tbuckley/cabot-search huggingface dataset:
Hollow microneedle-mediated intradermal delivery of model vaccine antigen-loaded PLGA nanoparticles elicits protective T cell-mediated immunity to an intracellular bacterium
Authors: Anne Marit de Groot, Guangsheng Du, Juha Mönkäre, Anouk C.M. Platteel, Femke Broere, Joke A. Bouwstra, Alice J.A.M. Sijts
Journal: Journal of Controlled Release (2017)

The skin is an attractive organ for immunization due to the presence of a large number of epidermal and dermal antigen-presenting cells. Hollow microneedles allow for precise and non-invasive intradermal delivery of vaccines. In this study, ovalbumin (OVA)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles with and without TLR3 agonist poly(I:C) were prepared and administered intradermally by hollow microneedles. The capacity of the PLGA nanoparticles to induce a cytotoxic T cell response, contributing to protection against intracellular pathogens, was examined. We show that a single injection of OVA-loaded PLGA nanoparticles, compared to soluble OVA, primed both adoptively transferred antigen-specific naïve transgenic CD8 + and CD4 + T cells with markedly high efficiency. Applying a triple immunization protocol, PLGA nanoparticles primed also endogenous OVA-specific CD8 + T cells. Immune response, following immunization with in particular anionic PLGA nanoparticles co -encapsulated with OVA and poly(I:C), provided protection against a recombinant strain of the intracellular bacterium Listeria monocytogenes , secreting OVA. Taken together, we show that PLGA nanoparticle formulation is an excellent delivery system for protein antigen into the skin and that protective cellular immune responses can be induced using hollow microneedles for intradermal immunizations.
Risk of relapse after antidepressant discontinuation in anxiety disorders, obsessive-compulsive disorder, and post-traumatic stress disorder: systematic review and meta-analysis of relapse prevention trials
Authors: Neeltje M Batelaan, Renske C Bosman, Anna Muntingh, Willemijn D Scholten, Klaas M Huijbregts, Anton J L M van Balkom
Journal: BMJ (2017)

<b>Objectives</b> To examine the risk of relapse and time to relapse after discontinuation of antidepressants in patients with anxiety disorder who responded to antidepressants, and to explore whether relapse risk is related to type of anxiety disorder, type of antidepressant, mode of discontinuation, duration of treatment and follow-up, comorbidity, and allowance of psychotherapy. <b>Design</b> Systematic review and meta-analyses of relapse prevention trials. <b>Data sources</b> PubMed, Cochrane, Embase, and clinical trial registers (from inception to July 2016). <b>Study selection</b> Eligible studies included patients with anxiety disorder who responded to antidepressants, randomised patients double blind to either continuing antidepressants or switching to placebo, and compared relapse rates or time to relapse. <b>Data extraction</b> Two independent raters selected studies and extracted data. Random effect models were used to estimate odds ratios for relapse, hazard ratios for time to relapse, and relapse prevalence per group. The effect of various categorical and continuous variables was explored with subgroup analyses and meta-regression analyses respectively. Bias was assessed using the Cochrane tool. <b>Results</b> The meta-analysis included 28 studies (n=5233) examining relapse with a maximum follow-up of one year. Across studies, risk of bias was considered low. Discontinuation increased the odds of relapse compared with continuing antidepressants (summary odds ratio 3.11, 95% confidence interval 2.48 to 3.89). Subgroup analyses and meta-regression analyses showed no statistical significance. Time to relapse (n=3002) was shorter when antidepressants were discontinued (summary hazard ratio 3.63, 2.58 to 5.10; n=11 studies). Summary relapse prevalences were 36.4% (30.8% to 42.1%; n=28 studies) for the placebo group and 16.4% (12.6% to 20.1%; n=28 studies) for the antidepressant group, but prevalence varied considerably across studies, most likely owing to differences in the length of follow-up. Dropout was higher in the placebo group (summary odds ratio 1.31, 1.06 to 1.63; n=27 studies). <b>Conclusions</b> Up to one year of follow-up, discontinuation of antidepressant treatment results in higher relapse rates among responders compared with treatment continuation. The lack of evidence after a one year period should not be interpreted as explicit advice to discontinue antidepressants after one year. Given the chronicity of anxiety disorders, treatment should be directed by long term considerations, including relapse prevalence, side effects, and patients' preferences.
Efficacy and safety data based on historical or pre-existing conditions at baseline for patients with active rheumatoid arthritis who were treated with baricitinib
Authors: Bernard Combe, Alejandro Balsa, Piercarlo Sarzi-Puttini, Hans-Peter Tony, Inmaculada de la Torre, Veronica Rogai, Frederick Durand, Sarah Witt, Jinglin Zhong, Maxime Dougados
Journal: Annals of the Rheumatic Diseases (2019)

Patients with rheumatoid arthritis (RA) have a high prevalence of comorbidities.1 This post-hoc analysis investigated the effect of select comorbidities (depression, osteoporosis, hepatic, cardiovascular or pulmonary disorders) on the efficacy and safety of baricitinib 4 mg once daily in patients with moderate-to-severe active RA and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs).

