tbuckley/cabot-search huggingface dataset:
Effects of a low carbohydrate diet on energy expenditure during weight loss maintenance: randomized trial
Authors: Cara B Ebbeling, Henry A Feldman, Gloria L Klein, Julia M W Wong, Lisa Bielak, Sarah K Steltz, Patricia K Luoto, Robert R Wolfe, William W Wong, David S Ludwig
Journal: BMJ (2018)

Abstract Objective To determine the effects of diets varying in carbohydrate to fat ratio on total energy expenditure. Design Randomized trial. Setting Multicenter collaboration at US two sites, August 2014 to May 2017. Participants 164 adults aged 18-65 years with a body mass index of 25 or more. Interventions After 12% (within 2%) weight loss on a run-in diet, participants were randomly assigned to one of three test diets according to carbohydrate content (high, 60%, n=54; moderate, 40%, n=53; or low, 20%, n=57) for 20 weeks. Test diets were controlled for protein and were energy adjusted to maintain weight loss within 2 kg. To test for effect modification predicted by the carbohydrate-insulin model, the sample was divided into thirds of pre-weight loss insulin secretion (insulin concentration 30 minutes after oral glucose). Main outcome measures The primary outcome was total energy expenditure, measured with doubly labeled water, by intention-to-treat analysis. Per protocol analysis included participants who maintained target weight loss, potentially providing a more precise effect estimate. Secondary outcomes were resting energy expenditure, measures of physical activity, and levels of the metabolic hormones leptin and ghrelin. Results Total energy expenditure differed by diet in the intention-to-treat analysis (n=162, P=0.002), with a linear trend of 52 kcal/d (95% confidence interval 23 to 82) for every 10% decrease in the contribution of carbohydrate to total energy intake (1 kcal=4.18 kJ=0.00418 MJ). Change in total energy expenditure was 91 kcal/d (95% confidence interval −29 to 210) greater in participants assigned to the moderate carbohydrate diet and 209 kcal/d (91 to 326) greater in those assigned to the low carbohydrate diet compared with the high carbohydrate diet. In the per protocol analysis (n=120, P&lt;0.001), the respective differences were 131 kcal/d (−6 to 267) and 278 kcal/d (144 to 411). Among participants in the highest third of pre-weight loss insulin secretion, the difference between the low and high carbohydrate diet was 308 kcal/d in the intention-to-treat analysis and 478 kcal/d in the per protocol analysis (P&lt;0.004). Ghrelin was significantly lower in participants assigned to the low carbohydrate diet compared with those assigned to the high carbohydrate diet (both analyses). Leptin was also significantly lower in participants assigned to the low carbohydrate diet (per protocol). Conclusions Consistent with the carbohydrate-insulin model, lowering dietary carbohydrate increased energy expenditure during weight loss maintenance. This metabolic effect may improve the success of obesity treatment, especially among those with high insulin secretion. Trial registration ClinicalTrials.gov NCT02068885 .
