Chromosome-level genome assembly of the diploid oat species Avena longiglumis.

Diploid wild oat Avena longiglumis has nutritional and adaptive traits which are valuable for common oat (A. sativa) breeding. The combination of Illumina, Nanopore and Hi-C data allowed us to assemble a high-quality chromosome-level genome of A. longiglumis (ALO), evidenced by contig N50 of 12.68 Mb with 99% BUSCO completeness for the assembly size of 3,960.97 Mb. A total of 40,845 protein-coding genes were annotated. The assembled genome was composed of 87.04% repetitive DNA sequences. Dotplots of the genome assembly (PI657387) with two published ALO genomes were compared to indicate the conservation of gene order and equal expansion of all syntenic blocks among three genome assemblies. Two recent whole-genome duplication events were characterized in genomes of diploid Avena species. These findings provide new knowledge for the genomic features of A. longiglumis, give information about the species diversity, and will accelerate the functional genomics and breeding studies in oat and related cereal crops.

Methods for Neuroscience Drug Development: Guidance on Standardization of the Process for Defining Clinical Outcome Strategies in Clinical Trials.

Neurosciences clinical trials continue to have notoriously high failure rates. Appropriate outcomes selection in early clinical trials is key to maximizing the likelihood of identifying new treatments in psychiatry and neurology. The field lacks good standards for designing outcome strategies, therefore The Outcomes Research Group was formed to develop and promote good practices in outcome selection. This article describes the first published guidance on the standardization of the process for clinical outcomes in neuroscience. A minimal step process is defined starting as early as possible, covering key activities for evidence generation in support of content validity, patient-centricity, validity requirements and considerations for regulatory acceptance. Feedback from expert members is provided, regarding the risks of shortening the process and examples supporting the recommended process are summarized. This methodology is now available to researchers in industry, academia or clinics aiming to implement consensus-based standard practices for clinical outcome selection, contributing to maximizing the efficiency of clinical research.

Real-World Outcomes for the Fifth-Generation Balloon Expandable Transcatheter Heart Valve in the United States.

BACKGROUND: The fifth-generation SAPIEN 3 Ultra Resilia valve (S3UR) incorporates several design changes as compared with its predecessors, the SAPIEN 3 (S3) and SAPIEN 3 Ultra (S3U) valves, including bovine leaflets treated with a novel process intended to reduce structural valve deterioration via calcification, as well as a taller external skirt on the 29-mm valve size to reduce paravalvular leak (PVL). The clinical performance of S3UR compared with S3 and S3U in a large patient population has not been previously reported. OBJECTIVES: The aim of this study was to compare S3UR to S3/S3U for procedural, in-hospital, and 30-day clinical and echocardiographic outcomes after transcatheter aortic valve replacement (TAVR). METHODS: Patients enrolled in the STS/ACC TVT (Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy) Registry between January 1, 2021, and June 30, 2023, who underwent TAVR with S3UR or S3U/S3 valve platforms were propensity-matched and evaluated for procedural, in-hospital, and 30-day clinical and echocardiographic outcomes. RESULTS: 10,314 S3UR patients were propensity matched with 10,314 patients among 150,539 S3U/S3 patients. At 30 days, there were no statistically significant differences in death, stroke, or bleeding, but a numerically higher hospital readmission rate in the S3UR cohort (8.5% vs 7.7%; P = 0.04). At discharge, S3UR patients exhibited significantly lower mean gradients (9.2 ± 4.6 mm Hg vs 12.0 ± 5.7 mm Hg; P < 0.0001) and larger aortic valve area (2.1 ± 0.7 cm2 vs 1.9 ± 0.6 cm2; P < 0.0001) than patients treated with S3/S3U. The 29-mm valve size exhibited significant reduction in mild PVL (5.3% vs 9.4%; P < 0.0001). CONCLUSIONS: S3UR TAVR is associated with lower mean gradients and lower rates of PVL than earlier generations of balloon expandable transcatheter heart valve platforms.

Cognitive and Functional Change Over Time in Cognitively Healthy Individuals According to Alzheimer Disease Biomarker-Defined Subgroups.

