Temperature and pore pressure effects on the shear strength of granite in the brittle-plastic transition regime

Currently published lithospheric strength profiles lack constraints from experimental data for shear failure of typical crustal materials in the brittle-plastic transition regime in wet environments. Conventional triaxial shear fracture experiments were conducted to determine temperature and pore pressure effects on shear fracture strength of wet and dry Tsukuba granite. Experimental conditions were 70MPa < P-C < 480MPa, 10MPa < P-p < 300MPa, 25 A degreesC < T < 480 degreesC, at a constant strain rate of 10(-5)s(-1). An empirical relation is proposed which can predict the shear strength of Tsukuba granite, within the range of experimental conditions. Mechanical pore pressure effects are incorporated in the effective stress law. Chemical effects are enhanced at temperatures above 300 degreesC. Below 300 degreesC wet and dry granite strengths are temperature insensitive and wholly within the brittle regime. Above 400 degreesC, semi-brittle effects and ductility are observed

Microbiological findings and prescribing trends in SARS- CoV-2 positive patients in two United Kingdom Hospitals

Objective: To describe antibiotic prescribing and microbiological findings in patients admitted to two London hospitals with COVID-19. Methods: This is a retrospective review of confirmed SARS-CoV-2 infected adults admitted between 9th February and 10th May 2020. Demographics, critical care unit (CCU) admission, antibiotic prescribing and microbiology results within 10 days of COVID-19 diagnosis were analysed. Results: 1155 patients were identified. 32.9% (380) died. 12.4% (143) had positive microbiology. After excluding likely contaminants, 6.9% (80) had clinically significant microbiology. The most common organisms isolated from blood cultures were Escherichia coli 9.5% (7), Klebsiella pneumoniae 4.0% (3), and Staphylococcus aureus 2.7% (2). A high percentage of blood cultures yielded coagulase negative staphylococci (51/74, 68.9%) and likely represented contamination. Organisms isolated from lower respiratory tract samples included Candida albicans 44.4% (12), Staphylococcus aureus 22.2% (6), Klebsiella species 11.0% (3), Pseudomonas aeruginosa 11.0% (3), and Citrobacter species 11% (3). Legionella and pneumococcal urinary antigen tests were positive in 0/117 and 2/71 (2.8%) samples. 91% (1051) of patients received antibiotics. Clarithromycin (24.2% total antibiotic use) and amoxicillin (21%) were most frequently used, followed by piperacillin-tazobactam (12.6%), gentamicin (10.6%), co-amoxiclav (9.3%) and meropenem (3.2%). Piperacillin-tazobactam or meropenem use was associated with a higher length of stay and mortality. Conclusions: Positive microbiology in COVID-19 patients is uncommon. Antibiotic use was widespread, despite lack of microbiological evidence of co-infection. When present, positive microbiology was more likely due to gram negative bacteria. Current local clinical and antimicrobial guidelines have incorporated these findings and recommend against routine antibiotic use in COVID-19 patients

Development of a novel platform for greater situational awareness in the urban military terrain

The conflicts in Afghanistan and Iraq and the more recent war in the Gaza Strip have emphasized the need for novel platforms which provide for greater situational awareness in the urban terrain. Without intelligent systems, which can accurately provide real-time information, collateral damage to property will result, together with unnecessary civilian deaths. This situation is exacerbated by the fact that within the next decade 75% of the world’s population will be living in urban areas. This paper outlines the current state of unmanned aerial vehicles throughout the world and presents a novel design of a multiple rotary wing platform which has great potential for both military and civilian application areas

Radiation dose differences between thoracic radiotherapy planning CT and thoracic diagnostic CT scans

