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Feasibility, acceptability, and short-term impact of a brief sexually transmitted infection intervention targeting US Military personnel and family members

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BMC PUBLIC HEALTH 2022年第1期22卷 640-640页

作者： Kunz, Anjali Moodley, Amber Colby, Donn J. Soltis, Michele Robb-McGrath, Wesley Fairchok, Alexandra Faestel, Paul Jungels, Amanda Bender, Alexis A. Kamau, Edwin Wingood, Gina DiClemente, Ralph Scott, Paul Madigan Army Med Ctr Joint Base Lewis McChord Tacoma WA 98431 USA Henry M Jackson Fdn Adv Mil Med Bethesda MD 20817 USA Walter Reed Army Inst Res US Mil HIV Res Program Silver Spring MD 20910 USA Army Publ Hlth Ctr Behav & Social Hlth Outcomes Program Edgewood MD USA Rice Univ Ctr Teaching Excellence Houston TX USA Emory Univ Sch Med Atlanta GA USA Columbia Univ Mailman Sch Publ Hlth New York NY USA NYU Sch Global Publ Hlth New York NY USA Walter Reed Army Inst Res Emerging Infect Dis Branch Silver Spring MD USA

Background Over the past 10 years, incidence of sexually transmitted infections (STIs) has increased to record numbers in the United States, with the most significant increases observed among adolescents and young adults. The US military, where the majority of active duty personnel are 18-30 years old, has seen similar increases. However, the US military does not yet have a standardized, service-wide program for STI education and prevention. Methods The KISS intervention (Knocking out Infections through Safer-sex and Screening) was adapted from an evidence-based intervention endorsed by the US Centers for Disease Control and Prevention and consisted of a one-time, small group session. Content included STI/HIV knowledge and prevention, condom use skills, and interpersonal communication techniques. The intervention was pilot tested for feasibility and acceptability among a population of service members and medical beneficiaries at Joint Base Lewis-McChord in Washington state. Results A total of 79 participants aged 18-30 years were consented to participate in the pilot study and met entry criteria, 66/79 (82.5%) attended the intervention session, and 46/66 (69.7%) returned at 3 months for the final follow-up assessment. The intervention sessions included 31 male (47.0%) and 35 female (53.0%) participants. Almost all participants felt comfortable discussing sexual issues in the group sessions, reported that they intended to practice safer sex after the intervention, and would also recommend the intervention to friends. Knowledge about STI/HIV prevention significantly increased after the intervention, and intervention effects were maintained at 3 months. About one-fifth of participants tested positive for N. gonorrhea or C. trachomatis infection at enrollment, while none had recurrent STIs at the final visit. Use of both male and female condoms increased after the intervention. Conclusions The KISS intervention was feasible to implement in the military setting and was a

关键词： Military Evidence-based interventions Prevention Sexually transmitted infections Human immunodeficiency virus

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Frontal language areas do not emerge in the absence of temporal language areas: A case study of an individual born without a left temporal lobe

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NEUROPSYCHOLOGIA 2022年第0期169卷 000-000页

作者： Tuckute, Greta Paunov, Alexander Kean, Hope Small, Hannah Mineroff, Zachary Blank, Idan Fedorenko, Evelina MIT Dept Brain & Cognit Sci E25-618 Cambridge MA 02139 USA MIT McGovern Inst Brain Res 77 Massachusetts Ave Cambridge MA 02139 USA CMU Eberly Ctr Teaching Excellence & Educ Innovat Pittsburgh PA 15213 USA Univ Calif Los Angeles Dept Psychol Los Angeles CA 90095 USA Harvard Univ Program Speech & Hearing Biosci & Technol Boston MA 02114 USA NeuroSpin Ctr Cognit Neuroimaging Unit UNICOG F-91191 Gif Sur Yvette France Johns Hopkins Univ Dept Cognit Sci Baltimore MD 21218 USA

Language processing relies on a left-lateralized fronto-temporal brain network. How this network emerges ontogenetically remains debated. We asked whether frontal language areas emerge in the absence of temporal language areas through a 'deep-data' investigation of an individual (EG) born without her left temporal lobe. Using fMRI methods that have been validated to elicit reliable individual-level responses, we find that-as ex-pected for early left-hemisphere damage-EG has a fully functional language network in her right hemisphere (comparable to the LH network in n = 145 controls) and intact linguistic abilities. However, we detect no response to language in EG's left frontal lobe (replicated across two sessions, 3 years apart). Another net-work-the multiple demand network-is robustly present in frontal lobes bilaterally, suggesting that EG's left frontal cortex can support non-linguistic cognition. The existence of temporal language areas therefore appears to be a prerequisite for the emergence of the frontal language areas.

