Ultrastructural analysis of changes in neurons of the mouse internal anal sphincter during ageing

Gastrointestinal disorders, including chronic constipation, faecal impaction and incontinence, are a major cause of morbidity in the elderly

Excimer laser processing of inkjet-printed and sputter-deposited transparent conducting SnO2:Sb for flexible electronics

The feasibility of low-temperature fabrication of transparent electrode elements from thin films of antimony-doped tin oxide (SnO2:Sb, ATO) has been investigated via inkjet printing, rf magnetron sputtering and post-deposition excimer laser processing. Laser processing of thin films on both glass and plastic substrates was performed using a Lambda Physik 305i excimer laser, with fluences in the range 20–100 mJ cm− 2 reducing sheet resistance from as-deposited values by up to 3 orders of magnitude. This is consistent with TEM analysis of the films that shows a densification of the upper 200 nm of laser-processed regions

Mapping a Quantitative Trait Locus (QTL) conferring pyrethroid resistance in the African malaria vector Anopheles funestus

BACKGROUND: Pyrethroid resistance in Anopheles funestus populations has led to an increase in malaria transmission in southern Africa. Resistance has been attributed to elevated activities of cytochrome P450s but the molecular basis underlying this metabolic resistance is unknown. Microsatellite and SNP markers were used to construct a linkage map and to detect a quantitative trait locus (QTL) associated with pyrethroid resistance in the FUMOZ-R strain of An. funestus from Mozambique. RESULTS: By genotyping 349 F(2 )individuals from 11 independent families, a single major QTL, rp1, at the telomeric end of chromosome 2R was identified. The rp1 QTL appears to present a major effect since it accounts for more than 60% of the variance in susceptibility to permethrin. This QTL has a strong additive genetic effect with respect to susceptibility. Candidate genes associated with pyrethroid resistance in other species were physically mapped to An. funestus polytene chromosomes. This showed that rp1 is genetically linked to a cluster of CYP6 cytochrome P450 genes located on division 9 of chromosome 2R and confirmed earlier reports that pyrethroid resistance in this strain is not associated with target site mutations (knockdown resistance). CONCLUSION: We hypothesize that one or more of these CYP6 P450s clustered on chromosome 2R confers pyrethroid resistance in the FUMOZ-R strain of An. funestus

Recommended Personal Protective Equipment for Cochlear Implant and Other Mastoid Surgery During the COVID-19 Era

© 2020 American Laryngological, Rhinological and Otological Society Inc, "The Triological Society" and American Laryngological Association (ALA) Objectives/Hypothesis: The overall aim of this study was to evaluate personal protective equipment (PPE) that may facilitate the safe recommencement of cochlear implantation in the COVID-19 era, with the broader goal of minimizing the period of auditory deprivation in prelingually deaf children and reducing the risk of cochlear ossification in individuals following meningitis. Methods: The study design comprised 1) an objective assessment of mastoid drilling-induced droplet spread conducted during simulated cochlear implant (CI) surgery and its mitigation via the use of a protective drape tent and 2) an evaluation of three PPE configurations by otologists while performing mastoid drilling on ex vivo temporal bones. The various PPE solutions were assessed in terms of their impact on communication, vital physiological parameters, visual acuity and fields, and acceptability to surgeons using a systematic risk-based approach. Results: Droplet spread during simulated CI surgery extended over 2 m, a distance greater than previously reported. A drape tent significantly reduced droplet spread. The ensemble of a half-face mask and safety spoggles (foam lined safety goggles) had consistently superior performance across all aspects of clinical usability. All other PPE options were found to substantially restrict the visual field, making them unsafe for microsurgery. Conclusions: The results of this preclinical study indicate that the most viable solution to enable the safe conduct of CI and other mastoid surgery is a combination of a filtering facepiece (FFP)3 mask or half-face respirator with safety spoggles as PPE. Prescription spoggles are an option for surgeons who need to wear corrective glasses to operate. A drape tent reduces droplet spread. A multicenter clinical trial to evaluate the effectiveness of PPE should be the next step toward safely performing CI surgery during the COVID-19 era. Level of Evidence: 4 Laryngoscope, 2020

Correction: Optimising a person-centred approach to stopping medicines in older people with multimorbidity and polypharmacy using the DExTruS framework: a realist review (BMC Medicine, (2022), 20, 1, (297), 10.1186/s12916-022-02475-1)

The original article [1] contained an error in the spelling of co-author, Michelle Maden’s name which has since been corrected

A De Novo Expression Profiling of Anopheles funestus, Malaria Vector in Africa, Using 454 Pyrosequencing

