👤 R Preston Mason

CLN3 disease, also called Juvenile Neuronal Ceroid Lipofuscinosis (JNCL), or Batten disease, is an ultra‑rare, neurodegenerative lysosomal storage disorder generally affecting individuals during the first decade of life. There can be a delay in diagnosis or misdiagnosis due to a lack of awareness, and when the most common presenting symptom of visual loss is attributed to more common conditions affecting vision. We used a previously published Expert Mapping Tool (EMT) to identify multidisciplinary professionals with diagnostic or clinical management expertise, as well as patient advocates with experience of CLN3 disease. A systematic literature review of published evidence using the Preferred Reporting Items for Systematic Reviews and Meta‑Analyses (PRISMA) guidance was conducted independently and simultaneously to develop key clinical care statements. Each statement was based on the strength of the evidence. The statements formed the basis of an international modified-Delphi consensus process using a virtual meeting platform (Within3). Experts were asked to agree or disagree with each statement and suggest any changes. Statements that reached a consensus of 75% or over are the guiding statements within this manuscript. The processes and manuscript have been independently assessed using the Appraisal of Guidelines for Research and Evaluation (AGREE II) criteria. Thirty‑nine international experts from eight specialities were identified, including a patient advocate. Fifty‑three recommendation statements were developed covering eleven domains: General statements, Diagnostics, Clinical Recommendations and Management, Assessments, Social Considerations, Ocular Management, Epilepsy/Seizures, Nutrition, Respiratory Health, Sleep and Rest, and End-of-Life Care. Consensus was reached after one round of voting for all except three statements. The overall AGREE II score for developing these recommendations was 6.4, where 1 represents the lowest and 7 is the highest quality. Currently, there are no comprehensive clinical recommendations for CLN3 disease. These recommendations provide a comprehensive, evidence- and consensus‑based tool that can be used by all healthcare professionals involved in the management of CLN3 disease and other similar neurodegenerative conditions. The goal is to address the unmet clinical need for CLN3 disease management and complement other information available. The online version contains supplementary material available at 10.1186/s13023-026-04298-2. Show less

CLN3 disease, or Juvenile Neuronal Ceroid Lipofuscinosis (JNCL), is a rare, genetic neurodegenerative condition, typically manifesting in the first decade of life and progressing in severity, with death typically occurring in early adulthood. Despite two decades of natural history research, a clear timeline of CLN3 disease symptom onset and progression remains poorly defined, limiting optimal patient management and therapeutic development. We conducted a literature review and analysed the natural history data to better understand the age of core symptom onset and chronological disease progression. A literature review was undertaken using a pre-defined search strategy focused on CLN3 disease natural history studies, where age at onset for one or more core symptoms was reported in cohorts of ≥ 15 subjects. For each symptom, weighted mean age at onset and weighted standard deviation were calculated, with 95% confidence intervals derived from the weighted standard error. Symptom onset ages were compared using ANOVA. We identified nine natural history studies that met our pre-defined criteria. In total, 423 discrete patients aged between 4 and 39 years were reported. Thirteen core symptoms and a weighted average age at onset and weighted standard deviation were (in years): vision loss (6.1 ± 1.6, This comprehensive summary of available natural history data illustrates mean age at onset of 13 core symptoms of CLN3 disease, and characterises a chronological timeline of disease progression. These results provide much-needed practical, anticipatory guidance to those involved in caring for individuals with CLN3 disease, and serve to highlight the critical importance of collecting globally standardised, quantifiable, longitudinal data for optimising patient management and advancing therapeutic approaches for CLN3 disease. The online version contains supplementary material available at 10.1186/s13023-025-04174-5. Show less

