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Background Nasopharyngeal qualitative reverse-transcription polymerase chain reaction (RT-PCR) is the gold standard for diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but it is not practical or sufficient in every clinical scenario due to its inability to distinguish active from resolved infection. Alternative or adjunct testing may be needed to guide isolation precautions and treatment in patients admitted to the hospital. Methods We performed a single-center, retrospective analysis of residual clinical specimens and medical record data to examine blood plasma nucleocapsid antigen as a candidate biomarker of active SARS-CoV-2. Adult patients admitted to the hospital or presenting to the emergency department with SARS-CoV-2 ribonucleic acid (RNA) detected by RT-PCR from a nasopharyngeal swab specimen were included. Both nasopharyngeal swab and a paired whole blood sample were required to be available for analysis. Results Fifty-four patients were included. Eight patients had positive nasopharyngeal swab virus cultures, 7 of whom (87.5%) had concurrent antigenemia. Nineteen (79.2%) of 24 patients with detectable subgenomic RNA and 20 (80.0%) of 25 patients with N2 RT-PCR cycle threshold ≤ 33 had antigenemia. Conclusions Most individuals with active SARS-CoV-2 infection are likely to have concurrent antigenemia, but there may be some individuals with active infection in whom antigenemia is not detectable. The potential for high sensitivity and convenience of a blood test prompts interest in further investigation as a screening tool to reduce reliance on nasopharyngeal swab sampling and as an adjunct diagnostic test to aid in clinical decision making during the period after acute coronavirus disease 2019.

PDF file, 109KB, S1: Genotype and allele frequency of the analyzed IL-10, IL-4R, TNFRI and II gene variations in patients with T-NHL (n = 117); S2: 2. 3-year survival rates for OS and EFS of patients suffering from T-NHL in relation to analyzed gene variation; S3: Real time PCR Taqman� assays used to analyze IL-10, IL-4R, TNFRI and TNFRII gene variations; S4: Primer for SNaPshot Assay used to analyze IL-10 gene variations.

Purpose: Peripheral T-cell non–Hodgkin lymphomas (T-NHL) represent a small but heterogeneous and clinically aggressive subset of NHLs with a poor outcome. Cytokines or their receptors might be associated with the clinical outcome of these lymphomas. Therefore, we tested whether gene variations and serum levels of soluble TNF receptor (TNFR)I (sTNFRI), sTNFRII, interleukin (IL)-10, or sIL-4R are predictive for treatment response in T-NHLs.Experimental Design: Peripheral blood DNA from 117 patients with T-NHL treated in prospective clinical trials was subjected to genotyping analysis. Whenever possible, pretreatment sera were obtained, and circulating levels of sTNFRI, sTNFRII, IL-10, and sIL-4R were determined with a specific capture enzyme-linked immunoassay.Results: Patients characterized by TNFRI-609GG (rs4149570) showed a trend toward better event free survival [EFS; univariate: P = 0.041; multivariate: HR, 1.76; confidence interval (CI), 0.99–3.14 with P = 0.056]. A protective role of IL-10–1087A, −824T, and −597A reported in another study was not confirmed in our cohort. Patients with circulating levels of soluble TNFRII ≥2.16 ng/mL had a 2.07-fold increased relative risk for shorter overall survival (OS; univariate: P = 0.0034; multivariate: HR, 2.07; CI, 0.92–4.70 with P = 0.081) and a 2.49-fold higher risk for shorter EFS (univariate: P = 0.00068; multivariate: HR, 2.49; CI, 1.22–5.08 with P = 0.012). Elevations of circulating levels of sTNFRI, IL-10, and sIL-4R are frequent, but the clinical response in these patients is not significantly different.Conclusions: Our findings suggest a critical role for TNF-TNFR signaling for the clinical outcome of patients with peripheral T-NHLs. Clin Cancer Res; 18(13); 3637–47. ©2012 AACR.

PDF file, 139KB, Overall and Event free survival of patients suffering from T-cell Non-Hodgkin lymphoma in relation to circulating serum levels of sTNFRI, IL-10 and sIL-4R. The survival curves (Kaplan-Meier plots) show a comparison of the OS (A,C,E) and EFS (B,D,F) of T-NHL patients with circulating serum levels of sTNFRI (A,B), IL-10 (C,D) and sIL-4R (E,F). The respective threshold used to define high and low producers is indicated in the figure legend (lower left). For high producers of sTNFRI (B) and sIL-4R (F) an insignificant trend for shorter EFS was observed (p=0.0886 and p=0.333). The other survival curves show no trends for associations of serum levels and survival periods. P refers to the log-rank test. Patients at risk represents the number of patients which still can develop an event (OS or EFS) at defined time points.

Objective The SENSCIS® trial demonstrated a significant reduction of lung function decline in patients with SSc-associated interstitial lung disease (SSc-ILD) treated with nintedanib, but no significant effect on health-related quality of life (HRQoL). To assess whether SSc/SSc-ILD severity and large changes in lung function correlate with HRQoL, a post-hoc analysis of SENSCIS®, aggregating treatment arms, was undertaken. Methods Patient-reported outcome (PRO) measures [St. George’s Respiratory Questionnaire (SGRQ), Functional Assessment of Chronic Illness Therapy (FACIT)-Dyspnoea, and HAQ–Disability Index (HAQ-DI), incorporating the Scleroderma HAQ visual analogue scale (SHAQ VAS)] at baseline and week 52 were assessed for associations to SSc-ILD severity. Results At baseline and at week 52, forced vital capacity (FVC) 30% fibrosis on high-resolution computed tomography at baseline demonstrated worse PRO measure scores at week 52. After 1 year, patients with a major (>10%) improvement/worsening in FVC demonstrated corresponding improvement/worsening in SGRQ and other PRO measures, significant for the SGRQ symptom domain (P Conclusion Severe SSc-ILD and major deteriorations in lung function have important impacts on HRQoL. Treatments that slow lung function decline and prevent severe SSc-ILD are important to preserve HRQoL. Trial registration clinicaltrials.gov, www.clinicaltrials.gov, NCT02597933

Context.— Diagnostic testing for SARS-CoV-2 in symptomatic and asymptomatic children remains integral to care, particularly for supporting return to and attendance in schools. The concordance of SARS-CoV-2 detection in children, using various specimen types, has not been widely studied. Objective.— To compare 3 sample types for SARS-CoV-2 polymerase chain reaction (PCR) testing in children, collected and tested at a single facility. Design.— We prospectively recruited 142 symptomatic and asymptomatic children/young adults into a sample comparison study performed in a single health care system. Each child provided self-collected saliva, and a trained health care provider collected a mid-turbinate nasal swab and nasopharyngeal (NP) swab. Specimens were assayed within 24 hours of collection by using reverse transcription–polymerase chain reaction (RT-PCR) to detect SARS-CoV-2 on a single testing platform. Results.— Concurrently collected saliva and mid-turbinate swabs had greater than 95% positive agreement with NP swabs when obtained within 10 days of symptom onset. Positive agreement of saliva and mid-turbinate samples collected from children with symptom onset >10 days prior, or without symptoms, was 82% compared to NP swab samples. Cycle threshold (Ct) values for mid-turbinate nasal samples more closely correlated with Ct values from NP samples than from saliva samples. Conclusions.— These findings suggest that all 3 sample types from children are useful for SARS-CoV-2 diagnostic testing by RT-PCR, and that concordance is greatest when the child has had symptoms of COVID-19 within the past 10 days. This study provides scientific justification for using sample types other than the NP swab for SARS-CoV-2 testing in pediatric populations.

Faced with the COVID-19 pandemic, the US system for developing and testing technologies was challenged in unparalleled ways. This article describes the multi-institutional, transdisciplinary team of the “RADxSM Tech Test Verification Core” and its role in expediting evaluations of COVID-19 testing devices. Expertise related to aspects of diagnostic testing was coordinated to evaluate testing devices with the goal of significantly expanding the ability to mass screen Americans to preserve lives and facilitate the safe return to work and school. Focal points included: laboratory and clinical device evaluation of the limit of viral detection, sensitivity, and specificity of devices in controlled and community settings; regulatory expertise to provide focused attention to barriers to device approval and distribution; usability testing from the perspective of patients and those using the tests to identify and overcome device limitations, and engineering assessment to evaluate robustness of design including human factors, manufacturability, and scalability.

