Garnet secondary ion mass spectrometry oxygen isotopes reveal crucial roles of pulsed magmatic fluid and its mixing with meteoric water in lode gold genesis.

SignificanceThere is a common consensus that lode gold deposits mostly precipitated from metamorphic fluids via fluid boiling and/or fluid-rock interaction, but whether magmatic hydrothermal fluids and the mixing of such fluids with an external component have played a vital role in the formation of lode gold deposits remains elusive. We use garnet secondary ion mass spectrometry oxygen isotope analysis to demonstrate that the world-class Dongping lode gold deposit has been formed by multiple pulses of magmatic hydrothermal fluids and their mixing with large volumes of meteoric water. This study opens an opportunity to tightly constrain the origin of lode gold deposits worldwide and other hydrothermal systems that may have generated giant ore deposits in the Earth's crust.

Developing a novel dual-injection FDG-PET imaging methodology to study the functional neuroanatomy of gait.

Gait is an excellent indicator of physical, emotional, and mental health. Previous studies have shown that gait impairments in ageing are common, but the neural basis of these impairments are unclear. Existing methodologies are suboptimal and novel paradigms capable of capturing neural activation related to real walking are needed. In this study, we used a hybrid PET/MR system and measured glucose metabolism related to both walking and standing with a dual-injection paradigm in a single study session. For this study, 15 healthy older adults (10 females, age range: 60.5-70.7 years) with normal cognition were recruited from the community. Each participant received an intravenous injection of [18F]-2-fluoro-2-deoxyglucose (FDG) before engaging in two distinct tasks, a static postural control task (standing) and a walking task. After each task, participants were imaged. To discern independent neural functions related to walking compared to standing, we applied a bespoke dose correction to remove the residual 18F signal of the first scan (PETSTAND) from the second scan (PETWALK) and proportional scaling to the global mean, cerebellum, or white matter (WM). Whole-brain differences in walking-elicited neural activity measured with FDG-PET were assessed using a one-sample t-test. In this study, we show that a dual-injection paradigm in healthy older adults is feasible with biologically valid findings. Our results with a dose correction and scaling to the global mean showed that walking, compared to standing, increased glucose consumption in the cuneus (Z = 7.03), the temporal gyrus (Z = 6.91) and the orbital frontal cortex (Z = 6.71). Subcortically, we observed increased glucose metabolism in the supraspinal locomotor network including the thalamus (Z = 6.55), cerebellar vermis and the brainstem (pedunculopontine/mesencephalic locomotor region). Exploratory analyses using proportional scaling to the cerebellum and WM returned similar findings. Here, we have established the feasibility and tolerability of a novel method capable of capturing neural activations related to actual walking and extended previous knowledge including the recruitment of brain regions involved in sensory processing. Our paradigm could be used to explore pathological alterations in various gait disorders.

Phase 3 Trials of Tapinarof Cream for Plaque Psoriasis.