Tuberculosis (TB) is the leading cause of death from a single infectious agent, with approximately 1.2 million deaths reported in 2023. While TB primarily affects the lungs, it can also spread to other organs, where it is classified as extrapulmonary TB. Tuberculous meningitis (TBM) is the most severe form of extrapulmonary TB, affecting 1–5% of TB cases. Delayed diagnosis contributes to its high mortality and severe neurological complications, with approximately 10% of affected individuals dying or suffering permanent neurological damage. When combined with adjunctive therapy, early detection and treatment can significantly improve survival outcomes. Currently, many studies have identified potential biomarkers of TBM; however, to date, there is no clear consensus on the markers altered in TBM. Hence, we conducted a systematic review aimed at identifying metabolites and proteins that are significantly altered in TBM when compared with healthy controls. Three databases — PubMed, Scopus, and Web of Science — were scanned by two independent reviewers for potential articles that met our inclusion and exclusion criteria. After quality assessment, 17 studies were included, comprising a total of 963 participants (healthy control, The online version contains supplementary material available at 10.1186/s12879-025-11740-6. Show less

Elevated lipoprotein(a) [Lp(a)] levels increase cardiovascular (CV) risk. Lp(a) contains oxidized phospholipids that may promote lipid oxidation more than other lipoproteins. The highly unsaturated omega-3 fatty acid eicosapentaenoic acid (EPA) has multiple double bonds that can trap free radicals in resonance structures. Purified ethyl-EPA reduced CV events in high-risk patients with elevated Lp(a) despite Lp(a)-associated risk elevation. Since Lp(a) is enriched in oxidized lipids, we hypothesized that Lp(a)-enriched plasma undergoes more rapid oxidation than other apolipoprotein B (ApoB)-containing particles and that EPA limits oxidation of Lp(a)-enriched plasma more effectively than less-unsaturated fatty acids or other lipid-lowering treatments. This property could limit the cellular stress responses in endothelial cells (ECs). Lp(a) was enriched to >50% total ApoB content to resemble an Lp(a)-associated 'high-risk' phenotype and compared with matching levels of small-dense LDL (sdLDL) and very-low-density lipoprotein by isopycnic centrifugation. Samples were then incubated with EPA (50 µM) or equivolume vehicle at 37°C for 30 min. Oxidation was initiated with copper sulfate and monitored by malondialdehyde formation. We also subjected EPA to oxidation before measuring its antioxidant activity when compared with other long chain, less saturated fatty acids and lipid-lowering agents. Human umbilical vein ECs (HUVECs) were incubated with Lp(a)-enriched plasma following oxidation in the absence and presence of EPA. Cell lysate samples were then analysed by global liquid chromatography-mass spectroscopy (LC/MS)-based proteomics for significant changes in protein expression (>1-fold). Lp(a)-enriched plasma contained the highest baseline oxidized lipid (P < 0.05) and underwent the most rapid oxidation. EPA, but neither the less-unsaturated fatty acids nor lipid agents attenuated oxidation of each fraction through 4 h (P < 0.01). Oxidized EPA had diminished antioxidant capacity corresponding to the extent of oxidation. Attenuation of Lp(a) oxidation with EPA also mitigated pro-inflammatory and cellular stress response changes in protein expression. Lp(a)-enriched plasma underwent more rapid oxidation than other ApoB-containing lipoproteins and promoted inflammatory changes in EC protein expression, a process attenuated by EPA. This action may contribute to reduced CV risk by EPA in those with elevated Lp(a) levels. Show less

