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This observational study evaluated the impact of a sponsor company-provided Patient Support Program (PSP) on discontinuation of adalimumab in adult Australian patients eligible for Pharmaceutical Benefit Scheme (PBS)-reimbursed adalimumab for Rheumatoid Arthritis (RA), Ankylosing Spondylitis (AS), Psoriatic Arthritis (PsA), Crohn's Disease (CD), Ulcerative Colitis (UC), or Hidradenitis Suppurativa (HS). Patients initiating adalimumab between May 2018 and September 2019 were enrolled into two prospective cohorts based on their decision to opt for or decline the PSP (PSP or non-PSP cohorts). In addition, a historical, retrospective Non-PSP cohort was established from the Services Australia 10% PBS dataset by extracting data of patients initiating adalimumab prior to the introduction of adalimumab PSPs and based on adalimumab PBS listing dates (AS: April 2007 to March 2009; PsA/RA: January 2007 to December 2008; CD: January 2009 to December 2010; HS and UC indications not included). Follow-up for all cohorts was 12 months. The primary endpoint was the time to discontinuation, compared between the prospective PSP cohort and the prospective or retrospective Non-PSP cohort. Inverse probability of treatment weighting was used to balance the cohorts. A Cox proportional hazards model indicated no difference in time to discontinuation between the prospective PSP (n = 162) and non-PSP (n = 65) cohorts (HR [95% CI] = 1.256 [0.616-2.563], p = 0.5304). The 12-month adalimumab persistence rates (95% CI) were 78% (69%, 84%) and 82% (67%, 90%), respectively. In contrast, discontinuation was less likely in the prospective PSP (n = 151) compared with the retrospective non-PSP (n = 297) cohort (HR [95% CI] = 0.44 [0.28-0.68], p<0.001). The 12-month persistence rates (95% CI) were 81% (76%, 90%) and 61% (56%, 67%), respectively. Overall, this study suggests that optimal adalimumab persistence can be achieved with either a structured PSP or healthcare support from other sources, but this was not the case more than a decade ago., Competing Interests: There are no patents or products in development associated with this research to declare. A marketed product (HUMIRA® [Adalimumab]) is associated with this research., (Copyright: © 2024 Jones et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: This study aimed to estimate the budget impact of the incorporation of venetoclax for the treatment of patients with Acute Myeloid Leukemia (AML) over 75 years of age or those with comorbidities and contraindications for the use of intensive chemotherapy, from the perspective of the social security and the private third-party payers in Argentina., Methods: A budget impact model was adapted to estimate the cost difference between the current scenario (azacitidine, decitabine and low doses of cytarabine) and the new scenario (incorporation of venetoclax) for a third-party payer over a time horizon of three years. Input parameters were obtained from a literature review, validated or complemented by expert opinion using a modified Panel Delphi approach. All direct medical costs were estimated by the micro-costing approach and were expressed in US dollars (USD) as of September 2020 (1 USD = 76.18 Argentine pesos)., Results: For a third-party payer with a cohort of 1,000,000 individuals covered, incorporating venetoclax was associated with an average budget impact per-member per-month (PMPM) of $0.11 USD for the social security sector and $0.07 USD for the private sector. The duration of treatment with venetoclax was the most influential parameter in the budget impact results., Conclusion: The introduction of venetoclax was associated with a positive and slight budget impact. These findings are informative to support policy decisions aimed to expand the current treatment landscape of AML., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests. Alfredo Palacios, Natalia Espinola, Juan Martin González, Carlos Rojas-Roque, Andrés Pichon-Riviere, Federico Augustovski and Ariel Bardach declare that they have no conflicts of interest. Diego Kanevsky and Pierre Morisset are employees of Abbvie and may own Abbvie stocks. Maria Marta Rivas has received speaker fees from Abbvie. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Palacios et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Uterine leiomyomas and adenomyosis are both common and often associated with abnormal uterine bleeding (AUB), including the symptom of heavy menstrual bleeding (HMB). Understanding the prevalence of adenomyosis in women with uterine leiomyomas could inform clinicians and patients in a way that may improve therapeutic approaches., Objective: To explore the prevalence of adenomyosis in a group of women who underwent hysterectomy for AUB-L, to determine the prevalence of submucous leiomyomas, and to examine the utility of preoperative ultrasound to detect the presence of adenomyosis., Methods: The Kaiser Permanente Hysterectomy Database (KPHD) was searched for women aged 18-52 undergoing hysterectomy for leiomyoma-associated chronic AUB (AUB-L) in 2018 and 2019. A target sample of 400 comprised those with at least 3 years in the Health System. Radiologists evaluated preoperative pelvic ultrasound images to determine leiomyoma size and level 2 FIGO type (submucous or other), and the linked electronic medical record abstracted for clinical features, including histopathological evidence of adenomyosis., Results: Of the 370 subjects that met the study criteria, adenomyosis was identified via histopathology in 170 (45.9%). There was no difference in the adenomyosis prevalence with (47.1%) and without (43.0%) at least one submucous leiomyoma. Subgroup analysis of ultrasound images by an expert radiologist for the presence of adenomyosis demonstrated a positive predictive value of 54.0% and a negative predictive value of 43.4%., Conclusions: Adenomyosis was present in almost half of this AUB-L cohort undergoing hysterectomy and was equally prevalent in those with and without submucous leiomyomas as determined by sonographic evaluation. The imaging findings are in accord with prior investigators and demonstrate that 2-D ultrasound is insensitive to the presence of adenomyosis when the uterus is affected by leiomyomas. Further research is necessary to determine the impact of various adenomyosis phenotypes on the presence and severity of the symptom of HMB., Competing Interests: Dr. Lonky reports a consultancy agreement with AbbVie following conclusion of this research, research support from AbbVie and Merk & Co. is the founder/shareholder of Histologics LLC. Dr Munro reports consultancy agreements with AbbVie Inc, American Regent, Daiichi Sankyo, Hologic Inc, Myovant Inc, Pharmacosmos, and Vifor Pharmaceuticals. He has also received indirect grant support from AbbVie Inc and Pharmacosmos. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Lonky et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Neurodegenerative diseases encompass a group of debilitating conditions resulting from progressive nerve cell death. Of these, Alzheimer's disease (AD) occurs most frequently, but is currently incurable and has limited treatment success. Late onset AD, the most common form, is highly heritable but is caused by a combination of non-genetic risk factors and many low-effect genetic variants whose disease-causing mechanisms remain unclear. By mining the FinnGen study database of phenome-wide association studies, we identified a rare variant, rs148726219, enriched in the Finnish population that is associated with AD risk and dementia, and appears to have arisen on a common haplotype with older AD-associated variants such as rs429358. The rs148726219 variant lies in an overlapping intron of the FosB proto-oncogene (FOSB) and ERCC excision repair 1 (ERCC1) genes. To understand the impact of this SNP on disease phenotypes, we performed CRISPR/Cas9 editing in a human induced pluripotent stem cell (hiPSC) line to generate isogenic clones harboring heterozygous and homozygous alleles of rs148726219. hiPSC clones differentiated into induced excitatory neurons (iNs) did not exhibit detectable molecular or morphological variation in differentiation potential compared to isogenic controls. However, global transcriptome analysis showed differential regulation of nearby genes and upregulation of several biological pathways related to neuronal function, particularly synaptogenesis and calcium signaling, specifically in mature iNs harboring rs148726219 homozygous and heterozygous alleles. Functional differences in iN circuit maturation as measured by calcium imaging were observed across genotypes. Edited mature iNs also displayed downregulation of unfolded protein response and cell death pathways. This study implicates a phenotypic impact of rs148726219 in the context of mature neurons, consistent with its identification in late onset AD, and underscores a hiPSC-based experimental model to functionalize GWAS-identified variants., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Stolzenburg et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The blood brain barrier (BBB) efficiently limits the penetration of biologics drugs from blood to brain. Establishment of an in vitro BBB model can facilitate screening of central nervous system (CNS) drug candidates and accelerate CNS drug development. Despite many established in vitro models, their application to biologics drug selection has been limited. Here, we report the evaluation of in vitro transcytosis of anti-human transferrin receptor (TfR) antibodies across human, cynomolgus and mouse species. We first evaluated human models including human cerebral microvascular endothelial cell line hCMEC/D3 and human colon epithelial cell line Caco-2 models. hCMEC/D3 model displayed low trans-epithelial electrical resistance (TEER), strong paracellular transport, and similar transcytosis of anti-TfR and control antibodies. In contrast, the Caco-2 model displayed high TEER value and low paracellular transport. Anti-hTfR antibodies demonstrated up to 70-fold better transcytosis compared to control IgG. Transcytosis of anti-hTfR.B1 antibody in Caco-2 model was dose-dependent and saturated at 3 μg/mL. Enhanced transcytosis of anti-hTfR.B1 was also observed in a monkey brain endothelial cell based (MBT) model. Importantly, anti-hTfR.B1 showed relatively high brain radioactivity concentration in a non-human primate positron emission tomography study indicating that the in vitro transcytosis from both Caco-2 and MBT models aligns with in vivo brain exposure. Typically, brain exposure of CNS targeted biologics is evaluated in mice. However, antibodies, such as the anti-human TfR antibodies, do not cross-react with the mouse target. Therefore, validation of a mouse in vitro transcytosis model is needed to better understand the in vitro in vivo correlation. Here, we performed transcytosis of anti-mouse TfR antibodies in mouse brain endothelial cell-based models, bEnd3 and the murine intestinal epithelial cell line mIEC. There is a good correlation between in vitro transcytosis of anti-mTfR antibodies and bispecifics in mIEC model and their mouse brain uptake. These data strengthen our confidence in the predictive power of the in vitro transcytosis models. Both mouse and human in vitro models will serve as important screening assays for brain targeted biologics selection in CNS drug development., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Deng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Glecaprevir/pibrentasvir (G/P) has demonstrated high rates (>95%) of sustained virologic response at posttreatment Week 12 (SVR12) in treatment-naïve (TN) patients with hepatitis C virus (HCV) infection and compensated cirrhosis (CC). Here, in a key real-world subset of TN Italian patients with CC, we evaluated the effectiveness and safety of 8-week G/P treatment, including subgroups of interest such as those with genotype 3 (GT3) infection, elderly patients, and those with more advanced liver disease., Methods: Subanalysis of Italian patients enrolled in the CREST study. The full analysis set (FAS) included all patients enrolled in the study; the modified analysis set (MAS) excluded patients who discontinued G/P for nonvirologic failure or who had missing SVR12 results. Primary and secondary endpoints included SVR12 and safety, respectively., Results: Of 42 patients included in the FAS, 1 discontinued for unknown reasons, and 2 had missing SVR12 data, leaving 39 patients included in the MAS. At treatment initiation, 74% of patients had ≥1 comorbidity, and 62% were receiving concomitant medications, including some that may potentially interact with G/P. SVR12 was achieved in 100% of patients in the MAS, and in 95% in the FAS. In subgroups of interest, the proportion of patients achieving SVR12 in the MAS (and FAS) was: 100% (94%) for patients ≥65 years, 100% (86%) for GT3, and 100% (100%) for patients with platelet count <150 × 109/L and FibroScan® >20 kPa. Overall, 2 (5%) patients had an adverse event and neither were serious., Conclusion: Results from this real-world Italian cohort demonstrated the safety and effectiveness of 8-week G/P, with SVR12 rate >95%, even in elderly patients. These findings further support real-world evidence of the use of short-course G/P treatment in all patients with CC, including those with GT3, and those with advanced liver disease., Competing Interests: Aghemo A: Grant support from AbbVie and Gilead; Advisory board for Alfasigma, Gilead, Intercept, MSD, Mylan, and Sobi. Persico M: Consultant and speaker for AbbVie, Gilead, and MSD. D’Ambrosio R: Advisory board for AbbVie, Gilead, Takeda; Speaking and teaching: for AbbVie, Gilead, MSD; Research support from Gilead. Andreoni M: Board membership for AbbVie, Gilead, Merck, and ViiV; Grant from Merck; Speaker for BMS, Gilead, and Janssen. Villa E: Nothing to disclose. Bhagat A, Gallinaro V, Gualberti G, and Merolla RCD: Employees of AbbVie and may hold stock/options. Gasbarrini A: Consultant for AbbVie, Actial, Alfasigma, Eisai, Gilead, MSD, Sandoz, Sanofi, and Takeda. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Aghemo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Over the past decade, therapeutic monoclonal antibodies (mAbs) have established their role as valuable agents in the treatment of various diseases ranging from cancers to infectious, cardiovascular and autoimmune diseases. Reactive groups of the amino acids within these proteins make them susceptible to many kinds of chemical modifications during manufacturing, storage and in vivo circulation. Among these reactions, the oxidation of methionine residues to their sulfoxide form is a commonly observed chemical modification in mAbs. When the oxidized methionine is in the complementarity-determining region (CDR), this modification can affect antigen binding and thus abrogate biological activity. For these reasons, it is essential to identify oxidation liabilities during the antibody discovery and development phases. Here, we present an in silico method, based on protein modeling and molecular dynamics simulations, to predict the oxidation-liable residues in the variable region of therapeutic antibodies. Previous studies have used the 2-shell water coordination number descriptor (WCN) to identify methionine residues susceptible to oxidation. Although the WCN descriptor successfully predicted oxidation liabilities when the residue was solvent exposed, the method was much less accurate for partially buried methionine residues. Consequently, we introduce a new descriptor, WCN-OH, that improves the accuracy of prediction of methionine oxidation susceptibility by extending the theoretical framework of the water coordination number to incorporate the effects of polar amino acids side chains in close proximity to the methionine of interest., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Tavella et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The FDA's Accelerated Approval program (AA) is a regulatory program to expedite availability of products to treat serious or life-threatening illnesses that lack effective treatment alternatives. Ideally, all of the many stakeholders such as patients, physicians, regulators, and health technology assessment [HTA] agencies that are affected by AA should benefit from it. In practice, however, there is intense debate over whether evidence supporting AA is sufficient to meet the needs of the stakeholders who collectively bring an approved product into routine clinical care. As AAs have become more common, it becomes essential to be able to determine their impact objectively and reproducibly in a way that provides for consistent evaluation of therapeutic decision alternatives. We describe the basic features of an approach for evaluating AA impact that accommodates stakeholder-specific views about potential benefits, risks, and costs. The approach is based on a formal decision-analytic framework combining predictive distributions for therapeutic outcomes (efficacy and safety) based on statistical models that incorporate findings from AA trials with stakeholder assessments of various actions that might be taken. The framework described here provides a starting point for communicating the value of a treatment granted AA in the context of what is important to various stakeholders., Competing Interests: The authors have declared that no competing interests exist.