Objective In the SENSCIS trial in subjects with systemic sclerosis-associated interstitial lung disease (SSc-ILD), nintedanib reduced the rate of decline in forced vital capacity (FVC) over 52 weeks by 44% versus placebo. This study was undertaken to investigate the effects of nintedanib on categorical changes in FVC and other measures of ILD progression. Methods In post hoc analyses, we assessed the proportions of subjects with categorical changes in FVC % predicted at week 52 and the time to absolute decline in FVC of ≥5% predicted or death and absolute decline in FVC of ≥10% predicted or death. Results A total of 288 subjects received nintedanib and 288 subjects received placebo. At week 52, in subjects treated with nintedanib and placebo, respectively, 55.7% and 66.3% had any decline in FVC % predicted, 13.6% and 20.1% had a decline in FVC of >5% to ≤10% predicted, and 3.5% and 5.2% had a decline in FVC of >10% to ≤15% predicted; 34.5% and 43.8% had a decrease in FVC of ≥3.3% predicted (proposed minimal clinically important difference [MCID] for worsening of FVC), while 23.0% and 14.9% had an increase in FVC of ≥3.0% predicted (proposed MCID for improvement in FVC). Over 52 weeks, the hazard ratio (HR) for an absolute decline in FVC of ≥5% predicted or death with nintedanib versus placebo was 0.83 (95% confidence interval [95% CI] 0.66-1.06) (P = 0.14), and the HR for an absolute decline in FVC of ≥10% predicted was 0.64 (95% CI 0.43-0.95) (P = 0.029). Conclusion These results suggest that nintedanib has a clinically relevant benefit on the progression of SSc-ILD.

To provide an accessible and inexpensive method to surveil for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutations, we developed a multiplex real-time reverse transcription-PCR (rRT-PCR) assay, the Spike single-nucleotide polymorphism (SNP) assay, to detect specific mutations in the spike receptor binding domain. A single primer pair was designed to amplify a 348-bp region of spike, and probes were initially designed to detect K417, E484K, and N501Y. The assay was evaluated using characterized variant sample pools and residual nasopharyngeal samples. Variant calls were confirmed by SARS-CoV-2 genome sequencing in a subset of samples. Subsequently, a fourth probe was designed to detect L452R. The lower limit of 95% detection was 2.46 to 2.48 log10 genome equivalents (GE)/ml for the three initial targets (∼1 to 2 GE/reaction). Among 253 residual nasopharyngeal swabs with detectable SARS-CoV-2 RNA, the Spike SNP assay was positive in 238 (94.1%) samples. All 220 samples with threshold cycle (CT) values of

While there has been significant progress in the development of rapid COVID-19 diagnostics, as the pandemic unfolds, new challenges have emerged, including whether these technologies can reliably detect the more infectious variants of concern and be viably deployed in non-clinical settings as “self-tests”. Multidisciplinary evaluation of the Abbott BinaxNOW COVID-19 Ag Card (BinaxNOW, a widely used rapid antigen test, included limit of detection, variant detection, test performance across different age-groups, and usability with self/caregiver-administration. While BinaxNOW detected the highly infectious variants, B.1.1.7 (Alpha) first identified in the UK, B.1.351 (Beta) first identified in South Africa, P.1 (Gamma) first identified in Brazil, B.1.617.2 (Delta) first identified in India and B.1.2, a non-VOC, test sensitivity decreased with decreasing viral loads. Moreover, BinaxNOW sensitivity trended lower when devices were performed by patients/caregivers themselves compared to trained clinical staff, despite universally high usability assessments following self/caregiver-administration among different age groups. Overall, these data indicate that while BinaxNOW accurately detects the new viral variants, as rapid COVID-19 tests enter the home, their already lower sensitivities compared to RT-PCR may decrease even more due to user error.

Inducing latency reversal to reveal infected cells to the host immune system represents a potential strategy to cure HIV infection. In separate studies, we have previously shown that CD8+ T cells may contribute to the maintenance of viral latency and identified a novel SMAC mimetic/IAP inhibitor (AZD5582) capable of reversing HIV/SIV latency in vivo by activating the non-canonical (nc) NF-κB pathway. Here, we use AZD5582 in combination with antibody-mediated depletion of CD8α+ cells to further evaluate the role of CD8+ T cells in viral latency maintenance. Six rhesus macaques (RM) were infected with SIVmac239 and treated with ART starting at week 8 post-infection. After 84-85 weeks of ART, all animals received a single dose of the anti-CD8α depleting antibody (Ab), MT807R1 (50mg/kg, s.c.), followed by 5 weekly doses of AZD5582 (0.1 mg/kg, i.v.). Following CD8α depletion + AZD5582 combined treatment, 100% of RMs experienced on-ART viremia above 60 copies per ml of plasma. In comparator groups of ART-suppressed SIV-infected RMs treated with AZD5582 only or CD8α depletion only, on-ART viremia was experienced by 56% and 57% of the animals respectively. Furthermore, the frequency of increased viremic episodes during the treatment period was greater in the CD8α depletion + AZD5582 group as compared to other groups. Mathematical modeling of virus reactivation suggested that, in addition to viral dynamics during acute infection, CD8α depletion influenced the response to AZD5582. This work suggests that the latency reversal induced by activation of the ncNF-κB signaling pathway with AZD5582 can be enhanced by CD8α+ cell depletion.

A favored approach to curing HIV infection aims at inducing viral expression using latency-reversing agents (LRAs) to allow the elimination of infected cells. Here, we tested a combination of two recently identified LRAs, the SMAC mimetic/IAP inhibitor AZD5582, which activates the noncanonical NF-κB pathway, and the antibody (Ab) MT807R1, which depletes CD8α+ cells, in SIV-infected rhesus macaques (RMs) on ART., Inducing latency reversal to reveal infected cells to the host immune system represents a potential strategy to cure human immunodeficiency virus (HIV) infection. In separate studies, we have shown previously that CD8+ T cells may contribute to the maintenance of viral latency and have identified a novel SMAC (second mitochondrial activator of caspases) mimetic/IAP (inhibitor of apoptosis protein) inhibitor (AZD5582) capable of reversing HIV/simian immunodeficiency virus (SIV) latency in vivo by activating the noncanonical (nc) NF-κB pathway. Here, we use AZD5582 in combination with antibody (Ab)-mediated depletion of CD8α+ cells to further evaluate the role of CD8+ T cells in the maintenance of viral latency. Six rhesus macaques (RMs) were infected with SIVmac239 and treated with antiretroviral therapy (ART) starting at week 8 postinfection. After 84 to 85 weeks of ART, all animals received a single dose of the anti-CD8α depleting Ab MT807R1 (50 mg/kg of body weight, administered subcutaneously [s.c.]), followed by five weekly doses of AZD5582 (0.1 mg/kg, administered intravenously [i.v.]). Following combined treatment with CD8α depletion and AZD5582, 100% of RMs experienced on-ART viremia levels above 60 copies per ml of plasma. In comparator groups of SIV-infected, ART-suppressed RMs treated with AZD5582 only or CD8α depletion only, on-ART viremia was experienced by 56% and 57% of the animals, respectively. Furthermore, the increased frequency of viremic episodes during the treatment period was greater in the group treated with CD8α depletion plus AZD5582 than in the other groups. Mathematical modeling of virus reactivation suggested that in addition to viral dynamics during acute infection, CD8α depletion influenced the response to AZD5582. This work suggests that the latency reversal induced by activation of the ncNF-κB signaling pathway with AZD5582 can be enhanced by CD8α+ cell depletion. IMPORTANCE A favored approach to curing HIV infection aims at inducing viral expression using latency-reversing agents (LRAs) to allow the elimination of infected cells. Here, we tested a combination of two recently identified LRAs, the SMAC mimetic/IAP inhibitor AZD5582, which activates the noncanonical NF-κB pathway, and the antibody (Ab) MT807R1, which depletes CD8α+ cells, in SIV-infected rhesus macaques (RMs) on ART. Latency reversal, as defined by increased on-ART viremia, was observed in all six SIV-infected, ART-treated RMs that received this combined treatment. Furthermore, comparison of viral reactivation between these animals and groups of SIV-infected, ART-treated RMs treated with AZD5582 only or CD8α+ cell depletion only showed more frequent increases in viremic episodes when the two treatments were combined. This study provides additional evidence that CD8+ T cells may contribute to the maintenance of HIV/SIV latency on ART and potentially inhibit latency reversal during HIV cure approaches.

