A phase 1 trial of the safety, tolerability and biological effects of intravenous Enadenotucirev, a novel oncolytic virus, in combination with chemoradiotherapy in locally advanced rectal cancer (CEDAR)

Background: Chemoradiotherapy remains the standard of care for locally advanced rectal cancer. Efforts to intensify treatment and increase response rates have yet to yield practice changing results due to increased toxicity and/or absence of increased radiosensitization. Enadenotucirev (EnAd) is a tumour selective, oncolytic adenovirus which can be given intravenously. Pre-clinical evidence of synergy with radiation warrants further clinical testing and assessment of safety with radiation. Methods: Eligibility include histology confirmed locally advanced rectal cancer that require chemoradiation. The trial will use a Time-to-Event Continual Reassessment Model-based (TiTE-CRM) approach using toxicity and efficacy as co-primary endpoints to recommend the optimal dose and treatment schedule 30 patients will be recruited. Secondary endpoints include pathological complete response the neoadjuvant rectal score. A translational program will be based on a mandatory biopsy during the second week of treatment for ‘proof-of-concept’ and exploration of mechanism. The trial opened to recruitment in July 2019, at an expected rate of 1 per month for up to 4 years. Discussion: Chemoradiation with Enadenotucirev as a radiosensitiser in locally Advanced Rectal cancer (CEDAR) is a prospective multicentre study testing a new paradigm in radiosensitization in rectal cancer. The unique ability of EnAd to selectively infect tumour cells following intravenous delivery is an exciting opportunity with a clear translational goal. The novel statistical design will make efficient use of both toxicity and efficacy data to inform subsequent studies. Trial registration: ClinicalTrial.gov, NCT03916510. Registered 16th April 2019

Prevalence of self-harm among lesbian, gay, bisexual, and transgender adolescents: a comparison of personal and social adversity with a heterosexual sample in Ghana

Objectives We sought to estimate the prevalence of self-reported self-harm among adolescents identifying as lesbian, gay, bisexual, and transgender (LGBT) in Ghana, and compare self-reported personal and social adversities related to self-harm in this group to those in a random sample of heterosexual adolescents from the same locality. Results A total of 444 adolescents aged 13-21 years, comprising 74 LGBT adolescents and 370 heterosexual adolescents, provided data. The lifetime prevalence estimate of self-harm was higher in the LGBT group (47%) than the heterosexual group (23%). The LGBT group reported a higher rate of self-harm during the previous 12 months (45%), compared to the heterosexual group (18%). LGBT adolescents reported more alcohol and substance use and more personal social adversities, including various forms of victimisation, than heterosexual adolescents. They were no more likely to report difficulty in making and keeping friends or schoolwork problems than were heterosexual adolescents

Track D Social Science, Human Rights and Political Science

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138414/1/jia218442.pd

Conserved determinants of lentiviral genome dimerization

Abstract Background Retroviruses selectively package two copies of their unspliced genomes by what appears to be a dimerization-dependent RNA packaging mechanism. Dimerization of human immunodeficiency virus Type-1 (HIV-1) genomes is initiated by “kissing” interactions between GC-rich palindromic loop residues of a conserved hairpin (DIS), and is indirectly promoted by long-range base pairing between residues overlapping the gag start codon (AUG) and an upstream Unique 5′ element (U5). The DIS and U5:AUG structures are phylogenetically conserved among divergent retroviruses, suggesting conserved functions. However, some studies suggest that the DIS of HIV-2 does not participate in dimerization, and that U5:AUG pairing inhibits, rather than promotes, genome dimerization. We prepared RNAs corresponding to native and mutant forms of the 5′ leaders of HIV-1 (NL4-3 strain), HIV-2 (ROD strain), and two divergent strains of simian immunodeficiency virus (SIV; cpz-TAN1 and -US strains), and probed for potential roles of the DIS and U5:AUG base pairing on intrinsic and NC-dependent dimerization by mutagenesis, gel electrophoresis, and NMR spectroscopy. Results Dimeric forms of the native HIV-2 and SIV leaders were only detectable using running buffers that contained Mg2+, indicating that these dimers are more labile than that of the HIV-1 leader. Mutations designed to promote U5:AUG base pairing promoted dimerization of the HIV-2 and SIV RNAs, whereas mutations that prevented U5:AUG pairing inhibited dimerization. Chimeric HIV-2 and SIV leader RNAs containing the dimer-promoting loop of HIV-1 (DIS) exhibited HIV-1 leader-like dimerization properties, whereas an HIV-1NL4-3 mutant containing the SIVcpzTAN1 DIS loop behaved like the SIVcpzTAN1 leader. The cognate NC proteins exhibited varying abilities to promote dimerization of the retroviral leader RNAs, but none were able to convert labile dimers to non-labile dimers. Conclusions The finding that U5:AUG formation promotes dimerization of the full-length HIV-1, HIV-2, SIVcpzUS, and SIVcpzTAN1 5′ leaders suggests that these retroviruses utilize a common RNA structural switch mechanism to modulate function. Differences in native and NC-dependent dimerization propensity and lability are due to variations in the compositions of the DIS loop residues rather than other sequences within the leader RNAs. Although NC is a well-known RNA chaperone, its role in dimerization has the hallmarks of a classical riboswitch.http://deepblue.lib.umich.edu/bitstream/2027.42/113284/1/12977_2015_Article_209.pd

Foul wind, spirits and witchcraft: illness conceptions and health-seeking behaviour for malaria in the Gambia.

BACKGROUND: As the disease burden in the Gambia has reduced considerably over the last decade, heterogeneity in malaria transmission has become more marked, with infected but asymptomatic individuals maintaining the reservoir. The identification, timely diagnosis and treatment of malaria-infected individuals are crucial to further reduce or eliminate the human parasite reservoir. This ethnographic study focused on the relationship between local beliefs of the cause of malaria and treatment itineraries of suspected cases. METHODS: An ethnographic qualitative study was conducted in twelve rural communities in the Upper River Region and the Central River Region in the Gambia. The data collection methods included in-depth interviews, participant observation, informal conversations, and focus group discussions. RESULTS: While at first glance, the majority of people seek biomedical treatment for 'malaria', there are several constraints to seeking treatment at health centres. Certain folk illnesses, such as Jontinooje and Kajeje, translated and interpreted as 'malaria' by healthcare professionals, are often not considered to be malaria by local populations but rather as self-limiting febrile illnesses--consequently not leading to seeking care in the biomedical sector. Furthermore, respondents reported delaying treatment at a health centre while seeking financial resources, and consequently relying on herbal treatments. In addition, when malaria cases present symptoms, such as convulsions, hallucinations and/or loss of consciousness, the illness is often interpreted as having a supernatural aetiology, leading to diagnosis and treatment by traditional healers. CONCLUSION: Although malaria diagnostics and treatment-seeking in the biomedical sector has been reported to be relatively high in the Gambia compared to other sub-Saharan African countries, local symptom interpretation and illness conceptions can delay or stop people from seeking timely biomedical treatment, which may contribute to maintaining a parasite reservoir of undiagnosed and untreated malaria patients