National quality improvement intervention to reduce high risk oral methotrexate prescribing.

BACKGROUND: Harmful or fatal errors related to accidental overdose of methotrexate tablets are well documented. In England, the coprescription of 2.5 mg and 10 mg methotrexate tablets is not recommended, because both tablets look similar, and may be confused with each other, leading to a potential overdose of methotrexate. It is recommended that one tablet strength (usually 2.5 mg) is prescribed and dispensed. A recent retrospective cohort study identified that while 97% of patients in England were prescribed only 2.5 mg methotrexate tablets, the prescribing of 10 mg tablets or combinations of 2.5 mg and 10 mg tablets was still common practice in a small number of geographical areas across the country. AIM AND METHODOLOGY: To reduce national variation in the prescription of oral methotrexate 10 mg tablets, for non-cancer treatment, by November 2021. A focused, five-stage quality improvement (QI) intervention was used, providing centralised support to a cohort of high prescribing integrated care systems (ICSs) in England. FINDINGS: 23% (10) of ICSs in England were responsible for 76% of prescribing of methotrexate 10 mg tablets. Eight of these high prescribing ICSs participated in the QI intervention between March and November 2021. During the action period, the high prescribing cohort saw a 54% reduction in the prescribing of methotrexate 10 mg tablets, with seven ICSs seeing reductions of between 41% and 75%, resulting in reduced variation between the high prescribing ICSs and all other ICSs. The intervention was well received by ICSs with all making structural changes to their respective systems so that improvement would be sustained. CONCLUSIONS: The success of this project raises several exciting opportunities for further work of this nature, particularly where this is significant variation in practice across the country.

Graphene Nanoplatelets as a Replacement for Carbon Black in Rubber Compounds.

In this work, we evaluated the processing and reinforcement characteristics of both carbon black (CB) and graphene nanoplatelets (GNPs) within a nitrile butadiene rubber (NBR) matrix. The aspect ratio of the GNPs was measured using atomic force microscopy (AFM) and related to the dispersion and agglomeration within the NBR matrix, as observed by scanning electron microscopy (SEM). The relationship between GNP aspect ratio and mechanical properties was studied by micromechanical modelling. The tensile and tear properties of NBR after compounding with GNPs were enhanced to a greater extent compared to carbon black, while curing times were smaller and scorch times longer, indicating some of the advantages of using GNPs. Overall, the inherent properties of GNPs along with their geometry led to the production of better-performing rubber compounds that can replace their CB-filled counterparts in applications where flexibility, tear strength and compliance are important. The influence of processing on dispersion, orientation and agglomeration of flakes was also highlighted with respect to the Young's modulus of the NBR compounds.

Phenotyping clonal populations of glioma stem cell reveals a high degree of plasticity in response to changes of microenvironment.

The phenotype of glioma-initiating cells (GIC) is modulated by cell-intrinsic and cell-extrinsic factors. Phenotypic heterogeneity and plasticity of GIC is an important limitation to therapeutic approaches targeting cancer stem cells. Plasticity also presents a challenge to the identification, isolation, and propagation of purified cancer stem cells. Here we use a barcode labelling approach of GIC to generate clonal populations over a number of passages, in combination with phenotyping using the established stem cell markers CD133, CD15, CD44, and A2B5. Using two cell lines derived from isocitrate dehydrogenase (IDH)-wildtype glioblastoma, we identify a remarkable heterogeneity of the phenotypes between the cell lines. During passaging, clonal expansion manifests as the emergence of a limited number of barcoded clones and a decrease in the overall number of clones. Dual-labelled GIC are capable of forming traceable clonal populations which emerge after as few as two passages from mixed cultures and through analyses of similarity of relative proportions of 16 surface markers we were able to pinpoint the fate of such populations. By generating tumour organoids we observed a remarkable persistence of dominant clones but also a significant plasticity of stemness marker expression. Our study presents an experimental approach to simultaneously barcode and phenotype glioma-initiating cells to assess their functional properties, for example to screen newly established GIC for tumour-specific therapeutic vulnerabilities.

The Hull Anterior Vitrectomy Simulation System (HAVSS): a validated novel simulation for training in the management of intra-operative vitreous loss.