Purpose: To compare the absorbed dose from computed tomography (CT) in radiotherapy planning (RP CT) against those from diagnostic CT (DG CT) examinations and to explore the possible reasons for any dose differences. Method: Two groups of patients underwent CT-scans of the thorax with either DG-CT (n=55) or RP-CT (n=55). Patients from each group had similar weight and body mass index (BMI) and were divided into low (25). Parameters including CTDIvol, DLP and scan length were compared. Results: The mean CTDIvol and DLP values from RP-CT (38.1 mGy, 1472 mGy·cm) are approximately four times higher than for DG-CT (9.63 mGy, 376.5 mGy·cm). For low BMI group, the CTDIvol in the RP-CT scans (36.4 mGy) is 6.3 times higher than the one in the DG-CT scans (5.8 mGy). For high BMI group, the CTDIvol in the RP-CT (39.6 mGy) is 2.5 times higher than the one in the DG-CT scans (15.8 mGy). In the DG-CT scans a strong negative linear correlation between noise index (NI) and mean CTDIvol was observed (r =-0.954, p=0.004); the higher NI, the lower CTDIvol. This was not the case in the RP-DG scans. Conclusion: The absorbed radiation dose is significantly higher and less BMI dependent for RP-CT scans compared to DG-CT. Image quality requirements of the examinations should be researched to ensure that radiation doses are not unnecessarily high

An experimental human blood stage model for studying Plasmodium malariae infection

Background: Plasmodium malariae is considered a ‘minor’ malaria parasite, although its global disease burden is underappreciated. The aim of this study was to develop an induced blood stage malaria (IBSM) model of P. malariae to study parasite biology, diagnostics, and treatment. Methods: This clinical trial involved two healthy subjects who were intravenously inoculated with cryopreserved P. malariae-infected erythrocytes. Subjects were treated with artemether-lumefantrine following development of clinical symptoms. Prior to antimalarial therapy, mosquito feeding assays were performed to investigate transmission, and blood samples were collected for rapid diagnostic testing and parasite transcription profiling. Serial blood samples were collected for biomarker analysis. Results: Both subjects experienced symptoms and signs typical of early malaria. Parasitaemia was detected 7 days post-inoculation and increased until antimalarial treatment was initiated 25 and 21 days post-inoculation for Subject 1 and 2 respectively (peak parasitaemia levels were 174,182 and 50,291 parasites/mL respectively). The parasite clearance half-life following artemether-lumefantrine treatment was 6.7 hours. Mosquito transmission was observed for one subject, while in vivo parasite transcription and biomarkers were successfully profiled. Conclusions: An IBSM model of P. malariae has been successfully developed and may be used to study the biology, diagnostics, and treatment of this neglected malaria species

Gabapentin for chronic pelvic pain in women (GaPP2): a multicentre, randomised, double-blind, placebo-controlled trial

Background: Chronic pelvic pain affects 2–24% of women worldwide and evidence for medical treatments is scarce. Gabapentin is effective in treating some chronic pain conditions. We aimed to measure the efficacy and safety of gabapentin in women with chronic pelvic pain and no obvious pelvic pathology. Methods: We performed a multicentre, randomised, double-blind, placebo-controlled randomised trial in 39 UK hospital centres. Eligible participants were women with chronic pelvic pain (with or without dysmenorrhoea or dyspareunia) of at least 3 months duration. Inclusion criteria were 18–50 years of age, use or willingness to use contraception to avoid pregnancy, and no obvious pelvic pathology at laparoscopy, which must have taken place at least 2 weeks before consent but less than 36 months previously. Participants were randomly assigned in a 1:1 ratio to receive gabapentin (titrated to a maximum dose of 2700 mg daily) or matching placebo for 16 weeks. The online randomisation system minimised allocations by presence or absence of dysmenorrhoea, psychological distress, current use of hormonal contraceptives, and hospital centre. The appearance, route, and administration of the assigned intervention were identical in both groups. Patients, clinicians, and research staff were unaware of the trial group assignments throughout the trial. Participants were unmasked once they had provided all outcome data at week 16–17, or sooner if a serious adverse event requiring knowledge of the study drug occurred. The dual primary outcome measures were worst and average pain scores assessed separately on a numerical rating scale in weeks 13–16 after randomisation, in the intention-to-treat population. Self-reported adverse events were assessed according to intention-to-treat principles. This trial is registered with the ISRCTN registry, ISCRTN77451762. Findings: Participants were screened between Nov 30, 2015, and March 6, 2019, and 306 were randomly assigned (153 to gabapentin and 153 to placebo). There were no significant between-group differences in both worst and average numerical rating scale (NRS) pain scores at 13–16 weeks after randomisation. The mean worst NRS pain score was 7·1 (standard deviation [SD] 2·6) in the gabapentin group and 7·4 (SD 2·2) in the placebo group. Mean change from baseline was −1·4 (SD 2·3) in the gabapentin group and −1·2 (SD 2·1) in the placebo group (adjusted mean difference −0·20 [97·5% CI −0·81 to 0·42]; p=0·47). The mean average NRS pain score was 4·3 (SD 2·3) in the gabapentin group and 4·5 (SD 2·2) in the placebo group. Mean change from baseline was −1·1 (SD 2·0) in the gabapentin group and −0·9 (SD 1·8) in the placebo group (adjusted mean difference −0·18 [97·5% CI −0·71 to 0·35]; p=0·45). More women had a serious adverse event in the gabapentin group than in the placebo group (10 [7%] of 153 in the gabapentin group compared with 3 [2%] of 153 in the placebo group; p=0·04). Dizziness, drowsiness, and visual disturbances were more common in the gabapentin group. Interpretation: This study was adequately powered, but treatment with gabapentin did not result in significantly lower pain scores in women with chronic pelvic pain, and was associated with higher rates of side-effects than placebo. Given the increasing reports of abuse and evidence of potential harms associated with gabapentin use, it is important that clinicians consider alternative treatment options to off-label gabapentin for the management of chronic pelvic pain and no obvious pelvic pathology. Funding: National Institute for Health Research

