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Fulltext International Consensus for the Dosing of Corticosteroids in Childhood-Onset Systemic Lupus Erythematosus With Proliferative Lupus Nephritis

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.
Fulltext Utilization of a Mixture Cure Rate Model based on the Generalized Modified Weibull Distribution for the Analysis of Leukemia Patients

Omer ME, Abu Bakar M, Adam M, Mustafa M

Asian Pac J Cancer Prev, 2021 Apr 01;22(4):1045-1053.
PMID: 33906295 DOI: 10.31557/APJCP.2021.22.4.1045

OBJECTIVE: Cure rate models are survival models, commonly applied to model survival data with a cured fraction. In the existence of a cure rate, if the distribution of survival times for susceptible patients is specified, researchers usually prefer cure models to parametric models. Different distributions can be assumed for the survival times, for instance, generalized modified Weibull (GMW), exponentiated Weibull (EW), and log-beta Weibull. The purpose of this study is to select the best distribution for uncured patients' survival times by comparing the mixture cure models based on the GMW distribution and its particular cases.
MATERIALS AND METHODS: A data set of 91 patients with high-risk acute lymphoblastic leukemia (ALL) followed for five years from 1982 to 1987 was chosen for fitting the mixture cure model. We used the maximum likelihood estimation technique via R software 3.6.2 to obtain the estimates for parameters of the proposed model in the existence of cure rate, censored data, and covariates. For the best model choice, the Akaike information criterion (AIC) was implemented.
RESULTS: After comparing different parametric models fitted to the data, including or excluding cure fraction, without covariates, the smallest AIC values were obtained by the EW and the GMW distributions, (953.31/969.35) and (955.84/975.99), respectively. Besides, assuming a mixture cure model based on GMW with covariates, an estimated ratio between cure fractions for allogeneic and autologous bone marrow transplant groups (and its 95% confidence intervals) were 1.42972 (95% CI: 1.18614 - 1.72955).
CONCLUSION: The results of this study reveal that the EW and the GMW distributions are the best choices for the survival times of Leukemia patients.
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Automated characterization of cardiovascular diseases using relative wavelet nonlinear features extracted from ECG signals

Adam M, Oh SL, Sudarshan VK, Koh JE, Hagiwara Y, Tan JH, et al.

Comput Methods Programs Biomed, 2018 Jul;161:133-143.
PMID: 29852956 DOI: 10.1016/j.cmpb.2018.04.018

Cardiovascular diseases (CVDs) are the leading cause of deaths worldwide. The rising mortality rate can be reduced by early detection and treatment interventions. Clinically, electrocardiogram (ECG) signal provides useful information about the cardiac abnormalities and hence employed as a diagnostic modality for the detection of various CVDs. However, subtle changes in these time series indicate a particular disease. Therefore, it may be monotonous, time-consuming and stressful to inspect these ECG beats manually. In order to overcome this limitation of manual ECG signal analysis, this paper uses a novel discrete wavelet transform (DWT) method combined with nonlinear features for automated characterization of CVDs. ECG signals of normal, and dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM) and myocardial infarction (MI) are subjected to five levels of DWT. Relative wavelet of four nonlinear features such as fuzzy entropy, sample entropy, fractal dimension and signal energy are extracted from the DWT coefficients. These features are fed to sequential forward selection (SFS) technique and then ranked using ReliefF method. Our proposed methodology achieved maximum classification accuracy (acc) of 99.27%, sensitivity (sen) of 99.74%, and specificity (spec) of 98.08% with K-nearest neighbor (kNN) classifier using 15 features ranked by the ReliefF method. Our proposed methodology can be used by clinical staff to make faster and accurate diagnosis of CVDs. Thus, the chances of survival can be significantly increased by early detection and treatment of CVDs.
Automated diagnosis of congestive heart failure using dual tree complex wavelet transform and statistical features extracted from 2s of ECG signals

Sudarshan VK, Acharya UR, Oh SL, Adam M, Tan JH, Chua CK, et al.

