Displaying publications 1 - 20 of 29 in total

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  1. Weaver SC, Reisen WK
    Antiviral Res, 2010 Feb;85(2):328-45.
    PMID: 19857523 DOI: 10.1016/j.antiviral.2009.10.008
    Arthropod-borne viruses (arboviruses) are important causes of human disease nearly worldwide. All arboviruses circulate among wild animals, and many cause disease after spillover transmission to humans and agriculturally important domestic animals that are incidental or dead-end hosts. Viruses such as dengue (DENV) and chikungunya (CHIKV) that have lost the requirement for enzootic amplification now produce extensive epidemics in tropical urban centers. Many arboviruses recently have increased in importance as human and veterinary pathogens using a variety of mechanisms. Beginning in 1999, West Nile virus (WNV) underwent a dramatic geographic expansion into the Americas. High amplification associated with avian virulence coupled with adaptation for replication at higher temperatures in mosquito vectors, has caused the largest epidemic of arboviral encephalitis ever reported in the Americas. Japanese encephalitis virus (JEV), the most frequent arboviral cause of encephalitis worldwide, has spread throughout most of Asia and as far south as Australia from its putative origin in Indonesia and Malaysia. JEV has caused major epidemics as it invaded new areas, often enabled by rice culture and amplification in domesticated swine. Rift Valley fever virus (RVFV), another arbovirus that infects humans after amplification in domesticated animals, undergoes epizootic transmission during wet years following droughts. Warming of the Indian Ocean, linked to the El Niño-Southern Oscillation in the Pacific, leads to heavy rainfall in east Africa inundating surface pools and vertically infected mosquito eggs laid during previous seasons. Like WNV, JEV and RVFV could become epizootic and epidemic in the Americas if introduced unintentionally via commerce or intentionally for nefarious purposes. Climate warming also could facilitate the expansion of the distributions of many arboviruses, as documented for bluetongue viruses (BTV), major pathogens of ruminants. BTV, especially BTV-8, invaded Europe after climate warming and enabled the major midge vector to expand is distribution northward into southern Europe, extending the transmission season and vectorial capacity of local midge species. Perhaps the greatest health risk of arboviral emergence comes from extensive tropical urbanization and the colonization of this expanding habitat by the highly anthropophilic (attracted to humans) mosquito, Aedes aegypti. These factors led to the emergence of permanent endemic cycles of urban DENV and CHIKV, as well as seasonal interhuman transmission of yellow fever virus. The recent invasion into the Americas, Europe and Africa by Aedes albopictus, an important CHIKV and secondary DENV vector, could enhance urban transmission of these viruses in tropical as well as temperate regions. The minimal requirements for sustained endemic arbovirus transmission, adequate human viremia and vector competence of Ae. aegypti and/or Ae. albopictus, may be met by two other viruses with the potential to become major human pathogens: Venezuelan equine encephalitis virus, already an important cause of neurological disease in humans and equids throughout the Americas, and Mayaro virus, a close relative of CHIKV that produces a comparably debilitating arthralgic disease in South America. Further research is needed to understand the potential of these and other arboviruses to emerge in the future, invade new geographic areas, and become important public and veterinary health problems.
  2. Bray RA, Palm HW, Cutmore SC, Cribb TH
    Syst Parasitol, 2017 05;94(4):443-462.
    PMID: 28337682 DOI: 10.1007/s11230-017-9717-5
