Multi-criteria analysis of strategies towards sustainable recycling of phosphorus from sewage sludge in Austria.

To promote optimal phosphorus (P) recovery from municipal wastewater and sewage sludge with viable legal instruments, it is imperative to understand the regional and national consequences of different legal requirements for recycling. In this study we develop a scenario-based analysis to assess the environmental and economic impact of different national P recovery strategies in the context of a detailed representation of the existing Austrian wastewater infrastructure. This assessment combines material flow analysis, life cycle assessment and life cycle costing and includes the indicators P recycling rate, P utilization degree, heavy metal removal rate, share of heavy metals' content in wastewater redirected to agricultural soils, global warming potential, cumulated energy demand, terrestrial acidification potential, volume of freight transport and annual costs. The following main conclusions can be drawn. P recovery from ash shows the highest potential regarding the utilization of P from wastewater. A high P utilization from wastewater should rely on recovery technologies that decontaminate products, otherwise pollutant loads to agricultural soils might increase. P recovery to the extent of 60-85 % of P in WWTPs influent can be achieved by savings/costs of -0.8 to +4.7 EUR inhabitant-1 yr-1 in addition to current cost of the wastewater treatment/sludge disposal system. Key factors to be considered for costs are the choice of recovery process, revenues from products, and the use of existing incineration infrastructure. P recovery can lead to the reduction of greenhouse gas emissions in Austria if nitrous oxide emissions from sludge incineration are limited and efficient heat utilization strategies are implemented. There is a trade-off in terms of environmental and economic costs in choosing a more centralized or decentralized mono-incineration strategy.

Exploring management and outcomes of elderly patients with glioblastoma using data from two randomised trials (GEINO1401/EX-TEM).

PURPOSE: The impact of age on optimal management of glioblastoma remains unclear. A recent combined analysis of two randomised trials, GEINO14-01 and EX-TEM, found no benefit from extending post-radiation temozolomide in newly diagnosed glioblastoma. Here, we explore the impact of age. METHODS: Relevant intergroup statistics were used to identify differences in tumour, treatment and outcome characteristics based on age with elderly patients (EP) defined as age 65 years and over. Survival was estimated using the Kaplan Meier method. RESULTS: Of the combined 205 patients, 57 (28%) were EP. Of these, 95% were ECOG 0-1 and 65% underwent macroscopic resection compared with 97% and 61% of younger patients (YP) respectively. There were numerically less MGMT-methylated (56% vs. 63%, p = 0.4) and IDH-mutated (4% vs. 13%, p = 0.1) tumours in EP vs. YP. Following surgery, EP were more likely to receive short course chemoradiation (17.5% vs. 6%, p = 0.017). At recurrence, EP tended to receive or best supportive care (28.3% vs. 15.4%, p = 0.09) or non-surgical options (96.2% vs. 84.6%, p = 0.06), but were less likely to receive bevacizumab (23.1% vs. 49.5%, p < 0.01). Median PFS was similar at 9.3months in EP and 8.5months in YP, with similar median OS at 20months. CONCLUSION: In this trial population of predominantly fit EP, survival was similar to YP despite a proportion receiving less aggressive therapy at diagnosis and recurrence. Advancing age does not appear to be an adverse prognostic factor for glioblastoma when patients are fit for treatment, and a less aggressive approach in selected patients may not compromise outcomes.

A combined analysis of two prospective randomised studies exploring the impact of extended post-radiation temozolomide on survival outcomes in newly diagnosed glioblastoma.

