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Background To understand barriers and enablers to use of curative-intent radiotherapy (RT) for muscle-invasive bladder cancer using the Theoretical Domains Framework (TDF). Methods Canadian urologists, radiation oncologists (ROs) and medical oncologists (MOs) participated in a web-based survey to assess barriers and enablers to use of RT. Survey questions were thematically mapped to TDF domains. Logistic regression was used to identify TDF domains associated with high referral/use of RT. Results 64 urologists, 29 ROs and 26 MOs participated. Participants reported comparable survival at five years with cystectomy (51%) and RT with concurrent chemotherapy (50%). Despite this, participants reported low RT referral/treatment rates: Urologists referred a median of 2/10 patients to RO; ROs treated a median of 5/10 patients referred; and MOs referred a median of 2/8 patients not referred to RO by urology. Among urologists, the TDF domains ‘beliefs about consequences’ (OR = 8.1, 95% CI 1.5–44.9), ‘social and professional role’ (OR = 11.2, 95% CI 2.3–53.6) and ‘environmental context and resources’ (OR = 5.9, 95% CI 1.5–23.3) were associated with higher rates of RO referral. Conclusions We have identified factors associated with referral for RT among patients with bladder cancer. These factors should be addressed as part of a concerted effort to increase utilization of RT. [ABSTRACT FROM AUTHOR]

Broadly neutralizing antibodies have been associated with spontaneous clearance of the hepatitis C infection as well as viral persistence by immune escape. Further study of neutralizing antibody epitopes is needed to unravel pathways of resistance to virus neutralization, and to identify conserved regions for vaccine design. All reported broadly neutralizing antibody (BNAb) epitopes in the HCV Envelope (E2) glycoprotein were identified. The critical contact residues of these epitopes were mapped onto the linear E2 sequence. All publicly available E2 sequences were then downloaded and the contact residues within the BNAb epitopes were assessed for the level of conservation, as well as the frequency of occurrence of experimentally-proven resistance mutations. Epitopes were also compared between two sequence datasets obtained from samples collected at well-defined time points from acute (< 180 days) and chronic (> 180 days) infections, to identify any significant differences in residue usage. The contact residues for all BNAbs were contained within 3 linear regions of the E2 protein sequence. An analysis of 1749 full length E2 sequences from public databases showed that only 10 out of 29 experimentally-proven resistance mutations were present at a frequency > 5%. Comparison of subtype 1a viral sequences obtained from samples collected during acute or chronic infection revealed significant differences at positions 610 and 655 with changes in residue ( p < 0.05), and at position 422 ( p < 0.001) with a significant difference in variability (entropy). The majority of experimentally-described escape variants do not occur frequently in nature. The observed differences between acute and chronically isolated sequences suggest constraints on residue usage early in infection. [ABSTRACT FROM AUTHOR]

This paper re-considers girls' education in Turkey from both a capabilities and a feminist perspective. First, it critically looks at the policies, legislation, and NGO and government led campaigns aiming to increase girls' enrolment, and points out the lack of feminist perspectives and concerns in these initiatives. Then, drawing from 20 in-depth interviews with girls and 5 interviews with teachers in the most socio-economically deprived region of Turkey, the paper explores girls' schooling and educational opportunities in Eastern Turkey from a combined capabilities and feminist perspective, in order to generate a richer information basis than numbers alone for policy and evaluation. The findings tease out capabilities which are missing in the focus of policies and campaigns, and invite a re-design of educational policies and initiatives from a capabilities-focused praxis that is context and gender sensitive. [ABSTRACT FROM AUTHOR]

Statistics show that student enrolment in higher education institutions in South Africa has dramatically increased over the past years, a clear indication that higher education (HE) is addressing issues of equitable access in the wake of an exclusionary apartheid past. Despite these positive trends, there are still marginalised groups in society about whom we know little, and who risk being overlooked both in access statistics and at the level of actual lives. The article therefore outlines the aspirations and challenges for vulnerable young people in accessing higher education, based on a case study conducted at Orange Farm informal settlement in South Africa. A qualitative approach, using Sen (2009, 1999a) and Nussbaum's (2011) capabilities approach (CA) was adopted as the conceptual frame for the light it casts on real lives, opportunities and plural achievements, with empirical data collected through face-to-face interviews with purposively selected young people living in an Orange Farm orphanage. [ABSTRACT FROM AUTHOR]