Reducing LDL cholesterol prevents atherosclerotic cardiovascular disease (ASCVD) events. The aim of this study was to evaluate the LDL cholesterol-lowering efficacy of a fixed-dose combination (FDC) of obicetrapib, a CETP inhibitor, and ezetimibe. This randomised, double-blind trial across 48 US sites including hospitals, private and group practices, and independent research centres included participants at least 18 years old with pre-existing or high risk for ASVCD or heterozygous familial hypercholesterolaemia with LDL cholesterol concentrations of 1·8 mmol/L (70 mg/dL) or greater despite maximally tolerated lipid-lowering therapy excluding ezetimibe, or having statin intolerance. Participants were randomly assigned (1:1:1:1) to obicetrapib 10 mg plus ezetimibe 10 mg FDC, obicetrapib 10 mg monotherapy, ezetimibe 10 mg monotherapy, or placebo administered daily for 84 days. The co-primary endpoints in the intention-to-treat population were the percent LDL cholesterol changes in the FDC group compared with placebo, ezetimibe monotherapy, and obicetrapib monotherapy, and the placebo-adjusted change in the obicetrapib monotherapy group. The trial was prospectively registered (NCT06005597) and is completed. Between March 4 and July 3, 2024, 407 participants were randomly assigned. The median age was 68·0 years (IQR 62·0-73·0) and 177 (43%) were female. Mean baseline LDL cholesterol was 2·4 mmol/L, 2·5 mmol/L, 2·6 mmol/L, and 2·5 mmol/L in the placebo (n=102), ezetimibe monotherapy (n=101), obicetrapib monotherapy (n=102), and FDC groups (n=102), respectively. At day 84, percent differences in LDL cholesterol reduction with the FDC were -48·6% (95% CI -58·3 to -38·9) versus placebo, -27·9% (-37·5 to -18·4) versus ezetimibe, and -16·8% (-26·4 to -7·1) versus obicetrapib. Obicetrapib monotherapy decreased LDL cholesterol by 31·9% (22·1 to 41·6) versus placebo. Adverse event rates were similar in the FDC (52 [51%] of 102), obicetrapib (55 [54%] of 102), and ezetimibe (54 [53%] of 101) groups and lowest with placebo (38 [37%] of 102). Serious adverse event rates were generally similar across FDC (three [3%] of 102), obicetrapib (six [6%] of 102), ezetimibe (seven [7%] of 101), and placebo (four [4%] of 102) groups. Deaths occurred in one [1%] of 102 participants with FDC, one [1%] of 102 with obicetrapib, one [1%] of 101 with ezetimibe, and none with placebo. Combination therapy of obicetrapib and ezetimibe significantly reduced LDL cholesterol. This oral, single-pill therapy could improve LDL cholesterol management in patients with pre-existing or high risk for ASCVD. NewAmsterdam Pharma. Show less

Both sexually selected traits and mate preferences for these traits can be context dependent, yet how variation in preferred traits could select for context dependent preferences has rarely been examined. The signal reliability hypothesis predicts that mate preferences vary across contexts (e.g., environments) in relation to the reliability of the information preferred traits provide in those contexts. Extensive variation in copy number of mc4r B alleles on the Y-chromosome that associates with male size in Xiphophorus multilineatus allowed us to use a split-sibling design to determine if male size is more likely to provide information about male genotype (i.e., dam) when males were reared in a warm as compared to a cold environment. We then examined strength of preference for male size by females reared in the same two environments. We found that males were larger in the cold environment, but male size was more variable across dams in the warm environment, and therefore male size would be a more reliable indicator of dam (i.e., genetics) in the warm environment. Females reared in the warm environment had stronger mate preferences based on male size than cold reared females, with a significant influence of dam on strength of preference. Therefore, strength of female preference for male size was influenced by the temperature in which they were reared, with the direction of the difference across treatments supporting the signal reliability hypothesis. Understanding how the reliability of male traits can select for contextual variation in the strength of the female mate preferences will further our discovery of adaptive mate preferences. For example, a relationship between the strength of a female's mate preference and their growth rates was detected in the context where females had a preference based on male size, supporting a hypothesis from previous work with this species of disassortative mating in relation to growth rates to mitigate a documented growth-mortality tradeoff. Show less

In addition to mutations, epigenetic alterations are important contributors to malignant transformation and tumor progression. The aim of this work was to identify epigenetic events in which promoter or gene body DNA methylation induces gene expression changes that drive melanocyte malignant transformation and metastasis. We previously developed a linear mouse model of melanoma progression consisting of spontaneously immortalized melanocytes, premalignant melanocytes, a nonmetastatic tumorigenic, and a metastatic cell line. Here, through the integrative analysis of methylome and transcriptome data, we identified the relationship between promoter and/or gene body DNA methylation alterations and gene expression in early, intermediate, and late stages of melanoma progression. We identified adenylate cyclase type 3 (Adcy3) and inositol polyphosphate 4-phosphatase type II (Inpp4b), which affect tumor growth and metastatic potential, respectively. Importantly, the gene expression and DNA methylation profiles found in this murine model of melanoma progression were correlated with available clinical data from large population-based primary melanoma cohorts, revealing potential prognostic markers. Show less

