The everydayness of falling: consequences and management for adults with cerebral palsy across the life course.

PURPOSE: To explore the cause, influences and consequences of falling for adults with cerebral palsy (CP) across their life course, and how this is managed. MATERIALS AND METHODS: We used interview data from a multimethod UK study exploring the effects of ageing with CP and healthcare across the life course. Twenty-six participants were recruited and interviewed using various digital platforms to maximise inclusive participation in the UK. Follow-up email semi-structured interviews were conducted to further explore experiences of falls. Transcribed interviews were analysed thematically. RESULTS: Falling and fear of falling (FoF) is problematic for over half of the participants in the sample. They perceived falls and FoF as limiting their participation, autonomy and independence in employment, social and cultural activities. Participants used their own management strategies, due to limited specialist interventions or practitioner knowledge to manage or prevent falls. Practices, such as the use of a wheelchair or avoiding activities prompted changes to relationships and identity. CONCLUSIONS: Falling for adults with CP happens earlier in life compared to the general population. Adults with CP may benefit from specialist falls prevention services to help maintain muscle strength and balance. Research is needed to evaluate effective interventions for people with CP.

Falling negatively impacts on the lives and identities of people with cerebral palsy, including younger adults.In other areas such as services for older people, or those who have experienced stroke, rehabilitation services have helped people reduce falls rates through maintaining strength and balance.Falls prevention rehabilitation services are needed for people with cerebral palsy and should include relevant mobility devices and assistive technologies while maintaining social participation and quality of life.

The impact of ageing on adults with cerebral palsy: the results of a national online survey.

BACKGROUND: Cerebral palsy (CP) is one of the most common neurological disorders in children and results in lifelong physical impairments. Adults with CP have approximately the same life expectancy as their non-disabled peers, so helping them to stay healthy throughout the life course will have long-term cost benefits via reductions in hospital admissions, long-term care, and unemployment rates. AIM: To explore how adults with CP experience ageing. DESIGN & SETTING: National online survey given to adults with CP in the UK. METHOD: The participants were adults with CP. Items for the online survey were taken from existing self-report measures, with additional items developed for the survey. Several domains of functioning were assessed including mobility, dexterity, fatigue, pain, speech, mental health, swallowing and health maintenance/self-care as well as healthcare usage. Data were analysed using χ2 to examine the relationships between the demographic variables and the survey responses. RESULTS: The survey was completed by 395 participants, of whom 74.2% were female and approximately 59.3% aged <45 years. Responders reported having problems with mobility, pain, and fatigue with older participants reporting higher levels of pain and more mobility problems, although the correlations were fairly small. Healthcare usage was surprisingly low. CONCLUSION: The study found that age was associated with a decline in mobility and a higher level of pain, although the relationships were weak. It is possible that the low healthcare usage among the responders is owing to services not being available to respond to their needs.

Optimization of green ammonia distribution systems for intercontinental energy transport.

Green ammonia is a promising hydrogen derivative which enables intercontinental transport of dispatchable renewable energy. This research describes the development of a model which optimizes a global green ammonia network, considering the costs of production, storage, and transport. In generating the model, we show economies of scale for green ammonia production are small beyond 1 million tonnes per annum (MMTPA), although benefits accrue up to a production rate of 10 MMTPA if a production facility is serviced by a new port or requires a long pipeline. The model demonstrates that optimal sites for ammonia production require not only an excellent renewable resource but also ample land from which energy can be harvested. Land limitations constrain project size in otherwise optimal locations and force production to more expensive sites. Comparison of current crude oil markets to future ammonia markets reveals a trend away from global supply hubs and toward demand centers serviced by regional production.

Exploring the impacts of social media and crowdsourcing on disaster resilience.

Social media and crowdsourcing (SMCS) are increasingly proving useful for addressing the effects of natural and human-made hazards. SMCS allow different stakeholders to share crucial information during disaster management processes and to strengthen community resilience through engagement and collaboration. To harvest these opportunities there is a need for better knowledge on SMCS for diverse disaster scenarios. These challenges are being addressed within the LINKS Horizon 2020 project. The project aims at strengthening societal resilience by producing advanced learning on the use of SMCS in disasters. This is done through an in-depth study across three knowledge domains (disaster risk perception and vulnerability, disaster management processes, SMCS technologies), the establishment of an interactive framework, and an online platform in which a community of relevant stakeholders can learn and share knowledge and experiences. This paper provides an overview of the project objectives and approaches and a summary of the initial results.

Biomimetic heterogenous elastic tissue development.