OBJECTIVES: To design and validate a feasible simulation to address an identified training gap in the management of intraoperative vitreous loss. METHODS: Our simulation consists of a two-part non-toxic mixture that polymerises upon contact within a silicone training eye, to resemble the appearance of vitreous after staining with triamcinolone. This gel can be cut and aspirated with an anterior vitrectomy probe. Experienced consultant ophthalmic surgeons were invited to assess the simulation and anonymously complete validity questionnaires. RESULTS: Seven senior surgeons participated. Four (57%) strongly agreed and three (43%) agreed that the tissue behaved like vitreous. Six (86%) strongly agreed and one (14%) agreed that instrument handling was realistic. Three (43%) strongly agreed and four (57%) agreed that simulated triamcinolone staining was realistic. Four (57%) strongly agreed and three (43%) agreed that the simulation was visually convincing. Six (86%) strongly agreed and one (14%) agreed that this simulation is useful for training. No participants disagreed with any validity statements. CONCLUSIONS: This novel simulation of anterior vitrectomy has good face and content validity, with unanimous agreement among experienced surgeons of its utility for training in the management of intraoperative vitreous loss.

Final Analysis of a Trial of M72/AS01E Vaccine to Prevent Tuberculosis.

BACKGROUND: Results of an earlier analysis of a trial of the M72/AS01E candidate vaccine against Mycobacterium tuberculosis showed that in infected adults, the vaccine provided 54.0% protection against active pulmonary tuberculosis disease, without evident safety concerns. We now report the results of the 3-year final analysis of efficacy, safety, and immunogenicity. METHODS: From August 2014 through November 2015, we enrolled adults 18 to 50 years of age with M. tuberculosis infection (defined by positive results on interferon-γ release assay) without evidence of active tuberculosis disease at centers in Kenya, South Africa, and Zambia. Participants were randomly assigned in a 1:1 ratio to receive two doses of either M72/AS01E or placebo, administered 1 month apart. The primary objective was to evaluate the efficacy of M72/AS01E to prevent active pulmonary tuberculosis disease according to the first case definition (bacteriologically confirmed pulmonary tuberculosis not associated with human immunodeficiency virus infection). Participants were followed for 3 years after the second dose. Participants with clinical suspicion of tuberculosis provided sputum samples for polymerase-chain-reaction assay, mycobacterial culture, or both. Humoral and cell-mediated immune responses were evaluated until month 36 in a subgroup of 300 participants. Safety was assessed in all participants who received at least one dose of M72/AS01E or placebo. RESULTS: A total of 3575 participants underwent randomization, of whom 3573 received at least one dose of M72/AS01E or placebo, and 3330 received both planned doses. Among the 3289 participants in the according-to-protocol efficacy cohort, 13 of the 1626 participants in the M72/AS01E group, as compared with 26 of the 1663 participants in the placebo group, had cases of tuberculosis that met the first case definition (incidence, 0.3 vs. 0.6 cases per 100 person-years). The vaccine efficacy at month 36 was 49.7% (90% confidence interval [CI], 12.1 to 71.2; 95% CI, 2.1 to 74.2). Among participants in the M72/AS01E group, the concentrations of M72-specific antibodies and the frequencies of M72-specific CD4+ T cells increased after the first dose and were sustained throughout the follow-up period. Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two groups. CONCLUSIONS: Among adults infected with M. tuberculosis, vaccination with M72/AS01E elicited an immune response and provided protection against progression to pulmonary tuberculosis disease for at least 3 years. (Funded by GlaxoSmithKline Biologicals and Aeras; ClinicalTrials.gov number, NCT01755598.).

Mutant IDH Sensitizes Gliomas to Endoplasmic Reticulum Stress and Triggers Apoptosis via miR-183-Mediated Inhibition of Semaphorin 3E.