Comput Biol Med, 2017 04 01;83:48-58.
PMID: 28231511 DOI: 10.1016/j.compbiomed.2017.01.019

Identification of alarming features in the electrocardiogram (ECG) signal is extremely significant for the prediction of congestive heart failure (CHF). ECG signal analysis carried out using computer-aided techniques can speed up the diagnosis process and aid in the proper management of CHF patients. Therefore, in this work, dual tree complex wavelets transform (DTCWT)-based methodology is proposed for an automated identification of ECG signals exhibiting CHF from normal. In the experiment, we have performed a DTCWT on ECG segments of 2s duration up to six levels to obtain the coefficients. From these DTCWT coefficients, statistical features are extracted and ranked using Bhattacharyya, entropy, minimum redundancy maximum relevance (mRMR), receiver-operating characteristics (ROC), Wilcoxon, t-test and reliefF methods. Ranked features are subjected to k-nearest neighbor (KNN) and decision tree (DT) classifiers for automated differentiation of CHF and normal ECG signals. We have achieved 99.86% accuracy, 99.78% sensitivity and 99.94% specificity in the identification of CHF affected ECG signals using 45 features. The proposed method is able to detect CHF patients accurately using only 2s of ECG signal length and hence providing sufficient time for the clinicians to further investigate on the severity of CHF and treatments.
A deep convolutional neural network model to classify heartbeats

Acharya UR, Oh SL, Hagiwara Y, Tan JH, Adam M, Gertych A, et al.

Comput Biol Med, 2017 10 01;89:389-396.
PMID: 28869899 DOI: 10.1016/j.compbiomed.2017.08.022

The electrocardiogram (ECG) is a standard test used to monitor the activity of the heart. Many cardiac abnormalities will be manifested in the ECG including arrhythmia which is a general term that refers to an abnormal heart rhythm. The basis of arrhythmia diagnosis is the identification of normal versus abnormal individual heart beats, and their correct classification into different diagnoses, based on ECG morphology. Heartbeats can be sub-divided into five categories namely non-ectopic, supraventricular ectopic, ventricular ectopic, fusion, and unknown beats. It is challenging and time-consuming to distinguish these heartbeats on ECG as these signals are typically corrupted by noise. We developed a 9-layer deep convolutional neural network (CNN) to automatically identify 5 different categories of heartbeats in ECG signals. Our experiment was conducted in original and noise attenuated sets of ECG signals derived from a publicly available database. This set was artificially augmented to even out the number of instances the 5 classes of heartbeats and filtered to remove high-frequency noise. The CNN was trained using the augmented data and achieved an accuracy of 94.03% and 93.47% in the diagnostic classification of heartbeats in original and noise free ECGs, respectively. When the CNN was trained with highly imbalanced data (original dataset), the accuracy of the CNN reduced to 89.07%% and 89.3% in noisy and noise-free ECGs. When properly trained, the proposed CNN model can serve as a tool for screening of ECG to quickly identify different types and frequency of arrhythmic heartbeats.
Computer aided diagnosis of diabetic foot using infrared thermography: A review

Adam M, Ng EYK, Tan JH, Heng ML, Tong JWK, Acharya UR

Comput Biol Med, 2017 12 01;91:326-336.
PMID: 29121540 DOI: 10.1016/j.compbiomed.2017.10.030

Diabetes mellitus (DM) is a chronic metabolic disorder that requires regular medical care to prevent severe complications. The elevated blood glucose level affects the eyes, blood vessels, nerves, heart, and kidneys after the onset. The affected blood vessels (usually due to atherosclerosis) may lead to insufficient blood circulation particularly in the lower extremities and nerve damage (neuropathy), which can result in serious foot complications. Hence, an early detection and treatment can prevent foot complications such as ulcerations and amputations. Clinicians often assess the diabetic foot for sensory deficits with clinical tools, and the resulting foot severity is often manually evaluated. The infrared thermography is a fast, nonintrusive and non-contact method which allows the visualization of foot plantar temperature distribution. Several studies have proposed infrared thermography-based computer aided diagnosis (CAD) methods for diabetic foot. Among them, the asymmetric temperature analysis method is more superior, as it is easy to implement, and yielded satisfactory results in most of the studies. In this paper, the diabetic foot, its pathophysiology, conventional assessments methods, infrared thermography and the different infrared thermography-based CAD analysis methods are reviewed.
Application of stacked convolutional and long short-term memory network for accurate identification of CAD ECG signals

Tan JH, Hagiwara Y, Pang W, Lim I, Oh SL, Adam M, et al.

