Burden of varicella in Central and Eastern Europe : findings from a systematic literature review

Funding Information: The authors take full responsibility for the scope, direction, and content of the manuscript, and have approved the submitted manuscript. Medical writing assistance was provided by Eleanor Finn of PAREXEL International and was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. The authors wish to thank the following for contributions in development of the manuscript: Barbara J. Kuter, PhD, MPH, Global Vaccines Medical Affairs, and Tracey J. Weiss, Center for Observational and Real-World Evidence (CORE), Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding Information: The study was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding Information: J. Wysocki received travel grants to attend international scientific conferences and fees for lectures from Pfizer and payment from a grant sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. I. Ivaskeviciene has received a USA travel grant to attend international scientific meeting, from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth. M. Pokorn has received a research grant from Pfizer and payment for lectures from Pfizer, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and GSK. L. Jancoriene has received travel grants to attend international scientific conferences and fees for lectures from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, AbbVie and Pfizer and payment for a clinical study sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. J. Pluta and L.J. Wolfson are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and stockholders of Merck & Co., Inc., Kenilworth, NJ, USA. Publisher Copyright: © 2019, © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.Introduction: Vaccination against varicella rapidly reduces disease incidence, resulting in reductions in both individual burden and societal costs. Despite these benefits, there is no standardization of varicella immunization policies in Europe, including countries in Central and Eastern Europe (CEE). Areas covered: This systematic literature review identified publications on the epidemiology of varicella, its associated health and economic burden, and vaccination strategies within the CEE region, defined as Albania, Bosnia-Herzegovina, Bulgaria, Croatia, Cyprus, Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Romania, Serbia, Slovakia, and Slovenia. Twenty-six studies were identified from a search of PubMed, Embase®, and MEDLINE® biomedical literature databases, supplemented by gray literature and country-specific/global websites. Expert commentary: Limited information exists in published studies on the burden of varicella in CEE. The wide variability in incidence rates between countries is likely explained by a lack of consistency in reporting systems. Funded universal varicella vaccination (UVV) in CEE is currently available only in Latvia as a one-dose schedule, but Hungary together with Latvia are introducing a two-dose strategy in 2019. For countries that do not provide UVV, introduction of vaccination is predicted to provide substantial reductions in cases and rates of associated complications, with important economic benefits.publishersversionPeer reviewe

Soluble human Suppression of Tumorigenicity 2 is associated with endoscopic activity in patients with moderate-to-severe ulcerative colitis treated with golimumab

Suppressor of Tumorigenicity 2 (ST2) is an IL33 receptor detected in the mucosa and serum of ulcerative colitis (UC) patients. We evaluated soluble ST2 (sST2) as a surrogate biomarker of disease outcome and therapeutic response, in moderate-to-severe UC patients treated with golimumab.Agência financiadora Merck Sharp and Dohme, Lda, Portugal MK8259-22info:eu-repo/semantics/publishedVersio

Pembrolizumab in Asian patients with microsatellite-instability-high/mismatch-repair-deficient colorectal cancer

The phase 3 KEYNOTE-177 study evaluated pembrolizumab versus chemotherapy with or without bevacizumab or cetuximab in patients with newly diagnosed, microsatellite-instability-high (MSI-H)/mismatch-repair-deficient (dMMR) metastatic colorectal cancer (mCRC). Primary endpoints were progression-free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR) and overall survival (OS). Secondary endpoints were overall response rate (ORR) per RECIST v1.1 by BICR and safety. Here, we report results from the post hoc analysis of patients who were enrolled in Asia from the final analysis (FA) of KEYNOTE-177. A total of 48 patients from Japan, Korea, Singapore, and Taiwan (pembrolizumab, n =?22; chemotherapy, n =?26) were included. At FA, median time from randomization to data cutoff (February 19, 2021) was 45.3 (range 38.1?57.8) months with pembrolizumab and 43.9 (range 36.6?55.1) months with chemotherapy. Median PFS was not reached (NR; 95% confidence interval [CI] 1.9 months?NR) with pembrolizumab versus 10.4 (95% CI 6.3?22.0) months with chemotherapy (hazard ratio [HR] 0.56, 95% CI 0.26?1.20). Median OS was NR (range 13.8 months?NR) versus 30.0 (14.7?NR) months (HR 0.65, 95% CI 0.27?1.55) and ORR was 50% (95% CI 28?72) versus 46% (95% CI 27?67). Grade 3/4 treatment-related adverse events (TRAEs) were reported by two patients (9%) in the pembrolizumab arm and 20 (80%) in the chemotherapy arm. Immune-mediated adverse events or infusion reactions were reported by six patients (27%) and 10 patients (40%), respectively. No deaths due to TRAEs occurred. These data support first-line pembrolizumab as a standard of care for patients from Asia with MSI-H/dMMR mCRC. ClinicalTrials.gov identifier: NCT02563002.FUNDING INFORMATION: The study was designed under the responsibility of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, in conjunction with the steering committee. The study was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Pembrolizumab was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. All authors had full access to all of the data in the study and had final responsibility for the decision to submit for publication. ACKNOWLEDGMENTS: This work was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. We thank the patients and their families and caregivers for participating in this trial, and all investigators and site personnel. Medical writing and editorial assistance were provided by Jemimah Walker, PhD, Mehak Aggarwal, PharmD, and Doyel Mitra, PhD, CMPP, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA

Development, manufacturing, and supply of MSD’s Ebola vaccine

Ebola was first discovered in 1976 and is a member of the filoviridae family of viruses. There are multiple strains of Ebola and infection can lead to hemorrhagic fever and death. In March 2014, a historic Ebola outbreak occurred in three Western African countries, Guinea, Liberia, and Sierra Leone. Over 28,000 cases were reported and led to more than 11,000 deaths, more than ten times the amount of cases compared to all past outbreaks combined. On August 8th 2014, the World Health Organization declared a Public Health Emergency of International Concern (PHEIC). Merck Sharp & Dohme (MSD) partnering with NewLink Genetics entered into an exclusive worldwide licensing agreement to research, develop, manufacture, and distribute an investigational Ebola vaccine candidate based on recombinant Vesicular Stomatitis Virus (rVSV) technology. Working with multiple partners, Merck Sharp & Dohme have brought forward an efficacious vaccine candidate from Phase I trials in October 2014, to Phase III consistency studies by August 2015. This presentation will provide background into Merck Sharp & Dohme’s strategy to bring the vaccine to licensure, product development activities to scale-up the process from clinical to commercial, and the challenges faced during product development

Clinical management of metastatic colorectal cancer in the era of precision medicine

Immunotherapy; Metastatic colorectal cancer; Precision medicineInmunoterapia; Cáncer colorrectal metastásico; Medicina de precisiónImmunoteràpia; Càncer colorectal metastàtic; Medicina de precisióColorectal cancer (CRC) represents approximately 10% of all cancers and is the second most common cause of cancer deaths. Initial clinical presentation as metastatic CRC (mCRC) occurs in approximately 20% of patients. Moreover, up to 50% of patients with localized disease eventually develop metastases. Appropriate clinical management of these patients is still a challenging medical issue. Major efforts have been made to unveil the molecular landscape of mCRC. This has resulted in the identification of several druggable tumor molecular targets with the aim of developing personalized treatments for each patient. This review summarizes the improvements in the clinical management of patients with mCRC in the emerging era of precision medicine. In fact, molecular stratification, on which the current treatment algorithm for mCRC is based, although it does not completely represent the complexity of this disease, has been the first significant step toward clinically informative genetic profiling for implementing more effective therapeutic approaches. This has resulted in a clinically relevant increase in mCRC disease control and patient survival. The next steps in the clinical management of mCRC will be to integrate the comprehensive knowledge of tumor gene alterations, of tumor and microenvironment gene and protein expression profiling, of host immune competence as well as the application of the resulting dynamic changes to a precision medicine-based continuum of care for each patient. This approach could result in the identification of individual prognostic and predictive parameters, which could help the clinician in choosing the most appropriate therapeutic program(s) throughout the entire disease journey for each patient with mCRC.Fortunato Ciardiello was supported by a grant from Regione Campania (I-Cure Research Project Cup 21C17000030007). Andres Cervantes was supported by grants from the Instituto de Salud Carlos III (PI18/01909 and PI21/00689). Fortunato Ciardiello reports institutional research grants from Amgen, Merck KGaA, Merck Sharp & Dohme, Pfizer, Pierre Fabre, Roche, and Servier; and service on advisory boards for Bayer, Merck KGaA, Merck Sharp & Dohme, Pierre Fabre, Roche, and Servier outside the submitted work. Davide Ciardiello reports a travel grant from Sanofi outside the submitted work. Stefania Napolitano reports honoraria from Bristol Myers Squibb and Novartis outside the submitted work. Josep Tabernero reports advisory board or scientific consultancy fees from Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, Daiichi-Sankyo, Roche, Genentech, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna Inc, IQVIA, Lilly, Menarini, Merck KGaA, Merus, Merck Sharp & Dohme, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Scandion Oncology, Servier, SotioBiotech, Taiho, Tessa Therapeutics, and TheraMyc outside the submitted work. Andres Cervantes reports institutional research grants from Genentech, Merck KGaA, Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Beigene, Bayer, Servier, Lilly, Novartis, Takeda, Astellas, Takeda, and Fibrogen; and honoraria or speaker’s fees from Amgen, Merck KGaA, Roche, Bayer, Servier, and Pierre Fabre outside the submitted work. Giulia Martini reports no conflicts of interest