关键词： Language development Case study Neuroimaging Plasticity

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Lassa virus in novel hosts: insights into the epidemiology of lassa virus infections in southern Nigeria

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EMERGING MICROBES & INFECTIONS 2024年第1期13卷 2294859页

作者： Happi, Anise Nkenjop Ogunsanya, Olusola Akinola Ayinla, Akeemat Opeyemi Sijuwola, Ayotunde Elijah Saibu, Femi Mudasiru Akano, Kazeem Nwofoke, Cecilia Elias, Obineche Tobias Achonduh-Atijegbe, Olivia Daodu, Richard Olumide Adedokun, Oluwatobi Abel Adeyemo, Abraham Ogundana, Kehinde Ebenezer Lawal, Omolola Zaheedat Parker, Edyth Nosamiefan, Iguosadolo Okolie, Johnson Parker, Zahra F. McCauley, Melanie D. Eller, Leigh Anne Lombardi, Kara Tiamiyu, Abdulwasiu Bolaji Iroezindu, Michael Akinwale, Edward Njatou, Thierry Lamare Fouapon Assedi Mebrahtu, Tsedal Broach, Erica Zuppe, Anastasia Prins, Petra Lay, Jenny Amare, Mihret Modjarrad, Kayvon Collins, Natalie D. Vasan, Sandhya Tucker, Cynthia Daye, Sharon Happi, Christian Tientcha Redeemers Univ African Ctr Excellence Genom Infect Dis Ede Osun State Nigeria Redeemers Univ Ede Osun Nigeria Alex Ekwueme Fed Univ Teaching Hosp Abakaliki Ebonyi State Nigeria Univ Nigeria Nsukka Nigeria Scripps Translat Sci Inst La Jolla CA USA Henry M Jackson Fdn Advancement Mil Med Bethesda MD USA Med Res Int Ltd Gte Henry M Jackson Fdn Abuja Nigeria Walter Reed Army Inst Res Ctr Infect Dis Res Emerging Infect Dis Branch Silver Spring MD USA Walter Reed Army Inst Res Ctr Infect Dis Res Hlth Branch 1 Silver Spring MD USA Walter Reed Army Inst Res Ctr Infect Dis Res Viral Dis Program Silver Spring MD USA Harvard TH Chan Sch Publ Hlth Dept Immunol & Infect Dis Boston MA USA

Identification of the diverse animal hosts responsible for spill-over events from animals to humans is crucial for comprehending the transmission patterns of emerging infectious diseases, which pose significant public health risks. To better characterize potential animal hosts of Lassa virus (LASV), we assessed domestic and non-domestic animals from 2021-2022 in four locations in southern Nigeria with reported cases of Lassa fever (LF). Birds, lizards, and domestic mammals (dogs, pigs, cattle and goats) were screened using RT-qPCR, and whole genome sequencing was performed for lineage identification on selected LASV positive samples. Animals were also screened for exposure to LASV by enzyme-linked immunosorbent assay (ELISA). Among these animals, lizards had the highest positivity rate by PCR. Genomic sequencing of samples in most infected animals showed sub-lineage 2 g of LASV. Seropositivity was highest among cattle and lowest in pigs. Though the specific impact these additional hosts may have in the broader virus-host context are still unknown - specifically relating to pathogen diversity, evolution, and transmission - the detection of LASV in non-rodent hosts living in proximity to confirmed human LF cases suggests their involvement during transmission as potential reservoirs. Additional epidemiological data comparing viral genomes from humans and animals, as well as those circulating within the environment will be critical in understanding LASV transmission dynamics and will ultimately guide the development of countermeasures for this zoonotic health threat.