PURPOSE: The optimal duration of post-radiation temozolomide in newly diagnosed glioblastoma remains unclear, with no published phase III randomised trials. Standard-of-care stipulates 6 months. However, in routine care, it is often extended to 12 months, despite lacking robust supporting data. METHODS: GEINO14-01 (Spain) and EX-TEM (Australia) studies enrolled glioblastoma patients without progression at the end of 6 months post-radiation temozolomide. Participants were randomised 1:1 to six additional months of temozolomide or observation. Primary endpoint was 6-month progression free survival from date of randomisation (6mPFS). Secondary endpoints included overall survival (OS) and toxicity. 204 patients were required to detect an improvement in 6mPFS from 50 to 60% (80% power). Neither study recruited sufficient patients. We performed a combined analysis of individual patient data. RESULTS: 205 patients were recruited: 159 in GEINO14-01 (2014-2018) and 46 in EX-TEM (2019-2022). Median follow-up was 20.0 and 14.5 months. Baseline characteristics were balanced. There was no significant improvement in 6mPFS (57.2% vs 64.0%, OR0.75, p = 0.4), nor across any subgroups, including MGMT methylated; PFS (HR0.92, p = 0.59, median 7.8 vs 9.7 months); or OS (HR1.03, p = 0.87, median 20.1 vs 19.4 months). During treatment extension, 64% experienced any grade adverse event, mainly fatigue and gastrointestinal (both 54%). Only a minority required treatment changes: 4.5% dose delay, 7.5% dose reduction, 1.5% temozolomide discontinuation. CONCLUSION: For glioblastoma patients, extending post-radiation temozolomide from 6 to 12 months is well tolerated but does not improve 6mPFS. We could not identify any subset that benefitted from extended treatment. Six months should remain standard-of-care.

The longitudinal loss of islet autoantibody responses from diagnosis of type 1 diabetes occurs progressively over follow-up and is determined by low autoantibody titres, early-onset, and genetic variants.

The clinical usefulness of post-diagnosis islet autoantibody levels is unclear and factors that drive autoantibody persistence are poorly defined in type 1 diabetes (T1D). Our aim was to characterise the longitudinal loss of islet autoantibody responses after diagnosis in a large, prospectively sampled UK cohort. Participants with T1D [n = 577] providing a diagnosis sample [range -1.0 to 2.0 years] and at least one post-diagnosis sample (<32.0 years) were tested for autoantibodies to glutamate decarboxylase 65 (GADA), islet antigen-2 (IA-2A), and zinc transporter 8 (ZnT8A). Select HLA and non-HLA SNPs were considered. Non-genetic and genetic factors were assessed by multivariable logistic regression models for autoantibody positivity at initial sampling and autoantibody loss at final sampling. For GADA, IA-2A, and ZnT8A, 70.8%, 76.8%, and 40.1%, respectively, remained positive at the final sampling. Non-genetic predictors of autoantibody loss were low baseline autoantibody titres (P < 0.0001), longer diabetes duration (P < 0.0001), and age-at-onset under 8 years (P < 0.01--0.05). Adjusting for non-genetic covariates, GADA loss was associated with low-risk HLA class II genotypes (P = 0.005), and SNPs associated with autoimmunity RELA/11q13 (P = 0.017), LPP/3q28 (P = 0.004), and negatively with IFIH1/2q24 (P = 0.018). IA-2A loss was not associated with genetic factors independent of other covariates, while ZnT8A loss was associated with the presence of HLA A*24 (P = 0.019) and weakly negatively with RELA/11q13 (P = 0.049). The largest longitudinal study of islet autoantibody responses from diagnosis of T1D shows that autoantibody loss is heterogeneous and influenced by low titres at onset, longer duration, earlier age-at-onset, and genetic variants. These data may inform clinical trials where post-diagnosis participants are recruited.

Topological Control of Magnetic Textures.

A micromagnetic study is carried out on the role of using topology to stabilize different magnetic textures, such as a vortex or an anti-vortex state, in a magnetic heterostructure consisting of a Permalloy disk coupled to a set of nanomagnetic bars. The topological boundary condition is set by the stray field contributions of the nanomagnet bars and thus by their magnetization configuration, and can be described by a discretized winding number that will be matched by the winding number of the topological state set in the disk. The lowest number of nanomagnets that defines a suitable boundary is four, and we identify a critical internanomagnet angle of 225° between two nanomagnets, at which the boundary fails because the winding number of the nanomagnet configuration no longer controls that of the disk magnetization. The boundary also fails when the disk-nanomagnets separation is > 50 nm and for disk diameters > 480 nm. Finally, we provide preliminary experimental evidence from magnetic force microscopy studies in which we demonstrate that an energetically unstable, anti-vortex-like structure can indeed be stabilized in a Permalloy disk, provided that the appropriate topological conditions are set.

Islet autoantibody profiles associated with higher diabetes risk in Lithuanian compared with English schoolchildren.