PENGARUH LIKUIDITAS, PROFITABILITAS, DAN STRUKTUR MODAL TERHADAP FINANCIAL DISTRESS: Studi Pada Perusahaan Farmasi PT Merck Sharp Dohme Pharma TBK tahun 20102014

Penelitian ini bertujuan untuk menguji pengaruh likuiditas, profitabilitas, dan struktur modal terhadap financial distress pada perusahaan farmasi PT Merck Sharp Dohme Pharma tahun 2010-2014. Likuiditas, profitabilitas, dan struktur modal digunakan sebagai variabel independent sedangkan financial distress sebagai variabel dependent. Jenis penelitian ini adalah penelitian kausal yaitu dengan mencari hubungan antara dua variabel atau lebih dan mencari sebab-akibat. Populasi pada penelitian ini adalah PT Merck Sharp Dohme Pharma. Sampel penelitian ini ditentukan dengan teknik purposive sampling dengan kriteria yang digunakan yaitu laporan keuangan periode 2010-2014 dimana pada 5 tahun tersebut perusahaan mengalami kerugian berturut-turut. Jenis data pada penelitian ini menggunakan data sekunder. Teknik analisis data yang digunakan yaitu regresi linear berganda dengan taraf signifikansi 5%. Hasil pengujian hipotesis pada penelitian ini menyatakan bahwa likuiditas, profitabilitas, dan struktur modal tidak berpengaruh terhadap financial distress baik itu secara partial (uji t) maupun secara simultan (uji f). Ketiga variabel independent yang digunakan tidak dapat menjadi penentu terjadinya financial distress pada objek penelitian yang diteliti.----------This study examines the influence of liquidity, profitability, and capital structure to financial distress in pharmacy company PT Merck Sharp Dohme Pharma during 2010-2014. liquidity, profitability, and capital structure is used as independent variable whereas financial distress is used as dependent variable. This type of research is causal research that find a relation between two or more variable and find a cause-effect. The population of this research is PT Merck Sharp Dohme Pharma. Research sample is choosen by using a criteria that is financial report during 20102014 where in that five years the company have always loss. The data used in this research is secondary data. The analyze data technic using multiple linear regression with level of significancy 5%. The result of this research explain that liquidity, profitability, and capital structure is not affect financial distress either by partial (t test) or simultaneous (f test). All three independent variable that used can not predict financial distress in research object