Data from the placebo-controlled periods of five baricitinib studies2–6 were pooled for baricitinib 4 mg; data for baricitinib 2 mg were not analysed due to low (n=302) patient numbers. Additional data for all baricitinib-treated patients with a median exposure of 2 years were derived from an ongoing open-label, long-term extension (LTE) study that included patients from phase II and III studies (RA-BEYOND; NCT01885078).7 Efficacy outcomes were evaluated at week 12 (vs placebo). Interaction of comorbidity-by-treatment was analysed using logistic regression or analysis of covariance. Safety observations up to week 16 (vs placebo) and during the LTE were summarised by the Medical Dictionary for Regulatory Activities preferred term.

Data from 1684 patients (803, baricitinib 4 mg; 881, placebo) from the placebo-controlled periods were analysed. The mean (SD) age was 52.7 (12.1) years, with only 38 (2.3%) patients aged ≥75 years; most patients (1506, 89.4%) were receiving background methotrexate, alone or in combination with another csDMARD. The numbers of patients receiving placebo and baricitinib 4 mg combined (with or without each comorbidity, respectively) were 133/1551 for depression, 247/1437 for osteoporosis, 424/1260 for hepatic disorders, 731/953 for cardiovascular disorders, and 166/1518 for pulmonary disorders. Demographic and clinical characteristics within each comorbidity subgroup were similar between patients randomised to baricitinib or placebo.

Higher …
Novel management of a necrotic pancreatic fluid collection with staged cystgastrostomy followed by cystgastrojejunostomy: the Lizzie Grace maneuver
Authors: Ming-ming Xu, Nikhil Kumta, Pawan Marfatia, Viviana Parra, Gustavo Silva, Elizabeth Brown, Amy Tyberg, Reem Sharaiha, Michel Kahaleh
Journal: Endoscopy (2017)

A 58-year-old man with severe alcohol-related necrotizing pancreatitis was admitted and was treated initially with conservative management including aggressive intravenous fluid hydration and placement of a percutaneous gastrojejunostomy tube for enteral nutrition. Endoscopic retrograde cholangiopancreatography (ERCP) was performed with no evidence of pancreatic duct disruption or contrast leakage, but sludge was swept from the bile duct and biliary sphincterotomy was performed. Endoscopic ultrasound (EUS) revealed acute inflammatory changes in the entire pancreas without any well-formed fluid collection that could be drained.
Association Between Laparoscopic Antireflux Surgery and Recurrence of Gastroesophageal Reflux
Authors: John Maret-Ouda, Karl Wahlin, Hashem B. El-Serag, Jesper Lagergren
Journal: JAMA (2017)