关键词： Lassa virus LASV genomes non-rodents animals Nigeria LASV lineages 2 g

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Exploring the role of university students' online self-regulated learning in the flipped classroom: a structural equation model

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INTERACTIVE LEARNING ENVIRONMENTS 2019年第8期27卷 1192-1206页

作者： Shih, Meilun Liang, Jyh-Chong Tsai, Chin-Chung Natl Taiwan Univ Ctr Gen Educ Taipei Taiwan Natl Taiwan Normal Univ Program Learning Sci Taipei Taiwan Natl Taiwan Univ Ctr Teaching & Learning Dev Taipei Taiwan Natl Taiwan Normal Univ Inst Res Excellence Learning Sci Taipei Taiwan

The flipped classroom has gained a great deal of attention in educational research and practice in recent years. The purposes of this study are to understand the relationship between students' online self-regulated learning (SRL) and their perceptions of learning in a flipped classrooms (FC), to identify possible mediators in this relationship, and to explain how this relationship predicts students' intentions to participate in an FC. Two questionnaires were used to gather data from 576 undergraduate or graduate students in Taiwan. The structural equation model showed that students' in-class interactions and online SRL are predictors of their perceived quality of usefulness of online learning activities and positive experience of FC, and these, in turn, associate with their intentional behaviours of participating in FC. While students' perceived value of interactions in physical classrooms directly related to their intentions to participate in FC, their online SRL predicts their intentions to participate in flipped learning only when mediated by the perceived quality of the usefulness of the online learning activities and positive experience of FC.

关键词： Flipped classroom self-regulated learning structural equation model

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Effects of extrinsic feedback in virtual rehabilitation for children with cerebral palsy: A comprehensive systematic review 1

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4th International Workshop on ICTs for Improving Patients Rehabilitation Research Techniques, REHAB 2016

作者： Jacho-Guanoluisa, Nancy Albiol-Pérez, Sergio Valdivia-Salas, Sonsoles Jariod-Gaudes, Ricardo Collazos, Cesar A. Fardoun, Habib M. Universidad de las Fuerzas Armadas ESPE Sangolquí Ecuador Universidad de Zaragoza Teruel Spain H.U. Miguel Servet Zaragoza Spain Systems Program University of Cauca Popayan Colombia Teaching Excellence Department Ahlia University Bahrain Systems Manama Bahrain

ISBN: (数字)9783030167851

ISBN: (纸本)9783030167844

Children with Cerebral Palsy (CP) have motor and cognitive disorders that make it difficult for them to perform activities of daily living (ADL). Virtual Rehabilitation (VR) is a relatively novel research line that tackles motor and cognitive abilities. Sensory feedback together with Virtual Environments (VE) enriches and improves motor control in children with CP. The use of VR together with intrinsic/extrinsic feedback in intervention periods is a complement of training sessions with clear and relevant outcomes. In this paper, we analyze the effects of extrinsic feedback together with virtual systems in children with CP. An exhaustive literature search was carried out in electronic databases, from 2008 to 2018 to identify studies. The American Academy for Cerebral Palsy and Developmental Medicine (AACPDM) systematic review methodology was used as a frame-work. Outcomes reveal improvements in gait, stride length, walking speed, and stride time by using extrinsic feedback. Future research should be focused on the design and validation of the these system with larger groups of children with CP. © 2019, Springer Nature Switzerland AG.

关键词： Virtual reality

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Antibodies from Sierra Leonean and Nigerian Lassa fever survivors cross-react with recombinant proteins representing Lassa viruses of divergent lineages

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SCIENTIFIC REPORTS 2020年第1期10卷 1-19页

