COAST (Cisplatin ototoxicity attenuated by aspirin trial): A phase II double-blind, randomised controlled trial to establish if aspirin reduces cisplatin induced hearing-loss

Background: Cisplatin is one of the most ototoxic chemotherapy drugs, resulting in a permanent and irreversible hearing loss in up to 50% of patients. Cisplatin and gentamicin are thought to damage hearing through a common mechanism, involving reactive oxygen species in the inner ear. Aspirin has been shown to minimise gentamicin-induced ototoxicity. We, therefore, tested the hypothesis that aspirin could also reduce ototoxicity from cisplatin-based chemotherapy. Methods: A total of 94 patients receiving cisplatin-based chemotherapy for multiple cancer types were recruited into a phase II, double-blind, placebo-controlled trial and randomised in a ratio of 1:1 to receive aspirin 975 mg tid and omeprazole 20 mg od, or matched placebos from the day before, to 2 days after, their cisplatin dose(s), for each treatment cycle. Patients underwent pure tone audiometry before and at 7 and 90 days after their final cisplatin dose. The primary end-point was combined hearing loss (cHL), the summed hearing loss at 6 kHz and 8 kHz, in both ears. Results: Although aspirin was well tolerated, it did not protect hearing in patients receiving cisplatin (p-value = 0.233, 20% one-sided level of significance). In the aspirin arm, patients demonstrated mean cHL of 49 dB (standard deviation [SD] 61.41) following cisplatin compared with placebo patients who demonstrated mean cHL of 36 dB (SD 50.85). Women had greater average hearing loss than men, and patients treated for head and neck malignancy experienced the greatest cHL. Conclusions: Aspirin did not protect from cisplatin-related ototoxicity. Cisplatin and gentamicin may therefore have distinct ototoxic mechanisms, or cisplatin-induced ototoxicity may be refractory to the aspirin regimen used here

Applying a new concept of embedding qualitative research: An example from a quantitative study of carers of people in later stage dementia

BACKGROUND: Qualitative methods are increasingly included in larger studies to provide a richer understanding of people's experience. This paper explores the potential of using a novel approach to embedded qualitative design as part of an observational study examining the effectiveness of home support for people in later stage dementia in England. The method involved collecting and analysing unsolicited conversational comments made by participants as they completed standardised measures. An evaluation of the method is presented using the voices of participants to illustrate its potential. METHODS: The conversations of 17 carers recruited to an observational study were audio recorded to gather commentary made while completing a structured interview. Data were interrogated using thematic analysis to investigate the feasibility of conducting an embedded qualitative study, the potential richness of the material and participants' reactions to formal questioning and participating in research. RESULTS: The findings revealed that qualitative data were available from this approach. Analysis generated three themes from carers: conflicting carer emotions; the importance of maintaining normality and agency within day-to-day life; and tensions between these desires and making use of formal services. Important issues for carers were revealed establishing the benefit of using the method. The advantages of exploiting unsolicited conversation included enhancing understanding of people's lived experience, reducing participant burden in research and easing the process of data collection. In addition, it provided an opportunity to evaluate individuals' experience of the research process. CONCLUSIONS: The findings demonstrate how unsolicited comments during structured interviews may appear incidental but can reveal important aspects of living with dementia. The method also emphasised methodological challenges for research in dementia, including the influence and impact of the research context. Further research is required to evaluate the method with other groups including people with dementia themselves

Isospin symmetry in B(E2) values: Coulomb excitation study of Mg-21

The $T_z$~=~$-\frac{3}{2}$ nucleus ${}^{21}$Mg has been studied by Coulomb excitation on ${}^{196}$Pt and ${}^{110}$Pd targets. A 205.6(1)-keV $\gamma$-ray transition resulting from the Coulomb excitation of the $\frac{5}{2}^+$ ground state to the first excited $\frac{1}{2}^+$ state in ${}^{21}$Mg was observed for the first time. Coulomb excitation cross-section measurements with both targets and a measurement of the half-life of the $\frac{1}{2}^+$ state yield an adopted value of $B(E2;\frac{5}{2}^+\rightarrow\frac{1}{2}^+)$~=~13.3(4)~W.u. A new excited state at 1672(1)~keV with tentative $\frac{9}{2}^+$ assignment was also identified in ${}^{21}$Mg. This work demonstrates large difference of the $B(E2;\frac{5}{2}^+\rightarrow\frac{1}{2}^+)$ values between $T$~=~$\frac{3}{2}$, $A$~=~21 mirror nuclei. The difference is investigated in the shell-model framework employing both isospin conserving and breaking USD interactions and using modern \textsl{ab initio} nuclear structure calculations, which have recently become applicable in the $sd$ shell.Comment: 8 pages, 6 figures, submitted to Phys. Rev. C, Rapid Communicatio