Background:Nintedanib has shown to slow FVC decline by 41ml over 52 weeks in systemic sclerosis-associated interstitial lung disease (SSc-ILD). However, the long-term effect of nintedanib treatment on ILD progression and mortality in SSc patients is so far unknown.Objectives:Here, the 52-week treatment efficacy of nintedanib was modeled and extrapolated on the long-term FVC course and survival in SSc-ILD patients from the European Scleroderma Trial and Research (EUSTAR) database.Methods:SSc patients from the EUSTAR database fulfilling the inclusion criteria of the SENSCIS trial (SSc classification criteria, ILD confirmed by imaging, disease duration of Results:Of the 236 included patients, 75% were females, 65% had diffuse cutaneous SSc. Mean age was 50.6 years, mean FVC 78.2%pred and DLCO 56.3%pred at time of inclusion. Mean FVC change after 12±3 months was -2.3 ±6.9%pred. These parameters were largely similar to the characteristics of the SENSCIS population.In the longitudinal follow up of this population, the natural course of FVC showed a total FVC decline of -16.3%pred over 5 years. With assumed SENSCIS effects (effects of nintedanib treatment reported in SENSCIS), the 5-year FVC decline was reduced to -10.3%pred (Figure 1).The reduced FVC progression translated into an improved survival. The natural 5-year survival of this SSc-ILD population was 88.2%. When extrapolating also a severe FVC decline early in the course, frequently terminated by early mortality of SSc patients excluding them from long-term outcome assessment, the estimated 5-year survival was reduced to 81.6%. When the SENSCIS effects on FVC were considered, the 5-year extrapolated survival was increased to 86.3% (Figure 2).Conclusion:Long-term experience of nintedanib treatment in SSc-ILD patients is lacking so far, therefore we modeled and extrapolated the 52-week treatment efficacy of nintedanib on the long-term FVC course and survival in SSc-ILD patients from the EUSTAR database. We could demonstrate a significant reduction of FVC decline by extrapolating the annual treatment effects of nintedanib from the SENSCIS trial from 1 to 5 years in EUSTAR. Translating these reductions of FVC decline into survival, the 5-year mortality rate was reduced from 18% to 13%.Disclosure of Interests:Anna-Maria Hoffmann-Vold Speakers bureau: Boehringer Ingelheim, Actelion, Roche, Merck Sharp & Dohme, Lilly, Consultant of: Actelion, Boehringer Ingelheim, Roche, Bayer, Merck Sharp & Dohme, ARXX, Lilly and Medscape, Grant/research support from: Boehringer Ingelheim, Dörte Huscher: None declared, Paolo Airò Speakers bureau: Boehringer Ingelheim, Consultant of: Bristol-Myers-Squibb, Novartis, Elisabetta Zanatta Speakers bureau: Boehringer Ingelheim, Actelion, GSK, Paid instructor for: GSK, Consultant of: Boehringer Ingelheim, GSK, Patricia Carreira Speakers bureau: Actelion, Boehringer Ingellheim, Janssen, GSK, Paid instructor for: Boehringer Ingelheim, Consultant of: AbbVie, Boehringer Ingelheim, VivaCell, Emerald Health Pharmaceuticals, Gesynta Pharma, Sanofi Genzyme, Grant/research support from: Roche, GSK, Yannick Allanore Consultant of: Honorarium received from Boehringer, MedsenicSanofi, Menarini, Grant/research support from: Grants received from Alpine, Ose Immunogenetics, Ulf Müller-Ladner Speakers bureau: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Alessandro Giollo: None declared, Maria Rosa Pozzi: None declared, CAROLINA SOUZA MULLER Speakers bureau: Boehinger Ingelheim, Janssen, Roche, LIBBS, Bristol-Myers-Squib, Radim Bečvář Consultant of: Actelion, Boehringer Ingelheim, Michele Iudici: None declared, Dominik Majewski Speakers bureau: Boehringer Ingelheim - 2 x paid as a speaker, Armando Gabrielli Grant/research support from: Pfizer, CSL Behring, Margarida Alves Employee of: Boehringer Ingelheim, Nils Schoof Employee of: Boehringer Ingelheim International GmbH, Oliver Distler Speakers bureau: Boehringer Ingelheim, Medscape, IQone, Roche, Consultant of: Abbvie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Blade Therapeutics, Bayer, Boehringer Ingelheim, ChemomAb, Corbus Pharmaceuticals, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, iQvia, Italfarmaco, Kymera Therapeutics, Lilly, Medac, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Topadur, Target Bioscience and UCB, Grant/research support from: Kymera Therapeutics, Mitsubishi Tanabe

Uncovering the sanctuaries of the long-lived HIV-1 reservoir is crucial to develop cure strategies. Pediatric immunity is distinct from that of adults, which may alter where the reservoir is established in infancy. Thus, it is important to utilize pediatric models to inform cure-directed approaches for HIV-1-infected children. We used an infant rhesus macaque model of HIV-1 infection via breastfeeding to identify key sites of viral persistence under antiretroviral therapy (ART). The gastrointestinal tract was found to be a site for low-level viral transcription during ART. We also show that naive CD4+ T cells harbored intact provirus and were a major contributor to blood and lymphoid reservoir size. This is particularly striking, as memory CD4+ T cells are generally regarded as the main source of latent HIV/simian immunodeficiency virus (SIV) infection of adult humans and rhesus macaques. Our findings highlight unique features of reservoir composition in pediatric infection that should be considered for eradication efforts., Mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) continues to cause new pediatric cases of infection through breastfeeding, a setting where it is not always possible to initiate early antiretroviral therapy (ART). Without novel interventions that do not rely on daily ART, HIV-1-infected children face lifelong medications to control infection. A detailed analysis of virus persistence following breast milk transmission of HIV-1 and ART has not been performed. Here, we used infant rhesus macaques orally infected with simian/human immunodeficiency virus (SHIV) (SHIV.C.CH505) to identify cellular and anatomical sites of virus persistence under ART. Viral DNA was detected at similar levels in blood and tissue CD4+ T cells after a year on ART, with virus in blood and lymphoid organs confirmed to be replication competent. Viral RNA/DNA ratios were elevated in rectal CD4+ T cells compared to those of other sites (P ≤ 0.0001), suggesting that the gastrointestinal tract is an active site of virus transcription during ART-mediated suppression of viremia. SHIV.C.CH505 DNA was detected in multiple CD4+ T cell subsets, including cells with a naive phenotype (CD45RA+ CCR7+ CD95–). While the frequency of naive cells harboring intact provirus was lower than in memory cells, the high abundance of naive cells in the infant CD4+ T cell pool made them a substantial source of persistent viral DNA (approximately 50% of the total CD4+ T cell reservoir), with an estimated 1:2 ratio of intact provirus to total viral DNA. This viral reservoir profile broadens our understanding of virus persistence in a relevant infant macaque model and provides insight into targets for cure-directed approaches in the pediatric population. IMPORTANCE Uncovering the sanctuaries of the long-lived HIV-1 reservoir is crucial to develop cure strategies. Pediatric immunity is distinct from that of adults, which may alter where the reservoir is established in infancy. Thus, it is important to utilize pediatric models to inform cure-directed approaches for HIV-1-infected children. We used an infant rhesus macaque model of HIV-1 infection via breastfeeding to identify key sites of viral persistence under antiretroviral therapy (ART). The gastrointestinal tract was found to be a site for low-level viral transcription during ART. We also show that naive CD4+ T cells harbored intact provirus and were a major contributor to blood and lymphoid reservoir size. This is particularly striking, as memory CD4+ T cells are generally regarded as the main source of latent HIV/simian immunodeficiency virus (SIV) infection of adult humans and rhesus macaques. Our findings highlight unique features of reservoir composition in pediatric infection that should be considered for eradication efforts.