Human astrocytomas and oligodendrogliomas are defined by mutations of the metabolic enzymes isocitrate dehydrogenase (IDH) 1 or 2, resulting in the production of the abnormal metabolite D-2 hydroxyglutarate. Here, we studied the effect of mutant IDH on cell proliferation and apoptosis in a glioma mouse model. Tumors were generated by inactivating Pten and p53 in forebrain progenitors and compared with tumors additionally expressing the Idh1 R132H mutation. Idh-mutant cells proliferated less in vitro and mice with Idh-mutant tumors survived significantly longer compared with Idh-wildtype mice. Comparison of miRNA and RNA expression profiles of Idh-wildtype and Idh-mutant cells and tumors revealed miR-183 was significantly upregulated in IDH-mutant cells. Idh-mutant cells were more sensitive to endoplasmic reticulum (ER) stress, resulting in increased apoptosis and thus reduced cell proliferation and survival. This was mediated by the interaction of miR-183 with the 5' untranslated region of semaphorin 3E, downregulating its function as an apoptosis suppressor. In conclusion, we show that mutant Idh1 delays tumorigenesis and sensitizes tumor cells to ER stress and apoptosis. This may open opportunities for drug treatments targeting the miR-183-semaphorin axis. SIGNIFICANCE: The pathologic metabolite 2-hydroxyglutarate, generated by IDH-mutant astrocytomas, sensitizes tumor cells to ER stress and delays tumorigenesis. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/19/4994/F1.large.jpg.

The management of diverticulitis: a review of the guidelines.

Radiological evidence of inflammation, using computed tomography (CT), is needed to diagnose the first occurrence of diverticulitis. CT is also warranted when the severity of symptoms suggests that perforation or abscesses have occurred. Diverticulitis is classified as complicated or uncomplicated based on CT scan, severity of symptoms and patient history; this classification is used to direct management. Outpatient treatment is recommended in afebrile, clinically stable patients with uncomplicated diverticulitis. For patients with uncomplicated diverticulitis, antibiotics have no proven benefit in reducing the duration of the disease or preventing recurrence, and should only be used selectively. For complicated diverticulitis, non-operative management, including bowel rest and intravenous antibiotics, is indicated for small abscesses; larger abscesses of 3-5 cm should be drained percutaneously. Patients with peritonitis and sepsis should receive fluid resuscitation, rapid antibiotic administration and urgent surgery. Surgical intervention with either Hartmann procedure or primary anastomosis, with or without diverting loop ileostomy, is indicated for peritonitis or in failure of non-operative management. Colonoscopy is recommended for all patients with complicated diverticulitis 6 weeks after CT diagnosis of inflammation, and for patients with uncomplicated diverticulitis who have suspicious features on CT scan or who otherwise meet national bowel cancer screening criteria.

Phase 2b Controlled Trial of M72/AS01E Vaccine to Prevent Tuberculosis.

BACKGROUND: A vaccine to interrupt the transmission of tuberculosis is needed. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 2b trial of the M72/AS01E tuberculosis vaccine in Kenya, South Africa, and Zambia. Human immunodeficiency virus (HIV)-negative adults 18 to 50 years of age with latent M. tuberculosis infection (by interferon-γ release assay) were randomly assigned (in a 1:1 ratio) to receive two doses of either M72/AS01E or placebo intramuscularly 1 month apart. Most participants had previously received the bacille Calmette-Guérin vaccine. We assessed the safety of M72/AS01E and its efficacy against progression to bacteriologically confirmed active pulmonary tuberculosis disease. Clinical suspicion of tuberculosis was confirmed with sputum by means of a polymerase-chain-reaction test, mycobacterial culture, or both. RESULTS: We report the primary analysis (conducted after a mean of 2.3 years of follow-up) of the ongoing trial. A total of 1786 participants received M72/AS01E and 1787 received placebo, and 1623 and 1660 participants in the respective groups were included in the according-to-protocol efficacy cohort. A total of 10 participants in the M72/AS01E group met the primary case definition (bacteriologically confirmed active pulmonary tuberculosis, with confirmation before treatment), as compared with 22 participants in the placebo group (incidence, 0.3 cases vs. 0.6 cases per 100 person-years). The vaccine efficacy was 54.0% (90% confidence interval [CI], 13.9 to 75.4; 95% CI, 2.9 to 78.2; P=0.04). Results for the total vaccinated efficacy cohort were similar (vaccine efficacy, 57.0%; 90% CI, 19.9 to 76.9; 95% CI, 9.7 to 79.5; P=0.03). There were more unsolicited reports of adverse events in the M72/AS01E group (67.4%) than in the placebo group (45.4%) within 30 days after injection, with the difference attributed mainly to injection-site reactions and influenza-like symptoms. Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two groups. CONCLUSIONS: M72/AS01E provided 54.0% protection for M. tuberculosis-infected adults against active pulmonary tuberculosis disease, without evident safety concerns. (Funded by GlaxoSmithKline Biologicals and Aeras; ClinicalTrials.gov number, NCT01755598 .).

