Shakespeare in the Theatre: Sir William Davenant and the Duke’s Company

Eubanks Winkler and Schoch reveal how – and why – the first generation to stage Shakespeare after Shakespeare’s lifetime changed absolutely everything. Founder of the Duke’s Company, Sir William Davenant influenced how Shakespeare was performed in a profound and lasting way. This open access book provides the first performance-based account of Restoration Shakespeare, exploring the precursors to Davenant’s approach to Restoration Shakespeare, the cultural context of Restoration theatre, the theatre spaces in which the Duke’s Company performed, Davenant’s adaptations of Shakespeare’s plays, acting styles, and the lasting legacy of Davenant’s approach to staging Shakespeare. The eBook editions of this work are available open access under a CC BY-NC-ND 4.0 licence on bloomsburycollections.com. Open access was funded by Queens University Belfast

Investigating well-being, work limitations and preferences for self-management education and peer support among younger people with hip and knee osteoarthritis: protocol for a cross-sectional study

Introduction:&nbsp;Osteoarthritis (OA) has traditionally&nbsp;been considered a condition of older age. However,&nbsp;younger people are also affected by hip and knee OA,&nbsp;often as a result of sporting and work-related injuries.&nbsp;As OA studies have generally focused on older&nbsp;individuals, little is known about the experience of&nbsp;younger adults with hip or knee OA who can face a&nbsp;distinct set of pressures including work responsibilities&nbsp;and parenting roles. This study aims to investigate&nbsp;well-being and work participation among younger&nbsp;people with hip or knee OA, as well as preferences for&nbsp;OA education and support.Methods and analysis: 200 people aged 20&ndash;55 years with a diagnosis of hip and/or knee OA will be&nbsp;recruited for this cross-sectional study. Participants will&nbsp;be recruited from three major public hospitals in the&nbsp;state of Victoria, Australia following screening of&nbsp;orthopaedic outpatient clinic lists and referrals, and&nbsp;through community-based advertisements. A study&nbsp;questionnaire will be mailed to all participants and&nbsp;written informed consent obtained. Validated measures&nbsp;of Health-Related Quality of Life (HRQoL), health status,&nbsp;psychological distress and work limitations will be used. Information on health services use will be collected,&nbsp;in addition to information on the perceived utility and&nbsp;accessibility of a range of existing and proposed&nbsp;education and peer support models. HRQoL data will be&nbsp;compared with Australian population norms using&nbsp;independent t tests, and associations between HRQoL,&nbsp;health status, psychological distress, work limitations&nbsp;and demographic factors will be evaluated using&nbsp;univariate and multivariate analyses. Data on the&nbsp;perceived utility and accessibility of education and peer&nbsp;support models will be analysed descriptively.&nbsp;Ethics and dissemination: Ethics approval for the&nbsp;study has been obtained. The study findings will be&nbsp;submitted to peer-reviewed journals and arthritis&nbsp;consumer organisations for broader dissemination, and&nbsp;presented at national and international scientific meetings.</div

The effects of creatine ethyl ester supplementation combined with heavy resistance training on body composition, muscle performance, and serum and muscle creatine levels

Numerous creatine formulations have been developed primarily to maximize creatine absorption. Creatine ethyl ester is alleged to increase creatine bio-availability. This study examined how a seven-week supplementation regimen combined with resistance training affected body composition, muscle mass, muscle strength and power, serum and muscle creatine levels, and serum creatinine levels in 30 non-resistance-trained males. In a double-blind manner, participants were randomly assigned to a maltodextrose placebo (PLA), creatine monohydrate (CRT), or creatine ethyl ester (CEE) group. The supplements were orally ingested at a dose of 0.30 g/kg fat-free body mass (approximately 20 g/day) for five days followed by ingestion at 0.075 g/kg fat free mass (approximately 5 g/day) for 42 days. Results showed significantly higher serum creatine concentrations in PLA (p = 0.007) and CRT (p = 0.005) compared to CEE. Serum creatinine was greater in CEE compared to the PLA (p = 0.001) and CRT (p = 0.001) and increased at days 6, 27, and 48. Total muscle creatine content was significantly higher in CRT (p = 0.026) and CEE (p = 0.041) compared to PLA, with no differences between CRT and CEE. Significant changes over time were observed for body composition, body water, muscle strength and power variables, but no significant differences were observed between groups. In conclusion, when compared to creatine monohydrate, creatine ethyl ester was not as effective at increasing serum and muscle creatine levels or in improving body composition, muscle mass, strength, and power. Therefore, the improvements in these variables can most likely be attributed to the training protocol itself, rather than the supplementation regimen