Safety, pharmacokinetics, and antimalarial activity of the novel plasmodium eukaryotic translation elongation factor 2 inhibitor M5717: a first-in-human, randomised, placebo-controlled, double-blind, single ascending dose study and volunteer infection study

M5717 is the first plasmodium translation elongation factor 2 inhibitor to reach clinical development as an antimalarial. We aimed to characterise the safety, pharmacokinetics, and antimalarial activity of M5717 in healthy volunteers. This first-in-human study was a two-part, single-centre clinical trial done in Brisbane, QLD, Australia. Part one was a double-blind, randomised, placebo-controlled, single ascending dose study in which participants were enrolled into one of nine dose cohorts (50, 100, 200, 400, 600, 1000, 1250, 1800, or 2100 mg) and randomly assigned (3:1) to M5717 or placebo. A sentinel dosing strategy was used for each dose cohort whereby two participants (one assigned to M5717 and one assigned to placebo) were initially randomised and dosed. Randomisation schedules were generated electronically by independent, unblinded statisticians. Part two was an open-label, non-randomised volunteer infection study using the Plasmodium falciparum induced blood-stage malaria model in which participants were enrolled into three dose cohorts. Healthy men and women of non-childbearing potential aged 18-55 years were eligible for inclusion; individuals in the volunteer infection study were required to be malaria naive. Safety and tolerability (primary outcome of the single ascending dose study and secondary outcome of the volunteer infection study) were assessed by frequency and severity of adverse events. The pharmacokinetic profile of M5717 was also characterised (primary outcome of the volunteer infection study and secondary outcome of the single ascending dose study). Parasite clearance kinetics (primary outcome of the volunteer infection study) were assessed by the parasite reduction ratio and the corresponding parasite clearance half-life; the incidence of recrudescence up to day 28 was determined (secondary outcome of the volunteer infection study). Recrudescent parasites were tested for genetic mutations (exploratory outcome). The trial is registered with ClinicalTrials.gov (NCT03261401). Between Aug 28, 2017, and June 14, 2019, 221 individuals were assessed for eligibility, of whom 66 men were enrolled in the single ascending dose study (eight per cohort for 50-1800 mg cohorts, randomised three M5717 to one placebo, and two in the 2100 mg cohort, randomised one M5717 to one placebo) and 22 men were enrolled in the volunteer infection study (six in the 150 mg cohort and eight each in the 400 mg and 800 mg cohorts). No adverse event was serious; all M5717-related adverse events were mild or moderate in severity and transient, with increased frequency observed at doses above 1250 mg. In the single ascending dose study, treatment-related adverse events occurred in three of 17 individuals in the placebo group; no individual in the 50 mg, 100 mg, or 200 mg groups; one of six individuals in each of the 400 mg, 1000 mg, and 1250 mg groups; two of six individuals in the 600 mg group; and in all individuals in the 1800 mg and 2100 mg groups. In the volunteer infection study, M5717-related adverse events occurred in no participants in the 150 mg or 800 mg groups and in one of eight participants in the 400 mg group. Transient oral hypoesthesia (in three participants) and blurred vision (in four participants) were observed in the 1800 mg or 2100 mg groups and constituted an unknown risk; thus, further dosing was suspended after dosing of the two sentinel individuals in the 2100 mg cohort. Maximum blood concentrations occurred 1-7 h after dosing, and a long half-life was observed (146-193 h at doses ≥200 mg). Parasite clearance occurred in all participants and was biphasic, characterised by initial slow clearance lasting 35-55 h (half-life 231·1 h [95% CI 40·9 to not reached] for 150 mg, 60·4 h [38·6 to 138·6] for 400 mg, and 24·7 h [20·4 to 31·3] for 800 mg), followed by rapid clearance (half-life 3·5 h [3·1 to 4·0] for 150 mg, 3·9 h [3·3 to 4·8] for 400 mg, and 5·5 h [4·8 to 6·4] for 800 mg). Recrudescence occurred in three (50%) of six individuals dosed with 150 mg and two (25%) of eight individuals dosed with 400 mg. Genetic mutations associated with resistance were detected in four cases of parasite recrudescence (two individuals dosed with 150 mg and two dosed with 400 mg). The safety, pharmacokinetics, and antimalarial activity of M5717 support its development as a component of a single-dose antimalarial combination therapy or for malaria prophylaxis. Wellcome Trust and the healthcare business of Merck KGaA, Darmstadt, Germany. [Abstract copyright: Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Safety and feasibility of apheresis to harvest and concentrate parasites from subjects with induced blood stage Plasmodium vivax infection