Tau protein is a key target of interest in developing therapeutics for neurodegenerative diseases. Here, we sought to develop a method that quantifies extracellular tau protein concentrations in human cerebrospinal fluid (CSF) without antibody-based enrichment strategies. We demonstrate that the fit-for-purpose validated method in Alzheimer's Disease CSF is limited to quasi quantitative measures of tau surrogate peptides. We also provide evidence that CSF total Tau measures by LC-MS are feasible in the presence of monoclonal therapeutic antibodies in human CSF. Our Tau LC-MS/MS method is a translational bioanalytical tool for assaying target engagement and pharmacodynamics for anti-tau antibody drug development campaigns., Competing Interests: The authors have declared that no competing interests exist.

Objective: To evaluate treatment satisfaction, disease outcomes, and perspectives of patients with poorly controlled rheumatoid arthritis (RA) treated with conventional synthetic, targeted synthetic, or biologic disease-modifying antirheumatic drugs (DMARDs), we conducted a subgroup (post hoc) analysis of Japanese patients participating in the SENSE study., Methods: Data for Japanese patients (n/N = 118/1629) from the global, multicenter, cross-sectional, observational SENSE study were analyzed. The primary endpoint was the global satisfaction subscore assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM) version 1.4. Other patient-reported outcomes included self-reported RA medication adherence and Work Productivity and Activity Impairment-RA. Patient perspectives included patients' expectations and preference of pharmacologic treatment., Results: Median (range) age and RA disease duration were 67.0 (18.0-87.0) years and 8 (0.0-54) years, respectively; 81.4% of patients were female. Mean (SD) TSQM global satisfaction subscore was 56.8 (17.5), and only 5.9% of patients reported good satisfaction with treatment (TSQM global ≥80). Mean (SD) self-reported treatment adherence using VAS was high (93.5% [13.8%]). Mean (SD) total work productivity impairment was 45.6% (32.0%); presenteeism contributed toward more total work productivity impairment (43.9% [30.4%]) than absenteeism (8.3% [24.4%]). Patients expected improvement in all parameters from their treatment, especially improvement in joint symptoms. Most patients (80.7%) preferred oral medication and 18.7% preferred monotherapy. Patient acceptability of potentially manageable side effects was high (7.5%-34.0%). Although most patients (81.3%) found combination therapy acceptable, 43.2% were receiving DMARD monotherapy., Conclusion: Although most Japanese patients with RA with moderate-to-high disease activity were dissatisfied with their current DMARD treatment, high treatment adherence, high acceptability of combination therapy, high acceptability of manageable potential side effects, and preference for oral medication were reported. Data support the development of a more individualized and patient-centric approach for RA treatment., Competing Interests: YK has received research grants from AbbVie Japan GK, Asahi Kasei Pharm, Astellas Pharma Inc., Ayumi Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Daiichi-Sankyo, Inc., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., and Teijin Pharma Ltd. for the submitted work. YK has also received speaker’s fee from AbbVie Japan GK, Ayumi Pharmaceutical Co. Ltd., Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Pfizer Japan Inc., and Teijin Pharma Ltd. outside of the submitted work. ES has received research support or speakers fee from AbbVie Japan GK, Asahi Kasei Pharma, Ayumi Pharmaceutical Co., Ltd, Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Janssen, Pfizer Japan Inc., Mitsubishi Tanabe Pharma Co., and UCB for the submitted work. NM is an employee of AbbVie and owns stock or stock options. ON was an employee of AbbVie at the time of the study and during publication development, and may have received stock and/or stock options from AbbVie. AM has received research grants from AbbVie, Asahi Kasei Pharma, Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical and speaker fees from Eli Lilly, AbbVie, Ono Pharmaceutical, Pfizer, Astellas Pharmaceutical, and Chugai Pharmaceutical Co., Ltd. YT do not have any conflicts of interest to disclose.

Despite the availability of highly effective and well-tolerated direct-acting antivirals, not all patients with chronic hepatitis C virus infection receive treatment. This retrospective, multi-centre, noninterventional, case-control study identified patients with chronic hepatitis C virus infection initiating (control) or not initiating (case) treatment at 43 sites in Germany from September 2017 to June 2018. It aimed to compare characteristics of the two patient populations and to identify factors involved in patient/physician decision to initiate/not initiate chronic hepatitis C virus treatment, with a particular focus on historical barriers. Overall, 793 patients were identified: 573 (72%) who received treatment and 220 (28%) who did not. In 42% of patients, the reason for not initiating treatment was patient wish, particularly due to fear of treatment (17%) or adverse events (13%). Other frequently observed reasons for not initiating treatment were in accordance with known historical barriers for physicians to initiate therapy, including perceived or expected lack of compliance (14.5%), high patient age (10.9%), comorbidities (15.0%), alcohol abuse (9.1%), hard drug use (7.7%), and opioid substitution therapy (4.5%). Patient wish against therapy was also a frequently reported reason for not initiating treatment in the postponed (35.2%) and not planned (47.0%) subgroups; of note, known historical factors were also common reasons for postponing treatment. Real-world and clinical trial evidence is accumulating, which suggests that such historical barriers do not negatively impact treatment effectiveness. Improved education is key to facilitate progress towards the World Health Organization target of eliminating viral hepatitis as a major public health threat by 2030., Competing Interests: PB has served as a speaker, a consultant and an advisory board member for AbbVie, Falk, Gilead, Intercept, Merck/MSD, and Norgine, and has received research funding from AbbVie, Falk, Gilead, Intercept, Merck/MSD, and Norgine. HH has served as a speaker and an advisory board member for AbbVie, Gilead, Janssen, MSD, and ViiV Healthcare. SM has served as a speaker and an advisory board member for AbbVie, Gilead, Janssen, and MSD. HG has served as a speaker and a consultant for AbbVie, Gilead, and Sanofi-Aventis; he has served as a speaker and an advisory board member for AbbVie, Gilead, and MSD. DH is an employee of AbbVie Inc and may own stocks and shares in AbbVie Inc. BK is an employee of AbbVie Inc and may own stocks and shares in AbbVie Inc. AGPS is an employee of AbbVie Inc and may own stocks and shares in AbbVie Inc. CN has served as a speaker, a consultant and an advisory board member for AbbVie, Alexion, Biogen, Bristol-Myers Squibb, Falk, Gilead, Janssen, MSD, Sanofi-Genzyme, and Shire-Takeda and has received research funding from AbbVie, Alexion, Biogen, Bristol-Myers Squibb, Falk, Gilead, Janssen, MSD, Sanofi-Genzyme, and Shire-Takeda. TB has served as a speaker and a consultant for AbbVie, Alexion, Bayer, Bristol-Myers Squibb, Eisai, Gilead, Humedics, Intercept, Ipsen, Janssen, Merck/MSD, Novartis, and Sequana Medical, and has received research funding from AbbVie, Alexion, Bayer, Bristol-Myers Squibb, Eisai, Gilead, Humedics, Intercept, Ipsen, Janssen, Merck/MSD, Novartis, and Sequana Medical. AbbVie sponsored the study, and also contributed to its design, and participated in the collection, analysis, and interpretation of the data and in the writing, reviewing, and approval of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

Idiopathic pulmonary fibrosis is a progressive and debilitating lung disease with large unmet medical need and few treatment options. We describe an analysis connecting single cell gene expression with bulk gene expression-based subsetting of patient cohorts to identify IPF patient subsets with different underlying pathogenesis and cellular changes. We reproduced earlier findings indicating the existence of two major subsets in IPF and showed that these subsets display different alterations in cellular composition of the lung. We developed classifiers based on the cellular changes in disease to distinguish subsets. Specifically, we showed that one subset of IPF patients had significant increases in gene signature scores for myeloid cells versus a second subset that had significantly increased gene signature scores for ciliated epithelial cells, suggesting a differential pathogenesis among IPF subsets. Ligand-receptor analyses suggested there was a monocyte-macrophage chemoattractant axis (including potentially CCL2-CCR2 and CCL17-CCR4) among the myeloid-enriched IPF subset and a ciliated epithelium-derived chemokine axis (e.g. CCL15) among the ciliated epithelium-enriched IPF subset. We also found that these IPF subsets had differential expression of pirfenidone-responsive genes suggesting that our findings may provide an approach to identify patients with differential responses to pirfenidone and other drugs. We believe this work is an important step towards targeted therapies and biomarkers of response., Competing Interests: All authors are employees of AbbVie, Inc. This does not alter our adherence to PLoS ONE policies on sharing data and materials.