MicroRNA profiling reveals marker of motor neuron disease in ALS models

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder marked by the loss of motor neurons (MNs) in the brain and spinal cord, leading to fatally debilitating weakness. Because this disease predominantly affects MNs, we aimed to characterize the distinct expression profile of that cell type to elucidate underlying disease mechanisms and to identify novel targets that inform on MN health during ALS disease time course. microRNAs (miRNAs) are short, noncoding RNAs that can shape the expression profile of a cell and thus often exhibit cell-type-enriched expression. To determine MN-enriched miRNA expression, we used Cre recombinase-dependent miRNA tagging and affinity purification in mice. By defining thein vivomiRNA expression of MNs, all neurons, astrocytes, and microglia, we then focused on MN-enriched miRNAs via a comparative analysis and found that they may functionally distinguish MNs postnatally from other spinal neurons. Characterizing the levels of the MN-enriched miRNAs in CSF harvested from ALS models of MN disease demonstrated that one miRNA (miR-218) tracked with MN loss and was responsive to an ALS therapy in rodent models. Therefore, we have used cellular expression profiling tools to define the distinct miRNA expression of MNs, which is likely to enrich future studies of MN disease. This approach enabled the development of a novel, drug-responsive marker of MN disease in ALS rodents.SIGNIFICANCE STATEMENTAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which motor neurons (MNs) in the brain and spinal cord are selectively lost. To develop tools to aid in our understanding of the distinct expression profiles of MNs and, ultimately, to monitor MN disease progression, we identified small regulatory microRNAs (miRNAs) that were highly enriched or exclusive in MNs. The signal for one of these MN-enriched miRNAs is detectable in spinal tap biofluid from an ALS rat model, where its levels change as disease progresses, suggesting that it may be a clinically useful marker of disease status. Furthermore, rats treated with ALS therapy have restored expression of this MN RNA marker, making it an MN-specific and drug-responsive marker for ALS rodents.</jats:p

Marrow transplantation from unrelated donors for patients with severe aplastic anemia who have failed immunosuppressive therapy

AbstractAllogeneic marrow transplantation offers curative therapy for patients with aplastic anemia. We analyzed retrospective results in 141 patients with severe aplastic anemia who received transplants between 1988 and 1995 from an unrelated volunteer donor identified through the National Marrow Donor Program (NMDP). All patients had failed one or more courses of immunosuppressive therapy. Of the patients, 121 (86%) received a radiation-containing conditioning regimen, and 20 (14%) were given chemotherapy only. Based on serologic human leukocyte antigen (HLA) typing (class I and II), 105 patients (74%) received HLA-matched marrow, and 36 (26%) received marrow mismatched for at least one HLA-A, -B, or -DR antigen. Allele-level (molecular) typing for HLA-DRB1 was available in 108 donor-recipient pairs; 77 patients received DRB -matched and 31 DRB1-mismatched transplants. All but 13% of patients were given a cyclosporine-containing regimen for graft-vs.-host disease (GVHD) prophylaxis, and 45 patients (32%) received marrow that was T cell-depleted. Among 131 evaluable patients, 116 (89%) achieved sustained engraftment and 15 (11%) did not. Among patients with engraftment, acute GVHD of grades II-IV developed in 60 patients (52%) and extensive chronic GVHD in 24 patients at risk (31%). Currently, 51 patients (36%) are surviving at 11-94 months (median 36) after transplantation. All but five have Karnofsky scores > or =80. Patients who received a serologically matched transplant fared somewhat better than did patients given a serologically mismatched transplant p = 0.03). Patients with donors matched by both serology and allele-level DRB1 typing had significantly better survival than DRB1-mismatched patients with 56 vs. 15% surviving at 3 years p = 0.001). Outcome in patients transplanted within 3 years of diagnosis was superior to that among patients transplanted with greater delay. Major causes of death were graft failure, GVHD, and infections. These data suggest that unrelated marrow transplantation offers successful therapy for a proportion of patients who have failed immunosuppressive therapy.Biol Blood Marrow Transplant 1999;5(4):243-52