BACKGROUND: Anopheles funestus is one of the major malaria vectors in Africa and yet there are few genomic tools available for this species compared to An. gambiae. To start to close this knowledge gap, we sequenced the An. funestus transcriptome using cDNA libraries developed from a pyrethroid resistant laboratory strain and a pyrethroid susceptible field strain from Mali. RESULTS: Using a pool of life stages (pupae, larvae, adults: females and males) for each strain, 454 sequencing generated 375,619 reads (average length of 182 bp). De novo assembly generated 18,103 contigs with average length of 253 bp. The average depth of coverage of these contigs was 8.3. In total 20.8% of all reads were novel when compared to reference databases. The sequencing of the field strain generated 204,758 reads compared to 170,861 from the insecticide resistant laboratory strain. The contigs most differentially represented in the resistant strain belong to the P450 gene family and cuticular genes which correlates with previous studies implicating both of these gene families in pyrethroid resistance. qPCR carried out on six contigs indicates that these ESTs could be suitable for gene expression studies such as microarray. 31,000 sites were estimated to contain Single Nucleotide Polymorphisms (SNPs) and analysis of SNPs from 20 contigs suggested that most of these SNPs are likely to be true SNPs. Gene conservation analysis confirmed the close phylogenetic relationship between An. funestus and An. gambiae. CONCLUSION: This study represents a significant advance for the genetics and genomics of An. funestus since it provides an extensive set of both Expressed Sequence Tags (ESTs) and SNPs which can be readily adopted for the design of new genomic tools such as microarray or SNP platforms

Assembly of infectious enteroviruses depends on multiple, conserved genomic RNA-coat protein contacts.

Picornaviruses are important viral pathogens, but despite extensive study, the assembly process of their infectious virions is still incompletely understood, preventing the development of anti-viral strategies targeting this essential part of the life cycle. We report the identification, via RNA SELEX and bioinformatics, of multiple RNA sites across the genome of a typical enterovirus, enterovirus-E (EV-E), that each have affinity for the cognate viral capsid protein (CP) capsomer. Many of these sites are evolutionarily conserved across known EV-E variants, suggesting they play essential functional roles. Cryo-electron microscopy was used to reconstruct the EV-E particle at ~2.2 Å resolution, revealing extensive density for the genomic RNA. Relaxing the imposed symmetry within the reconstructed particles reveals multiple RNA-CP contacts, a first for any picornavirus. Conservative mutagenesis of the individual RNA-contacting amino acid side chains in EV-E, many of which are conserved across the enterovirus family including poliovirus, is lethal but does not interfere with replication or translation. Anti-EV-E and anti-poliovirus aptamers share sequence similarities with sites distributed across the poliovirus genome. These data are consistent with the hypothesis that these RNA-CP contacts are RNA Packaging Signals (PSs) that play vital roles in assembly and suggest that the RNA PSs are evolutionarily conserved between pathogens within the family, augmenting the current protein-only assembly paradigm for this family of viruses

A phase I pharmacokinetic and pharmacodynamic study of the oral mitogen-activated protein kinase kinase (MEK) inhibitor, WX-554, in patients with advanced solid tumours

Purpose: We performed a multi-centre phase I study to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the orally available small molecule mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, WX-554, and to determine the optimal biological dose for subsequent trials. Experimental design: Patients with treatment-refractory, advanced solid tumours, with adequate performance status and organ function were recruited to a dose-escalation study in a standard 3 + 3 design. The starting dose was 25 mg orally once weekly with toxicity, PK and PD guided dose-escalation with potential to explore alternative schedules. Results: Forty-one patients with advanced solid tumours refractory to standard therapies and with adequate organ function were recruited in eight cohorts up to doses of 150 mg once weekly and 75 mg twice weekly. No dose-limiting toxicities were observed during the study, and a maximum tolerated dose (MTD) was not established. The highest dose cohorts demonstrated sustained inhibition of extracellular signal-regulated kinase (ERK) phosphorylation in peripheral blood mononuclear cells following ex-vivo phorbol 12-myristate 13-acetate stimulation. There was a decrease of 70 ± 26% in mean phosphorylated (p)ERK in C1 day 8 tumour biopsies when compared with pre-treatment tumour levels in the 75 mg twice a week cohort. Prolonged stable disease (>6 months) was seen in two patients, one with cervical cancer and one with ampullary carcinoma. Conclusions: WX-554 was well tolerated, and an optimal biological dose was established for further investigation in either a once or twice weekly regimens. The recommended phase 2 dose is 75 mg twice weekly

Report: Deprescribing medicines in older people living with multimorbidity and polypharmacy: the TAILOR evidence synthesis