Background: Psoriatic arthritis (PsA) is a progressive erosive joint disorder that causes functional impairment; therefore, early diagnosis and management are essential. This study evaluated the association between clinical specialty and the time to management in patients with PsA in Japan., Methods: This was a subgroup analysis of a cross-sectional, multicenter, observational study that was conducted in 17 countries outside the United States, including 17 sites at 8 institutions in Japan, from June 2016 to October 2017. Data from consecutive patients (age ≥18 years) with a suspected or established diagnosis of PsA on a routine visit to a participating rheumatology/orthopedic or dermatology clinic in Japan were analyzed. The primary endpoints were time from onset of inflammatory musculoskeletal symptoms to PsA diagnosis, PsA diagnosis to first conventional synthetic disease-modifying antirheumatic drug (csDMARD), PsA diagnosis to first biologic DMARD (bDMARD), and first csDMARD to first bDMARD., Results: Of 109 patients with a confirmed diagnosis of PsA, 39.4% (n = 43) and 60.6% (n = 66) were recruited by rheumatologists/orthopedists and dermatologists, respectively. Most patients were prescribed tumor necrosis factor inhibitors (58.7%) or methotrexate (56.0%). The mean duration from symptom onset to PsA diagnosis was significantly longer (p = 0.044) for patients treated by rheumatologists/orthopedists (70.6 months) than those treated by dermatologists (30.1 months). In the rheumatology/orthopedic and dermatology settings, the mean time from PsA diagnosis to first csDMARD administration was -0.9 and -2.9 months, and from PsA diagnosis to first bDMARD 21.4 and 14.9 months, respectively. The mean duration from administration of first csDMARD to first bDMARD was comparable in the rheumatology/orthopedic (31.8 months) and dermatology (31.5 months) settings., Conclusions: Treatment approach was slightly different between rheumatology/orthopedic and dermatology setting in clinical practice in Japan, suggesting that an integrated dermo-rheumatologic approach can optimize the management of patients with PsA., Competing Interests: MO is a consultant for AbbVie, Eli Lilly, and is on the speaker’s bureau of AbbVie Japan, Eli Lilly and Company, Mitsubishi Tanabe Pharma, and Ono Pharmaceutical. SK is a former employee of AbbVie GK. FG is an employee of AbbVie AG. W-HB received grant/research support from Pfizer and Pantec Biosolutions, is a consultant for AbbVie, Biogen Idec, Celgene, Covagen, Galderma, Janssen, Leo, Lilly, Novartis, and UCB, and is on the speakers bureau of AbbVie, Janssen, Leo, Novartis, and UCB. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Rheumatoid arthritis (RA) is a systemic and incurable autoimmune disease characterized by chronic inflammation in synovial lining of joints. To identify the signaling pathways involved in RA, its disease activity, and treatment response, we adapted a systems immunology approach to simultaneously quantify 42 signaling nodes in 21 immune cell subsets (e.g., IFNα→p-STAT5 in B cells) in peripheral blood mononuclear cells (PBMC) from 194 patients with longstanding RA (including 98 patients before and after treatment), and 41 healthy controls (HC). We found multiple differences between patients with RA compared to HC, predominantly in cytokine-induced Jak/STAT signaling in many immune cell subsets, suggesting pathways that may be associated with susceptibility to RA. We also found that high RA disease activity, compared to low disease activity, was associated with decreased (e.g., IFNα→p-STAT5, IL-10→p-STAT1) or increased (e.g., IL-6→STAT3) response to stimuli in multiple cell subsets. Finally, we compared signaling in patients with established, refractory RA before and six months after initiation of methotrexate (MTX) or TNF inhibitors (TNFi). We noted significant changes from pre-treatment to post-treatment in IFNα→p-STAT5 signaling and IL-10→p-STAT1 signaling in multiple cell subsets; these changes brought the aberrant RA signaling profiles toward those of HC. This large, comprehensive functional signaling pathway study provides novel insights into the pathogenesis of RA and shows the potential of quantification of cytokine-induced signaling as a biomarker of disease activity or treatment response., Competing Interests: The authors have read the journal’s policies and declare the following competing interest: Nodality, Inc., a now inactive company, provided in-kind support for this work and investigators at Nodality played important roles in the study design, hands-on analysis of samples, and preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Introduction: Chronic idiopathic constipation (CIC) is a prevalent functional gastrointestinal disorder diagnosed based on patient-reported symptoms and the absence of structural gastrointestinal abnormalities. Individuals with CIC typically institute dietary changes and use stool softeners or over-the-counter (OTC) laxatives, possibly at the direction of a healthcare provider, before prescription medications for CIC are initiated. Although highly prevalent, there is limited information regarding CIC patient experiences with OTC medications., Methods: This post-hoc analysis used patient-reported data from a questionnaire administered during patient screening for a prospective linaclotide Phase 3b clinical trial in patients with CIC (N = 1482 screened). The questionnaire asked patients to report their experiences with OTC CIC medications over the preceding 6 months., Results: Among patients with screening responses (N = 1423), most were female (85%) and white (66%), with a mean age of 48.9 years. A high proportion of patients had used one or more OTC medications (70% had ≥1 OTC; 19% had ≥3 OTCs), with the majority being bisacodyl (33%) and polyethylene glycol (30%). The most commonly cited reason for stopping an OTC medication was insufficient symptom relief (17-40%). The majority of patients taking OTC medications reported no or little satisfaction with the medication's effect on their constipation (62%) and CIC-specific abdominal symptoms (78%). Many patients had little to no confidence in bowel movement (BM) frequency after taking OTC medications and their confidence in their ability to predict BM timing was also low (49-81% not at all confident)., Conclusions: Treatment effects on individual CIC symptoms, predictability of bowel habits, and satisfaction with treatment are all important factors for healthcare providers and patients to consider when establishing an effective treatment regimen for CIC., Trial Registration Number: NCT01642914., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Brian E. Lacy is a participant on the scientific advisory boards of Allergan plc (prior to acquisition by AbbVie Inc.), Ironwood Pharmaceuticals, Inc., Salix, and Takeda. Elizabeth P. Shea and Douglas C.A. Taylor are employees of Ironwood Pharmaceuticals, Inc. and hold stock and stock options. Hancheng Jiang and Machelle Manuel are former employees of Ironwood Pharmaceuticals, Inc. and may hold stock. Jessica L. Abel is an employee of AbbVie Inc. and holds stock and stock options. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Aim: Fatigue is the most commonly reported symptom of Hepatitis C Virus (HCV) infected patients and severely impacts their quality of life. The aim of this study was to measure the impact of 3D regimen treatment on the fatigue, daytime physical activity and sleep efficiency of HCV infected patients with fatigue., Methods: HEMATITE was an observational, prospective, open-label, single-arm, Swiss multi-centric study in mono-infected HCV genotype 1 patients. The 28 week observation period comprised of 4 weeks preparation, 12 weeks treatment and 12 weeks follow-up. Fatigue was assessed using the fatigue severity scale (FSS) questionnaire. Patients with FSS ≥ 4 (clinically significant fatigue) were included. The activity tracker, ActiGraph GT9X Link®, was used to measure daytime physical activity and sleep efficiency. Outcome analysis was performed on a scaled down intention to treat (sdITT) population, which excluded patients with insufficient tracker data at all study visits and a modified ITT (mITT) population, which consisted of patients with complete tracker data at all study visits., Results: Forty of 41 patients in the ITT population had a sustained virologic response 12 weeks post-treatment (SVR12). Mean baseline FSS score was 6.0 for the sdITT population and 5.9 for the mITT population and decreased from baseline to 12 weeks post-treatment by 2.6 (95% confidence interval [CI]: 2.1, 3.1) for the sdITT (n = 37) population and 2.8 (95% CI: 2.2, 3.4) for the mITT (n = 24) population. Mean daytime physical activity or sleep efficiency did not change considerably over the course of the study., Conclusion: Measurement by the activity tracker of mean day time physical activity did not show a considerable change from baseline to SVR12 upon treatment with 3D regimen. Nevertheless, a reduction of fatigue as assessed with the validated fatigue severity scale (FSS) was observed, suggesting a causative role of HCV in this extrahepatic manifestation., Trial Registration: ClinicalTrials.gov identifier: NCT03002818., Competing Interests: Nasser Semmo has received research grants, consulting fees and/or speaker fees from AbbVie and Gilead and consulting fees from MSD. Beat Müllhaupt has received speaking and/or consulting fees from Merck/MSD, AbbVie, Intercept, Astra, Bayer, BMS, Gilead and research support from Gilead. Lorenzo Magenta has received research grants, consulting fees and/or speaker fees from AbbVie, Gilead, Janssen, BMS and MSD. Olivier Clerc has received consulting fees from AbbVie. David Semela has received research grants, consulting fees and/or speaker fees from AbbVie, Bayer, BMS, Gilead, Intercept and MSD. Ralph Torgler and Lisa Ruckstuhl are employees of AbbVie and own stock/options of AbbVie. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Here we present a discrete-time-evolution model with one day interval to forecast the propagation of Covid-19. The proposed model can be easily implemented with daily updated data sets of the pandemic publicly available by distinct online sources. It has only two adjustable parameters and it predicts the evolution of the total number of infected people in a country for the next 14 days if parameters do not change during the analyzed period. The model incorporates the main aspects of the disease such as the fact that there are asymptomatic and symptomatic phases (both capable of propagating the virus), and that these phases take almost two weeks before the infected person status evolves to the next (asymptomatic becomes symptomatic or symptomatic becomes either recovered or dead). A striking advantage of the model for its implementation by the health sector is that it gives directly the number of total infected people in each day (in thousands, tens of thousands or hundred of thousands). Here, the model is tested with data from Brazil, UK and South Korea, presenting low error rates on the prediction of the evolution of the disease in all analyzed countries. We hope this model may be a useful tool to estimate the propagation of the disease., Competing Interests: Author EMFC has no competing interests to declare. Author MRC is employee of AbbVie Deutschland GmbH & Co. KG. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

ClinicalTrials.gov was started with the intention to create a consumer-friendly database for patients and others in search of information on clinical trials. However, there is no research on whether the content of ClinicalTrials.gov aligns with patient preferences. The TransCelerate Clinical Research Access & Information Exchange Initiative convened patient advisory boards and conducted a global online survey (N = 1070) to determine patient preferences when searching for clinical trials for participation. Patient feedback and ClinicalTrials.gov guidance documents were used to construct instruments to assess patient focus and guidance adherence of the Brief Title (a short lay title of the clinical trial) and Brief Summary (a high-level summary of study features) data fields in a representative sample (N = 346) of ClinicalTrials.gov records of interventional trials. When searching for clinical trials, survey participants rated condition (66.4%), trial location (57.0%), trial dates (52.9%), age and gender (48.6%), and health measurements (i.e., what the study measures) (45.5%) as the most important items. When presented with a list of trials from an initial search, participants saw condition, brief summary, study drug name, and brief title as the most helpful items. In a Brief Title, they wanted condition, health measurements, participant age, and study drug name. For Brief Summaries, participants preferred additional information on treatment duration, condition, study goal, health measurements, and frequency of visits. The assessment of patient focus in a representative sample of current ClinicalTrials.gov records showed that patient focus was underdeveloped as study records achieved only 52% (brief titles) and 50% (brief summaries) of the best possible score. The analysis of adherence to ClinicalTrials.gov guidance showed better scores (brief titles 69%, brief summaries 66%). We identified key information elements for registry users when evaluating clinical trials for participation. We found that aspects of patient focus are not common in current ClinicalTrials.gov entries. To support more user-friendly study records, we developed a tool to assess the quality of the plain language fields in study records prior to submission., Competing Interests: All authors are employed by a pharmaceutical company as indicated in by their affiliation [TMS -Boehringer-Ingelheim Pharma, FG - UCB BioSciences, AZ - Merck Sharp & Dohme Corp., RR - Astellas Pharma, KCK - AbbVie Inc., AE - UCB BioScience, CP - UCB BioScience, KH - F. Hoffmann-La Roche Ltd, CC - GSK]. In addition, all authors were members of the TransCelerate Clinical Research Access and Information Exchange Initiative. None of the authors have any additional role or function in TransCelerate outside of the Clinical Research Access and Information Exchange Initiative. No author received any additional remuneration for participating in this research. None of the pharmaceutical companies nor TransCelerate had any role in the study design; collection, analysis, and interpretation of data; writing of the paper; and/or decision to submit for publication. This does not alter our adherence to PLOS ONE policies on sharing data and materials. None of authors has any other competing interest. The article, its figures, and Supporting Information files are licensed under a Creative Commons Attribution (CC BY 4.0) license and in care of TransCelerate.

