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Background: In an ageing population, low impact fragility fractures are becoming increasingly common. However, fracture risk can be reduced where low bone density can be identified at an early stage. In this study we aim to demonstrate that IBEX Bone Health (IBEX BH) can provide a clinically useful prediction from wrist radiographs of aBMD and T-score at the ultra-distal (UD) and distal-third (DT) regions of the radius., Methods: A 261-participant single-centre, non-randomised, prospective, study was carried out to compare a) IBEX BH, a quantitative digital radiography software device, to b) Dual-energy X-ray Absorptiometry (DXA). A total of 257 participants with wrist digital radiograph (DR), forearm DXA pairs were included in the analysis after exclusions., Results: The adjusted R 2 value for IBEX BH outputs to the radial areal bone mineral density (aBMD) produced by a GE Lunar DXA system for the UD region is 0.87 (99% Confidence Interval (CI) [0.84, 0.89]). The adjusted R 2 value for IBEX BH outputs to aBMD for the DT region is 0.88 (99% CI [0.85, 0.90]). The Area Under the Receiver Operating Characteristic curve (AUC) for the forearm T-score ≤  - 2.5 risk prediction model at the UD region is 0.95 (99% CI [0.93, 0.98]). The AUC for the forearm T-score ≤  - 2.5 risk prediction model at the DT region is 0.98 (99% CI [0.97, 0.99])., Conclusion: From a DR of the wrist, IBEX BH provides a clinically useful i) estimate of aBMD at the two regions of interest on the radius and ii) risk prediction model of forearm T-score ≤  - 2.5 at the UD and DT regions., (© 2024. The Author(s).)

Osteoporosis and associated fractures are an increasingly prevalent concern with an ageing population. This study reports testing of IBEX Bone Health (IBEX BH) software, applied following acquisition of forearm radiographs. IBEX Bone Health analyses the radiograph to measure areal bone mineral density (aBMD) at the examination site. A non-randomized cross-sectional study design was performed involving 261 (254 after exclusions) participants (112/142 m/f; mean age 70.8 years (SD+/-9.0); 53 with osteoporosis). They underwent posterior-anterior distal forearm radiographs; dual X-ray absorptiometry (DXA) of the wrists, hips, and lumbar spine; and questionnaires exploring clinical risk factors. IBEX Bone Health automatically identifies regions of interest (ROI) at the ultra-distal (UD) and distal third (TD) regions of the radius. Analysis investigated area under the receiver operating characteristics curve performance of IBEX BH for prediction of (i) osteoporosis (based on clinical reporting of the hip and spine DXA) and (ii) treatment recommendations by Fracture Risk Assessment Tool (FRAX) inclusive of neck of femur (NoF) areal bone mineral density (aBMD) results following National Osteoporosis Guideline Group (NOGG) guidelines. Area under the receiver operating characteristics curve for osteoporosis prediction at the UD and TD ROIs were 0.86 (99% confidence interval (CI) [0.80, 0.91]) and 0.81 (99% CI [0.75, 0.88]), respectively. Area under the receiver operating characteristics curve for treatment recommendation using FRAX inclusive of NoF aBMD at the UD and TD ROIs were 0.95 (99% CI [0.91, 1.00]) and 0.97 (99% CI [0.93,1.00]), respectively. With a matched sensitivity to FRAX (without NoF aBMD) 0.93 (99% CI [0.78, 0.99]), IBEX BH predicted at the UD and TD ROIs recommended treatment outcomes by NOGG guidelines using FRAX (with NoF aBMD) with specificity 0.89 (99% CI 0.83, 0.94]) and 0.93 (99% CI [0.87, 0.97]), respectively. This is compared with 0.60 (99% CI [0.51, 0.69]) for FRAX (without NoF aBMD). Results demonstrate the potential clinical utility of IBEX BH as an opportunistic screening tool., Competing Interests: The co-authors on this paper from IBEX Innovations hold the intellectual property rights over the IBEX BH technology and have a vested interest in the adoption of this technology into clinical practice. There are no other conflicts of interest to declare., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Hematopoiesis is a continuous process of blood and immune cell production. It is orchestrated by thousands of gene products that respond to extracellular signals by guiding cell fate decisions to meet the needs of the organism. Although much of our knowledge of this process comes from work in model systems, we have learned a great deal from studies on human genetic variation. Considerable insight has emerged from studies on presumed monogenic blood disorders, which continue to provide key insights into the mechanisms critical for hematopoiesis. Furthermore, the emergence of large-scale biobanks and cohorts has uncovered thousands of genomic loci associated with blood cell traits and diseases. Some of these blood cell trait-associated loci act as modifiers of what were once thought to be monogenic blood diseases. However, most of these loci await functional validation. Here, we discuss the validation bottleneck and emerging methods to more effectively connect variant to function. In particular, we highlight recent innovations in genome editing, which have paved the path forward for high-throughput functional assessment of loci. Finally, we discuss existing barriers to progress, including challenges in manipulating the genomes of primary hematopoietic cells., Competing Interests: Competing interests V.G.S. serves as an advisor to and/or has equity in Branch Biosciences, Ensoma, Novartis, Forma and Cellarity, all unrelated to the present work. The authors have no other competing interests to declare., (© 2023. Published by The Company of Biologists Ltd.)