    Three species of Opisthomonorcheides Parukhin, 1966 are reported for the first time from Indonesian waters: O. pampi (Wang, 1982) Liu, Peng, Gao, Fu, Wu, Lu, Gao & Xiao, 2010 and O. ovacutus (Mamaev, 1970) Machida, 2011 from Parastromateus niger (Bloch), and O. decapteri Parukhin, 1966 from Atule mate (Cuvier). Both O. pampi and O. ovacutus can now be considered widespread in the Indo-Pacific region, with earlier records of these species being from Fujian Province, China and Penang, Malaysia, respectively. We redescribe O. decapteri from one of its original hosts, Atule mate, off New Caledonia, and report this species from Jakarta Bay, Indonesia, extending its range throughout the Indian Ocean into the south-western Pacific. All three species possess a genital atrium that is long, sometimes very long, and a genital pore that is located in the forebody. This validates the interpretation that the original description was erroneous in reporting the genital pore in the hindbody, well posterior to the ventral sucker. These observations verify the synonymy of Retractomonorchis Madhavi, 1977 with Opisthomonorcheides. A major discrepancy between the species of Opisthomonorcheides is that some are described with the uterus entering the terminal organ laterally and some with it entering terminally; this feature needs further analysis. Based on the length of the genital atrium and the posterior extent of the vitellarium, the 27 species of Opisthomonorcheides considered valid can be divided into four groups. Among the 53 host records analysed, the families Carangidae (53% of records), Stromateidae (17%) and Serranidae (5.7%) are the most common; the reports are overwhelmingly from members of the Perciformes (91%), with further records in the Clupeiformes (5.7%), Gadiformes (1.9%) and Pleuronectiformes (1.9%). Two fish genera (Parastromateus Bleeker and Pampus Bonaparte) dominate the recorded hosts, with the black pomfret Parastromateus niger harbouring six species, the silver pomfret Pampus argenteus (Euphrasen) harbouring six, and the Chinese silver pomfret P. chinensis (Euphrasen) two. A host-parasite checklist is presented. We discuss the host-specificity of members of the genus, questioning some records such as that of O. decapteri in a deep-sea macrourid. We also comment on the morphological similarity, but phylogenetic distance, between the various Pomfret species, advancing the possibility that a series of host misidentifications has occurred. Sequences of the ITS2 rDNA gene generated for O. pampi and O. ovacutus are briefly discussed and molecular data are lodged in the GenBank database.
  3. Foster HE, Scott C, Tiderius CJ, Dobbs MB
    Pediatr Rheumatol Online J, 2020 Jul 14;18(1):60.
    PMID: 32664961 DOI: 10.1186/s12969-020-00451-8
    There is increasing concern about the emerging global non-communicable diseases (NCDs) burden. The focus has mainly been on NCDs in adults but it is important that MSK morbidity in both children and adults is included in strategic planning. There have been considerable advances in the understanding and treatment options for children and young people (CYP) and clinical outcomes are improving for those who can access such high quality care. However vast inequity exists and there are many CYP who live in areas of the world with high burden of health care challenges, compounded by paucity of specialist care and limited access to treatments. The Paediatric Global Musculoskeletal Task Force aims to raise awareness about unmet needs for CYP with MSK conditions, promotion of MSK health through lifestyle and the avoidance of injury. We aim to leverage change through 'working together better'.
  4. Moo EK, Han SK, Federico S, Sibole SC, Jinha A, Abu Osman NA, et al.
    J Biomech, 2014 Mar 21;47(5):1004-13.
    PMID: 24480705 DOI: 10.1016/j.jbiomech.2014.01.003
    Cartilage lesions change the microenvironment of cells and may accelerate cartilage degradation through catabolic responses from chondrocytes. In this study, we investigated the effects of structural integrity of the extracellular matrix (ECM) on chondrocytes by comparing the mechanics of cells surrounded by an intact ECM with cells close to a cartilage lesion using experimental and numerical methods. Experimentally, 15% nominal compression was applied to bovine cartilage tissues using a light-transmissible compression system. Target cells in the intact ECM and near lesions were imaged by dual-photon microscopy. Changes in cell morphology (N(cell)=32 for both ECM conditions) were quantified. A two-scale (tissue level and cell level) Finite Element (FE) model was also developed. A 15% nominal compression was applied to a non-linear, biphasic tissue model with the corresponding cell level models studied at different radial locations from the centre of the sample in the transient phase and at steady state. We studied the Green-Lagrange strains in the tissue and cells. Experimental and theoretical results indicated that cells near lesions deform less axially than chondrocytes in the intact ECM at steady state. However, cells near lesions experienced large tensile strains in the principal height direction, which are likely associated with non-uniform tissue radial bulging. Previous experiments showed that tensile strains of high magnitude cause an up-regulation of digestive enzyme gene expressions. Therefore, we propose that cartilage degradation near tissue lesions may be due to the large tensile strains in the principal height direction applied to cells, thus leading to an up-regulation of catabolic factors.