A Cross-Sectional Survey-Based Study of Medical Oncologists

Funding Information: We would like to thank Andrea Bothwell who wrote the manuscript outline and first draft on behalf of Springer Healthcare Communications. We also thank Prof. Carina Silva (ESTEsL – Escola Superior de Tecnologias de Saúde de Lisboa) who performed the preliminary statistical analysis of this study. This medical writing assistance and statistical analysis was funded by CUF Oncologia. Funding Information: Diogo Alpuim Costa has received honoraria from the Portuguese Navy, CUF Oncologia, and NTT DATA, and has served as a speaker, advisory board member, or has received research or education funding from CUF Oncologia, AstraZeneca, Hoffmann-La Roche, Merck KGaA, Novartis, Pfizer, Uriage, Daiichi Sankyo, Gilead, Merck Sharp & Dohme, Nanobiotix, Puma Biotechnology Inc., Sanofi, and Seagen Inc. Margarida Brito has participated as advisory board member for Roche, Novartis, Merck Sharp & Dohme, and Pfizer. Mário Fontes-Sousa has served as a speaker or advisory board member for Bristol Myers Squibb, Daiichi Sankyo, Gilead, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Servier. Diogo Martins-Branco received honoraria and advisory board fees from Janssen, Pfizer, Merck Sharp & Dohme, Angelini, AstraZeneca, and Novartis, meeting and travel grants from LEO Farmacêuticos, Merck Sharp & Dohme, Ipsen, Janssen, and Roche, and institutional grants from F. Hoffmann-La Roche Ltd. José Guilherme Gonçalves Nobre, João Paulo Fernandes, Marta Vaz Batista, Ana Simas, Carolina Sales, Helena Gouveia, Leonor Abreu Ribeiro, Andreia Coelho, Mariana Inácio, André Cruz, Mónica Mariano, Joana Savva-Bordalo, Ricardo Fernandes, André Oliveira, Andreia Chaves, Mafalda Sampaio-Alves, and Noémia Afonso have nothing to declare. Publisher Copyright: © 2022, The Author(s).Introduction: Cancer care providers have faced many challenges in delivering safe care for patients during the COVID-19 pandemic. This cross-sectional survey-based study investigated the impact of the pandemic on clinical practices of Portuguese medical oncologists caring for patients with breast cancer. Methods: An anonymous online survey comprising 42 questions gathered information regarding COVID-19 testing, treatment in (neo)adjuvant and metastatic settings, and other aspects of breast cancer management. Practices before and during the pandemic were compared, and potential differences in outcomes according to respondents’ regions, case volumes, and practice type were explored. Results: Of 129 respondents, 108 worked in the public health system, giving a representative national picture of the impact of the COVID-19 pandemic on breast cancer management. Seventy-one percent of respondents reported a reduction in visits for new cases of breast cancer, and there was a shift towards increased use of telemedicine. Clinical decision-making was largely unaffected in the most aggressive indications (i.e., triple-negative, HER2-positive, visceral crisis). The use of neoadjuvant therapy increased when access to surgery was difficult, whereas dose-dense regimens decreased, and cyclin-dependent kinase 4/6 inhibitor treatment decreased for less aggressive disease and increased for more aggressive disease. The use of oral formulations and metronomic chemotherapy regimens increased, and clinical trial participation decreased. Some differences by respondents’ region and case volume were noted. Conclusion: Medical oncologists in Portugal implemented many changes during the COVID-19 pandemic, most of which were logical and reasonable responses to the current healthcare emergency; however, the true impact on patient outcomes remains unknown.publishersversionepub_ahead_of_prin

Association of Genetic Variants in NUDT15 with Thiopurine-Induced Myelosuppression in Patients with Inflammatory Bowel Disease