Abstract: The purpose of this paper is to understand historically and contextually the well-being and agency of selected female teachers in Turkey. The paper develops a justice model based on the capability approach to build on the relation between freedom and equality, and to take gender and cultural diversity as a key element. The research draws on results from in-depth biographical narratives of 15 participants from west Turkey, examining the real freedoms and opportunities of three different generations of female teachers through constructing a gendered look into women''s lives. The study begins by developing a framework linking women''s opportunities and freedoms drawing its normative compass from Martha Nussbaum''s capabilities approach. It explores how female teachers’ well-being can be understood in relation to key capabilities that individuals, communities and society have reason to value and how these capabilities and functionings can be expanded or constrained. The paper argues for the significance of thinking about capabilities in the professional lives of teachers who work for social change. Through a historical and generational sequence, it captures the egalitarian aspects of the capability approach, and strengthens its emphasis on freedoms of women. The findings of this enquiry indicate that there are persistent economic, cultural, ethnical, structural and gendered inequalities in women''s lives, but that women also have agency to bring changes in their lives and through their teaching. [Copyright &y& Elsevier]

Abstract: In a world of tremendous inequalities, this paper explores two contrasting normative models for education policy, and the relationship of each to policy, practices and outcomes that can improve lives by reducing injustice and building societies which value capabilities for all. The first model is that of human capital which currently dominates contemporary education policy globally, harnessing education policy to economic growth imperatives so that development through education is the means to the end of increased resources and income. The second model draws on the work of Amartya Sen to present a human capabilities model of education policy in which human lives are the end of development and the education focus is on promoting capabilities and functionings to choose a good life. An argument is advanced for capabilities as the superior approach. The paper closes by noting the problematic of social change and struggle demanded by a transformative view of education and how or if the capability approach is adequate to the task. [Copyright &y& Elsevier]

Abstract: Two patients with giant cell arteritis (GCA) had a malignant course despite aggressive immunosuppressive therapy. A 63-year-old woman presented with symptoms of headache, jaw claudication, scalp paresthesia, and visual disturbances. A temporal artery biopsy showed GCA. While on prednisone, she suffered ischemic strokes, and serial cerebral angiograms demonstrated bilateral, severe and progressive narrowing of distal vertebral and internal carotid arteries. Despite escalating immunosuppressive therapies, she suffered more infarcts and eventually died. Postmortem examination of arteries showed no active inflammation. A 65-year-old man presented with extrapyramidal symptoms though no symptoms typical of GCA. Imaging showed multiple ischemic strokes. Because serial angiograms demonstrated findings similar to the first patient, he underwent temporal artery biopsy that showed GCA. He died 7months after his presentation with complications of aggressive immunosuppressive therapy. These two patients confirm that GCA can follow a lethal course despite escalating immunosuppressive therapies. Our two patients were unique in that eventually both anterior and posterior circulations were involved bilaterally in a characteristic location where the arteries penetrate the dura. This pattern should always raise the possibility of GCA and, if confirmed, should prompt aggressive immunosuppressive therapy. The dismal outcomes despite this approach may suggest a non-inflammatory arteriopathy, as seen on necropsy in one of our patients. Such an arteriopathy may require novel therapies to be considered for this severe variant of GCA. [Copyright &y& Elsevier]

Abstract: This paper reports on a research project investigating the role of universities in South Africa in contributing to poverty reduction through the quality of their professional education programmes. The focus here is on theorising and the early operationalisation of multi-layered, multi-dimensional transformation based on ideas from Amartya Sen''s capability approach. Key features of a professionalism oriented to public service, which in South Africa must mean the needs and lives of the poor, are outlined. These features include: the demand from justice; the expansion of the comprehensive capabilities both of the poor and professional capability formation to be able to act in ‘pro-poor’ ways; and, praxis pedagogies which shape this connected process. This theorisation is then tentatively operationalised in a process of selecting transformation dimensions. [Copyright &y& Elsevier]

