Selective acceptance of acute whiplash guidelines: a qualitative analysis of perceptions of health professionals in Australia.

PURPOSE: To explore health professionals' acceptance of the guidelines for acute whiplash associated disorders (WAD), and to identify barriers and facilitators to adherence. MATERIALS AND METHODS: Qualitative descriptive study involving focus group discussions among health professionals who treat people with WAD in primary and secondary care settings in New South Wales and Queensland, Australia. Twenty-eight health professionals (physiotherapists = 19; chiropractors = 6; osteopaths = 3) participated in six semi-structured focus group discussions that were held in independent offices in Sydney and Brisbane, Australia between September and December 2015. Discussions were audio recorded and verbatim, de-identified transcripts produced. Thematic analysis was conducted using an inductive approach to identify commonly held beliefs. RESULTS: Acceptance of guideline recommendations appeared to be influenced by factors related to the guideline itself, practitioner and practice characteristics, and patient-related factors. Specifically, acceptance was hindered by conflicting belief systems, ambiguity in guideline recommendations, and patient characteristics and expectations. CONCLUSIONS: Practitioners demonstrated a positive attitude towards the use of the guidelines in general; however, in some cases, acceptance of key recommendations appeared selective. Future guideline revision and implementation might focus on explaining the underlying principles of the guidelines, providing more detailed recommendations, and involving strategies that challenge inconsistent beliefs and promote informed decision-making. IMPLICATIONS FOR REHABILITATIONSelective acceptance of guideline recommendations in favour of those not requiring practice change may present a challenge for the implementation of evidence-based practice in the management of whiplash.Participants demonstrated variable, sometimes polar attitudes to guideline key messages and recommendations.Guideline developers need to focus more strongly on changing practitioner beliefs and attitudes, as well as better explaining the underlying principles of the guidelines, and providing more detailed recommendations.

"It made you feel like you've still got it": experiences of people with chronic low back pain undertaking a single session of body image training in virtual reality.

INTRODUCTION: Embodying fit avatars in virtual reality (VR) is proposed as a possible treatment for cortical body representations and pain-related self-perceptions. OBJECTIVE: To explore consumer perceptions of a novel VR intervention (VR-BiT) for chronic low back pain. METHODS: Adults (n = 17, mean age(SD) = 52(14)) with chronic low back pain who had undergone a single session of VR-BiT as part of a randomized controlled trial underwent a semi-structured interview using open-ended questions. Interviews were audio-recorded, transcribed verbatim, and analyzed thematically. RESULTS: Data reduction identified four themes: clinically beneficial and beyond; helping and hindering use; desire for more; and individualized future. Participants experienced wide ranging effects, including improved physical self-efficacy, pain, ability to perform physical activity and psychological symptoms. The intervention was well tolerated, except for two reports of nausea, and a few participants indicating pain associated with unaccustomed movement. Most participants were motivated to use VR-BiT again, despite some having technical issues. Participants suggested that personalizing VR-BiT and regular use would be beneficial. CONCLUSIONS: There was strong consumer support for further use of VR-BiT. Future studies of VR-BiT effectiveness are warranted and should consider incorporating individual user preferences, including people with diverse pain presentations, and involving a multi-session design.

A randomized controlled pilot study examining immediate effects of embodying a virtual reality superhero in people with chronic low back pain.

PURPOSE: In virtual reality, avatar embodiment can spur perceptions and behaviours related the avatars' characteristics. We tested whether embodying superhero-like avatars can change self-perceptions in people with chronic low back pain (CLBP). DESIGN: A non-blinded pilot randomized controlled trial. METHODS: Participants were randomly allocated to embody a superhero (VR-SH, n = 20) or a neutral, non-superhero (VR-Play, n = 10) avatar. Primary outcomes related to body image (e.g., self-perceived vulnerability) and pain intensity were assessed at baseline, during exposure, immediately after and at one-week follow-up. Fear of movement, strength and patient impression of change were also recorded. RESULTS: The VR-SH group reported gains in body image during (p < .001, Î·p2=0.71) and immediately after (p < .001, Î·p2=0.66) VR, whereas the VR-Play group reported small gains during VR (p = .021, Î·p2=0.46) but not immediately after (p = .076, ηp2=0.31). Pain, strength and fear of movement did not change and there were no sustained effects at follow-up (all ps > .05). A greater proportion of people in the VR-SH group reported at least minimal improvement at follow-up (7/20 vs. 1/10). CONCLUSION: A VR-SH session produced temporary positive effects on body image. Future research may consider whether larger and sustained effects can be obtained with multisession exposures or explore combined interventions. Implications for rehabilitationPhysical confidence and bodily trust can be significantly enhanced in people with chronic back pain using virtual reality.These positive body image effects may have implications for rehabilitation, such as in enhancing confidence with movementWhether a multisession intervention might produce more robust effects and changes in pain is yet to be determined.