During a 15-year period, the incidence of type 1 diabetes has doubled in Lithuania, while increasing by a third in England; however, England still has a higher incidence. Analysis of sera collected from non-diabetic schoolchildren from Lithuania and England more than 20 years ago showed a similar number of multiple autoantibody-positive schoolchildren between the populations, but a higher prevalence of islet antigen-2 autoantibodies (IA-2A) in English schoolchildren. We aimed to use recently developed, more specific islet autoantibody tests to characterize differences in humoral autoimmunity between these two general population cohorts in greater detail. Samples from 88 Lithuanian and 133 English schoolchildren previously found islet autoantibody-positive were selected for measurement of additional islet autoantibodies by radioimmunoassay. Samples were tested for autoantibodies to zinc transporter 8 (ZnT8A), GAD (96-585), the protein tyrosine phosphatase region of islet antigen-2 (PTPA) and the related IA-2ßA, while autoantibodies to IA-2A were reassayed using the current harmonized method. IA-2-related autoantibodies PTPA (0·13 versus 0·45%, P = 0·027) and IA-2ßA (0 versus 0·35%, P < 0·001), but not IA-2A measured using the harmonized method, were less common in Lithuanian compared to English schoolchildren. Lithuanian schoolchildren who were islet autoantibody-positive were positive for fewer biochemical autoantibodies compared with English schoolchildren (P = 0·043). Background rates of islet autoimmunity in childhood differ subtly between countries, which have different incidences of type 1 diabetes. The optimal screening strategy (age and combination of markers) for detection of islet autoimmunity may vary between countries, dependent upon the pattern of autoantibodies found in the general population.

Hypermobility Assessment in 1,004 Adult Patients Presenting with Hip Pain: Correlation with Diagnoses and Demographics.

BACKGROUND: The strength of the association between hypermobility and developmental dysplasia of the hip (DDH) in adults is unknown. We sought to analyze this relationship in a prospective, blinded, institutional review board-approved, observational study. The hypothesis was that the prevalence of generalized joint hypermobility (GJH) would be significantly higher in patients with hip dysplasia than in those with other hip diagnoses on the basis of clinical observations of joint laxity. METHODS: One thousand and four consecutive new patients (390 males and 614 females) seen over a 4-year period were evaluated for hypermobility of the hip using 2 criteria: the Beighton 9-point physical examination criteria and the Hakim-Grahame 5-item history questionnaire. Diagnosis, age, sex, and race were tested as predictors of hypermobility. Patient-reported outcome scores from the International Hip Outcome Tool (iHOT-12) and the modified Harris hip score (mHHS) were also assessed. RESULTS: DDH was the primary diagnosis in 33.2% of the patient population. Patients who had dysplasia without osteoarthritis (OA) had a significantly elevated prevalence of GJH (77.9%) compared with those with nondysplastic hips (32.8%; p < 0.0001) or with patients who had dysplasia and OA (35.7%; p < 0.0001) according to either method. The odds ratio (OR) for patients with DDH versus those with other diagnoses was 7.1 (95% confidence interval [CI]: 5.1 to 10.0). The prevalence of hypermobility was significantly greater in females than in males (OR = 4.2 [95% CI: 3.2 to 5.5]; p < 0.0001). The prevalence of GJH was inversely proportional to age. There was a significantly reduced prevalence of GJH observed in Hispanic patients (p < 0.05) compared with other races. GJH was not a predictor of patient-reported outcome scores (p = 0.51 for iHOT-12 and p = 0.44 for mHHS). CONCLUSIONS: To our knowledge, this study is the first to establish a strong association between hypermobility and DDH in adults, confirming the hypothesis. We recommend utilizing both the Beighton and Hakim-Grahame scoring systems together as routine components of the history and physical examination for patients with hip dysplasia. Further research is warranted to explore the genetic basis and potential causal relationships between soft-tissue laxity and skeletal dysplasia, as well as improvements in assessment tools. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

A bolt from the blue; A case report of an unusual asthma exacerbation.