BACKGROUND AND OBJECTIVES: It is unclear to what extent cognitive outcome measures are sensitive to capture decline in Alzheimer disease (AD) prevention trials. We aimed to analyze the sensitivity to changes over time of a range of neuropsychological tests in several cognitively unimpaired, biomarker-defined patient groups. METHODS: Cognitively unimpaired individuals from the Amsterdam Dementia Cohort and the SCIENCe project with available AD biomarkers, obtained from CSF, PET scans, and plasma at baseline, were followed over time (4.5 ± 3.1 years, range 0.6-18.9 years). Based on common inclusion criteria for clinical trials, we defined groups (amyloid, phosphorylated tau [p-tau], APOE ε4). Linear mixed models, adjusted for age, sex, and education, were used to estimate change over time in neuropsychological tests, a functional outcome, and 2 cognitive composite measures. Standardized regression coefficients of time in years (ßtime) were reported as outcome of interest. We analyzed change over time with full follow-up, as well as with follow-up limited to 1.5 and 3 years. RESULTS: We included 387 individuals (aged 61.7 ± 8.6 years; 44% female) in the following (partly overlapping) biomarker groups: APOE ε4 carriers (n = 212), amyloid-positive individuals (n = 109), amyloid-positive APOE ε4 carriers (n = 66), CSF p-tau-positive individuals (n = 127), plasma p-tau-positive individuals (n = 71), and amyloid and CSF p-tau-positive individuals (n = 50), or in a control group (normal biomarkers; n = 65). An executive functioning task showed most decline in all biomarker groups (ßtime range -0.30 to -0.71), followed by delayed word list recognition (ßtime range -0.18 to -0.50). Functional decline (ßtime range -0.17 to -0.63) was observed in all, except the CSF and plasma tau-positive groups. Both composites showed comparable amounts of change (ßtime range -0.12 to -0.62) in all groups, except plasma p-tau-positive individuals. When limiting original follow-up duration, many effects disappeared or even flipped direction. DISCUSSION: In conclusion, functional, composite, and neuropsychological outcome measures across all cognitive domains detect changes over time in various biomarker-defined groups, with changes being most evident among individuals with more AD pathology. AD prevention trials should use sufficiently long follow-up duration and/or more sensitive outcome measures to optimally capture subtle cognitive changes over time.

What's in a score: A longitudinal investigation of scores based on item response theory and classical test theory for the Amsterdam Instrumental Activities of Daily Living Questionnaire in cognitively normal and impaired older adults.

OBJECTIVE: We aimed to investigate whether item response theory (IRT)-based scoring allows for a more accurate, responsive, and less biased assessment of everyday functioning than traditional classical test theory (CTT)-based scoring, as measured with the Amsterdam Instrumental Activities of Daily Living Questionnaire. METHOD: In this longitudinal multicenter study including cognitively normal and impaired individuals, we examined IRT-based and CTT-based score distributions and differences between diagnostic groups using linear regressions, and investigated scale attenuation. We compared change over time between scoring methods using linear mixed models with random intercepts and slopes for time. RESULTS: Two thousand two hundred ninety-four participants were included (66.6 ± 7.7 years, 54% female): n = 2,032 (89%) with normal cognition, n = 93 (4%) with subjective cognitive decline, n = 79 (3%) with mild cognitive impairment, and n = 91 (4%) with dementia. At baseline, IRT-based and CTT-based scores were highly correlated (r = -0.92). IRT-based scores showed less scale attenuation than CTT-based scores. In a subsample of n = 1,145 (62%) who were followed for a mean of 1.3 (SD = 0.6) years, IRT-based scores declined significantly among cognitively normal individuals (unstandardized coefficient [B] = -0.15, 95% confidence interval, 95% CI [-0.28, -0.03], effect size = -0.02), whereas CTT-based scores did not (B = 0.20, 95% CI [-0.02, 0.41], effect size = 0.02). In the other diagnostic groups, effect sizes of change over time were similar. CONCLUSIONS: IRT-based scores were less affected by scale attenuation than CTT-based scores. With regard to responsiveness, IRT-based scores showed more signal than CTT-based scores in early disease stages, highlighting the IRT-based scores' superior suitability for use in preclinical populations. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Genome-wide expansion and reorganization during grass evolution: from 30 Mb chromosomes in rice and Brachypodium to 550 Mb in Avena.