Funding Information: reported serving as a consultant for AbbVie UK; receiving honoraria from Falk and AbbVie UK; receiving grants from Crohn’s & Colitis UK and Tillott’s Pharmaceuticals; having a fellowship from the UK National Institute for Health Research; and receiving travel reimbursement from Merck Sharp & Dohme and Norgine. Dr Heap reported receiving travel reimbursement from AbbVie; and being a current employee of AbbVie and owning stock in the company. Dr Andersen reported receiving personal fees from Merck Sharp & Dohme and Janssen. Dr Ananthakrishnan reported receiving a grant from Pfizer; and receiving personal fees from Takeda. Dr Beaugerie reported receiving advisory board fees from Allergan, Janssen, and Pfizer; receiving a grant from Hospira; and receiving grants and honoraria from AbbVie, Merck Sharp & Dohme, Ferring, Takeda, and Tillott’s Pharmaceuticals. Dr Cummings reported receiving personal fees from AbbVie, Takeda, Biogen, Janssen, Merck Sharp & Dohme, Amgen, Hakim Pharmaceuticals, and Pfizer/Hospira; and receiving grants from Takeda, Biogen, AstraZeneca, and Pfizer/Hospira. Dr Halfvarson reported receiving personal fees from AbbVie, Hospira, Janssen, Medivir, Merck Sharp & Dohme, Pfizer, RenapharmaVifor, Takeda, Tillott’s Pharmaceuticals, Celgene, Sandoz, and Shire; and receiving grants from Janssen, Merck Sharp & Dohme, and Takeda. Dr Hart reported receiving advisory board fees from AbbVie, Atlantic, Bristol-Myers Squibb, Celltrion, Janssen, Merck Sharp & Dohme, Pfizer, Shire, and Takeda; receiving honoraria from Falk and Ferring; and receiving a grant from Takeda. Dr Irving reported receiving personal fees from Janssen, AbbVie, Takeda, Ferring, Pfizer, Lilly, Merck Sharp & Dohme, Samsung, and Sandoz; and receiving grants from Takeda and Merck Sharp & Dohme. Dr Lindsay reported receiving advisory board fees from Atlantic Health, AbbVie UK/global, Merck Sharp & Dohme, Shire UK, Vifor Pharma, Ferring International, Celltrion, Takeda, Napp, Pfizer, and Janssen; serving as a consultant for AbbVie UK/global, Takeda, and Pfizer; receiving grants from Shire UK, AbbVie UK/global, Warner Chilcott, Funding Information: Takeda, Hospira, Ferring International, and Merck Sharp & Dohme; receiving honoraria from Takeda, Cornerstones US, Tillott’s Pharmaceuticals, Napp, Shire International, Janssen, AbbVie, and Pfizer; and receiving travel reimbursement from AbbVie UK, Merck Sharp & Dohme, Warner Chilcott, Takeda, and Shire International. Dr McGovern reported receiving grants from the National Institutes of Health, Helmsley Charitable Trust, and Janssen; and serving as a consultant for Pfizer, Q Biologics, Cidara, Gilead, and Janssen. Dr Seksik reported receiving advisory board fees from Astellas; receiving honoraria from Takeda, AbbVie, and Ferring; and receiving grants from Merck Sharp & Dohme and Biocodex. Dr Sokol reported receiving grants from Biocodex, Danone, and BiomX; serving as a consultant for Enterome, Takeda, AbbVie, Roche, Amgen, Danone, BiomX, Ferring, Bristol-Myers Squibb, Astellas, Merck Sharp & Dohme, Novartis, Tillott’s Pharmaceuticals, and Biose; and being the co-founder of Nextbiotix. Dr Annese reported receiving advisory board fees from Takeda, AbbVie, and Medtronic; and receiving honoraria from Janssen, Takeda, AbbVie, and Medtronic. Dr Weersma reported receiving grants from Takeda, Ferring, and Tramedico; and receiving personal fees from AbbVie. Dr Goodhand reported receiving honoraria from Falk, AbbVie, and Shield Therapeutics. Dr Kennedy reported serving as a consultant for Falk; receiving honoraria from Falk, Allergan, Pharmacosmos, and Takeda; and being a deputy editor of Alimentary Pharmacology & Therapeutics. Dr Ahmad reported receiving unrestricted grants, advisory board fees, speaker honoraria, and support to attend international meetings from AbbVie, Merck Sharp & Dohme, Janssen, Takeda, Ferring, Tillott’s Pharmaceuticals, Ferring, Pfizer, Napp, Celltrion, and Hospira. No other disclosures were reported. Funding Information: Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California), Alistair McNair, PhD (Queen Elizabeth Hospital, London, UK), Anita Modi, MD (Luton and Dunstable University Hospital, Luton, UK), Kevin Monahan, PhD (West Middlesex University Hospital, Middlesex, UK), Alex Moran, MD (Northern Devon Healthcare Trust, Barnstaple, UK), Mary-Anne Morris, MD (Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK), Marianne Mortimore, MBBS (Mater Research Institute, University of Queensland, South Brisbane, Australia), Craig Mowat, MD (Ninewells Hospital, NHS Tayside, Dundee, UK), Rafeeq Muhammed, MD (Birmingham Children's Hospital, Birmingham, UK), Charles D. R. Murray, PhD (Royal Free Hospital, Royal Free London NHS Foundation Trust, London, UK), Hanlie Olivier (IBD Pharmacogenetics Group, University of Exeter, Exeter, UK), Timothy R. Orchard, DM (Imperial College Healthcare NHS Trust, London, UK), Simon Panter, MD (South Tyneside District Hospital, South Tyneside, UK), Vinod Patel, MBBS (Tameside