Background and Aims: Hepatitis C virus (HCV) and its sequelae present a significant source of economic and societal burden. Introduction of highly effective curative therapies has made HCV elimination attainable. The study used a predictive model to assess the clinical and economic impact of implementing national screening and treatment policies toward HCV elimination in Korea., Methods: A previously validated Markov disease progression model of HCV infection was employed to analyze the clinical and economic impact of various strategies for HCV diagnosis and treatment in Korea. In this analysis, the model compared the clinical and economic outcomes of current HCV-related interventions in Korea (7,000 patients treated and 4,200 patients newly diagnosed annually, starting in 2017) to four elimination scenarios: 1) initiating sufficient diagnosis and treatment interventions to meet the World Health Organization's GHSS elimination targets by 2030, 2) delaying initiation of interventions by one year, 3) delaying initiation of interventions by two years and 4) accelerating initiation of interventions to meet elimination targets by 2025. Modelled historical incidence of HCV was calibrated to match a viremic HCV prevalence of 0.44% in 2009. Elimination scenarios required 24,000 treatments and 34,000 newly diagnosed patients annually, starting in 2018, to reach the 2030 targets., Results: Compared to current "status quo" interventions, elimination (or accelerated elimination by 2025) would avert 23,700 (27,000) incident cases of HCV, 1,300 (1,400) liver-related deaths (LRDs) and 2,900 (3,100) cases of end-stage liver disease (ESLD) over the 2017-2030 time period. Postponing interventions by one (or two) years would avert 21,100 (18,600) new HCV infections, 920 (660) LRDs and 2,000 (1,400) cases of ESLD by 2030. Following elimination or accelerated elimination strategies would save 860 million USD or 1.1 billion USD by 2030, respectively, compared to the status quo, requiring an up-front investment in prevention that decreases spending on liver-related complications and death., Conclusions: By projecting the impact of interventions and tracking progress toward GHSS elimination targets using modelling, we demonstrate that Korea can prevent significant morbidity, mortality and spending on HCV. Results should serve as the backbone for policy and decision-making, demonstrating how aggressive prevention measures are designed to reduce future costs and increase the health of the public., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests. Homie Razavi is an employee of Center for Disease Analysis (CDA). CDA has received funding from AbbVie Inc. for this project. CDA has also received research funding from AbbVie, Gilead, Intercept, and Pfizer. Ellen Dugan, Kwang-Hyub Han, Sang Hoon Ahn, Mi Young Jeon and Do Young Kim have nothing to declare. Yuri Sanchez Gonzalez, Kyung Sik Kang, Yong Kyun Won are employees of AbbVie and may own stock/stock options.

Inflammatory bowel diseases (IBD) are complex, multifactorial disorders characterized by chronic relapsing intestinal inflammation. IBD is diagnosed around 1 in 1000 individuals in Western countries with globally increasing incident rates. Association studies have identified hundreds of genes that are linked to IBD and potentially regulate its pathology. The further dissection of the genetic network underlining IBD pathogenesis and pathophysiology is hindered by the limited capacity to functionally characterize each genetic association, including generating knockout animal models for every associated gene. Cutting-edge CRISPR/Cas9-based technology may transform the field of IBD research by efficiently and effectively introducing genetic alterations. In the present study, we used CRISPR/Cas9-based technologies to genetically modify hematopoietic stem cells. Through cell sorting and bone marrow transplantation, we established a system to knock out target gene expression by over 90% in the immune system of reconstituted animals. Using a CD40-mediated colitis model, we further validated our CRISPR/Cas9-based platform for investigating gene function in experimental IBD. In doing so, we developed a model system that delivers genetically modified mice in a manner much faster than conventional methodology, significantly reducing the time from target identification to in vivo target validation and expediting drug development., Competing Interests: RW, SG, DM, RP, JE, LO, XZ, RD, SW, NC and TG are employees of AbbVie. NS, MW, and JG were employees of AbbVie at the time of the study. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. This does not alter our adherence to all PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

Vedolizumab is the first gut-selective integrin blocker indicated for patients with Crohn's disease (CD) and ulcerative colitis (UC). This study aimed to examine the adverse events (AEs) profile of vedolizumab compared to anti-tumor necrosis factors (anti-TNFs) indicated for CD and UC using the FDA Adverse Event Reporting System (FAERS) database. AE reports with vedolizumab (5/20/2014-6/30/2015) and CD/UC-indicated anti-TNF drugs (adalimumab, infliximab, certolizumab pegol, and golimumab, during 8/1/1998-6/30/2015) as primary suspects were extracted from the FAERS database. AEs associated with vedolizumab were compared for signals of disproportionate reporting against anti-TNF drugs and all other drugs (1969-6/30/2015), using the proportional reporting ratio (PRR) and the empirical Bayesian geometric mean (EBGM) algorithms. The search retrieved 499 reports for vedolizumab and 119,620 reports for anti-TNFs, with 35.9% and 32.1% of these, respectively, being serious AEs. With the PRR approach, vedolizumab-associated reports had signals for 22 groups of AEs (9 were associated with serious outcomes) relative to anti-TNFs and had 34 signals relative to all other drugs. Signals detected included those reported as warnings in prescribing information and new AEs related to cardiovascular disease. Due to the voluntary nature of FAERS, this finding should be considered hypothesis generating (rather than hypothesis testing). Longer-term observational studies are required to evaluate the safety of vedolizumab., Competing Interests: Anthony W. Wang is an employee of and owns stock/stock options in AbbVie. Additionally, during employment at AbbVie he was a health economic and outcomes researcher at the initiation of the study and manuscript and subsequently transitioned to a regional marketing manager position prior to completion of the manuscript. Jingdong Chao was employed by AbbVie at the time the study was conducted. Francis Vekeman and Yongling Xiao are employed by Groupe d’analyse at the time of this analysis. Eric Wu is employed by Analysis Group, Inc. Raymond K. Cross has received consultancy fees from AbbVie, Galen/Atlantica, LabCorp, and UCB; has served on scientific advisory boards for AbbVie, Janssen, Pfizer, Samsung Bioepsis, Takeda, and UCB; and received educational/research grants from AbbVie, Janssen, Shire, and Takeda. Michael Chiorean has received consultancy fees from AbbVie, Shire, and Janssen; and received educational/research grants from AbbVie. There are no patents, products in development, or marketed products to declare. This does not alter the authors’ adherence to all PLOS ONE policies on sharing data and materials.

