First Dark Matter Search with Nuclear Recoils from the XENONnT Experiment.

We report on the first search for nuclear recoils from dark matter in the form of weakly interacting massive particles (WIMPs) with the XENONnT experiment, which is based on a two-phase time projection chamber with a sensitive liquid xenon mass of 5.9 ton. During the (1.09±0.03) ton yr exposure used for this search, the intrinsic ^{85}Kr and ^{222}Rn concentrations in the liquid target are reduced to unprecedentedly low levels, giving an electronic recoil background rate of (15.8±1.3) events/ton yr keV in the region of interest. A blind analysis of nuclear recoil events with energies between 3.3 and 60.5 keV finds no significant excess. This leads to a minimum upper limit on the spin-independent WIMP-nucleon cross section of 2.58×10^{-47} cm^{2} for a WIMP mass of 28 GeV/c^{2} at 90% confidence level. Limits for spin-dependent interactions are also provided. Both the limit and the sensitivity for the full range of WIMP masses analyzed here improve on previous results obtained with the XENON1T experiment for the same exposure.

Searching for Heavy Dark Matter near the Planck Mass with XENON1T.

Multiple viable theoretical models predict heavy dark matter particles with a mass close to the Planck mass, a range relatively unexplored by current experimental measurements. We use 219.4 days of data collected with the XENON1T experiment to conduct a blind search for signals from multiply interacting massive particles (MIMPs). Their unique track signature allows a targeted analysis with only 0.05 expected background events from muons. Following unblinding, we observe no signal candidate events. This Letter places strong constraints on spin-independent interactions of dark matter particles with a mass between 1×10^{12} and 2×10^{17} GeV/c^{2}. In addition, we present the first exclusion limits on spin-dependent MIMP-neutron and MIMP-proton cross sections for dark matter particles with masses close to the Planck scale.

Search for New Physics in Electronic Recoil Data from XENONnT.

We report on a blinded analysis of low-energy electronic recoil data from the first science run of the XENONnT dark matter experiment. Novel subsystems and the increased 5.9 ton liquid xenon target reduced the background in the (1, 30) keV search region to (15.8±1.3) events/(ton×year×keV), the lowest ever achieved in a dark matter detector and ∼5 times lower than in XENON1T. With an exposure of 1.16 ton-years, we observe no excess above background and set stringent new limits on solar axions, an enhanced neutrino magnetic moment, and bosonic dark matter.

Understanding farmers' and veterinarians' behavior in relation to antimicrobial use and resistance in dairy cattle: A systematic review.

To tackle antimicrobial resistance, it is vital that farmers' and veterinarians' antimicrobial use behaviors and attitudes toward resistance are understood so that we can identify how beliefs and motives influence practices. Current literature details qualitative and quantitative research that explores the knowledge, attitudes and perceptions of dairy farmers and veterinarians with respect to antimicrobial resistance and antimicrobial practices, and the reported findings are varied and conflicting. Our objective was to conduct a systematic review to assess the evidence and knowledge gaps in the published literature. We identified articles via database searches of Embase, Medline, PubMed, Scopus, and Web of Science; we limited findings to published articles available in English with no publication year restrictions. Article screening was conducted at 3 levels: title, abstract, and full text. Of the 349 articles identified, 35 were retained for systematic review. Transparency of reporting was assessed for each study using the Consolidated Criteria for Reporting Qualitative Research (COREQ) framework. Quality was assessed using the Critical Appraisal Skills Programme qualitative checklist. Findings relating to dairy farmers' and veterinarians' knowledge, attitudes, and perceptions on antimicrobial resistance and practices were thematically analyzed. The comprehensiveness of reporting was variable: studies reported 5 to 26 of the 32 COREQ checklist items. Five key themes emerged from the data: knowledge and awareness of antimicrobial resistance; factors influencing farmer and veterinarian decision-making; perceived barriers and facilitators to reduced antimicrobial use; perceived responsibility for antimicrobial resistance; and the role of the farmer and veterinarian relationship in reducing antimicrobial use. Awareness of prudent antimicrobial use was not uniform between studies. Many factors influence farmers' and veterinarians' decisions to use antimicrobials, including animal welfare and available resources. The farmer-veterinarian relationship is a potential barrier or facilitator of reduced antimicrobial use, depending on the perceived relationship dynamic. Encouraging collaboration between farmers and veterinarians could lead to shared responsibility for reducing antimicrobial use. This review provided a coherent picture of what is currently known and identified gaps in the current knowledge to inform future behavioral intervention research. Increased knowledge, skill development, resources, engagement, and further research to address the gaps we identified are the main recommendations to effectively overcome barriers, elicit appropriate behavior change, and achieve reduced antimicrobial use in dairy cattle.