作者： Heinrich, Megan L. Boisen, Matthew L. Nelson, Diana K. S. Bush, Duane J. Cross, Robert W. Koval, Anatoliy P. Hoffmann, Andrew R. Beddingfield, Brandon J. Hastie, Kathryn M. Rowland, Megan M. Aimukanova, Irina Koval, Sophia Lathigra, Raju Borisevich, Viktoriya Momoh, Mambu Sandi, John Demby Goba, Augustine Odia, Ikponmwosa Baimba, Francis Aiyepada, John O. Ebo, Benevolence Eromon, Philomena Ugwu, Chinedu Folarin, Onikepe Olumade, Testimony Onyechi, MacDonald N. Etafo, Johnson Adeyemi, Rashidat Ella, Elijah E. Aminu, Maryam Gomerep, Simji S. Eke, Matthew Afam Ogunsanya, Olusola Akpede, George O. Asogun, Danny O. Okogbenin, Sylvanus A. Okokhere, Peter O. Holst, Johan Shaffer, Jeffrey G. Schieffelin, John S. Geisbert, Thomas W. Saphire, Erica Ollmann Happi, Christian T. Grant, Donald S. Garry, Robert F. Branco, Luis M. Zalgen Labs LCC Germantown MD 20876 USA Univ Texas Med Branch Dept Microbiol & Immunol Galveston TX 77555 USA Galveston Natl Lab Galveston TX USA Tulane Univ Sch Med Dept Microbiol & Immunol 1430 Tulane AveJBJ56870118 New Orleans LA 70112 USA La Jolla Inst Immunol La Jolla CA 92037 USA Univ Texas Med Branch Dept Pathol Galveston TX 77555 USA Eastern Polytech Inst Kenema Sierra Leone Kenema Govt Hosp Viral Hemorrhag Fever Program Kenema Sierra Leone Minist Hlth & Sanitat Freetown Sierra Leone Irrua Specialist Teaching Hosp Inst Lassa Fever Res & Control Irrua Edo State Nigeria Redeemers Univ African Ctr Excellence Genom Infect Dis Ede Osun State Nigeria Redeemers Univ Dept Biol Sci Coll Nat Sci Ede Osun State Nigeria Fed Med Ctr Owo Owo Nigeria Ahmadu Bello Univ Zaria Nigeria Univ Teaching Hosp Jos Nigeria Fed Med Ctr Abakaliki Nigeria Univ Ibadan Ibadan Nigeria Irrua Specialist Teaching Hosp Dept Paediat Irrua Nigeria Ambrose Alli Univ Coll Med Dept Paediat Ekpoma Nigeria Irrua Specialist Teaching Hosp Dept Community Med Irrua Nigeria Irrua Specialist Teaching Hosp Dept Obstet & Gynaecol Irrua Nigeria Irrua Specialist Teaching Hosp Dept Med Irrua Edo State Nigeria Ambrose Alli Univ Fac Clin Sci Dept Med Ekpoma Edo State Nigeria CEPI Coalit Epidem Preparedness Innovat Oslo Norway Tulane Sch Publ Hlth & Trop Med Dept Biostat & Bioinformat New Orleans LA USA Tulane Univ Sch Med Dept Pediat Infect Dis Sect New Orleans LA 70112 USA Tulane Univ Sch Med Dept Internal Med Infect Dis Sect 1430 Tulane Ave New Orleans LA 70112 USA Redeemers Univ Ctr Excellence Genom Infect Dis ACEGID Dept Mol Biol & Genom Ede Osun State Nigeria

Lassa virus (LASV) is the causative agent of Lassa fever, an often-fatal hemorrhagic disease that is endemic in West Africa. Seven genetically distinct LASV lineages have been identified. As part of CEPI's (Coalition for Epidemic Preparedness Innovations) Lassa vaccine development program, we assessed the potential of the human immune system to mount cross-reactive and cross-protective humoral immune responses to antigens from the most prevalent LASV lineages, which are lineages II and III in Nigeria and lineage IV in Sierra Leone. IgG and IgM present in the blood of Lassa fever survivors from Nigeria or Sierra Leone exhibited substantial cross-reactivity for binding to LASV nucleoprotein and two engineered (linked and prefusion) versions of the glycoproteins (GP) of lineages II-IV. There was less cross-reactivity for the Zinc protein. Serum or plasma from Nigerian Lassa fever survivors neutralized LASV pseudoviruses expressing lineage II GP better than they neutralized lineage III or IV GP expressing pseudoviruses. Sierra Leonean survivors did not exhibit a lineage bias. Neutralization titres determined using LASV pseudovirus assays showed significant correlation with titres determined by plaque reduction with infectious LASV. These studies provide guidance for comparison of humoral immunity to LASV of distinct lineages following natural infection or immunization.