Comput Biol Med, 2018 03 01;94:19-26.
PMID: 29358103 DOI: 10.1016/j.compbiomed.2017.12.023

Coronary artery disease (CAD) is the most common cause of heart disease globally. This is because there is no symptom exhibited in its initial phase until the disease progresses to an advanced stage. The electrocardiogram (ECG) is a widely accessible diagnostic tool to diagnose CAD that captures abnormal activity of the heart. However, it lacks diagnostic sensitivity. One reason is that, it is very challenging to visually interpret the ECG signal due to its very low amplitude. Hence, identification of abnormal ECG morphology by clinicians may be prone to error. Thus, it is essential to develop a software which can provide an automated and objective interpretation of the ECG signal. This paper proposes the implementation of long short-term memory (LSTM) network with convolutional neural network (CNN) to automatically diagnose CAD ECG signals accurately. Our proposed deep learning model is able to detect CAD ECG signals with a diagnostic accuracy of 99.85% with blindfold strategy. The developed prototype model is ready to be tested with an appropriate huge database before the clinical usage.
Fulltext Complete vertebrate mitogenomes reveal widespread repeats and gene duplications

Formenti G, Rhie A, Balacco J, Haase B, Mountcastle J, Fedrigo O, et al.

Genome Biol, 2021 04 29;22(1):120.
PMID: 33910595 DOI: 10.1186/s13059-021-02336-9

BACKGROUND: Modern sequencing technologies should make the assembly of the relatively small mitochondrial genomes an easy undertaking. However, few tools exist that address mitochondrial assembly directly.
RESULTS: As part of the Vertebrate Genomes Project (VGP) we develop mitoVGP, a fully automated pipeline for similarity-based identification of mitochondrial reads and de novo assembly of mitochondrial genomes that incorporates both long (> 10 kbp, PacBio or Nanopore) and short (100-300 bp, Illumina) reads. Our pipeline leads to successful complete mitogenome assemblies of 100 vertebrate species of the VGP. We observe that tissue type and library size selection have considerable impact on mitogenome sequencing and assembly. Comparing our assemblies to purportedly complete reference mitogenomes based on short-read sequencing, we identify errors, missing sequences, and incomplete genes in those references, particularly in repetitive regions. Our assemblies also identify novel gene region duplications. The presence of repeats and duplications in over half of the species herein assembled indicates that their occurrence is a principle of mitochondrial structure rather than an exception, shedding new light on mitochondrial genome evolution and organization.
CONCLUSIONS: Our results indicate that even in the "simple" case of vertebrate mitogenomes the completeness of many currently available reference sequences can be further improved, and caution should be exercised before claiming the complete assembly of a mitogenome, particularly from short reads alone.
Fulltext The north-south policy divide in transnational healthcare: a comparative review of policy research on medical tourism in source and destination countries

Virani A, Wellstead AM, Howlett M

Global Health, 2020 04 22;16(1):37.
PMID: 32321561 DOI: 10.1186/s12992-020-00566-3

Medical tourism occupies different spaces within national policy frameworks depending on which side of the transnational paradigm countries belong to, and how they seek to leverage it towards their developmental goals. This article draws attention to this policy divide in transnational healthcare through a comparative bibliometric review of policy research on medical tourism in select source (Canada, United States and United Kingdom) and destination countries (Mexico, India, Thailand, Malaysia and Singapore), using a systematic search of the Web of Science (WoS) database and review of grey literature. We assess cross-national differences in policy and policy research on medical tourism against contextual policy landscapes and challenges, and examine the convergence between research and policy. Our findings indicate major disparities in development agendas and national policy concerns, both between and among source and destination countries. Further, we find that research on medical tourism does not always address prevailing policy challenges, just as the policy discourse oftentimes neglects relevant policy research on the subject. Based on our review, we highlight the limited application of theoretical policy paradigms in current medical tourism research and make the case for a comparative policy research agenda for the field.
Fulltext International consensus statement on allergy and rhinology: Allergic rhinitis - 2023

Wise SK, Damask C, Roland LT, Ebert C, Levy JM, Lin S, et al.

