Genetic predisposition to mosaic Y chromosome loss in blood.

Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism1-5, yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases.

Rapid prototyping of arbitrary 2D and 3D wireframe DNA origami.

Wireframe DNA origami assemblies can now be programmed automatically from the top-down using simple wireframe target geometries, or meshes, in 2D and 3D, using either rigid, six-helix bundle (6HB) or more compliant, two-helix bundle (DX) edges. While these assemblies have numerous applications in nanoscale materials fabrication due to their nanoscale spatial addressability and high degree of customization, no easy-to-use graphical user interface software yet exists to deploy these algorithmic approaches within a single, standalone interface. Further, top-down sequence design of 3D DX-based objects previously enabled by DAEDALUS was limited to discrete edge lengths and uniform vertex angles, limiting the scope of objects that can be designed. Here, we introduce the open-source software package ATHENA with a graphical user interface that automatically renders single-stranded DNA scaffold routing and staple strand sequences for any target wireframe DNA origami using DX or 6HB edges, including irregular, asymmetric DX-based polyhedra with variable edge lengths and vertices demonstrated experimentally, which significantly expands the set of possible 3D DNA-based assemblies that can be designed. ATHENA also enables external editing of sequences using caDNAno, demonstrated using asymmetric nanoscale positioning of gold nanoparticles, as well as providing atomic-level models for molecular dynamics, coarse-grained dynamics with oxDNA, and other computational chemistry simulation approaches.

Facts and values: on the acceptability of risks in children's sport using the example of rugby - a narrative review.

A clash of values has been identified between those who assert that:1. all childhood injuries, regardless of origin, are inherently undesirable and should be prevented and;2. those who believe that some measure of injury to children is an acceptable compromise for the physical benefits associated with physical activity and the development of abilities to appraise and deal with risks.A debate regarding whether the tackles and collisions permitted in schools' rugby represent acceptable risks, and what steps should be taken if they do not, exemplifies the issue.Questions regarding the magnitude of injury risks in sport are issues of fact and can be quantified via the results of injury surveillance studies. Risks are neither high nor low in isolation; they are relatively high or low with reference to other activities or across groups participating in an activity. Issues of the acceptability of a given degree of risk are value dependent. Research regarding perceptions of risk reveals wide variations in the degree of risk people view as acceptable. Factors impacting on risk perception include whether the risks are well known and understood, whether they are 'dread' risks and the degree to which people undertake the risks voluntarily and feel they have control over them.Based on the evidence currently available, the risks to children playing rugby do not appear to be inordinately high compared with those in a range of other childhood sports and activities, but better comparative information is urgently needed. Further evidence, however, should not necessarily be expected to result in the resolution of acceptable risk debates-pre-existing values shape our perspectives on whether new evidence is relevant, valid and reliable.

Prevalence and Characterization of Salmonella during Pork Sausage Manufacturing.

Pork carcasses and meat may harbor Salmonella and may contaminate other products during harvest and fabrication. Sources of contamination include manure on hides, environmental contamination, ingredients from external sources, and lymph nodes. Swine lymph nodes are often incorporated into ground meat, as their anatomical location makes removal labor prohibitive. A sausage processing plant in the midwestern United States was sampled monthly (except for December) from May 2021 to April 2022 to enumerate Salmonella and Enterobacteriaceae (EB) throughout the sausage manufacturing process to determine high-risk stages and efficiency of existing in-plant interventions. Salmonella serotypes and antimicrobial susceptibility were evaluated on a subset of isolates recovered at the end phases of sausage production. In each collection, samples were taken from the carcasses of eight sows through 11 stages of sausage manufacturing. A total of 830 samples were cultured. Thirty-four Salmonella were isolated from the final three production stages; of these, there were eleven serotypes. Three isolates displayed resistance to ampicillin, whereas the remainder of the isolates were pan-susceptible to the antimicrobials tested. Salmonella and EB were significantly reduced (p < 0.001) by acid washes at different stages of production, and the results point to the beneficial effects of interventions to lessen Salmonella concentrations in retail products.

A closer look into the microbiome of microalgal cultures.

Although bacteria are commonly co-occurring in microalgal cultivation and production systems, little is known about their community structure and how it might be affected by specific microalgal groups or growth conditions. A better understanding about the underlying factors that determine the growth of specific bacterial populations is not only important for optimizing microalgal production processes, but also in the context of product quality when the algal biomass is to be used for future food or feed. We analyzed the bacterial community composition associated with nine microalgal strains in stock culture, maintained in two different growth media, to explore how specific taxonomic microalgal groups, microalgal origin, or the growth medium affect the bacterial community composition. Furthermore, we monitored the bacterial community composition for three Phaeodactylum strains during batch cultivation in bubble columns to examine if the bacterial composition alters during cultivation. Our results reveal that different microalgal genera, kept at the same cultivation conditions over many years, displayed separate and unique bacterial communities, and that different strains of the same genus had very similar bacterial community compositions, despite originating from different habitats. However, when maintained in a different growth medium, the bacterial composition changed for some. During batch cultivation, the bacterial community structure remained relatively stable for each Phaeodactylum strain. This indicates that microalgae seem to impact the development of the associated bacterial communities and that different microalgal genera could create distinct conditions that select for dominance of specific bacteria. However, other factors such as the composition of growth medium also affect the formation of the bacterial community structure.