  5. Zemla A, Kostova T, Gorchakov R, Volkova E, Beasley DW, Cardosa J, et al.
    Bioinform Biol Insights, 2014 Jan 8;8:1-16.
    PMID: 24453480 DOI: 10.4137/BBI.S13076
    A computational approach for identification and assessment of genomic sequence variability (GeneSV) is described. For a given nucleotide sequence, GeneSV collects information about the permissible nucleotide variability (changes that potentially preserve function) observed in corresponding regions in genomic sequences, and combines it with conservation/variability results from protein sequence and structure-based analyses of evaluated protein coding regions. GeneSV was used to predict effects (functional vs. non-functional) of 37 amino acid substitutions on the NS5 polymerase (RdRp) of dengue virus type 2 (DENV-2), 36 of which are not observed in any publicly available DENV-2 sequence. 32 novel mutants with single amino acid substitutions in the RdRp were generated using a DENV-2 reverse genetics system. In 81% (26 of 32) of predictions tested, GeneSV correctly predicted viability of introduced mutations. In 4 of 5 (80%) mutants with double amino acid substitutions proximal in structure to one another GeneSV was also correct in its predictions. Predictive capabilities of the developed system were illustrated on dengue RNA virus, but described in the manuscript a general approach to characterize real or theoretically possible variations in genomic and protein sequences can be applied to any organism.
  6. Haddow AD, Schuh AJ, Yasuda CY, Kasper MR, Heang V, Huy R, et al.
    PLoS Negl Trop Dis, 2012;6(2):e1477.
    PMID: 22389730 DOI: 10.1371/journal.pntd.0001477
    Zika virus (ZIKV) is a mosquito-borne flavivirus distributed throughout much of Africa and Asia. Infection with the virus may cause acute febrile illness that clinically resembles dengue fever. A recent study indicated the existence of three geographically distinct viral lineages; however this analysis utilized only a single viral gene. Although ZIKV has been known to circulate in both Africa and Asia since at least the 1950s, little is known about the genetic relationships between geographically distinct virus strains. Moreover, the geographic origin of the strains responsible for the epidemic that occurred on Yap Island, Federated States of Micronesia in 2007, and a 2010 pediatric case in Cambodia, has not been determined.
  7. Lazarus JV, Wyka K, White TM, Picchio CA, Gostin LO, Larson HJ, et al.
    Nat Med, 2023 Feb;29(2):366-375.
    PMID: 36624316 DOI: 10.1038/s41591-022-02185-4
    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continued to mutate and spread in 2022 despite the introduction of safe, effective vaccines and medications. Vaccine hesitancy remains substantial, fueled in part by misinformation. Our third study of Coronavirus Disease 2019 (COVID-19) vaccine hesitancy among 23,000 respondents in 23 countries (Brazil, Canada, China, Ecuador, France, Germany, Ghana, India, Italy, Kenya, Mexico, Nigeria, Peru, Poland, Russia, Singapore, South Africa, South Korea, Spain, Sweden, Turkey, the United Kingdom and the United States), surveyed from 29 June to 10 July 2022, found willingness to accept vaccination at 79.1%, up 5.2% from June 2021. Hesitancy increased in eight countries, however, ranging from 1.0% (United Kingdom) to 21.1% (South Africa). Almost one in eight (12.1%) vaccinated respondents are hesitant about booster doses. Overall support for vaccinating children under 18 years of age increased slightly but declined among parents who were personally hesitant. Almost two in five (38.6%) respondents reported paying less attention to new COVID-19 information than previously, and support for vaccination mandates decreased. Almost a quarter (24%) of those who became ill reported taking medications to combat COVID-19 symptoms. Vaccination remains a cornerstone of the COVID-19 pandemic response, but broad public support remains elusive. These data can be used by health system decisionmakers, practitioners, advocates and researchers to address COVID-19 vaccine hesitancy more effectively.
