Faculty Bibliography
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Large-scale exome analyses reveal new rare variant contributions in amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS) is a heritable disorder where rare variants with low-to-moderate penetrance are thought to dominate genetic risk. To identify such rare variants, we harmonized and analyzed exome data from 22 cohorts, totaling 17,919 individuals with ALS and 200,703 controls across discovery and replication phases. Rare variant analyses identified several new risk genes, with replication confirming association of YKT6 and supporting HTR3C, GBGT1 and KNTC1. We also provide strong, independent validation for genes with limited previous evidence: ARPP21, DNAJC7 and CFAP410. Notably, in ARPP21, we identified a new high-effect variant (p.P747L) and confirmed that p.P563L is an ALS-associated variant leading to an aggressive disease course. Beyond new discoveries, our analyses largely recapitulated the known genetic architecture of ALS, identifying risk variants in over 20% of cases and supporting a cumulative oligogenic risk model. These findings highlight new translational targets and show that rare variant analyses capture substantially more genetic risk than common variant genome-wide association studies.
PMCID:13083253
PMID: 41917433
ISSN: 1546-1718
CID: 6041162
Authors' Response [Letter]
PMID: 41931070
ISSN: 1943-4723
CID: 6041262
Global, regional, and national burden of meningitis, its risk factors, and aetiologies, 1990-2023: a systematic analysis for the Global Burden of Disease Study 2023
BACKGROUND:Meningitis remains the leading infectious cause of neurological disabilities globally, disproportionately affecting children younger than 5 years and populations in the African meningitis belt. Whereas previous global estimates focused on ten pathogen categories, this study presents the most comprehensive analysis to date, assessing the meningitis burden attributable to 17 causative pathogens based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 framework. METHODS:GBD is a systematic, scientific effort aimed at quantifying the comparative magnitude of health loss caused by diseases, injuries, and risk factors across age groups, sexes, and geographical locations over time. We estimated meningitis mortality using the Cause of Death Ensemble model (CODEm) and morbidity using DisMod-MR 2.1, incorporating data from vital registration, verbal autopsy, surveillance, hospital data, and systematic reviews. Aetiology-specific estimates were generated with pathogen-linked case-fatality ratios and splined binomial regression models. Risk factor attribution was based on established risk-outcome pairs and population attributable fractions. FINDINGS/RESULTS:In 2023, there were 259 000 (95% uncertainty interval 202 000-335 000) global deaths and 2·54 million (2·20-2·93) incident cases of meningitis. Children younger than 5 years accounted for more than a third of deaths (86 600 [53 300-149 000]). Streptococcus pneumoniae, Neisseria meningitidis, non-polio enteroviruses, and other viruses were the leading causes of death, while non-polio enteroviruses caused the most cases. The four WHO-defined preventable meningitis pathogens of interest (S pneumoniae, N meningitidis, Haemophilus influenzae, and Group B streptococcus) contributed to 98 700 deaths (77 000-127 000) and 594 000 cases (514 000-686 000). Low birthweight, short gestation, and household air pollution were the top risk factors for meningitis-related mortality. INTERPRETATION/CONCLUSIONS:Although mortality and incidence have declined significantly since 1990, progress is insufficient to meet WHO 2030 targets. Despite marked progress in reducing bacterial meningitis via global vaccination campaigns, a substantial meningitis burden persists, attributable both to common pathogens such as S pneumoniae and N meningitidis and to emerging non-bacterial pathogens such as Candida spp and drug-resistant fungi. Achieving WHO goals will require sustained investment in surveillance, vaccination, maternal screening, and health-system strengthening, especially in high-burden settings. FUNDING/BACKGROUND:Gates Foundation, Wellcome Trust, and UK Department of Health and Social Care.