BACKGROUND: We describe this case of a young gentleman presenting with acute dyspnoea on a background history of known, long-standing asthma. His dramatic presentation, notable for profound hypoxia and cyanosis, led to an unexpected additional diagnosis of type one congenital methaemoglobinaemia. CASE PRESENTATION: A 26-year-old Irish gentleman was transferred urgently to the emergency department resuscitation room with marked cyanosis and tachypnoea. His oxygen saturation was 70% on 100% high flow oxygen. His arterial blood gas (On Fi02 90%) demonstrated a PaO2 = 76.8 kPa, SpO2 = 99%, pCO2 = 3 kPa and pH = 7.51. A saturation gap was evident and on further analysing the arterial blood gas, the methaemoglobin level was noted to be 28%. No contributing drugs were identified. Our patient was diagnosed with type one congenital methaemoglobinaemia. He recovered well from this admission, however, has had recurrent presentations to hospital since with high methaemoglobin levels noted on each occasion. DISCUSSION: Congenital methemoglobinemia is a rare, often overlooked differential diagnosis in patients presenting with cyanosis and dyspnoea. This is the only case, to our knowledge, of a patient with both asthma and congenital methaemoglobinaemia. Congenital methaemoglobinaemia was first described in 1943 by Dr Deeny who described two siblings as suffering from 'Familial Idiopathic Methaemoglobinaemia'. The case we present is the first reported Irish case of congenital methaemoglobinaemia, we are aware of, since 1943.Current treatment strategies include high-flow oxygen, methylene blue infusion (contraindicated in glucose-6-phosphate-dehydrogenase deficiency) and red cell exchange transfusions in the emergency setting whilst oral ascorbic acid and riboflavin are preventative.

[Doppler ultrasonography of the renal artery: Guidelines and predictive factors for the presence of a tight stenosis. Retrospective analysis of 450 consecutive examinations]. / Échographie Doppler des artères rénales. Recommandations et facteurs prédictifs de la présence d'une sténose serrée. Analyse rétrospective de 450 examens consécutifs.

Duplex ultrasonography screening for renal artery stenosis has been the object of guidelines published by four societies designed to optimize the cost-effectiveness of the examination. OBJECTIVES: To determine how well guideline indications for ultrasonography matched with requests and results in our university hospital; to determine whether compliance with guidelines was predictive of renal artery stenosis; to identify guidelines predictive of presence of stenosis; and to determine whether other predictive factors can be recognized. MATERIAL AND METHODS: Requests and results of 450 Duplex ultrasonography examinations of the renal arteries performed from January 1st 2014 to December 31st 2015 were compared with published guidelines. RESULTS: At least one guideline indication was identified for 212 of the 450 examinations performed (47.1%). Among these examinations, renal artery stenosis≥70% was identified in 18 patients (8.0%). No case of stenosis was identified during examinations performed outside guideline indications. Factors predictive of stenosis were: compliance with guidelines (OR=21.86 [2.88; 165.8]). Predictive guidelines were: resistant hypertension in spite of appropriate treatment (OR=3.85, [1.44; 10.33], P=0.011), accelerated hypertension (OR=7.30, [1.40; 37.99], P=0.049), sudden unexplained pulmonary edema (OR=7.30, [1.40; 37.99], P=0.049), unexplained renal insufficiency (OR=3.58, [1.37; 9.37], P=0.011), unexplained renal hypotrophy (OR=16.69, [4.38; 63.69], P<0.001), renal asymmetry (OR=4.32, [1.45; 12.85], P<0.016). No other factor was predictive of renal stenosis. These examinations had therapeutic consequences in only 50% of patients. CONCLUSION: This study confirms the relevance of published guidelines. The diagnostic-effectiveness of Duplex ultrasonography examinations to search for renal artery stenosis depends upon compliance with these guidelines.

Chair based exercise in community settings: a cluster randomised feasibility study.