Injection Drug Use–Associated Infective Endocarditis
Authors: David Phillip Serota, J. Deanna Wilson, Jessica S. Merlin
Journal: JAMA (2018)

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Immunosuppressive mechanisms induced by tumor cells during epithelial-mesenchymal transition leading to tumor metastasis
Authors: Chie Kudo-Saito, Hiromi Shirako, Yutaka Kawakami
Journal: Cancer Research (2008)

2465   Purpose: Epitherial-mesenchymal transition (EMT) is a dynamic trans-differentiation process to acquire cell mobility for body organization such as embryonic development or wound healing, and characterized by decreased epitherial features and increased mesenchymal features. EMT is recently reported to be a key step toward tumor metastasis, which is still a critical issue in cancer therapy. Many EMT inducers are identified, and the molecular mechanisms in tumor cells have been elucidated in detail. However, the interaction between host immunity and tumor cells during EMT has not investigated yet. We hypothesized that during EMT, tumor cells might negatively influence host immune system to escape efficiently. In this study, we established human pancreatic cancer cell line Panc-1 cells transduced with snail gene, which is an essential transcription factor governing EMT, and then analyzed effect of the snail transfectant on immune responses.  Results: When human PBMCs were co-cultured with the snail transfectants showing typical EMT features (increased migration/invasion with less E-cadherin expression), CD11c+ cell differentiation was significantly inhibited, and CD4+CD25-cells were transformed into immunosuppressive cells with increased FoxP3 expression, as compared with those to the parental cells or mock-transfected cells. The role of snail expression in tumor cells for the immunosuppression were determined by snail knockdown using snail-specific siRNA. Such induction of immunosuppressive cells was also observed in vivo where SCID mice were injected with human PBMCs and the snail transfectant. We conducted GeneChip array analysis to compare gene expression between snail transfectants and the parental cells, particularly focusing on immunoregulatory molecules, and identified the specific mediators involved in the effects induced by snail transfectants.  Conclusion: We demonstrate that snail expression in tumor cells induces the immunosuppressive microenvironment involving impaired dendritic cells and regulatory T cells, resulting in promotion of tumor metastasis. Blockade of the molecules identified is effective in simultaneously suppressing both tumor metastasis and immunosuppression. This strategy targeting such factors commonly regulating both tumor metastasis and immunosuppression could possibly improve anti-tumor efficacies induced by a range of therapies for cancer patients.
Severe enterovirus A71 associated hand, foot and mouth disease, Vietnam, 2018: preliminary report of an impending outbreak
Authors: Le Nguyen Thanh Nhan, Nguyen Thi Thu Hong, Le Nguyen Truc Nhu, Lam Anh Nguyet, Nguyen Thi Han Ny, Tran Tan Thanh, Do Duong Kim Han, Hoang Minh Tu Van, C Louise Thwaites, Tran Tinh Hien, Phan Tu Qui, Pham Van Quang, Ngo Ngoc Quang Minh, H. Rogier van Doorn, Truong Huu Khanh, Nguyen Van Vinh Chau, Guy Thwaites, Nguyen Thanh Hung, Le Van Tan
Journal: Eurosurveillance (2018)

Since January 2018, over 53,000 hospitalisations and six deaths due to hand, foot and mouth disease (HFMD) have occurred across Vietnam with most cases from September onward. In a large tertiary referral hospital, Ho Chi Minh City, enterovirus A71 subgenogroup C4 was predominant, while B5 was only sporadically detected. The re-emergence of C4 after causing a severe HFMD outbreak with &gt; 200 deaths in 2011–12 among susceptible young children raises concern of another impending severe outbreak.
SAT0432 Membranous versus proliferative lupus nephritis: two different diseases?
Authors: F. Farinha, B.S. Bernstein, R. Pepper, D.A. Isenberg, A. Rahman