BACKGROUND: Tapinarof cream is a topical aryl hydrocarbon receptor-modulating agent under investigation for the treatment of psoriasis. Tapinarof modulates the expression of interleukin-17 and the skin-barrier proteins filaggrin and loricrin. METHODS: We conducted two identical phase 3 randomized trials of tapinarof in patients with mild-to-severe plaque psoriasis. Adults with a baseline Physician's Global Assessment (PGA) score of 2 (mild) to 4 (severe) (on a scale from 0 to 4, with higher scores indicating more severe psoriasis) and a percent of total body-surface area affected of 3 to 20% were randomly assigned in a 2:1 ratio to use tapinarof 1% cream or vehicle cream once daily for 12 weeks. The primary end point, PGA response, was a PGA score of 0 (clear) or 1 (almost clear) and a decrease from baseline of at least 2 points at week 12. Secondary efficacy end points at week 12 were a reduction of at least 75% in the Psoriasis Area and Severity Index (PASI) score, a PGA score of 0 or 1, the mean change from baseline in the percent of body-surface area affected, and a reduction of at least 90% in the PASI score. Patient-reported outcomes were the mean changes from baseline to week 12 in the proportion of patients who had a decrease of at least 4 points in the Peak Pruritus Numeric Rating Scale (PP-NRS) score (range, 0 [no itch] to 10 [worst imaginable itch]), the PP-NRS total score, the Dermatology Life Quality Index total score, and the Psoriasis Symptom Diary score. RESULTS: In trials 1 and 2, a total of 692 and 674 patients, respectively, were screened, with 510 and 515 patients being enrolled. A PGA response occurred in 35.4% of the patients in the tapinarof group and in 6.0% of those in the vehicle group in trial 1 and in 40.2% and 6.3%, respectively, in trial 2 (P<0.001 for both comparisons). Results for secondary end points and patient-reported outcomes were generally in the same direction as those for the primary end point. Adverse events with tapinarof cream included folliculitis, nasopharyngitis, contact dermatitis, headache, upper respiratory tract infection, and pruritus. CONCLUSIONS: Tapinarof 1% cream once daily was superior to vehicle control in reducing the severity of plaque psoriasis over a period of 12 weeks but was associated with local adverse events and headache. Larger and longer trials are needed to evaluate the efficacy and safety of tapinarof cream as compared with existing treatments for psoriasis. (Funded by Dermavant Sciences; PSOARING 1 and 2 ClinicalTrials.gov numbers, NCT03956355 and NCT03983980, respectively.).

Tapinarof cream 1% once daily: Significant efficacy in the treatment of moderate to severe atopic dermatitis in adults and children down to 2 years of age in the pivotal phase 3 ADORING trials.

BACKGROUND: Tapinarof cream 1% once daily (QD), a topical aryl hydrocarbon receptor agonist, downregulates pro-inflammatory Th2 cytokines, upregulates skin-barrier components, and reduces oxidative stress. OBJECTIVE: To assess tapinarof efficacy and safety in adults and children down to 2 years of age with atopic dermatitis (AD). METHODS: Eight hundred and thirteen patients were randomized to tapinarof or vehicle QD in two 8-week phase 3 trials. RESULTS: The primary efficacy endpoint, Validated Investigator Global Assessment for Atopic Dermatitis score of 0 or 1 and ≥2-grade improvement from baseline at Week 8, was met with statistical significance in both trials: 45.4% versus 13.9% and 46.4% versus 18.0% (tapinarof vs vehicle; both P < .0001). Significantly superior Eczema Area and Severity Index 75 (EASI75) responses were also observed with tapinarof versus vehicle at Week 8: 55.8% versus 22.9% and 59.1% versus 21.2% (both P < .0001). Rapid improvements in patient-reported pruritus were also significant with tapinarof versus vehicle. Common adverse events (≥5%) of folliculitis, headache, and nasopharyngitis were mostly mild or moderate, with lower discontinuations due to adverse events in the tapinarof groups than with vehicle. LIMITATIONS: Long-term efficacy was not assessed. CONCLUSION: Tapinarof demonstrated highly significant efficacy and favorable safety and tolerability in a diverse population of patients with AD down to 2 years of age.

Targeting the Aryl Hydrocarbon Receptor to Address the Challenges of Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic relapsing–remitting disease with a multifactorial etiology involving epidermal barrier and immunologic dysfunction. Topical therapies form the mainstay of AD treatment, but options are limited by adverse effects and restrictions on application site, duration, and extent of use. Tapinarof (VTAMA; Dermavant Sciences, Inc.) is a first-in-class, non-steroidal, topical aryl hydrocarbon receptor (AhR) agonist approved for the treatment of plaque psoriasis. AhR is a ligand-dependent transcription factor with wide-ranging roles, including regulation of homeostasis and immune response in skin cells. AhR expression and signaling are altered in many inflammatory skin diseases, and clinical trials with tapinarof have validated AhR as a therapeutic target capable of delivering significant efficacy. Tapinarof cream 1% once daily demonstrated efficacy versus vehicle in adults and adolescents with AD and is being investigated in the ADORING trials for the treatment of AD in adults and children down to 2 years of age. J Drugs Dermatol. 2024;23(2):23-28.  doi:10.36849/JDD.8026.