The “shock-and-kill” human immunodeficiency virus type 1 (HIV-1) cure strategy involves latency reversal followed by immune-mediated clearance of infected cells. We have previously shown that activation of the noncanonical NF-κB pathway using an inhibitor of apoptosis (IAP), AZD5582, reverses HIV/simian immunodeficiency virus (SIV) latency. Here, we combined AZD5582 with bispecific HIVxCD3 DART molecules to determine the impact of this approach on persistence. Rhesus macaques (RMs) (n = 13) were infected with simian/human immunodeficiency virus SHIV.C.CH505.375H.dCT, and triple antiretroviral therapy (ART) was initiated after 16 weeks. After 42 weeks of ART, 8 RMs received a cocktail of 3 HIVxCD3 DART molecules having human A32, 7B2, or PGT145 anti-HIV-1 envelope (Env) specificities paired with a human anti-CD3 specificity that is rhesus cross-reactive. The remaining 5 ART-suppressed RMs served as controls. For 10 weeks, a DART molecule cocktail was administered weekly (each molecule at 1 mg/kg of body weight), followed 2 days later by AZD5582 (0.1 mg/kg). DART molecule serum concentrations were well above those considered adequate for redirected killing activity against Env-expressing target cells but began to decline after 3 to 6 weekly doses, coincident with the development of antidrug antibodies (ADAs) against each of the DART molecules. The combination of AZD5582 and the DART molecule cocktail did not increase on-ART viremia or cell-associated SHIV RNA in CD4(+) T cells and did not reduce the viral reservoir size in animals on ART. The lack of latency reversal in the model used in this study may be related to low pre-ART viral loads (median

Introduction Systemic sclerosis-associated interstitial lung disease (SSc-ILD) places a substantial burden on patients and healthcare systems. The objectives of this study were to describe clinical characteristics and assess healthcare resource utilization and costs of patients with SSc-ILD in England, compared with patients with non-pulmonary organ involvement related to SSc (SSc-OOI). Methods This population-based retrospective study used data from the Clinical Practice Research Datalink linked to Hospital Episode Statistics. Data were extracted from medical records dated January 1, 2005 to March 31, 2016. Patients with SSc were identified and placed in subgroups based on organ involvement: SSc-ILD, SSc-OOI, and both (SSc-ILD-OOI). Patients with SSc-ILD-OOI were included in both the SSc-ILD and SSc-OOI subgroups. All-cause healthcare costs, excluding medication costs, were calculated to 2016 British pounds sterling (£). Results This study included 675 patients with SSc: 174 (26%) had neither ILD nor other organ involvement (OOI); 127 (19%) had SSc-ILD; 477 (71%) had SSc-OOI; 103 (15%) had SSc-ILD-OOI. Age-weighted median [interquartile range (IQR)] annual healthcare costs per patient were: £1496 (£664–£2817) in SSc only; £6375 (£3451–£15,041) in SSc-ILD; £4084 (£1454–£10,105) in SSc-OOI; £6632 (£4023–£17,009) in SSc-ILD-OOI. In multivariate analysis, older age at diagnosis, diagnosis of anemia, and number of comorbid diseases were associated with higher yearly healthcare costs. Conclusion The annual healthcare cost for patients with SSc-ILD is substantial, and higher than that of patients with SSc-OOI or SSc only. These results quantify the economic burden of SSc-ILD in a real-world setting, and highlight the need for treatment of this disease. Electronic supplementary material The online version of this article (10.1007/s12325-020-01330-0) contains supplementary material, which is available to authorized users., Plain Language Summary SSc is a rare disease that causes fibrosis, or thickening, of the skin. In some patients, SSc can also affect the lungs (‘SSc-ILD’) or other organs, e.g., the heart (‘SSc-OOI’). Patients with SSc-ILD typically have high healthcare costs; however, it is not clear how costs for SSc-ILD compare with those for SSc-OOI. To investigate this, we evaluated the costs associated with SSc-ILD and compared them with those for SSc only or SSc-OOI. In this England-based study, the annual healthcare costs for patients with SSc-ILD were approximately 50% higher than for those without lung disease (SSc only) or SSc-OOI. These results highlight the importance of promptly diagnosing and treating patients with lung fibrosis complicating SSc. Electronic supplementary material The online version of this article (10.1007/s12325-020-01330-0) contains supplementary material, which is available to authorized users.

BACKGROUND: Disease progression and acute exacerbations in patients with idiopathic pulmonary fibrosis (IPF) are associated with high morbidity and mortality. They usually require a visit to a specialist or a general practitioner (GP) in less severe cases or hospitalisation in more severe cases. OBJECTIVE: The objective of this study was to identify factors that influence resource use in IPF. METHODS: Clinical and healthcare resource use data were collected in two large, international, multi-centre, randomised controlled trials (RCTs) that studied nintedanib for the treatment of IPF (INPULSIS-1 and -2). The pooled data of nintedanib and placebo included 1014 patients followed for 12 months. The trial data were analysed in 3-month intervals. We studied two dependent variables: the occurrence of all-cause hospitalisation and visits to a physician (GP or specialist). The independent variables included the change in forced vital capacity percent predicted (FVC%pred), investigator-reported acute exacerbation events, age, time since diagnosis, smoking status, and sex. RESULTS: Hospitalisation during a 3-month interval was significantly associated with a drop of at least 5 or 10 points in FVC%pred (odds ratios [ORs] 1.58 [p = 0.009] and 2.62 [p

Background Systemic sclerosis (SSc), or systemic scleroderma, is a chronic multisystem autoimmune disease characterised by widespread vascular injury and progressive fibrosis of the skin and internal organs. Patients with SSc have decreased survival, with pulmonary involvement as the main cause of death. Current treatments for SSc manage a range of symptoms but not the cause of the disease. Our review describes the humanistic and cost burden of SSc. Methods A structured review of the literature was conducted, using predefined search strategies to search PubMed, Embase, and the Cochrane Library. Grey literature searches also were conducted. Results In total, 2226 articles were identified in the databases and 52 were included; an additional 10 sources were included from the grey literature. The review identified six studies reporting relevant cost estimates conducted in five different countries and four studies that assessed the humanistic burden of SSc. Total direct annual medical costs per patient for Europe varied from €3544 to €8452. For Canada, these costs were reported to be from Can$5038 to Can$10,673. In the United States, the total direct health care costs were reported to be US$17,365 to US$18,396. Different key drivers of direct costs were reported, including hospitalisations, outpatients, and medication. The total annual costs per patient were reported at Can$18,453 in Canada and varied from €11,074 to €22,459 in Europe. Indirect costs represented the largest component of the total costs. EQ-5D utility scores were lower for patients with SSc than those observed in the general population, with reported mean values of 0.49 and 0.68, respectively. The average value of the Health Assessment Questionnaire for patients with SSc was significantly higher than the control population (0.94), and the average value of the SF-36 was significantly lower than the control population: 49.99 for the physical dimension and 58.42 for the mental dimension. Conclusions Overall, there is a paucity of information on the burden of SSc. Nonetheless, our review indicates that the quality of life of patients with SSc is considerably lower than that of the general population. In addition, SSc places a considerable economic burden on health care systems and society as a whole.