Aging, frailty and complex networks.

When people age their mortality rate increases exponentially, following Gompertz's law. Even so, individuals do not die from old age. Instead, they accumulate age-related illnesses and conditions and so become increasingly vulnerable to death from various external and internal stressors. As a measure of such vulnerability, frailty can be quantified using the frailty index (FI). Larger values of the FI are strongly associated with mortality and other adverse health outcomes. This association, and the insensitivity of the FI to the particular health variables that are included in its construction, makes it a powerful, convenient, and increasingly popular integrative health measure. Still, little is known about why the FI works so well. Our group has recently developed a theoretical network model of health deficits to better understand how changes in health are captured by the FI. In our model, health-related variables are represented by the nodes of a complex network. The network has a scale-free shape or "topology": a few nodes have many connections with other nodes, whereas most nodes have few connections. These nodes can be in two states, either damaged or undamaged. Transitions between damaged and non-damaged states are governed by the stochastic environment of individual nodes. Changes in the degree of damage of connected nodes change the local environment and make further damage more likely. Our model shows how age-dependent acceleration of the FI and of mortality emerges, even without specifying an age-damage relationship or any other time-dependent parameter. We have also used our model to assess how informative individual deficits are with respect to mortality. We find that the information is larger for nodes that are well connected than for nodes that are not. The model supports the idea that aging occurs as an emergent phenomenon, and not as a result of age-specific programming. Instead, aging reflects how damage propagates through a complex network of interconnected elements.

Cervical spine meniscoids: an update on their morphological characteristics and potential clinical significance.

PURPOSE: Cervical spine meniscoids are intra-articular folds of synovial membrane that have been theorised to have potential clinical significance in neck pain. Recent anatomical and clinical research has re-visited the pathoanatomical capacity of these structures. The purpose of this review is to discuss cervical spine meniscoid morphology in light of recently published work, to provide an update on the plausible relevance of these structures to clinical practice. METHODS: Narrative review critically discussing basic science and clinical research regarding cervical spine meniscoids, with focus upon implications for clinical practice. RESULTS: Basic science research indicates that cervical spine meniscoids can be innervated and appear to vary in morphology in the presence of articular degeneration. In a clinical population, associations have been observed between cervical spine meniscoid morphology and presence of cervical spine symptoms. CONCLUSIONS: Recent studies regarding cervical spine meniscoid morphology provide further evidence of pathoanatomical capacity of these structures. Further research is required, however, in clinical populations to empirically investigate specific theorised mechanisms of cervical spine meniscoid involvement in neck pain.

Pilot evaluation of an online weight management programme.

This intervention examined the efficacy of a six-week online weight loss programme. Students and staff of a third level institution (n=183) were recruited to the programme which provided individualised dietary advice for weight loss. Eighty-five participants (mean age 29.7 years, mean BMI 28.9kg/m2, 33% male) met the minimum inclusion criterion of logging on to the study website at least twice. All participants who completed the full six-week programme lost weight (n=31), with significant reductions in mean weight (2.8kg), BMI (0.9kg/m2) and waist circumference (4.1cm) observed between the start and end of the programme (all P<0.001). Among "completers", males lost more weight than females (4.2kg vs. 1.9kg, P=0.004). One in four completers lost >5% of their bodyweight, with reductions in biscuit and alcohol consumption being most predictive of weight loss. These findings suggest that individualised online dietary advice is effective in achieving short-term weight loss, especially in males.