  8. Wang HY, Yang H, Holm M, Tom H, Oltion K, Al-Khdhairawi AAQ, et al.
    Nat Chem, 2022 Dec;14(12):1443-1450.
    PMID: 36123449 DOI: 10.1038/s41557-022-01039-3
    Ternatin-family cyclic peptides inhibit protein synthesis by targeting the eukaryotic elongation factor-1α. A potentially related cytotoxic natural product ('A3') was isolated from Aspergillus, but only 4 of its 11 stereocentres could be assigned. Here, we synthesized SR-A3 and SS-A3-two out of 128 possible A3 epimers-and discovered that synthetic SR-A3 is indistinguishable from naturally derived A3. Relative to SS-A3, SR-A3 exhibits an enhanced residence time and rebinding kinetics, as revealed by single-molecule fluorescence imaging of elongation reactions catalysed by eukaryotic elongation factor-1α in vitro. An increased residence time-stereospecifically conferred by the unique β-hydroxyl in SR-A3-was also observed in cells. Consistent with its prolonged duration of action, thrice-weekly dosing with SR-A3 led to a reduced tumour burden and increased survival in an aggressive Myc-driven mouse lymphoma model. Our results demonstrate the potential of SR-A3 as a cancer therapeutic and exemplify an evolutionary mechanism for enhancing cyclic peptide binding kinetics via stereospecific side-chain hydroxylation.
  9. Raymond AA, Gilmore WV, Scott CA, Fish DR, Smith SJ
    Epileptic Disord, 1999 Jun;1(2):101-6.
    PMID: 10937139
    Video-EEG telemetry is often used to support the diagnosis of non-epileptic seizures (NES). Although rare, some patients may have both epileptic seizures (ES) and NES. It is crucially important to identify such patients to avoid the hazards of inappropriate anticonvulsant withdrawal. To delineate the electroclinical characteristics and diagnostic problems in this group of patients, we studied the clinical, EEG and MRI features of 14 consecutive patients in whom separate attacks, considered to be both NES and ES were recorded using video-EEG telemetry. Only two patients were drug-reduced during the telemetry. Most patients had their first seizure (ES or NES) in childhood (median age 7 years; range: 6 months-24 years); 8/14 patients were female. Brain MRI was abnormal in 10/14 patients. Interictal EEG abnormalities were present in all patients; 13/14 had epileptiform and 1/14 only background abnormalities. Over 70 seizures were recorded in these 14 patients: in 12/14 patients, the first recorded seizure was a NES (p < 0.001), and 7 of these patients had at least one more NES before an ES was recorded. Only 3/14 patients had more than 5 NES before an ES was recorded. Recording a small number of apparently NES in an individual by no means precludes the possibility of additional epilepsy. Particular care should be taken, and multiple (> 5) seizure recording may be advisable, in patients with a young age of seizure onset, interictal EEG abnormalities, or a clear, potential aetiology for epilepsy.
  10. Foster HE, Scott C, Tiderius CJ, Dobbs MB, Members of the Paediatric Global Musculoskeletal Task Force
    Best Pract Res Clin Rheumatol, 2020 Oct;34(5):101566.
    PMID: 32727697 DOI: 10.1016/j.berh.2020.101566
    This chapter describes the musculoskeletal (MSK) context in children and young people as an important contributor to the global non-communicable disease burden. Through selected MSK conditions, we describe the impact on patients, families and communities and highlight the challenges that need to be addressed. We focus on opportunities for better working together and describe exemplar initiatives to raise awareness, workforce capacity building, models of care and research agendas to have a greater global context.
  11. Mackenzie SC, Dickson J, Mehar S, Yusof BNM, Alselmi A, Aksi B, et al.
    Prim Care Diabetes, 2024 Mar 15.
    PMID: 38493066 DOI: 10.1016/j.pcd.2024.03.002
    AIMS: Ramadan-focused diabetes education is critical to facilitate safer Ramadan fasting amongst Muslim people living with diabetes. We present the design, delivery, and evaluation of two parallel massive open online courses (MOOCs) in Ramadan-focused diabetes education for people with diabetes and HCPs.