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Lupus nephritis (LN) is currently classified according to the 2003 <i>International Society of Nephrology/Renal pathology Society</i> (ISN/RPS) classification system, which is based on histology. Most patients have proliferative lupus nephritis (PLN), which has been the most studied type of LN. Membranous lupus nephritis (MLN) is less frequent, accounting for 10%–20% of the cases. In some patients there is a combination of the two types. <h3>Objectives</h3> To compare MLN and PLN with respect to demographic, clinical and laboratory characteristics. <h3>Methods</h3> Single-centre retrospective observational study. All patients with biopsy-proven proliferative (class III and IV), membranous (class V) and mixed (class III or IV+V) LN (according to the 2003 ISN/RPS classification), followed at UCLH Rheumatology department from 1975 to 2017, were included. Individual clinical files were reviewed to obtain demographic, clinical, laboratory and pathological data. We also recorded data on treatment with corticosteroids, immunosuppressants and antimalarials. We compared groups using Pearson's chi-squared test for qualitative variables and Mann-Whitney test for quantitative variables. Renal survival was analysed through the Kaplan-Meier method. Significance level was defined at 0.05. <h3>Results</h3> 187 patients were included (table 1). Age at diagnosis was not significantly different between groups (p=0.474). The groups differ regarding ethnicity – higher proportion of Caucasians with PLN versus higher proportion of Afro-Caribbeans with MLN. Patients with MLN present with higher C3 levels and significantly lower anti-dsDNA levels than the ones with proliferative changes. Thirty-four patients with PLN, 3 with MLN and 2 with mixed nephritis, progressed to end-stage renal disease. Cumulative renal survival rates at 5, 10, 15 and 20 years were 91, 81, 75% and 66% for PLN and 100, 97, 92% and 84% for MLN, respectively (Image 1). <h3>Conclusions</h3> In spite of presenting in the context of the same autoimmune systemic disease, PLN and MLN appear to be very different entities, showing significant differences regarding serologic profiles and renal survival. <h3>Disclosure of Interest</h3> None declared
Preventing Lck Activation in CAR T Cells Confers Treg Resistance but Requires 4-1BB Signaling for Them to Persist and Treat Solid Tumors in Nonlymphodepleted Hosts
Authors: Carter M. Suryadevara, Rupen Desai, S. Harrison Farber, Bryan D. Choi, Adam M. Swartz, Steven H. Shen, Patrick C. Gedeon, David J. Snyder, James E. Herndon, Patrick Healy, Elizabeth A. Reap, Gary E. Archer, Peter E. Fecci, John H. Sampson, Luis Sanchez-Perez
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Chimeric antigen receptor (CAR) T cells have shown promise against solid tumors, but their efficacy has been limited, due in part, to immunosuppression by CD4+FoxP3+ regulatory T cells (Tregs). Although lymphodepletion is commonly used to deplete Tregs, these regimens are nonspecific, toxic, and provide only a narrow window before Tregs repopulate hosts. Importantly, CARs have also been shown to inadvertently potentiate Tregs by providing a source of IL2 for Treg consumption. We explored whether disruption of the IL2 axis would confer efficacy against solid tumors without the need for lymphodepletion. Experimental Design: We developed second- (CD28z) and third- (CD28-4-1BBz) generation CARs targeting EGFRvIII. To eliminate secretion of IL2, 2 amino acid substitutions were introduced in the PYAP Lck–binding motif of the CD28 domain (ΔCD28). We evaluated CARs against B16 melanomas expressing EGFRvIII. Results: CD28z CARs failed to engraft in vivo. Although 4-1BB addition improved expansion, CD28-4-1BBz CARs required lymphodepletion to treat solid tumors. CARs deficient in Lck signaling, however, significantly retarded tumor growth without a need for lymphodepletion and this was dependent on inclusion of 4-1BB. To evaluate CAR vulnerability to Tregs, we lymphodepleted mice and transferred CARs alone or with purified Tregs. Cotransfer with Tregs abrogated the efficacy of CD28-4-1BBz CARs, whereas the efficacy of ΔCD28-4-1BBz CARs remained unperturbed. Conclusions: In the absence of lymphodepletion, CARs targeting solid tumors are hindered by Treg immunosuppression and poor persistence. Here, CARs were modified to circumvent Treg suppression and to simultaneously improve in vivo engraftment. Modified CARs treated solid tumors without a need for lymphodepletion.