Arachidonic acid (AA) is metabolized by cyclooxygenases and lipoxygenases to pro-inflammatory eicosanoids, which according to experimental research modulate tumor cell proliferation, differentiation, and apoptosis. We employed the Mendelian randomization design to test the hypothesis that higher plasma phospholipid AA concentrations are associated with increased risk of 10 site-specific cancers. Two genetic variants associated with plasma phospholipid concentrations of AA (rs174547 in FADS1 [P = 3.0 × 10 Higher genetically predicted plasma phospholipid AA concentrations were associated with increased risk of colorectal and lung cancer. Results were consistent across data sources and variants. The combined odds ratios per standard deviation increase of AA concentrations were 1.08 (95% CI 1.05-1.11; P = 6.3 × 10 These results indicate that AA may be implicated in the development of colorectal and lung cancer and possibly esophageal cancer. Treatments with plasma AA-lowering properties should be evaluated for clinical benefit. Show less

There is growing recognition that recent global increases in obesity are the product of a complex interplay between genetic and environmental factors. However, in gene-environment studies of obesity, 'environment' usually refers to individual behavioural factors that influence energy balance, whereas more upstream environmental factors are overlooked. We examined gene-environment interactions between genetic risk of obesity and two neighbourhood characteristics likely to be associated with obesity (proximity to takeaway/fast-food outlets and availability of physical activity facilities). We used data from 335 046 adults aged 40-70 in the UK Biobank cohort to conduct a population-based cross-sectional study of interactions between neighbourhood characteristics and genetic risk of obesity, in relation to body mass index (BMI). Proximity to a fast-food outlet was defined as distance from home address to nearest takeaway/fast-food outlet, and availability of physical activity facilities as the number of formal physical activity facilities within 1 km of home address. Genetic risk of obesity was operationalised by weighted Genetic Risk Scores of 91 or 69 single nucleotide polymorphisms (SNP), and by six individual SNPs considered separately. Multivariable, mixed-effects models with product terms for the gene-environment interactions were estimated. After accounting for likely confounding, the association between proximity to takeaway/fast-food outlets and BMI was stronger among those at increased genetic risk of obesity, with evidence of an interaction with polygenic risk scores (p=0.018 and p=0.028 for 69-SNP and 91-SNP scores, respectively) and in particular with a SNP linked to Individuals at an increased genetic risk of obesity may be more sensitive to exposure to the local fast-food environment. Ensuring that neighbourhood residential environments are designed to promote a healthy weight may be particularly important for those with greater genetic susceptibility to obesity. Show less

Laboratory studies have suggested oncogenic roles of lipids, as well as anticarcinogenic effects of statins. Here we assess the potential effect of statin therapy on cancer risk using evidence from human genetics. We obtained associations of lipid-related genetic variants with the risk of overall and 22 site-specific cancers for 367,703 individuals in the UK Biobank. In total, 75,037 individuals had a cancer event. Variants in the Show less