The demand for revision knee replacement (RKR) has increased dramatically with rising patient life expectancy and younger recipients for primary TKR. However, significant challenges to RKR arise from osseous defects, reduced bone quality, potential bone volume loss from implant removal and the need to achieve implant stability. This study utilizes the outcomes of an ongoing RKR clinical trial using porous metaphyseal cones 3D-printed of titanium, to investigate 1) bone mineral density (BMD) changes in three fixation zones (epiphysis, metaphysis, and diaphysis) over a year and 2) the biomechanical effects of the cones at 6 months post-surgery. It combines dual-energy x-ray absorptiometry (DXA), computed tomography (CT) with patient-specific based finite element (FE) modelling. Bone loss (-0.086 ± 0.05 g/cm 2 ) was found in most patients over the first year. The biomechanical assessment considered four different loading scenarios from standing, walking on a flat surface, and walking downstairs, to a simulated impact of the knee. The patient-specific FE models showed that the cones marginally improved the strain distribution in the bone and shared the induced load but played a limited role in reducing the risks of bone fracture or cement debonding. This technique of obtaining real live data from a randomized clinical trial and inserting it into an in-silico FE model is unique and innovative in RKR research. The tibia RKR biomechanics examined open up further possibilities, allowing the in-silico testing of prototypes and implant combinations without putting patients at risk as per the recommended IDEAL framework standards. This process with further improvements could allow rapid innovation, optimization of implant design, and improve surgical planning., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This study examined whether our ability to accurately estimate unfamiliar faces' ages declines when they are wearing sunglasses or surgical-style face masks and whether these disguises make it harder to later recognise those faces when undisguised. In theory, both disguises should harm age estimation accuracy and later face recognition as they occlude facial information that is used to determine a face's age and identity. To establish whether this is the case, we had participants estimate the age of unfamiliar faces that were pictured wearing no disguises, sunglasses, or face masks. The participants then completed a face recognition test where they had to distinguish between the previously seen faces and new faces. Importantly, none of faces wore disguises in this latter test. Participants' estimates of the undisguised faces' ages were inaccurate by a Median of 5.15 years. Their accuracy barely changed when the faces wore sunglasses but declined by a Median of 1.30 years when they wore face masks. Moreover, subsequent undisguised face recognition was less likely to occur when the faces previously wore sunglasses or face masks, with large effects observed. These findings demonstrate the relative importance of different facial areas when estimating faces' ages and later recognising them. They also have implications for policing as they suggest it may be harder for eyewitnesses to accurately estimate the age of criminals who wear face masks during offences, and it may be harder for them to later recognise criminals in line-ups if the criminals wear sunglasses or face masks during offences., (© 2022. The Author(s).)

We report a novel single-cell whole-genome amplification method (LCS-WGA) that can efficiently capture spontaneous DNA damage existing in single cells. We refer to these damage-associated single-nucleotide variants as "damSNVs," and the whole-genome distribution of damSNVs as the damagenome. We observed that in single human neurons, the damagenome distribution was significantly correlated with three-dimensional genome structures. This nonuniform distribution indicates different degrees of DNA damage effects on different genes. Next, we identified the functionals that were significantly enriched in the high-damage genes. Similar functionals were also enriched in the differentially expressed genes (DEGs) detected by single-cell transcriptome of both Alzheimer's disease (AD) and autism spectrum disorder (ASD). This result can be explained by the significant enrichment of high-damage genes in the DEGs of neurons for both AD and ASD. The discovery of high-damage genes sheds new lights on the important roles of DNA damage in human diseases and disorders., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