Background: Tackling problematic polypharmacy requires tailoring the use of medicines to individual needs and circumstances. This may involve stopping medicines (deprescribing) but patients and clinicians report uncertainty on how best to do this. The TAILOR medication synthesis sought to help understand how best to support deprescribing in older people living with multimorbidity and polypharmacy. Objectives: We identified two research questions: (1) what evidence exists to support the safe, effective and acceptable stopping of medication in this patient group, and (2) how, for whom and in what contexts can safe and effective tailoring of clinical decisions related to medication use work to produce desired outcomes? We thus described three objectives: (1) to undertake a robust scoping review of the literature on stopping medicines in this group to describe what is being done, where and for what effect; (2) to undertake a realist synthesis review to construct a programme theory that describes ‘best practice’ and helps explain the heterogeneity of deprescribing approaches; and (3) to translate findings into resources to support tailored prescribing in clinical practice. Data sources: Experienced information specialists conducted comprehensive searches in MEDLINE, Cumulative Index to Nursing and Allied Health Literature,Web of Science, EMBASE, The Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials), Joanna Briggs Institute Database of Systematic Reviews and Implementation Reports, Google (Google Inc., Mountain View, CA, USA) and Google Scholar (targeted searches). Review methods: The scoping review followed the five steps described by the Joanna Briggs Institute methodology for conducting a scoping review.The realist review followed the methodological and publication standards for realist reviews described by the Realist And Meta-narrative Evidence Syntheses: Evolving Standards (RAMESES) group. Patient and public involvement partners ensured that our analysis retained a patient-centred focus. Results: Our scoping review identified 9528 abstracts: 8847 were removed at screening and 662 were removed at full-text review. This left 20 studies (published between 2009 and 2020) that examined the effectiveness, safety and acceptability of deprescribing in adults (aged ≥ 50 years) with polypharmacy (five or more prescribed medications) and multimorbidity (two or more conditions). Our analysis revealed that deprescribing under research conditions mapped well to expert guidance on the steps needed for good clinical practice. Our findings offer evidence-informed support to clinicians regarding the safety, clinician acceptability and potential effectiveness of clinical decision-making that demonstrates a structured approach to deprescribing decisions. Our realist review identified 2602 studies with 119 included in the final analysis. The analysis outlined 34 context–mechanism–outcome configurations describing the knowledge work of tailored prescribing under eight headings related to organisational, health-care professional and patient factors, and interventions to improve deprescribing. We conclude that robust tailored deprescribing requires attention to providing an enabling infrastructure, access to data, tailored explanations and trust. Limitations: Strict application of our definition of multimorbidity during the scoping review may have had an impact on the relevance of the review to clinical practice. The realist review was limited by the data (evidence) available. Conclusions: Our combined reviews recognise deprescribing as a complex intervention and provide support for the safety of structured approaches to deprescribing, but also highlight the need to integrate patient-centred and contextual factors into best practice models

Deprescribing medicines in older people living with multimorbidity and polypharmacy: the TAILOR evidence synthesis

Background Tackling problematic polypharmacy requires tailoring the use of medicines to individual needs and circumstances. This may involve stopping medicines (deprescribing) but patients and clinicians report uncertainty on how best to do this. The TAILOR medication synthesis sought to help understand how best to support deprescribing in older people living with multimorbidity and polypharmacy. Objectives We identified two research questions: (1) what evidence exists to support the safe, effective and acceptable stopping of medication in this patient group, and (2) how, for whom and in what contexts can safe and effective tailoring of clinical decisions related to medication use work to produce desired outcomes? We thus described three objectives: (1) to undertake a robust scoping review of the literature on stopping medicines in this group to describe what is being done, where and for what effect; (2) to undertake a realist synthesis review to construct a programme theory that describes ‘best practice’ and helps explain the heterogeneity of deprescribing approaches; and (3) to translate findings into resources to support tailored prescribing in clinical practice. Data sources Experienced information specialists conducted comprehensive searches in MEDLINE, Cumulative Index to Nursing and Allied Health Literature, Web of Science, EMBASE, The Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials), Joanna Briggs Institute Database of Systematic Reviews and Implementation Reports, Google (Google Inc., Mountain View, CA, USA) and Google Scholar (targeted searches). Review methods The scoping review followed the five steps described by the Joanna Briggs Institute methodology for conducting a scoping review. The realist review followed the methodological and publication standards for realist reviews described by the Realist And Meta-narrative Evidence Syntheses: Evolving Standards (RAMESES) group. Patient and public involvement partners ensured that our analysis retained a patient-centred focus. Results Our scoping review identified 9528 abstracts: 8847 were removed at screening and 662 were removed at full-text review. This left 20 studies (published between 2009 and 2020) that examined the effectiveness, safety and acceptability of deprescribing in adults (aged ≥ 50 years) with polypharmacy (five or more prescribed medications) and multimorbidity (two or more conditions). Our analysis revealed that deprescribing under research conditions mapped well to expert guidance on the steps needed for good clinical practice. Our findings offer evidence-informed support to clinicians regarding the safety, clinician acceptability and potential effectiveness of clinical decision-making that demonstrates a structured approach to deprescribing decisions. Our realist review identified 2602 studies with 119 included in the final analysis. The analysis outlined 34 context–mechanism–outcome configurations describing the knowledge work of tailored prescribing under eight headings related to organisational, health-care professional and patient factors, and interventions to improve deprescribing. We conclude that robust tailored deprescribing requires attention to providing an enabling infrastructure, access to data, tailored explanations and trust. Limitations Strict application of our definition of multimorbidity during the scoping review may have had an impact on the relevance of the review to clinical practice. The realist review was limited by the data (evidence) available. Conclusions Our combined reviews recognise deprescribing as a complex intervention and provide support for the safety of structured approaches to deprescribing, but also highlight the need to integrate patient-centred and contextual factors into best practice models. Future work The TAILOR study has informed new funded research tackling deprescribing in sleep management, and professional education. Further research is being developed to implement tailored prescribing into routine primary care practice. Study registration This study is registered as PROSPERO CRD42018107544 and PROSPERO CRD42018104176. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 32. See the NIHR Journals Library website for further project information