Discordant dry eye disease and chronic pain: A systematic review and meta-analysis.

PURPOSE: To evaluate the relative contributions of objective and subjective indicators of dry eye disease (DED) in individuals with chronic pain conditions compared with controls. METHODS: A systematic review and meta-analysis was conducted of studies that reported the signs and symptoms of DED and/or their prevalence in individuals with chronic pain compared with controls. International Association for the Study of Pain (IASP) International Classification of Diseases (ICD)-11 codes for chronic pain conditions were applied, and outcomes defined as DED signs and symptoms. A search strategy utilised the EMBASE, Web of Science, Cochrane Library and MEDLINE databases. Risk of bias assessment was performed with the Newcastle-Ottawa scale. Random effects meta-analysis calculated mean differences (MD) and odds ratios (OR), while subgroup analysis of different chronic pain conditions explored their relative association with the signs and symptoms of DED. Evidence certainty was evaluated using Grades of Recommendation, Assessment, Development, and Evaluation (GRADE). RESULTS: Fourteen observational studies comprising 3,281,882 individuals were included. Meta-analysis found high quality evidence that individuals with chronic pain were more likely to experience symptoms of DED than controls (OR = 3.51 [95 %CI: 3.45,3.57]). These symptoms were more severe (MD = 18.53 [95 %CI: 11.90, 25.15]) than controls with a clinically meaningful effect size. Individuals with chronic pain had more rapid tear film disruption (MD = -2.45 [95 %CI: -4.20, -0.70]) and reduced tear production (MD = -5.57 [95 %CI: -9.56, -1.57]) compared with controls (with moderate evidence quality). High quality evidence revealed individuals with chronic pain had lower basal tear production (anaesthetised) than controls (MD = -2.59 [95 %CI: -3.60, -1.58]). Tear film osmolarity showed no significant differences between the chronic pain and pain-free groups. Group differences for DED signs were not considered clinically meaningful. CONCLUSION: More severe, clinically meaningful symptoms of DED were reported in individuals with chronic pain than controls, however group differences for the signs of DED were typically of limited or questionable clinical relevance. This ocular phenotype where DED is felt more than it is seen in chronic pain may reflect underlying sensory hypersensitivity, shared by both conditions and contributing to their frequent comorbidity. Advancing understanding of this potential pathophysiological mechanism may guide clinical management.

A tale of two sisters - delayed diagnosis of genetic hyperinsulinaemic hypoglycaemia.

Summary: Congenital hyperinsulinism is the leading cause of persistent hypoglycaemia in infants and children; however, it is uncommon to be diagnosed in adulthood. We describe the cases of two sisters who presented with hyperinsulinaemic hypoglycaemia aged 47 and 57 years old, who were subsequently diagnosed with compound heterozygous likely pathogenic variants in the ABCC8 gene, a known cause of monogenic congenital hyperinsulinism. We discuss the typical presenting features, investigation findings, and treatment strategies for patients with this condition. Learning Points: Congenital hyperinsulinism is a rare cause of hyperinsulinaemic hypoglycaemia diagnosed in adulthood. Clinical presentation is similar to an insulinoma, and imaging modalities may assist in differentiation. There are minimal medical therapies currently available for patients non-responsive to diazoxide (such as those with ABCC8 and KCNJ11 variants). Continuous glucose monitoring can be helpful in giving patients autonomy in managing their disease, as well as relieving anxiety and fear associated with hypoglycaemia.

A multinational survey of companion animal veterinary clinicians: How can antimicrobial stewardship guidelines be optimised for the target stakeholder?