Aim: We describe the effectiveness and safety of the interferon-free regimen ombitasvir/paritaprevir/ritonavir plus dasabuvir with or without ribavirin (OBV/PTV/r ± DSV ± RBV) in a nationwide representative sample of the hepatitis C virus (HCV) monoinfected and human immunodeficiency virus-1/hepatitis C virus (HIV/HCV) coinfected population in Spain., Material and Methods: Data were collected from patients infected with HCV genotypes 1 or 4, with or without HIV-1 coinfection, treated with OBV/PTV/r ± DSV ± RBV at 61 Spanish sites within the initial implementation year of the first government-driven "National HCV plan." Effectiveness was assessed by sustained virologic response at post-treatment week 12 (SVR12) and compared between monoinfected and coinfected patients using a non-inferiority margin of 5% and a 90% confidence interval (CI). Sociodemographic and clinical characteristics or patients and adverse events (AEs) were also recorded., Results: Overall, 2,408 patients were included in the intention-to-treat analysis: 386 (16%) were patients with HIV/HCV. Patient selection reflected the real distribution of patients treated in each participating region in Spain. From the total population, 96.6% (95% CI, 95.8-97.3%) achieved SVR12. Noninferiority of SVR12 in coinfected patients was met, with a difference between monoinfected and coinfected patients of -2.2% (90% CI, -4.5% - 0.2%). Only genotype 4 was associated with non-response to OBV/PTV/r ± DSV ± RBV treatment (p<0.001) in the multivariate analysis. Overall, 286 patients (11.9%) presented AEs potentially related to OBV/PTV/r ± DSV, whereas 347 (29.0%) presented AEs potentially related to ribavirin and 61 (5.1%) interrupted ribavirin., Conclusions: Our results confirm that OBV/PTV/r ± DSV ± RBV is effective and generally well tolerated in a representative sample of the HCV monoinfected and HCV/HIV coinfected population in Spain within the experience of a national strategic plan to tackle HCV., Competing Interests: José Manuel Sousa has received fees as speaker from AbbVie, MSD and Gilead. Mercedes Vergara has received fees as an advisory board member from Gilead and has given lectures for AbbVie, Intercept, MSD, Janssen-Cilag and Gilead. Federico Pulido has received fees as speaker and advisor from AbbVie, Gilead, Janssen and MSD. Gloria Sánchez-Antolín has acted as speaker for AbbVie, MSD, Gilead Science, Novartis and Astellas. Diego Rincón has given lectures for AbbVie and MSD. Javier Salmerón has received speaker fees and grant funding from AbbVie; he declares no further conflict of interest. Luisa García-Buey has received speaker fees and travel grants from Abbvie, MSD and Gilead. José A. Carrión has received speaker fees from Abbvie, Gilead and MSD and has received fees as Advisor for AbbVie. Manuel Hernández-Guerra has been a consultant to Gilead Sciences, Intercept Pharmaceuticals, Abbvie and Bayer; he has received grant funding from Gilead Sciences and Abbvie. Nuria Espinosa has participated in Clinical Trials managed by Gilead and ViiV Healthcare; she has received advisory board, conference and course fees as well as expenses for attending congresses from Janssen-Cilag, Gilead Sciences, ViiV Healthcare, MSD and Abbvie. Rosa Mª Morillas has acted as a speaker for Gilead, Merck, AbbVie and Intercept, and has participated in advisory boards for AbbVie, Gilead and Intercept. Raul J. Andrade: Advisor/Speaker Bureau: Abbvie, Gilead Sciences, Merck Sharp and Dohme, Bristol-Myers Squibb, Janssen; Research Grants: Willmar Schwabe GmbH & Co, Gedeon Richter/Preglem S.A. Manuel Delgado has received scientific advisor fees from Abbie, Gilead, MSD. José M Moreno-Planas has received speaker fees from AbbVie, MSD, Gilead and Bayer. Fernando Menéndez has received fees as advisor from Bayer. Luis Morano has acted as speaker, advisor and/or investigator for Abbvie, Gilead Sciences, Merck Sharp and Dohme, Bristol-Myers Squibb, Janssen, Boehringer Ingelheim, Novartis, and Roche Farma. Manuel Rodríguez consults for and is on the speaker’s bureau for Gilead and AbbVie. Sara Lorente has received lecture fees from Abbvie, Gilead Sciences and MSD. Miguel Ángel Von-Wichmann has received fees as speaker and advisor from Abbvie, BMS, Gilead, Janssen, MSD and VIIV. Amanda Manzanares is employee of AbbVie and may hold stock or options. Lander Hijona, Fernando Carnicer, Beatriz Mateos-Muñoz, Antoni Jou, Benjamín Polo-Lorduy, Ángel Rubín, Ana Escarda, Patricia Aguilar, Teresa Aldámiz-Echevarría, Sonia Chimeno-Hernández, Adolfo Gallego, Marta Magaz, Ángel Estébanez, Mikel Rico, Blanca Sampedro, Sonia Izquierdo, José Manuel Zozaya, Senador Morán-Sánchez, Ignacio Martín-Granizo, Marcial Delgado declare no conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background and Aims: Limited data are available on the effectiveness and tolerability of direct-acting antivirals (DAAs) therapies in the real world for HCV-infected patients with comorbidities. This study aimed to describe the effectiveness of OBV/PTV/r ± DSV (3D/2D regimen) with or without ribavirin (RBV) in HCV or HCV/HIV co-infected patients with GT1/GT4 and CKD (IIIb-V stages), including those under hemodialysis and peritoneal dialysis in routine clinical practice in Spain in 2015., Material and Methods: Non-interventional, retrospective, multicenter data collection study in 31 Spanish sites. Socio-demographic, clinical variables, study treatment characteristics, effectiveness and tolerability data were collected from medical records., Results: Data from 135 patients with a mean age (SD) of 58.3 (11.4) years were analyzed: 92.6% GT1 (81.6% GT1b and 17.6% GT1a) and 7.4% GT4, 14 (10.4%) HIV/HCV co-infected, 19.0% with fibrosis F3 and 28.1% F4 by FibroScan®, 52.6% were previously treated with pegIFN and RBV. 11.1%, 14.8% and 74.1% of patients had CKD stage IIIb, IV and V respectively. 68.9% of patients were on hemodialysis; 8.9% on peritoneal dialysis and 38.5% had history of renal transplant. A total of 125 (96.2%) of 135 patients were treated with 3D, 10 (7.4%) with 2D and 30.4% received RBV. The overall intention-to-treat (ITT) sustained virologic response at week 12 (SVR12) was 92.6% (125/135) and the overall modified-ITT (mITT) SVR12 was 99.2% (125/126). The SVR12 rates (ITT) per sub-groups were: HCV mono-infected (91.7%), HCV/HIV co-infected (100%), GT1 (92.0%), GT4 (100%), CKD stage IIIb (86.7%), stage IV (95%) and stage V (93%). Among the 10 non-SVR there was only 1 virologic failure (0.7%); 4 patients had missing data due lost to follow up (3.0%) and 5 patients discontinued 3D/2D regimen (3.7%): 4 due to severe adverse events (including 3 deaths) and 1 patient´s decision., Conclusions: These results have shown that 3D/2D regimens are effective and tolerable in patients with advanced CKD including those in dialysis with GT 1 or 4 chronic HCV mono-infection and HIV/HCV coinfection in a real-life cohort. The overall SVR12 rates were 92.6% (ITT) and 99.2% (mITT) without clinically relevant changes in eGFR until 12 weeks post-treatment. These results are consistent with those reported in clinical trials., Competing Interests: MCL has served as consultant for AbbVie, MSD, Janssen, BMS and Gilead; MRB has received grant Research from Gilead Science, and speaker fees from AbbVie, Gilead and MSD; MR has received speaker fees from AbbVie; MJDM has served as speaker for AbbVie, Gilead, Janssen, and MSD and as a consultant for MSD; MAS has served as advisor for AbbVie, BMS, Gilead, MSD and Roche; CAN has served as consultant for AbbVie and Bayer, and has received speaker fees from AbbVie and Gilead; SMS has served as speaker for AbbVie and MSD; AC has served as consultant for Janssen, and has received speaker fees from Gilead and Janssen; MD has received grant support and consultancy fees from AbbVie, Bayer, Bristol-Myers Squibb, Gilead and Merck, Sharp & Dhome; FGR has served as speaker for AbbVie, Gilead and BMS; MLM has served as a speaker for AbbVie, BMS, Gilead, Janssen, MSD and ViiV; as a consultant for AbbVie, BMS and Janssen and has received research funding from FIPSE 36465/03, FIPSE 36680/07.-NEAT IG5 (NEAT is a project funded by the European Union under the 6th Framework programme) contract number LSHP-CT-2006–037570; MAC has served as a consultant for Gilead and and ViiV healthcare, and has received speaker fees from Janssens, Gilead, ViiV Healthcare; MMA reports personal fees from ViiV Healthcare, Gilead Sciences, Merck, Janssen, AbbVie and ABBOTT Laboratories, outside the submitted work; AR has received consultancy and speaker fees from AbbVie, Gilead Sciences and Merck Sharp & Dohme; JM has received honoraria, speaker fees, consultant fees or funds for research from AbbVie, BMS, Boehringer-Ingelheim, Gilead, Janssen, MSD, Roche and ViiV; GB has served as speaker for Nutricia and Palex Medical, and has participated in mentoring for Nefralia and Vifor Fresenius; EGP has received speaker fees from AbbVie and Gilead; LGB has served as consultant for AbbVie and Intercept and has received speaker fees from Gilead and MSD; AA, RMG, CB, TAE, MLG, BPL, LIC, SB, LB, JGS, MJP, IMG, LM, LIdlS, ML and JEL don’t have a financial interest or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this paper; CdA and AM are paid employees of AbbVie and may hold stock or options. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Introduction: Despite guidance towards minimally invasive, outpatient procedures for endometriosis, many patients nonetheless receive inpatient care. Our objective was to assess trends in patient and hospital characteristics, surgical complications and hospital charges for women with an endometriosis-related inpatient admission in the United States., Methods: We conducted a pooled cross-sectional analysis of Healthcare Cost and Utilization Project Nationwide Inpatient Sample data. Visits were stratified into three time-period-defined cohorts (2006-2007, 2010-2011, and 2014 through the first three quarters of 2015). Visits were included if the patient was aged 18-49 years and the primary diagnosis code was for endometriosis (International Classification of Diseases, 9th Revision code 617.xx). We evaluated counts of inpatient admissions and rates of patient and hospital characteristics., Results: The number of inpatient admissions with a primary diagnosis code for endometriosis decreased by 72.8% from 2006 to 2015. At the same time, among those admitted for inpatient care for endometriosis, the proportions who had Medicaid insurance and multiple documented comorbidities increased. From 2006 to 2015, mean total hospital charges increased by 75% to $39,662 in 2015 US dollars, although average length of stay increased by <1 day., Conclusions: The number of inpatient admissions with a primary diagnosis of endometriosis decreased over the past decade, while surgical complications and associated hospital charges increased. The share of patients with multiple comorbidities increased and an increasing proportion of inpatient endometriosis admissions were covered by Medicaid and occurred at urban teaching hospitals. These findings suggest a demographic shift in patients receiving inpatient care for endometriosis towards more complex, vulnerable patients., Competing Interests: This study was funded by AbbVie, Inc., a commercial pharmaceutical company that manufactures a medication to treat endometriosis (URL: https://www.abbvie.com/). AbbVie participated in study design, data analysis, interpretation and review of results, preparation of the manuscript, and decision to publish. The development of this study and manuscript followed the Principles of Good Publication Practice (GPP3) for Company-Sponsored Medical Research. AS and KG are employees of AbbVie and may hold AbbVie stocks or stock options. AE and JB are employees of Medicus Economics, which received a research contract from AbbVie to conduct this research. SE and SM have served as research consultants for AbbVie. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Type 1 IFNs stimulate secretion of IP-10 (CXCL10) which is a critical chemokine to recruit effector T cells to the tumor microenvironment and IP-10 knockout mice exhibit a phenotype with compromised effector T cell generation and trafficking. Type 1 IFNs also induce MHC class 1 upregulation on tumor cells which can enhance anti-tumor CD8 T cell effector response in the tumor microenvironment. Although type 1 IFNs show great promise in potentiating anti-tumor immune response, systemic delivery of type 1 IFNs is associated with toxicity thereby limiting clinical application. In this study, we fused tumor targeting antibodies with IFN-α and showed that the fusion proteins can be produced with high yields and purity. IFN fusions selectively induced IP-10 secretion from antigen positive tumor cells, which was critical in recruiting the effector T cells to the tumor microenvironment. Further, we found that treatment with the anti-PDL1-IFN- α fusion at concentrations as low as 1 pM exhibited potent activity in mediating OT1 CD8+ T cell killing against OVA expressing tumor cells, while control IFN fusion did not exhibit any activity at the same concentration. Furthermore, the IFN-α fusion antibody was well tolerated in vivo and demonstrated anti-tumor efficacy in an anti-PD-L1 resistant syngeneic mouse tumor model. One of the potential mechanisms for the enhanced CD8 T cell killing by anti-PD-L1 IFN fusion was up-regulation of MHC class I/tumor antigen complex. Our data supports the hypothesis of targeting type 1 IFN to the tumor microenvironment may enhance effector T cell functions for anti-tumor immune response., Competing Interests: JG, YX, RI, XL, ML, UL, JH, TS, GB, AS, and TH are employees of AbbVie. MT & CD were AbbVie employees at the time of the study. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

Hepatitis C virus (HCV) infection is prevalent among people in prison and prisons could therefore represent a unique opportunity to test risk groups for HCV. The aim of this sero-epidemiological study was to determine the incidence and prevalence of HCV infection and the corresponding risk factors in Danish prisons. Participants, recruited from eight Danish prisons, were tested for HCV using dried blood spots and filled out a questionaire with demographic data and risk factors for HCV infection. In total, 76.9% (801/1041) of all eligible prisoners consented to participate. The prevalence of HCV RNA positive prisoners was 4.2% (34/801) and the in-prison incidence rate was 0.7-1.0 per 100PY overall and 18-24/100PY among PWIDs. Infected prisoners were older than the overall population with a mean age of 42 years and only 17.6% (6/34) were younger than 35 years. The prevalence of PWID was 8.5% (68/801) and only 3% (2/68) of PWID were younger than 25 years. Among the PWID, 85.3% (58/68) had ever received opioid substitution therapy (OST) and 47.1% (32/68) were currently receiving OST. Risk factors associated with HCV infection were intravenous drug use, age ≥ 40 years, and being incarcerated ≥ 10 years. In conclusion, the prevalence of PWID in Danish prisons is low, possibly reflecting a decrease in injecting among the younger generation. This together with OST coverage could explain the low prevalence of HCV infection. However among PWIDs in prison the incidence remains high, suggesting a need for improved HCV prevention in prison., Competing Interests: TA is an employee of AbbVie, but doesn’t owe AbbVie stock or stock options. NW has been clinical investigator, lecturer and advisory board member for BMS, MSD and AbbVie; lecturer and/or advisory board member for Gilead and GSK. Honorarium paid to her institution. APS has received payment for serving as an advisory board member for AbbVie. The authors confirm that no other known conflicts of interest associated with this publication apart from those disclosed. This does not alter our adherence to PLOS ONE’s policies on sharing data and materials.