SAT0601 Anti-il6-receptor tocilizumab in graves’ orbitopathy. multicenter study of 29 patients
Authors: B. Atienza-Mateo, V. Calvo-Río, J.L. Martín-Varillas, R. Demetrio-Pablo, E. Valls-Pascual, B. Valls-Espinosa, O. Maiz-Alonso, A. Blanco, I. Torre, V. Rodriguez-Mendez, Á. García-Aparicio, R. Veroz González, V. Jovaní Casano, D. Peiteado López, M. Sanchez Orgaz, S. Castañeda Sanz, E. Tomero, F.J. Toyos Sáenz, M. Valvanera Pinillos, E. Aurrecoechea, Á. Mora, M. Á. González-Gay, R. Blanco
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Objectives</h3> To assess the efficacy of Tocilizumab (TCZ) in refractory thyroid associated orbitopathy (TAO) due to Grave's disease. <h3>Methods</h3> Multicenter study of 29 patients with TAO refractory to conventional immunosuppressive therapy. <h3>Results</h3> We studied 29 patients (58 eyes) (23 women/6 men); mean age at diagnosis 48.79±12.39 years. Besides oral corticosteroids and before the onset of TCZ, patients had been treated with pulses of intravenous methylprednisolone (n=24), methotrexate (n=2) and other drugs (methimazole in 4 cases, leflunomide in 1, selenium in 9). Urgent decompressive surgery had to be performed in 2 patients. According to the classification of severity of the EUGOGO group (European Group on Graves' Orbitopathy) using the clinical activity score (CAS), before TCZ onset patients whose data were available had severe (n=14 eyes) or moderate (n=22 eyes) disease. Moreover, patients presented exophthalmos (n=30 eyes), strabismus (n=17 eyes), muscle fibrosis (n=15 eyes) and dysthyroid optic neuropathy (n=1). TCZ was used in monotherapy (n=27) or combined with methotrexate (n=2) at 8 mg/kg/iv/4 weeks (n=24) or 162 mg/sc/week (n=5). TCZ yielded rapid and maintained improvement in all ocular parameters (<b>TABLE</b>). After a mean follow-up of 8.96±7.55 months using TCZ, all patients experienced ocular improvement, with TCZ withdrawal in 16 cases due to complete remission (n=5) or stability of ocular inflammation (n=11). Only 4 adverse effects were observed (neutropenia, external otitis, otitis media, costal osteitis). <h3>Conclusions</h3> TCZ appears to be useful in TAO treatment. <h3>Reference</h3> [1] Bartalena L, Baldeschi L, Dickinson AJ, et al. Consensus statement of the European group on Graves' orbitopathy (EUGOGO) on management of Graves' orbitopathy. Thyroid2008;18(3):333–346. <h3>Disclosure of Interest</h3> None declared
Effectiveness of influenza vaccination on influenza-associated hospitalisations over time among children in Hong Kong: a test-negative case-control study
Authors: Shuo Feng, Susan S Chiu, Eunice L Y Chan, Mike Y W Kwan, Joshua S C Wong, Chi-Wai Leung, Yiu Chung Lau, Sheena G Sullivan, J S Malik Peiris, Benjamin J Cowling
Journal: The Lancet Respiratory Medicine (2018)
THU0700 Perinatal exposure to disease modifying antirheumatic drugs in women with inflammatory arthritis and the risk of small-for-gestational-age newborns: a population-based cohort study
Authors: N.W. Tsao, E.C. Sayre, A. Howren, M.A. De Vera
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Currently there exists limited data on pregnancy outcomes among women with inflammatory arthritis (IA) using conventional synthetic DMARDs (csDMARDs), and the risk of small-for-gestational-age (SGA) births. <h3>Objectives</h3> To investigate the association between csDMARD use before and during pregnancy and SGA births. <h3>Methods</h3> We linked population-based health data in British Columbia, Canada over a 10 year study period (01/01/2002 – 12/31/2012) on all physician visits, hospital admissions, and dispensed medications with a perinatal registry containing valid information on date of conception. We created a pregnancy cohort of women with IA using a case definition of 2 outpatient physician ICD9 codes≥2 months and ≤2 years apart for rheumatoid arthritis, systemic autoimmune rheumatic diseases, ankylosing spondylitis, juvenile idiopathic arthritis, and psoriatic arthritis. We categorised csDMARDs according to accepted safety profiles - antimalarials, cyclosporine-A, gold, and sulfasalazine (Group 1); and methotrexate, leflunomide, azathioprine, cyclophosphamide, chlorambucil, penicillamine, mycophenolate mofetil, and minocycline (Group 2). We determined exposure as binary use (yes/no) during the 90 days preconception; and during pregnancy from date of conception until date of delivery. The