Aim: To evaluate the association between bystander cardiopulmonary resuscitation (CPR), automated external defibrillator (AED) use, and survival after out-of-hospital cardiac arrest (OHCA) across the urban-rural spectrum.Methods: This was a retrospective cohort study of 325,477 adult OHCAs within the Cardiac Arrest Registry to Enhance Survival from 2013 to 2019. Bystander interventions were categorized into no bystander intervention, bystander CPR alone, and bystander AED use (with or without CPR). The primary outcome was survival to hospital discharge with good neurological outcome. Multivariable logistic regression was used to evaluate the association between bystander interventions and survival by geographical status (urban, suburban, large rural, small town, or rural).Results: Bystander CPR alone occurred most often in rural areas (50.8%), and least often in urban areas (35.4%). Bystander AED use in public settings was similar across the urban-rural spectrum (10.5-13.1%). Survival with good neurological outcome varied for urban (8.1%), suburban (7.7%), large rural (9.1%), small town (7.1%), and rural areas (6.1%). In comparison to no bystander intervention, the adjusted odds ratios (95% confidence intervals) for bystander AED use and survival were 2.57 (2.37-2.79) in urban areas, 2.58 (1.81-3.67) in suburban areas, 1.99 (1.44-2.76) in large rural areas, 1.90 (1.27-2.86) in small towns, and 3.05 (1.99-4.68) in rural areas. Bystander CPR alone was also associated with survival in all areas (adjusted odds ratio range: 1.29-1.45). There was no strong evidence of interaction between bystander interventions and geographical status on the primary outcome (p = 0.63).Conclusion: Bystander CPR and AED use are associated with positive clinical outcomes after OHCA in all areas along the urban-rural spectrum. [ABSTRACT FROM AUTHOR]

Tuberous sclerosis (TS) is caused by point mutations in the TSC1 or TSC2 genes on chromosomes 9q33–34 or 16p13, respectively. Clinical manifestations can be quite variable but are primarily limited to cutaneous, neurologic, and cardiovascular abnormalities. Phenotypes range from neurologically devastated to those with silent lesions. A 34-year-old patient with genetically documented TSC1 developed progressive ataxia over a decade, without TS lesions to correlate with this finding. After evaluation of common causes including long-term antiepileptic regimens, DNA testing for hereditary ataxias was performed and revealed the presence of an additional mutation on chromosome 9. The patient was homozygous for the Friedreich ataxia (FA) mutation, with 500 and 700 GAA repeats in the FRDA gene on chromosome 9q13. There is no established relationship between these two disorders and the occurrence of two mutations on the same chromosome is probably coincidental but emphasizes the importance of searching for additional genetic causes when the phenotype does not fit with an established genetic diagnosis. [Copyright &y& Elsevier]

We report an immunocompetent patient with the Ramsay Hunt syndrome (RHS) followed days later by brainstem disease. Extensive virological studies proved that varicella zoster virus (VZV) was the causative agent. Treatment with intravenous acyclovir resulted in prompt resolution of all neurological deficits except peripheral facial palsy. This case demonstrates that after geniculate zoster, brainstem disease may develop even in an immunocompetent individual and effective antiviral therapy can be curative. [Copyright &y& Elsevier]

Stenting with flow diverter devices (FDDs) has increasingly emerged as a treatment for intracranial aneurysms. The use of FDDs in the developing world has not been described. A retrospective review was performed of a cohort of patients who underwent flow diversion at 4 tertiary-care centers in Lima, Peru between January 2017 and June 2021. Demographics, clinical features, and aneurysm morphology were evaluated. Clinical outcomes were observed 3 months after discharge and occlusion rates were assessed 12 months after treatment. Sixty-nine patients (mean age, 46 ±14.5 years; 17% female) were treated with FDDs; 4% (n = 3) of the treated aneurysms were ruptured. Most aneurysms were saccular (n = 65; 94%), <10 mm in maximum size (n = 60; 87%), and located in the anterior circulation (n = 67; 97%). Minor complications, such as groin hematoma, occurred in 7 cases. No serious complications or deaths occurred. Patients' functional status was excellent (modified Rankin Scale score 0–1) in 99% (n = 66) at discharge and 100% (n = 67) at 3 months. Although some patients were lost to follow-up, complete occlusion was seen in 76% (n = 31) of 41 treated patients at 12 months. We report the largest multicenter experience of FDDs for cerebral aneurysm treatment in Peru, with reasonable outcomes that are comparable to other settings despite various challenges, suboptimal circumstances, and lack of resources. [ABSTRACT FROM AUTHOR]