Background: We present a new family of ECG biomarkers for assessing drug effects on ventricular repolarization. We show that drugs blocking inward (depolarizing) ion currents cause a relative increase of the T vector velocity (TVV) and accelerate repolarization, while drugs blocking outward ion currents cause a relative decrease of the TVV and delay repolarization. The results suggest a link between the TVV and the instantaneous change of the cellular action potentials that may contribute to bridge the gap between the surface ECG and myocardial cellular processes., Methods: We measure TVV as the time required to reach X% of the total Trajectory length of the T vector loop, denoted as TrX. Applied to data from two FDA funded studies (22+22 subjects, 5232+4208 ECGs) which target ECG effects of various ion-channel blocking drugs, the TrX effect profiles indicate increasingly delayed electrical activity over the entire repolarization process for drugs solely reducing outward potassium current (dofetilide, moxifloxacin). For drugs eliciting block of the inward sodium or calcium currents (mexiletine, lidocaine), the TrX effect profiles were consistent with accelerated electrical activity in the initial repolarization phase. For multichannel blocking drugs (ranolazine) or drug combinations blocking multiple ion currents (dofetilide + mexiletine, dofetilide + lidocaine), the overall TrX effect profiles indicate a superposition of the individual TrX effect profiles., Results: The parameter Tr40c differentiates pure potassium channel blocking drugs from multichannel blocking drugs with an area under the ROC curve (AUC) of 0.90, CI = [0.88 to 0.92]. This is significantly better than the performance of J-Tpeakc (0.81, CI = [0.78 to 0.84]) identified as the best parameter in the second FDA study. Combining the ten parameters Tr10c to Tr100c in a logistic regression model further improved the AUC to 0.94, CI = [0.92 to 0.96]., Conclusions: TVV analysis substantially improves assessment of drug effects on cardiac repolarization, providing a plausible and improved mechanistic link between drug effects on ionic currents and overall ventricular repolarization reflected in the body surface ECG. TVV contributes to an enhanced appraisal of the proarrhythmic risk of drugs beyond QTc prolongation and J-Tpeakc., Competing Interests: W declare the following competing interests statements: Authors WB CM are consultants for AbbVie, Inc. and authors GG DB KK PW DC are employees of AbbVie Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Finding safe and effective treatments for chronic hepatitis C virus (HCV) infection in the elderly is of clinical interest given the comorbidities and associated polypharmacy in this population. However, the number of patients older than age 65 years enrolled into clinical trials of anti-HCV medications generally have been limited and thus reaching meaningful conclusions for this demographic has been difficult. Glecaprevir/pibrentasvir is a once-daily, all-oral, ribavirin-free, pangenotypic direct-acting antiviral (DAA) combination therapy that has demonstrated high sustained virologic response rates at post-treatment week 12 (SVR12) and a favorable safety profile in patients with chronic HCV infection. This analysis evaluated the safety and efficacy of glecaprevir/pibrentasvir in patients aged ≥65 years. Data were pooled for treatment-naïve and -experienced patients with chronic HCV genotype (GT) 1-6 infections who received glecaprevir/pibrentasvir for 8, 12, or 16 weeks in 9 Phase 2 and 3 trials. SVR12 and adverse events (AEs) were evaluated for patients aged ≥65 versus <65 years. Of the 2369 patients enrolled, 328 (14%) were aged ≥65 years. Among patients aged ≥65 years, 42% and 34% had GT1 and GT2, respectively; 40% were treatment-experienced and 20% had compensated cirrhosis. Glecaprevir/pibrentasvir treatment resulted in SVR12 rates of 97.9% (95% CI, 96.3-99.4; n/N = 321/328) for patients aged ≥65 years and 97.3% (95% CI, 96.6-98.0; n/N = 1986/2041) for patients aged <65 years. The rates were not significantly different between the two age groups (P = 0.555). DAA-related AEs leading to treatment discontinuation, or serious AEs were similarly rare (<0.5%) for patients ≥65 and <65 years old. Glecaprevir/pibrentasvir is an efficacious and well-tolerated treatment option for patients aged ≥65 years with chronic HCV infection., Competing Interests: Graham R Foster has received fees for serving as a speaker, consultant, and advisory board member for Gilead, Janssen, AbbVie, Merck, and GSK. Tarik Asselah has been a clinical investigator, speaker, and consultant for AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals, Merck Sharp & Dohme, and Roche. Sarah Kopecky-Bromberg, Yang Lei, Armen Asatryan, Roger Trinh, Neddie Zadeikis, and Federico J Mensa are employees of AbbVie and may hold stock or options. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Data will be made available to all interested researchers upon request.

Vascular cognitive impairment dementia (VCID) is a major cause of cognitive loss in the elderly. Matrix metalloproteinases (MMPs) are a family of proteases involved in remodeling the extracellular matrix in development, injury and repair. Blood-brain barrier (BBB) disruption due to inflammation mediated by MMPs is a mechanism of white matter injury. Currently there are no treatments besides the control of vascular risk factors. We tested two MMP-9 inhibitors that improved outcome in acute stroke: DP-460 and SB-3CT. We hypothesized that these inhibitors would have a beneficial effect in chronic stroke by reducing edema in white matter and improving behavioral outcomes. Spontaneously hypertensive stroke-prone rats (SHRSPs) with unilateral carotid artery occlusion (UCAO) fed a Japanese Permissive Diet (JPD) were used as a model of VCID. JPD was begun in the 12th week of life. Rats were treated with DP-460 (500 mg/kg) for 4 weeks, or SB-3CT (10 mg/kg) for 8 weeks, beginning at the UCAO/JPD onset. Rats treated with a dextrose or DMSO solution served as vehicle controls. Naïve SHRSPs on a standard diet served as sham control. Magnetic resonance imaging (MRI) analyses of the corpus callosum, external capsule, hippocampus and Morris water maze behavioral tests were conducted. We found an increase in body weight (p = 0.004) and blood pressure (p = 0.007) at 15 weeks with the DP-460 drug. SB-3CT increased body weight at 14 weeks (p = 0.015) and had significant but variable effects on blood pressure. Neither drug affected imaging parameters. Behavioral studies showed an impaired ability to learn with DP-460 (p<0.001) and no effect on learning with SB-3CT. Unchanged MMP-9 levels were detected in DP-460-treated rats via gel zymography. Our findings suggest that MMPs are not major factors in white matter damage in the SHRSP model of VCID and that drugs that are relatively selective for MMP-9 can interfere with learning., Competing Interests: One of the authors, John Pesko, is currently employed by AbbVie Inc. However, Dr. Pesko was not affiliated with AbbVie at the time of the study and the affiliation does not alter our adherence to PLOS ONE policies on sharing data and materials.

Hepatitis C virus (HCV) is genetically diverse and includes 7 genotypes and 67 confirmed subtypes, and the global distribution of each HCV genotype (GT) varies by geographic region. In this report, we utilized a large dataset of NS3/4A and NS5A sequences isolated from 2348 HCV GT1-6-infected patients treated with the regimen containing glecaprevir/pibrentasvir (GLE/PIB) to assess genetic diversity within HCV subtypes by geographic region using phylogenetic analyses, and evaluated the prevalence of baseline amino acid polymorphisms in NS3 and NS5A by region/country and phylogenetic cluster. Among 2348 NS3/4A and NS5A sequences, phylogenetic analysis identified 6 genotypes and 44 subtypes, including 3 GT1, 8 GT2, 3 GT3, 13 GT4, 1 GT5, and 16 GT6 subtypes. Phylogenetic analysis of HCV subtype 1a confirmed the presence of two clades, which differed by geographic region distribution and NS3 Q80K prevalence. We detected phylogenetic clustering by country in HCV subtypes 1a, 1b, 2a, 2b, and 5a, suggesting that genetically distinct virus lineages are circulating in different countries. In addition, two clades were detected in HCV GT4a and GT6e, and NS5A amino acid polymorphisms were differentially distributed between the 2 clades in each subtype. The prevalence of NS3 and NS5A baseline polymorphisms varied substantially by genotype and subtype; therefore, we also determined the activity of GLE or PIB against replicons containing NS3/4A or NS5A from HCV GT1-6 clinical samples representing 6 genotypes and 21 subtypes overall. GLE and PIB retained activity against the majority of HCV replicons containing NS3/4A or NS5A from HCV GT1-6 clinical samples, with a median EC50 of 0.29 nM for GLE and 1.1 pM for PIB in a transient replicon assay. The data presented in this report expands the available data on HCV epidemiology, subtype diversity by geographic region, and NS3 and NS5A baseline polymorphism prevalence., Competing Interests: All authors are employees of AbbVie and may hold AbbVie stock or stock options. The design, study conduct, and financial support for these studies were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

The ability to restrict low molecular weight compounds to the gastrointestinal (GI) tract may enable an enhanced therapeutic index for molecular targets known to be associated with systemic toxicity. Using a triazolopyrazine CSF1R inhibitor scaffold, a broad range of prodrugs were synthesized and evaluated for enhanced delivery to the colon in mice. Subsequently, the preferred cyclodextrin prodrug moiety was appended to a number of CSF1R inhibitory active parent molecules, enabling GI-restricted delivery. Evaluation of a cyclodextrin prodrug in a dextran sodium sulfate (DSS)-induced mouse colitis model resulted in enhanced GI tissue levels of active parent. At a dose where no significant depletion of systemic monocytes were detected, the degree of pharmacodynamic effect-measured as reduction in macrophages in the colon-was inferior to that observed with a systemically available positive control. This suggests that a suitable therapeutic index cannot be achieved with CSF1R inhibition by using GI-restricted delivery in mice. However, these efforts provide a comprehensive frame-work in which to pursue additional gut-restricted delivery strategies for future GI targets., Competing Interests: The authors have read the journal's policy and have the following conflicts: all authors are employees of AbbVie. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials. There are no patents, products in development, or marketed products to declare.