SGA outcome was defined as &lt;10 th percentile of sex- and gestational-age specific weights for singleton births or with ICD9/10 codes. We used logistic regression models fitted with generalised estimating equations and adjusted for baseline covariates. <h3>Results</h3> There were 611 pregnancies in 513 women (32±5 years), and 5638 pregnancies in 4077 women (31±5 years) in the csDMARDs exposed and unexposed groups, respectively. We identified 13%, 18%, and 42% of newborns as SGA in unexposed pregnancies and exposed to Group 1 and 2 csDMARDs, respectively. The adjusted odds ratio (OR) for exposure to Group 1 csDMARDs preconception and during pregnancy and risk of SGA births was 1.49 (95%CI 1.12, 1.97) (table 1). The risk of SGA births was higher in those exposed to Group 2 csDMARDs (OR 1.78, 95% CI 1.14, 2.78). With respect to specific csDMARDs, we observed an OR of 1.25 (95% CI, 0.41, 3.82) for methotrexate. <h3>Conclusions</h3> Our findings suggesting a risk of SGA births with exposure to csDMARDs preconception and during pregnancy have implications for informing women with inflammatory arthritis who are pregnant or planning to become pregnant. <h3>Disclosure of Interest</h3> None declared
Risk of Malignant Ovarian Cancer Based on Ultrasonography Findings in a Large Unselected Population
Authors: Rebecca Smith-Bindman, Liina Poder, Eric Johnson, Diana L. Miglioretti
Journal: JAMA Internal Medicine (2018)

The risk of malignant ovarian cancer associated with simple cysts is unknown.To quantify the risk of ovarian cancer based on ultrasonographic characteristics of ovarian masses, including simple cysts, in a large unselected population.This was a nested case-control study of patients enrolled in Kaiser Permanente Washington, a large integrated health care system in Washington State. Participants were 72 093 women who underwent pelvic ultrasonography between January 1, 1997, and December 31, 2008. Analysis was completed in April 2017.Ultrasonographic characteristics of ovarian masses measured in 1043 women, and also, using weights derived from the sampling strategy, estimated frequencies for the entire cohort.Malignant ovarian cancer, identified through December 31, 2011, by cancer registry linkage.Among 210 women who were diagnosed as having ovarian cancer, 49 were younger than 50 years, and 161 were 50 years or older. Ultrasonography findings were predictive of cancer (C statistic, 0.89). The risk of cancer was significantly elevated in women with complex cysts or solid masses, with likelihood ratios relative to women with normal ovaries ranging from 8 to 74 and the 3-year risk of cancer ranging from 9 to 430 cases per 1000 women based on patient age and ultrasonography findings. In contrast, the 23.8% of women younger than 50 years and the 13.4% of women 50 years or older with simple cysts were not at a significantly increased risk of ovarian cancer compared with women with normal ovaries. Likelihood ratios associated with the detection of a simple cyst were 0.00 in women younger than 50 years (no cancers were identified) and 0.10 (95% CI, 0.01-0.48) in women 50 years or older, and the absolute 3-year risk of cancer ranged from 0 to 0.5 cases per 1000 women.According to this study, the ultrasonographic appearance of ovarian masses is strongly associated with a woman's risk of ovarian cancer. Simple cysts are not associated with an increased risk of ovarian cancer, whereas complex cysts or solid masses are associated with a significantly increased risk of ovarian cancer.
ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm
Authors: Russell A. Gould, Hamza Aziz, Courtney E. Woods, Manuel Alejandro Seman-Senderos, Elizabeth Sparks, Christoph Preuss, Florian Wünnemann, Djahida Bedja, Cassandra R. Moats, Sarah A. McClymont, Rebecca Rose, Nara Sobreira, Hua Ling, Gretchen MacCarrick, Ajay Anand Kumar, Ilse Luyckx, Elyssa Cannaerts, Aline Verstraeten, Hanna M. Björk, Ann-Cathrin Lehsau, Vinod Jaskula-Ranga, Henrik Lauridsen, Asad A. Shah, Christopher L. Bennett, Patrick T. Ellinor, Honghuang Lin, Eric M. Isselbacher, Christian Lacks Lino Cardenas, Jonathan T. Butcher, G. Chad Hughes, Mark E. Lindsay, Luc Mertens, Anders Franco-Cereceda, Judith M. A. Verhagen, Marja Wessels, Salah A. Mohamed, Per Eriksson, Seema Mital, Lut Van Laer, Bart L. Loeys, Gregor Andelfinger, Andrew S. McCallion, Harry C. Dietz
Journal: Nature Genetics (2018)