Antimicrobial stewardship initiatives are widely regarded as a cornerstone for ameliorating the global health impact of antimicrobial resistance. Within companion animal health, such efforts have largely focused on development and dissemination of antimicrobial stewardship guidelines (ASGs). However, there have been few attempts to understand veterinarian attitudes towards and knowledge of ASGs or to determine how awareness regarding ASGs might best be increased. An online survey regarding ASGs was formulated for veterinarians who treat companion animals. The survey was distributed across 46 European and associated countries between 12 January and 30 June, 2022. In total, 2271 surveys were completed, with 64.9% of respondents (n = 1474) reporting awareness and usage of at least one ASG. Respondents from countries with greater awareness of ASGs tended to report more appropriate use of antimicrobials (Spearman's rank coefficient = 0.6084, P ≤ 0.001), with respondents from countries with country-specific ASGs tending to score highest across both awareness and appropriate use domains. Respondents prioritised guidance around antimicrobial choice (82.0%, n = 1863), duration of treatment (66.0%, n = 1499), and dosage (51.9%, n = 1179) for inclusion in future ASGs, with 78.0% (n = 1776) of respondents preferring ASGs to be integrated into their patient management system. Awareness of ASGs and their use in companion animal veterinary practice appears to be greater than previously reported, with respondents tending to report antimicrobial prescription decision making broadly in line with current clinical recommendations. However, further initiatives aimed at maximising accessibility to ASGs both within countries and individual veterinary practices are recommended.

The XENONnT dark matter experiment.

The multi-staged XENON program at INFN Laboratori Nazionali del Gran Sasso aims to detect dark matter with two-phase liquid xenon time projection chambers of increasing size and sensitivity. The XENONnT experiment is the latest detector in the program, planned to be an upgrade of its predecessor XENON1T. It features an active target of 5.9 tonnes of cryogenic liquid xenon (8.5 tonnes total mass in cryostat). The experiment is expected to extend the sensitivity to WIMP dark matter by more than an order of magnitude compared to XENON1T, thanks to the larger active mass and the significantly reduced background, improved by novel systems such as a radon removal plant and a neutron veto. This article describes the XENONnT experiment and its sub-systems in detail and reports on the detector performance during the first science run.

The increasing role of pharmacists in antimicrobial stewardship in English hospitals.

OBJECTIVES: To evaluate the development of pharmacist-led antimicrobial stewardship activities in English hospitals. METHODS: Distribution of an electronic questionnaire to antimicrobial pharmacists or chief pharmacists in National Health Service hospitals in England. RESULTS: Since a previous study, in 2005, overall numbers of specialist antimicrobial pharmacists, and their levels of experience, had increased. Over 95% of hospitals provided empirical usage guidance, antimicrobial formularies and surgical prophylaxis guidelines. Two-thirds of pharmacy departments provided antimicrobial usage reports in terms of defined daily doses at least yearly, and over 80% conducted yearly antimicrobial point prevalence studies. The vast majority of pharmacy departments indicated a willingness to supply data and audit results to a national database for benchmarking purposes. CONCLUSIONS: The increasing role of specialist pharmacists and general pharmacists in antibiotic stewardship in acute care in England has enabled hospitals to deliver on the antibiotic stewardship agenda, although opportunity remains to expand this role further and ensure greater multidisciplinary engagement.

Parathyromatosis following spontaneous rupture of a parathyroid adenoma: natural history and the challenge of management.

Parathyromatosis, the presence of small nodules of hyper-functioning parathyroid tissue scattered throughout the soft tissues of the neck and superior mediastinum, is a rare cause of persistent primary hyperparathyroidism. We report the first case of parathyromatosis secondary to spontaneous rupture of a parathyroid adenoma. Despite running an indolent course, this case highlights the potential challenges of management of parathyromatosis and the value of calcimimetic therapy as an adjunct to surgery for disease control.

Comparing the Tonojet disposable tonometer with the traditional Goldmann tonometer in glaucomatous and non-glaucomatous eyes.