International Guidelines for mineral bone disorders recommend that in Non Dialytic-Chronic Kidney Disease (ND-CKD) clinical decisions should be based on the trend of serum PTH changes over time rather than on a single value. However, the prognostic impact of these changes in ND-CKD patients remains unknown. We performed a multicenter cohort study in ND-CKD patients (stage 1-5) followed for 36 months in 24 Italian Nephrology Units. PTH changes (ΔPTH) were defined as the absolute differences between all available PTH measurements following the first control and basal value. Primary endpoint in this subanalysis was renal death (End-Stage Renal Disease (ESRD) or all-causes death before ESRD). Association between renal death and ΔPTH was assessed by time-dependent Cox model for repeated measurements. Out of the original cohort (N = 884), we selected 543 patients (66.3±15.4 ys, 58.4% males) with at least two serum PTH measurements. At baseline, eGFR was 36 (IQR: 22.4-56.8) mL/min/1.73m2 and serum PTH 46 (IQR: 28-81) pg/mL. ΔPTH was in median 0 (IQR:-18/18) pg/mL. Basal predictors of longitudinal PTH increments were higher serum phosphate, more advanced CKD stages and lower serum PTH. Fully adjusted Cox model with ΔPTH quartiles as discrete time-dependent covariate showed a significant risk of renal death in the highest quartile (HR: 1.91; 95%CI:1.08-3.38; P = 0.026). Considering ΔPTH, as continuous time-dependent variable, (HR:1.02; 95%C.I.: 1.01-1.04; P = 0.004), risk of renal death progressively rose as ΔPTH increased. An increment in serum PTH over time is associated with a worse prognosis in ND-CKD patients, independently from baseline or any absolute concentration of serum PTH and phosphate., Competing Interests: The authors declare the following interests: This study was funded by AbbVie. MGC declares grant support from Abbvie, Shire; speaker Honoraria from Abbvie, Amgen, Vifor Fresenius, Genzyme, Shire. RM declares lecture fees from Amgen, Roche, Abbvie. GG is an Abbvie employee and AMC was an AbbVie employee and may own Abbvie stocks/options. RG is affiliated with Azienda SocioSanitaria Territoriale. There are no patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

Background: Hidradenitis Suppurativa (HS) is a painful, chronic inflammatory skin disease. Global estimates of prevalence vary between 0.03% and 4% of the population. Our main aim was to determine HS prevalence in the Australian adult population focussing on the demographics, management pathways and diagnosis rate of individuals living with HS., Methods: In this population-based cross-sectional study, 17,050 individuals representative of the Australian adult population were asked through face-to-face household interviews to answer a previously validated HS screening questionnaire with high diagnostic power. Individuals who screened positive were asked additional questions, including previous diagnosis of HS and number/type of physicians consulted regarding their condition., Results: 11,433 Australian residents answered the HS questionnaire, 88 screening positive for HS (0.77%; 95% CI 0.62-0.95). Considering the previously reported sensitivity (0.97) and positive predictive value (0.85) of the screening questionnaire, HS prevalence was estimated to be 0.67% (95% CI 0.53%-0.84%). 6 of 88 suspected HS individuals reported a pre-existing HS diagnosis (6.8%; 95% CI 3.2%-14.1%). 25.6% of the undiagnosed individuals suspected of having HS had not seen any clinicians regarding their boils; the remaining ones had consulted General Practitioners (96.7%), and clinicians from different specialties. Comparisons of individuals who screened positive for HS versus those who screened negative demonstrated statistically significant differences in gender (p = 0.0046), age (p<0.0001), BMI (p = 0.0307), smoking status (p<0.0001), employment status (p<0.0001) and income (p = 0.0321)., Conclusions: The prevalence of HS in Australia was estimated to be 0.67% (95% CI 0.53%-0.84%). The diagnosis rate amongst the suspected HS cases was low, which appeared to be due to a combination of patients not seeking help and decentralization of care. Individuals suspected of having HS were more likely to be females, young, obese, smokers, unemployed or at home duties and having lower annual personal income in comparison with individuals not suspected of having HS., Competing Interests: AbbVie Pty Ltd funded the research for these studies and participated in the studies design; studies research; analysis and interpretation of data; and writing, reviewing and approving of this publication. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials. M Calao, JL Wilson, A Watts receive a salary as employees of AbbVie and may also receive AbbVie stock and/or stock grants. D Rubel is principal investigator for the following HS studies: M11-810 and M12-555, HS registry H13-147, HS validation study 10610, and HS epidemiology study 10756, as well as M13-674 Adalimumab nail psoriasis study; and has served on the Advisory Boards for Abbvie, Eli Lilly, Celgene, Galderma, GlaxoSmithKline, Janssen, Leo Pharma, Novartis, and Sanofi. L Spelman has served on the advisory Boards for Abbvie, Eli Lilly, Novartis and Sanofi; and undertakes sponsored clinical research for AbbVie, Amgen, Ascend Biopharmaceuticals, Australian Wool Innovation Limited, Celgene, Dermira, Eli Lilly, Galderma, Genentech, GlaxoSmithKline, Leo Pharma, Merck, Novartis, Phosphagenics, Regeneron, and has received sponsored travel from AbbVie, Novartis, and Janssen- Cilag. GB Jemec disclosures are as follows: AbbVie: Adboard, consultant, investigator, speaker, unrestricted grant. Coloplast: Consultant, speaker. Leo pharma: Consultant, investigator, speaker, unrestricted grant. Galderma: Speaker. Janssen-Pharma: Adboard MSD: Adboard. Novartis: Adboard, consultant, investigator, unrestricted grant. Regeneron: Investigator. UCB: Consultant and investigator. InflaRX: Consultant and investigator. L Billot is an employee of The George Institute for Global Health which has received payment from AbbVie for the conduct and analysis of the prevalence study.

Background: Genetic variants of inosine triphosphatase (ITPA) that confer reduced ITPase activity are associated with protection against ribavirin(RBV)-induced hemolytic anemia in peginterferon(IFN)/RBV-based treatment of hepatitis C virus (HCV). Patients with reduced ITPase activity showed improved treatment efficacy when treated with IFN/RBV. In addition, a genetic polymorphism near the IL28B gene is associated with an improved response to IFN/RBV treatment. RBV has been an important component of IFN-containing regimens, and is currently recommended in combination with several IFN-free regimens for treatment of harder to cure HCV infections., Aim: To evaluate whether genetic variations that reduce ITPase activity impact RBV-induced anemia in IFN-free/RBV regimens., Methods: In this study, genetic analyses were conducted in the PEARL-IV trial to investigate the effect of activity-reducing ITPA variants as well as IL28B polymorphism on anemia, platelet (PLT) counts, and virologic response in HCV genotype1a-infected patients treated with the direct-acting antiviral (DAA) regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir±RBV., Results: Reduction in ITPase activity and homozygosity for the IL28Brs12979860 CC genotype protected against RBV-induced anemia. In patients receiving RBV, reduced ITPase activity was associated with reduced plasma RBV concentration and higher PLT counts. ITPase activity had no impact on response to DAA treatment, viral kinetics, or baseline IP-10 levels., Conclusions: Our study demonstrates that genetics of ITPA and IL28B may help identify patients protected from RBV-induced anemia when treated with IFN-free regimens. Our work demonstrates for the first time that IL28B genetics may also have an impact on RBV-induced anemia. This may be of particular significance in patients with difficult-to-cure HCV infections, such as patients with decompensated cirrhosis where RBV-containing regimens likely will continue to be recommended., Competing Interests: AV, JWD, MA, JS, JZ, EOD, DEC, and JW are AbbVie employees and may hold AbbVie stock/options. ML is an employee of the University of Gothenberg, Sweden and has no further relationships to disclose. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Anti-drug antibody formation occurs with most biological agents across disease states, but the mechanism by which they are formed is unknown. The formation of anti-drug antibodies to adalimumab (AAA) may decrease its therapeutic effects in some patients. HLA alleles have been reported to be associated with autoantibody formation against interferons and other TNF inhibitors, but not adalimumab. We analyzed samples from 634 subjects with either rheumatoid arthritis (RA) or hidradenitis suppurativa (HS): 37 subjects (17 RA and 20 HS) developed AAA (AAA+) during adalimumab treatment and 597 subjects (348 RA, 249 HS) did not develop AAA (AAA-) during the clinical trials. Using next-generation sequencing-based HLA typing, we identified three protective HLA alleles (HLA-DQB1*05, HLA-DRB1*01,and HLA-DRB1*07) that were less prevalent in AAA+ than AAA-subjects (ORs: 0.4, 0.25 and 0.28, respectively; and P values: 0.012, 0.012 and 0.018, respectively) and two risk HLA alleles (HLA-DRB1*03 and HLA-DRB1*011) that were more abundant in AAA+ than AAA-subjects (ORs: 2.52, and 2.64, respectively; and P values: 0.006 and 0.019). Similar to the finding of Billiet et al. who found that carriage of the HLA-DRB1*03 allele was more prevalent in those with anti-infliximab antibodies (OR = 3.6, p = 0.002, 95% CI: [1.5,8.6]).), we found HLA-DRB1*03 allele was also more prevalent in anti-adalimumab positive (OR = 2.52, p = 0.006, 95% CI: [1.37,4.63]). The results suggest that specific HLA alleles may play a key role in developing AAAs in RA and HS patients treated with adalimumab.

Mutations in the Interleukin (IL)-23/IL-23 receptor loci are associated with increased inflammatory bowel disease (IBD) susceptibility, and IL-23 neutralization has shown efficacy in early clinical trials. To better understand how an excess of IL-23 affects the gastrointestinal tract, we investigated chronic systemic IL-23 exposure in healthy wildtype mice. As expected, IL-23 exposure resulted in early activation of intestinal type 3 innate lymphoid cells (ILC3), followed by infiltration of activated RORγt+ T helper cells. Surprisingly, however, sustained IL-23 stimulus also dramatically reduced classical ILC3 populations within the proximal small intestine, and a phenotypically distinct T-bet expressing ILC3 population emerged. TNFα neutralization, a widely used IBD therapy, reduced several aspects of the IL-23 driven ILC3 response, suggesting a synergy between IL-23 and TNFα in ILC3 activation. In vitro studies supported these findings, revealing previously unappreciated effects of IL-23 and TNFα within the intestine.

To determine if a multi-analyte cerebrospinal fluid (CSF) peptide signature can be used to differentiate Alzheimer's Disease (AD) and normal aged controls (NL), and to determine if this signature can also predict progression from mild cognitive impairment (MCI) to AD, analysis of CSF samples was done on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. The profiles of 320 peptides from baseline CSF samples of 287 subjects over a 3-6 year period were analyzed. As expected, the peptide most able to differentiate between AD vs. NL was found to be Apolipoprotein E. Other peptides, some of which are not classically associated with AD, such as heart fatty acid binding protein, and the neuronal pentraxin receptor, also differentiated disease states. A sixteen-analyte signature was identified which differentiated AD vs. NL with an area under the receiver operating characteristic curve of 0.89, which was better than any combination of amyloid beta (1-42), tau, and phospho-181 tau. This same signature, when applied to a new and independent data set, also strongly predicted both probability and rate of future progression of MCI subjects to AD, better than traditional markers. These data suggest that multivariate peptide signatures from CSF predict MCI to AD progression, and point to potentially new roles for certain proteins not typically associated with AD.

Protein kinases are highly tractable targets for drug discovery. However, the biological function and therapeutic potential of the majority of the 500+ human protein kinases remains unknown. We have developed physical and virtual collections of small molecule inhibitors, which we call chemogenomic sets, that are designed to inhibit the catalytic function of almost half the human protein kinases. In this manuscript we share our progress towards generation of a comprehensive kinase chemogenomic set (KCGS), release kinome profiling data of a large inhibitor set (Published Kinase Inhibitor Set 2 (PKIS2)), and outline a process through which the community can openly collaborate to create a KCGS that probes the full complement of human protein kinases.