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Inhibition of T-cell-mediated immune response via the PD-1/PD-L1 axis in cholangiocarcinoma cells

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EUROPEAN JOURNAL OF PHARMACOLOGY 2021年第0期897卷 173960-173960页

作者： Suriyo, Tawit Fuangthong, Mayuree Artpradit, Charlermchai Ungtrakul, Teerapat Sricharunrat, Thaniya Taha, Fatma Satayavivad, Jutamaad Chulabhorn Res Inst Lab Pharmacol 54 Kamphaeng Phet 6 Rd Laksi Bangkok 10210 Thailand Ctr Excellence Environm Hlth & Toxicol Bangkok 10400 Thailand Chulabhorn Royal Acad Chulabhorn Grad Inst Grad Program Appl Biol Sci Bangkok 10210 Thailand Chulabhorn Res Inst Translat Res Unit Bangkok 10210 Thailand Chulabhorn Royal Acad HRH Princess Chulabhorn Coll Med Sci Fac Med & Publ Hlth Bangkok 10210 Thailand Chulabhorn Royal Acad Chulabhorn Hosp Bangkok 10210 Thailand Chulabhorn Royal Acad Chulabhorn Grad Inst Grad Program Environm Toxicol Bangkok 10210 Thailand El Sahel Teaching Hosp 2 Youssef Karam Cairo Governorate 11697 Egypt

Cholangiocarcinoma (CCA) is a malignant biliary tract epithelium tumor. The programmed death-1 (PD-1)/programmed receptor-ligand 1 (PD-L1) signaling pathway has been implicated as an immune escape mechanism in several cancers. The present study aimed to assess the expression of PD-L1 on human CCA cell lines and its potential role in suppressing CD8(+) T- cell function. A panel of intrahepatic CCA cell lines was evaluated for immune regulatory checkpoint ligands and inflammation markers. Effects of pro-inflammatory cytokine, interferon gamma (IFN-gamma), on the expression of immune regulatory checkpoint ligands and inflammation markers were determined. The PD-L1 function was measured by co-culturing CCA cells with lymphocytes. Most of the selected Thai CCA cell lines, including HuCCA-1, RMCCA-1, KKU-100, and KKU-213, expressed higher PD-L1 than normal cholangiocyte MMNK-1 and ANK-1 cells. Both PD-L1 and cyclooxygenase-2 (COX-2) expressions were highest in HuCCA-1 cells. A 48 h treatment with IFN-gamma increased the expression of PD-L1 and COX-2 in CCA cells. The expression of CTLA-4 ligands, including H7-1 and H7-2, did not change after IFN-gamma treatment. Rofecoxib, a specific COX-2 inhibitor, mitigated IFN-gamma-induced PD-L1 expression. After 48 h co-incubation, CD8(+) T-cell apoptosis was increased as compared to the control group. Pretreatment of CCA cells with IFN-gamma further increased CD8(+) T-cell apoptosis. Pembrolizumab, an anti-PD-1 antibody, mitigated CCA cell escape phenomenon. The inhibition of T-cell-mediated immune response via the PD-Ll/PD-1 axis are evidenced in intrahepatic CCA. Immunotherapy with checkpoint inhibitor offers a potentially therapeutic strategy for CCA patients;however, further in vivo and clinical studies are required.

关键词： Cholangiocarcinoma Immune checkpoint PD-L1 PD-1 COX-2 Pembrolizumab

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Sustainability practices at higher education institutions in Asia

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INTERNATIONAL JOURNAL OF SUSTAINABILITY IN HIGHER EDUCATION 2022年第6期23卷 1250-1276页

作者： Leal Filho, Walter Dinis, Maria Alzira Pimenta Sivapalan, Subarna Begum, Halima Ng, Theam Foo Al-Amin, Abul Quasem Alam, Gazi Mahabubul Sharifi, Ayyoob Salvia, Amanda Lange Kalsoom, Qudsia Saroar, Mustafa Neiva, Samara Hamburg Univ Appl Sci Sch Sustainabil Sci & Res ESSSR Hamburg Germany Manchester Metropolitan Univ Sch Sci & Environm Manchester Lancs England Univ Fernando Pessoa UFP UFP Energy Environm & Hlth Res Unit FP ENAS Porto Portugal Univ Teknol Petronas Ctr Excellence Teaching & Learning Ctr Social Innovat Tronoh Malaysia Univ Utara Malaysia Sch Econ Finance & Banking SEFB Sintok Kedah Malaysia Univ Sains Malaysia Ctr Global Sustainabil Studies CGSS George Town Malaysia Univ Waterloo Fac Environm Dept Geog & Environm Management Waterloo ON Canada Univ Ave West Ctr Asian Climate & Environm Policy Studies Windsor ON Canada Univ Putra Malaysia Dept Fdn Educ Fac Educ Studies Serdang Malaysia Hiroshima Univ Grad Sch Humanities & Social Sci Network Educ & Res Peace & Sustainabil Higashihiroshima Japan Univ Passo Fundo FEAR Passo Fundo RS Brazil Beaconhouse Natl Univ Dept Educ Leadership & Management Lahore Pakistan Khulna Univ Engn & Technol Fac Civil Engn Dept Urban & Reg Planning Khulna Bangladesh Univ Fed Santa Catarina Univ Management Grad Program Florianopolis SC Brazil