Background:Current treatments for systemic sclerosis-associated interstitial lung disease (SSc-ILD) are characterised by different attributes such as mode of administration, adverse events (AE) and efficacy. Physicians and patients often have different perspectives on treatments, thus shared decision-making between patients and physicians is essential. An understanding of patients’ decision processes when weighing treatment attributes and the trade-offs they are willing to make is important for shared decision-making.Objectives:The study aimed to 1) identify relevant treatment attributes, 2) elicit patient preferences for these attributes and 3) quantify preference as relative attribute importance (RAI; a higher RAI indicates that more of the variability in patients’ responses may be explained by changes in the attribute); and maximum acceptable risk (MAR) of diarrhoea, nausea and/or vomiting (MAR is a trade-off measure that evaluates attributes in risk-equivalences as a unit of measurement).Methods:A discrete choice experiment (DCE) was created, based on a literature review, a patient advisory board, qualitative patient interviews, and a workshop involving SSc-ILD expert physicians. Seven SSc-ILD treatment attributes were identified: 1) mode of administration; 2) shortness of breath; 3) skin tightness; 4) cough; 5) tiredness; 6) risk of gastrointestinal tract (GIT) AEs; and 7) risk of serious and non-serious infections. The levels of AE risk were informed by frequencies observed in clinical trials and patient input during the interviews. The DCE was integrated into an online survey, which asked patients to make repeated choices between two alternatives described by varying levels of included attributes. Patients with SSc-ILD were recruited by physician referral from Switzerland, Norway, France, Germany and the USA. DCE data were analysed using a logit model, and RAI and MAR measures were calculated.Results:A total of 231 patients with physician-confirmed SSc-ILD (mean age 52.6±13.2 years; 54% diagnosed for >5 years) completed the survey. Patients with SSc-ILD mostly preferred twice-daily oral treatments (pPatients accepted an additional 21% risk (95% CI 13–29%) of GIT AEs if they could reduce the frequency of infusions from monthly to 6–12 monthly, or accepted an extra 15% (95% CI 7–23%) increase in risk if changing to an oral treatment twice daily. Among symptoms, an additional 28% (95% CI 20–36%) risk of GIT AEs was considered acceptable if the severity of patients’ persistent cough was reduced to a level that was easier to tolerate, even if it remained persistent. Similarly, a 37% (95% CI 28–46%) increase in the risk of GIT AEs was acceptable if it resulted in breathlessness during routine activities rather than breathlessness at rest. Finally, patients were willing to accept an additional 36% risk (95% CI 27–45%) of GIT AEs if it reduced their risk of non-serious infections from 30% to 15% and of serious infections from 10% to 5%.Conclusion:This is the first study to quantitatively elicit patients’ preferences for attributes of SSc-ILD treatments. Preferences were driven by safety, efficacy and technical considerations. Patients showed willingness to make trade-offs, providing a firm basis for shared decision-making in routine clinical practice.Disclosure of Interests:Cosimo Bruni Speakers bureau: Actelion, Consultant of: Eli Lilly, Grant/research support from: Gruppo Italiano Lotta alla Scleroderma (GILS), Fondazione Italiana per la Ricerca sull’Artrite (FIRA), New Horizon Fellowship, European Scleroderma Trial and Research (EUSTAR), Foundation for Research in Rheumatology (FOREUM)., Sebastian Heidenreich Consultant of: Sebastian Heidenreich, PhD is employed by Evidera Inc, a business unit of PPD. Evidera is a CRO that offers paid research services to pharmaceutical companies., Ashley Duenas Consultant of: Yes. I am an employee of Evidera which received funding from Boehringer Ingelheim for work related to this study., Anna-Maria Hoffmann-Vold Speakers bureau: Boehringer Ingelheim, Actelion, Roche, Merck Sharp & Dohme, Lilly, Consultant of: Actelion, Boehringer Ingelheim, Roche, Bayer, Merck Sharp & Dohme, ARXX, Lilly and Medscape, Grant/research support from: Boehringer Ingelheim, Armando Gabrielli Grant/research support from: Pfizer Bhering, Yannick Allanore Consultant of: Honorarium received from Boehringer, Medsenic,Sanofi, Menarini, Grant/research support from: Grants received from Alpine, Ose Immunogenetics, Emmanuel Chatelus: None declared, Jörg H.W. Distler Shareholder of: JHWD is stock owner of 4D Science, Consultant of: JHWD has consultancy relationships with Actelion, Active Biotech, Anamar, ARXX, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, JB Therapeutics, Medac, Pfizer, RuiYi and UCB, Grant/research support from: JHWD has received research funding from Anamar, Active Biotech, Array Biopharma, ARXX, aTyr, BMS, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, Novartis, Sanofi-Aventis, RedX, UCB, Eric Hachulla: None declared, Vivian Hsu Speakers bureau: I am a speaker for Boehringer Ingelheim Pharmaceuticals, Consultant of: with Boehringer Ingelheim Pharmaceuticals, Grant/research support from: Principal Investigator for several clinical trials, currently with Genentech, Corbus Pharmaceutical, and EICOS, Nicolas Hunzelmann Speakers bureau: Boehringer, Roche, Sanofi, Dinesh Khanna Shareholder of: Eicos Sciences, Inc (less than 5%), Consultant of: Paid Consultant for: Acceleron, Actelion, Abbvie, Amgen, Bayer, Boehringer Ingelheim, CSL Behring, Corbus, Gilead, Galapagos, Genentech/Roche, GSK, Horizon, Merck, Mitsubishi Tanabe Pharma, Sanofi-Aventis, and United Therapeutics, Grant/research support from: Research Grant support from: Immune Tolerance Network, Bayer, BMS, Horizon, Pfizer, Employee of: Leadership/Equity position – Chief Medical Officer, CiviBioPharma/Eicos Sciences, Inc – recieves a stipend for role as Chief Medical Officer, which would technically qualify as emplyoment., Marie-Elise Truchetet Speakers bureau: Abbvie, Lilly, Sobi, Boehringer, Paid instructor for: Lilly, Consultant of: UCB, Sobi, Abbvie, Grant/research support from: UCB, Gilead, Ulrich Walker Shareholder of: Bayer, NASDAQ, MSCI-World ETF’s, Speakers bureau: All companies producing pharmaceuticals used in AIDS, Paid instructor for: Roche, Abbvie, Novartis, Consultant of: All companies producing pharmaceuticals used in AIDS, Grant/research support from: Gilead, Abbvie, (in the last two years). Other companies in previous years., Margarida Alves Employee of: Boehringer Ingelheim, Nils Schoof Employee of: Employee of Boehringer Ingelheim International GmbH, Lesley Ann Saketkoo Speakers bureau: Boehringer Ingelheim, Actelion, Janssen, Mallinckrodt, United Therapeutics, Consultant of: Actelion, Boehringer Ingelheim, Bayer, Bristol Meyer Squibb, Corbus, EICOS, Janssen, Horizon, United Therapeutics, Inc, Grant/research support from: Mallinckrodt, United Therapeutics, Oliver Distler Speakers bureau: Boehringer Ingelheim, Medscape, IQone, Roche, Consultant of: OD has/had consultancy relationship and/or has received research funding in the area of potential treatments for systemic sclerosis and its complications from (last three years):Abbvie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Blade Therapeutics, Bayer, Boehringer Ingelheim, ChemomAb, Corbus Pharmaceuticals, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, iQvia, Italfarmaco, iQone, Kymera Therapeutics, Lilly, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Topadur, Target Bioscience and UCB. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143)., Grant/research support from: Kymera Therapeutics, Mitsubishi Tanabe

Long-lasting, latently infected resting CD4+ T cells are the greatest obstacle to obtaining a cure for HIV infection, as these cells can persist despite decades of treatment with antiretroviral therapy (ART). Estimates indicate that more than 70 years of continuous, fully suppressive ART are needed to eliminate the HIV reservoir1. Alternatively, induction of HIV from its latent state could accelerate the decrease in the reservoir, thus reducing the time to eradication. Previous attempts to reactivate latent HIV in preclinical animal models and in clinical trials have measured HIV induction in the peripheral blood with minimal focus on tissue reservoirs and have had limited effect2–9. Here we show that activation of the non-canonical NF-κB signalling pathway by AZD5582 results in the induction of HIV and SIV RNA expression in the blood and tissues of ART-suppressed bone-marrow–liver–thymus (BLT) humanized mice and rhesus macaques infected with HIV and SIV, respectively. Analysis of resting CD4+ T cells from tissues after AZD5582 treatment revealed increased SIV RNA expression in the lymph nodes of macaques and robust induction of HIV in almost all tissues analysed in humanized mice, including the lymph nodes, thymus, bone marrow, liver and lung. This promising approach to latency reversal—in combination with appropriate tools for systemic clearance of persistent HIV infection—greatly increases opportunities for HIV eradication. Activation of the non-canonical NF-κB signalling pathway by AZD5582 results in the induction of HIV and SIV RNA expression in the blood and tissues of antiretroviral-therapy-treated humanized mice and rhesus macaques.