Tapinarof validates the aryl hydrocarbon receptor as a therapeutic target: A clinical review.

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that has wide-ranging roles, including regulation of inflammation and homeostasis. AhR is not a cell surface receptor; rather, it exists in a cytoplasmic complex that responds to a wide variety of structurally dissimilar endogenous, microbial, and environmental ligands. The ubiquitous expression of AhR, its ability to be activated by a wide range of ligands, and its capacity to act as a master regulator for gene expression and homeostasis make it a promising new therapeutic target. Clinical trials of tapinarof cream have now validated AhR agonism as a therapeutic approach that can deliver significant efficacy for treating inflammatory skin diseases, including psoriasis and atopic dermatitis. Tapinarof 1% cream is a first-in-class, nonsteroidal, topical, AhR agonist with a pharmacokinetic profile that results in localized exposure at sites of disease, avoiding systemic safety concerns, drug interactions, or off-target effects. Psoriasis and atopic dermatitis both involve epidermal inflammation, cellular immune responses, dysregulation of skin barrier protein expression, and oxidative stress. On the basis of the clinical effectiveness of tapinarof cream for treating inflammatory skin diseases, we review how targeting AhR may offer a significant opportunity in other conditions that share key aspects of pathogenesis, including asthma, inflammatory bowel disease, eosinophilic esophagitis, ophthalmic, and nervous system diseases.

Protecting and restoring freshwater biodiversity across urban areas in Aotearoa New Zealand: Citizens' reporting of pollution in stormwater drains and waterways.

Urbanization poses numerous challenges to freshwater biodiversity. This paper describes two studies with the joint aim of demonstrating the benefits of applying a systematic behaviour change framework and providing the foundational knowledge to inform future behavior change work to protect and restore urban freshwater biodiversity. In Study 1 we used a mixed-methods research design, involving 14 key informant interviews followed by an online survey targeting 17 freshwater biodiversity experts and another targeting a representative sample of 550 urban residents, to identify and prioritize the most promising resident behaviors to target to reduce stormwater pollution and improve natural waterway habitats in urban areas. Study 2 focused on the top-ranked short-term behavior identified in Study 1, citizen reporting of pollution in stormwater drains and waterways. We surveyed a representative sample of 1901 urban residents across Aoteraoa New Zealand to identify four main determinants influencing this behavior: awareness and uncertainty about reporting, lack of opportunity to report, social motivation and personal motivation to report, and five potential target audiences: 'Supportive', 'Unaware but receptive', 'Motivated but lack support', 'Reluctant', and 'Not my problem'. We make recommendations for the most appropriate intervention designs to target each of these audience segments to promote the reporting of stormwater pollution in urban areas. This knowledge will allow for a more coordinated and effective approach for addressing the 'human element' that lies at the heart of many urban freshwater management problems.

Micro-RNA content of circulating extracellular vesicles in early rheumatoid arthritis as biomarkers and mediators of methotrexate efficacy.

OBJECTIVES: Extracellular vesicles (EVs) are abundant in body fluids, contributing to intercellular signalling by transferring cargo that includes microRNAs (miRs) - themselves implicated in pathobiology. For the first time we evaluated the potential of EV miRs to contribute diagnostic information in early RA, predict methotrexate (MTX) efficacy or shed light on the drug's mechanism of action. METHODS: 798 miRs isolated from serum-derived EVs of 46 patients with untreated RA, 23 with untreated polymyalgia rheumatica (PMR; inflammatory disease control group) and 12 in whom significant inflammatory disease had been excluded (non-inflammatory controls; NICs) were profiled (Nanostring); the same measurements were made for RA patients after 6 months' MTX treatment. Analyses took multiple testing into account. RESULTS: 28 EV miRs were robustly differentially expressed between early RA (but not PMR) patients and NICs after correction for age and sex, suggesting discriminatory value. Cross-validated partial least squared-discriminant analysis also indicated the predictive potential of a distinct baseline EV miR signature with respect to MTX-induced remission at 6 months. The change in expression of 13 miRs over the course of MTX treatment differed significantly between responders and non-responders, and four of those exhibiting increased relative abundance amongst responders have known roles in regulating the pathogenic potential of synovial fibroblasts, namely miR-212-3p, miR-338-5p, miR-410-3p, and miR-537. CONCLUSION: Our data highlight the potential of serum EV miRs as diagnostic and therapeutic biomarkers, highlighting a novel potential mechanism via which MTX may exert its therapeutic effect in early RA that warrants further investigation.