Applanation tonometry is widely performed as the most accurate method of measuring intraocular pressure in the clinical setting. Disposable tonometer heads reduce the risk of transmitting infection during applanation and eliminate tonometer head cleaning, which is time-consuming. We performed a study to investigate whether the Tonojet disposable tonometer (Luneau, France) gave comparable intraocular pressure measurements to the standard Goldmann tonometer produced by Haag Streit (Switzerland). The study was performed in a busy general secondary referral ophthalmology clinic in Beaumont Hospital over a 15-day period. We measured intraocular pressure with the Goldmann and Tonojet tonometers in 293 eyes. Patients were randomised as to which tonometer was used first. A diagnosis of glaucoma or ocular hypertension was noted. Central corneal thickness (CCT) was measured. The measurements taken with the Tonojet were on average 2.2 mmHg lower than corresponding measurements taken with the Goldmann applanation tonometer head. The bias was present over the entire range of pressures. The 95 % limits of agreement between the two tonometers ranged from -5.9 to +1.4 mmHg. In the cohort of eyes with ocular hypertension/glaucoma the difference was significantly higher (2.8 vs. 2.1 mmHg). The bias was independent of CCT. We found that the Tonojet disposable tonometer tends to underestimate intraocular pressure compared with the Goldmann. The bias is non-systematic, present over the entire range of pressures and independent of corneal thickness. We conclude that the Tonojet is not sufficiently accurate to constitute a suitable alternative to the Goldmann.

Relationship between 1-, 3-, and 6-Month Gingival Bleeding Outcomes.

INTRODUCTION: Results from systematic reviews and meta-analyses show generally consistent antigingivitis effects between 3- and 6-mo observation time points with twice-daily use of stannous fluoride (SnF2) dentifrice. However, the relationship between 1-, 3-, and 6-mo gingivitis responses has not been investigated. METHODS: This pooled analysis was conducted to understand the relationship of 1-, 3-, and 6-mo gingival bleeding outcomes. Number of bleeding sites, derived from Löe-Silness Gingival Index (LSGI) or Gingival Bleeding Index, was identified as the primary end point of the analysis for the biological and clinical relevance. Randomized, double-blinded, controlled clinical studies meeting the following predefined selection criteria were identified: 1) published and unpublished gingivitis clinical trials conducted from 1995 to 2022 comparing efficacy of 0.454% SnF2 dentifrices to negative controls (sodium fluoride or sodium monofluorophosphate dentifrice) and 2) studies with a 3-mo assessment and at least a 1- or 6-mo assessment. RESULTS: The search resulted in ten 6-mo and fourteen 3-mo studies meeting selection criteria. A mixed-effects model was performed on the pooled data to assess gingival bleeding outcomes across time. The bleeding efficacy significantly increased between months 1 and 3 (P < 0.0001) and plateaued between months 3 and 6 (P = 0.007), supporting the fact that bleeding reduction relative to control established by 1 mo will increase and be maintained through 3 and 6 mo (R2 = 0.857). In addition, gingival bleeding and gingivitis efficacy, as measured by LSGI, were found to be highly correlated (R2 = 0.874). CONCLUSION: A clear relationship has been demonstrated between 1-, 3-, and 6-mo gingival bleeding outcomes in gingivitis clinical studies comparing SnF2 dentifrice to negative control dentifrice. These findings have important implications to the dental practice and scientific research as antigingivitis efficacy evaluations can be observed as early as 1 mo and are consistent with those seen at 3 or 6 mo. KNOWLEDGE TRANSFER STATEMENT: Outcomes from this investigation indicate that the clinical evaluation of antigingivitis efficacy at 1 mo is predictive of that at 3 and 6 mo, supporting studies of 1-mo duration as a viable method of knowledge acquisition. This more efficient, expedited research design has positive implications for patient care, clinical practice guidelines, protocols, and policies.

Mental health support across the sight loss pathway: a qualitative exploration of eye care patients, optometrists, and ECLOs.