BACKGROUND: Some older people who find standard exercise programmes too strenuous may be encouraged to exercise while remaining seated - chair based exercises (CBE). We previously developed a consensus CBE programme (CCBE) following a modified Delphi process. We firstly needed to test the feasibility and acceptability of this treatment approach and explore how best to evaluate it before undertaking a definitive trial. METHODS: A feasibility study with a cluster randomised controlled trial component was undertaken to 1. Examine the acceptability, feasibility and tolerability of the intervention and 2. Assess the feasibility of running a trial across 12 community settings (4 day centres, 4 care homes, 4 community groups). Centres were randomised to either CCBE, group reminiscence or usual care. Outcomes were collected to assess the feasibility of the trial parameters: level of recruitment interest and eligibility, randomisation, adverse events, retention, completion of health outcomes, missing data and delivery of the CCBE. Semi- structured interviews were conducted with participants and care staff following the intervention to explore acceptability. RESULTS: 48% (89 out of 184 contacted) of eligible centres were interested in participating with 12 recruited purposively. 73% (94) of the 128 older people screened consented to take part with 83 older people then randomised following mobility testing. Recruitment required greater staffing levels and resources due to 49% of participants requiring a consultee declaration. There was a high dropout rate (40%) primarily due to participants no longer attending the centres. The CCBE intervention was delivered once a week in day centres and community groups and twice a week in care homes. Older people and care staff found the CCBE intervention largely acceptable. CONCLUSION: There was a good level of interest from centres and older people and the CCBE intervention was largely welcomed. The trial design and governance procedures would need to be revised to maximise recruitment and retention. If the motivation for a future trial is physical health then this study has identified that further work to develop the CCBE delivery model is warranted to ensure it can be delivered at a frequency to elicit physiological change. If the motivation for a future trial is psychological outcomes then this study has identified that the current delivery model is feasible. TRIAL REGISTRATION: ISRCTN27271501 . Date registered: 30/01/2018.

Clinicopathological features of squamous cell carcinoma of the oral cavity and oropharynx in young patients.

Our aim was to examine the clinicopathological features of squamous cell carcinoma (SCC) of the oral cavity and oropharynx in a group of young patients who were dignosed during a 15-year period (2000-2014). Patients' clinical details, risk factors, and survival were obtained from medical records. Formalin-fixed, paraffin-embedded, tissue was tested for high-risk human papillomavirus (HPV). The results were compared with those of a matching group of older patients. We identified 91 patients who were younger than 45 years old, and the 50 youngest patients were studied in detail. The male:female ratio was 2:1, with more tumours located in the oral cavity than in the oropharynx (35 compared with 15). HPV-related SCC was restricted to the oropharynx. When matched for site, stage and HPV status, five-year overall survival was similar in young and matched older patients (log-rank test, p=0.515). Our findings suggest that young patients with oral SCC have a disease profile similar to that of older patients with the condition. It is plausible that prognostic information generally available for oral cancers is applicable to young patients with the disease.

The first 142 amino acids of glutamate decarboxylase do not contribute to epitopes recognized by autoantibodies associated with Type 1 diabetes.

AIMS: Glutamate decarboxylase (GAD) antibodies are the most widely used predictive marker for Type 1 diabetes, but many individuals currently found to be GAD antibody-positive are unlikely to develop diabetes. We have shown previously that radioimmunoassays using N-terminally truncated 35 S-GAD65 (96-585) offer better disease specificity with similar sensitivity to full-length 35 S-GAD65 (1-585). To determine whether assay performance could be improved further, we evaluated a more radically truncated 35 S-GAD65 (143-585) radiolabel. METHODS: Samples from people with recent-onset Type 1 diabetes (n = 157) and their first-degree relatives (n = 745) from the Bart's-Oxford family study of childhood diabetes were measured for GAD antibodies using 35 S-labelled GAD65 (143-585). These were screened previously using a local radioimmunoassay with 35 S-GAD65 (1-585). A subset was also tested by enzyme-linked immunosorbent assay (ELISA), which performs well in international workshops, but requires 10 times more serum. Results were compared with GAD antibody measurements using 35 S-GAD65 (1-585) and 35 S-GAD65 (96-585). RESULTS: Sensitivity of GAD antibody measurement was maintained using 35 S-GAD65 (143-585) compared with 35 S-GAD65 (1-585) and 35 S-GAD65 (96-585). Specificity for Type 1 diabetes was improved compared with 35 S-GAD65 (1-585), but was similar to 35 S-GAD65 (96-585). Relatives found to be GAD antibody-positive using these truncated labels were at increased risk of diabetes progression within 15 years, compared with those positive for GAD(1-585) antibody only, and at similar risk to those found GAD antibody-positive by ELISA. CONCLUSIONS: The first 142 amino acids of GAD65 do not contribute to epitopes recognized by Type 1 diabetes-associated GAD antibodies. Low-volume radioimmunoassays using N-terminally truncated 35 S-GAD65 are more specific than those using full-length GAD65 and offer practical alternatives to the GAD antibody ELISA for identifying children at increased risk of Type 1 diabetes.

