up, there was resolution of the hypoglycemia. We review the challenges of diagnosing an insulinoma in ESRD and describe a successful intra-arterial calcium stimulation test done in an ESRD patient while continuing diazoxide.

Objective To identify possible differences in baseline characteristics, initial treatment and treatment response between RA patient subgroups based on age at disease onset. Methods Daily practice data from the worldwide METEOR registry were used. Patients (7912) were stratified into three age-groups (age at disease diagnosis 65 years). Initial treatment was compared between the different age-groups. With Cox regression analyses the effect of age-group on time-to-switch from first to second treatment was investigated, and with linear mixed models differences in response to treatment (DAS and HAQ) between the age-groups were assessed, after correction for potential confounders. Results The >65 years age-group included more men, and more seronegative RA with somewhat higher inflammatory markers. Initial treatment choices differed only slightly between the age-groups, and the time-to-switch from initial treatment to the next was similar. DAS and HAQ improvement were dependent on the age-group, reflected by a significant interaction between age-group and outcome. The stratified analysis showed a difference of −0.02 and −0.05 DAS points and, −0.01 and 0.02 HAQ points per month in the 65 year age group, a difference that did not seem clinically relevant. Conclusion In this international study on worldwide clinical practice, patients with RA onset >65 years include more men and seronegative arthritis, and were initially treated slightly differently than younger patients. We observed no clinically relevant differences in timing of a next treatment step, or response to treatment measured by DAS and HAQ.

Background Evidence for the effectiveness of treatments in early-onset psychosis is sparse. Current guidance for the treatment of early-onset psychosis is mostly extrapolated from trials in adult populations. The UK National Institute for Health and Care Excellence has recommended evaluation of the clinical effectiveness and cost-effectiveness of antipsychotic drugs versus psychological intervention (cognitive behavioural therapy [CBT] and family intervention) versus the combination of these treatments for early-onset psychosis. The aim of this study was to establish the feasibility of a randomised controlled trial of antipsychotic monotherapy, psychological intervention monotherapy, and antipsychotics plus psychological intervention in adolescents with first-episode psychosis. Methods We did a multicentre pilot and feasibility trial according to a randomised, single-blind, three-arm, controlled design. We recruited participants from seven UK National Health Service Trust sites. Participants were aged 14–18 years; help-seeking; had presented with first-episode psychosis in the past year; were under the care of a psychiatrist; were showing current psychotic symptoms; and met ICD-10 criteria for schizophrenia, schizoaffective disorder, or delusional disorder, or met the entry criteria for an early intervention for psychosis service. Participants were assigned (1:1:1) to antipsychotics, psychological intervention (CBT with optional family intervention), or antipsychotics plus psychological intervention. Randomisation was via a web-based randomisation system, with permuted blocks of random size, stratified by centre and family contact. CBT incorporated up to 26 sessions over 6 months plus up to four booster sessions, and family intervention incorporated up to six sessions over 6 months. Choice and dose of antipsychotic were at the discretion of the treating consultant psychiatrist. Participants were followed up for a maximum of 12 months. The primary outcome was feasibility (ie, data on trial referral and recruitment, session attendance or medication adherence, retention, and treatment acceptability) and the proposed primary efficacy outcome was total score on the Positive and Negative Syndrome Scale (PANSS) at 6 months. Primary outcomes were analysed by intention to treat. Safety outcomes were reported according to as-treated status, for all patients who had received at least one session of CBT or family intervention, or at least one dose of antipsychotics. The study was prospectively registered with ISRCTN, ISRCTN80567433. Findings Of 101 patients referred to the study, 61 patients (mean age 16·3 years [SD 1·3]) were recruited from April 10, 2017, to Oct 31, 2018, 18 of whom were randomly assigned to psychological intervention, 22 to antipsychotics, and 21 to antipsychotics plus psychological intervention. The trial recruitment rate was 68% of our target sample size of 90 participants. The study had a low referral to recruitment ratio (around 2:1), a high rate of retention (51 [84%] participants retained at the 6-month primary endpoint), a high rate of adherence to psychological intervention (defined as six or more sessions of CBT; in 32 [82%] of 39 participants in the monotherapy and combined groups), and a moderate rate of adherence to antipsychotic medication (defined as at least 6 consecutive weeks of exposure to antipsychotics; in 28 [65%] of 43 participants in the monotherapy and combined groups). Mean scores for PANSS total at the 6-month primary endpoint were 68·6 (SD 17·3) for antipsychotic monotherapy (6·2 points lower than at randomisation), 59·8 (13·7) for psychological intervention (13·1 points lower than at randomisation), and 62·0 (15·9) for antipsychotics plus psychological intervention (13·9 points lower than at randomisation). A good clinical response at 6 months (defined as ≥50% improvement in PANSS total score) was achieved in four (22%) of 18 patients receiving antipsychotic monotherapy, five (31%) of 16 receiving psychological intervention, and five (29%) of 17 receiving antipsychotics plus psychological intervention. In as-treated groups, serious adverse events occurred in eight [35%] of 23 patients in the combined group, two [13%] of 15 in the antipsychotics group, four [24%] of 17 in the psychological intervention group, and four [80%] of five who did not receive any treatment. No serious adverse events were considered to be related to participation in the trial. Interpretation This trial is the first to show that a head-to-head clinical trial comparing psychological intervention, antipsychotics, and their combination is safe in young people with first-episode psychosis. However, the feasibility of a larger trial is unclear because of site-specific recruitment challenges, and amendments to trial design would be needed for an adequately powered clinical and cost-effectiveness trial that provides robust evidence. Funding National Institute for Health Research.

Cyclophilin D (CypD) is a mitochondrial peptidyl-prolyl cis-trans isomerase, well known for regulating the mitochondrial permeability transition pore (PTP), a non-specific large conductance pore whose opening leads to cell death and has been implicated in ischemia/reperfusion injury in multiple organs, in neurodegenerative disorders and in muscular dystrophies. While the main target of CypD is a matter of ongoing research, inhibiting CypD protects in models of those diseases making it an interesting therapeutic target. The present review focuses on post-translational modifications of CypD that have been identified by recent studies, which can alter the regulation of the PTP, and contribute to understanding the mechanisms of action of CypD.

Background: We examine the implementation of a DPP in the San Francisco Health Network, a safety net serving over 140,000 patients. We also evaluate the success of patients referred to a YMCA DPP, including the role of incentives (gym memberships and food vouchers). Methods: Overweight patients with prediabetes were referred, screened for eligibility and readiness, and invited to participate in a CDC-approved digital or in-person DPP. The YMCA’s DPP groups were led by a trained lifestyle coach, in English or Spanish, with 16 weekly core sessions followed by nine maintenance sessions over a year. Sessions were held at health care sites or at a YMCA (3 of 5 sites had gyms). Gym memberships were offered at no cost to all participants. Continued membership required meeting attendance metrics. Food vouchers became available to participants in Spring 2019. Results: From August 2017 to October 2019, 650 patients were referred to the DPP, 168 (25.8%) were reached, passed a readiness assessment and chose to participate. Of those, 110 patients expressed interest in the YMCA and 73 have registered for one of eight classes that are now past 16 weeks. Of those 73 patients, 64 officially enrolled (e.g. attended at least one session in the first four weeks). Enrolled patients were majority female (78.1%) and 45.3% reported a family history of DM. Average age was 47.9 ± 12.2 y, BMI 37.7 ± 8.4, A1c 5.8% ± 0.3. More than half (56.3%) were Hispanic/Latino, 17.2% Black, 9.4% Asian. Exactly half were English- and half Spanish-speaking. Of the 64 enrolled patients, 42 were retained in the DPP (e.g. attended four or more sessions). These patients attended an average of 11.8 ± 3.4 of the core 16 sessions. At wk 16, average weight loss was 2.2% ± 3.9 (N=40, range -4.4, 16.7); 20% of patients lost at least 5% of their initial body weight. Regarding incentives, 76% of the retained patients activated their gym membership. Average monthly gym attendance was 9.1 ± 9.1 visits with monthly visits maintained over 180 days. Gym visits positively correlated with weight loss (r2= 0.42) and there was a non-significant trend towards more frequent gym visits by patients enrolled at sites with a gym (11.8 ± 10.9 vs 6.5 ± 6.2). Comparison of Spanish-speaking participants who received food vouchers to those who did not showed a non-significant trend towards improved attendance (12.1 ± 3.0 vs 9.6 ± 3.7 of 16) and 16 wk weight loss (2.2% ± 3.4 vs 0.3% ± 2.4). Additional follow-up data at 36 wks available on 19 patients showed a sustained weight loss of 3.8% ± 6.6 compared to 2.4% ± 4.3 at 16 wks. Conclusion: While DPPs have been widely promoted, real-world implementation has been challenging. Understanding the delivery of DPPs in safety net populations is important given barriers to attendance. Our results show early modest weight loss in those enrolled in the YMCA DPP and suggest incentives such as gym memberships and food vouchers may improve attendance and weight loss.

