Parent values and preferences underpinning treatment decision-making in poor-prognosis childhood cancer: a scoping review.

BACKGROUND: Parents of children who are diagnosed with a poor-prognosis cancer want to be involved in making treatment-related decisions for their child. They often make repeated decisions depending on their child's response to treatment and can experience decisional regret as a consequence. Understanding parent values and preferences when making treatment-related decisions may help enhance discussions with healthcare professionals and identify additional ways of providing support to this parent population. OBJECTIVES: To explore parent values and preferences underpinning treatment decision-making for children receiving cancer-directed therapy for a poor prognosis cancer. METHODS: A scoping review of research literature and systematic reviews from qualitative, quantitative, and mixed methods studies was conducted following Joanna Briggs Institute methodology. Articles which included parents of a child who received cancer-directed therapy for a poor-prognosis childhood cancer, under the age of eighteen years were considered. Four electronic databases were searched (CINAHL, Medline, PsychINFO, Web of Science Core Collections). Reference and citation lists of all included full-text articles were also searched. Summative content analysis was used to synthesise findings and develop themes. RESULTS: Twelve articles were included. Parent decision-making was affected by underpinning factors: hope for a cure, fear of their child dying and uncertainty. Influencing factors: opinions of others, child's wishes, and faith and religion had the potential to inform decision-making processes. Parents valued having enough time, being a good parent and being involved in decision-making. Preferences within these values varied resulting in the potential for conflict and 'trade-offs' in making decisions. CONCLUSIONS: Parent decision-making in poor-prognosis childhood cancer is complex and extends beyond values and preferences. Underpinning factors and values are consistent through the decision-making process with influencing factors and preferences varying between parents. Preferences can conflict when parents want to continue cancer-directed therapy whilst maintaining their child's quality of life or can change depending on a parents' cognitive state as they realise cure might be unlikely.

Proteogenomic-based discovery of minor histocompatibility antigens with suitable features for immunotherapy of hematologic cancers.

Pre-clinical studies have shown that injection of allogeneic T cells primed against a single minor histocompatibility antigen (MiHA) could cure hematologic cancers (HC) without causing any toxicity to the host. However, translation of this approach in humans has been hampered by the paucity of molecularly defined human MiHAs. Using a novel proteogenomic approach, we have analyzed cells from 13 volunteers and discovered a vast repertoire of MiHAs presented by the most common HLA haplotype in European Americans: HLA-A*02:01;B*44:03. Notably, out of >6000 MiHAs, we have identified a set of 39 MiHAs that share optimal features for immunotherapy of HCs. These 'optimal MiHAs' are coded by common alleles of genes that are preferentially expressed in hematopoietic cells. Bioinformatic modeling based on MiHA allelic frequencies showed that the 39 optimal MiHAs would enable MiHA-targeted immunotherapy of practically all HLA-A*02:01;B*44:03 patients. Further extension of this strategy to a few additional HLA haplotypes would allow treatment of almost all patients.

Increasing polymorphism of the RAET1E/ULBP4 gene in humans.

Description of three novel RAET1E/ULBP4 allele and promoter polymorphisms identified by sequence-based typing.

Is the way an oil spill response is reported in the media important for the final perception of the clean-up?

This research investigates the media coverage during the C/V Rena grounding in New Zealand (NZ), in 2011, to analyze if information reported in printed media is important for the final perception of the overall oil spill response. We took all articles available from NZ's largest circulated newspaper and the regional newspaper closest to the incident and analyzed the themes within each article; the article's tone (positive, neutral or negative); the time of the report relative to incident events and any differences between the regional and national papers. This analysis indicates that oil spills are reported and perceived as inherently negative incidents. However, along with coordinating an effective spill response, fast, factual and frequent media releases and increased effect in media liaison in areas of response with high public intrinsic value such as oiled wildlife response can significantly influence tone of media coverage and likely overall public perception.

Further diversity of the 5' promoter region of the MHC class I-related chain B gene.

We have now found a total of 15 individual MICB promoter sequences, varying by combination of 18 polymorphic positions within the MICB minimal promoter sequence. Sequence-based typing and cloning characterized the three new 5' promoter sequences as MICB-P13, MICB-P14 and MICB-P15.

Endogenous c-Myc is essential for p53-induced apoptosis in response to DNA damage in vivo.