Tapinarof cream 1% once daily for the treatment of plaque psoriasis: Patient-reported outcomes from the PSOARING 3 trial.

BACKGROUND: Tapinarof cream 1% once daily demonstrated significant efficacy versus vehicle and was well tolerated in two 12-week, phase 3 pivotal trials in adults with mild-to-severe plaque psoriasis. OBJECTIVE: To assess long-term, health-related quality of life and patient satisfaction with tapinarof. METHODS: Patients completing the 12-week trials were eligible for 40 weeks of open-label tapinarof based on Physician Global Assessment score in PSOARING 3, with a 4-week follow-up. Dermatology Life Quality Index was assessed at every visit; Patient Satisfaction Questionnaire responses were assessed at week 40 or early termination. RESULTS: Seven hundred sixty-three (91.6%) eligible patients enrolled; 78.5% completed the Patient Satisfaction Questionnaire. DLQI scores improved and were maintained. By week 40, 68.0% of patients had a DLQI of 0 or 1, indicating no impact of psoriasis on health-related quality of life. Most patients strongly agreed or agreed with all Patient Satisfaction Questionnaire questions assessing confidence in tapinarof and satisfaction with efficacy (62.9%-85.8%), application ease and cosmetic elegance (79.9%-96.3%), and preference for tapinarof versus prior psoriasis therapies (55.3%-81.7%). LIMITATIONS: Open-label; no control; may not be generalizable to all forms of psoriasis. CONCLUSIONS: Continued and durable improvements in health-related quality of life, high rates of patient satisfaction, and positive perceptions of tapinarof cream were demonstrated.

Assessing real-world gait with digital technology? Validation, insights and recommendations from the Mobilise-D consortium.

BACKGROUND: Although digital mobility outcomes (DMOs) can be readily calculated from real-world data collected with wearable devices and ad-hoc algorithms, technical validation is still required. The aim of this paper is to comparatively assess and validate DMOs estimated using real-world gait data from six different cohorts, focusing on gait sequence detection, foot initial contact detection (ICD), cadence (CAD) and stride length (SL) estimates. METHODS: Twenty healthy older adults, 20 people with Parkinson's disease, 20 with multiple sclerosis, 19 with proximal femoral fracture, 17 with chronic obstructive pulmonary disease and 12 with congestive heart failure were monitored for 2.5 h in the real-world, using a single wearable device worn on the lower back. A reference system combining inertial modules with distance sensors and pressure insoles was used for comparison of DMOs from the single wearable device. We assessed and validated three algorithms for gait sequence detection, four for ICD, three for CAD and four for SL by concurrently comparing their performances (e.g., accuracy, specificity, sensitivity, absolute and relative errors). Additionally, the effects of walking bout (WB) speed and duration on algorithm performance were investigated. RESULTS: We identified two cohort-specific top performing algorithms for gait sequence detection and CAD, and a single best for ICD and SL. Best gait sequence detection algorithms showed good performances (sensitivity > 0.73, positive predictive values > 0.75, specificity > 0.95, accuracy > 0.94). ICD and CAD algorithms presented excellent results, with sensitivity > 0.79, positive predictive values > 0.89 and relative errors < 11% for ICD and < 8.5% for CAD. The best identified SL algorithm showed lower performances than other DMOs (absolute error < 0.21 m). Lower performances across all DMOs were found for the cohort with most severe gait impairments (proximal femoral fracture). Algorithms' performances were lower for short walking bouts; slower gait speeds (< 0.5 m/s) resulted in reduced performance of the CAD and SL algorithms. CONCLUSIONS: Overall, the identified algorithms enabled a robust estimation of key DMOs. Our findings showed that the choice of algorithm for estimation of gait sequence detection and CAD should be cohort-specific (e.g., slow walkers and with gait impairments). Short walking bout length and slow walking speed worsened algorithms' performances. Trial registration ISRCTN - 12246987.