Background: In the absence of a method to culture Plasmodium vivax, the only way to source parasites is ex vivo. This hampers many aspects of P. vivax research. This study aimed to assess the safety of apheresis, a method for selective removal of specific components of blood as a means of extracting and concentrating P. vivax parasites. Methods: An iterative approach was employed across four non-immune healthy human subjects in single subject cohorts. All four subjects were inoculated with ~ 564 blood stage P. vivax (HMP013-Pv) and subjected to apheresis 10 to 11 days later. Blood samples collected during apheresis (haematocrit layers 0.5% to 11%) were tested for the presence and concentration of P. vivax by microscopy, flow cytometry, 18S rDNA qPCR for total parasites, and pvs25 qRT-PCR for female gametocyte transcripts. Safety was determined by monitoring adverse events. Malaria transmission to mosquitoes was assessed by membrane feeding assays. Results: There were no serious adverse events and no significant safety concerns. Apheresis concentrated asexual parasites by up to 4.9-fold (range: 0.9–4.9-fold) and gametocytes by up to 1.45-fold (range: 0.38–1.45-fold) compared to pre-apheresis densities. No single haematocrit layer contained > 40% of all the recovered P. vivax asexual parasites. Ex vivo concentration of parasites by Percoll gradient centrifugation of whole blood achieved greater concentration of gametocytes than apheresis. Mosquito transmission was enhanced by up to fivefold in a single apheresis sample compared to pre-apheresis. Conclusion: The modest level of parasite concentration suggests that the use of apheresis may not be an ideal method for harvesting P. vivax. Trial Registration Australia New Zealand Clinical Trials Registry (ANZCTR) Trial ID: ACTRN12617001502325 registered on 19th October 2017. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373812

Antiglucocorticoid RU38486 reduces net protein catabolism in experimental acute renal failure

BACKGROUND: In acute renal failure, a pronounced net protein catabolism occurs that has long been associated with corticoid action. By competitively blocking the glucocorticoid receptor with the potent antiglucocorticoid RU 38486, the present study addressed the question to what extent does corticoid action specific to uremia cause the observed muscle degradation, and does inhibition of glucocorticoid action reduce the protein wasting? METHODS: RU 38486 was administered in a dose of 50 mg/kg/24 h for 48 h after operation to fasted bilaterally nephrectomized (BNX) male adult Wistar rats and sham operated (SHAM) controls. Protein turnover was evaluated by high performance liquid chromatography (HPLC) of amino acid efflux in sera from isolated perfused hindquarters of animals treated with RU 38486 versus untreated controls. RESULTS: Administration of RU 38486 reduces the total amino acid efflux (TAAE) by 18.6% in SHAM and 15.6% in BNX and efflux of the indicator of net protein turnover, phenylalanine (Phe) by 33.3% in SHAM and 13% in BNX animals as compared to the equally operated, but untreated animals. However, the significantly higher protein degradation observed in BNX (0.6 ± 0.2 nmol/min/g muscle) versus SHAM (0.2 ± 0.1 nmol/min/g muscle) rats, as demonstrated by the marker of myofribrillar proteolytic rate, 3-Methylhistidine (3 MH) remains unaffected by administration of RU 38486 (0.5 ± 0.1 v. 0.2 ± 0.1 nmol/min/g muscle in BNX v. SHAM). CONCLUSION: RU 38486 does not act on changes of muscular protein turnover specific to uremia but reduces the effect of stress- stimulated elevated corticosterone secretion arising from surgery and fasting. A potentially beneficial effect against stress- induced catabolism in severe illness can be postulated that merits further study