    METHODS: Two Ramadan-focused diabetes education MOOCs were developed and delivered for Ramadan 2023: one for HCPs in English, and another for people with diabetes in English, Arabic and Malay. A user-centred iterative design process was adopted, informed by user feedback from a 2022 pilot MOOC. Evaluation comprised a mixed-methods evaluation of pre- and post-course user surveys.

    RESULTS: The platform was utilised by people with diabetes and their family, friends and healthcare professionals. Overall, a total of 1531 users registered for the platform from 50 countries, 809 started a course with a 48% subsequent completion rate among course starters. Qualitative analysis showed users found the course a user-friendly and authoritative information source. In the HCP MOOC, users reported improved post-MOOC Ramadan awareness, associated diabetes knowledge and ability to assess and advise patients in relation to their diabetes during Ramadan (p<0.01).

    CONCLUSIONS: We demonstrate the potential of MOOCs to deliver culturally tailored, high-quality, scalable, multilingual Ramadan-focused diabetes education to HCPs and people with diabetes.

  12. Tangcheewinsirikul S, Tang SP, Smith N, Sukharomana M, Charuvanij S, Vilaiyuk S, et al.
    Pediatr Rheumatol Online J, 2021 Jan 23;19(1):11.
    PMID: 33485337 DOI: 10.1186/s12969-021-00498-1
    BACKGROUND: Paediatric rheumatic diseases are a leading cause of acquired disability in Southeast Asia and Asia-Pacific Countries (SE ASIA/ASIAPAC). The aims of this study were to identify and describe the challenges to the delivery of patient care and identify solutions to raise awareness about paediatric rheumatic diseases.

    METHODS: The anonymised online survey included 27 items about paediatric rheumatology (PR) clinical care and training programmes. The survey was piloted and then distributed via Survey-Monkey™ between March and July 2019. It was sent to existing group lists of physicians and allied health professionals (AHPs), who were involved in the care pathways and management of children with rheumatic diseases in SE ASIA/ASIAPAC.

    RESULTS: Of 340 participants from 14 countries, 261 participants had been involved in PR care. The majority of the participants were general paediatricians. The main reported barriers to providing specialised multidisciplinary service were the absence or inadequacy of the provision of specialists and AHPs in addition to financial issues. Access to medicines was variable and financial constraints cited as the major obstacle to accessing biological drugs within clinical settings. The lack of a critical mass of specialist paediatric rheumatologists was the main perceived barrier to PR training.

    CONCLUSIONS: There are multiple challenges to PR services in SE ASIA/ASIAPAC countries. There is need for more specialist multidisciplinary services and greater access to medicines and biological therapies. The lack of specialist paediatric rheumatologists is the main barrier for greater access to PR training.

  13. Smith EMD, Ainsworth S, Beresford MW, Buys V, Costello W, Egert Y, et al.
    Pediatr Rheumatol Online J, 2020 Sep 11;18(1):71.
    PMID: 32917217 DOI: 10.1186/s12969-020-00465-2
    There is a lack of awareness of paediatric rheumatic diseases (PRDs), among the public, and certain groups of healthcare professionals (HCPs), including general practitioners. To help improve international awareness and understanding of PRDs, World yOung Rheumatic Diseases (WORD) Day was established on 18 March 2019. Its aim was to raise awareness of PRDs and the importance of timely referral plus early diagnosis and access to appropriate treatment and support. A steering committee was established, and an external agency provided digital support. A social media campaign was launched in December 2018 to promote it, and analytics were used to measure its impact. Face-to-face and virtual events took place globally on or around WORD Day 2019, with 34 countries reporting events. Examples included lectures, social gatherings and media appearances. A total of 2585 and 660 individuals followed the official Facebook and Twitter accounts respectively, up until WORD Day. The official #WORDDay2019 hashtag was seen by 533,955 unique accounts on 18 March 2019 alone, with 3.3 million impressions. WORD Day 2019 was the first international campaign focused solely on PRDs. It demonstrated that despite awareness events being often resource-light, they can be implemented across a range of diverse settings. WORD Day has now become an annual global awareness event, facilitated by a growing network of patient, parent and professional community supporters.
  14. Burton A, Byrnes G, Stone J, Tamimi RM, Heine J, Vachon C, et al.
    Breast Cancer Res, 2016 12 19;18(1):130.
    PMID: 27993168
    BACKGROUND: Inter-women and intra-women comparisons of mammographic density (MD) are needed in research, clinical and screening applications; however, MD measurements are influenced by mammography modality (screen film/digital) and digital image format (raw/processed). We aimed to examine differences in MD assessed on these image types.