The development of automatic methods for segmenting anatomy from medical images is an important goal for many medical and healthcare research areas. Datasets that can be used to train and test computer algorithms, however, are often small due to the difficulties in obtaining experts to segment enough examples. Citizen science provides a potential solution to this problem but the feasibility of using the public to identify and segment anatomy in a medical image has not been investigated. Our study therefore aimed to explore the feasibility, in terms of performance and motivation, of using citizens for such purposes. Public involvement was woven into the study design and evaluation. Twenty-nine citizens were recruited and, after brief training, asked to segment the spine from a dataset of 150 magnetic resonance images. Participants segmented as many images as they could within three one-hour sessions. Their accuracy was evaluated by comparing them, as individuals and as a combined consensus, to the segmentations of three experts. Questionnaires and a focus group were used to determine the citizens' motivation for taking part and their experience of the study. Citizen segmentation accuracy, in terms of agreement with the expert consensus segmentation, varied considerably between individual citizens. The citizen consensus, however, was close to the expert consensus, indicating that when pooled, citizens may be able to replace or supplement experts for generating large image datasets. Personal interest and a desire to help were the two most common reasons for taking part in the study., Competing Interests: The authors have declared that no competing interests exist.

Clinical trials are currently underway to assess the efficacy of forniceal deep brain stimulation (DBS) for improvement of memory in Alzheimer's patients, and forniceal DBS has been shown to improve learning and memory in a mouse model of Rett syndrome (RTT), an intellectual disability disorder caused by loss-of-function mutations in MECP2 . The mechanism of DBS benefits has been elusive, however, so we assessed changes in gene expression, splice isoforms, DNA methylation, and proteome following acute forniceal DBS in wild-type mice and mice lacking Mecp2 . We found that DBS upregulates genes involved in synaptic function, cell survival, and neurogenesis and normalized expression of ~25% of the genes altered in Mecp2 -null mice. Moreover, DBS induced expression of 17-24% of the genes downregulated in other intellectual disability mouse models and in post-mortem human brain tissue from patients with Major Depressive Disorder, suggesting forniceal DBS could benefit individuals with a variety of neuropsychiatric disorders., Competing Interests: AP, HY, AR, YW, MG, SH, HJ, JT, ZL No competing interests declared, HZ Senior editor, eLife, (© 2018, Pohodich et al.)

DNA mutations are the inevitable consequences of errors that arise during replication and repair of DNA damage. Because of their random and infrequent occurrence, quantification and characterization of DNA mutations in the genome of somatic cells has been difficult. Random, low-abundance mutations are currently inaccessible by standard high-throughput sequencing approaches because they cannot be distinguished from sequencing errors. One way to circumvent this problem and simultaneously account for the mutational heterogeneity within tissues is whole genome sequencing of a representative number of single cells. Here, we show elevated mutation levels in single cells from Drosophila melanogaster S2 and mouse embryonic fibroblast populations after treatment with the powerful mutagen N-ethyl-N-nitrosourea. This method can be applied as a direct measure of exposure to mutagenic agents and for assessing genotypic heterogeneity within tissues or cell populations.

DNA mutations are the source of genetic variation within populations. The majority of mutations with observable effects are deleterious. In humans mutations in the germ line can cause genetic disease. In somatic cells multiple rounds of mutations and selection lead to cancer. The study of genetic variation has progressed rapidly since the completion of the draft sequence of the human genome. Recent advances in sequencing technology, most importantly the introduction of massively parallel sequencing (MPS), have resulted in more than a hundred-fold reduction in the time and cost required for sequencing nucleic acids. These improvements have greatly expanded the use of sequencing as a practical tool for mutation analysis. While in the past the high cost of sequencing limited mutation analysis to selectable markers or small forward mutation targets assumed to be representative for the genome overall, current platforms allow whole genome sequencing for less than $5000. This has already given rise to direct estimates of germline mutation rates in multiple organisms including humans by comparing whole genome sequences between parents and offspring. Here we present a brief history of the field of mutation research, with a focus on classical tools for the measurement of mutation rates. We then review MPS, how it is currently applied and the new insight into human and animal mutation frequencies and spectra that has been obtained from whole genome sequencing. While great progress has been made, we note that the single most important limitation of current MPS approaches for mutation analysis is the inability to address low-abundance mutations that turn somatic tissues into mosaics of cells. Such mutations are at the basis of intra-tumor heterogeneity, with important implications for clinical diagnosis, and could also contribute to somatic diseases other than cancer, including aging. Some possible approaches to gain access to low-abundance mutations are discussed, with a brief overview of new sequencing platforms that are currently waiting in the wings to advance this exploding field even further., (Copyright © 2011 Elsevier B.V. All rights reserved.)