Gabapentin for chronic pelvic pain in women (GaPP2):a multicentre, randomised, double-blind, placebo-controlled trial

BackgroundChronic pelvic pain affects 2–24% of women worldwide and evidence for medical treatments is scarce. Gabapentin is effective in treating some chronic pain conditions. We aimed to measure the efficacy and safety of gabapentin in women with chronic pelvic pain and no obvious pelvic pathology.MethodsWe performed a multicentre, randomised, double-blind, placebo-controlled randomised trial in 39 UK hospital centres. Eligible participants were women with chronic pelvic pain (with or without dysmenorrhoea or dyspareunia) of at least 3 months duration. Inclusion criteria were 18–50 years of age, use or willingness to use contraception to avoid pregnancy, and no obvious pelvic pathology at laparoscopy, which must have taken place at least 2 weeks before consent but less than 36 months previously. Participants were randomly assigned in a 1:1 ratio to receive gabapentin (titrated to a maximum dose of 2700 mg daily) or matching placebo for 16 weeks. The online randomisation system minimised allocations by presence or absence of dysmenorrhoea, psychological distress, current use of hormonal contraceptives, and hospital centre. The appearance, route, and administration of the assigned intervention were identical in both groups. Patients, clinicians, and research staff were unaware of the trial group assignments throughout the trial. Participants were unmasked once they had provided all outcome data at week 16–17, or sooner if a serious adverse event requiring knowledge of the study drug occurred. The dual primary outcome measures were worst and average pain scores assessed separately on a numerical rating scale in weeks 13–16 after randomisation, in the intention-to-treat population. Self-reported adverse events were assessed according to intention-to-treat principles. This trial is registered with the ISRCTN registry, ISCRTN77451762.FindingsParticipants were screened between Nov 30, 2015, and March 6, 2019, and 306 were randomly assigned (153 to gabapentin and 153 to placebo). There were no significant between-group differences in both worst and average numerical rating scale (NRS) pain scores at 13–16 weeks after randomisation. The mean worst NRS pain score was 7·1 (standard deviation [SD] 2·6) in the gabapentin group and 7·4 (SD 2·2) in the placebo group. Mean change from baseline was −1·4 (SD 2·3) in the gabapentin group and −1·2 (SD 2·1) in the placebo group (adjusted mean difference −0·20 [97·5% CI −0·81 to 0·42]; p=0·47). The mean average NRS pain score was 4·3 (SD 2·3) in the gabapentin group and 4·5 (SD 2·2) in the placebo group. Mean change from baseline was −1·1 (SD 2·0) in the gabapentin group and −0·9 (SD 1·8) in the placebo group (adjusted mean difference −0·18 [97·5% CI −0·71 to 0·35]; p=0·45). More women had a serious adverse event in the gabapentin group than in the placebo group (10 [7%] of 153 in the gabapentin group compared with 3 [2%] of 153 in the placebo group; p=0·04). Dizziness, drowsiness, and visual disturbances were more common in the gabapentin group.InterpretationThis study was adequately powered, but treatment with gabapentin did not result in significantly lower pain scores in women with chronic pelvic pain, and was associated with higher rates of side-effects than placebo. Given the increasing reports of abuse and evidence of potential harms associated with gabapentin use, it is important that clinicians consider alternative treatment options to off-label gabapentin for the management of chronic pelvic pain and no obvious pelvic pathology.FundingNational Institute for Health Research