Helicopter-Based Search and Rescue Operations in the Dutch Caribbean: A Retrospective Analysis.

INTRODUCTION: Search and rescue (SAR) operations in the Dutch Caribbean offer basic and advanced prehospital care and transport for definitive care. Helicopter-based SAR in this geographic area has not been previously studied. Data from the Dutch Caribbean Coast Guard were analyzed with the aim of describing the current operational setting and optimizing SAR operations in the future. METHODS: Data were collected retrospectively from March 2018 through April 2021. Epidemiologic data, patient demographics, details of flight operations, medical interventions, and outcomes were collected and analyzed for this period. RESULTS: A total of 91 individuals were assisted through SAR, of whom 40 (44%) had a medical emergency. Most incidents occurred during high-tourism seasons. A yearly increase in helicopter tasking was observed. Boating was the most common activity (25%) requiring SAR. Injuries to the extremities were the most common injury (27%). The median time to reach the scene of SAR was 46 (interquartile range [IQR], 33-66) min. The most frequent reason for delay was the unavailability of a winch operator (15%). Of 16 fatalities, most (63%) were attributed to drowning. A total of 18 persons were transported to a hospital, with a median travel time of 63 (IQR, 47-79) min. CONCLUSIONS: The number of SAR missions in the Dutch Caribbean is increasing. The response times might be reduced by the inclusion of an on-call winch operator. A hospital helipad would likely decrease the time to definitive care. Stand-by physicians might improve the quality of medical care. Collection of data should be optimized in the future.

Locked down: Ontological security and the experience of COVID-19 while living in poor-quality housing.

The aim of the paper is to illustrate how the housing system in the United Kingdom (UK) has contributed to creating vulnerabilities during the COVID-19 pandemic. Drawing on the concept of ontological security we look at how living with housing insecurity whilst enduring poor housing conditions has impacted the lives of those living in households. The paper draws on semi-structured interviews with 50 residents and 8 housing professionals. The findings outline the grinding impact of the pandemic on the ontological security of residents and the coping strategies adopted by a wider range of households who are now increasingly vulnerable. A number of people went into lockdown in vulnerable situations, experiencing deep inequalities and living in poorly maintained homes. This has weakened the ontological security experienced by many households. These represent significant failings of the housing system and housing policy impacting on the health and wellbeing of a wider cohort of people creating additional vulnerabilities.

17-Beta Hydroxysteroid Dehydrogenase 13 Deficiency Does Not Protect Mice From Obesogenic Diet Injury.

BACKGROUND AND AIMS: 17-Beta hydroxysteroid dehydrogenase 13 (HSD17B13) is genetically associated with human nonalcoholic fatty liver disease (NAFLD). Inactivating mutations in HSD17B13 protect humans from NAFLD-associated and alcohol-associated liver injury, fibrosis, cirrhosis, and hepatocellular carcinoma, leading to clinical trials of anti-HSD17B13 therapeutic agents in humans. We aimed to study the in vivo function of HSD17B13 using a mouse model. APPROACH AND RESULTS: Single-cell RNA-sequencing and quantitative RT-PCR data revealed that hepatocytes are the main HSD17B13-expressing cells in mice and humans. We compared Hsd17b13 whole-body knockout (KO) mice and wild-type (WT) littermate controls fed regular chow (RC), a high-fat diet (HFD), a Western diet (WD), or the National Institute on Alcohol Abuse and Alcoholism model of alcohol exposure. HFD and WD induced significant weight gain, hepatic steatosis, and inflammation. However, there was no difference between genotypes with regard to body weight, liver weight, hepatic triglycerides (TG), histological inflammatory scores, expression of inflammation-related and fibrosis-related genes, and hepatic retinoid levels. Compared to WT, KO mice on the HFD had hepatic enrichment of most cholesterol esters, monoglycerides, and certain sphingolipid species. Extended feeding with the WD for 10 months led to extensive liver injury, fibrosis, and hepatocellular carcinoma, with no difference between genotypes. Under alcohol exposure, KO and WT mice showed similar hepatic TG and liver enzyme levels. Interestingly, chow-fed KO mice showed significantly higher body and liver weights compared to WT mice, while KO mice on obesogenic diets had a shift toward larger lipid droplets. CONCLUSIONS: Extensive evaluation of Hsd17b13 deficiency in mice under several fatty liver-inducing dietary conditions did not reproduce the protective role of HSD17B13 loss-of-function mutants in human NAFLD. Moreover, mouse Hsd17b13 deficiency induces weight gain under RC. It is crucial to understand interspecies differences prior to leveraging HSD17B13 therapies.