Background Coronavirus disease 2019 (COVID-19) is a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first detected in China in December, 2019. In January, 2020, state, local, and federal public health agencies investigated the first case of COVID-19 in Illinois, USA. Methods Patients with confirmed COVID-19 were defined as those with a positive SARS-CoV-2 test. Contacts were people with exposure to a patient with COVID-19 on or after the patient's symptom onset date. Contacts underwent active symptom monitoring for 14 days following their last exposure. Contacts who developed fever, cough, or shortness of breath became persons under investigation and were tested for SARS-CoV-2. A convenience sample of 32 asymptomatic health-care personnel contacts were also tested. Findings Patient 1-a woman in her 60s-returned from China in mid-January, 2020. One week later, she was hospitalised with pneumonia and tested positive for SARS-CoV-2. Her husband (Patient 2) did not travel but had frequent close contact with his wife. He was admitted 8 days later and tested positive for SARS-CoV-2. Overall, 372 contacts of both cases were identified; 347 underwent active symptom monitoring, including 152 community contacts and 195 health-care personnel. Of monitored contacts, 43 became persons under investigation, in addition to Patient 2. These 43 persons under investigation and all 32 asymptomatic health-care personnel tested negative for SARS-CoV-2. Interpretation Person-to-person transmission of SARS-CoV-2 occurred between two people with prolonged, unprotected exposure while Patient 1 was symptomatic. Despite active symptom monitoring and testing of symptomatic and some asymptomatic contacts, no further transmission was detected. Funding None.

Objective.To assess differences in initial treatment and treatment response in male and female patients with rheumatoid arthritis (RA) in daily clinical practice.Methods.The proportion of patients with RA starting different antirheumatic treatments (disease-modifying antirheumatic drugs; DMARD) and the response to treatment were compared in the international, observational METEOR register. All visits from start of the first DMARD until the first DMARD switch or the end of followup were selected. The effect of sex on time to switch from first to second treatment was calculated using Cox regression. Linear mixed model analyses were performed to assess whether men and women responded differently to treatments, as measured by Disease Activity Score (DAS) or Health Assessment Questionnaire.Results.Women (n = 4393) more often started treatment with hydroxychloroquine, as monotherapy or in combination with methotrexate (MTX) or a glucocorticoid, and men (n = 1142) more often started treatment with MTX and/or sulfasalazine. Time to switch DMARD was shorter for women than for men. Women had a statistically significantly higher DAS over time than men (DAS improvement per year β −0.69, 95% CI −0.75 to −0.62 for men and −0.58, 95% CI −0.62 to −0.55 for women). Subanalyses per DMARD group showed for the conventional synthetic DMARD combination therapy a slightly greater decrease in DAS over time in men (−0.89, 95% CI −1.07 to −0.71) compared to women (−0.59, 95% CI −0.67 to −0.51), but these difference between the sexes were clinically negligible.Conclusion.This worldwide observational study suggests that in daily practice, men and women with RA are prescribed different initial treatments, but there were no differences in response to treatment between the sexes.

The regulatory control of cardiac endoplasmic reticulum (ER) stress is incompletely characterized. As ER stress signaling upregulates the E3-ubiquitin ligase Parkin, we investigated the role of Parkin in cardiac ER stress. Parkin knockout mice exposed to aortic constriction-induced cardiac pressure-overload or in response to systemic tunicamycin (TM) developed adverse ventricular remodeling with excessive levels of the ER regulatory C/EBP homologous protein CHOP. CHOP was identified as a Parkin substrate and its turnover was Parkin-dose and proteasome-dependent. Parkin depletion in cardiac HL-1 cells increased CHOP levels and enhanced susceptibility to TM-induced cell death. Parkin reconstitution rescued this phenotype and the contribution of excess CHOP to this ER stress injury was confirmed by reduction in TM-induced cell death when CHOP was depleted in Parkin knockdown cardiomyocytes. Isogenic Parkin mutant iPSC-derived cardiomyocytes showed exaggerated ER stress induced CHOP and apoptotic signatures and myocardium from subjects with dilated cardiomyopathy showed excessive Parkin and CHOP induction. This study identifies that Parkin functions to blunt excessive CHOP to prevent maladaptive ER stress-induced cell death and adverse cardiac ventricular remodeling. Additionally, Parkin is identified as a novel post-translational regulatory moderator of CHOP stability and uncovers an additional stress-modifying function of this E3-ubiquitin ligase.

Aims and objectives To evaluate the effect of an ‘insulin introduction’ group visit on insulin initiation and A1C in adults with type 2 diabetes. Background The clinical course of type 2 diabetes involves eventual beta-cell failure and the need for insulin therapy. Patient psychological insulin resistance, provider-related delays and system barriers to timely initiation of insulin are common. Group visits are widely accepted by patients and represent a potential strategy for improving insulin initiation. Design A single two-hour group visit in English or Spanish, facilitated by advanced practice nurses, addressed psychological insulin resistance and encouraged mock injections to overcome needle anxiety. Methods A retrospective review of 273 patients referred from 2008–2012, determined characteristics of group attenders, rates of mock self-injection, rates of insulin initiation and changes in A1C from baseline to 2–6 and 7–12 months postgroup. Change in A1C was compared to patients referred to the group who did not attend (‘nonattenders’). Results Of 241 patients eligible for analysis, 87·6% were racial/ethnic minorities with an average A1C of 9·99%. Group attendance rate was 66%; 92% performed a mock injection, 55% subsequently started insulin. By 2–6 months, A1C decreased by 1·37% among group attenders, and by 1·6% in those who did a mock injection and started insulin. Fewer nonattenders started insulin in primary care (40%), experiencing an A1C reduction of 0·56% by 2–6 months. A1C improvements were sustained by 7–12 months among group attenders and nonattenders who started insulin. Relevance to clinical practice Nurses can effectively address patient fears and engage patients in reframing insulin therapy within group visits. Conclusions This one-time nurse-facilitated group visit addressing psychological barriers to insulin in a predominantly minority patient population resulted in increased insulin initiation rates and clinically meaningful A1C reductions.

This study aimed to confirm the factor structure of the Beliefs about Paranoia Scale (BaPS), a self-report measure to assess metacognitive beliefs about paranoia, and to test hypotheses of a metacognitive model. We hypothesised that positive and negative beliefs about paranoia would be associated with severity of suspiciousness, and that the co-occurrence of positive and negative beliefs would be associated with increased suspiciousness. A total of 335 patients meeting criteria for a schizophrenia spectrum disorder completed the BaPS, the Positive and Negative Syndromes Scale (PANSS), and the Psychotic Symptom Rating Scales (PSYRATS). Confirmatory factor analysis verified that the three BaPS subscales (negative beliefs about paranoia, paranoia as a survival strategy, and normalizing beliefs) were an adequate fit of the data. Ordinal regression showed that positive beliefs about paranoia as a survival strategy and negative beliefs were both associated with severity of suspiciousness. This was the first study to show that the co-occurrence of positive and negative beliefs was associated with increased suspiciousness. All hypotheses were confirmed, suggesting that a metacognitive approach has utility for the conceptualization of paranoia. Clinical implications suggest a role for metacognitive therapy, including strategies such as detached mindfulness and worry postponement.