Improving access to services through a collaborative learning system at East London NHS Foundation Trust.

Early intervention following initial referral into healthcare services can have a significant impact on the prognosis and outcomes of patients. Long waiting times and non-attendance can have an immediate and enduring negative impact on patients and healthcare service providers. The traditional management options in reducing waiting times have largely revolved around setting performance targets, providing financial incentives or additional resourcing. This large-scale quality improvement project aimed to reduce waiting times from referral to first appointment and non-attendance for a wide range of services providing primary and secondary care mental health and community health services at East London NHS Foundation Trust (ELFT). Fifteen community-based teams across ELFT came together with the shared goal of improving access. These teams were diverse in both nature and geography and included adult community mental health teams, child and adolescent mental health services, secondary care psychological therapy services, memory services, a musculoskeletal physiotherapy service and a sickle cell service. A collaborative learning system was developed to support the teams to come together at regular intervals, share data, test and scale-up ideas through quality improvement and have access to coaching from skilled improvement advisors in the ELFT central quality improvement team. Over the course of the 2-year project, waiting time from referral to first face-to-face appointment reduced from an average of 60.6 days to 46.7 days (a 23% reduction), non-attendance at first face-to-face appointment reduced from an average of 31.7% to an average of 20.5% (a 36% reduction), while referral volume increased from an average of 1021 per month to an average of 1280 per month (a 25% increase).

Negative Stain Single-particle EM of the Maltose Transporter in Nanodiscs Reveals Asymmetric Closure of MalK2 and Catalytic Roles of ATP, MalE, and Maltose.

The Escherichia coli MalE-MalFGK2 complex is one of the best characterized members of the large and ubiquitous family of ATP-binding cassette (ABC) transporters. It is composed of a membrane-spanning heterodimer, MalF-MalG; a homodimeric ATPase, MalK2; and a periplasmic maltose receptor, MalE. Opening and closure of MalK2 is coupled to conformational changes in MalF-MalG and the alternate exposition of the substrate-binding site to either side of the membrane. To further define this alternate access mechanism and the impact of ATP, MalE, and maltose on the conformation of the transporter during the transport cycle, we have reconstituted MalFGK2 in nanodiscs and analyzed its conformations under 10 different biochemical conditions using negative stain single-particle EM. EM map results (at 15-25 Å resolution) indicate that binding of ATP to MalK2 promotes an asymmetric, semi-closed conformation in accordance with the low ATPase activity of MalFGK2 In the presence of MalE, the MalK dimer becomes fully closed, gaining the ability to hydrolyze ATP. In the presence of ADP or maltose, MalE·MalFGK2 remains essentially in a semi-closed symmetric conformation, indicating that release of these ligands is required for the return to the initial state. Taken together, this structural information provides a rationale for the stimulation of MalK ATPase activity by MalE as well as by maltose.

New vistas in the molecular chemistry of thorium: low oxidation state complexes.

Although the molecular chemistry of thorium is dominated by the +4 oxidation state accounts of Th(iii) complexes have continued to increase in frequency since the first structurally characterised example was reported thirty years ago. The isolation of the first Th(ii) complexes in 2015 and exciting recent Th(iii) and Th(ii) reactivity studies both indicate that this long-neglected area is set to undergo a rapid expansion in research activity over the next decade, as previously seen since the turn of the millennium for analogous U(iii) small molecule activation chemistry. In this perspective article, we review synthetic routes to Th(iii) and Th(ii) complexes and summarise their distinctive physical properties. We provide a near-chronological discussion of these systems, focusing on structurally characterised examples, and cover complementary theoretical studies that rationalise electronic structures. All reactivity studies of Th(iii) and Th(ii) complexes that have been reported to date are described in detail.

Pseudo-Monocular Nystagmus Associated with Duane's Syndrome: Report of Two Cases.