BACKGROUND: The BOP (Bambusoideae, Oryzoideae, and Pooideae) clade of the Poaceae has a common ancestor, with similarities to the genomes of rice, Oryza sativa (2n = 24; genome size 389 Mb) and Brachypodium, Brachypodium distachyon (2n = 10; 271 Mb). We exploit chromosome-scale genome assemblies to show the nature of genomic expansion, structural variation, and chromosomal rearrangements from rice and Brachypodium, to diploids in the tribe Aveneae (e.g., Avena longiglumis, 2n = 2x = 14; 3,961 Mb assembled to 3,850 Mb in chromosomes). RESULTS: Most of the Avena chromosome arms show relatively uniform expansion over the 10-fold to 15-fold genome-size increase. Apart from non-coding sequence diversification and accumulation around the centromeres, blocks of genes are not interspersed with blocks of repeats, even in subterminal regions. As in the tribe Triticeae, blocks of conserved synteny are seen between the analyzed species with chromosome fusion, fission, and nesting (insertion) events showing deep evolutionary conservation of chromosome structure during genomic expansion. Unexpectedly, the terminal gene-rich chromosomal segments (representing about 50 Mb) show translocations between chromosomes during speciation, with homogenization of genome-specific repetitive elements within the tribe Aveneae. Newly-formed intergenomic translocations of similar extent are found in the hexaploid A. sativa. CONCLUSIONS: The study provides insight into evolutionary mechanisms and speciation in the BOP clade, which is valuable for measurement of biodiversity, development of a clade-wide pangenome, and exploitation of genomic diversity through breeding programs in Poaceae.

Does correction of carpal malalignment influence the union rate of scaphoid nonunion surgery?

The aim of this retrospective study was to assess the relation between carpal malalignment correction and radiological union rates in surgery for scaphoid nonunions. A total of 59 scaphoid waist fracture nonunions treated with open reduction and palmar tricortical autograft were divided according to their pre- and postoperative scapholunate (SL) and radiolunate (RL) angles. We found that carpal malalignment failed to correct in 32 of 59 (54.2%) patients despite meticulous surgical technique and placement of an appropriately sized wedge-shaped graft. In total, 43 (72.9%) fractures united at a mean of 4.47 months (range 3-11). Of the 27 fractures with postoperative SL and RL angles within the normal range, 21 united, whereas 22 of the 32 remaining fractures that failed to achieve postoperative angles within the normal range went on to union. The postoperative SL and RL angles were not related to union. Our findings suggest that in scaphoid fracture nonunion surgery, carpal malalignment may not be corrected in a substantial proportion of patients, but such correction may not be essential for bony union. Our findings also show that there is no marked collapse of the scaphoid graft in the early postoperative period. LEVEL OF EVIDENCE: IV.

Practical pathway for the management of depression in the workplace: a Canadian perspective.

Major depressive disorder (MDD) and other mental health issues pose a substantial burden on the workforce. Approximately half a million Canadians will not be at work in any week because of a mental health disorder, and more than twice that number will work at a reduced level of productivity (presenteeism). Although it is important to determine whether work plays a role in a mental health condition, at initial presentation, patients should be diagnosed and treated per appropriate clinical guidelines. However, it is also important for patient care to determine the various causes or triggers including work-related factors. Clearly identifying the stressors associated with the mental health disorder can help clinicians to assess functional limitations, develop an appropriate care plan, and interact more effectively with worker's compensation and disability programs, as well as employers. There is currently no widely accepted tool to definitively identify MDD as work-related, but the presence of certain patient and work characteristics may help. This paper seeks to review the evidence specific to depression in the workplace, and provide practical tips to help clinicians to identify and treat work-related MDD, as well as navigate disability issues.

Separation and Characterization of Plastic Waste Packaging Contaminated with Food Residues.

In this paper, we present the development of a novel processing technology to tackle hard-to-recycle plastic packaging waste contaminated with food residues. The proof-of-concept (POC) technology can effectively separate food residual amounts from plastic waste materials to a level acceptable for further re-use or recycling of the plastic packaging. To assess this technology, we have conducted spectroscopic, thermal, and calorimetric characterizations of the obtained fractions, such as cleaned mixed plastics (CMP), food waste with mixed plastics (FWMP), and a mixture of microplastics (MP). The analyses were carried out with the aid of Fourier-Transform Infrared spectroscopy (FT-IR), Thermo-Gravimetric Analysis (TGA), Microcone Combustion Calorimetry (MCC), and 'bomb' calorimetry. The highest ratio of CMP to FWMP and the lowest amount of MP were obtained utilizing 700 rpm blade rotational speed and 15 s residence time of contaminated plastics in a cutting mill chamber. The plastics were freed from food contamination by 93-97%, which highlights a strong potential of the POC as a solution for 'dry-cleaning' of similar wastes on a larger scale. The main components of the CMP fraction were low-density polyethylene (LDPE), polypropylene (PP), and polyethylene terephthalate (PET), which are recyclable plastics. The knowledge and understanding of thermal degradation behaviours and calorimetric attributes of separated fractions, determined in this study, are essential in informing the industrial players using pyrolysis as a technique for recycling plastics.