Carbon Catabolite Repression Governs Diverse Physiological Processes and Development in Aspergillus nidulans.

Carbon catabolite repression (CCR) is a common phenomenon of microorganisms that enable efficient utilization of carbon nutrients, critical for the fitness of microorganisms in the wild and for pathogenic species to cause infection. In most filamentous fungal species, the conserved transcription factor CreA/Cre1 mediates CCR. Previous studies demonstrated a primary function for CreA/Cre1 in carbon metabolism; however, the phenotype of creA/cre1 mutants indicated broader roles. The global function and regulatory mechanism of this wide-domain transcription factor has remained elusive. Here, we applied two powerful genomics methods (transcriptome sequencing and chromatin immunoprecipitation sequencing) to delineate the direct and indirect roles of Aspergillus nidulans CreA across diverse physiological processes, including secondary metabolism, iron homeostasis, oxidative stress response, development, N-glycan biosynthesis, unfolded protein response, and nutrient and ion transport. The results indicate intricate connections between the regulation of carbon metabolism and diverse cellular functions. Moreover, our work also provides key mechanistic insights into CreA regulation and identifies CreA as a master regulator controlling many transcription factors of different regulatory networks. The discoveries for this highly conserved transcriptional regulator in a model fungus have important implications for CCR in related pathogenic and industrial species. IMPORTANCE The ability to scavenge and use a wide range of nutrients for growth is crucial for microorganisms' survival in the wild. Carbon catabolite repression (CCR) is a transcriptional regulatory phenomenon of both bacteria and fungi to coordinate the expression of genes required for preferential utilization of carbon sources. Since carbon metabolism is essential for growth, CCR is central to the fitness of microorganisms. In filamentous fungi, CCR is mediated by the conserved transcription factor CreA/Cre1, whose function in carbon metabolism has been well established. However, the global roles and regulatory mechanism of CreA/Cre1 are poorly defined. This study uncovers the direct and indirect functions of CreA in the model organism Aspergillus nidulans over diverse physiological processes and development and provides mechanistic insights into how CreA controls different regulatory networks. The work also reveals an interesting functional divergence between filamentous fungal and yeast CreA/Cre1 orthologues.

An Interactive Website for Whiplash Management (My Whiplash Navigator): Process Evaluation of Design and Implementation.

BACKGROUND: Whiplash is a health and economic burden worldwide. Contributing to this burden is poor guideline adherence and variable management by health care professionals (HCPs). Web-based tools that facilitate clinical pathways of care are an innovative solution to improve management. OBJECTIVE: The study aimed to develop, implement, and evaluate a Web-based tool to support whiplash management following a robust process. METHODS: This study followed the first 3 processes of a research translation framework (idea generation, feasibility, and efficacy) to inform the development, implementation, and evaluation of a website that supports HCPs in whiplash management. Development followed the idea generation and feasibility processes to inform the content, design, features, and functionality of the website. This involved stakeholder (eg, industry partners, website developers, and HCPs) consultations through face-to-face meetings, surveys, and focus group discussions. Implementation followed the feasibility process to determine the practicality of the website for clinical use and the most effective strategy to promote wider uptake. Implementation strategies included classroom education, educational meetings, educational outreach, reminders, and direct phone contact. The analysis of website use and practicality of implementation involved collection of website metrics. Evaluation followed the feasibility and efficacy processes to investigate the acceptability and extent to which the website assisted HCPs in gaining knowledge about whiplash management. Surveys were conducted among student, primary, and specialist HCPs to explore ease of access, use, and satisfaction with the website, as well as self-rated improvements in knowledge of risk assessment, management, and communication between HCPs. Website logs of specialist management decisions (eg, shared care, specialist care, and referred care) were also obtained to determine actual practice. RESULTS: The development process delivered an interactive, user-friendly, and acceptable website, My Whiplash Navigator, tailored to the needs of HCPs. A total of 260 registrations were recorded from June 2016 to March 2018, including 175 student, 65 primary, and 20 specialist HCPs. The most effective implementation strategies were classroom education for students (81% uptake, 175/215) and educational meetings for primary HCPs (43% uptake, 47/110). Popular pages visited included advice and exercises and risk assessment. Most HCPs agreed that their knowledge about risk management (79/97, 81%) and exercises (85/97, 88%) improved. The specialists' most common management decision was shared care, an improvement from a previous cohort. Areas to improve were navigation and access to outcome measures. CONCLUSIONS: A robust process resulted in an innovative, interactive, user-friendly, and acceptable website, the My Whiplash Navigator. Implementation with HCPs was best achieved through classroom education and educational meetings. Evaluation of the website showed improved knowledge and practice to be more consistent with a risk-based clinical care pathway for whiplash. The positive results provide sufficient evidence to scale implementation nationally and involve other target markets such as people with whiplash, insurers, and insurance regulators.