PURPOSE: To present clinical findings and eye movement recordings of two children who had clinically apparent monocular nystagmus. METHODS: Full orthoptic and ophthalmological examination and eye movement recordings. RESULTS: An 8-year-old girl (patient 1) and a 13-month-old girl (patient 2) presented with right monocular nystagmus and right esotropia. A magnetic resonance imaging (MRI) scan of the brain obtained previously had been unremarkable for patient 2. Patient 1 had right amblyopia with visual acuity (VA) reduced to 20/400. Both patients had left abduction deficit and left palpebral fissure narrowing on adduction indicative of Duane's retraction syndrome. Patient 2 also had mild enophthalmos. Both patients had constant horizontal nystagmus in the right eye and very fine nystagmus in the left eye, which could only be detected on video and eye movement recordings. CONCLUSION: The existence of Duane's syndrome in both patients was masking the presence of nystagmus in the left eye, highlighting that detailed examination in this case can eliminate the need for neuroimaging. Interestingly, the dominant eye of both patients was on the side which was affected by Duane's syndrome, as there was less nystagmus in this eye.

Medication-administration errors in an urban mental health hospital: a direct observation study.

In the present study, we aimed to identify the incidence, type, and potential clinical consequence of medication-administration errors made in a mental health hospital, and to investigate factors that might increase the risk of error. A prospective, direct observational technique was used to collect data from nurse medication rounds on each of the hospital's 43 inpatient wards. Regression analysis was used to identify potential error predictors. During the 172 medication rounds observed, 139 errors were detected in 4177 (3.3%) opportunities. The most common error was incorrect dose omission (52/139, 37%). Other common errors included incorrect dose (25/139, 18%), incorrect form (16/139, 12%), and incorrect time (12/139, 9%). Fifteen (11%) of the errors were of serious clinical severity; the rest were of negligible or minor severity. Factors that increased the risk of error included the nurse interrupting the medication round to attend to another activity, an increased number of 'when required' doses of medication administered, a higher number of patients on the ward, and an increased number of doses of medication due. These findings suggest that providers of inpatient mental health-care services should adopt medicine-administration systems that minimize task interruption and the use of 'when required' medication, as well as taking steps to reduce nursing workload.

A quantitative metric to identify critical elements within seafood supply networks.

A theoretical basis is required for comparing key features and critical elements in wild fisheries and aquaculture supply chains under a changing climate. Here we develop a new quantitative metric that is analogous to indices used to analyse food-webs and identify key species. The Supply Chain Index (SCI) identifies critical elements as those elements with large throughput rates, as well as greater connectivity. The sum of the scores for a supply chain provides a single metric that roughly captures both the resilience and connectedness of a supply chain. Standardised scores can facilitate cross-comparisons both under current conditions as well as under a changing climate. Identification of key elements along the supply chain may assist in informing adaptation strategies to reduce anticipated future risks posed by climate change. The SCI also provides information on the relative stability of different supply chains based on whether there is a fairly even spread in the individual scores of the top few key elements, compared with a more critical dependence on a few key individual supply chain elements. We use as a case study the Australian southern rock lobster Jasus edwardsii fishery, which is challenged by a number of climate change drivers such as impacts on recruitment and growth due to changes in large-scale and local oceanographic features. The SCI identifies airports, processors and Chinese consumers as the key elements in the lobster supply chain that merit attention to enhance stability and potentially enable growth. We also apply the index to an additional four real-world Australian commercial fishery and two aquaculture industry supply chains to highlight the utility of a systematic method for describing supply chains. Overall, our simple methodological approach to empirically-based supply chain research provides an objective method for comparing the resilience of supply chains and highlighting components that may be critical.

A multi-criteria assessment of fishing gear impacts in demersal fisheries.