Article as accepted for publication in Philosophy, Psychiatry, and Psychology published by John Hopkins University Press

Successful critiques of health policies for people with impaired cognition identify a need for alternatives that go beyond individualism. ‘Choice’ policy was examined as young people with severe intellectual disabilities moved from special schools to adult services. We draw on three cases from a longitudinal cohort study to examine the way decisions with and for these young people were made and accounted for. It was not a simple matter of parents and transition workers hearing about these young people’s choices and facilitating what they wanted. The data raise questions about discourses of choice in ID when referring to people with severe intellectual disabilities: few ‘choices’ could be considered informed nor made by young people with capacity to make them and many decisions were informed by other ethics. Findings were interpreted through a Deleuzean ethical–relational lens. We identify implications for theory and practice to show how Deleuzean thinking can reinvigorate intellectual disability.

The clinical course of patients with recently diagnosed early stage chronic lymphocytic leukemia (CLL) is highly variable. We examined the relationship between CLL-cell birth rate and treatment-free survival (TFS) in 97 patients with recently diagnosed, Rai stage 0-II CLL in a blinded, prospective study, using in vivo 2H2O labeling. Birth rates ranged from 0.07 to 1.31% new cells per day. With median follow-up of 4.0 years, 33 subjects (34%) required treatment by NCI criteria. High-birth rate was observed in 44% of subjects and was significantly associated with shorter TFS, unmutated IGHV status and expression of ZAP70 and of CD38. In multivariable modeling considering age, gender, Rai stage, expression of ZAP70 or CD38, IGHV mutation status and FISH cytogenetics, only CLL-cell birth rate and IGHV mutation status met criteria for inclusion. Hazard ratios were 3.51 (P=0.002) for high-birth rate and 4.93 (P

Background Cryptococcal meningoencephalitis (CM) is a major cause of mortality in HIV/AIDS, transplant recipients and previously healthy individuals. In the latter, a post-infectious inflammatory response syndrome (PIIRS) is associated with poor clinical response despite prior amphotericin therapy and CSF culture conversion. Data on effective treatment is limited. Methods Between March 2015 and March 2020, 15 patients with CM/PIIRS were treated with adjunctive pulse – taper corticosteroid therapy (PCT) consisting of intravenous methylprednisolone 1 gm daily for 1 week followed by oral prednisone 1 mg/kg/d, tapered based on clinical and radiological response plus oral fluconazole. Montreal cognitive assessments (MOCA), Karnofsky Performance scores, MRI brain scans, eye and audiologic exams were conducted at baseline and after pulse completion. CSF parameters were assessed prior to and after the pulse. Results 80% of patients were male, median age 51 years. Median time from antifungal treatment to steroid initiation was 6 weeks. The most common symptoms at PIIRS diagnosis were progressive deterioration in mental status and vision changes. There was a significant improvement in MOCA(n=14) and Karnofsky(n=15) scores at 3 weeks (p< 0.0003), which was accompanied by improvements in CSF: serum, glucose ratios, CSF WBC, protein and activated CD4 T cells (n=14) post-pulse (p< 0.003). Additionally, soluble CSF IL-6 and sCD25 levels improved (p = 0.03). Neurofilament light chain levels (NFL), a biomarker of axonal damage, showed significant reductions over a 30-month period (Generalized Estimating Equation coefficient = 0.128) and a negative correlation with post pulse MOCA scores (r = - 0.8; p = 0.01). Papilledema (n=8) and visual field deficits (n=11) improved significantly (p< 0.0005) after 2 months of pulse completion. Brain MRI showed improvement of radiological findings in 11 patients (p=0.001). Five out of 7 patients who underwent audiological testing demonstrated hearing improvement after 3 weeks post-pulse. CSF cultures remained negative. Conclusion PCT in this small cohort of PIIRS patients was associated with persistent improvements in CM-related complications with minimal toxicity and no recurrence of infection. Disclosures All Authors: No reported disclosures

Background Translocation of miR‐181c into cardiac mitochondria downregulates the mitochondrial gene, mt‐ COX 1. miR‐181c/d −/− hearts experience less oxidative stress during ischemia/reperfusion (I/R) and are protected against I/R injury. Additionally, miR‐181c overexpression can increase mitochondrial matrix Ca 2+ ([Ca 2+ ] m ), but the mechanism by which miR‐181c regulates [Ca 2+ ] m is unknown. Methods and Results By RNA sequencing and analysis, here we show that hearts from miR‐181c/d −/− mice overexpress nuclear‐encoded Ca 2+ regulatory and metabolic pathway genes, suggesting that alterations in miR‐181c and mt‐ COX 1 perturb mitochondria‐to‐nucleus retrograde signaling and [Ca 2+ ] m regulation. Quantitative polymerase chain reaction validation of transcription factors that are known to initiate retrograde signaling revealed significantly higher Sp1 (specificity protein) expression in the miR‐181c/d −/− hearts. Furthermore, an association of Sp1 with the promoter region of MICU 1 was confirmed by chromatin immunoprecipitation‐quantitative polymerase chain reaction and higher expression of MICU 1 was found in the miR‐181c/d −/− hearts. Conversely, downregulation of Sp1 by small interfering RNA decreased MICU 1 expression in neonatal mouse ventricular myocytes. Changes in PDH activity provided evidence for a change in [Ca 2+ ] m via the miR‐181c/ MICU 1 axis. Moreover, this mechanism was implicated in the pathology of I/R injury. When MICU 1 was knocked down in the miR‐181c/d −/− heart by lentiviral expression of a short‐hairpin RNA against MICU 1, cardioprotective effects against I/R injury were abrogated. Furthermore, using an in vitro I/R model in miR‐181c/d −/− neonatal mouse ventricular myocytes, we confirmed the contribution of both Sp1 and MICU 1 in ischemic injury. Conclusions miR‐181c regulates mt‐ COX 1, which in turn regulates MICU 1 expression through the Sp1‐mediated mitochondria‐to‐nucleus retrograde pathway. Loss of miR‐181c can protect the heart from I/R injury by modulating [Ca 2+ ] m through the upregulation of MICU 1.

Background Heart failure is one of the leading causes of death in Western countries, and there is a need for new therapeutic approaches. Relaxin‐2 is a peptide hormone that mediates pleiotropic cardiovascular effects, including antifibrotic, angiogenic, vasodilatory, antiapoptotic, and anti‐inflammatory effects in vitro and in vivo. Methods and Results We developed RELAX 10, a fusion protein composed of human relaxin‐2 hormone and the Fc of a human antibody, to test the hypothesis that extended exposure of the relaxin‐2 peptide could reduce cardiac hypertrophy and fibrosis. RELAX 10 demonstrated the same specificity and similar in vitro activity as the relaxin‐2 peptide. The terminal half‐life of RELAX 10 was 7 days in mouse and 3.75 days in rat after subcutaneous administration. We evaluated whether treatment with RELAX 10 could prevent and reverse isoproterenol‐induced cardiac hypertrophy and fibrosis in mice. Isoproterenol administration in mice resulted in increased cardiac hypertrophy and fibrosis compared with vehicle. Coadministration with RELAX 10 significantly attenuated the cardiac hypertrophy and fibrosis compared with untreated animals. Isoproterenol administration significantly increased transforming growth factor β1 (TGF‐β1)–induced fibrotic signaling, which was attenuated by RELAX 10. We found that RELAX 10 also significantly increased protein kinase B/endothelial NO synthase signaling and protein S‐nitrosylation. In the reversal study, RELAX 10‐treated animals showed significantly reduced cardiac hypertrophy and collagen levels. Conclusions These findings support a potential role for RELAX 10 in the treatment of heart failure.