Health risks from radioactive particles on Cumbrian beaches near the Sellafield nuclear site.

A monitoring programme, in place since 2006, continues to recover radioactive particles (<2 mm diameter) and larger objects from the beaches of West Cumbria. The potential risks to members of the public using the beaches are mainly related to prolonged skin contact with or the inadvertent ingestion of small particles. Most particles are classified as either 'beta-rich' or 'alpha-rich' and are detected as a result of their caesium-137 or americium-241 content. Beta-rich particles generally also contain strontium-90, with90Sr:137Cs ratios of up to about 1:1, but typically <0.1:1. Alpha-rich particles contain plutonium isotopes, with Pu:241Amαratios usually around 0.5-0.6:1. 'Beta-rich' particles have the greatest potential to cause localised skin damage if held in stationary contact with the skin for prolonged periods. However, it is concluded that only particles of >106Bq of137Cs, with high90Sr:137Cs ratios, would pose a significant risk of causing acute skin ulceration. No particles of this level of activity have been found. Inadvertent ingestion of a particle will result in the absorption to blood of a small proportion of the radionuclide content of the particle. The subsequent retention of radionuclides in body organs and tissues presents a potential risk of the development of cancer. For 'beta-rich' particles with typical activities (mean 2 × 104Bq137Cs, Sr:Cs ratio of 0.1:1), the estimated committed effective doses are about 30µSv for adults and about 40µSv for 1 year old infants, with lower values for 'alpha-rich' particles of typical activities. The corresponding estimates of lifetime cancer incidence following ingestion for both particle types are of the order of 10-6for adults and up to 10-5for infants. These estimates are subject to substantial uncertainties but provide an indication of the low risks to members of the public.

Designing a zero-order energy transition model: How to create a new Starter Data Kit.

The Paris Agreement was signed by 192 Parties, who committed to reducing emissions. Reaching such commitments by developing national decarbonisation strategies requires significant analyses and investment. Analyses for such strategies are often delayed due to a lack of accurate and up-to-date data for creating energy transition models. The Starter Data Kits address this issue by providing open-source, zero-level country datasets to accelerate the energy planning process. There is a strong demand for replicating the process of creating Starter Data Kits because they are currently only available for 69 countries in Africa, Asia, and South America. Using an African country as an example, this paper presents the methodology to create a Starter Data Kit made of tool-agnostic data repositories and OSeMOSYS-specific data files. The paper illustrates the steps involved, provides additional information for conducting similar work in Asia and South America, and highlights the limitations of the current version of the Starter Data Kits. Future development is proposed to expand the datasets, including new and more accurate data and new energy sectors. Therefore, this document provides instructions on the steps and materials required to develop a Starter Data Kit.•The methodology presented here is intended to encourage practitioners to apply it to new countries and expand the current Starter Data Kits library.•It is a novel process that creates data pipelines that feed into a single Data Collection and Manipulation Tool (DaCoMaTool).•It allows for tool-agnostic data creation in a consistent format ready for a modelling analysis using one of the available tools.

Anatomic Monopolar Press-fit Radial Head Arthroplasty; High Rate of Loosening at Mid-Term Follow Up.

Introduction: Radial head arthroplasty (RHA) is used for the management of unstable or unreconstructable injuries of the radial head. Our aim was to investigate clinical and radiographic outcomes in patients treated with the Acumed anatomic radial head press-fit system for trauma. Methods: Clinical and radiographic assessment of RHAs undertaken for trauma with minimum 2-year follow-up. Results: 16 consecutive patients, mean age 53 (21-82) and 66 month ± 27 (26-122) clinical follow-up were included. There were marked radiographic changes with 11/16 showing periprosthetic lucent lines and 13/16 showing subcollar osteolysis. Radiographic changes occurred early post-surgery. Stem loosening was associated with larger cantilever quotients (0.47 vs 0.38, p = 0.004). Overall survivability was 81.2%, with 3 RHAs removed. Clinical outcomes for the retained RHAs were acceptable with mean flexion 134°, extension deficit of 10°, pronation of 82°, and supination of 73°. Mean VAS scores were 8.5 ± 14.4, QuickDASH 13.8 ± 18.9, Mayo Elbow Performance Scores were 91.5 ± 12.5 with no poor scores. Conclusion: Mid-term clinical functional outcomes following the Acumed anatomic RHA are acceptable in most cases. However, in view of the extensive periprosthetic lucencies and surgical removal due to loosening, patients should be cautioned when consented for implantation of the prosthesis, especially if a large collar is anticipated.