PMID: 41911930
ISSN: 1474-4465
CID: 6041152
Clinical efficacy and patient-reported outcomes of coconut oil as adjunctive periodontitis treatment: triple-blinded pilot randomized trial
BACKGROUND:Periodontitis is a prevalent chronic disease commonly managed with nonsurgical therapy and adjunctive antimicrobial rinses, though their side effects can hinder long-term use. Coconut oil has emerged as a potential natural alternative due to its antimicrobial and anti-inflammatory effects. This study aimed to evaluate the clinical and patient-reported outcomes of periodontal patients treated with nonsurgical therapy with or without coconut oil as an adjunctive method. METHODS:Thirty participants with stage II-III periodontitis were randomly assigned to three groups: coconut oil, 0.12% chlorhexidine, and placebo (coconut-flavored water) mouth rinse for one month, followed by nonsurgical periodontal therapy. A blinded examiner assessed the plaque index, bleeding on probing, probing pocket depth, clinical attachment level, saliva pH, tooth color, sulfur compounds in breath, and patient-reported outcomes, including the Oral Health Impact Profile-14 before starting the use of mouth rinse (T1), one month after starting the mouth rinse (T2) and one month after nonsurgical periodontal therapy (T3). RESULTS:Compared with the placebo, both coconut oil and chlorhexidine significantly reduced the plaque index at T2 (p = 0.001; p = 0.006), bleeding on probing at T2 (p = 0.001; p = 0.001) and T3 (p = 0.006; p = 0.009), probing depth at T2 (p = 0.001; p = 0.001), clinical attachment level at T2 (p = 0.001; p = 0.015) and sulfur compounds at T2(p = 0.045; p = 0.003). Compared with chlorhexidine, coconut oil was more effective at decreasing clinical attachment loss at T2 (p = 0.006). At T2, chlorhexidine was associated with increased burning sensation (p = 0.03) and color changes (p < 0.001), whereas coconut oil reduced the degree of mouth dryness perception (p < 0.001). Coconut oil and chlorhexidine improved breath perception (p = 0.003; p = 0.030). Patients preferred the placebo over coconut oil or chlorhexidine (p = 0.006; p = 0.015). The quality of life significantly improved in the coconut oil group at T2 (p = 0.024). CONCLUSIONS:Compared with placebo, coconut oil and chlorhexidine improved periodontal parameters. However, coconut oil reduces mouth dryness and improves quality of life without the adverse effects associated with chlorhexidine. Nonetheless, participants in the placebo group reported a higher preference for the mouth rinse, suggesting that taste and mouthfeel play a crucial role in patient compliance. ETHICAL APPROVAL AND TRIAL REGISTRATION:The study protocol was approved by the Comité de Ética de la Investigación con Medicamentos de Galicia (CEIm-G) under protocol number 2017/247, registered at ClinicalTrials.gov (NCT06049589) on September 1st 2023 and conducted in compliance with the Declaration of Helsinki and Good Clinical Practice guidelines. All participants provided written informed consent before enrollment.
PMCID:13188242
PMID: 42057009
ISSN: 1472-6831
CID: 6041302
Eponyms in Dentistry - Periodontics and Oral Microbiology [Historical Article]
This paper explores twenty dental eponyms related to periodontal disease and oral microbiology, highlighting key pathogens such as the Koch bacillus (Mycobacterium tuberculosis), Actinomyces israelii, Treponema vincentii, Prevotella intermedia, and Veillonella parvula. It also examines seminal contributions to infection control and diagnostics, including Listerine, pasteurization, and histological stains such as the Gram and Giemsa stains. These eponyms commemorate the pioneering work of scientists like Koch, Pasteur, and Löffler, who made foundational discoveries under challenging conditions with limited laboratory resources. By revisiting their achievements, this paper underscores the importance of preserving historical memory in dental education and practice, ensuring that new generations appreciate the origins and enduring impact of these milestones in microbiology and periodontology.
PMID: 41926375
ISSN: 1089-6287
CID: 6041252
Eponyms in Dentistry - Endodontics [Historical Article]
This paper explores the historical evolution of dentistry through the lens of eponyms, focusing particularly on endodontics. From the era of extractions to the introduction of restorations by Pierre Fauchard and the development of prosthodontics and root preservation in the 19th century, dentistry has advanced in parallel with scientific breakthroughs in microbiology and technology. These innovations enabled the understanding and treatment of pulpal disease and the creation of effective root canal techniques. We highlight 31 key eponyms-32 individuals whose contributions to instruments, methods, materials, or classifications shaped modern endodontics and whose legacies remain embedded in practice.
PMID: 41926371
ISSN: 1089-6287
CID: 6041212
Microbial alteration after intensive fluoride varnish treatment in children with early childhood caries: An exploratory study
OBJECTIVE:In this study, we aimed to evaluate the effect of an intensive fluoride varnish (FV) regimen on oral microbial communities in children with early childhood caries (ECC). METHODS:Twenty-six children, aged 2 to 5 years, diagnosed with early-stage ECC, were included. They were treated with 5% NaF varnish three times over 2 weeks. Pooled supragingival plaque samples (n = 70) were collected and used for extracting total bacterial DNA. The microbial composition was analyzed using the Human Oral Microbe Identification Next-Generation Sequencing (HOMINGS) method. RESULTS:Analysis of 6172,618 high-quality 16S rRNA amplicons revealed significant changes in the relative abundance of oral microbiome taxa at the phylum level immediately after FV treatment (p = 0.021). Although the relative abundance of several known cariogenic species decreased, none of the shifts were statistically significant at the 1-week visit or persisted at the 2-week visit. At the genus level, children with higher mutans streptococci levels showed higher relative abundance of Bacteroidetes, Firmicutes, and Spirochaetes (p = 0.001, p = 0.023, and p = 0.001), respectively. At the species level, FV treatment significantly increased the relative abundance of Corynebacterium durum (p = 0.009) and Neisseria sicca (p = 0.031) but did not significantly disrupt commensals within the microbial community. CONCLUSIONS:Intensive FV application alone does not significantly alter the core oral microbiome of children with untreated ECC. The treatment may temporarily reduce the cariogenic microbial burden immediately after treatment. However, the long-term effects of FV on the oral microbiome still remain uncertain.