Agreement is very low between a clinical prediction rule and physiotherapist assessment for classifying the risk of poor recovery of individuals with acute whiplash injury.

BACKGROUND: A prognostic clinical prediction rule (whiplash CPR) has been validated for use in individuals with acute whiplash associated disorders (WAD). The clinical utility of this tool is unknown. OBJECTIVES: To investigate: 1) the level of agreement between physiotherapist- and whiplash CPR-determined prognostic risk classification of people with acute WAD; 2) which clinical findings are used by physiotherapists to classify prognostic risk; and 3) whether physiotherapists plan to differ the number of treatment sessions provided based on prognostic risk classification. DESIGN: Pragmatic, observational. METHOD: 38 adults with acute WAD were classified as low, medium, or high risk of poor recovery by their treating physiotherapist (n = 24) at the conclusion of the initial consultation. A weighted Cohen's kappa examined the agreement between physiotherapist estimated risk classification and the whiplash CPR. Physiotherapists' reasons for classification were provided and summarised descriptively. Kruskal-Wallis and post-hoc Dunn's tests compared projected number of treatment sessions between risk subgroups. RESULTS: Physiotherapist agreement with the whiplash CPR occurred in 29% of cases (n = 11/38), which was less than what is expected by chance (K = -0.03; 95%CI -0.17 to 0.12). Physiotherapists most frequently considered range of movement (n = 23/38, 61%), a premorbid pain condition (n = 14/38, 37%), response to initial physiotherapy treatment (n = 12/38, 32%), and pain intensity (n = 12/38, 32%) when classifying prognostic risk. The projected number of treatment sessions was not different between risk groups using classifications provided by the physiotherapists (χ2(2) = 2.69, p = 0.26). CONCLUSIONS: Physiotherapists should consider incorporating the whiplash CPR into current assessment processes to enhance accuracy in prognostic decision-making.

Are HCAHPS Scores Higher for Private vs Double-Occupancy Inpatient Rooms in Total Joint Arthroplasty Patients?

BACKGROUND: Private hospital rooms have a number of potential advantages compared to shared rooms, including reduced noise and increased control over the hospital environment. However, the association of room type with patient experience metrics in total joint arthroplasty (TJA) patients is currently unclear. METHODS: For private versus shared rooms, we compared our institutional Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) scores in patients who underwent primary TJA over a 2-year period. Regression model odds ratios (ORs) were adjusted for surgeon, date of surgery, and length of stay. RESULTS: Patients in private rooms were more likely to report a top-box score for overall hospital rating (85.6% vs 79.4%, OR = 1.53, P = .011), hospital recommendation (89.3% vs 83.0%, OR = 1.78, P = .002), call button help (76.0% vs 68.7%, OR = 1.40, P = .028), and quietness (70.4% vs 59.0%, OR = 1.78, P < .001). There were no significant differences on surgeon metrics including listening (P = .225), explanations (P = .066), or treatment with courtesy and respect (P = .396). CONCLUSION: For patients undergoing TJA, private hospital rooms were associated with superior performance on patient experience metrics. This association appears specific for global and hospital-related metrics, with little impact on surgeon evaluations. With the utilization of HCAHPS data in value-based initiatives, placement of TJA patients in private rooms may lead to increased reimbursement and higher hospital rankings. LEVEL OF EVIDENCE: Level III, retrospective cohort.

Physiotherapist-delivered Stress Inoculation Training for acute whiplash-associated disorders: A qualitative study of perceptions and experiences.