<h3>Importance</h3> Cohort studies, mainly based on questionnaires and interviews, have reported high rates of reflux recurrence after antireflux surgery, which may have contributed to a decline in its use. Reflux recurrence after laparoscopic antireflux surgery has not been assessed in a long-term population-based study of unselected patients. <h3>Objectives</h3> To determine the risk of reflux recurrence after laparoscopic antireflux surgery and to identify risk factors for recurrence. <h3>Design and Setting</h3> Nationwide population-based retrospective cohort study in Sweden between January 1, 2005, and December 31, 2014, based on all Swedish health care and including 2655 patients who underwent laparoscopic antireflux surgery according to the Swedish Patient Registry. Their records were linked to the Swedish Causes of Death Registry and Prescribed Drug Registry. <h3>Exposures</h3> Primary laparoscopic antireflux surgery due to gastroesophageal reflux disease in adults (&gt;18 years). <h3>Main Outcomes and Measures</h3> The outcome was recurrence of reflux, defined as use of antireflux medication (proton pump inhibitors or histamine<sub>2</sub>receptor antagonists for &gt;6 months) or secondary antireflux surgery. Multivariable Cox regression was used to assess risk factors for reflux recurrence. <h3>Results</h3> Among all 2655 patients who underwent antireflux surgery (median age, 51.0 years; interquartile range, 40.0-61.0 years; 1354 men [51.0%]) and were followed up for a median of 5.6 years, 470 patients (17.7%) had reflux recurrence; 393 (83.6%) received long-term antireflux medication and 77 (16.4%) underwent secondary antireflux surgery. Risk factors for reflux recurrence included female sex (hazard ratio [HR], 1.57 [95% CI, 1.29-1.90]; 286 of 1301 women [22.0%] and 184 of 1354 men [13.6%] had recurrence of reflux), older age (HR, 1.41 [95% CI, 1.10-1.81] for age ≥61 years compared with ≤45 years; recurrence among 156 of 715 patients and 133 of 989 patients, respectively), and comorbidity (HR, 1.36 [95% CI, 1.13-1.65] for Charlson comorbidity index score ≥1 compared with 0; recurrence among 180 of 804 patients and 290 of 1851 patients, respectively). Hospital volume of antireflux surgery was not associated with risk of reflux recurrence (HR, 1.09 [95% CI, 0.77-1.53] for hospital volume ≤24 surgeries compared with ≥76 surgeries; recurrence among 38 of 266 patients [14.3%] and 271 of 1526 patients [17.8%], respectively). <h3>Conclusions and Relevance</h3> Among patients who underwent primary laparoscopic antireflux surgery, 17.7% experienced recurrent gastroesophageal reflux requiring long-term medication use or secondary antireflux surgery. Risk factors for recurrence were older age, female sex, and comorbidity. Laparoscopic antireflux surgery was associated with a relatively high rate of recurrent gastroesophageal reflux disease requiring treatment, diminishing some of the benefits of the operation.
FRI0403 Increased crp level is interrelated with clinical and serological phenotypes of systemic scleroderma and associated with crp rs1205 gene polymorphism
Authors: M Krylov, L Ananieva, O Koneva, M Starovoytova, O Desinova, O Ovsaynnikova, E Aleksandrova, A Novikov, I Guseva, N Konovalova, D Varlamov
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Recent studies report on increased serum levels of C-reactive protein (CRP) in systemic scleroderma (SSc) pts. <h3>Objectives</h3> The current study was aimed at identifying potential correlations between CRP levels, immunologic SSc phenotypes and <i>CRP</i> rs1205 gene polymorphism in the Russian cohort. <h3>Methods</h3> 92 SSc pts were enrolled in the study. Mean age (± SD) was 49,4±12,6 years, mean (± SD) SSc duration was 11,1±9,0 years, increased CRP levels &gt;5 mg/l were documented in 43% pts. CRP levels were analyzed in the following subgroups: with limited (lcSSc) and diffuse (dcSSC) types, with SSc duration &lt;3 years &gt;3, with or without interstitial lung disease (ILD+) and (ILD-), as well as in subgroups with positive antibody titers to DNA topoisomerase I (ATA+) and antibody to centromeres (ACA+). CRP concentrations were measured with highly sensitive immunoturbidimertry method. Allele-specific real time PCR was used to study <i>CRP</i> rs1205 gene polymorphism. <h3>Results</h3> Mean