Recently, we described a new animal model of CNS primitive neuroectodermal tumors (CNS-PNET), which was generated by orthotopic transplantation of human Radial Glial (RG) cells into NOD-SCID mice's brain sub-ventricular zone. In the current study we conducted comprehensive RNA-Seq analyses to gain insights on the mechanisms underlying tumorigenesis in this mouse model of CNS-PNET. Here we show that the RNA-Seq profiles derived from these tumors cluster with those reported for patients' PNETs. Moreover, we found that (i) stabilization of HIF-1α and HIF-2α, which are involved in mediation of the hypoxic responses in the majority of cell types, (ii) up-regulation of MYCC, a key onco-protein whose dysregulation occurs in ~70% of human tumors, and (iii) accumulation of stabilized p53, which is commonly altered in human cancers, constitute hallmarks of our tumor model, and might represent the basis for CNS-PNET tumorigenesis in this model. We discuss the possibility that these three events might be interconnected. These results indicate that our model may prove invaluable to uncover the molecular events leading to MYCC and TP53 alterations, which would be of broader interest considering their relevance to many human malignancies. Lastly, this mouse model might prove useful for drug screening targeting MYCC and related members of its protein interaction network.

Background: Preterm infants are at high risk of developing respiratory syncytial virus (RSV)-associated lower respiratory tract infection (LRTI). This observational epidemiologic study evaluated RSV disease burden and risk factors for RSV-associated LRTI hospitalization in preterm infants 33 weeks+0 days to 35 weeks+6 days gestational age not receiving RSV prophylaxis., Methods: Preterm infants ≤6 months of age during RSV season (1 October 2013-30 April 2014) were followed at 72 sites across 23 countries from September 2013-July 2014 (study period). RSV testing was performed according to local clinical practice. Factors related to RSV-associated hospitalization for LRTI were identified using multivariable logistic regression with backward selection., Results: Of the 2390 evaluable infants, 204 and 127 were hospitalized for LRTI during the study period and RSV season, respectively. Among these subjects, 64/204 and 46/127, respectively, were hospitalized for confirmed RSV LRTI. Study period and RSV season normalized RSV hospitalization rates (per 100 infant years) were 4.1 and 6.1, respectively. Factors associated with an increased risk of RSV-related LRTI hospitalization in multivariable analyses were smoking of family members (P<0.0001), non-hemodynamically significant congenital heart disease diagnosis (P = 0.0077), maternal age of ≤25 years at delivery (P = 0.0009), low maternal educational level (P = 0.0426), household presence of children aged 4 to 5 years (P = 0.0038), age on 1 October ≤3 months (P = 0.0422), and presence of paternal atopy (P<0.0001)., Conclusions: During the 2013-2014 RSV season across 23 countries, for preterm infants 33-35 weeks gestation ≤6 months old on 1 October not receiving RSV prophylaxis, confirmed RSV LRTI hospitalization incidence was 4.1 per 100 infant years during the study period and 6.1 per 100 infant years during the RSV season. This study enhances the findings of single-country studies of common risk factors for severe RSV infection in preterm infants and suggests that combinations of 4-6 risk factors may be used to accurately predict risk of RSV hospitalization. These findings may be useful in the identification of infants most at risk of severe RSV infection.

Objective: We reviewed the current literature regarding antiretroviral (ARV)-sparing therapy strategies to determine whether these novel regimens can be considered appropriate alternatives to standard regimens for the initial treatment of ARV-naive patients or as switch therapy for those patients with virologically suppressed HIV infection., Methods: A search for studies related to HIV dual therapy published from January 2000 through April 2014 was performed using Biosis, Derwent Drug File, Embase, International Pharmaceutical Abstracts, Medline, Pascal, SciSearch, and TOXNET databases; seven major trial registries, and the abstracts of major conferences. Using predetermined criteria for inclusion, an expert review committee critically reviewed and qualitatively evaluated all identified trials for efficacy and safety results and potential limitations., Results: Sixteen studies of dual therapy regimens were critiqued for the ARV-naive population. Studies of a protease inhibitor/ritonavir in combination with the integrase inhibitor raltegravir or the nucleoside reverse transcriptase inhibitor lamivudine provided the most definitive evidence supporting a role for dual therapy. In particular, lopinavir/ritonavir or darunavir/ritonavir combined with raltegravir and lopinavir/ritonavir combined with lamivudine demonstrated noninferiority to standard of care triple therapy after 48 weeks of treatment. Thirteen trials were critiqued in ARV-experienced, virologically suppressed patients. The virologic efficacy outcomes were mixed. Although overall data regarding toxicity are limited, when compared with standard triple therapy, certain dual therapy regimens may offer advantages in renal function, bone mineral density, and limb fat changes; however, some dual combinations may elevate lipid or bilirubin levels., Conclusions: The potential benefits of dual therapy regimens include reduced toxicity, improved tolerability and adherence, and reduced cost. Although the data reviewed here provide valuable insights into the effectiveness and tolerability of dual therapy regimens, it remains unclear whether these potential benefits can be maintained long-term. Appropriately powered studies with longer follow-up periods are needed to more definitively assess potential toxicity reduction advantages with dual therapy.

Background: In patients with immune-mediated inflammatory disorders, poor adherence to medication is associated with increased healthcare costs, decreased patient satisfaction, reduced quality of life and unfavorable treatment outcomes., Objective: To determine the impact of different interventions on medication adherence in patients with immune-mediated inflammatory disorders., Design: Systematic review., Data Sources: MEDLINE, EMBASE and Cochrane Library., Study Eligibility Criteria for Selecting Studies: Included studies were clinical trials and observational studies in adult outpatients treated for psoriasis, Crohn's disease, ulcerative colitis, rheumatoid arthritis, spondyloarthritis, psoriatic arthritis or multiple sclerosis., Study Appraisal and Synthesis Methods: Intervention approaches were classified into four categories: educational, behavioral, cognitive behavioral, and multicomponent interventions. The risk of bias/study limitations of each study was assessed using the GRADE system., Results: Fifteen studies (14 clinical trials and one observational study) met eligibility criteria and enrolled a total of 1958 patients. Forty percent of the studies (6/15) was conducted in patients with inflammatory bowel disease, half (7/15) in rheumatoid arthritis patients, one in psoriasis patients and one in multiple sclerosis patients. Seven out of 15 interventions were classified as multicomponent, four as educational, two as behavioral and two as cognitive behavioral. Nine studies, of which five were multicomponent interventions, had no serious limitations according to GRADE criteria. Nine out of 15 interventions showed an improvement of adherence: three multicomponent interventions in inflammatory bowel disease; one intervention of each category in rheumatoid arthritis; one multicomponent in psoriasis and one multicomponent in multiple sclerosis., Conclusion: The assessment of interventions designed for increasing medication adherence in IMID is rare in the literature and their methodological quality may be improved in upcoming studies. Nonetheless, multicomponent interventions showed the strongest evidence for promoting adherence in patients with IMID.

Histone methyltransferases are epigenetic regulators that modify key lysine and arginine residues on histones and are believed to play an important role in cancer development and maintenance. These epigenetic modifications are potentially reversible and as a result this class of enzymes has drawn great interest as potential therapeutic targets of small molecule inhibitors. Previous studies have suggested that the histone lysine methyltransferase G9a (EHMT2) is required to perpetuate malignant phenotypes through multiple mechanisms in a variety of cancer types. To further elucidate the enzymatic role of G9a in cancer, we describe herein the biological activities of a novel peptide-competitive histone methyltransferase inhibitor, A-366, that selectively inhibits G9a and the closely related GLP (EHMT1), but not other histone methyltransferases. A-366 has significantly less cytotoxic effects on the growth of tumor cell lines compared to other known G9a/GLP small molecule inhibitors despite equivalent cellular activity on methylation of H3K9me2. Additionally, the selectivity profile of A-366 has aided in the discovery of a potentially important role for G9a/GLP in maintenance of leukemia. Treatment of various leukemia cell lines in vitro resulted in marked differentiation and morphological changes of these tumor cell lines. Furthermore, treatment of a flank xenograft leukemia model with A-366 resulted in growth inhibition in vivo consistent with the profile of H3K9me2 reduction observed. In summary, A-366 is a novel and highly selective inhibitor of G9a/GLP that has enabled the discovery of a role for G9a/GLP enzymatic activity in the growth and differentiation status of leukemia cells.

Epidermal growth factor receptor (EGFR) and receptor tyrosine-protein kinase 3 (ErbB3) are two well-established targets in cancer therapy. There is significant crosstalk among these two receptors and others. To block signaling from both EGFR and ErbB3, we generated anti-EGFR and anti-ErbB3 DVD-Ig proteins. Two DVD-Ig proteins maintained the functions of the combination of the two parental antibodies. The DVD-Ig proteins inhibit cell signaling and proliferation in A431 and FaDu cells while half DVD-Ig proteins lost proliferation inhibition function. Interestingly, in the presence of β-Heregulin (HRG), the DVD-Ig proteins show synergies with respect to inhibiting cell proliferation. The DVD-Ig proteins downregulate EGFR protein expression in the presence of HRG, which may be due to receptor internalization. Furthermore, the DVD-Ig proteins remarkably disrupt β-Heregulin binding to FaDu cells.

Background: Understanding the patterns of HCV RNA levels during acute hepatitis C virus (HCV) infection provides insights into immunopathogenesis and is important for vaccine design. This study evaluated patterns of HCV RNA levels and associated factors among individuals with acute infection., Methods: Data were from an international collaboration of nine prospective cohorts of acute HCV (InC3 Study). Participants with well-characterized acute HCV infection (detected within three months post-infection and interval between the peak and subsequent HCV RNA levels ≤ 120 days) were categorised by a priori-defined patterns of HCV RNA levels: i) spontaneous clearance, ii) partial viral control with persistence (≥ 1 log IU/mL decline in HCV RNA levels following peak) and iii) viral plateau with persistence (increase or <1 log IU/mL decline in HCV RNA levels following peak). Factors associated with HCV RNA patterns were assessed using multinomial logistic regression., Results: Among 643 individuals with acute HCV, 162 with well-characterized acute HCV were identified: spontaneous clearance (32%), partial viral control with persistence (27%), and viral plateau with persistence (41%). HCV RNA levels reached a high viraemic phase within two months following infection, with higher levels in the spontaneous clearance and partial viral control groups, compared to the viral plateau group (median: 6.0, 6.2, 5.3 log IU/mL, respectively; P = 0.018). In the two groups with persistence, Interferon lambda 3 (IFNL3) CC genotype was independently associated with partial viral control compared to viral plateau (adjusted odds ratio [AOR]: 2.75; 95%CI: 1.08, 7.02). In the two groups with viral control, female sex was independently associated with spontaneous clearance compared to partial viral control (AOR: 2.86; 95%CI: 1.04, 7.83)., Conclusions: Among individuals with acute HCV, a spectrum of HCV RNA patterns is evident. IFNL3 CC genotype is associated with initial viral control, while female sex is associated with ultimate spontaneous clearance.

Constitutive activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) axis is fundamental to the molecular pathogenesis of a host of hematological disorders, including acute leukemias and myeloproliferative neoplasms (MPN). We demonstrate here that the major JAK2 mutation observed in these diseases (JAK2V617F) enforces Mcl-1 transcription via STAT3 signaling. Targeting this lesion with JAK inhibitor I (JAKi-I) attenuates STAT3 binding to the Mcl-1 promoter and suppresses Mcl-1 transcript and protein expression. The neutralization of Mcl-1 in JAK2V617F-harboring myelodyssplastic syndrome cell lines sensitizes them to apoptosis induced by the BH3-mimetic and Bcl-xL/Bcl-2 inhibitor, ABT-263. Moreover, simultaneously targeting JAK and Bcl-xL/-2 is synergistic in the presence of the JAK2V617F mutation. These findings suggest that JAK/Bcl-xL/-2 inhibitor combination therapy may have applicability in a range of hematological disorders characterized by activating JAK2 mutations.