Background Systemic sclerosis-associated interstitial lung disease (SSc-ILD) places a substantial burden on patients and on healthcare services. Despite this, assessments of healthcare resource utilisation and costs incurred during the management of SSc-ILD are limited. Objectives To assess healthcare resource utilisation and costs among patients with SSc-ILD compared with SSc overall and patients with SSc and other organ involvement (SSc-OOI). Methods This was a population-based cohort study. Routinely collected healthcare data were extracted from medical records (dated 1 January 2005 to 31 March 2016) in the Clinical Practice Research Datalink (CPRD) and the Hospital Episode Statistics (HES) databases. Patients with SSc, with or without ILD and/or OOI, were identified from primary and secondary care records in combination with modified European League Against Rheumatism (EULAR) classification criteria. Patients were included in the OOI sub-cohort if their SSc affected cardiac, gastrointestinal, renal or oral function. Eligible patients were aged at least 18 years at first diagnosis, were diagnosed within the study period, and had at least 12 months of available data in CPRD/HES before and after diagnosis. All-cause healthcare resource utilisation (inpatient stays; AE outpatient visits; general practitioner visits) and costs among patients with SSc, SSc-ILD and SSc-OOI were calculated to 2016 GBP. Medication costs were not included. Predictors of total healthcare costs were estimated using a multivariate generalised linear model, with a gamma distribution and log link function to allow for non-normal distributed costs. Comorbid diseases were categorised using the Charlson Comorbidity Index. Results Of 675 patients with SSc, 127 (19%) had ILD and 477 (71%) had OOI; a subset of 103 (15%) patients had both ILD and OOI. The remaining 174 patients (26%) had SSc without ILD or OOI. Median (interquartile range) annual healthcare costs per patient were: £2,601 (£962–6,885) in SSc; £3,449 (£1,271–8,717) in SSc-OOI; £5,899 (£2,986–13,905) in SSc-ILD; £6,375 (£3,046–15,041) in SSc-ILD-OOI. Patients with SSc-ILD (with or without OOI) had the highest rates of inpatient stays, outpatient visits, A&E attendances, and general practitioner visits per person-year. Inpatient stays alone accounted for >60% of the total healthcare costs among SSc patients with ILD (median cost >£3,600 per patient per year). Each patient with SSc-ILD had, on average, 10 outpatient visits per year, at a total yearly median cost of >£840. In comparison, patients with SSc-OOI averaged 7 outpatient visits at a total yearly median cost of £615. Characteristics significantly associated with higher yearly healthcare costs among SSc patients were: older age at diagnosis, diagnosis of anaemia, and number of comorbid diseases. Conclusion The annual healthcare cost for a patient with SSc-ILD is substantial (£2,986–13,905), with inpatient stays the major cause of costs, and is much higher than for patients with SSc-OOI (without ILD). Healthcare costs are also higher among older SSc patients and those with more comorbidities. These results quantify the economic burden of SSc-ILD in a real-world setting, which will be useful when evaluating the cost-effectiveness of new treatment options for SSc-ILD. There is an unmet need for effective therapies for SSc-ILD. Acknowledgement Funding: Boehringer Ingelheim International GmbH, Germany Disclosure of Interests Alicia Gayle Employee of: Employee of Boehringer Ingelheim, Nils Schoof Employee of: Employee of Boehringer Ingelheim, Margarida Alves Employee of: Employee of Boehringer Ingelheim, Deborah Clarke Employee of: Employee of Boehringer Ingelheim, Christina Raabe Employee of: Employee of Boehringer Ingelheim, Prithwiraj Das Employee of: Employee of Boehringer Ingelheim, Toby Maher Grant/research support from: Received funds from BI advisory board participation and conference travel. Received research funding and/or consulting fees or other remuneration from GSK, UCB, AstraZeneca, Roche, Bayer, Biogen Idec, Cipla, Prometic, and Sanumed. Toby Maher has, via his institution, received industry-academic funding from GlaxoSmithKline RD and has received consultancy fees from Galecto.

Background Idiopathic pulmonary fibrosis (IPF) is a debilitating condition with significant morbidity and poor survival. Since 2010, there has been increased activity in the development of treatments that aim to delay progression of the disease. Objective Our study involves a comprehensive review of the literature for evidence on health-related quality of life (HRQoL), healthcare resource use (HCRU) and costs, and an assessment of the burden of illness of the condition. Methods We carried out a systematic literature review (SLR) to identify economic evaluations and HRQoL studies. We searched EMBASE, MEDLINE and MEDLINE In Process for relevant studies from database origins to April 2017. Alongside the presentation of the study characteristics and the available evidence, we carried out a qualitative comparison using reference population estimates for HRQoL and national health expenditure for costs. Results Our search identified a total of 3241 records. After removing duplicates and not relevant articles, we analysed 124 publications referring to 88 studies published between 2000 and 2017. Sixty studies were HRQoL and 28 were studies on costs or HCRU. We observed an exponential growth of publications in the last 3–5 years, with the majority of the studies conducted in Europe and North America. Among the HRQoL studies, and despite regional differences, there was some agreement between estimates on the absolute and relative level of HRQoL for patients with IPF compared with the general population. Regarding costs, after adjustments for the cost years and currency, the suggested annual per capita cost of patients with IPF in North America was estimated around US$20,000, 2.5–3.5 times higher than the national healthcare expenditure. Additionally, studies that analysed patients with IPF alongside a matched control cohort suggested a significant increase in resource use and cost. Conclusion The reviewed evidence indicates that IPF has considerable impact on HRQoL, relative to the general population levels. Furthermore, in studies of cost and resource use, most estimates of the burden were consistent in suggesting an excess cost for patients with IPF compared with a control cohort or the national health expenditure. This confirms IPF as a growing threat for public health worldwide, with considerable impact to the patients and healthcare providers. Electronic supplementary material The online version of this article (10.1007/s40273-018-0631-8) contains supplementary material, which is available to authorized users.

We assessed whether variants in 22 oxidative stress-related genes are associated with mortality of breast cancer patients and whether the associations differ according to radiotherapy. Using a prospective cohort of 1348 postmenopausal breast cancer patients, we estimated hazard ratios (HR) and 95% confidence intervals (CI) for 109 single nucleotide polymorphisms (SNPs) using Cox proportional hazards regression. Validation of results was attempted using two Scandinavian studies. Eleven SNPs in MT2A , NFE2L2 , NQO1 , PRDX1 , and PRDX6 were significantly associated with overall mortality after a median follow-up of 5.7 years. Three SNPs in NQO1 (rs2917667) and in PRDX6 (rs7314, rs4916362) were consistently associated with increased risk of dying across all three study populations (pooled: HR NQO1_rs2917667 1.20, 95% CI 1.00–1.44, p = 0.051; HR PRDX6_rs7314 1.16, 95% CI 1.00–1.35, p = 0.056, HR PRDX6_rs4916362 1.14 95% CI 1.00–1.32, p = 0.062). Potential effect modification by radiotherapy was found for CAT _rs769218. In conclusion, genetic variants in NQO1 and PRDX6 may modify breast cancer prognosis.

BACKGROUND: Individual differences in breast size are a conspicuous feature of variation in human females and have been associated with fecundity and advantage in selection of mates. To identify common variants that are associated with breast size, we conducted a large-scale genotyping association meta-analysis in 7169 women of European descent across three independent sample collections with digital or screen film mammograms. METHODS: The samples consisted of the Swedish KARMA, LIBRO-1 and SASBAC studies genotyped on iCOGS, a custom illumina iSelect genotyping array comprising of 211 155 single nucleotide polymorphisms (SNPs) designed for replication and fine mapping of common and rare variants with relevance to breast, ovary and prostate cancer. Breast size of each subject was ascertained by measuring total breast area (mm(2)) on a mammogram. RESULTS: We confirm genome-wide significant associations at 8p11.23 (rs10086016, p=1.3×10(-14)) and report a new locus at 22q13 (rs5995871, p=3.2×10(-8)). The latter region contains the MKL1 gene, which has been shown to impact endogenous oestrogen receptor α transcriptional activity and is recruited on oestradiol sensitive genes. We also replicated previous genome-wide association study findings for breast size at four other loci. CONCLUSIONS: A new locus at 22q13 may be associated with female breast size. KARMA and LIBRO-1 were supported by Märit and Hans Rausings Initiative Against Breast Cancer. SASBAC was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institute of Health (NIH) and the Susan G. Komen Breast Cancer Foundation. All three studies are genotyped as part of the Collaborative Oncological Gene-environment Study (COGS), which is supported by the European Community's Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS). Genotyping of the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer program and the Ministry of Economic Development, Innovation and Export Trade of Quebec (grant PSR-SIIRI-701). BCAC is funded by Cancer Research UK (C1287/A10118 and C1287/A12014). Combining the GWAS data was supported in part by the US National Institutes of Health (NIH) Cancer Post-Cancer GWAS initiative grant 1 U19 CA 148065-01 (DRIVE, part of the GAME-ON initiative). KC was financed by the Swedish Cancer Society (5128-B07-01PAF). KH was supported by the Swedish Research Council (523-2006-972) and the Swedish E Science Research Centre. This work was also supported, in part, by the Intramural Research Program of the U.S. National Cancer Institute, Department of Health and Human Services, USA. We wish to thank Aki Tuuliainen, Kimberley Sio Kim Chua, Sander Canisius, Grethe I.G. Alnæs, Torben Luders and Lodewyk Wessels for their help in data collection and analysis Sí