Recent studies have suggested that C-MYC may be an excellent therapeutic cancer target and a number of new agents targeting C-MYC are in preclinical development. Given most therapeutic regimes would combine C-MYC inhibition with genotoxic damage, it is important to assess the importance of C-MYC function for DNA damage signalling in vivo. In this study, we have conditionally deleted the c-Myc gene in the adult murine intestine and investigated the apoptotic response of intestinal enterocytes to DNA damage. Remarkably, c-Myc deletion completely abrogated the immediate wave of apoptosis following both ionizing irradiation and cisplatin treatment, recapitulating the phenotype of p53 deficiency in the intestine. Consistent with this, c-Myc-deficient intestinal enterocytes did not upregulate p53. Mechanistically, this was linked to an upregulation of the E3 Ubiquitin ligase Mdm2, which targets p53 for degradation in c-Myc-deficient intestinal enterocytes. Further, low level overexpression of c-Myc, which does not impact on basal levels of apoptosis, elicited sustained apoptosis in response to DNA damage, suggesting c-Myc activity acts as a crucial cell survival rheostat following DNA damage. We also identify the importance of MYC during DNA damage-induced apoptosis in several other tissues, including the thymus and spleen, using systemic deletion of c-Myc throughout the adult mouse. Together, we have elucidated for the first time in vivo an essential role for endogenous c-Myc in signalling DNA damage-induced apoptosis through the control of the p53 tumour suppressor protein.

Inappropriate prescribing in patients accessing specialist palliative day care services.

BACKGROUND: For patients accessing specialist palliative care day services, medication is prescribed routinely to manage acute symptoms, treat long-term conditions or prevent adverse events associated with these conditions. As such, the pharmacotherapeutic burden for these patients is high and polypharmacy is common. Consequently, the risk of these patients developing drug-related toxicities through drug­drug interactions is exacerbated. Medication use in this group should, therefore, be evaluated regularly to align with achievable therapeutic outcomes considering remaining life expectancy. OBJECTIVE: To (1) assess the prevalence of inappropriate medication use; (2) identify potential drug­drug interactions; and, (3) determine how many potential drug­ drug interactions could be prevented by discontinuing inappropriate medication. SETTING: A specialist tertiary care palliative care centre in Northern England serving a population of 330,000. MAIN OUTCOME MEASURE: Prescribing of inappropriate medication. METHOD: Medication histories for patients accessing a specialist palliative day care centre were established and a modified Delphi method was used to reach consensus of medication appropriateness. The Delphi method utilized a framework considering the following factors: remaining life expectancy of the patient, time until benefit of the treatment, goals of care and treatment targets. Potential drug interactions were established using drug interaction recognition software and categorised by their ability to cause harm. RESULTS: A total number of 132 patients were assessed during the study period who were prescribed 1,532 (mean = 12/patient) medications; 238 (16 %) were considered inappropriate in the context of limited life expectancy. The most common class of medications considered inappropriate were the statins, observed in 35 (27 %) patients. A total of 267 potential drug­drug interactions were identified; 112 were clinically significant and 155 were not considered clinically significant. Discontinuation of inappropriate medication would reduce the total number of medications taken to 1,294 (mean = 10/patient) and prevent 31 clinically significant potential drug­drug interactions. CONCLUSION: Patients accessing specialist palliative day care services take many inappropriate medications. These medications not only increase the pharmacotherapeutic burden for the patient but they also contribute to potential drug­drug interactions. These patients should have their medication reviewed in the context of life limiting illness aligned with achievable therapeutic outcomes.

Pathogen presence in feral pigs and their movement around two commercial piggeries in Queensland, Australia.

Feral pigs are wild animal reservoirs of infectious pathogens transmissible to other species, all of which are transmissible to domestic pigs. The objective of this study was to detect the presence of harmful production-limiting pathogens; Brucella suis, Leptospira species, Lawsonia intracellularis, Mycoplasma hyopneumoniae and Actinobacillus pleuropneumoniae in a feral pig population within a 10 km radius of two large-scale commercial piggeries in Southern Queensland, Australia. The movement pattern of six pigs within the feral population was also investigated using geographic positioning system collars. All pathogens were present in the feral pig population except for A pleuropneumoniae. The true seroprevalence (TP) from 83 serum samples was 10.5 per cent for B suis, 48.6 per cent for Leptospira species, 100 per cent for L intracellularis and 42.1 per cent for M hyopneumoniae. Of 72 lung samples, 27.6 per cent were positive for M hyopneumoniae. Serum samples from 86 domestic sows within the study region were positive for Leptospira species (TP 2.1 per cent), L intracellularis (TP 100 per cent) and M hyopneumoniae (TP 100 per cent). The majority of feral pig movement was within 5 km of the piggeries, with one approaching to 100 m of the free-range piggery. The presence of pathogens in feral pigs in such close proximity to commercial piggeries could pose a biosecurity risk.