Int Forum Allergy Rhinol, 2023 Apr;13(4):293-859.
PMID: 36878860 DOI: 10.1002/alr.23090

BACKGROUND: In the 5 years that have passed since the publication of the 2018 International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis (ICAR-Allergic Rhinitis 2018), the literature has expanded substantially. The ICAR-Allergic Rhinitis 2023 update presents 144 individual topics on allergic rhinitis (AR), expanded by over 40 topics from the 2018 document. Originally presented topics from 2018 have also been reviewed and updated. The executive summary highlights key evidence-based findings and recommendation from the full document.
METHODS: ICAR-Allergic Rhinitis 2023 employed established evidence-based review with recommendation (EBRR) methodology to individually evaluate each topic. Stepwise iterative peer review and consensus was performed for each topic. The final document was then collated and includes the results of this work.
RESULTS: ICAR-Allergic Rhinitis 2023 includes 10 major content areas and 144 individual topics related to AR. For a substantial proportion of topics included, an aggregate grade of evidence is presented, which is determined by collating the levels of evidence for each available study identified in the literature. For topics in which a diagnostic or therapeutic intervention is considered, a recommendation summary is presented, which considers the aggregate grade of evidence, benefit, harm, and cost.
CONCLUSION: The ICAR-Allergic Rhinitis 2023 update provides a comprehensive evaluation of AR and the currently available evidence. It is this evidence that contributes to our current knowledge base and recommendations for patient evaluation and treatment.
Fulltext A Study of Psychometric Instruments and Constructs of Work-Related Stress among Seafarers: A Qualitative Approach

Ali SNM, Cioca LI, Kayati RS, Saputra J, Adam M, Plesa R, et al.

Int J Environ Res Public Health, 2023 Feb 06;20(4).
PMID: 36833563 DOI: 10.3390/ijerph20042866

Due to unpredictable and demanding working circumstances and the significant potential for dangers and accidents, seafaring has been characterised as one of the world's riskiest and stressful vocations that lead to physical and mental health problems. However, very few instruments measure work-related stress, particularly in a seafaring context. None of the instruments are psychometrically sound. Therefore, a valid and reliable instrument to measure seafaring work-related stress is indispensable. This study aims to review work-related stress instruments and to explore the work-related stress construct among seafarers in Malaysia. This study uses a systematic review and semi-structured interviews across two phases. In Phase 1, we conducted a systematic review of several databases: Academic Search Ultimate, Emerald Journal Premier, Journal Storage (JSTOR), ScienceDirect, Springer Link, Taylor and Francis Online, and Wiley Online Library based on Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA). In 8975 articles, only 4 (four) studies used psychological instruments and 5 (five) studies used survey questionnaires to measure work-related stress. In Phase 2, we conducted a semi-structured interview with 25 (twenty-five) seafarers, online due to COVID-19 restrictions. The semi-structured interview indicated 6 (six) themes, namely, physical stress, personal issues, social living onboard, technostress, work factors, and the effect of the COVID-19 pandemic. In conclusion, the present study has identified three psychometric instruments for measuring work-related stress among seafarers: The Psychological General Well-Being Index, Perceived Stress Scale, and Job Content Questionnaire. We also found psychometric elements in some of the instruments are questionable, such as theoretical basis, construct development, and inadequate internal consistency value. In addition, this study also found that work-related stress is a multidimensional construct that needs to be studied based on work contexts. The findings of this study can contribute to the body of knowledge of a work-related stress construct in a seafaring context and could help to inform policy makers in the maritime industry. This study suggests a psychological instrument to measure work-related stress among seafarers in future studies.
Impact of Article Page Count and Number of Authors on Citations in Disability Related Fields: A Systematic Review Article

Ahmed A, Adam M, Ghafar NA, Muhammad M, Ebrahim NA

Iran J Public Health, 2016 Sep;45(9):1118-1125.
PMID: 27957456

BACKGROUND: Citation metrics and total publications in a field has become the gold standard for rating researchers and viability of a field. Hence, stimulating demand for citation has led to a search for useful strategies to improve performance metric index. Meanwhile, title, abstract and morphologic qualities of the articles attract researchers to scientific publications. Yet, there is relatively little understanding of the citation trend in disability related fields. We aimed to provide an insight into the factors associated with citation increase in this field. Additionally, we tried to know at what page number an article might appear attractive to disability researchers needs. Thus, our focus is placed on the article page count and the number of authors contributing to the fields per article.
METHODS: To this end, we evaluated the quantitative characteristics of top cited articles in the fields with a total citation (≥50) in the Web of Science (WoS) database. Using one-way independent ANOVA, data extracted spanning a period of 1980-2015 were analyzed, while the non-parametric data analysis uses Kruskal-Walis test.
RESULTS: Articles with 11 to 20 pages attract more citations followed by those within the range of zero to 10. Articles with upward 21 pages are the least cited. Surprisingly, articles with more than two authors are significantly (P<0.05) less cited and the citation decreases as the number of authors increased.
CONCLUSION: Collaborative studies enjoy wider utilization and more citation, yet discounted merit of additional pages and limited collaborative research in disability field is revealed in this study.
Fulltext Laryngopharyngeal tuberculosis mimicking hypopharyngeal carcinoma

Adam, M., Irfan, M., Muhammad Nasri AB, Arfahiza S.

