AIDS-related mycoses: the way forward.

The contribution of fungal infections to the morbidity and mortality of HIV-infected individuals is largely unrecognized. A recent meeting highlighted several priorities that need to be urgently addressed, including improved epidemiological surveillance, increased availability of existing diagnostics and drugs, more training in the field of medical mycology, and better funding for research and provision of treatment, particularly in developing countries

RESEARCH Open Access Inhibition of the checkpoint kinase Chk1 induces

DNA damage and cell death in human Leukemi

Reconsidering Diagnosis, Treatment, and Postoperative Care in Children with Cloacal Malformations

Cloacal malformations are among the most complex types of anorectal malformation and are characterized by the urological, genital, and intestinal tracts opening through a single common channel in the perineum. Long-term outcome is affected by multiple factors, which include anatomical variants of the malformation itself, associated anomalies, and the surgical approach. Reconsidering these variables and their influence on “patient important” function might lead to strategies that are more outcome-driven than focused on the creation of normal anatomy. Key outcomes reflect function in each of the involved tracts and the follow-up needed should therefore not only include the classical fields of colorectal surgery and urology but also focus on items such as gynecology, sexuality, family-building, and quality of life as well as other psychological aspects. Involving patients and families in determining optimal treatment strategies and outcome measures could lead to improved outcomes for the individual patient. A strategy to support delivery of personalized care for patients with cloacal malformations by aiming to define the best functional outcomes achievable for any individual, then select the treatment pathway most likely deliver that, with the minimum morbidity and cost, would be attractive. Combining the current therapies with ongoing technological advances such as tissue expansion might be a way to achieve this

On-Surface Synthesis of a Doubly Anti-Aromatic Carbon Allotrope: Cyclo[16]carbon

The synthetic carbon allotropes graphene, carbon nanotubes and fullerenes have revolutionised materials science and led to new technologies. Recently, unconventional synthetic strategies such as dynamic covalent chemistry and on-surface synthesis have been used to create new forms of carbon, including γ-graphyne, covalent fullerene polymers, and biphenylene networks, as well as cyclo[10]carbon, cyclo[14]carbon and cyclo[18]carbon. Here, by using tip-induced on-surface chemistry, we report the synthesis and characterisation of an anti-aromatic carbon allotrope, cyclo[16]carbon. In addition to structural information from atomic force microscopy (AFM), we probed its electronic structure by recording orbital density maps with scanning tunnelling microscopy (STM), which have not been reported previously for any cyclocarbon. The observation of bond-length alternation in cyclo[16]carbon confirms its double anti-aromaticity, in concordance with theory. The simple structure of C16 renders it an interesting model system for studying the limits of aromaticity, and its high reactivity makes it a promising precursor to novel carbon allotropes

Targeting conserved water molecules: Design of 4-aryl-5-cyanopyrrolo[2,3-d]pyrimidine Hsp90 inhibitors using fragment-based screening and structure-based optimization

Inhibitors of the Hsp90 molecular chaperone are showing promise as anti-cancer agents. Here we describe a series of 4-aryl-5-cyanopyrrolo[2,3-d]pyrimidine ATP competitive Hsp90 inhibitors that were identified following structure-driven optimization of purine hits revealed by NMR based screening of a proprietary fragment library. Ligand-Hsp90 X-ray structures combined with molecular modeling led to the rational displacement of a conserved water molecule leading to enhanced affinity for Hsp90 as measured by fluorescence polarization, isothermal titration calorimetry and surface plasmon resonance assays. This displacement was achieved with a nitrile group, presenting an example of efficient gain in binding affinity with minimal increase in molecular weight. Some compounds in this chemical series inhibit the proliferation of human cancer cell lines in vitro and cause depletion of oncogenic Hsp90 client proteins and concomitant elevation of the co-chaperone Hsp70. In addition, one compound was demonstrated to be orally bioavailable in the mouse. This work demonstrates the power of structure-based design for the rapid evolution of potent Hsp90 inhibitors and the importance of considering conserved water molecules in drug design

Stakeholders’ perspectives on clinical trial acceptability and approach to consent within a limited timeframe: a mixed methods study

Objectives The Bronchiolitis Endotracheal Surfactant Study (BESS) is a randomised controlled trial to determine the efficacy of endo-tracheal surfactant therapy for critically ill infants with bronchiolitis. To explore acceptability of BESS, including approach to consent within a limited time frame, we explored parent and staff experiences of trial involvement in the first two bronchiolitis seasons to inform subsequent trial conduct.Design A mixed-method embedded study involving a site staff survey, questionnaires and interviews with parents approached about BESS.Setting Fourteen UK paediatric intensive care units.Participants Of the 179 parents of children approached to take part in BESS, 75 parents (of 69 children) took part in the embedded study. Of these, 55/69 (78%) completed a questionnaire, and 15/69 (21%) were interviewed. Thirty-eight staff completed a questionnaire.Results Parents and staff found the trial acceptable. All constructs of the Adapted Theoretical Framework of Acceptability were met. Parents viewed surfactant as being low risk and hoped their child’s participation would help others in the future. Although parents supported research without prior consent in studies of time critical interventions, they believed there was sufficient time to consider this trial. Parents recommended that prospective informed consent should continue to be sought for BESS. Many felt that the time between the consent process and intervention being administered took too long and should be ‘streamlined’ to avoid delays in administration of trial interventions. Staff described how the training and trial processes worked well, yet patients were missed due to lack of staff to deliver the intervention, particularly at weekends.Conclusion Parents and staff supported BESS trial and highlighted aspects of the protocol, which should be refined, including a streamlined informed consent process. Findings will be useful to inform proportionate approaches to consent in future paediatric trials where there is a short timeframe for consent discussions.Trial registration number ISRCTN11746266