Fishing gears have multiple impacts on the marine environment, and policies to reduce these impacts through modifying fishing gears are becoming common place. Different modifications result in different changes in the set of environmental impacts, and imply different sets of costs and benefits for different stakeholder groups. In this study, the analytic hierarchy process (AHP) is used to quantify the relative importance of the environmental impacts of fishing to different stakeholder groups. Forty eight individuals representing six different stakeholder groups (ecologists, biologists, economists, gear technologists, fishers and fisheries managers) were surveyed. As expected, fishers and gear technologists placed substantially greater importance on reducing discarding of commercial fish species than on habitat damage. Priorities of other stakeholder groups varied, but all placed greater priority on habitats than the commercial sector. The results suggest that management aimed at reducing environmental impacts of fishing broader than just discarding is appropriate, but such moves are likely to be opposed by the fishing industry. The derived weights also have a direct application to fisheries management, as they allow otherwise non-commensurate impacts to be aggregated into an overall impact to compare environmental benefits from alternative modifications of fishing gear.

Recurrence of Congenital Pupillary-Iris-Lens Membrane After Surgical Excision.

The authors present a case of congenital pupillary-iris-lens membrane that demonstrated the previously unreported feature of membrane recurrence after surgical excision.

Fire suppression and fuels treatment effects on mixed-conifer carbon stocks and emissions.

Depending on management, forests can be an important sink or source of carbon that if released as CO2 could contribute to global warming. Many forests in the western United States are being treated to reduce fuels, yet the effects of these treatments on forest carbon are not well understood. We compared the immediate effects of fuels treatments on carbon stocks and releases in replicated plots before and after treatment, and against a reconstruction of active-fire stand conditions for the same forest in 1865. Total live-tree carbon was substantially lower in modern fire-suppressed conditions (and all of the treatments) than the same forest under an active-fire regime. Although fire suppression has increased stem density, current forests have fewer very large trees, reducing total live-tree carbon stocks and shifting a higher proportion of those stocks into small-diameter, fire-sensitive trees. Prescribed burning released 14.8 Mg C/ha, with pre-burn thinning increasing the average release by 70% and contributing 21.9-37.5 Mg C/ha in milling waste. Fire suppression may have incurred a double carbon penalty by reducing stocks and contributing to emissions with fuels-treatment activities or inevitable wildfire combustion. All treatments reduced fuels and increased fire resistance, but most of the gains were achieved with understory thinning, with only modest increases in the much heavier overstory thinning. We suggest modifying current treatments to focus on reducing surface fuels, actively thinning the majority of small trees, and removing only fire-sensitive species in the merchantable, intermediate size class. These changes would retain most of the current carbon-pool levels, reduce prescribed burn and potential future wildfire emissions, and favor stand development of large, fire-resistant trees that can better stabilize carbon stocks.

Review article: Adenosine use in the emergency department.

OBJECTIVE: To perform a review of the efficacy of adenosine, including its potential role as first-line treatment in unstable supraventricular tachycardia (SVT) and its use in wide complex tachycardias and diagnosing difficult arrhythmias. The dose and administration, nature and frequency of side-effects and relevant interactions and dosage adjustments are also discussed. METHODS: A search of the Medline database from 1950 to 2007 and the Embase Database from 1974 to 2007 was carried out. A manual search was performed of references of each article. RESULTS: Adenosine is efficacious at treating stable SVT, but it is no more effective than cheaper alternatives. It has a possible role in the first-line treatment of unstable SVT and is generally safe and effective when used to treat and/or diagnose wide complex tachycardias. There is a small risk of inducing serious arrhythmias, such as prolonged atrioventricular blockade and ventricular fibrillation. There is evidence that recommended initial doses for infants might be too low, but initial doses for children and adults are adequate. There is evidence that central venous administration requires lower doses, but there are no studies addressing peripheral sites of administration and size of flush. Minor and self-limiting side-effects are common. The need for dosage adjustments in the presence of interacting medications is well documented, but no studies have addressed how to rationally effect these adjustments. CONCLUSION: There is extensive evidence showing adenosine to be efficacious at treating SVT, but no more efficacious than cheaper alternatives. More studies are required to investigate other areas of adenosine use.

Focal dermal hypoplasia with subependymal heterotopia and hypoplastic corpus callosum.

A case is reported with right-sided abnormalities involving the brain, eyelid, eye, face and chest. The features described are similar to those found in conditions including focal dermal hypoplasia, microphthalmia with linear skin defects, oculocerebrocutaneous syndrome and terminal osseous dysplasia and pigmentary defects. However, none of these conditions, fully explains the collection of abnormalities found in this patient.