One-year safety and efficacy of tapinarof cream for the treatment of plaque psoriasis: Results from the PSOARING 3 trial.

BACKGROUND: Tapinarof cream 1% once daily, an aryl hydrocarbon receptor-modulating agent, was significantly more efficacious than vehicle and well tolerated in two 12-week phase 3 trials in adults with mild to severe plaque psoriasis. OBJECTIVE: To assess long-term safety, efficacy, remittive effect, durability of response, and tolerability of tapinarof. METHODS: Patients completing the 12-week trials were eligible for 40-weeks' open-label treatment and 4-weeks' follow-up. Treatment was based on the Physician Global Assessment (PGA) score. Patients entering with PGA≥1 received tapinarof until PGA = 0. Patients with PGA = 0 discontinued tapinarof and were monitored for remittive effect. Patients with PGA≥2 were re-treated until PGA = 0. RESULTS: Overall, 91.6% (n = 763) of eligible patients enrolled; 40.9% of patients achieved complete disease clearance (PGA = 0), and 58.2% entering with PGA≥2 achieved PGA = 0 or 1. Mean duration of off therapy remittive effect for patients achieving PGA = 0 was 130.1 days. No new safety signals were observed. Most frequent adverse events were folliculitis (22.7%), contact dermatitis (5.5%), and upper respiratory tract infection (4.7%). LIMITATIONS: Open-label; no control; may not be generalizable to all forms of psoriasis; remittive effect/response rate potentially underestimated. CONCLUSIONS: Efficacy improved beyond the 12-week trials, with a 40.9% complete disease clearance rate, ∼4-month off therapy remittive effect, durability on therapy, and consistent safety.

Variability in Opioid-Related Drug Overdoses, Social Distancing, and Area-Level Deprivation during the COVID-19 Pandemic: a Bayesian Spatiotemporal Analysis.

Monitoring the spatial and temporal course of opioid-related drug overdose mortality is a key public health determinant. Despite previous studies exploring the evolution of drug-related fatalities following the stay-at-home mandates during the COVID-19 pandemic, little is known about the spatiotemporal dynamics that mitigation efforts had on overdose deaths. The purpose of this study was to describe the spatial and temporal dynamics of overdose death relative risk using a 4-week interval over a span of 5 months following the implementation of the COVID-19 lockdown in the city of Chicago, IL. A Bayesian space-time model was used to produce posterior risk estimates and exceedance probabilities of opioid-related overdose deaths controlling for measures of area-level deprivation and stay-at-home mandates. We found that area-level temporal risk and inequalities in drug overdose mortality increased significantly in the initial months of the pandemic. We further found that a change in the area-level deprivation from the first to the fourth quintile increased the relative risk of a drug overdose risk by 44.5%. The social distancing index measuring the proportion of persons who stayed at home in each census block group was not associated with drug overdose mortality. We conclude by highlighting the importance of contextualizing the spatial and temporal risk in overdose mortality for implementing effective and safe harm reduction strategies during a global pandemic.