Purpose It is still unclear how Asian universities incorporate the theory or practice of sustainable development (SD) in their research and education programmes. To address this gap, the purpose of this paper is to report on a study that has examined how universities in Asian countries handle and address matters related to SD. Design/methodology/approach The study used a bibliometric analysis and an online survey-method. The online survey data were analysed through descriptive analysis and one-sample student's t-test. Findings The study indicates that there is considerable variation among the Asian countries regarding sustainability practices in higher education institutions (HEIs). The HEIs in far eastern countries, such as Indonesia, Malaysia and Thailand are perceived to demonstrate more sustainability practices. Research limitations/implications Even though a substantial number of participants participated in the survey, it did not cover all Asian countries. The online survey was carried out over a limited period of time, and not all HEIs in the field may have received information about the study. Practical implications Asia is the largest continent facing a number of sustainability challenges. In this context, the contribution of HEIs is very important. The findings of the current study may serve as a baseline for Asian HEIs to take more initiatives towards SD goals, as HEIs are responsible for the education and training of hundreds of thousands of students who will be occupying key positions in industry, government or education in the coming years. Originality/value The study contributes to the existing literature in two distinct ways. First, it was possible to develop a comprehensive instrument to measure sustainability practices in HEIs. Second, this study has filled the gap of the scarcity of studies regarding sustainability practices in HEIs in Asia.

关键词： Sustainability Higher education institutions Drivers Challenges Education for sustainable development

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Do subjects from high and low context cultures attribute different meanings to tourism services with 9-ending prices?

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TOURISM MANAGEMENT 2018年 64卷 110-118页

作者： Jeong, Ji Youn Crompton, John L. Texas A&M Univ Doctoral Program College Stn TX 77843 USA Texas A&M Univ Teaching Excellence College Stn TX 77843 USA

Four symbolic meanings have been associated with 9-ending prices: Discount price, enhanced value, low quality, and misleading action. Scales were developed to measure each meaning and the relative strength of these meanings in influencing tourists' purchases among samples from the U.S., Korea and China was investigated. The analyses found no differences in the likelihood of tourists selecting 9-ending rather than even-ending prices when purchasing a sandwich, a pizza or show tickets;in their relative importance across cultures;or in the influence on purchase decisions of different symbolic meanings associated with 9-endings. However, a 9-ending discount was perceived to be more effective when compared to even-ended price discounts in the context of a hotel room. Again, however, its effectiveness could not be explained by the different symbolic meanings associated with 9-ending prices. (C) 2017 Elsevier Ltd. All rights reserved.

关键词： 9-Ehding prices Symbolic meanings High and low context cultures

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The genetic dissection of fetal haemoglobin persistence in sickle cell disease in Nigeria

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HUMAN MOLECULAR GENETICS 2024年第10期33卷 919-929页