Objective There is an ongoing debate about excluding patient's global assessment (PtGA) from composite and Boolean-based definitions of rheumatoid arthritis (RA) remission. This study aimed at determining the influence of PtGA on RA disease states, exploring differences across countries, and understanding the association between PtGA, measures of disease impact (symptoms), and markers of disease activity (inflammation). Methods Cross-sectional data from the Measurement of Efficacy of Treatment in the Era of Outcome in Rheumatology international database were used. We calculated the proportion of patients failing American College of Rheumatology/European League Against Rheumatism Boolean-based remission (4-variable remission) solely due to PtGA (PtGA-near-remission) in the overall sample and in the most representative countries (i.e., those with >3,000 patients in the database). Multivariable linear regression models were used to identify the main determinants of PtGA, grouped in predominantly inflammatory impact factors (28 tender joint counts, 28 swollen joint counts, and C-reactive protein level) and disease impact factors (pain and function). Results This study included 27,768 patients. Excluding PtGA from the Boolean-based definition (3-variable remission) increased the remission rate from 5.8% to 15.8%. The rate of PtGA-near-remission varied considerably between countries, from 1.7% in India to 17.9% in Portugal. One-third of the patients in PtGA-near-remission group scored PtGA >4 of 10. Pain and function were the main correlates of PtGA, with inflammation-related variables contributing less to the model (R2 = 0.57). Conclusion PtGA is moderately related to joint inflammation overall, but only weakly so in low levels of disease activity. A considerable proportion of patients otherwise in biologic remission still perceive high PtGA, putting them at risk of excessive immunosuppressive treatment.

ObjectiveTo investigate associations between baseline presence of erosions and/or anti-citrullinated protein antibodies (ACPA) on functional ability, disease activity and treatment survival over time.MethodsReal life data from newly diagnosed rheumatoid arthritis patients were identified in the international METEOR registry. Patients were grouped according to presence/absence of ACPA and/or erosions at baseline. Associations between the presence of ACPA and/or erosions (four groups) with the change of Disease Activity Score (DAS) and Health Assessment Questionnaire (HAQ) over time were assessed using linear mixed models during maximum 6 or maximum 12 months from baseline. Treatment survival was assessed using multiple failure-times Cox regression.ResultsData were included from 701 ACPA‒/erosions‒, 334 ACPA‒/erosions+, 1585 ACPA+/erosions‒ and 1993 ACPA+/erosions+ patients. We found statistically significant differences in DAS and HAQ change over time between the four groups, both after maximum follow-up durations of 6 and of 12 months, but after stratification differences proved small and not clinically meaningful. Patients in the ACPA‒/erosions‒ group were less likely to switch treatment compared with the ACPA+/erosions‒ reference group (pConclusionsIn this analysis of worldwide real life data, we found statistically significant, but clinically irrelevant differences in treatment response to initial disease modifying anti-rheumatic drug therapies as measured by DAS and HAQ in ACPA‒/erosions‒, ACPA‒/erosions+, ACPA+/erosions‒ and ACPA+/erosions+ rheumatoid arthritis patients. However, after maximum follow-up durations of 6 and 12 months all groups had a similar response to initial treatment, but with a lower likelihood to switch treatment for ACPA‒/erosions‒ patients during the first year of follow-up.

Introduction HSE is estimated to occur in approximately 1 in 250,000 to 1 in 500, 000 individuals per year, with approximately one third of cases occurring in children and adolescents. Poorer prognosis and neurological sequelae are associated with delayed treatment of HSE. We retrospectively reviewed all cases of HSV meningoencephalitis admitted to our centre over a ten year period from Jan 2008 to Jan 2018. Four cases were identified based on PCR confirmation of HSV 1 or 2 in cerebrospinal fluid samples. Here we discuss the clinical presentation, as well as electroencelphalogram, neuroimaging and clinical outcomes, to highlight the importance of early recognition and timely treatment of such cases. Case series Case 1: Nineteen month old male infant presented with prolonged focal febrile seizure, on a preceding history of pyrexia and lethargy for one day, and cough for one week. EEG showed excess slowing over both posterior regions, more marked on the left posterior region, consistent with bilateral cerebral dysfunction without epileptiform discharges. MRI brain demonstrated deep white matter changes in the left parietal and posterior parietal/occipital regions and adjacent grey matter and two small punctate haemorrhages in the left midparietal region. Case 2: Four week old male infant presented with recurrent focal seizures. No pyrexia or preceding symptoms were documented. EEG recorded two seizures with origin near the right midline with spread to right motor cortex and right hemisphere. MRI brain showed right deep white matter changes and left subcortical lesion. Case 3: Eleven week old female infant admitted with pyrexia and lethargy. She had 6 episodes of febrile generalised tonic seizures over 48 hours, each less than 5 minutes in duration. EEG demonstrated some asymmetry and excess slow activities over right temporal region in sleep, with no epileptiform features. MRI brain was normal. Case 4: Thirteen month old female presented with febrile status epilepticus, on a background history of pyrexia and diarrhoea for 3 days. EEG showed three epileptic spasms with background continuous epileptiform discharges, which were multifocal; predominantly right posterior and some frontal discharges were seen in sleep. MRI brain showed subtle high signal white matter changes in the frontal lobes bilaterally and multiple high signal areas throughout corpus callosum. Discussion This case series demonstrates that HSV encephalitis should be considered in children with atypical febrile seizures which are prolonged, focal or recurrent. Timely recognition of HSE is essential to minimise patient morbidity and mortality.

Background Despite efforts to predict treatment response, treatment of rheumatoid arthritis (RA) patients remains mostly a case of trial and error. Presence of erosions and ACPA are often considered poor prognostic factors based on their association with radiographic damage progression, but with the introduction of treat-to-target ever fewer patients develop significant radiographic damage. Therefore research into prognostic factors should focus on clinical outcomes. Objectives To investigate in newly diagnosed RA patients if presence of erosions and/or ACPA are associated with functional ability, disease activity and treatment survival during the first year of treatment in daily practice. Methods Newly diagnosed patients with a clinical diagnosis of RA, ≥3 months follow-up and available data on ACPA, erosions and medication were identified in the international, observational METEOR registry (n patients=4623). Timing and frequency of follow-up visits were according to daily practice. We focused at results after a maximum follow-up duration of 6 months or of 1 year from baseline. Associations between the presence of erosions and/or ACPA (4 groups) with the change of DAS and HAQ over time were assessed using linear mixed models. Time to treatment change during the first year of follow-up was compared between the ACPA/erosions groups using multiple failure-times Cox regression. Treatment change was defined as a change in type of treatment. A change in medication dose or tapering was not considered a treatment change. Missing data were imputed using multiple chained equations (40 cycles) and models were adjusted for the potential confounders age, gender, smoking, symptom duration, BMI, initial medication and country. In case of statistically significant effect modification (p 5 years), results were stratified. Results Baseline characteristics and follow-up duration of each ACPA/erosions group are shown in table 1. Baseline DAS and HAQ were slightly higher in erosions+ patients. Follow-up duration was similar between the 4 groups. We found statistically significant differences in DAS and HAQ change over time between the 4 groups, both after maximum follow-up durations of 6 months and of 1 year (table 1), but differences were small and not clinically relevant. Patients who were erosions-/ACPA- were less likely to switch treatment [HR (95% CI) 0.79 (0.69; 0.90)] compared to a reference group of erosions-/ACPA+ patients. Patients who were erosions+/ACPA- [HR (95% CI) 0.92 (0.79; 1.08)] or erosions+/ACPA+ [HR (95% CI) 1.01 (0.92; 1.10)] were not statistically significantly different from the reference group in their likelihood to switch treatment. No effect modification was found by country, medication or symptom duration. Conclusion In this analysis of worldwide real life data, we found statistically significant, but no clinically relevant differences in treatment response to initial DMARD therapies as measured by DAS and HAQ in ACPA-/erosions-, ACPA-/erosions+, ACPA+/erosions- and ACPA+/erosions+ RA patients. However, ACPA-/erosions- patients were less likely to switch treatment. Thus, in newly diagnosed RA patients who are treated according to modern treatment strategies, the (combined presence of) ACPA and erosions was no risk factor for worse disease activity or physical functioning, although ACPA-/erosions- patients had fewer treatment changes. Disclosure of Interests Sytske Anne Bergstra Grant/research support from: Bristol-Myers Squibb provided funding for the completion of this study and the development of the abstract., Maura Couto: None declared, Nimmisha Govind: None declared, Arvind Chopra Grant/research support from: Pfizer Inc, Karen Solomon-Escoto: None declared, Elizabeth Murphy Consultant for: Has received support from Roche to audit work on behalf of the Scottish Society for Rheumatology., Thomas Huizinga Consultant for: Merck, UCB, Bristol Myers Squibb, Biotest AG, Pfizer, GSK, Novartis, Roche, Sanofi-Aventis, Abbott, Crescendo Bioscience Inc., Nycomed, Boeringher, Takeda, Zydus, Epirus, Eli Lilly, Cornelia Allaart: None declared