Design and validation of a multi-task, multi-context protocol for real-world gait simulation.

BACKGROUND: Measuring mobility in daily life entails dealing with confounding factors arising from multiple sources, including pathological characteristics, patient specific walking strategies, environment/context, and purpose of the task. The primary aim of this study is to propose and validate a protocol for simulating real-world gait accounting for all these factors within a single set of observations, while ensuring minimisation of participant burden and safety. METHODS: The protocol included eight motor tasks at varying speed, incline/steps, surface, path shape, cognitive demand, and included postures that may abruptly alter the participants' strategy of walking. It was deployed in a convenience sample of 108 participants recruited from six cohorts that included older healthy adults (HA) and participants with potentially altered mobility due to Parkinson's disease (PD), multiple sclerosis (MS), proximal femoral fracture (PFF), chronic obstructive pulmonary disease (COPD) or congestive heart failure (CHF). A novelty introduced in the protocol was the tiered approach to increase difficulty both within the same task (e.g., by allowing use of aids or armrests) and across tasks. RESULTS: The protocol proved to be safe and feasible (all participants could complete it and no adverse events were recorded) and the addition of the more complex tasks allowed a much greater spread in walking speeds to be achieved compared to standard straight walking trials. Furthermore, it allowed a representation of a variety of daily life relevant mobility aspects and can therefore be used for the validation of monitoring devices used in real life. CONCLUSIONS: The protocol allowed for measuring gait in a variety of pathological conditions suggests that it can also be used to detect changes in gait due to, for example, the onset or progression of a disease, or due to therapy. TRIAL REGISTRATION: ISRCTN-12246987.

Solidarity, not charity: Learning the lessons of the COVID-19 pandemic to reconceptualise the radicality of mutual aid.

The COVID-19 pandemic has significantly ruptured our global society. We have seen health care systems, governments and commerce buckle under the strain of disease, lockdowns and unrest, but the rupture has also created space for radical (and anarchist) politics of mutual aid, as societal organising principles, to move into a more prominent position (and offers potential for this shift to remain after the crisis has subsided). However, in the short time since mutual aid has been thrust into the limelight, we have seen a multiplicity and spectrum of geographies, applications and approaches. Indeed, we have also seen its appropriation by government(s) that takes advantage of mutual aid's rallying cry of "solidarity not charity"; absolving the state's responsibilities to sufficiently fund social welfare when good neighbours will do it for free. In this paper we map out how mutual aid has been enacted during the COVID-19 pandemic by charity, contributory and radical groups to address specific and novel forms of vulnerabilities, and the opportunities and challenges this offers for the future. In particular we highlight potential tensions between the enacting of mutual aid practices and the political activism (or not) of the mutual aid actors. Our contribution is to reconceptualise mutual aid to (i) show where the real "mutualism" of mutual aid is, and (ii) create a better understanding of how mutual aid can be mobilised in future emergencies which will inevitably arise in the current climate emergency.

Efficacy and safety of leadless pacemaker: A systematic review, pooled analysis and meta-analysis.

BACKGROUND: Leadless pacemakers have been designed as an alternative to transvenous systems which avoid some of the complications associated with transvenous devices. We aim to perform a systematic review of the literature to report the safety and efficacy findings of leadless pacemakers. METHODS: We searched MEDLINE and EMBASE to identify studies reporting the safety, efficacy and outcomes of patients implanted with a leadless pacemaker. The pooled rate of adverse events was determined and random-effects meta-analysis was performed to compare rates of adverse outcomes for leadless compared to transvenous pacemakers. RESULTS: A total of 18 studies were included with 2496 patients implanted with a leadless pacemaker and success rates range between 95.5 and 100%. The device or procedure related death rate was 0.3% while any complication and pericardial tamponade occurred in 3.1% and 1.4% of patients, respectively. Other complications such as pericardial effusion, device dislodgement, device revision, device malfunction, access site complications and infection occurred in less than 1% of patients. Meta-analysis of four studies suggests that there was no difference in hematoma (RR 0.67 95%CI 0.21-2.18, 3 studies), pericardial effusion (RR 0.59 95%CI 0.15-2.25, 3 studies), device dislocation (RR 0.33 95%CI 0.06-1.74, 3 studies), any complication (RR 0.44 95%CI 0.17-1.09, 4 studies) and death (RR 0.45 95%CI 0.15-1.35, 2 studies) comparing patients who received leadless and transvenous pacemakers. CONCLUSION: Leadless pacemakers are safe and effective for patients who have an indication for single chamber ventricular pacing and the findings appear to be comparable to transvenous pacemakers.