Protocol for Nearly Full-Length Sequencing of HIV-1 RNA from Plasma

Nearly full-length genome sequencing of HIV-1 using peripheral blood mononuclear cells (PBMC) DNA as a template for PCR is now a relatively routine laboratory procedure. However, this has not been the case when using virion RNA as the template and this has made full genome analysis of circulating viruses difficult. Therefore, a well-developed procedure for sequencing of full-length HIV-1 RNA directly from plasma was needed. Plasma from U.S. donors representing a range of viral loads (VL) was used to develop the assay. RNA was extracted from plasma and reverse-transcribed. Two or three overlapping regions were PCR amplified to cover the entire viral genome and sequenced for verification. The success of the procedure was sensitive to VL but was routinely successful for VL greater than 105 and the rate declined in proportion to the VL. While the two-amplicon strategy had an advantage of increasing the possibility of amplifying a single species of HIV-1, the three-amplicon strategy was more successful in amplifying samples with low viral loads. This protocol provides a useful tool for molecular analysis to understand the HIV epidemic and pathogenesis, as well as diagnosis, therapy and future vaccine strategies

Independent Origins of Cultivated Coconut (Cocos nucifera L.) in the Old World Tropics

As a portable source of food, water, fuel, and construction materials, the coconut (Cocos nucifera L.) played a fundamental role in human migrations and the development of civilization across the humid tropics. Here we investigated the coconut's domestication history and its population genetic structure as it relates to human dispersal patterns. A sample of 1,322 coconut accessions, representing the geographical and phenotypic diversity of the species, was examined using ten microsatellite loci. Bayesian analyses reveal two highly genetically differentiated subpopulations that correspond to the Pacific and Indo-Atlantic oceanic basins. This pattern suggests independent origins of coconut cultivation in these two world regions, with persistent population structure on a global scale despite long-term human cultivation and dispersal. Pacific coconuts show additional genetic substructure corresponding to phenotypic and geographical subgroups; moreover, the traits that are most clearly associated with selection under human cultivation (dwarf habit, self-pollination, and “niu vai” fruit morphology) arose only in the Pacific. Coconuts that show evidence of genetic admixture between the Pacific and Indo-Atlantic groups occur primarily in the southwestern Indian Ocean. This pattern is consistent with human introductions of Pacific coconuts along the ancient Austronesian trade route connecting Madagascar to Southeast Asia. Admixture in coastal east Africa may also reflect later historic Arab trading along the Indian Ocean coastline. We propose two geographical origins of coconut cultivation: island Southeast Asia and southern margins of the Indian subcontinent

Genetic differentiation and admixture between sibling allopolyploids in the Dactylorhiza majalis complex

Allopolyploidization often happens recurrently, but the evolutionary significance of its iterative nature is not yet fully understood. Of particular interest are the gene flow dynamics and the mechanisms that allow young sibling polyploids to remain distinct while sharing the same ploidy, heritage and overlapping distribution areas. By using eight highly variable nuclear microsatellites, newly reported here, we investigate the patterns of divergence and gene flow between 386 polyploid and 42 diploid individuals, representing the sibling allopolyploids Dactylorhiza majalis s.s. and D. traunsteineri s.l. and their parents at localities across Europe. We make use in our inference of the distinct distribution ranges of the polyploids, including areas in which they are sympatric (that is, the Alps) or allopatric (for example, Pyrenees with D. majalis only and Britain with D. traunsteineri only). Our results show a phylogeographic signal, but no clear genetic differentiation between the allopolyploids, despite the visible phenotypic divergence between them. The results indicate that gene flow between sibling Dactylorhiza allopolyploids is frequent in sympatry, with potential implications for the genetic patterns across their entire distribution range. Limited interploidal introgression is also evidenced, in particular between D. incarnata and D. traunsteineri. Altogether the allopolyploid genomes appear to be porous for introgression from related diploids and polyploids. We conclude that the observed phenotypic divergence between D. majalis and D. traunsteineri is maintained by strong divergent selection on specific genomic areas with strong penetrance, but which are short enough to remain undetected by genotyping dispersed neutral markers.UE FWF; P22260UE: Y66