Introduction Malignant Mesothelioma (MM) is a rare invasive neoplasm arising from the mesothelial lining of several organs, primarily the pleura and peritoneum1. A causal relationship with asbestos exposure is well established, however; MM can occur in the absence of well-defined risk factors and at an earlier age2. Case Presentation A 15 year old boy, presented to the Emergency Department with a 6-week history of cough, 5 kilogram weight loss and right sided pleuritic chest pain. He had attended the ED 4 weeks prior to this with chest pain, cough, temperature and a chest infection was diagnosed. Repeat chest x-raydemonstrated a right lower lobe consolidation with obscuration of the hemidiaphragm and a suspected pleural based opacification. Laboratory investigations showed a hypochromic microcytic anaemia, hyponatremia and raised inflammatory markers. A CT of thorax, abdomen and pelvis showed lobulated rind of pleural based soft tissue densities in the right thorax with downward invasion through the hemidiaphragm into the liver. On transfer to a tertiary Paediatric Oncology centre, A CT-guided biopsy demonstrated a malignant epithelioid neoplasm confirming a diagnosis of malignant mesothelioma with EWSR-ATF1 rearrangement. He was treated with 2 cycles of Pemetrexed and Cisplatin Chemotherapy (NCCP guideline). Follow up imaging demonstrated disease progression which coincided with clinical deterioration. NG feeding, PleuralX drain and Oxygen therapy are part of his treatment regimen. Vinorelbine monotherapy was commenced and a Palliative approach has been adopted. Currently he is stable awaiting further imaging. Discussion MM is rare is young people. The genetic susceptibility to MM is complex and recently an EWSR1-ATF1 fusion transcript has been described in 4 younger patients without prior asbestos exposure2. The prognosis in MM is poor but improved survival in younger patients has been observed1. We wish to highlight this case because it is rarely encountered in a paediatric setting.

Discordance between A1C and fasting glucose (FBG) or oral glucose tolerance glucose (OGTT) in the detection of dysglycemia has been observed in multiracial and multiethnic populations. In most instances, A1C under detected diabetes or prediabetes compared to glucose tests. To determine the relationship between FBG, OGTT and A1C for the diagnosis of prediabetes in a Filipino American population we studied 154 self-reported nondiabetic adult subjects from the Filipino Health study living in the U.S. > 3 year. Mean age 42 ± 18 y, BMI 25.8 ± 3.8, 58% female, and 67% with a family history of diabetes. Using ADA criteria, 5 subjects met the diagnosis of diabetes (4 by A1C and 1 by OGTT, the later subject is not included in Table 1) while 61 (40%) had prediabetes. Prevalence of prediabetes was only 6.5% by FBG and 7.1% by OGTT. However, the prediabetes prevalence was 36% by A1C. Kruskal Wallis was used to test the difference in insulin resistance by HOMA-IR and insulin between HbA1C categories. Subjects with an A1C of 5.7-6.4% (41 of whom had normal FBG and OGTT) were significantly more insulin resistant than those with an A1C < 5.7%. This suggests A1C may be a more sensitive test of abnormal glucose regulation in a Filipino population living in the U.S. than FBG or OGTT. Outcome studies assessing progression to diabetes will be needed to confirm this hypothesis. Disclosure M.P. Mercado: None. S. Kim: None. E.C. Cutiongco de la Paz: None. M. Seielstad: None. E. Paz-Pacheco: None. E. Murphy: None. Funding Philippine-California Advanced Research Institutes

Introduction Food allergy has become an increasingly common condition in the paediatric community over recent decades1. Many of these patients are at risk of developing anaphylaxis following exposure to food allergens. Adrenaline Auto-Injector (AAI) devices are prescribed to these patients to be used in the event of anaphylaxis following accidental exposure. Guidance The Irish Food Allergy Network (IFAN) recommends that patients who are prescribed AAIs should carry two AAIs at all times. For school-going children, it is recommended that two AAIs should be stored in their school in the event of accidental exposure2. Aims To evaluate parental compliance with carriage of AAI devices according to guidelines. To review parental confidence on when and how to use AAIs. Methodology A one-page questionnaire was compiled, which was approved by Tallaght University Hospital Clinical Audit Committee. We invited parents of children attending the paediatric allergy outpatient and day-ward services who had been prescribed AAI devices to complete this questionnaire anonymously and return it to clinical staff. This audit was carried out from October 2018 to January 2019 in five outpatient and four day-ward clinics each month. Data was compiled in a spreadsheet and interpreted. Results 53 parents completed our questionnaire. Patients ranged from nine months to sixteen years of age. 71% (n=38) reported carrying AAI devices. Of these, 66% (n=35) carried two devices. 88% (n=47) reported that their AAIs were within date. Of those without devices, 15% (n=8) reported AAIs were left in the car while another 11% (n=6) stated their AAIs were left at home. Regarding confidence in AAI training, 75% (n=40) of parents surveyed felt confident in knowing when an AAI should be given, giving a score of 4 or 5 on a scale of 1 to 5. 86% (n=46) were confident in knowing how to administer an AAI device. Conclusion Our audit shows that 1 in 3 patients who were prescribed AAIs did not carry the recommended two devices with them when attending our outpatient services. Only 75% of patients and parents felt confident in knowing when they should give an AAI. This audit highlights the importance of taking the time to educate and re-educate patients and parents. Emphasis should be made on the importance of carrying AAIs at all times. References Ben-Shoshan M et al, Curr Allergy Asthma Rep (2012)12:346. https://doi.org/10.1007/s11882–012–0274–3 IFAN[Internet], Food Allergy in School. Cork Irl. 2017(cited Jan 2019) http://ifan.ie/childcare-schools/Save

Introduction Severe Combined Immunodeficiency (SCID) is a heterogenous group of primary immunodeficiency disorders with impaired cellular and humoral immunity. This leads to increased susceptibility to life-threatening bacterial, viral and fungal infections. Incidence is approximately 1 per 58,000 live births.1Typically, SCID presents in the first months of life with severe, recurrent infections, failure to thrive, dermatologic manifestations or chronic diarrhoea. We present a case of newly diagnosed SCID and examine parechovirus viral loads before and after treatment. Case A thriving, term five-month old infant was admitted with symptoms suggestive of bronchiolitis and lower respiratory tract infection. In her medical history she had mild eczema at eight weeks old, was exclusively breastfed from birth and was unvaccinated. Admission investigations showed an elevated c-reactive protein of 41 mg/L, and white cell count (WCC) of 7.8*109/L with lymphocytes of 0.7*109/L. Chest radiography showed bilateral lung field opacifications. She was treated with intravenous(IV) amoxicillin and supplemental oxygen. Viral throat swab and stool samples respectively isolated rhino/enterovirus and norovirus. Cough swab and nasopharyngeal aspirate (NPA) isolated methicillin-sensitive staphylococcus aureus and scanty haemophilus influenzae respectively. Good clinical response to therapy was observed and she was discharged after 10 days. Her respiratory symptoms returned following discharge; she developed a purulent ear discharge treated with oral co-amoxiclav by her GP. She was readmitted with persistent bilateral pneumonia shortly after this. Repeat investigations showed a WCC of 3.2*109/L with lymphocyte count of 0.1*109/L. IV cefuroxime, PO azithromycin and oxygen therapy were commenced. Repeat NPA was positive for rhino/enterovirus and parechovirus. Immunoglobulin subsets showed severe deficiency of IgG, IA and IgM. Lymphocyte subsets demonstrated undetectable B cells, minimal T cells and deficient NK cells consistent with SCID. IV ceftriaxone and co-trimoxazole were commenced with aciclovir and fluconazole prophylaxis. Weekly intravenous immunoglobulin therapy (IVIG) was commenced and definitive treatment with haematopoietic stem cell transplant (HSCT) is planned. Genetic testing revealed RAG2 mutation. Serial viral load testing showed a gradual increase in the CT (crossing target) with weekly IVIG treatment indicating significant reduction in parechovirus viral load. Discussion Without timely diagnosis and management, SCID is typically fatal within the first year of life. Although HSCT is the only definitive treatment option, IVIG and broad antimicrobial prophylaxis is life-saving. In this case, repeated IVIG therapy correlated with reduction in parechovirus viral load and clinical improvement. Reference Kwan, et al. Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States. JAMA,2014312:729