作者： Ojewunmi, Oyesola O. Adeyemo, Titilope A. Oyetunji, Ajoke, I Inyang, Bassey Akinrindoye, Afolashade Mkumbe, Baraka S. Gardner, Kate Rooks, Helen Brewin, John Patel, Hamel Lee, Sang Hyuck Chung, Raymond Rashkin, Sara Kang, Guolian Chianumba, Reuben Sangeda, Raphael Mwita, Liberata Isa, Hezekiah Agumadu, Uche-Nnebe Ekong, Rosemary Faruk, Jamilu A. Jamoh, Bello Y. Adebiyi, Niyi M. Umar, Ismail A. Hassan, Abdulaziz Grace, Christopher Goel, Anuj Inusa, Baba P. D. Falchi, Mario Nkya, Siana Makani, Julie Ahmad, Hafsat R. Nnodu, Obiageli Strouboulis, John Menzel, Stephan Kings Coll London Sch Canc & Pharmaceut Sci 123 Coldharbour Lane London SE5 9NU England London Sch Hyg & Trop Med Dept Noncommunicable Dis Epidemiol Keppel St London WC1E 7HT England Univ Lagos Coll Med Dept Haematol & Blood Transfus PMB 12003 Lagos Nigeria Sickle Cell Fdn Nigeria Ishaga RdPOB 3463 Lagos Nigeria Univ Abuja Dept Vet Physiol & Biochem Mohammed Maccido RdAirport RdPMB 117 Abuja Nigeria Univ Greenwich Sch Sci Cent Ave Chatham ME4 4TB Kent England Muhimbili Univ Hlth & Allied Sci Dept Biochem & Mol Biol POB 65001United Nations Rd Dar Es Salaam Tanzania Tohoku Univ Grad Sch Med Dept Artificial Intelligence & Innovat Med 2-1 Seiryo MachiAoba Ku Sendai Miyagi 9808573 Japan Guys Hosp Haematol & Oncol Directorate Clin Haematol London SE1 9RT England Kings Coll Hosp London Dept Haematol Med London SE5 9RS England South London & Maudsley NHS Fdn Trust SLaM NIHR BioResource Ctr Maudsley NIHR Maudsley Biomed Res Ctr BRC London England Inst Psychiat Psychol & Neurosci IoPPN Kings Coll London London England St Jude Childrens Res Hosp 262 Danny Thomas Pl Memphis TN 38105 USA Univ Abuja Ctr Excellence Sickle Cell Dis Res & Training CESR Mohammed Maccido RdAirport RdPMB 117 Abuja Nigeria Muhimbili Univ Hlth & Allied Sci Dept Pharmaceut Microbiol POB 65001 Dar Es Salaam Tanzania Univ Abuja Teaching Hosp PMB 228 Gwagwalada Fct Abuja Nigeria Univ Abuja Coll Hlth Sci Dept Paediat Mohammed Maccido RdAirport RdPMB 117 Abuja Nigeria UCL Res Dept Genet Evolut & Environm Gower St London WC1E 6BT England Ahmadu Bello Univ Teaching Hosp Dept Paediat PMB 006 Zaria Nigeria Ahmadu Bello Univ Teaching Hosp Dept Internal Med PMB 006 Zaria Nigeria Ahmadu Bello Univ Fac Life Sci Dept Biochem Sokoto RdPMB 006 Samaru Zaria Nigeria Ahmadu Bello Univ Dept Haematol & Blood Transfus Sokoto RdPMB 006 Samaru Zaria Nigeria Univ Oxford Ctr Human Genet Radcliffe Dept Med Div Cardiovasc Med Roosevelt Dr Oxford OX37BN England Guys & St

The clinical severity of sickle cell disease (SCD) is strongly influenced by the level of fetal haemoglobin (HbF) persistent in each patient. Three major HbF loci (BCL11A, HBS1L-MYB, and Xmn1-HBG2) have been reported, but a considerable hidden heritability remains. We conducted a genome-wide association study for HbF levels in 1006 Nigerian patients with SCD (HbSS/HbS beta 0), followed by a replication and meta-analysis exercise in four independent SCD cohorts (3,582 patients). To dissect association signals at the major loci, we performed stepwise conditional and haplotype association analyses and included public functional annotation datasets. Association signals were detected for BCL11A (lead SNP rs6706648, beta = -0.39, P = 4.96 x 10(-34)) and HBS1L-MYB (lead SNP rs61028892, beta = 0.73, P = 1.18 x 10(-9)), whereas the variant allele for Xmn1-HBG2 was found to be very rare. In addition, we detected three putative new trait-associated regions. Genetically, dissecting the two major loci BCL11A and HBS1L-MYB, we defined trait-increasing haplotypes (P < 0.0001) containing so far unidentified causal variants. At BCL11A, in addition to a haplotype harbouring the putative functional variant rs1427407-'T', we identified a second haplotype, tagged by the rs7565301-'A' allele, where a yet-to-be-discovered causal DNA variant may reside. Similarly, at HBS1L-MYB, one HbF-increasing haplotype contains the likely functional small indel rs66650371, and a second tagged by rs61028892-'C' is likely to harbour a presently unknown functional allele. Together, variants at BCL11A and HBS1L-MYB SNPs explained 24.1% of the trait variance. Our findings provide a path for further investigation of the causes of variable fetal haemoglobin persistence in sickle cell disease. [Graphical abstract]

关键词： fetal haemoglobin sickle cell disease genome-wide association study heritability haplotype analysis

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