and Glossop Integrated Care NHS Foundation Trust, Ashton-under-Lyne, UK), Rosemary Phillips, MD (Princess Alexandra Hospital, Essex, UK), Neeraj Prasad, MSc (Wrightington Hospital, Wrightington, UK), Cathryn Preston, MBChB (Bradford Royal Infirmary, Bradford, UK), Graham Radford-Smith, PhD (Royal Brisbane and Women’s Hospital, Brisbane, Australia), Praveen Rajasekhar, MD (Northumbria NHS Trust, Tyne and Wear, UK), Dipak Roy, PhD (Tameside and Glossop Integrated Care NHS Foundation Trust, Ashton-under-Lyne, UK), Rebecca Saich, PhD (Basingstoke and North Hampshire Hospital, Basingstoke, UK), Jack Satsangi, PhD (Western General Hospital, NHS Lothian, Edinburgh, UK), Stefan Schreiber, PhD (Kiel University, Kiel, Germany), Sandip Sen, MD (Royal Stoke University Hospital, Stoke-on-Trent, UK), Neil Shah, MD (Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK), Richard Shenderay, MBBS (Airedale NHS Foundation Trust, Keighley, UK), Acuth Shenoy, MD (Colchester Hospital University NHS Foundation Trust, Colchester, UK), James Shutt, DM (Dorset County Hospital NHS Foundation Trust, Dorchester, UK), Mark Silverberg, PhD (Mount Sinai Hospital, Toronto, Ontario, Canada), Alison Simmons, PhD (Oxford University Hospitals, Oxford, UK), Jonathan Simmons, DM (Royal Berkshire Hospital, Royal Berkshire NHS Foundation Trust, Reading, UK), Salil Singh, PhD (Bolton NHS Foundation Trust, Bolton, UK), Malcolm Smith, MBChB (Aberdeen Royal Infirmary, Aberdeen, UK), Mark Smith, MD (Shrewsbury and Telford Hospital NHS Trust, Shrewsbury, UK), Melissa Smith, MB (Royal Sussex County Hospital, Brighton, UK), Jonathon A. Snook, DPhil (Poole Hospital NHS Foundation Trust, Poole, UK), Sunil Sonwalker, MD (Calderdale Royal Hospital, Halifax, UK), Christine R. Stevens, PhD (Broad Institute, Harvard University, Cambridge, Massachusetts), Giacomo Sturniolo, PhD (Univerita di Padova, Padova, Italy), Sreedhar Subramanian, MD (Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK), Amanda Thomas, MBBS (Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, UK), Mark Tighe, BM (Poole Hospital NHS Foundation Trust, Poole, UK), Franco Torrente, MD (Department of Gastroenterology, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK), Mark Tremelling, MD (Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK), Epameinondas Tsianos, PhD (University Hospital of Ioannina, Ioannina, Greece), Deven Vani, MD (Mid Yorkshire Hospitals NHS Trust, Wakefield, UK), Alissa Walsh, MBBS (St Vincent’s Hospital, Sydney, Australia), Gillian Watermeyer, MBChB (Groote Schuur Hospital, Cape Town, South Africa), David Watts, MBChB (Forth Valley Royal Hospital, Larbert, UK), Gill Watts, MD (Wythenshawe Hospital, South Manchester, UK), Sean Weaver, PhD (Royal Bournemouth General Hospital, Bournemouth, UK), Emma Wesley, MBBS (Musgrove Park Hospital, Taunton and Somerset NHS Hospitals, Taunton, UK), Anne Willmott, MBChB (Leicester Royal Infirmary-Paediatric, Leicester, UK), Karen Yearsley, BM (Nevill Hall Hospital, Abergavenny, UK), Veena Zambar, MBBS (Leeds General Infirmary, Leeds, UK), and Sebastian Zeissig, MD (University Medical Center Schleswig-Hostein, Kiel, Germany). These individuals identified and recruited patient s to the study and provided comments on a draft of the manuscript. Funding Information: Adverse Events Consortium funded the sample collection and genotyping at the Broad Institute. The UK National Institute for Health Research provided research nurse support to facilitate recruitment at all UK research sites. Crohn’s & Colitis UK and forCrohns provided funding support and publicized this study to their members. The Exeter National Institute for Health Research Clinical Research Facility provided DNA storage and management. Institutional strategic support award WT097835MF from Wellcome Trust supported the management of the study. Samples from Cedars-Sinai were collected and processed through the MIRIAD biobank that was funded by grant P01DK046763 from the National Institutes of Health. Publisher Copyright: © 2019 American Medical Association. All rights reserved.IMPORTANCE Use of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM). OBJECTIVE To identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD). DESIGN, SETTING, AND PARTICIPANTS Case-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients. EXPOSURES Genetic variants associated with TIM. MAIN OUTCOMES AND MEASURES Thiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 x 10(9)/L or less or a decline in absolute neutrophil cell count to 1.0 x 10(9)/L or less leading to a dose reduction or drug withdrawal. RESULTS Among 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 x 10(-9)). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 x 10(-8)), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P = .03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 x 10(-7)) of TIM, independent of TPMT genotype and thiopurine dose. CONCLUSIONS AND RELEVANCE Among patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required.Peer reviewe