The mitochondrial genome of the diploid oat Avena longiglumis.

BACKGROUND: Avena longiglumis Durieu (2n = 2x = 14) is a wild relative of cultivated oat (Avena sativa, 2n = 6x = 42) with good agronomic and nutritional traits. The plant mitochondrial genome has a complex organization and carries genetic traits of value in exploiting genetic resources, not least male sterility alleles used to generate F1 hybrid seeds. Therefore, we aim to complement the chromosomal-level nuclear and chloroplast genome assemblies of A. longiglumis with the complete assembly of the mitochondrial genome (mitogenome) based on Illumina and ONT long reads, comparing its structure with Poaceae species. RESULTS: The complete mitochondrial genome of A. longiglumis can be represented by one master circular genome being 548,445 bp long with a GC content of 44.05%. It can be represented by linear or circular DNA molecules (isoforms or contigs), with multiple alternative configurations mediated by long (4,100-31,235 bp) and medium (144-792 bp) size repeats. Thirty-five unique protein-coding genes, three unique rRNA genes, and 11 unique tRNA genes are identified. The mitogenome is rich in duplications (up to 233 kb long) and multiple tandem or simple sequence repeats, together accounting for more than 42.5% of the total length. We identify homologous sequences between the mitochondrial, plastid and nuclear genomes, including the exchange of eight plastid-derived tRNA genes, and nuclear-derived retroelement fragments. At least 85% of the mitogenome is duplicated in the A. longiglumis nuclear genome. We identify 269 RNA editing sites in mitochondrial protein-coding genes including stop codons truncating ccmFC transcripts. CONCLUSIONS: Comparative analysis with Poaceae species reveals the dynamic and ongoing evolutionary changes in mitochondrial genome structure and gene content. The complete mitochondrial genome of A. longiglumis completes the last link of the oat reference genome and lays the foundation for oat breeding and exploiting the biodiversity in the genus.

US regulations to curb alleged cancer causes are ineffectual and compromised by scientific, constitutional and ethical violations.

The 1958 Delaney amendment to the Federal Food Drug and Cosmetics Act prohibited food additives causing cancer in animals by appropriate tests. Regulators responded by adopting chronic lifetime cancer tests in rodents, soon challenged as inappropriate, for they led to very inconsistent results depending on the subjective choice of animals, test design and conduct, and interpretive assumptions. Presently, decades of discussions and trials have come to conclude it is impossible to translate chronic animal data into verifiable prospects of cancer hazards and risks in humans. Such conclusion poses an existential crisis for official agencies in the US and abroad, which for some 65 years have used animal tests to justify massive regulations of alleged human cancer hazards, with aggregated costs of $trillions and without provable evidence of public health advantages. This article addresses suitable remedies for the US and potentially worldwide, by critically exploring the practices of regulatory agencies vis-á-vis essential criteria for validating scientific evidence. According to this analysis, regulations of alleged cancer hazards and risks have been and continue to be structured around arbitrary default assumptions at odds with basic scientific and legal tests of reliable evidence. Such practices raise a manifold ethical predicament for being incompatible with basic premises of the US Constitution, and with the ensuing public expectations of testable truth and transparency from government agencies. Potential remedies in the US include amendments to the US Administrative Procedures Act, preferably requiring agencies to justify regulations compliant with the Daubert opinion of the Daubert ruling of the US Supreme Court, which codifies the criteria defining reliable scientific evidence. International reverberations are bound to follow what remedial actions may be taken in the US, the origin of current world regulatory procedures to control alleged cancer causing agents.

Effective doses and risks from medical diagnostic x-ray examinations for male and female patients from childhood to old age.