PMID: 42061740
ISSN: 1879-176x
CID: 6041312
Investigating the analytical robustness of the social and behavioural sciences
The same dataset can be analysed in different justifiable ways to answer the same research question, potentially challenging the robustness of empirical science1-3. In this crowd initiative, we investigated the degree to which research findings in the social and behavioural sciences are contingent on analysts' choices. We examined a stratified random sample of 100 studies published between 2009 and 2018, in which, for one claim per study, at least five reanalysts independently reanalysed the original data. The statistical appropriateness of the reanalyses was assessed in peer evaluations, and the robustness indicators were inspected along a range of research characteristics and study designs. We found that 34% of the independent reanalyses yielded the same result (within a tolerance region of ±0.05 Cohen's d) as the original report; with a four times broader tolerance region, this indicator increased to 57%. Of the reanalyses conducted, 74% reached the same conclusion as the original investigation, 24% yielded no effects or inconclusive results and 2% reported the opposite effect. This exploratory study indicates that the common single-path analyses in social and behavioural research should not be simply assumed to be robust to alternative analyses4. Therefore, we recommend the development and use of practices to explore and communicate this neglected source of uncertainty.
PMID: 41922703
ISSN: 1476-4687
CID: 6041172
Eponyms in Dentistry - Anatomy and Histology [Historical Article]
This article, the second in a series of eight, highlights the lives and original works of 21 scientists whose names are preserved in 20 enduring eponyms still found in dental anatomy and histology textbooks. Though frequently referenced in education, the historical context and the original publications behind these terms are often overlooked. By revisiting their biographies and citing the original sources where each eponym was first described, this work offers a long-overdue acknowledgment of their lasting contributions to dental science.
PMID: 41926369
ISSN: 1089-6287
CID: 6041192
AI Methods for Implementation Science (AIM-IS): developing a framework, toolkit, and reporting standard for the responsible use of AI in implementation practice and research
BACKGROUND:Artificial intelligence (AI), including machine learning, natural language processing, and large language models, may support implementation practice and research in tasks such as evidence synthesis, determinant assessment, strategy selection, monitoring, adaptation, and theory development. However, these applications of AI do not form a single, uniform category. They span a continuum from practice-facing applications that support local implementation work to research- and methods-facing applications that support evidence generation and synthesis. The guidance on how to classify, evaluate, and report these uses of AI remains limited. The AI Methods for Implementation Science (AIM-IS) program aims to develop, validate, and maintain a suite of products to guide the responsible use of AI across implementation practice, implementation research, and bridging use cases. METHODS:AIM-IS is a multi-phase, multi-method methodological development program. The unit of analysis is the AI-for-implementation use case: a specific AI capability supporting a defined implementation practice or research task within a workflow, decision point, and governance context. Phase 1 is a living scoping review mapping published AI use cases in implementation science, including how they are evaluated and what risks they raise. Phase 2 is a qualitative interview study with implementation researchers, practitioners, AI experts, community members, and data infrastructure and governance experts to refine use cases and identify feasibility constraints, outcome priorities, and reporting needs. Phase 3 will integrate findings from Phases 1 and 2 to develop the draft AIM-IS products, including a framework, a taxonomy of use cases, guardrails for responsible use, a practical guide, outcome domains, and reporting items. Phase 4 will use an eDelphi process and consensus meeting to refine and finalize these products. Phase 5 will conduct usability testing to improve clarity and ease of use, resulting in the finalized AIM-IS products. AIM-IS is informed by implementation science, sociotechnical systems, equity, and responsible AI frameworks, and includes a living-update approach to support ongoing refinement. DISCUSSION/CONCLUSIONS:The AIM-IS program will deliver a suite of products, including a framework, toolkit and reporting standard, to support the specification, governance, evaluation, and reporting of AI in implementation science. Together, these products aim to strengthen transparency, comparability, accountability, and attention to equity in how AI is used by implementation practitioners and researchers over time. REGISTRATION/BACKGROUND:Open Science Framework, March 15, 2026: https://doi.org/10.17605/OSF.IO/BX35K.
PMCID:13192042
PMID: 41975498
ISSN: 1748-5908
CID: 6041292