BACKGROUND: Formally trained and accredited physiotherapists delivered Stress Inoculation Training (SIT) integrated with guideline-based physiotherapy management to individuals with acute whiplash associated disorders (WAD) as part of a randomised controlled trial. The delivery of SIT by physiotherapists is new. OBJECTIVES: To investigate physiotherapists' perspectives on delivering SIT as part of the trial and in routine practice. DESIGN: Qualitative descriptive. METHOD: Physiotherapists (n = 11) participated in semi-structured interviews. Interviews were audio-recorded, transcribed verbatim, and analysed thematically. Findings were triangulated against an audit of physiotherapists' adherence to the SIT protocol. RESULTS: Three themes were identified: perceived value; capacity to deliver; and adaptation and implementation. Physiotherapists' saw value in SIT in that they perceived the program to have improved patient outcomes, enhanced their therapeutic alliance, and provided new skills to manage psychological contributors to WAD. Physiotherapists' capacity to deliver the program was facilitated through the development of confidence in their ability to deliver sessions, viewing SIT as falling within their current professional identity, and having confidence in their ability to manage mismatches in patients' expectations of care. All physiotherapists reported having used SIT to some extent in routine practice, by selectively delivering sessions and/or integrating the content with other management. Physiotherapists were able to deliver SIT as was intended (94.6% adherence). CONCLUSIONS: Physiotherapists' supported adding SIT to usual management of individuals with acute WAD. Education on SIT principles is recommended during pre-professional training to facilitate future implementation.

Referral to specialist physiotherapists in the management of whiplash associated disorders: Perspectives of healthcare practitioners.

BACKGROUND: Guidelines for whiplash associated disorders (WAD) recommend early referral to specialists (e.g. specialist physiotherapists) of people who are not recovering. This recommendation is a key component of a proposed clinical pathway of care for WAD. OBJECTIVE: To explore healthcare practitioners' opinions about referral to specialist physiotherapists of people with WAD at high risk of non-recovery. DESIGN: Qualitative descriptive study. METHODS: Six focus groups were conducted among primary care allied-health practitioners (n = 16) and specialist physiotherapists (n = 12) in New South Wales and Queensland, Australia. Discussions were audio recorded and transcribed for thematic analysis. RESULTS: Ten themes were generated from analysis. Practitioners appeared to have good knowledge of indicators for referral; however, referrals were often made to the medical practitioner, less commonly to specialist physiotherapists. There was general support for referral to specialist physiotherapists, which was deemed as a viable alternative for people who are not recovering. Practitioners, however, had differing views about the attributes of a specialist physiotherapist and referral timeframe. A number of factors have been identified to influence the referral process and practitioners expressed specific expectations of the desired outcomes of referral as well as considerations for specialist management approaches. There was strong support for a collaborative approach in management that involved the referring practitioner. CONCLUSION: Results support the feasibility of referral to specialist physiotherapists despite limited uptake in practice and recognised barriers to referral. These findings have implications for further study and adopting strategies to facilitate effective implementation and translation of the proposed pathway into primary care practice.

A eukaryotic nicotinate-inducible gene cluster: convergent evolution in fungi and bacteria.

Nicotinate degradation has hitherto been elucidated only in bacteria. In the ascomycete Aspergillus nidulans, six loci, hxnS/AN9178 encoding the molybdenum cofactor-containing nicotinate hydroxylase, AN11197 encoding a Cys2/His2 zinc finger regulator HxnR, together with AN11196/hxnZ, AN11188/hxnY, AN11189/hxnP and AN9177/hxnT, are clustered and stringently co-induced by a nicotinate derivative and subject to nitrogen metabolite repression mediated by the GATA factor AreA. These genes are strictly co-regulated by HxnR. Within the hxnR gene, constitutive mutations map in two discrete regions. Aspergillus nidulans is capable of using nicotinate and its oxidation products 6-hydroxynicotinic acid and 2,5-dihydroxypyridine as sole nitrogen sources in an HxnR-dependent way. HxnS is highly similar to HxA, the canonical xanthine dehydrogenase (XDH), and has originated by gene duplication, preceding the origin of the Pezizomycotina. This cluster is conserved with some variations throughout the Aspergillaceae. Our results imply that a fungal pathway has arisen independently from bacterial ones. Significantly, the neo-functionalization of XDH into nicotinate hydroxylase has occurred independently from analogous events in bacteria. This work describes for the first time a gene cluster involved in nicotinate catabolism in a eukaryote and has relevance for the formation and evolution of co-regulated primary metabolic gene clusters and the microbial degradation of N-heterocyclic compounds.