Neutralising antibodies (NAbs) play a key role in clearance of HCV. NAbs have been isolated and mapped to several domains on the HCV envelope proteins. However, the immunodominance of these epitopes in HCV infection remains unknown, hindering efforts to elicit optimal epitope-specific responses. Furthermore, it remains unclear which epitope-specific responses are associated with broad NAb (bNAb) activity in primary HCV infection. The aim of this study was to define B cell immunodominance in primary HCV, and its implications on neutralisation breadth and clearance. Using samples from 168 patients with primary HCV infection, the antibody responses targeted 2 immunodominant domains, termed domains B and C. Genotype 1 and 3 infections were associated with responses targeted towards different bNAb domains. No epitopes were uniquely targeted by clearers compared to those who developed chronic infection. Samples with bNAb activity were enriched for multi-specific responses directed towards the epitopes antigenic region 3, antigenic region 4, and domain D, and did not target non-neutralising domains. This study outlines for the first time a clear NAb immunodominance profile in primary HCV infection, and indicates that it is influenced by the infecting virus. It also highlights the need for a vaccination strategy to induce multi-specific responses that do not target non-neutralising domains. Neutralising antibodies will likely form a key component of a protective hepatitis C virus vaccine. In this work we characterise the predominant neutralising and non-neutralising antibody (epitope) targets in acute hepatitis C virus infection. We have defined the natural hierarchy of epitope immunodominance, and demonstrated that viral genotype can impact on this hierarchy. Our findings highlight key epitopes that are associated with broadly neutralising antibodies, and the deleterious impact of mounting a response towards some of these domains on neutralising breadth. These findings should guide future efforts to design immunogens aimed at generating neutralising antibodies with a vaccine candidate. • Neutralising antibodies will likely form a key component of an HCV vaccine. • We characterise the immunodominance of neutralising and non-neutralising epitopes in primary HCV infection. • We identify that virus genotype might influence the epitopes targeted. • We also identify that certain epitope target combinations are associated with greater breadth. [ABSTRACT FROM AUTHOR]

Hepatitis C (HCV) is a rapidly mutating RNA virus, with a strong propensity to cause chronic infection and progressive liver disease. Recent evidence has shown that early appearance of neutralizing antibodies in primary infection is associated with clearance. Little is known about the characteristics of HCV-specific B cells and their correlation with outcomes in primary infection, as there is a lack of sensitive tools for HCV-specific B cells which are present at very low frequency. We describe the development and optimisation of tetramer staining for flow cytometric detection of HCV-specific B cells using a cocktail of two recombinant HCV Envelope-2 (rE2) glycoproteins (from genotype 1a and 3a; Gt1a and Gt3a) and streptavidin dyes. The optimal weight to weight (w /w) ratio of streptavidin-phycoerythrin (PE) and rE2 proteins were determined for sensitive detection using HCV E2-specific hybridoma cell lines and peripheral blood mononuclear cells (PBMC) from HCV-infected individuals. In a cross-sectional set of PBMC samples collected from 33 subjects with either chronic infection or previous clearance, HCV E2-specific B cells (CD19+CD20+CD10−IgD−tetramer+) were detected in 29 subjects (87.8%), with a mean frequency of 0.45% (0.012–2.20%). To validate the specificity of tetramer staining, 367 HCV E2-specific B cells were single cell sorted from 9 PBMC samples before monoclonal antibodies (mAbs) were synthesised, with 87.5% being reactive to E2 via ELISA. Of these mAbs, 284 and 246 clones were reactive to either Gt1a or Gt3a E2 proteins, respectively. This is a sensitive and robust method for future studies investigating B cell responses against the HCV Envelope protein. [ABSTRACT FROM AUTHOR]

Purpose: Based on our demonstration of a circadian rhythm in the human oral mucosa cell cycle, with most cells in the G1 phase in the morning and M phase at night, we hypothesized that morning radiotherapy (RT) would lead to less oral mucositis than afternoon RT. Methods and Materials: A total of 216 patients were randomized to morning (8–10 AM) vs. afternoon (4–6 PM) RT and stratified by radiation dose, smoking status, and center. Patients receiving primary or postoperative RT alone were eligible. Oral mucositis was scored using the Radiation Therapy Oncology Group (RTOG) criteria and a validated scoring system. Results: Of 205 evaluable patients, 52.9% vs. 62.4% developed RTOG Grade 3 or greater mucositis after morning vs. afternoon RT, respectively (p = 0.17). Morning RT was also associated with significantly less weight loss after 5 months (p = 0.024). In a subgroup of 111 patients treated to a dose of 66–70 Gy in 33–35 fractions, exploratory analyses revealed a significant reduction in Grade 3 or greater mucositis with morning RT (44.6% vs. 67.3%, p = 0.022) and a longer interval to the development of Grade 3 or greater mucositis (median, >7.9 vs. 5.6 weeks, p = 0.033). In 53 patients, who smoked during therapy, a significant reduction was found in Grade 3 or greater mucositis with morning RT (42.9% vs. 76%, p = 0.025). Conclusion: In this proof of principle study, morning RT was associated with significantly less weight loss after 5 months and an apparent reduction in oral mucositis in a subset of patients receiving ≥66 Gy and in patients who smoked during therapy. [Copyright &y& Elsevier]