Journal of Biomedical and Clinical Sciences, 2018;3(1):8-10.
MyJurnal

Laryngopharyngeal tuberculosis (TB) is a rare disease and usually associated with pulmonary tuberculosis. Mostly, it occurs in adults without BCG vaccination or in immuno-compromised patients (such as AIDS patients). A 34-year-old gentleman with odynophagia and poor oral intake was referred to us to rule out malignancy. Direct laryngoscopy examination revealed ulcerative lesion involving right tonsillar fossa extending downward till right pyriform sinus. Panendoscopy and biopsy was performed. Laryngopharyngeal TB was diagnosed based on the histopathological examination and Ziehl-Neelsen staining.
Medical student perceptions of research and research-orientated careers: An international questionnaire study

Funston G, Piper RJ, Connell C, Foden P, Young AM, O'Neill P

Med Teach, 2016 Oct;38(10):1041-1048.
PMID: 27008336 DOI: 10.3109/0142159X.2016.1150981

BACKGROUND: Engaging and inspiring the next generation of physician-scientists at an early stage is recognised as key to ensure the future of medical research. However, little is known about medical student perceptions of research.
OBJECTIVES: We attempted to ascertain perceptions of research and research-orientated careers from medical students studying in different countries.
METHODS: An online questionnaire was developed, piloted, and promoted to medical students in various countries.
RESULTS: 1625 responses were collected from 38 countries. Analysis was restricted to data collected from countries with >100 responses (n = 890). Less than half the respondents felt their medical school provided adequate research training. Key perceived barriers to research participation as a student included lack of time and difficulty finding mentors or projects. A significant gender disparity existed in research ambitions of students with females desiring less research involvement. The importance of barriers and satisfaction with research training differed significantly between countries.
CONCLUSIONS: Students perceive a number of key barriers to research involvement and pursuit of research-orientated careers. Programmes designed to engage students with research should focus on overcoming identified barriers. Greater effort is needed to engage female students who report more significant barriers and less desire to follow research-orientated careers.
Global status and conservation potential of reef sharks

MacNeil MA, Chapman DD, Heupel M, Simpfendorfer CA, Heithaus M, Meekan M, et al.

Nature, 2020 07;583(7818):801-806.
PMID: 32699418 DOI: 10.1038/s41586-020-2519-y

Decades of overexploitation have devastated shark populations, leaving considerable doubt as to their ecological status1,2. Yet much of what is known about sharks has been inferred from catch records in industrial fisheries, whereas far less information is available about sharks that live in coastal habitats3. Here we address this knowledge gap using data from more than 15,000 standardized baited remote underwater video stations that were deployed on 371 reefs in 58 nations to estimate the conservation status of reef sharks globally. Our results reveal the profound impact that fishing has had on reef shark populations: we observed no sharks on almost 20% of the surveyed reefs. Reef sharks were almost completely absent from reefs in several nations, and shark depletion was strongly related to socio-economic conditions such as the size and proximity of the nearest market, poor governance and the density of the human population. However, opportunities for the conservation of reef sharks remain: shark sanctuaries, closed areas, catch limits and an absence of gillnets and longlines were associated with a substantially higher relative abundance of reef sharks. These results reveal several policy pathways for the restoration and management of reef shark populations, from direct top-down management of fishing to indirect improvement of governance conditions. Reef shark populations will only have a high chance of recovery by engaging key socio-economic aspects of tropical fisheries.
Author Correction: Global status and conservation potential of reef sharks

MacNeil MA, Chapman DD, Heupel M, Simpfendorfer CA, Heithaus M, Meekan M, et al.

Nature, 2020 09;585(7825):E11.
PMID: 32848253 DOI: 10.1038/s41586-020-2692-z

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.
Fulltext Author Correction: Dense sampling of bird diversity increases power of comparative genomics

Feng S, Stiller J, Deng Y, Armstrong J, Fang Q, Reeve AH, et al.