Tactile acuity testing at the neck: A comparison of methods.

BACKGROUND: Interest in measurement of tactile acuity in musculoskeletal practice has emerged following its link to functional reorganization of the somatosensory cortex in ongoing pain states. Several tactile acuity measurement methods have been described but have not been thoroughly investigated in the cervical region. OBJECTIVE: This study examined reliability, concurrent validity and responsiveness of four tests of tactile acuity-Two-point discrimination, Point-to-point, Graphesthesia, and Localisation tests-at the cervical region. METHOD: Forty-two healthy participants were included. In Part 1 (n = 22), participants' tactile acuity was assessed at two time points, 30 min apart, to determine the test-retest reliability and concurrent validity of each of the tests. In Part 2 (n = 20), participants received five daily tactile training sessions, delivered via a vibro-tactile device. Tactile acuity was assessed pre- and post-training to examine responsiveness of each test. RESULTS: Two-point discrimination demonstrated excellent test-retest reliability (ICC = 0.85, SEM = 3.7 mm), Point-to-point and Localisation tests demonstrated good reliability (ICC = 0.60, SEM = 2.8 mm; ICC = 0.60, SEM = 8.8%), and Graphesthesia demonstrated fair reliability (ICC = 0.48, SEM = 1.9/20). There was no significant correlation among measures. Only Graphesthesia failed to show responsiveness to change following training. CONCLUSION: The reliability of Two-point discrimination appears superior to other examined tests of tactile acuity, however measurement variability should be considered. Two-point discrimination, Point-to-point, and Localisation tests appear responsive to change, although testing in clinical samples is needed. The lack of concurrent validity among tests suggests that they cannot be used interchangeably.

Health practitioners' perceptions of adopting clinical prediction rules in the management of musculoskeletal pain: a qualitative study in Australia.

OBJECTIVES: To investigate health practitioners' understanding and practice behaviours with regards to clinical prediction rules (CPRs) and explore their perceptions of adopting a new whiplash CPR. DESIGN: Qualitative study using six semistructured focus groups. SETTING: Primary and secondary care in New South Wales and Queensland, Australia. PARTICIPANTS: Physiotherapists (n=19), chiropractors (n=6) and osteopaths (n=3) were purposively sampled to include health practitioners who provide routine treatment to people with whiplash-associated disorders. METHODS: Focus group discussions (n=6) were audio-recorded, transcribed verbatim and analysed using an inductive thematic approach. RESULTS: Health practitioners' understanding and use of CPRs were mixed. Clinicians considered components relating to acceptability ('whether I agree with it') and implementation ('how I'll use it') when deciding on whether to adopt a new CPR. Acceptability was informed by four themes: knowledge and understanding, CPR type, congruence and weighted value. Consideration of matters that promote implementation occurred once a CPR was deemed to be acceptable. Three themes were identified as potentially enhancing whiplash CPR implementation: the presence of an external driver of adoption, flexibility in how the CPR could be administered and guidance regarding communication of CPR output to patients. CONCLUSIONS: Education on CPR purpose and fit with practice is needed to enhance the perceived acceptability of CPRs. Strategies that facilitate practitioner motivation, enable administrative flexibility and assist clinicians in communicating the results of the whiplash CPR could promote adoption of the whiplash CPR.

The CreB deubiquitinating enzyme does not directly target the CreA repressor protein in Aspergillus nidulans.

Ubiquitination/deubiquitination pathways are now recognized as key components of gene regulatory mechanisms in eukaryotes. The major transcriptional repressor for carbon catabolite repression in Aspergillus nidulans is CreA, and mutational analysis led to the suggestion that a regulatory ubiquitination/deubiquitination pathway is involved. A key unanswered question is if and how this pathway, comprising CreB (deubiquitinating enzyme) and HulA (ubiquitin ligase) and other proteins, is involved in the regulatory mechanism. Previously, missense alleles of creA and creB were analysed for genetic interactions, and here we extended this to complete loss-of-function alleles of creA and creB, and compared morphological and biochemical phenotypes, which confirmed genetic interaction between the genes. We investigated whether CreA, or a protein in a complex with it, is a direct target of the CreB deubiquitination enzyme, using co-purifications of CreA and CreB, first using strains that overexpress the proteins and then using strains that express the proteins from their native promoters. The Phos-tag system was used to show that CreA is a phosphorylated protein, but no ubiquitination was detected using anti-ubiquitin antibodies and Western analysis. These findings were confirmed using mass spectrometry, which confirmed that CreA was differentially phosphorylated but not ubiquitinated. Thus, CreA is not a direct target of CreB, and nor are proteins that form part of a stable complex with CreA a target of CreB. These results open up new questions regarding the molecular mechanism of CreA repressing activity, and how the ubiquitination pathway involving CreB interacts with this regulatory network.