BACKGROUND: The process of becoming visually impaired or blind is undoubtedly a highly emotional experience, requiring practical and psychological support. Information on mental health support provision in the UK across the sight-loss pathway, however, is largely unknown, especially amongst healthcare practitioners that are often sought after for advice: the referring optometrist and eye clinic liaison officer (ECLO). This study aims to ascertain the perceived accessibility and quality of mental health support across the sight-loss pathway. METHODS: Semi-structured individual interviews were conducted with patients with a diagnosed eye condition who had received care from a hospital eye service, referring optometrists, and ECLOs. Following interview transcription, results were synthesised in a narrative analysis. RESULTS: A total of 28 participants were included in the analysis, of which 17 were participants with various eye conditions, five were referring optometrists, and five were ECLOs. After analysis, three broad themes emerged: (1) The emotional trauma of diagnosis (2) Availability of mental health support; (3) The point where mental health support is most needed across the sight-loss pathway. Several patients reporting that they had received no offer of support nor were they signposted to any possible sources. Referring optometrists and ECLO's agreed. CONCLUSION: It is important that referring optometrists are aware of the need for mental health support services and can signpost to local support services including the third sector anytime during the referral process. Future large-scale, UK-wide research into referral practice and signposting for mental health support for patients is warranted, to identify how services can be improved in order to ensure that the wellbeing of patients is maintained.

Material radiopurity control in the XENONnT experiment.

The selection of low-radioactive construction materials is of the utmost importance for rare-event searches and thus critical to the XENONnT experiment. Results of an extensive radioassay program are reported, in which material samples have been screened with gamma-ray spectroscopy, mass spectrometry, and 222 Rn emanation measurements. Furthermore, the cleanliness procedures applied to remove or mitigate surface contamination of detector materials are described. Screening results, used as inputs for a XENONnT Monte Carlo simulation, predict a reduction of materials background ( ∼ 17%) with respect to its predecessor XENON1T. Through radon emanation measurements, the expected 222 Rn activity concentration in XENONnT is determined to be 4.2 ( - 0.7 + 0.5 )  µ Bq/kg, a factor three lower with respect to XENON1T. This radon concentration will be further suppressed by means of the novel radon distillation system.

Antimicrobial use in agriculture: critical review of the factors influencing behaviour.

Antimicrobial resistance (AMR) is a global health emergency affecting humans and animals, diminishing the effectiveness of medication used to treat illness. The agri-food sector has attracted increased attention for imprudent antimicrobial use (AMU) and its contribution to AMR. Thus, ascertaining farmers' and veterinarians' behaviours surrounding AMU is essential to address imprudent AMU and generate behaviour change within the agri-food sector. Therefore, the aim of this critical review is to investigate, assess and collate the current body of evidence to identify psychosocial factors including knowledge, understanding, perceptions, attitudes and behaviours surrounding AMU. Database searches were limited to articles utilizing qualitative and quantitative methodologies, available in English with no restriction on publication year. Of the 1156 articles identified, 103 were retained for this review. Findings on the psychosocial aspects were thematically analysed. Five key themes emerged from the data: (i) knowledge and awareness of antimicrobials; (ii) attitudes towards antimicrobials; (iii) influential relationships; (iv) resources; and (v) factors influencing AMU. Results indicated that to overcome barriers experienced by key stakeholders, a carefully considered, evidence-based approach, incorporating behaviour change theory, is required when designing intricate interventions/strategies, in order to elicit successful and sustained AMU behaviour change.

Neuroablative surgical treatments for pain due to cancer.

Cancer pain is common and challenging to manage - it is estimated that approximately 30% of cancer patients have pain that is not adequately controlled by analgesia. This paper discusses safe and effective neuroablative treatment options for refractory cancer pain. Current management of cancer pain predominantly focuses on the use of medications, resulting in a relative loss of knowledge of these surgical techniques and the erosion of the skills required to perform them. Here, we review surgical methods of modulating various points of the neural axis with the aim to expand the knowledge base of those managing cancer pain. Integration of neuroablative approaches may lead to higher rates of pain relief, and the opportunity to dose reduce analgesic agents with potential deleterious side effects. With an ever-increasing population of cancer patients, it is essential that neurosurgeons maintain or train in these techniques in tandem with the oncological multi-disciplinary team.