    METHODS: We obtained 1294 pairs of images saved in both raw and processed formats from Hologic and General Electric (GE) direct digital systems and a Fuji computed radiography (CR) system, and 128 screen-film and processed CR-digital pairs from consecutive screening rounds. Four readers performed Cumulus-based MD measurements (n = 3441), with each image pair read by the same reader. Multi-level models of square-root percent MD were fitted, with a random intercept for woman, to estimate processed-raw MD differences.

    RESULTS: Breast area did not differ in processed images compared with that in raw images, but the percent MD was higher, due to a larger dense area (median 28.5 and 25.4 cm2 respectively, mean √dense area difference 0.44 cm (95% CI: 0.36, 0.52)). This difference in √dense area was significant for direct digital systems (Hologic 0.50 cm (95% CI: 0.39, 0.61), GE 0.56 cm (95% CI: 0.42, 0.69)) but not for Fuji CR (0.06 cm (95% CI: -0.10, 0.23)). Additionally, within each system, reader-specific differences varied in magnitude and direction (p 

  15. McCormack VA, Burton A, dos-Santos-Silva I, Hipwell JH, Dickens C, Salem D, et al.
    Cancer Epidemiol, 2016 Feb;40:141-51.
    PMID: 26724463 DOI: 10.1016/j.canep.2015.11.015
    Mammographic density (MD) is a quantitative trait, measurable in all women, and is among the strongest markers of breast cancer risk. The population-based epidemiology of MD has revealed genetic, lifestyle and societal/environmental determinants, but studies have largely been conducted in women with similar westernized lifestyles living in countries with high breast cancer incidence rates. To benefit from the heterogeneity in risk factors and their combinations worldwide, we created an International Consortium on Mammographic Density (ICMD) to pool individual-level epidemiological and MD data from general population studies worldwide. ICMD aims to characterize determinants of MD more precisely, and to evaluate whether they are consistent across populations worldwide. We included 11755 women, from 27 studies in 22 countries, on whom individual-level risk factor data were pooled and original mammographic images were re-read for ICMD to obtain standardized comparable MD data. In the present article, we present (i) the rationale for this consortium; (ii) characteristics of the studies and women included; and (iii) study methodology to obtain comparable MD data from original re-read films. We also highlight the risk factor heterogeneity captured by such an effort and, thus, the unique insight the pooled study promises to offer through wider exposure ranges, different confounding structures and enhanced power for sub-group analyses.
  16. Burton A, Maskarinec G, Perez-Gomez B, Vachon C, Miao H, Lajous M, et al.
    PLoS Med, 2017 Jun;14(6):e1002335.
    PMID: 28666001 DOI: 10.1371/journal.pmed.1002335
    BACKGROUND: Mammographic density (MD) is one of the strongest breast cancer risk factors. Its age-related characteristics have been studied in women in western countries, but whether these associations apply to women worldwide is not known.