At present, there is no clear understanding of the effect of long-duration spaceflight on the major enzymes that govern the metabolism of omega-6 and omega-3 fatty acids. To address this gap in knowledge, we used data from the NASA Twins Study, which includes a multiscale omics investigation of the changes that occurred during a year-long (340 days) human spaceflight. Embedded within the NASA Twins data are specific analytes associated with fatty acid metabolism. To examine the long-chain fatty acid desaturases and elongases in a single human during 1 year in space. One male twin was on board the International Space Station (ISS) for 1 year, while his monozygotic twin served as a genetically matched ground control. Longitudinal assessments included the genome, epige-nome, transcriptome, proteome, metabolome, microbiome, and immunome during the mission, as well as 6 months before and after. The gene-specific fatty acid desaturase and elongase transcriptome data (FADS1, FADS2, ELOVL2, and ELOVL5) were extracted from untargeted RNA-seq measurements derived from white blood cell fractions. Most data from the elongases and desaturases exhibited relatively similar expression profiles (R2 >0.6) over time for the CD8, CD19, and lymphocyte-depleted (LD) cell fractions, indicating overall conservation of function within and between the subjects. Both cell-type and temporal specificity was observed in some cases, and some differences were also apparent between the polyadenylated (polyA) fraction of processed RNAs versus the ribodepleted (ribo-) fraction. The flight subject showed a stronger enrichment of the fatty acid metabolic process pathway across almost all cell types (columns, CD4, CD8, CPT, and LD), most especially in the ribodepleted fraction of RNA, but also with the polyA+ fraction of RNA. Gene set enrichment analysis (GSEA) measures across three related fatty acid metabolism pathways showed a differential between the ground and the flight subject. There appears to be no persistent alteration of desaturase and elongase gene expression associated with 1 year in space. However, these data provide evidence that cellular lipid metabolism can be responsive and dynamic to spaceflight, even though it appears cell-type and context specific, most notably in terms of the fraction of RNA measured and the collection protocols. These results also provide new evidence of mid-flight spikes in expression of selected genes, which may indicate transient responses to specific insults during spaceflight. Show less

Whether circulating fatty acids (FAs) play a causal role in the development of cardiovascular disease (CVD) remains unclear. We conducted a Mendelian randomisation study to explore the associations between plasma phospholipid FA levels and 15 CVDs. Summary-level data from the CARDIoGRAMplusC4D, MEGASTROKE, and Atrial Fibrillation consortia and UK Biobank were used. Sixteen single-nucleotide polymorphisms (SNPs) associated with ten plasma FAs were used as instrumental variables. SNPs in or close to the Show less

Testosterone supplementation has been linked to increased cardiovascular disease risk in some observational studies. The causal role of testosterone can be investigated using a Mendelian randomization approach. We assessed genetic associations of variants in two gene regions (SHBG and JMJD1C) with several cardiovascular risk factors (lipids, adiponectin, blood pressure, anthropometric traits) plus male pattern baldness, including control outcomes and potential mediators. We assessed genetic associations with coronary artery disease (CAD) risk in the CARDIoGRAMplusC4D consortium (171,191 individuals including 60,801 cases), and associations with CAD and ischaemic stroke risk in the UK Biobank (367,643 individuals including 25,352 CAD cases and 3650 ischaemic stroke cases). Genetic predictors of increased serum testosterone were associated with lipids, blood pressure, and height. There was some evidence of an association with risk of CAD (SHBG gene region: odds ratio (OR) 0.95 per 1 unit increase in log-transformed testosterone [95% confidence interval: 0.81-1.12, p = 0.55]; JMJD1C gene region: OR 1.24 [1.01-1.51, p = 0.04]) and ischaemic stroke both overall (SHBG: OR 1.05 [0.64, 1.73, p = 0.83]; JMJD1C: OR 2.52 [1.33, 4.77, p = 0.005]) and in men. However, associations with some control outcomes were in the opposite direction to that expected. Sex hormone-related mechanisms appear to be relevant to cardiovascular risk factors and for stroke (particularly for men). However, the extent that these findings are specifically informative about endogenous testosterone or testosterone supplementation is unclear. These findings underline a fundamental limitation for the use of Mendelian randomization where biological knowledge about the function of genetic variants is uncertain. Show less

Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91,462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 × 10(-8)).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee. Show less