There is a crucial need for successful strategies for DPP enrollment and implementation in safety net populations which are disproportionally affected by diabetes. We examine enrollment outcomes in a DPP referral program in the San Francisco Health Network, a safety net serving over 140,000 patients. Overweight patients with prediabetes are referred via an electronic consultation system from 20 community primary care and weight management clinics. Eligible Spanish- or English-speaking patients are contacted by a patient navigator, screened for eligibility, given a readiness assessment and if appropriate, invited to participate in either a digital or in-person DPP. Patients interested in an in-person program but not ready for the full DPP are offered the 6-week Diabetes Empowerment Education Program (DEEP). From August 2017 to November 2018, 305 patient referrals were evaluated: 44 (14.4%) did not qualify after chart review (e.g., they already had diabetes, were not prediabetic, or were out of network), 124 (40.7%) were unable to be reached (13 did not have a working phone, 23 had no voicemail, 88 did not return calls) and 137 (44.9%) patients were reached. Of those 137, 26 (19.0%) were unaware that their provider had referred them or were not interested while 111 (81.0%) were interested. Ten of those patients were not ready for the full DPP and chose DEEP. The remaining 101 patients completed the intake process, passed a readiness assessment and chose to enroll in a DPP: 25 (24.8%) chose a digital DPP and 76 (75.2%) an in-person DPP with a nonsignificant trend towards a preference for a digital DPP by younger patients. Thus, of 305 initial referrals less than half (36.4%) were successfully enrolled. The primary challenge was difficulty reaching and engaging patients. Potential strategies to improve patient yield include better education of referring providers on initial readiness assessments, DPP eligibility, and the importance of a good contact number. Measuring weight loss outcomes in these patients will be crucial. Disclosure S. Kim: None. A.H. Tang: None. C. Kuo: None. R.S. Garcia: None. S. Kim: None. E. Murphy: None.

TRIM72 is a membrane repair protein that protects against ischemia reperfusion (I/R) injury. We previously identified Cys144 (C144) on TRIM72 as a site of S-nitrosylation. To study the importance of C144, we generated a knock-in mouse with C144 mutated to a serine (TRIM72 C144S). We subjected ex vivo perfused mouse hearts to 20 min of ischemia followed by 90 min of reperfusion and observed less injury in TRIM72 C144S compared to WT hearts. Infarct size was smaller (54 vs 27% infarct size) and cardiac functional recovery (37 vs 62% RPP) was higher for the TRIM72 C144S mouse hearts. We also demonstrated that TRIM72 C144S hearts were protected against I/R injury using an in vivo LAD occlusion model. As TRIM72 has been reported to be released from muscle we tested whether C144 is involved in TRIM72 release. After I/R there was significantly less TRIM72 in the perfusate normalized to total released protein from the TRIM72 C144S compared to WT hearts, suggesting that C144 of TRIM72 regulates myocardial TRIM72 release during I/R injury. In addition to TRIM72's protective role in I/R injury, TRIM72 has also been implicated in cardiac hypertrophy and insulin resistance, and secreted TRIM72 has recently been shown to impair insulin sensitivity. However, insulin sensitivity (measured by glucose and insulin tolerance) of TRIM72 C144S mice was not impaired. Further, whole body metabolism, as measured using metabolic cages, was not different in WT vs TRIM72 C144S mice and we did not observe enhanced cardiac hypertrophy in the TRIM72 C144S mice. In agreement, protein levels of the TRIM72 ubiquitination targets insulin receptor β, IRS1, and focal adhesion kinase were similar between WT and TRIM72 C144S hearts. Overall, these data indicate that mutation of TRIM72 C144 is protective during I/R and reduces myocardial TRIM72 release without impairing insulin sensitivity or enhancing the development of hypertrophy.

© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ., Objectives: To compare consecutive disease modifying antirheumatic drug (DMARD)-treatment regimes in daily practice in patients with rheumatoid arthritis (RA) who failed on initial methotrexate, while using a multiple propensity score (PS) method to control for the spurious effects of confounding by indication. Methods: Patients with newly diagnosed RA who had failed initial treatment with methotrexate were selected from METEOR, an international, observational registry. Subsequent DMARD-treatment regimens were categorised as: (1) conventional synthetic DMARD(s) (csDMARD(s)) only (143 patients), (2) csDMARD(s)+glucocorticoid (278 patients) and (3) biological DMARD (bDMARD)±csDMARD(s) (89 patients). Multiple PS that reflect the likelihood of treatment with each treatment-regime were estimated per patient using multinomial regression. Linear mixed model analyses were performed to analyse treatment responses per category (Disease Activity Score (DAS)) after a maximum follow-up duration of 6 and 12 months, and results were presented with adjustment for the multiple PS. Results: After 6 months, follow-up PS-adjusted treatment responses yielded a change in DAS per year (95% CI) of -2.00 (-2.65 to -1.36) if patients received a bDMARD; of -0.96 (-1.33 to -0.59) if patients received csDMARD(s)+glucocorticoids and of -0.73 (-1.21 to -0.25) if patients received csDMARDs only. These changes were -0.91 (-1.23 to -0.60); -0.43 (-0.62 to -0.23) and -0.39 (-0.66 to -0.13), respectively after 1 year of follow-up. Conclusions: In this analysis of worldwide common practice data with adjustment for multiple PS, patients with RA who had failed initial treatment with methotrexate monotherapy had a better DAS-response after a subsequent switch to a bDMARD-containing treatment regimen than to a regimen with csDMARD(s) only, with or without glucocorticoids.

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Introduction: Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor of thyroid parafollicular C cells. About 25% of cases are hereditary, associated with MEN2 syndromes. RET M918 mutation (somatic or germline) is associated with the most aggressive form of MTC. If MTC is hereditary, further tumor genomic analysis is not routinely performed. Therefore, the somatic mutational landscape of hereditary MTCs is not frequently described in the literature. We present an unusual case of MTC with a germline M918 RET mutation, displaying an initial smoldering course followed by rapidly fatal widespread metastases. Whole exome sequencing (WES) of primary tumor and metastases revealed intertumoral heterogeneity with many somatic mutations including p53 mutation. Clinical Case: The patient with characteristic facies of MEN 2B presented with a neck mass at age 28. She had no family history of MEN. At diagnosis, calcitonin was 11,392 pg/mL and CEA was 729.7 ug/L. Pathology showed MTCs of 5 cm (right) and 2.1 cm (left) with lymph node metastases (pT3N1bMx). Genetic testing showed RET M918 mutation. Postoperative calcitonin and CEA were 3.3 pg/ml and 1.7 ug/L respectively. Tumor markers doubling time was initially about 1 year, but progressively shortened over time. Three years after surgery, calcitonin and CEA were 101 pg/ml and 387 ug/L respectively. CT chest and abdomen identified no distant metastasis. Over the next 4 months, calcitonin and CEA increased dramatically to 1821pg/ml and 3974 ug/L. The patient was admitted for acute liver failure and passed away. Autopsy revealed widely metastatic disease to liver, lungs, spleen, pituitary, right adrenal gland, bones, and brain. WES revealed 87, 283 and 591 somatic mutations in the primary tumor, lung and liver metastases respectively. The primary tumor had chromosome 1p loss whereas liver and lung metastases had somatic mutation of TP53 and single copy loss of chromosome 17 (biallelic inactivation of p53). Conclusion: This case illustrates intertumoral spatial and temporal genetic heterogeneity. Mutations detected by WES may or may not be cancer-related and their clinical relevance is often uncelar. We hypothesize TP53 biallelic loss might have contributed to the aggressive phenotype of this tumor. Also of note, even before the appearance of metastases, CEA was disproportionately higher than calcitonin, reflecting tumor dedifferentiation. Further studies are needed to address CEA threshold for additional imaging and imaging modality for early detection of metastases.