What is the abdomen? Rationalising clinical and anatomical perspectives using formal semantics.

The meaning of the term 'abdomen' has become increasingly ambiguous, as it has to satisfy the contemporary requirements of natural language discourse, literature, gross and radiological anatomy and its role in ontologies supporting electronic records and data modelling. It is critical that there is an agreed understanding of the semantics of the abdominopelvic cavity, its component volumes including the abdomen proper, true and false pelvic cavities, and its boundaries and regional contents. The expression of part-whole (meronymic) relationships is essential for inferences to be drawn by computer algorithms, but unless these are rigorously reviewed and tested incorrect assumptions are drawn. The SNOMED CT terminology descriptions and hierarchy of anatomical concepts relating to the trunk were scrutinised for ambiguity and sub-optimal relationships using a panel of reference sources. Any identified errors were corrected and the impact of any changes reviewed iteratively by evaluating their effect on dependant hierarchies (modelled with the associated anatomical concepts). Anatomical concepts are generally structured according to a traditional gross standpoint, but in clinical practice covert complex regional notions are frequently used and during the evaluation process a new viewpoint relating to projectional (transmissive) or emissive radiological perspective was identified. The subtle but important differences in the boundaries, volumes and contents of these distinctive perspectives of the 'abdomen' are presented. Three significant complex variants have been identified which relate to the most common uses of the word 'abdomen'. The merits and disadvantages of using 'abdomen' as common synonym to more than one concept (polysemy) are briefly discussed and the solution adopted by SNOMED International described. The review of existing ontologies and academic literature confirmed the frequent varied use of the word 'abdomen', which raises concerns when derived data are increasingly being used remotely from the point of clinical contact, potentially leading to incorrect inferences. The documented regional truncal volumes from an anatomical regional, segmental and cross-sectional perspective have been integrated into a logical and comprehensive model suitable for computer processing. The robust modelling of meronymic hierarchies has to be rigorous to avoid systematic errors and it is thus timely that a proposed standard description of these subtly related volumes and structures is made available for discussion and comment.

Utilizing 3D-Printed Orbital Floor Stamps to Create Patient-Specific Implants for Orbital Floor Reconstruction.

PURPOSE: This study seeks to test a novel technique of custom-printed midface contour models with orbital floor "stamps" to guide reconstruction of orbital floor blowout fractures, with or without concomitant zygomaticomaxillary complex injury. METHODS: A series of 4 consecutive patients with orbital floor blowout fractures (including 3 with zygomatic maxillary complex fractures) were retrospectively examined for outcomes associated with orbital floor reconstruction using 3-dimensional-printed stamps and midface models. Data collected included demographics, pre- and postoperative visual globe malposition, motility, and visual field disturbances. Three-dimensional printing methodology is reported, as well as associated costs and time required to generate the models and stamps. RESULTS: The cost of producing a midface-contour model and orbital floor stamps was $131, inclusive of labor and materials. Cases averaged 170 minutes to segment, design, and print. Patients with preoperative diplopia and motility restrictions had resolution of their symptoms. Two patients had resolution of their enophthalmos, while one patient with a concomitant zygomaticomaxillary fracture had persistent mild enophthalmos. CONCLUSIONS: Midface contour models and orbital floor stamps may be produced in a timely and cost-effective manner. Use of these "homemade" stamps allows for patient-specific custom-contoured orbital floor reconstruction. Further studies are warranted to examine long-term visual and esthetic outcomes for these patients.