Scrib heterozygosity predisposes to lung cancer and cooperates with KRas hyperactivation to accelerate lung cancer progression in vivo.

Lung cancer is the leading cause of cancer deaths worldwide with non small-cell lung cancer (NSCLC) accounting for 80% of all lung cancers. Although activating mutations in genes of the RAS-MAPK pathway occur in up to 30% of all NSCLC, the cooperating genetic lesions that are required for lung cancer initiation and progression remain poorly understood. Here we identify a role for the cell polarity regulator Scribble (Scrib) in NSCLC. A survey of genomic databases reveals deregulation of SCRIB in human lung cancer and we show that Scrib(+/-) mutant mice develop lung cancer by 540 days with a penetrance of 43%. To model NSCLC development in vivo, we used the extensively characterized LSL-KRas(G12D) murine model of NSCLC. We show that loss of Scrib and activated oncogenic KRas cooperate in vivo, resulting in more aggressive lung tumors, likely due to a synergistic elevation in RAS-MAPK signaling. Finally, we provide data consistent with immune infiltration having an important role in the acceleration of tumorigenesis in KRas(G12D) lung tumors following Scrib loss.

Effects of balance-focused interactive games compared to therapeutic balance classes for older women.

OBJECTIVE: The prospective pre-post control study was designed to evaluate the effect of introducing balance-focused interactive virtual-reality games to community-dwelling older women to improve their agility, balance and functional mobility. METHOD: The study was set in a senior citizens' club in Cheras, Kuala Lumpur, Malaysia. The participants were 36 community-dwelling older women. Participants were randomly divided into either a group undertaking balance-focused virtual-reality games or a group doing therapeutic balance exercises. The program lasted 6 weeks and was conducted twice a week for 40 min during each session. As the main outcome measures, the results of the Ten Step Test (TST), postural sway (overall performance index, OPI) and the Timed Up and Go test (TUG) were measured pre- and post-intervention to evaluate agility, balance and functional mobility, respectively. RESULTS: Although both groups improved in OPI (F = 4.63, p < 0.001), TST (F = 46.15, p < 0.001) and TUG (F = 52.57, p = 0.03), combined time and group interaction only improved in the TUG (F = 4.54, p < 0.05). No significant differences between the two groups were found in terms of TST (F = 0.02, p = 0.86), OPI (F = 0.66, p = 0.42), and TUG (F = 0.11, p = 0.74). CONCLUSION: Older people could improve their agility, balance and functional mobility by complementing therapeutic balance exercises with active participation in interactive virtual-reality games at home or in the community.

An International reference reagent for the detection of anti-human neutrophil antigen-1a.

BACKGROUND AND OBJECTIVES: Testing for neutrophil antibodies has become more common as awareness of transfusion-related acute lung injury (TRALI) has increased. However, unlike other areas of blood cell antibody testing, there are no certified reference reagents available with which laboratories can determine the sensitivity of detection of their assays. This report describes the production and evaluation of a freeze-dried preparation of human plasma, code 09/284, containing anti-human neutrophil antigen-1a (anti-HNA-1a) for use as a minimum sensitivity reagent. MATERIALS AND METHODS: One-millilitre of aliquots of plasma containing anti-HNA-1a were freeze-dried in glass ampoules. To characterize the material, 24 laboratories took part in an international collaborative study. The participants evaluated doubling dilutions of the material using their in-house routine assays and recorded the highest dilution in which the antibody could be detected. RESULTS: When diluted 1 in 4, most laboratories were able to detect the anti-HNA-1a in the material, and the participants agreed that this was an appropriate level to set as the minimum sensitivity required. CONCLUSIONS: In October 2011, the WHO Expert Committee on Biological Standardization approved the material 09/284 as an International Reference Reagent for the detection of anti-HNA-1a.

Molecular properties of lysine dendrimers and their interactions with Aß-peptides and neuronal cells.