CRP (± SD) level was significantly higher in dcSSc vs lcSSc (11,9±15,5 mg/l; vs 4,7±7,4 mg/l, respectively, <i>p</i>=0,006). Pts with disease duration &lt;3 years had higher mean CRP levels as compared to pts with SSc duration &gt;3 years, although the difference was not significant. In pts with disease duration &gt;3 years mean CRP levels were significantly higher among subjects with dcSSc than lcSSc (11,0±15,5 mg/l vs 4,8±7,7 mg/l, respectively, <i>p</i>=0,027). Mean CRP level was higher in (ATA+) pts than in (ATA-) pts (11,0±15,4 mg/l vs 5,5±13,7 mg/l, respectively, <i>p</i>=0,032). No statistical difference in CRP levels was found between (ILD+) and (ILD-) pts, as well as between (ACA+) and (ACA-) pts. Carriers of rs1205 CC genotype had higher CRP levels than carriers of rs1205 T allele,<i>p</i>=0,087). In pts with SSc duration &gt;3 years and carriers of rs1205 CC genotype mean CRP level was significantly higher than in T-allele carriers (12,0±17,4 mg/l vs 5,4±7,4 mg/l, respectively, <i>p</i>=0,021). Similar trends for CRP levels depending on genotypes were established among (ATA+) pts (16,9±20,1 mg/l and 7,3±10,5 mg/l, respectively, <i>p</i>=0,031). <h3>Conclusions</h3> Increased CRP levels were found almost in 50% of Russian SSc pts. Higher CRP levels were associated with specific clinical and immunological SSc parameters and <i>CRP</i> rs1205 CC genotype, signifying unfavorable prognosis. <h3>Disclosure of Interest</h3> None declared
THU0226 Differential susceptibility of TH17 and T regulatory cells to apoptosis in systemic lupus erythematosus patients – the modulatory effects of statin
Authors: J Sun, J Frostegard, A Liu
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder. Patients with SLE have accelerated cardiovascular disease. Recent studies show there are more Th17 while less T regulatory (Treg) cells in the SLE patients. Th17/Treg imbalance may contribute to the pathogenesis of SLE. <h3>Objectives</h3> To investigate the underlying mechanisms of Th17/Treg imbalance, we test the proportion and susceptibility of Th17 and Treg to apoptosis, and the modulatory effects of statin in the SLE patients. <h3>Methods</h3> Totally 17 SLE patients and 20 gender- and age-matched control subjects were enrolled for this study. Peripheral blood mononuclear cells were isolated, either analyzed ex vivo, or cultured in the conditions to induce Th17 and/or Treg polarization. The proportion of Th17/Treg cells and frequency responding to apoptosis were analyzed by multiple color flow cytometry. Cytokines in cell culture supernatants and plasma were tested by ELISA. T cell polarization-related transcription factors were detected by quantitative real time PCR. <h3>Results</h3> The proportion of Th17 (CD4<sup>+</sup>IL17<sup>+</sup>) cells were higher in SLE patients, both in ex vivo and in the Th17-polarizing cultures. While the frequencies of Treg (CD4<sup>+</sup>CD25<sup>+</sup>CD127<sup>dim/-</sup>) cells were lower in the corresponding populations. Higher levels of IL17 and IL6 were detected in plasma of SLE patients. Responding to CD95-induced apoptosis the frequency of CD4<sup>+</sup>IL17<sup>+</sup> cells from SLE patients was substantially lower, but that of CD4<sup>+</sup>CD25<sup>+</sup>CD127<sup>dim/-</sup> cells from Treg-polarizing cultures was considerably higher. With treatment of atorvastatin, CD4<sup>+</sup>IL17<sup>+</sup> cell population in cultures derived from SLE patients showed an increased susceptibility to CD95-induced apoptosis. However, the CD4<sup>+</sup>CD25<sup>+</sup>CD127<sup>dim/-</sup> cell population had reduced response to apoptosis. Accordingly, the ratio of transcription factor RORC/FoxP3 decreased in T cell cultures of SLE patients. <h3>Conclusions</h3> Th17 cells were more resistant than Treg cells to CD95-induced apoptosis in SLE as compared to control subjects. Statins counteracted the dysregulated susceptibility of SLE T cells to apoptosis. Our findings reveal a novel mechanism underlying the imbalance of Th17/Treg and show a potential interest to the treatment of the patients with SLE. <h3>Disclosure of Interest</h3> None declared
An invisible disease: severe asthma is more than just “bad asthma”
Authors: Sally E. Wenzel, Sheila Brillhart, Kristin Nowack
Journal: European Respiratory Journal (2017)