Clinical audit in European radiology: current status and recommendations for improvement endorsed by the European Society of Radiology (ESR).

Clinical audit is an important quality improvement activity and has significant benefits for patients in terms of enhanced care, safety, experience and outcomes. Clinical audit in support of radiation protection is mandated within the European Council Basic Safety Standards Directive (BSSD), 2013/59/Euratom. The European Society of Radiology (ESR) has recognised clinical audit as an area of particular importance in the delivery of safe and effective health care. The ESR, alongside other European organisations and professional bodies, has developed a range of clinical audit-related initiatives to support European radiology departments in developing a clinical audit infrastructure and fulfilling their legal obligations. However, work by the European Commission, the ESR and other agencies has demonstrated a persisting variability in clinical audit uptake and implementation across Europe and a lack of awareness of the BSSD clinical audit requirements. In recognition of these findings, the European Commission supported the QuADRANT project, led by the ESR and in partnership with ESTRO (European Association of Radiotherapy and Oncology) and EANM (European Association of Nuclear Medicine). QuADRANT was a 30-month project which completed in Summer 2022, aiming to provide an overview of the status of European clinical audit and identifying barriers and challenges to clinical audit uptake and implementation. This paper summarises the current position of European radiological clinical audit and considers the barriers and challenges that exist. Reference is made to the QuADRANT project, and a range of potential solutions are suggested to enhance radiological clinical audit across Europe.

Justification of CT practices across Europe: results of a survey of national competent authorities and radiology societies.

OBJECTIVES: Published literature on justification of computed tomography (CT) examinations in Europe is sparse but demonstrates consistent sub-optimal application. As part of the EU initiated CT justification project, this work set out to capture CT justification practices across Europe. METHODS: An electronic questionnaire consisting of mostly closed multiple-choice questions was distributed to national competent authorities and to presidents of European radiology societies in EU member states as well as Iceland, Norway, Switzerland, and the UK (n = 31). RESULTS: Fifty-one results were received from 30 European countries. Just 47% (n = 24) stated that advance justification of individual CT examinations is performed by a medical practitioner. Radiologists alone mostly (n = 27, 53%) perform daily justification of CT referrals although this is a shared responsibility in many countries. Imaging referral guidelines are widely available although just 13% (n = 6) consider them in daily use. Four countries (Cyprus, Ireland, Sweden, UK) reported having them embedded within clinical decision support systems. Justification of new practices with CT is mostly regulated (77%) although three countries (Belgium, Iceland and Portugal) reported not having any national system in place for generic justification. Health screening with CT was reported by seven countries as part of approved screening programmes and by eight countries outside. When performed, CT justification audits were reported to improve CT justification rates. CONCLUSIONS: CT justification practices vary across Europe with less than 50% using advance justification and a minority having clinical decision support systems in place. CT for health screening purposes is not currently widely used in Europe.

Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with aminoindane and phenylpyrrolidine P4 motifs.

The rational design, syntheses and evaluation of potent sulfonamidopyrrolidin-2-one-based factor Xa inhibitors incorporating aminoindane and phenylpyrrolidine P4 motifs are described. These series delivered highly potent anticoagulant compounds with excellent oral pharmacokinetic profiles; however, significant time dependant P450 inhibition was an issue for the aminoindane series, but this was not observed with the phenylpyrrolidine motif, which produced candidate quality molecules with potential for once-daily oral dosing in humans.

Outcome of untreated meningiomas.

BACKGROUND: Nowadays meningiomas are frequently detected incidentally. Their natural history has not yet been established because it is difficult to predict the growth pattern. Therefore, the management, after the radiological diagnosis, is still controversial. OBJECTIVES: To evaluate the clinical outcome and growth rate of conservatively treated meningiomas at our tertiary center, identify prognostic factors of tumor growth, and suggest guidelines based on the available data and our experience. METHODS: We reviewed the clinical records of 56 patients with 63 untreated meningiomas. Most were diagniosed incidentally. Clinical features and imaging findings at diagnosis and during follow-up were compared between growing and non-growing tumors. Potential patient- and tumor-related predictive factors for growth were analyzed. RESULTS: The study group included 46 women (52 meningiomas) and 10 men (11 meningiomas) aged 39-83 years. Mean tumor size was 18 +/- 11 mm (range 3-70 mm) at diagnosis and 22 +/- 11 mm (range 8-70 mm) at last follow-up; mean follow-up time was 65 +/- 34 months (range 15-152 months). During follow-up 24 tumors (38%) grew ata rate of 4 mm per year; none became symptomatic. Only two prognostic factors were statistically significantly associated with low growth rate: older age and tumor calcifications. CONCLUSIONS: Given our finding of a low growth incidence of meningiomas in the elderly, we support conservative management in patients aged 70 years or older. Calcifications into the meningioma are also indicative of slow growth, suggesting a conservative strategy. Surgery is recommended in younger patients in whom tumor growth occurs more often and a longer follow-up is necessary.