CME Learning Objectives Discuss whether and how genetic variations influence clinical outcomes of Hodgkin lymphoma patients. Evaluate evidence that proximal IL10 promoter gene variations are associated with clinical courses of Hodgkin lymphoma patients. Compare host genetic variations from different cytokine/cytokine receptor gene variations. Background. Hodgkin lymphoma (HL) is a lymphoid malignancy characterized by the production of various cytokines possibly involved in immune deregulation. Interleukin-10 (IL-10) serum levels have been associated with clinical outcome in patients with HL. Because host genetic variations are known to alter the expression and function of cytokines and their receptors, we investigated whether genetic variations influence clinical outcome of patients with HL. Methods. A total of 301 patients with HL who were treated within randomized trials by the German Hodgkin Study Group were included in this exploratory retrospective study. Gene variations of IL-10 (IL-10-597AC, rs1800872; IL-10-824CT, rs1800871; IL-10-1087AG, rs1800896; IL-10-3538AT, rs1800890; IL-10-6208CG, rs10494879; IL-10-6752AT, rs6676671; IL-10-7400InDel), IL-13 (IL-13-1069CT, rs1800925; IL-13Q144R, rs20541), and IL-4R (IL-4RI75V, rs1805010; IL-4RQ576R, rs1801275) were genotyped. Results. Inferior freedom from treatment failure (FFTF) was found in patients harboring the IL-10-597AA, IL-10-824TT, or the IL-10-1087AA genotype. In contrast, the IL-10-1087G-824C-597C haplotype present in about 48% of analyzed HL patients is nominally significant for a better FFTF in a Cox-Regression model accounting for stage and treatment. No associations were observed between the other IL-10 gene variations, IL-13-1069CT, IL-13Q144R, IL-4RI75V, IL-4RQ576R and the clinical outcome of patients with HL. Conclusions. Our study provides further evidence that proximal IL-10 promoter gene variations are associated with clinical course of patients with HL. However, treatment success and survival rates are already at a very high rate, supporting the need to design studies focusing on identification of predictors to reduce the side effects of therapy.

Contains fulltext : 167177.pdf (Publisher’s version ) (Open Access) BACKGROUND: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. METHODS: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. RESULTS: The most significant global associations for all genes in the pathway were seen in endometrioid (p = 0.082) and clear cell (p = 0.083), with the most significant gene level association seen with TGFBR2 (p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 (p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA (p = 0.035, endometrioid and mucinous), LGALS1 (p = 0.03, mucinous), STAT5B (p = 0.022, clear cell), TGFBR1 (p = 0.021 endometrioid) and TGFBR2 (p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). CONCLUSIONS: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.

Aims The introduction of non-VKA oral anticoagulants (NOACs), which differ from the earlier vitamin K antagonist (VKA) treatments, has changed the approach to stroke prevention in atrial fibrillation (AF). GLORIA-AF is a prospective, global registry programme describing the selection of antithrombotic treatment in newly diagnosed AF patients at risk of stroke. It comprises three phases: Phase I, before the introduction of NOACs; Phase II, during the time of the introduction of dabigatran, the first NOAC; and Phase III, once NOACs have been established in clinical practice. Methods and results In Phase I, 1063 patients were eligible from the 1100 enrolled (54.3% male; median age 70 years); patients were from China (67.1%), Europe (EU; 27.4%), and the Middle East (ME; 5.6%). The majority of patients using VKAs had high stroke risk (CHA2DS2-VASc ≥ 2; 86.5%); 13.5% had moderate risk (CHA2DS2-VASc = 1). Vitamin K antagonist use was higher for persistent/permanent AF (47.7%) than that for paroxysmal (23.9%). Most patients in China were treated with antiplatelet agents (53.7%) vs. 27.1% in EU and 28.8% in ME. In China, 25.9% of patients had no antithrombotic therapy, vs. 8.6% in EU and 8.5% in ME. Conclusion Phase I of GLORIA-AF shows that VKAs were mostly used in patients with persistent/permanent (vs. paroxysmal) AF and in those with high stroke risk. Furthermore, there were meaningful geographical differences in the use of VKA therapy in the era before the availability of NOACs, including a much lower use of VKAs in China, where most patients either received antiplatelet agents or no antithrombotic treatment.

Background Recently published data indicate that host germline variations in immune genes can influence the outcome of lymphoma patients. Interleukin (IL)-4 and IL13 are crucial immune factors and may influence the course of the disease. Both cytokines signal through the interleukin-4 receptor (IL4R). Therefore, we investigated whether polymorphisms of IL4, IL13 and IL4R genes could predict the outcome of diffuse large B-cell lymphoma (DLBCL) patients. Methods In 228 DLBCL samples of the German High-Grade Non-Hodgkin's Lymphoma Study Group, the polymorphisms of IL4 (-524CT, rs2243250), IL13 (-1069CT, rs1800925) and IL4R (I75V, rs1805010; S503P, rs1805015; Q576R, rs1801275) were analyzed and the soluble interleukin-4 receptor (sIL4R) serum level was measured before the start of chemotherapy. Results Patients harboring IL4R V75 (IL4RI75V-AG and IL4RI75V-GG) had shorter overall survival (OS) (P = 0.044) and event-free survival (EFS) (P = 0.056) periods compared with I75 carriers (IL4RI75V-AA). Multivariate analysis adjusted to the International Prognostic Index revealed a relative risk of 1.9 for carriers of the IL4R V75 (P = 0.011) in relation to OS. DLBCL patients homozygous for the IL4R I75 and low sIL4R serum levels have the most favorable OS and EFS. Conclusions These data support the role for host germline gene variations of immunologically important factors like the IL4R I75V gene variation to predict the survival in DLBCL patients.

Purpose: Current chemotherapy can achieve high response rates in aggressive non-Hodgkin's lymphoma (NHL), but the factors that influence regression and survival remain unknown. The present exploratory study tested the hypothesis whether interleukin-10 (IL-10) polymorphisms predict clinical outcome, leukocytopenia, or infectivity during therapy. IL-10 was chosen because immune alterations are a major risk factor for NHL, and IL-10 is a cytokine involved in inflammatory processes associated with clinical outcome. Experimental Design: Five hundred patients with aggressive NHL treated with CHOP/CHOEP were analyzed for IL-10 gene polymorphisms, including distal loci -7400InDel, -6752AT (rs6676671), and -6208CG (rs10494879) in comparison with proximal loci -3538AT (rs1800890), -1087AG (rs1800896), and -597AC (rs1800872) according to the incidence and outcome of the lymphoma. Results: No differences in allele frequencies or haplotypes were found comparing a cohort of patients with aggressive NHL/diffuse large B-cell lymphoma with a healthy control group. Patients with aggressive NHL characterized by IL-10-7400DelDel had shorter overall survival periods compared with the other genotypes (P = 0.004). The 3-year rate is 43.4% for IL-10-7400DelDel and 73.4% for IL-10-7400InIn and IL-10-7400InDel together. A significant increased risk for event-free survival is found for carriers of the genotype IL-10-6752TT-6208CC-3538AA (P = 0.047). Multivariate analysis of IL-10-7400 gene variation in relation to overall survival adjusted to international prognostic index revealed a relative risk of 1.9 for carriers of IL-10-7400DelDel (P = 0.037). No associations were found analyzing diffuse large B-cell lymphoma patients separately. Conclusion: Our results indicate that IL-10 gene variations could be associated to the clinical course of aggressive NHL, which points out the importance of host factors and respective genetic elements for treatment response.