A quarter of patients with type 1 diabetes have co-existing non-islet autoimmunity: the findings of a UK population-based family study.

Individuals with type 1 diabetes (T1D) are at increased risk of coeliac disease (CD), autoimmune thyroiditis and autoimmune gastritis, but the absolute risks are unclear. The aim of this study was to investigate the prevalence of autoantibodies to tissue transglutaminase (TGA), thyroid peroxidase (TPOA) and gastric H+ /K+ -ATPase (ATPA) and their genetic associations in a well-characterized population-based cohort of individuals with T1D from the Bart's-Oxford family study for whom islet autoantibody prevalence data were already available. Autoantibodies in sera from 1072 patients (males/females 604/468; median age 11·8 years, median T1D duration 2·7 months) were measured by radioimmunoassays; HLA class II risk genotype was analysed in 973 (91%) using polymerase chain reaction with sequence specific primers (PCR-SSP). The prevalence of TGA (and/or history of CD), TPOA and ATPA in patients was 9·0, 9·6 and 8·2%, respectively; 3·1% had two or more autoantibodies. Females were at higher risk of multiple autoimmunity; TGA/CD were associated with younger age and TPOA with older age. ATPA were uncommon in patients under 5 years, and more common in older patients. Anti-glutamate decarboxylase autoantibodies were predictive of co-existing TPOA/ATPA. TGA/CD were associated with human leucocyte antigen (HLA) DR3-DQ2, with the DR3-DQ2/DR3-DQ2 genotype conferring the highest risk, followed by DR4-DQ8/DR4-DQ8. ATPA were associated with DR3-DQ2, DRB1*0404 (in males) and the DR3-DQ2/DR4-DQ8 genotype. TPOA were associated with the DR3-DQ2/DR3-DQ2 genotype. Almost one-quarter of patients diagnosed with T1D aged under 21 years have at least one other organ-specific autoantibody. HLA class II genetic profiling may be useful in identifying those at risk of multiple autoimmunity.

Genotype by random environmental interactions gives an advantage to non-favored minor alleles.

Fixation probability, the probability that the frequency of a newly arising mutation in a population will eventually reach unity, is a fundamental quantity in evolutionary genetics. Here we use a number of models (several versions of the Moran model and the haploid Wright-Fisher model) to examine fixation probabilities for a constant size population where the fitness is a random function of both allelic state and spatial position, despite neither allele being favored on average. The concept of fitness varying with respect to both genotype and environment is important in models of cancer initiation and progression, bacterial dynamics, and drug resistance. Under our model spatial heterogeneity redefines the notion of neutrality for a newly arising mutation, as such mutations fix at a higher rate than that predicted under neutrality. The increased fixation probability appears to be due to rare alleles having an advantage. The magnitude of this effect can be large, and is an increasing function of the spatial variance and skew in fitness. The effect is largest when the fitness values of the mutants and wild types are anti-correlated across environments. We discuss results for both a spatial ring geometry of cells (such as that of a colonic crypt), a 2D lattice and a mass-action (complete graph) arrangement.

Exposure-Response Analysis of Necitumumab Efficacy in Squamous Non-Small Cell Lung Cancer Patients.

We sought to describe the exposure-response relationship of necitumumab efficacy in squamous non-small cell lung cancer patients and evaluate intrinsic and extrinsic patient descriptors that may guide dosing. SQUIRE was a phase III study comparing necitumumab in combination with gemcitabine and cisplatin vs. gemcitabine and cisplatin alone in 1,014 patients. An integrated model for tumor size dynamics and overall survival was developed, where reduction in tumor size results in a decrease in survival hazard. The change in tumor size was characterized using linear growth and first-order shrinkage. Overall survival was described using a combination of a Weibull function and Gompertz function for the hazard, with dynamic tumor size being a predictor for the hazard. Although body weight resulted in higher clearance and lower exposure, simulations showed that an 800 mg flat dose provided optimal response regardless of body weight.