Looking beyond the exome: a phenotype-first approach to molecular diagnostic resolution in rare and undiagnosed diseases.

PurposeTo describe examples of missed pathogenic variants on whole-exome sequencing (WES) and the importance of deep phenotyping for further diagnostic testing.MethodsGuided by phenotypic information, three children with negative WES underwent targeted single-gene testing.ResultsIndividual 1 had a clinical diagnosis consistent with infantile systemic hyalinosis, although WES and a next-generation sequencing (NGS)-based ANTXR2 test were negative. Sanger sequencing of ANTXR2 revealed a homozygous single base pair insertion, previously missed by the WES variant caller software. Individual 2 had neurodevelopmental regression and cerebellar atrophy, with no diagnosis on WES. New clinical findings prompted Sanger sequencing and copy number testing of PLA2G6. A novel homozygous deletion of the noncoding exon 1 (not included in the WES capture kit) was detected, with extension into the promoter, confirming the clinical suspicion of infantile neuroaxonal dystrophy. Individual 3 had progressive ataxia, spasticity, and magnetic resonance image changes of vanishing white matter leukoencephalopathy. An NGS leukodystrophy gene panel and WES showed a heterozygous pathogenic variant in EIF2B5; no deletions/duplications were detected. Sanger sequencing of EIF2B5 showed a frameshift indel, probably missed owing to failure of alignment.ConclusionThese cases illustrate potential pitfalls of WES/NGS testing and the importance of phenotype-guided molecular testing in yielding diagnoses

Identifying complications requiring re-operation following primary hip or knee arthroplasty: a consecutive series of 98 patients

BackgroundThe number of hip and knee arthroplasties completed is expected to double over the next decade. In public hospitals, regular post-arthroplasty orthopaedic review has commonly occurred for the duration of a patient&rsquo;s life, which requires substantial outpatient resources. However, there is limited evidence regarding the utility of these reviews for identifying complications. The current study investigated when and where complications requiring re-operation were identified following primary hip or knee arthroplasty.MethodsThe medical records of all patients requiring re-operation for complications following primary hip arthroplasty (n&thinsp;=&thinsp;48, 2004 to 2015) or knee primary arthroplasty (n&thinsp;=&thinsp;50, 1998 to 2015) at a large regional health service were evaluated. Data were extracted by one of four investigators using a standardised electronic data extraction tool. Variables of interest included the health setting where the complication was initially identified, how long following the original operation the complication was identified and whether the complication was symptomatic.ResultsRoutine post-arthroplasty orthopaedic appointments identified 15 (15.3%) complications requiring re-operation; all were identified in the first-year post-surgery. For each complication identified in the first-year post-surgery, approximately 1000 orthopaedic outpatient appointments were required. After the first year, all complications were identified in Emergency Departments (n =&thinsp;30, 30.6%), General Practice (n =&thinsp;24, 24.5%) or non-routine orthopaedic outpatient appointments (n =&thinsp;19, 19.4%). All patients with complications reported symptoms.ConclusionsRoutine post-arthroplasty review appointments were an inefficient mechanism for identifying complications requiring re-operation more than one year following surgery. Public health services should consider assessing and redesigning post-arthroplasty review services to reduce the burden on patients and the demand for outpatient appointments.<br /