In order to understand characteristics of atrial fibrillation patients in the era of new oral anticoagulants (NOACs), this study explores differences in characteristics between patients treated with dabigatran etexilate (DE) and warfarin (W) that may be due to patient channeling in ‘real-world’ clinical practice. Medco claims data were used to characterize 41,805 non-valvular atrial fibrillation (NVAF) patients from the US with a DE (N = 7055) or W (N = 34,750) prescription between February 2011 and April 2012. The first prescription for each treatment in this period defined the index date. The treatment groups were stratified by newly diagnosed or warfarin-experienced patients. Characteristics, comedications, and comorbidities in the 12 month period prior to index date were assessed. Newly diagnosed patients initiating DE had overall lower use of comedications compared to W patients. In contrast, warfarin-experienced patients switching from W to DE showed higher use of antibiotics, beta blockers, gastrointestinal drugs and NSAIDs compared to patients remaining on W. Newly diagnosed NVAF patients initiating DE showed lower proportions for comorbidities such as myocardial infarction, congestive heart failure, and renal disease. This was also reflected in the Charlson comorbidity index (CCI) (mean DE 2.1 vs. W 3.0) and the CHA2DS2-VASc score (mean DE 3.4 vs. W 4.0). For warfarin-experienced NVAF patients, these differences were not seen. Interpretation of results is limited by the fact that administrative claims data are not gathered for scientific research. Underreporting of non-serious conditions might occur and life-style variables, laboratory values and over-the-counter medication were not available. As also seen for other newly marketed drugs, differences in baseline characteristics, comedication, and comorbidities were detected between DE and W in newly diagnosed patients, as well as in warfarin-experienced patients. This channeling may have significant impact on comparative outcome studies if not properly addressed in study design and analysis.

OBJECTIVES: Atrial fibrillation (AF) is the most common cardiac rhythm disorder with a significant health burden. The aim of this study was to characterise patients with recently diagnosed AF and to estimate the rates of comorbidities and outcome events requiring hospitalisation in routine clinical practice. DESIGN: Pharmacoepidemiological cohort study using observational data. METHODS/SETTING: This study included 16 513 patients with a first diagnosis of AF between 1 January 2005 and 28 February 2010 (newly diagnosed patients) using data from the UK Clinical Practice Research Datalink (CPRD) linked to Hospital Episode Statistics (HES) and the Office for National Statistics mortality data. Exposure was stratified by vitamin K antagonist (VKA) exposure (non-use, current, recent and past exposure) based on prescriptions and/or international normalised ratio measurements, and followed for outcome events of interest based on diagnosis codes in the databases, that is, vascular outcomes, bleeding events and others. The main focus of the study was on outcome events requiring hospitalisation using the HES data. RESULTS: The incidence of vascular outcome hospitalisations (myocardial infarction (MI), stroke or systemic arterial peripheral embolism) was 3.8 (95% CI 3.5 to 4.0)/100 patient-years. The incidence of stroke was 0.9 (0.8 to 1.1) during current VKA exposure, 2.2 (1.6 to 2.9) for recent, 2.4 (1.9 to 2.9) for past and 3.4 (3.1 to 3.7) during non-use. MI incidence was 0.7 (0.6 to 0.9) for current VKA exposure, 0.7 (0.4 to 1.2) for recent, 1.1 (0.8 to 1.5) for past and 1.9 (1.7 to 2.1) during non-use. The incidence of bleeding event hospitalisations was 3.8 (3.4 to 4.2) for current VKA exposure, 4.5 (3.7 to 5.5) for recent, 2.7 (2.2 to 3.3) for past and 2.9 (2.6 to 3.2) during non-use; 38% of intracranial bleeds and 6% of gastrointestinal bleeds were fatal. CONCLUSIONS: This population-based study from recent years provides a comprehensive characterisation of newly diagnosed patients with AF and incidence estimates of common outcomes with a focus on hospitalised events stratified by VKA exposure. This study will help to place future data on new oral anticoagulants into perspective.

Introduction We have previously shown that a tag single nucleotide polymorphism (rs10235235), which maps to the CYP3A locus (7q22.1), was associated with a reduction in premenopausal urinary estrone glucuronide levels and a modest reduction in risk of breast cancer in women age ≤50 years. Methods We further investigated the association of rs10235235 with breast cancer risk in a large case control study of 47,346 cases and 47,570 controls from 52 studies participating in the Breast Cancer Association Consortium. Genotyping of rs10235235 was conducted using a custom Illumina Infinium array. Stratified analyses were conducted to determine whether this association was modified by age at diagnosis, ethnicity, age at menarche or tumor characteristics. Results We confirmed the association of rs10235235 with breast cancer risk for women of European ancestry but found no evidence that this association differed with age at diagnosis. Heterozygote and homozygote odds ratios (ORs) were OR = 0.98 (95% CI 0.94, 1.01; P = 0.2) and OR = 0.80 (95% CI 0.69, 0.93; P = 0.004), respectively (Ptrend = 0.02). There was no evidence of effect modification by tumor characteristics. rs10235235 was, however, associated with age at menarche in controls (Ptrend = 0.005) but not cases (Ptrend = 0.97). Consequently the association between rs10235235 and breast cancer risk differed according to age at menarche (Phet = 0.02); the rare allele of rs10235235 was associated with a reduction in breast cancer risk for women who had their menarche age ≥15 years (ORhet = 0.84, 95% CI 0.75, 0.94; ORhom = 0.81, 95% CI 0.51, 1.30; Ptrend = 0.002) but not for those who had their menarche age ≤11 years (ORhet = 1.06, 95% CI 0.95, 1.19, ORhom = 1.07, 95% CI 0.67, 1.72; Ptrend = 0.29). Conclusions To our knowledge rs10235235 is the first single nucleotide polymorphism to be associated with both breast cancer risk and age at menarche consistent with the well-documented association between later age at menarche and a reduction in breast cancer risk. These associations are likely mediated via an effect on circulating hormone levels.

Menopausal hormone therapy (MHT) is associated with an elevated risk of breast cancer in postmenopausal women. To identify genetic loci that modify breast cancer risk related to MHT use in postmenopausal women, we conducted a two-stage genome-wide association study (GWAS) with replication. In stage I, we performed a case-only GWAS in 731 invasive breast cancer cases from the German case-control study Mammary Carcinoma Risk Factor Investigation (MARIE). The 1,200 single nucleotide polymorphisms (SNPs) showing the lowest P values for interaction with current MHT use (within 6 months prior to breast cancer diagnosis), were carried forward to stage II, involving pooled case-control analyses including additional MARIE subjects (1,375 cases, 1,974 controls) as well as 795 cases and 764 controls of a Swedish case-control study. A joint P value was calculated for a combined analysis of stages I and II. Replication of the most significant interaction of the combined stage I and II was performed using 5,795 cases and 5,390 controls from nine studies of the Breast Cancer Association Consortium (BCAC). The combined stage I and II yielded five SNPs on chromosomes 2, 7, and 18 with joint P values

Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1. © 2013 The American Society of Human Genetics.

Contains fulltext : 118401.pdf (Publisher’s version ) (Open Access) Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with 23 single nucleotide polymorphisms were modified by 10 established environmental risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity) in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood ratio tests to assess gene-environment interactions. All statistical tests were two-sided. We replicated previously reported potential interactions between LSP1-rs3817198 and parity (Pinteraction = 2.4 x 10(-6)) and between CASP8-rs17468277 and alcohol consumption (Pinteraction = 3.1 x 10(-4)). Overall, the per-allele odds ratio (95% confidence interval) for LSP1-rs3817198 was 1.08 (1.01-1.16) in nulliparous women and ranged from 1.03 (0.96-1.10) in parous women with one birth to 1.26 (1.16-1.37) in women with at least four births. For CASP8-rs17468277, the per-allele OR was 0.91 (0.85-0.98) in those with an alcohol intake of /= 20 g/day. Additionally, interaction was found between 1p11.2-rs11249433 and ever being parous (Pinteraction = 5.3 x 10(-5)), with a per-allele OR of 1.14 (1.11-1.17) in parous women and 0.98 (0.92-1.05) in nulliparous women. These data provide first strong evidence that the risk of breast cancer associated with some common genetic variants may vary with environmental risk factors.