A Directional Crack Damage Memory Effect in Sandstone Under True Triaxial Loading

We thank J.G. Van Munster for providing access to the true triaxial apparatus at KSEPL and for technical support during the experimental program. This work was partly funded by NERC awards NE/N002938/1, NE/N003063/1, and by a NERC Doctoral Studentship, which we gratefully acknowledge. Supporting data are included in an SI file; any additional data may be obtained from JB (email: [email protected]).Peer reviewedPublisher PD

Understanding the life experiences of people with multiple complex needs: peer research in a health needs assessment

Background Multiple complex needs (MCN) describe a population experiencing a combination of homelessness, substance use, offending and/or mental ill-health. Using peer researchers, this study aimed to explore the perspectives of individuals with lived experience of MCN with regards to (i) issues leading to MCN and (ii) key intervention opportunities. Methods As part of a health needs assessment in Gateshead (North East England), trained peer researchers interviewed 27 adults (aged ≥18 years) with experience of MCN, identified using purposive sampling methods. Peer researchers designed a topic guide for interviews which were audio recorded and thematically analyzed. Results Interviewees reported adverse childhood experiences leading to MCN including abuse, bereavement, parental imprisonment, family break-up and inadequate support. Mental ill-health, substance use, poverty, early experiences of unstable housing and acute homelessness were identified as major precedents for adulthood experiences of MCN. Between 16 and 20 years, access to housing, social and mental health support was perceived as having the potential to prevent circumstances worsening. Individuals perceived removing barriers to mental health, housing and welfare and financial supports could help. Conclusions This study highlights the perceived role austerity, adverse childhood events and current service provision have in current and future experiences of MCN. Individuals expressed a need for future interventions and support to be judgement free and provided by workers who are educated about MCN and related adversity. Involving peer researchers and individuals with experience of MCN in future research and service provision could ensure appropriate measures and supports are put in place

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Quantifying the role of microporosity in fluid flow within carbonate reservoirs

Micropores can constitute up to 100% of the total porosity within carbonate hosted hydrocarbon reservoirs, usually existing within micritic fabrics. There is, however, only a rudimentary understanding of the contribution that these pores make to reservoir performance and hydrocarbon recovery. To further our understanding, a flexible, object-based algorithm has been developed to produce 3D computational representations of end-point micritic fabrics. By methodically altering model parameters, the state-space of microporous carbonates is explored. Flow properties are quantified using lattice-Boltzmann and network modelling methods. In purely micritic fabrics, it has been observed that average pore radius has a positive correlation with single-phase permeability and results in decreasing residual oil saturations under both water-wet and 50% fractionally oil-wet states. Similarly, permeability increases by an order of magnitude (from 0.6md to 7.5md) within fabrics of varying total matrix porosity (from 18% to 35%) due to increasing pore size, but this has minimal effect on multi-phase flow. Increased pore size due to micrite rounding notably increases permeability in comparison to original rhombic fabrics with the same porosity, but again, multi-phase flow properties are unaffected. The wetting state of these fabrics, however, can strongly influence multi-phase flow; residual oil saturations vary from 30% for a water-wet state and up to 50% for an 80% oil wet fraction. flow when directly connected. Otherwise, micropores control single-phase permeability magnitude. Importantly in these fabrics, recovery is dependent on both wetting scenario and pore-network homogeneity; under water-wet imbibition, increasing proportions of microporosity yield lower residual oil saturations. Finally, in grain-based fabrics where mesopores form an independently connected pore network, micropores do not affect permeability, even when they constitute up to 50% of the total porosity. Through examination of these three styles of microporous carbonates, it is apparent that micropores can have a significant impact on flow and sweep characteristics in such fabrics

Magmatic evolution and textural development of the 1739 CE Pietre Cotte lava flow, Vulcano, Italy