There is an unmet need for artificial tissue to address current limitations with donor organs and problems with donor site morbidity. Despite the success with sophisticated tissue engineering endeavours, which employ cells as building blocks, they are limited to dedicated labs suitable for cell culture, with associated high costs and long tissue maturation times before available for clinical use. Direct 3D printing presents rapid, bespoke, acellular solutions for skull and bone repair or replacement, and can potentially address the need for elastic tissue, which is a major constituent of smooth muscle, cartilage, ligaments and connective tissue that support organs. Thermoplastic polyurethanes are one of the most versatile elastomeric polymers. Their segmented block copolymeric nature, comprising of hard and soft segments allows for an almost limitless potential to control physical properties and mechanical behaviour. Here we show direct 3D printing of biocompatible thermoplastic polyurethanes with Fused Deposition Modelling, with a view to presenting cell independent in-situ tissue substitutes. This method can expeditiously and economically produce heterogenous, biomimetic elastic tissue substitutes with controlled porosity to potentially facilitate vascularisation. The flexibility of this application is shown here with tubular constructs as exemplars. We demonstrate how these 3D printed constructs can be post-processed to incorporate bioactive molecules. This efficacious strategy, when combined with the privileges of digital healthcare, can be used to produce bespoke elastic tissue substitutes in-situ, independent of extensive cell culture and may be developed as a point-of-care therapy approach.

A potential platform for developing 3D tubular scaffolds for paediatric organ development.

Children suffer from damaged or loss of hollow organs i.e. trachea, oesophagus or arteries from birth defects or diseases. Generally these organs possess an outer matrix consisting of collagen, elastin, and cells such as smooth muscle cells (SMC) and a luminal layer consisting of endothelial or epithelial cells, whilst presenting a barrier to luminal content. Tissue engineering research enables the construction of such organs and this study explores this possibility with a bioabsorbable nanocomposite biomaterial, polyhedral oligomeric silsesquioxane poly(ε-caprolactone) urea urethane (POSS-PCL).Our established methods of tubular graft extrusion were modified using a porogen-incorporated POSS-PCL and a new lamination method was explored. Porogen (40, 60 or 105 µm) were introduced to POSS-PCL, which were fabricated into a bilayered, dual topography matching the exterior and luminal interior of tubular organs. POSS-PCL with different amounts of porogen were tested for their suitability as a SMC layer by measuring optimal interactions with human adipose derived stem cells. Angiogenesis potential was tested with the chorioallantoic membrane assay. Tensile strength and burst pressures of bilayared tubular grafts were determined. Scaffolds made with 40 µm porogen demonstrated optimal adipose derived stem cell integration and the scaffolds were able to accommodate angiogenesis. Mechanical properties of the grafts confirmed their potential to match the relevant physiological and biophysical parameters. This study presents a platform for the development of hollow organs for transplantation based on POSS-PCL. These bilayered-tubular structures can be tailor-made for cellular integration and match physico-mechanical properties of physiological systems of interest. More specific luminal cell integration and sources of SMC for the external layer could be further explored.

Discovery of 4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an orally bioavailable, potent inhibitor of Akt kinases.

Wide-ranging exploration of analogues of an ATP-competitive pyrrolopyrimidine inhibitor of Akt led to the discovery of clinical candidate AZD5363, which showed increased potency, reduced hERG affinity, and higher selectivity against the closely related AGC kinase ROCK. This compound demonstrated good preclinical drug metabolism and pharmacokinetics (DMPK) properties and, after oral dosing, showed pharmacodynamic knockdown of phosphorylation of Akt and downstream biomarkers in vivo, and inhibition of tumor growth in a breast cancer xenograft model.

Preclinical pharmacology of AZD5363, an inhibitor of AKT: pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background.

AKT is a key node in the most frequently deregulated signaling network in human cancer. AZD5363, a novel pyrrolopyrimidine-derived compound, inhibited all AKT isoforms with a potency of 10 nmol/L or less and inhibited phosphorylation of AKT substrates in cells with a potency of approximately 0.3 to 0.8 µmol/L. AZD5363 monotherapy inhibited the proliferation of 41 of 182 solid and hematologic tumor cell lines with a potency of 3 µmol/L or less. Cell lines derived from breast cancers showed the highest frequency of sensitivity. There was a significant relationship between the presence of PIK3CA and/or PTEN mutations and sensitivity to AZD5363 and between RAS mutations and resistance. Oral dosing of AZD5363 to nude mice caused dose- and time-dependent reduction of PRAS40, GSK3ß, and S6 phosphorylation in BT474c xenografts (PRAS40 phosphorylation EC(50) ~ 0.1 µmol/L total plasma exposure), reversible increases in blood glucose concentrations, and dose-dependent decreases in 2[18F]fluoro-2-deoxy-D-glucose ((18)F-FDG) uptake in U87-MG xenografts. Chronic oral dosing of AZD5363 caused dose-dependent growth inhibition of xenografts derived from various tumor types, including HER2(+) breast cancer models that are resistant to trastuzumab. AZD5363 also significantly enhanced the antitumor activity of docetaxel, lapatinib, and trastuzumab in breast cancer xenografts. It is concluded that AZD5363 is a potent inhibitor of AKT with pharmacodynamic activity in vivo, has potential to treat a range of solid and hematologic tumors as monotherapy or a combinatorial agent, and has potential for personalized medicine based on the genetic status of PIK3CA, PTEN, and RAS. AZD5363 is currently in phase I clinical trials.

Novel thienopyrimidine and thiazolopyrimidine kinase inhibitors with activity against Tie-2 in vitro and in vivo.