The consideration of risks from medical diagnostic x-ray examinations and their justification commonly relies on estimates of effective dose, although the quantity is actually a health-detriment-weighted summation of organ/tissue-absorbed doses rather than a measure of risk. In its 2007 Recommendations, the International Commission on Radiological Protection (ICRP) defines effective dose in relation to a nominal value of stochastic detriment following low-level exposure of 5.7 × 10-2Sv-1, as an average over both sexes, all ages, and two fixed composite populations (Asian and Euro-American). Effective dose represents the overall (whole-body) dose received by a person from a particular exposure, which can be used for the purposes of radiological protection as set out by ICRP, but it does not provide a measure that is specific to the characteristics of the exposed individual. However, the cancer incidence risk models used by ICRP can be used to provide estimates of risk separately for males and females, as a function of age-at-exposure, and for the two composite populations. Here, these organ/tissue-specific risk models are applied to estimates of organ/tissue-specific absorbed doses from a range of diagnostic procedures to derive lifetime excess cancer incidence risk estimates; the degree of heterogeneity in the distribution of absorbed doses between organs/tissues will depend on the procedure. Depending on the organs/tissues exposed, risks are generally higher in females and notably higher for younger ages-at-exposure. Comparing lifetime cancer incidence risks per Sv effective dose from the different procedures shows that overall risks are higher by about a factor of two to three for the youngest age-at-exposure group, 0-9 yr, than for 30-39 yr adults, and lower by a similar factor for an age-at-exposure of 60-69 yr. Taking into account these differences in risk per Sv, and noting the substantial uncertainties associated with risk estimates, effective dose as currently formulated provides a reasonable basis for assessing the potential risks from medical diagnostic examinations.

The ambivalence toward neuropsychology in dementia research, diagnosis, and drug development: Myths and misconceptions.

Clinical assessment remains the gold standard for diagnosing dementia, monitoring progression, and conducting clinical research. Biomarkers hold promise for targeted therapeutic approaches, selection of participants in clinical trials, and direct physiological efficacy readouts. However, the anchoring of biomarker research to clinical symptomatology is often based on short and insensitive cognitive screening. This gives the impression that cognitive symptoms occur relatively late and that their progression in the early stages of the disease is slow. A thorough cognitive assessment is a powerful tool and has a key role in the accurate and early diagnosis of dementia. It is very different from the cognitive testing usually seen in biomarker research and drug development. Yet the distinction between these approaches is unclear to many. This paper highlights the misconceptions around cognitive research in dementia and suggests a way forward to facilitate biomarker and drug development through the improved utility of cognitive assessment tools.

Techno-economic data and assumptions for long-term energy systems modelling in Viet Nam.

Viet Nam is at a critical juncture in planning for its future energy mix due to its fast-growing economy and recent climate commitments. Robust modelling analyses examining the potential and practical energy mix alternatives are therefore key in providing key stakeholders with critical information on energy policy decision-making. The challenge is that a large volume of data is required to accurately model various energy pathways at the national scale. This data note, therefore, aims to bridge the current data gap by providing key information on input data and assumptions for long-term energy planning in Viet Nam. Historical and/or projected data regarding electricity generation and consumption, electricity imports and exports, fuel prices, emissions, refineries, power transmission and distribution, electricity generation technologies, and renewable energy potential and reserves for the years 2015 to 2050 are described in this article.

Is the disease risk and penetrance in Leber hereditary optic neuropathy actually low?

Pedigree analysis showed that a large proportion of Leber hereditary optic neuropathy (LHON) family members who carry a mitochondrial risk variant never lose vision. Mitochondrial haplotype appears to be a major factor influencing the risk of vision loss from LHON. Mitochondrial variants, including m.14484T>C and m.11778G>A, have been added to gene arrays, and thus many patients and research participants are tested for LHON mutations. Analysis of the UK Biobank and Australian cohort studies found more than 1 in 1,000 people in the general population carry either the m.14484T>C or the m.11778G>A LHON variant. None of the subset of carriers examined had visual acuity at 20/200 or worse, suggesting a very low penetrance of LHON. Haplogroup analysis of m.14484T>C carriers showed a high rate of haplogroup U subclades, previously shown to have low penetrance in pedigrees. Penetrance calculations of the general population are lower than pedigree calculations, most likely because of modifier genetic factors. This Matters Arising Response paper addresses the Watson et al. (2022) Matters Arising paper, published concurrently in The American Journal of Human Genetics.