Backgrounds and aims: Low concentrations of plasma HDL-C are associated with the development of atherosclerotic cardiovascular diseases and type 2 diabetes. Here we aimed to explore the relationship between the in vivo fractional synthesis of triglycerides (fTG) in subcutaneous (s.q.) abdominal adipose tissue (AT), HDL-C concentrations and HDL particle size composition in non-diabetic humans. Methods: The fTG in s.q. abdominal AT was measured in 16 non-diabetic volunteers (7 women, 9 men; Age: 49 ± 20 years; BMI: 31 ± 5 kg/m; Fasting Plasma Glucose: 90 ± 10 mg/dl) after 2H2O labeling. HDL-C concentration and subclasses, large (L-HDL), intermediate (I-HDL) and small (S-HDL) were measured. Results: Linear regression analyses demonstrated significant associations of fTG with plasma concentration of HDL-C (r = 0.625,p = 0.009) and percent contribution of L-HDL (r = 0.798,p < 0.001), I-HDL (r = -0.765,p < 0.001) and S-HDL (r = -0.629, p = 0.009). When analyses were performed by gender, the associations remained significant in women (HDL-C: r = 0.822,p = 0.023; L-HDL: r = 0.892,p = 0.007; I-HDL: r = -0.927,p = 0.003) but not men. Conclusions: Our study demonstrated an in vivo association between subcutaneous abdominal adipose tissue lipid dynamics and HDL parameters in humans, but this was true for women not men. Positive association with L-HDL and negative with I-HDL suggest that subcutaneous abdominal adipose tissue lipid dynamics may play an important role in production of mature functional HDL particles. Further studies evaluating the mechanism responsible for these associations and the observed gender differences are important and warranted to identify potential novel targets of intervention to increase the production of atheroprotective subclasses of HDL-Cs and thus decreasing the risks of development of atherosclerotic conditions.

Supplemental Digital Content is available in the text, Objective: To determine if preoperative intravenous (IV) iron improves outcomes in abdominal surgery patients. Summary Background Data: Preoperative iron deficiency anemia (IDA) occurs frequently; however if left untreated, increases the risk of blood transfusion allogeneic blood transfusion (ABT). Limited evidence supports IDA treatment with preoperative IV iron. This randomized controlled trial aimed to determine whether perioperative IV iron reduced the need for ABT. Methods: Between August 2011 and November 2014, 72 patients with IDA were assigned to receive either IV iron or usual care. The primary endpoint was incidence of ABT. Secondary endpoints were various hemoglobin (Hb) levels, change in Hb between time points, length of stay, iron status, morbidity, mortality, and quality of life 4 weeks postsurgery. Results: A 60% reduction in ABT was observed in the IV iron group compared with the usual care group (31.25% vs 12.5%). Hb values, although similar at randomization, improved by 0.8 g/dL with IV iron compared with 0.1 g/dL with usual care (P = 0.01) by the day of admission. The IV iron group had higher Hb 4 weeks after discharge compared with the usual care group (1.9 vs 0.9 g/dL, P = 0.01), and a shorter length of stay (7.0 vs 9.7 d, P = 0.026). There was no difference in discharge Hb levels, morbidity, mortality, or quality of life. Conclusions: Administration of perioperative IV iron reduces the need for blood transfusion, and is associated with a shorter hospital stay, enhanced restoration of iron stores, and a higher mean Hb concentration 4 weeks after surgery.

We aimed to evaluate the feasibility of Cognitive Therapy (CT) as an intervention for internalised stigma in people with psychosis. We conducted a single-blind randomised controlled pilot trial comparing CT plus treatment as usual (TAU) with TAU only. Participants were assessed at end of treatment (4 months) and follow-up (7 months). Twenty-nine participants with schizophrenia spectrum disorders were randomised. CT incorporated up to 12 sessions over 4 months (mean sessions = 9.3). Primary outcome was the Internalised Stigma of Mental Illness Scale – Revised (ISMI-R) total score, which provides a continuous measure of internalised stigma associated with mental health problems. Secondary outcomes included self-rated recovery, internalised shame, emotional problems, hopelessness and self-esteem. Recruitment rates and retention for this trial were good. Changes in outcomes were analysed following the intention-to-treat principle, using ANCOVAs adjusted for baseline symptoms. There was no effect on our primary outcome, with a sizable reduction observed in both groups, but several secondary outcomes were significantly improved in the group assigned to CT, in comparison with TAU, including internalised shame, hopelessness andself-rated recovery. Stigma-focused CT appears feasible and acceptable in people with psychosis who have high levels of internalised stigma. A larger, definitive trial is required.

Background Measurements of maternal fat mass (FM) are important for studies of maternal and fetal health. Common methods of estimating FM have not been previously compared in pregnancy with measurements using more complete body composition models. Objectives The goal of this pilot study was to compare multiple methods that estimate FM, including 2-, 3- and 4-compartment models in pregnant women at term, and to determine how these measures compare with FM by dual-energy X-ray absorptiometry (DXA) 2 wk postpartum. Design Forty-one healthy pregnant women with prepregnancy body mass index (in kg/m(2)) 19 to 46 underwent skinfold thickness (SFT), bioelectrical impedance analysis (BIA), body density (Db) via air displacement plethysmography (ADP), and deuterium dilution of total body water (TBW) with and without adjustments for gestational age using van Raaij (VRJ) equations at 37-38 wk of gestation and 2 wk postpartum to derive 8 estimates of maternal FM. Deming regression analysis and Bland-Altman plots were used to compare methods of FM assessment. Results Systematic differences in FM estimates were found. Methods for FM estimates from lowest to highest were 4-compartment, DXA, TBW(VRJ), 3-compartment, Db(VRJ), BIA, air displacement plethysmography body density, and SFT ranging from a mean ± SD of 29.5 ± 13.2 kg via 4-compartment to 39.1 ± 11.7 kg via SFT. Compared with postpartum DXA values, Deming regressions revealed no substantial departures from trend lines in maternal FM in late pregnancy for any of the methods. The 4-compartment method showed substantial negative (underestimating) constant bias, and the air displacement plethysmography body density and SFT methods showed positive (overestimating) constant bias. ADP via Db(VRJ)and 3-compartment methods had the highest precision; BIA had the lowest. Conclusions ADP that uses gestational age-specific equations may provide a reasonable and practical measurement of maternal FM across a spectrum of body weights in late pregnancy. SFT would be acceptable for use in larger studies. This trial was registered at clinicaltrials.gov as NCT02586714.

ObjectivesTo study whether there is an association between body mass index (BMI) category and survival of various tumour necrosis factor inhibitors (TNFi) in rheumatoid arthritis (RA) patients in a real-life longitudinal international registry.MethodsData from 5230 patients with RA starting treatment with any TNFi were selected from the METEOR registry. Patients were divided into six BMI categories: 3.7% underweight, BMI2; 46% normal weight, BMI 18.5–25 kg/m2; 32% pre-obesity, BMI 25–30 kg/m2; 13% obesity class I, BMI 30–35 kg/m2; 3.4% obesity class II, BMI 35–40 kg/m2; and 1.6% obesity class III, BMI >40 kg/m2. Time on treatment in the different BMI categories was compared for all TNFi combined and for the infliximab, adalimumab and etanercept separately, using Kaplan–Meier curves and Cox regression analyses. Cox regression analyses were adjusted for potential confounders, with follow-up censored at 5000 days.ResultsPatients in obesity class II (HR 1.28, 95% CI 1.06 to 1.54) and III (HR 1.67, 95% CI 1.29 to 2.18) and underweight patients (HR 1.30, 95% CI 1.07 to 1.58) showed statistically significantly shorter TNFi survival than normal weight patients. The effect in underweight patients was strongest for infliximab (HR 1.82, 95% CI 1.20 to 2.76), the effect in overweight patients was strongest for infliximab (category II (HR 1.49, 95% CI 0.98 to 2.26); category III (HR 1.46, 95% CI 0.79 to 2.71)) and etanercept (category II (HR 1.27 95% CI 0.98 to 1.65); category III (HR 1.79, 95% CI 1.25 to 2.55)). No significant effect modification from reported pain was found.ConclusionBoth underweight and overweight patients discontinued TNFi treatment earlier than normal weight patients, without evidence of reported pain as the main determinant. It remains uncertain what determines TNFi survival in individual patients.