Improving justification of medical exposures using ionising radiation: considerations and approaches from the European Society of Radiology.

This discussion paper has been produced within the context of the European Society of Radiology EuroSafe Imaging initiative and considers primarily the issues and challenges associated with justification of medical exposures using ionising radiation for individual patient diagnostic imaging procedures. It addresses both regulatory requirements and practical considerations and discusses approaches that are intended to improve justification.

ESR EuroSafe Imaging and its role in promoting radiation protection - 6 years of success.

This article introduces the European Society of Radiology's EuroSafe Imaging initiative in the year of its 6th anniversary. The European and global radiation protection frameworks are outlined and the role of the EuroSafe Imaging initiative's Call for Action in successfully achieving international radiation protection goals as set out by those frameworks is detailed.

Genetic variants associated with mosaic Y chromosome loss highlight cell cycle genes and overlap with cancer susceptibility.

The Y chromosome is frequently lost in hematopoietic cells, which represents the most common somatic alteration in men. However, the mechanisms that regulate mosaic loss of chromosome Y (mLOY), and its clinical relevance, are unknown. We used genotype-array-intensity data and sequence reads from 85,542 men to identify 19 genomic regions (P < 5 × 10-8) that are associated with mLOY. Cumulatively, these loci also predicted X chromosome loss in women (n = 96,123; P = 4 × 10-6). Additional epigenome-wide methylation analyses using whole blood highlighted 36 differentially methylated sites associated with mLOY. The genes identified converge on aspects of cell proliferation and cell cycle regulation, including DNA synthesis (NPAT), DNA damage response (ATM), mitosis (PMF1, CENPN and MAD1L1) and apoptosis (TP53). We highlight the shared genetic architecture between mLOY and cancer susceptibility, in addition to inferring a causal effect of smoking on mLOY. Collectively, our results demonstrate that genotype-array-intensity data enables a measure of cell cycle efficiency at population scale and identifies genes implicated in aneuploidy, genome instability and cancer susceptibility.

Justification of CT for Individual Health Assessment of Asymptomatic Persons: A World Health Organization Consultation.

An international expert consultation was convened by the World Health Organization (WHO). The purpose of the meeting was to review the use of CT in examining asymptomatic people. This is often referred to as individual health assessment (IHA). IHA was identified as a global phenomenon unenthusiastically tolerated, and not actively promoted, structured, or regulated in most countries. This paper identifies the state of the art for IHA and some considerations in relation to its justification, in different regions of the world. The outcomes reached include the following: questions around terminology and culture of IHA practice; review of IHA in some countries, regions, and international bodies; dilemmas for participants in IHA; risk communication, education, and training for professions and public; the desirability of guidelines and clinical audit; social, ethical, public health, and resource considerations; and a framework for IHA and regulatory considerations. Three subcategories of examination for asymptomatic individuals were identified: formal screening programs; examinations for which the evidence base or risk profile is incomplete; and opportunistic examinations with little or no evidence or risk profile to suggest they have any merit. The latter challenges the justification principle of radiation protection. In addition, the issue of the costs, direct and indirect, associated with false positives and/or equivocal/incidental findings were highlighted. These and other considerations make it difficult to view some IHA as a bona fide medical activity. To allow it to be viewed as such requires that it be conducted within a robust clinical governance framework that includes regulatory dimensions.

Monitoring of clinical imaging guidelines part 3: norms, standards, and regulations.

It is known that the use of imaging in clinical situations is not always optimal, leading to suboptimal health care and potential radiation risk. There may be overuse of imaging, underuse, or use of the wrong modality. The use of clinical imaging guidelines is likely to improve the use of imaging, but roadblocks exist. Some of these relate to regulatory oversight and mandates. There is wide variation by country and region in the regulatory setting, ranging from actual absence of regulatory authorities to mandated availability of clinical imaging guidelines in the European Community. Collaborative efforts to ensure that clinical imaging guidelines are at least available is a good starting point. Regulatory oversight and support are necessary to ensure the use of clinical imaging guidelines. Regulations should address 3 areas: availability, clinical utilization, and adherence to and revision of guidelines. The use of both internal and external audits, with the aim of both use of and adherence to guidelines and quality improvement, is the best tool for enhancing use. The major challenges that need to be addressed, collaboratively, to ensure the dissemination and use of clinical imaging guidelines are the development of regulations, of regulatory structures that can be effectively deployed, and of benchmarks for adherence and for utility.