The SAR and improvement in potency against Tie2 of novel thienopyrimidine and thiazolopyrimidine kinase inhibitors are reported. The crystal structure of one of these compounds bound to the Tie-2 kinase domain is consistent with the SAR. These compounds have moderate potency in cellular assays of Tie-2 inhibition, good physical properties, DMPK, and show evidence of in vivo inhibition of Tie-2.

Discovery of imidazole vinyl pyrimidines as a novel class of kinase inhibitors which inhibit Tie-2 and are orally bioavailable.

Tie-2 is a receptor tyrosine kinase which is involved in angiogenesis and thereby growth of human tumours. The discovery and SAR of a novel class of imidazole-vinyl-pyrimidine kinase inhibitors, which inhibit Tie-2 in vitro is reported. Their synthesis was carried out by condensation of imidazole aldehydes with methyl pyrimidines. These compounds are lead-like, with low molecular weight, good physical properties and oral bioavailability.

Aminoimidazolylmethyluracil analogues as potent inhibitors of thymidine phosphorylase and their bioreductive nitroimidazolyl prodrugs.

Thymidine phosphorylase (TP) is an important target enzyme for cancer chemotherapy because it is expressed at high levels in the hypoxic regions of many tumors and inhibitors of TP have been shown in animal model studies to inhibit angiogenesis and metastasis, and to promote tumor cell apoptosis. The 5-halo-6-[(2'-aminoimidazol-1'-yl)methyl]uracils (3, X = Cl, Br) are very potent inhibitors of E. coli and human TP with IC(50) values of approximately 20 nM when the enzyme concentration is approximately 40 nM. Their 4'-aminoimidazol-1'-yl analogues (4, X = Cl, Br) are >350-fold less active with IC(50) values of approximately 7 microM. The 5-unsubstituted analogues (3 and 4, X = H) were both less active than their 5-halo derivatives. Determination of pK(a) values and molecular modeling studies of these compounds in the active site of human TP was used to rationalize their activities. The finding that 3, X = Br has a poor pharmacokinetic (PK) profile in mice, coupled with the desire for tumor selectivity, led us to design prodrugs. The corresponding 2'-nitroimidazol-1'-ylmethyluracils (5, X = Cl, Br) are >1000-fold less active (IC(50) 22-24 microM) than their 2'-amino analogues and are reduced to the 2'-amino inhibitors (3, X = Cl, Br) by xanthine oxidase (XO). As XO is also highly expressed in many tumors, the 2'-nitro prodrugs have the potential to selectively deliver the potent 2'-aminoimidazol-1'-yl TP inhibitors into hypoxic solid tumors.

Infection and food: a factor in sudden infant death syndrome?

Despite the identification of risk factors for sudden infant death syndrome (SIDS) and decreased SIDS rates in many countries, there is still no coherent, widely accepted, mechanistic explanation for SIDS. As an extension of our work on the infectious aetiology of SIDS, we have explored the prediction that infectious agents might reach susceptible infants and babies, via particular sources of food. In this ecological study, we demonstrated significant correlations between SIDS rates and exposure to meat from some sources, and we propose that more detailed studies be carried out.

Crystal structure of human thymidine phosphorylase in complex with a small molecule inhibitor.

Human thymidine phosphorylase (HTP), also known as platelet-derived endothelial cell growth factor (PD-ECGF), is overexpressed in certain solid tumors where it is linked to poor prognosis. HTP expression is utilized for certain chemotherapeutic strategies and is also thought to play a role in tumor angiogenesis. We determined the structure of HTP bound to the small molecule inhibitor 5-chloro-6-[1-(2-iminopyrrolidinyl) methyl] uracil hydrochloride (TPI). The inhibitor appears to mimic the substrate transition state, which may help explain the potency of this inhibitor and the catalytic mechanism of pyrimidine nucleotide phosphorylases (PYNPs). Further, we have confirmed the validity of the HTP structure as a template for structure-based drug design by predicting binding affinities for TPI and other known HTP inhibitors using in silico docking techniques. This work provides the first structural insight into the binding mode of any inhibitor to this important drug target and forms the basis for designing novel inhibitors for use in anticancer therapy.

Synthesis of cytidine ribonucleotides by stepwise assembly of the heterocycle on a sugar phosphate.

Although various syntheses of the nucleic acid bases exist and ribose is a product of the formose reaction, no prebiotically plausible methods for attaching pyrimidine bases to ribose to give nucleosides have been described. Kinetic and thermodynamic factors are thought to mitigate against such condensation reactions in aqueous solution. This inability to produce pyrimidine nucleosides and hence nucleotides is a major stumbling block of the "RNA World" hypothesis and has led to suggestions of alternative nucleic acids as evolutionary precursors to RNA. Here, we show that a process in which the base is assembled in stages on a sugar phosphate can produce cytidine nucleotides. The sequential action of cyanamide and cyanoacetylene on arabinose-3-phosphate produces cytidine-2',3'-cyclophosphate and arabinocytidine-3'-phosphate.