Textural evidence from occurrences of mingled magmas in lava flows often yields insights into chemical and thermal disequilibrium between multiple magma batches at depth. An understanding of these interactions is key as they can occur on short timescales and may act as eruption triggers, particularly important in very active volcanic settings. This paper focuses on the Pietre Cotte lava flow (Vulcano, Aeolian Islands, Italy), a short (<1 km in length), texturally-heterogeneous rhyolitic extrusion on the northern slope of the active Fossa Cone. The occurrence of (i) multiple magma compositions, (ii) distinct magmatic cumulates (as glomerocrysts) and (iii) mineral resorption textures within glomerocrysts and isolated feldspar phenocrysts in the Pietre Cotte lava flow highlight a complex pre-eruptive magmatic history, including crystal mush remobilisation. Petrographic observations and mineral, bulk rock and glass geochemistry suggest that multiple mingling events occurred during the evolution of the Pietre Cotte magmatic system, evidenced by the recognition of the following components: (1) a remobilised predominantly mafic crystal mush, evident as macrocrysts (crystals >500 μm), which form glomerocrysts within enclaves, (2) a microlitic (<100 μm) trachytic enclave groundmass with microcrysts (100–500 μm), and (3) a rhyolitic glass, which hosts both the enclaves and the glomerocrysts. The macrocrystic mafic assemblage includes clinopyroxene (En38-47Wo45–50; Mg# 0.72–0.89), olivine (Fo49–66) and magnetite (Usp7–26), with plagioclase (An40–63Ab5–50) and rare alkali feldspar (Or41–57) also present. Enclaves are comprised of a groundmass of plagioclase (An43–47) and alkali feldspar (Or33–57) microlites, with clinopyroxene microcrysts (En39-42Wo47–51; Mg# 0.75–0.81) and trachyte groundmass glass. The rhyolitic host is characterised by glass, spherulites, microlites and enclave-derived macrocrysts. Compositionally and texturally distinct magmas are attributed to storage and interactions of distinct magma batches and their cumulates at various temperatures and depths beneath the Fossa Cone. Compositions vary from basaltic-shoshonitic, through latitic-trachytic and rhyolitic magmas. The macrocrystic glomerocryst assemblage shows resorbed, chemically-zoned and cumulate textures; the glomerocrysts are attributed to a shoshonitic parent and remobilisation from a crystal mush. Macrocrysts formed at a pressure of 825 ± 80 MPa and temperatures of 789–1117 °C at around the Moho (~23–28 km). Pressure and temperature calculations of the shoshonitic mineral assemblage give average crystallisation conditions of 710 ± 80 MPa (above the Moho) and 1128 ± 25 °C, respectively. The trachytic magma crystallised at ~640 ± 75 MPa and 1000–1130 °C. The average liquidus of the rhyolitic magma has been calculated at 970 ± 7 °C, at depths of <5 km (<60 MPa). New textural observations and intensive variable calculations permit the development of a new pressure and temperature-constrained model of the magmatic evolution of the Pietre Cotte system prior to eruption, with useful insights into the interactions of different magmatic components prior to and during the rapid onset of eruptions linked to magma mingling/mixing

Acceptability of point of care testing for antipsychotic medication levels in schizophrenia

We surveyed 106 patients with schizophrenia who were being treated with either oral clozapine or oral aripiprazole. For each patient, the plasma level of the medication was measured using i) a venous blood sample and a conventional lab-based assay and ii) a novel point of care assay that used a capillary blood sample taken with a fingerprick. Immediately after providing the two samples, participants completed a brief questionnaire. We also surveyed 10 members of staff who were directly involved in the care of these patients.98% of patients found the capillary point-of-care approach acceptable, and 85% preferred it to the conventional venous blood procedure. 78% of patients said it was useful to have access to the result at the point of care (as opposed to at a later date), and 90% felt that POC testing improved clinical care. 83% said that the POC test made them feel more involved in their treatment. 100% of staff said their experience with the POC test was good, that it was easier than venous collection, and that it was very useful to receive the medication level while the patient was still in the clinic