Nature, 2021 Apr;592(7856):E24.
PMID: 33833441 DOI: 10.1038/s41586-021-03473-8
Fulltext Dense sampling of bird diversity increases power of comparative genomics

Feng S, Stiller J, Deng Y, Armstrong J, Fang Q, Reeve AH, et al.

Nature, 2020 11;587(7833):252-257.
PMID: 33177665 DOI: 10.1038/s41586-020-2873-9

Whole-genome sequencing projects are increasingly populating the tree of life and characterizing biodiversity1-4. Sparse taxon sampling has previously been proposed to confound phylogenetic inference5, and captures only a fraction of the genomic diversity. Here we report a substantial step towards the dense representation of avian phylogenetic and molecular diversity, by analysing 363 genomes from 92.4% of bird families-including 267 newly sequenced genomes produced for phase II of the Bird 10,000 Genomes (B10K) Project. We use this comparative genome dataset in combination with a pipeline that leverages a reference-free whole-genome alignment to identify orthologous regions in greater numbers than has previously been possible and to recognize genomic novelties in particular bird lineages. The densely sampled alignment provides a single-base-pair map of selection, has more than doubled the fraction of bases that are confidently predicted to be under conservation and reveals extensive patterns of weak selection in predominantly non-coding DNA. Our results demonstrate that increasing the diversity of genomes used in comparative studies can reveal more shared and lineage-specific variation, and improve the investigation of genomic characteristics. We anticipate that this genomic resource will offer new perspectives on evolutionary processes in cross-species comparative analyses and assist in efforts to conserve species.
Fulltext Towards complete and error-free genome assemblies of all vertebrate species

Rhie A, McCarthy SA, Fedrigo O, Damas J, Formenti G, Koren S, et al.

Nature, 2021 Apr;592(7856):737-746.
PMID: 33911273 DOI: 10.1038/s41586-021-03451-0

High-quality and complete reference genome assemblies are fundamental for the application of genomics to biology, disease, and biodiversity conservation. However, such assemblies are available for only a few non-microbial species1-4. To address this issue, the international Genome 10K (G10K) consortium5,6 has worked over a five-year period to evaluate and develop cost-effective methods for assembling highly accurate and nearly complete reference genomes. Here we present lessons learned from generating assemblies for 16 species that represent six major vertebrate lineages. We confirm that long-read sequencing technologies are essential for maximizing genome quality, and that unresolved complex repeats and haplotype heterozygosity are major sources of assembly error when not handled correctly. Our assemblies correct substantial errors, add missing sequence in some of the best historical reference genomes, and reveal biological discoveries. These include the identification of many false gene duplications, increases in gene sizes, chromosome rearrangements that are specific to lineages, a repeated independent chromosome breakpoint in bat genomes, and a canonical GC-rich pattern in protein-coding genes and their regulatory regions. Adopting these lessons, we have embarked on the Vertebrate Genomes Project (VGP), an international effort to generate high-quality, complete reference genomes for all of the roughly 70,000 extant vertebrate species and to help to enable a new era of discovery across the life sciences.
Fulltext TLR7 promotes smoke-induced experimental lung damage through the activity of mast cell tryptase

Liu G, Haw TJ, Starkey MR, Philp AM, Pavlidis S, Nalkurthi C, et al.

Nat Commun, 2023 Nov 14;14(1):7349.
PMID: 37963864 DOI: 10.1038/s41467-023-42913-z

Toll-like receptor 7 (TLR7) is known for eliciting immunity against single-stranded RNA viruses, and is increased in both human and cigarette smoke (CS)-induced, experimental chronic obstructive pulmonary disease (COPD). Here we show that the severity of CS-induced emphysema and COPD is reduced in TLR7-deficient mice, while inhalation of imiquimod, a TLR7-agonist, induces emphysema without CS exposure. This imiquimod-induced emphysema is reduced in mice deficient in mast cell protease-6, or when wild-type mice are treated with the mast cell stabilizer, cromolyn. Furthermore, therapeutic treatment with anti-TLR7 monoclonal antibody suppresses CS-induced emphysema, experimental COPD and accumulation of pulmonary mast cells in mice. Lastly, TLR7 mRNA is increased in pre-existing datasets from patients with COPD, while TLR7+ mast cells are increased in COPD lungs and associated with severity of COPD. Our results thus support roles for TLR7 in mediating emphysema and COPD through mast cell activity, and may implicate TLR7 as a potential therapeutic target.

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