Clinical imaging guidelines part 4: challenges in identifying, engaging and collaborating with stakeholders.

The effective development and use of clinical imaging guidelines requires an understanding of who the stakeholders are, what their interests in the process are, and what roles they should play. If the appropriate stakeholders are not engaged in the right roles, it is unlikely that clinical imaging guidelines will be successfully developed, relied on, and actually used. Some stakeholders are obvious: for the development of clinical imaging guidelines, both imagers and those who request examinations, such as general practitioners, internists, and medical specialists, must be involved. To gain acceptance, other relevant groups are stakeholders, including medical societies, other health care professionals, insurers, health IT experts and vendors, and patients. The role of stakeholders must be dictated by their specific interest. For some, involvement in the creation of guidelines is the right role. For others, such as regulators or insurers, reviews or invitations to comment are required, and for others, such as medical educators, it is probably sufficient to provide information and create awareness. Only through a careful consideration of who the stakeholders are and what are their interests are the successful development, acceptance, and use of clinical imaging guidelines likely to occur. Future efforts must focus on collaboration, particularly among groups that create clinical imaging guidelines and those that can support their use, and on regulatory roles and mandates.

Improved patient care and reduced costs: results of Baptist Health Systems' acute coronary syndromes project.

Acute coronary syndromes are deadly conditions that affect millions of people across the nation. As our data show, significant opportunities for quality improvement exist. Heathcare professionals, especially those involved in cardiovascular management, should spearhead quality improvement initiatives at their facilities. These efforts may result in decreased costs, increased patient satisfaction, and more importantly, decreased mortality.

Is the post-take ward round standardised?

BACKGROUND: The importance of the post-take ward round to both patient safety and medical education cannot be overemphasised. Despite this, significant variation exists between consultants and senior doctors in the conduct and content of ward rounds. This discrepancy prompted the idea of using a checklist to audit whether essential components were being consistently addressed during post-take ward rounds. This would allow an exploration of whether introducing a checklist would benefit both patient safety and medical education. METHODS: The post-take ward round was audited by a small group of medical students over a few months using a checklist. This checklist contained 17 evidence-based items that had been identified as important for patient safety. A number of different consultants were included in the audit. RESULTS: Results of the audit analysis confirmed that there was significant variability between consultants in both the approach and the content of the post-take ward round. Although some areas were completed most of the time, there were other areas in which inconsistent approaches were demonstrated. DISCUSSION: As such variability was demonstrated between consultants in their conduct of the ward rounds, it was concluded that the introduction of this checklist would provide a standardised approach that junior doctors could learn from. Therefore, the introduction of this checklist into clinical practice was identified as a worthwhile teaching resource for juniors in order to enhance patient safety and foundation doctor learning.

Soliciting an herbal medicine and supplement use history at hospice admission.

BACKGROUND: Reconciling medication use and performing drug utilization review on admission of a patient into hospice care are essential in order to safely prescribe medications and to prevent possible adverse drug events and drug-drug interactions. As part of this process, fully assessing herbal medicine and supplement use in hospice patients is crucial, as patients in hospice may be likely to use these medications and may be more vulnerable to their potential adverse effects. OBJECTIVE: Our purpose was to identify herbals, vitamins, and supplements that should be routinely assessed on every hospice admission because of their higher likelihood of use or higher risk of adverse effects or drug interactions. METHODS: Experts in the fields of palliative medicine, pharmacy, and alternative medicine were asked to complete a Web-based survey on 37 herbals, vitamins, supplements, and natural products, rating likelihood of use, potential for harm, and recommendation to include it on the final list on a scale of 1 to 5 (least to most likely to agree). RESULTS: Twenty experts participated in the survey. Using a cutoff of 3.75 for inclusion of a medication on the final list, 12 herbal medicines were identified that should be routinely and specifically assessed on hospice admission. CONCLUSIONS: Although assessing all herbal medicine use is ideal, thorough detection of herbals may be challenging. The list of herbals and supplements identified by this survey could be a useful tool for medication reconciliation in hospice and could aid in identifying potentially harmful medication use at the end of life.

Sets meeting isometric copies of the lattice Z2 in exactly one point.

The construction of a subset S of (2) such that each isometric copy of (2) (the lattice points in the plane) meets S in exactly one point is indicated. This provides a positive answer to a problem of H. Steinhaus [Sierpinski, W. (1958) Fund. Math. 46, 191-194].