Prevention of amyloidosis by chemical compounds is a potential therapeutic strategy in Alzheimer's, prion and other neurodegenerative diseases. Regularly branched dendrimers and less regular hyperbranched polymers have been suggested as promising inhibitors of amyloid aggregation. As demonstrated in our previous studies, some widely used dendrimers (PAMAM, PPI) could not only inhibit amyloid aggregation in solution but also dissolve mature fibrils. In this study we have performed computer simulation of polylysine dendrimers of 3rd and 5th generations (D3 and D5) and analysed the effect of these dendrimers and some hyperbranched polymers on a lysine base (HpbK) on aggregation of amyloid peptide in solution. The effects of dendrimers on cell viability and their protective action against Aß-induced cytotoxicity and alteration of K+channels was also analysed using human neuroblastoma SH-SY5Y cells. In addition, using fluorescence microscopy, we analysed uptake of FITC-conjugated D3 by SH-SY5Y cells and its distribution in the brain after intraventricular injections to rats. Our results demonstrated that dendrimers D3 and D5 inhibited amyloid aggregation in solution while HpbK enhanced amyloid aggregation. Cell viability and patch-clamp studies have shown that D3 can protect cells against Aß-induced cytotoxicity and K+channel modulation. In contrast, HpbK had no protective effect against Aß. Fluorescence microscopy studies demonstrated that FITC-D3 accumulates in the vacuolar compartments of the cells and can be detected in various brain structures and populations of cells after injections to the brain. As such, polylysine dendrimers D3 and D5 can be proposed as compounds for developing antiamyloidogenic drugs.

The removal of thermo-tolerant coliform bacteria by immobilized waste stabilization pond algae.

This study investigated the potential of laboratory- scale columns of immobilized micro-algae to disinfect effluents using thermo-tolerant coliforms (TTC) as a model system. Cells of a Chlorella species isolated from a waste stabilization pond complex in Northeast Brazil were immobilized in calcium alginate, packed into glass columns and incubated in contact with TTC suspensions for up to 24 hours. Five to six log removals of TTC were achieved in 6 hours and 11 log removals in 12 hours contact time. The results were similar under artificial light and shaded sunlight. However little or no TTC removal occurred in the light in columns of alginate beads without immobilized algae present or when the immobilized algae were incubated in the dark suggesting that the presence of both algae and light were necessary for TTC decay. There was a positive correlation between K(b) values for TTC and increasing pH in the effluent from the immobilized algal columns within the range pH 7.2 and 8.9. The potential of immobilized algal technology for wastewater disinfection may warrant further investigation.

Baffled primary facultative ponds with inlets and outlets set at different levels treating domestic wastewater in northeast Brazil.

This study evaluates the performance of four 2.3 m deep pilot-scale, independently loaded, primary facultative ponds treating predominantly domestic sewage in northeast Brazil. The ponds contained longitudinal baffles giving different length to width ratios from 3.55 to 32.4. The ponds had mean hydraulic retention times of ~15 days, and mean surface organic loadings of 330 kg BOD(5).ha.d(-1) during the first experimental phase and 375 kg BOD(5).ha.d(-1) in the second. The vertical inlets and outlets pipes were positioned at 1.8 m and 5 cm respectively below the pond surface in the first phase and at 50 cm and 1.8 m respectively in the second. All the ponds functioned as efficient primary facultative ponds but statistical analysis demonstrated no differences in effluent quality for most of the parameters measured for the various configurations of baffles and inlet and outlet depths. All behaved similarly to the unbaffled pond. The only exceptions were suspended solids and chlorophyll a concentrations which tended to be lower for all combinations of baffles with the outlets set 1.8 m below the surface. This study suggested that the longitudinal baffling of primary facultative ponds when using vertical inlets and outlets may well not significantly improve pond performance.

Thermo-tolerant coliform bacteria decay rates in a full scale waste stabilization pond system in northeast Brazil.

This paper presents the results for thermo-tolerant coliform (TTC) decay rates (K(b)) in a full scale WSP system located in Natal-RN, northeast Brazil. The series comprises a primary facultative pond (2 m deep), followed by two maturation ponds (1.5 m deep) giving a total area of 11 ha. The influent sewage and the pond effluents were monitored weekly during a seven month period. The results showed that the K(b) values predicted by the Marais equation assuming a hydraulic regime of complete mixing overestimated TTC die-off rates. The K(b) value adopted in the project design was 6.20 d(-1) but the mean value found for the WSP system during the monitoring programme was only 0.85 d(-1). This value is low compared to the values cited in the literature for shallow ponds (<1.25 m deep) but similar to values for deeper ponds. The sub optimal TTC removal rate in this WSP system may be caused by the adoption of too high a K(b) value at the design stage and the negative influence of high wind conditions on the mixing regime in the water columns of the ponds. Thus values for K(b) adopted at the design stage of WSP systems should be coherent with the hydraulic flow model, the type of pond, pond depth, and with the surface organic loading.