Equity research - Merck Sharp and Dohme

Mestrado Bolonha em FinançasThe following research report follows the official CFA Institute recommended structure for an Equity Research. Merck & Co., Inc (“Merck Sharp and Dohme” or “Merck”) can be defined as one of the largest healthcare companies in the world, with a range of operations that include health solutions through medicines, vaccines, prescriptions, therapies, and animal health. These operations are all divided into two major segments: Pharmaceutical and Animal Health. The company trades its shares on the New York Stock Exchange (NYSE) with the ticker symbol of “MRK”. The current closing stock price as of September 15th is $72.81 and the total assets of the company accounted for$91.59Bn in FY2020, with a market capitalization of $185.246Bn.Merck has a price target of$83.59, which leads to a BUY recommendation for 2022F, representing an upside potential of 15%, or an annualized potential of 9.65%, with a considerable medium risk. Vanguard Group, BlackRock Institutional Trust Company, and State Street Global Advisors currently represent the three major shareholders, with 8.89%, 5.15% and 4.45% of Merck’s shares, respectively. The turnover (or liquidity) of the stock is low for all top investors, meaning that it can be hard to buy in shares. Wellington Management Company, Geode Capital Management and Capital International Investors are also part of the top 10 investors of the company. Merck has currently 2531 million shares outstanding and a stock’s free float of 99.92%, meaning that the company has the majority of its shares available to public trade and not held by insiders.Este relatório segue a estrutura oficial recomendada pelo Instituto de CFA para uma Equity Research. Merck & Co., Inc. (“Merck Sharp and Dohme” ou “Merck”) pode ser definida como uma das maiores empresas de saúde mundiais, com um conjunto de operações que incluem soluções de saúde por via de medicamentos, vacinas, prescrições, terapias, e saúde animal. Todas as operações mencionadas estão divididas em dois grandes segmentos: Farmacêutica e Saúde Animal. A empresa negoceia as suas ações na Bolsa de Valores de Nova Iorque (NYSE) com o símbolo “MRK”. O preço atual das ações, em 15 de setembro de 2021. é de $72,81 e os Total de ativos da empresa contabilizou$91,59 bilhões no ano fiscal de 2020, com uma capitalização de mercado de $185,246 mil milhões. A Merck tem um preço-alvo de$83,59, o que leva a uma recomendação de “BUY” para 2022F, o que representa um ganho potencial de 15%, ou de 9,65% depois de anualizado, com um risco médio considerável. O Vanguard Group, a BlackRock Institutional Trust Company e a State Street Global Advisors representam atualmente os três principais acionistas, com 8,89%, 5,15% e 4,45% das ações da Merck, respectivamente. O “turnover” (ou liquidez) das ações é baixo para todos os principais investidores, o que significa que pode ser difícil comprar ações. Wellington Management Company, Geode Capital Management e Capital International Investors também fazem parte dos 10 maiores investidores da empresa. A Merck tem atualmente 2531 milhões de ações em circulação e um “free float” de 99,92%, o que significa que a empresa tem a maioria de suas ações disponíveis para negociação pública e não detidas por “insiders”.info:eu-repo/semantics/publishedVersio

Compared to Palliative Care, Working in Intensive Care More than Doubles the Chances of Burnout: Results from a Nationwide Comparative Study

Professionals working in intensive and palliative care units, hence caring for patients at the end-of-life, are at risk of developing burnout. Workplace conditions are determinant factors to develop this syndrome among professionals providing end-of-life care.This study was partially supported by Fundação Grünenthal and Fundação Merck, Sharp and Dohme (2007/2011), which provided financial support during the period of data collectioninfo:eu-repo/semantics/publishedVersio