    METHODS AND FINDINGS: We examined cross-sectional differences in MD by age and menopausal status in over 11,000 breast-cancer-free women aged 35-85 years, from 40 ethnicity- and location-specific population groups across 22 countries in the International Consortium on Mammographic Density (ICMD). MD was read centrally using a quantitative method (Cumulus) and its square-root metrics were analysed using meta-analysis of group-level estimates and linear regression models of pooled data, adjusted for body mass index, reproductive factors, mammogram view, image type, and reader. In all, 4,534 women were premenopausal, and 6,481 postmenopausal, at the time of mammography. A large age-adjusted difference in percent MD (PD) between post- and premenopausal women was apparent (-0.46 cm [95% CI: -0.53, -0.39]) and appeared greater in women with lower breast cancer risk profiles; variation across population groups due to heterogeneity (I2) was 16.5%. Among premenopausal women, the √PD difference per 10-year increase in age was -0.24 cm (95% CI: -0.34, -0.14; I2 = 30%), reflecting a compositional change (lower dense area and higher non-dense area, with no difference in breast area). In postmenopausal women, the corresponding difference in √PD (-0.38 cm [95% CI: -0.44, -0.33]; I2 = 30%) was additionally driven by increasing breast area. The study is limited by different mammography systems and its cross-sectional rather than longitudinal nature.

    CONCLUSIONS: Declines in MD with increasing age are present premenopausally, continue postmenopausally, and are most pronounced over the menopausal transition. These effects were highly consistent across diverse groups of women worldwide, suggesting that they result from an intrinsic biological, likely hormonal, mechanism common to women. If cumulative breast density is a key determinant of breast cancer risk, younger ages may be the more critical periods for lifestyle modifications aimed at breast density and breast cancer risk reduction.

  17. Chalhoub NE, Wenderfer SE, Levy DM, Rouster-Stevens K, Aggarwal A, Savani SI, et al.
    Arthritis Rheumatol, 2022 Feb;74(2):263-273.
    PMID: 34279063 DOI: 10.1002/art.41930
    OBJECTIVE: To develop a standardized steroid dosing regimen (SSR) for physicians treating childhood-onset systemic lupus erythematosus (SLE) complicated by lupus nephritis (LN), using consensus formation methodology.

    METHODS: Parameters influencing corticosteroid (CS) dosing were identified (step 1). Data from children with proliferative LN were used to generate patient profiles (step 2). Physicians rated changes in renal and extrarenal childhood-onset SLE activity between 2 consecutive visits and proposed CS dosing (step 3). The SSR was developed using patient profile ratings (step 4), with refinements achieved in a physician focus group (step 5). A second type of patient profile describing the course of childhood-onset SLE for ≥4 months since kidney biopsy was rated to validate the SSR-recommended oral and intravenous (IV) CS dosages (step 6). Patient profile adjudication was based on majority ratings for both renal and extrarenal disease courses, and consensus level was set at 80%.

    RESULTS: Degree of proteinuria, estimated glomerular filtration rate, changes in renal and extrarenal disease activity, and time since kidney biopsy influenced CS dosing (steps 1 and 2). Considering these parameters in 5,056 patient profile ratings from 103 raters, and renal and extrarenal course definitions, CS dosing rules of the SSR were developed (steps 3-5). Validation of the SSR for up to 6 months post-kidney biopsy was achieved with 1,838 patient profile ratings from 60 raters who achieved consensus for oral and IV CS dosage in accordance with the SSR (step 6).

    CONCLUSION: The SSR represents an international consensus on CS dosing for use in patients with childhood-onset SLE and proliferative LN. The SSR is anticipated to be used for clinical care and to standardize CS dosage during clinical trials.

  18. Kramer I, Hooning MJ, Mavaddat N, Hauptmann M, Keeman R, Steyerberg EW, et al.
    Am J Hum Genet, 2020 11 05;107(5):837-848.
    PMID: 33022221 DOI: 10.1016/j.ajhg.2020.09.001
    Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.
  19. Dörk T, Peterlongo P, Mannermaa A, Bolla MK, Wang Q, Dennis J, et al.
    Sci Rep, 2019 08 29;9(1):12524.
    PMID: 31467304 DOI: 10.1038/s41598-019-48804-y
    Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44-1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.
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