Colonisation and shedding of Lawsonia intracellularis in experimentally inoculated rodents and in wild rodents on pig farms.

Lawsonia intracellularis is an intracellular bacterium causing proliferative enteropathy in various animal species, and is considered an economically important pathogen of pigs. Rats and mice have been implicated as external vectors for a wide range of pig pathogens, including L. intracellularis. Previous studies have demonstrated L. intracellularis infection and proliferative enteropathy in rodents, but did not show the duration of shedding or the number of L. intracellularis shed by infected rodents, and therefore the infection risk that rodents pose to pigs. In this study, the number of L. intracellularis shed in the faeces and intestinal mucosa of wild rats trapped on pig farms was determined by a quantitative real time polymerase chain reaction assay. The prevalence of L. intracellularis in wild rats trapped on pig farms with endemic proliferative enteropathy (PE) was very high (≥ 70.6%), and large numbers of L. intracellularis were shed (10(10)/g of faeces) in a small proportion of wild rats. The duration of colonisation in laboratory rats and mice challenged with porcine isolates of L. intracellularis was also shown. Faecal shedding of L. intracellularis persisted for 14-21 days in rats and mice that were mildly affected with histological lesions of PE. The humoral immune response to L. intracellularis persisted for 40 days in both species. This study demonstrates that rodents may be an important reservoir of L. intracellularis on piggeries, and hence rodent control is important in disease eradication programs on pig farms.

The removal of ammonia from sanitary landfill leachate using a series of shallow waste stabilization ponds.

This study evaluated the efficiency of a shallow (0.5 m deep) waste stabilization pond series to remove high concentrations of ammonia from sanitary landfill leachate. The pond system was located at EXTRABES, Campina Grande, Paraiba, Northeast Brazil. The pond series was fed with sanitary landfill leachate transported by road tanker to the experimental site from the sanitary landfill of the City of Joao Pessoa, Paraiba. The ammoniacal-N surface loading on the first pond of the series was equivalent to 364 kg ha(-1) d(-1) and the COD surface loading equivalent to 3,690 kg ha(-1) d(-1). The maximum mean ammonia removal efficiency was 99.5% achieved by the third pond in the series which had an effluent concentration of 5.3 mg L(-1) ammoniacal-N for an accumulative HRT of 39.5 days. The removal process was mainly attributed to ammonia volatilization (stripping) from the pond surfaces as a result of high surface pH values and water temperatures of 22-26°C. Shallow pond systems would appear to be a promising technology for stripping ammonia from landfill leachate under tropical conditions.

Giant colonic mucocele following palliative surgery for metastatic adenocarcinoma.

We report an unusual case of a giant colonic mucocele following ileo-sigmoid bypass surgery in a patient with advanced adenocarcinoma of the splenic flexure. The formation of a giant colonic mucocele resulted from distal splenic flexure obstruction due to tumour relapse and proximal caecal obstruction due to peritoneal disease with subsequent accumulation of mucus in the closed loop.

Report on the 14th International Society of Blood Transfusion Platelet Immunology Workshop.

BACKGROUND AND OBJECTIVES: The aims of the 14th ISBT Platelet Immunology Workshop were to evaluate in-house methods for detection of antibodies to human platelet antigens, to compare the sensitivity and specificity of antibody detection using a panel of monoclonal antibodies and to evaluate genotyping methods and establish procedures for drug-dependent antibody detection. MATERIALS AND METHODS: Forty-two laboratories from 23 countries participated. Samples and reagents provided for the five different exercises. RESULTS: The ability of participating laboratories to correctly identify the HPA antibody specificity in the nine samples ranged from 20% to 97%. The greatest difficulty was observed with samples that contained antibodies against HPA-3b and GPIV. The significant differences in optical density values by monoclonal antibody of immobilization of platelet antigens (MAIPA) assay were observed when testing the same platelet-specific antibodies. HPA genotyping of DNA with novel mutations did not significantly affect the results. The overall average discrepancy rate was 2·15% for genotyping of 10 DNA samples from well-characterized Epstein­Barr virus transformed cell lines. For detection of drug-dependent antibodies, excellent results for specificity and sensitivity were obtained by the laboratories using the MAIPA and flow cytometry. CONCLUSIONS: Most laboratories were able to identify the majority of HPA antibodies; however, significant disparities were observed in proficiency testing. MAIPA assay sensitivity is influenced by the monoclonal antibody clone used. DNA with new mutations and EBV cell lines are valuable samples to ensure accurate genotyping. A sensitive and specific drug-dependent antibody assay performed well in the hands of participants.