Severe asthma, although a small portion of all asthma, still impacts millions of patients worldwide. It drives more morbidity, mortality and costs than milder asthma [1, 2]. However, its human toll is much less appreciated. In their timely, moving article, Foster et al. [3] describe the enormous impact of severe asthma on patient's lives [4]. Interviewing 25 severe asthmatic patients, the authors identified four common themes, including those related to personal interactions, medications, isolation and adaptation of their life. The quotes are simple and pointed. For many reasons, much of this patient perspective has not been appreciated by healthcare providers, the general public, and even by close family members and associates. Thus, this report, detailing the burden that severe asthmatics bear every day, begins to make "visible" a disease that has until now been mostly "invisible". Severe asthma inflicts a tremendous burden on patients with this disease, which is often invisible to others <http://ow.ly/RpGk30cTjIF>
FRI0270 Urinary and serum neutrophil gelatinase-associated lipocalin as a biomarker in indian children with systemic lupus erythematosus: relation to renal involvement and overall disease activity
Authors: B Abujam, S Singh
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Renal involvement often results in long-term morbidity in childhood Systemic Lupus Erythematosus (cSLE). Neutrophil gelatinase associated lipocalin (NGAL) has been shown to be a reliable structural biomarker for the early diagnosis of kidney injury in many clinical scenarios. <h3>Objectives</h3> This study aimed to detect levels of urinary and serum NGAL and changes in flare and improvement on longitudinal follow up in cSLE in a real world clinical scenario. <h3>Methods</h3> Children &lt;14 years of age attending the Pediatric Rheumatology clinic, fulfilling the 1997 SLE criteria were recruited. Urine and serum samples were collected during routine clinical review and SLE Disease Activity Index (SLEDAI) assessed. Children were divided into 3 categories, active renal, active non-renal and inactive lupus. Active lupus was defined as SLEDAI &gt;4. Urinary and serum levels of NGAL (uNGAL; sNGAL) were assessed by ELISA. Urinary values were normalized for urinary spot creatinine. In addition, some patients were longitudinally followed up and resampled when their disease activity changed. <h3>Results</h3> The study included 122 (F:M =91:31) children, 54 had active renal,14 had active non-renal and 54 had inactive disease. Median (IQR) age was 8.8 (6.5–10.7) years and disease duration was 10 (3–24) months.26 children with nephrotic syndrome and 49 age and gender matched healthy controls were also recruited. Children with active renal lupus had significantly higher uNGAL as compared to other categories.Although sNGAL was significantly higher in active renal as compared to inactive lupus,there was no difference between renal and non-renal active lupus (Table 1). On longitudinal follow up, uNGAL levels increased markedly prior to a flare, significantly higher in renal compared to a non-renal flare (p&lt;0.05). On the other hand, active lupus children had a significant fall in their uNGAL on follow up. Their was good correlation between change in SLEDAI and change in absolute uNGAL levels (r =0.84, p&lt;0.01). Overall, on ROC analysis, uNGAL classified active renal versus active non-renal and inactive combined with an AUC of 0.986 (95% CI 0.972–1.0). The sensitivity and specificity of a uNGAL cutoff off value of 25750 ng/ml was 96.3 and 91.2% respectively. <h3>Conclusions</h3> Urinary NGAL is a sensitive marker of renal involvement in SLE disease activity and can also be a reliable tool for monitoring renal disease activity changes. <h3>Disclosure of Interest</h3> None declared
AB0344 Subclinical vascular damage and its association with acpa and rf in patients with rheumatoid arthritis
Authors: M Aguilar-Zamora, M Robustillo-Villarino, C Vergara-Dangond, L Montolio-Chiva, E Valls-Pascual, A Martínez-Ferrer, D Ybañez-Garcia, V Nuñez-Monje, JJ Alegre-Sancho
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Accelerated atherosclerosis (AE) and increased arterial stiffness are comorbidities of rheumatoid arthritis (RA) and are related to the inflammatory burden of the disease, as well as to certain clinical and genetic characteristics of the disease. There is controversy about the role of ACPA in the development of AE in these patients. <h3>Objectives</h3> To explore the relation between ACPA and RF titres and subclinical vascular damage in RA patients. <h3>Methods</h3> Descriptive cross-sectional study with analytical components. A total of 244 RA patients were recruited consecutively over a period of 18 months (2013–2014) in a rheumatology department of a tertiary hospital. Patients with high vascular risk (vascular ischemic events, renal failure and diabetes mellitus) were excluded. Demographics, clinical data (ACPA and RF titres, duration of disease, hypertension and dyslipidemia) and vascular damage (atheroma plaque, carotid intima thickness [IMTc] and pulse wave velocity [PWV]) were collected. The atheroma plaque and IMTc measurement was performed by ultrasonography of the carotid arterial tree using an Esaote® MyLab70XVG with a 7–12 MHz linear transducer and an automated program measuring intima-media thickness (IMT) through radiofrequency (Quality intima media Thickness in real time, QIMT). PWV was obtained by analysis of brachial pulse waves with an automated and validated system (Mobil O Graph®). Statistical analysis was performed with the SPSS 17.0 program. <h3>Results</h3> We included 181 patients, 141 (77.9%) women and 40 (22.1%) men, with a mean age of 60.4 years (SD 13.2) and a mean duration of the disease of 13.1 years (SD 10.5); 107 patients (59.1%) were smokers or ex-smokers, 56 (30.9%) hypertensive and 77 (42.5%) dyslipemic. 118 patients (65.2%) had positive ACPA, with a mean value of 330 (SD 621.5), and 107 (59.1%) had a positive value of RF with a mean of 114 (SD 164.5). No association was found between the positivity of ACPA and RF and the presence of atheroma plaques or with the values of IMTc and/or PWV. In patients with positive ACPA, a positive correlation was observed between ACPA titers and PWV values (p&lt;0.05). In particular, ACPA titers over 1600 were the ones that discriminated the highest values of PWV in our population (p&lt;0.009). The ACPA and RF values, on the other hand, were not related to the presence of plaques or to IMTc. <h3>Conclusions</h3> No relation was found between the positivity of RF and ACPA titers and the presence of pathological carotid ultrasound in our RA patient population. However, higher arterial stiffness was observed in patients with high ACPA titers. <h3>Disclosure of Interest</h3> None declared