A two phased study on health care professionals' perceptions of single or multi-use of intermittent catheters.

AIMS: This two phase study aimed to explore health care professionals' teaching and prescribing practice related to intermittent catheterisation and to identify their perceptions about the possible implementation of a mixed (single and multi-use) package for intermittent catheterization. INTRODUCTION: Single-use intermittent catheters are the norm in the UK although multi-use is common in some other countries. A recent Cochrane review found no difference in complications, including urinary tract infection rates, between those using single or multi-use catheters. A flexible option of both multi-use and single use intermittent catheters could provide users with more flexible choices in self-care. However, understanding health care professionals' perspectives is one of the keys to developing a multi-use intervention. DESIGN: A qualitative research framework using in-depth interviews to inform an on line survey. METHOD: In-depth interviews were conducted with health care professionals based in the UK who prescribe catheters, teach intermittent catheterisation or manage an intermittent catheterisation service. The interviewees were selected to represent a range of clinical areas, experience and professions - continence advisors, urology, multiple sclerosis (MS) and spinal cord injury specialist nurses, and General Practitioners. Following framework analysis the themes and factors identified were used to develop an on-line survey which was disseminated through health care professional networks whose members saw patients who use intermittent catheters. RESULTS: Nineteen health care professionals participated in the telephone interviews; 206 completed the survey. A wide range of professionals in terms of experience and specialty afforded rich information regarding the contextual issues around the teaching and prescribing of intermittent catheters. The primary finding was that health care professionals were concerned about 'minimising health risk' and maximising 'normalcy' for those using intermittent self-catheterisation. Health care professionals who worked in the acute setting or had no experience of re-use were most resistant to the re-use of catheters. Professionals requested evidence that a multi-use package would not increase the risk of developing a urinary tract infection or increase the burden of use to a patient before a mixed package would be considered. CONCLUSIONS: For multi-use to be acceptable, evidence based guidelines must be available for healthcare professionals and cleaning methods must be acceptable and safe for intermittent catheter users. Further evidence may be required to establish that a mixed catheter package is equivalent to single use only, particularly for outcomes such as urinary tract infection, urethral injury and quality of life. RELEVANCE TO CLINICAL PRACTICE: This paper highlights that if multi-use catheters are to be successfully introduced into clinical practice, the ease of use, safety and effectiveness of the cleaning technique will need to be convincingly demonstrated by a range of well-defined users.

Mitochondrial stress-induced p53 attenuates HIF-1α activity by physical association and enhanced ubiquitination.

Retrograde signaling is a mechanism by which mitochondrial dysfunction is communicated to the nucleus for inducing a metabolic shift essential for cell survival. Previously, we showed that partial mitochondrial DNA (mtDNA) depletion in different cell types induced mitochondrial retrograde signaling pathway (MtRS) involving Ca+2-sensitive Calcineurin (Cn) activation as an immediate upstream event of stress response. In multiple cell types, this stress signaling was shown to induce tumorigenic phenotypes in immortalized cells. In this study we show that MtRS also induces p53 expression, which was abrogated by Ca2+ chelators and short hairpin RNA-mediated knockdown of CnAß mRNA. Mitochondrial dysfunction induced by mitochondrial ionophore, carbonyl cyanide m-chlorophenyl hydrazone and other respiratory inhibitors, which perturb the transmembrane potential, were equally efficient in inducing the expression of p53 and downregulation of MDM2. Stress-induced p53 physically interacted with hypoxia-inducible factor-1α (HIF-1α) and attenuated the latter's binding to promoter DNA motifs. In addition, p53 promoted ubiquitination and degradation of HIF-1α in partial mtDNA-depleted cells. The mtDNA depleted cells, with inhibited HIF-1α, showed upregulation of glycolytic pathway genes, glucose transporter 1-4 (Glut1-4), phosphoglycerate kinase 1 and Glucokinase but not of prolyl hydroxylase isoforms. For the first time we show that p53 is induced as part of MtRS and it renders HIF-1α inactive by physical interaction. In this respect, our results show that MtRS induces tumor growth independent of the HIF-1α pathway.