Common genetic variants have been recently associated with fasting glucose and insulin levels in white populations. Whether these associations replicate in pre-diabetes is not known. We extended these findings to the Diabetes Prevention Program, a clinical trial in which participants at high risk for diabetes were randomized to placebo, lifestyle modification or metformin for diabetes prevention. We genotyped previously reported polymorphisms (or their proxies) in/near G6PC2, MTNR1B, GCK, DGKB, GCKR, ADCY5, MADD, CRY2, ADRA2A, FADS1, PROX1, SLC2A2, GLIS3, C2CD4B, IGF1, and IRS1 in 3,548 Diabetes Prevention Program participants. We analyzed variants for association with baseline glycemic traits, incident diabetes and their interaction with response to metformin or lifestyle intervention. We replicated associations with fasting glucose at MTNR1B (P<0.001), G6PC2 (P = 0.002) and GCKR (P = 0.001). We noted impaired β-cell function in carriers of glucose-raising alleles at MTNR1B (P<0.001), and an increase in the insulinogenic index for the glucose-raising allele at G6PC2 (P<0.001). The association of MTNR1B with fasting glucose and impaired β-cell function persisted at 1 year despite adjustment for the baseline trait, indicating a sustained deleterious effect at this locus. We also replicated the association of MADD with fasting proinsulin levels (P<0.001). We detected no significant impact of these variants on diabetes incidence or interaction with preventive interventions. The association of several polymorphisms with quantitative glycemic traits is replicated in a cohort of high-risk persons. These variants do not have a detectable impact on diabetes incidence or response to metformin or lifestyle modification in the Diabetes Prevention Program. Show less

Intraplaque hemorrhage (IPH) drives atherosclerosis through the dual metabolic stresses of cholesterol-enriched erythrocyte membranes and pro-oxidant heme/iron. When clearing tissue hemorrhage, macrophages are typically seen storing either iron or lipid. We have recently defined hemorrhage-associated macrophages (HA-mac) as a plaque macrophage population that responds adaptively to IPH. This study aimed to define the key transcription factor(s) involved in HO-1 induction by heme. To address this question, we used microarray analysis and transfection with siRNA and plasmids. To maintain physiological relevance, we focused on human blood-derived monocytes. We found that heme stimulates monocytes through induction of activating transcription factor 1 (ATF-1). ATF-1 coinduces heme oxygenase-1 (HO-1) and Liver X receptor beta (LXR-β). Heme-induced HO-1 and LXR-β were suppressed by knockdown of ATF-1, and HO-1 and LXR-β were induced by ATF-1 transfection. ATF-1 required phosphorylation for full functional activity. Expression of LXR-β in turn led to induction of other genes central to cholesterol efflux, such as LXR-α and ABCA1. This heme-directed state was distinct from known macrophage states (M1, M2, Mox) and, following the same format, we have designated them Mhem. These results show that ATF-1 mediates HO-1 induction by heme and drives macrophage adaptation to intraplaque hemorrhage. Our definition of an ATF-1-mediated pathway for linked protection from foam cell formation and oxidant stress may have therapeutic potential. Show less

Repair of demyelinated axons in diseases such as multiple sclerosis requires activation of the myelination program in existing or newly recruited oligodendrocyte precursor cells (OPCs). The control of OPC differentiation and initiation of myelination during repair is poorly understood. In this study, we test the ability of anti-LINGO-1 reagents to promote myelination in vitro and remyelination in the rodent adult central nervous system in vivo. The effects of LINGO-1 antagonists on the differentiation of OPCs and the promotion of myelination has been assayed using a combination of coculture and slice culture preparations. Using three different animal models of demyelination and remyelination, we morphologically and functionally assessed the effects of LINGO-1 antagonists on OPC differentiation and myelin repair. The data indicate that in vitro treatment with antagonists of LINGO-1 promote OPC differentiation and myelination, whereas in vivo remyelination is accelerated in lysophosphatidylcholine- or cuprizone-induced demyelination. This remyelination is associated with enhanced OPC differentiation and functional recovery of conduction velocities in demyelinated axons. Our studies demonstrate that LINGO-1 antagonism promotes OPC differentiation and remyelination, and suggest LINGO-1 functions as an inhibitor of OPC differentiation to retard central nervous system remyelination. Show less