Background:BMI appears to be associated with treatment response on TNFi(nhibitors) in rheumatoid arthritis (RA), but large heterogeneity between studies exists. More extreme BMI categories are rarely studied and it is unclear if differences exist between various TNFi.1Table 1Characteristics of RA patientsFemale, n (%)935 (79.8)Age, years*51.0 ±13.7Current smokers, n (%)256 (23.2)RF Positivity, n (%)404 (55.6)Anti-CCP Positivity, n (%)430 (58.2)X-ray Erosion, n (%)317 (61.9)ESR, mm/h*31.2±21.9CRP, mg/L*17.2±3.9DAS 28-CRP*3.8±1.6VAS global*46.6±28.6HAQ*0.9±0.7First TNFi Etanercept, n (%)525 (38.7) Adalimumab, n (%)379 (27.9) Infliximab, n (%)118 (8.7) Certolizumab, n (%)188 (13.8) Golimumab, n (%)147 (10.9)* mean ±S.DRF, Rheumatoid factor; Anti-CCP, Anti- cyclic citrullinated peptid; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; DAS28–CRP, Disease Activity Score using 28 joints–CRP; VAS, Visual analog scale; HAQ, Health Assessment QuestionnaireObjectives:To study whether there is an association between BMI category and drug survival in RA patients starting treatment with various TNFi in a real life longitudinal international registry.Methods:Data from 5230 RA patients starting a TNFi were included from the METEOR registry. Timing of follow-up visits was daily practice based. Follow-up was censored at 5000 days (±13.5 years). Patients were divided into 6 BMI categories (WHO definition): underweight BMI 40. Missing data were imputed using chained equations. The association between BMI category and time on treatment was investigated using Kaplan-Meier (KM) curves and Cox regression analyses, for time on first TNFi and for the first prescribed course of adalimumab (ADA), etanercept (ETA) and infliximab (IFX) separately. All analyses were adjusted for the potential confounders age, gender, smoking, baseline DAS28, concomitant glucocorticoid use and country. Potential effect modification by reported pain was tested by adding an interaction term between BMI category and baseline pain category (VAS pain 0-25, 25-50, 50-75 and 75-100).Results:Most patients had a normal weight (46%) or pre-obesity (32%). 4% of patients were underweight, 10% had obesity class I, 3% obesity class II and 1% obesity class III. N=2936 patients ever started ETA, n=2069 ADA, n=1390 IFX, n=263 certolizumab and n=84 golimumab. The KM curve in fig 1A shows TNFi survival in patient starting their first TNFi per BMI category. Patients with normal weight and pre-obesity had longest drug survival and patients with obesity class II and especially patients with obesity class III had shortest drug survival. The adjusted Cox regression support these findings, with statistically significantly shorter drug survival for patients with obesity class III [HR (95% CI) 1.67 (1.29; 2.18)] and class II [1.28 (1.06; 1.54)], but also for underweight patients [1.3 (1.07; 1.58)], compared to normal weight patients. KM curves for individual TNFi showed shorter drug survival on ADA for patients with obesity class II and III (fig 1B), on ETA for patients with obesity, especially in class III (fig 1C) and on IFX, for patients with obesity class II and III and underweight patients (fig 1D). After adjustment in Cox regression, statistical significant BMI-drug survival associations remained for patients with pre-obesity starting ADA [HR (95% CI) 0.86 (0.75; 0.99)], for patients starting ETA with obesity class II [HR (95% CI) 1.27 (0.98; 1.65) or class III [1.79 (1.25; 2.55)] and for patients on IFX who were underweight [HR (95% CI) 1.82 (1.20; 2.76)] or in obesity class II [1.49 (0.98; 2.26)]. No effect modification was found for reported pain.Conclusion:Both underweight (as identified in IFX treated patients) and overweight patients (in ADA, ETA and IFX treated patients) discontinued a first TNFi treatment earlier than normal weight patients. Reported pain was not the main determinant. It remains uncertain what determines TNFi survival in individual patients.References:[1] Singh, et al.PloS One2018; 13:e0195123Disclosure of Interests:Sytske Anne Bergstra: None declared, David Vega-Morales: None declared, Elizabeth Murphy: None declared, Marieke de Buck: None declared, Karen Solomon-Escoto: None declared, Thomas Huizinga Grant/research support from: Ablynx, Bristol-Myers Squibb, Roche, Sanofi, Consultant of: Ablynx, Bristol-Myers Squibb, Roche, Sanofi, Cornelia Allaart: None declared

Mono-ADP-ribosylation of an (arginine) protein catalyzed by ADP-ribosyltransferase 1 (ART1) - i.e., transfer of ADP-ribose from NAD to arginine - is reversed by ADP-ribosylarginine hydrolase 1 (ARH1) cleavage of the ADP-ribose-arginine bond. ARH1-deficient mice developed cardiomyopathy with myocardial fibrosis, decreased myocardial function under dobutamine stress, and increased susceptibility to ischemia/reperfusion injury. The membrane repair protein TRIM72 was identified as a substrate for ART1 and ARH1; ADP-ribosylated TRIM72 levels were greater in ARH1-deficient mice following ischemia/reperfusion injury. To understand better the role of TRIM72 and ADP-ribosylation, we used C2C12 myocytes. ARH1 knockdown in C2C12 myocytes increased ADP-ribosylation of TRIM72 and delayed wound healing in a scratch assay. Mutant TRIM72 (R207K, R260K) that is not ADP-ribosylated interfered with assembly of TRIM72 repair complexes at a site of laser-induced injury. The regulatory enzymes ART1 and ARH1 and their substrate TRIM72 were found in multiple complexes, which were coimmunoprecipitated from mouse heart lysates. In addition, the mono-ADP-ribosylation inhibitors vitamin K1 and novobiocin inhibited oligomerization of TRIM72, the mechanism by which TRIM72 is recruited to the site of injury. We propose that a mono-ADP-ribosylation cycle involving recruitment of TRIM72 and other regulatory factors to sites of membrane damage is critical for membrane repair and wound healing following myocardial injury.

A pulmonary embolism (PE) is an acute life-threatening respiratory event that results in upwards of 200,000 deaths per year in the United States. While anticoagulation is currently the standard of treatment for PEs, there is increasing evidence to suggest that in certain cases anticoagulation in combination with thrombolytic therapy may improve patient outcomes and reduce mortality. This article aims to compare the effects of combined intervention with thrombolytic therapy and anticoagulation to the effects of anticoagulation alone in patients with submassive PEs in terms of various outcome measures, including but not limited to: mortality, hemodynamic status, length of hospital stay, and safety. The methodology consisted of the critical appraisal of the primary literature articles pertaining to intervention with thrombolytic agents in cases of a submassive or intermediate risk PE, including a discussion of each study’s strengths and limitations. Ultimately, this review found that the use of thrombolytic agents in conjunction with anticoagulants has been associated with decreased hemodynamic decompensation and decreased length of hospital stay, with no change in mortality outcomes, at a cost of increased rate of bleeding and stroke. The use of thrombolytic agents with anticoagulants may be warranted in a specific subset of patients, but clinicians should consider the potential benefits and harms of this intervention.