Proteins interacting with CreA and CreB in the carbon catabolite repression network in Aspergillus nidulans.

In Aspergillus nidulans, carbon catabolite repression (CCR) is mediated by the global repressor protein CreA. The deubiquitinating enzyme CreB is a component of the CCR network. Genetic interaction was confirmed using a strain containing complete loss-of-function alleles of both creA and creB. No direct physical interaction was identified between tagged versions of CreA and CreB. To identify any possible protein(s) that may form a bridge between CreA and CreB, we purified both proteins from mycelia grown in media that result in repression or derepression. The purified proteins were analysed by LC/MS and identified using MaxQuant and Mascot databases. For both CreA and CreB, 47 proteins were identified in repressing and derepressing conditions. Orthologues of the co-purified proteins were identified in S. cerevisiae and humans. Gene ontology analyses of A. nidulans proteins and yeast and human orthologues were performed. Functional annotation analysis revealed that proteins that preferentially interact with CreA in repressing conditions include histones and histone transcription regulator 3 (Hir3). Proteins interacting with CreB tend to be involved in cellular transportation and organization. Similar findings were obtained using yeast and human orthologues, although the yeast background generated a number of other biological processes involving Mig1p which were not present in the A. nidulans or human background analyses. Hir3 was present in repressing conditions for CreA and in both growth conditions for CreB, suggesting that Hir3, or proteins interacting with Hir3, could be a possible target of CreB.

Clinical prediction rules for prognosis and treatment prescription in neck pain: A systematic review.

Clinical prediction rules (CPRs) developed to identify sub-groups of people with neck pain for different prognoses (i.e. prognostic) or response to treatments (i.e. prescriptive) have been recommended as a research priority to improve health outcomes for these conditions. A systematic review was undertaken to identify prognostic and prescriptive CPRs relevant to the conservative management of adults with neck pain and to appraise stage of development, quality and readiness for clinical application. Six databases were systematically searched from inception until 4th July 2016. Two independent reviewers assessed eligibility, risk of bias (PEDro and QUIPS), methodological quality and stage of development. 9840 records were retrieved and screened for eligibility. Thirty-two studies reporting on 26 CPRs were included in this review. Methodological quality of included studies varied considerably. Most prognostic CPR development studies employed appropriate designs. However, many prescriptive CPR studies (n = 12/13) used single group designs and/or analysed controlled trials using methods that were inadequate for identifying treatment effect moderators. Most prognostic (n = 11/15) and all prescriptive (n = 11) CPRs have not progressed beyond the derivation stage of development. Four prognostic CPRs relating to acute whiplash (n = 3) or non-traumatic neck pain (n = 1) have undergone preliminary validation. No CPRs have undergone impact analysis. Most prognostic and prescriptive CPRs for neck pain are at the initial stage of development and therefore routine clinical use is not yet supported. Further validation and impact analyses of all CPRs are required before confident conclusions can be made regarding clinical utility.

Role of HxkC, a mitochondrial hexokinase-like protein, in fungal programmed cell death.

Apoptosis is a form of programmed cell death (PCD) that occurs during animal development and is also triggered by a variety of signals including nutrient or oxidative stress, hypoxia, DNA damage, viral infection and oncogenic transformation. Though apoptotic-like PCD also occurs in plants and fungi, genes encoding several of the key players in mammalian apoptosis (p53 and BH-domain proteins) have not been identified in these kingdoms. In this report we investigated whether HxkC, a mitochondrial hexokinase-like protein, and XprG, a putative p53-like transcription factor similar to Ndt80, play a role in programmed cell death in the filamentous fungus Aspergillus nidulans. We show that a mutant lacking HxkC is more sensitive to oxidative stress. Autolysis, a form of fungal programmed cell death triggered by carbon starvation, is accelerated in the hxkCΔ1 mutant but not the hxkCΔ1 xprGΔ1 double mutant. In the absence of nutrient stress, the hxkCΔ1 mutant displays XprG-dependent DNA fragmentation typical of apoptosis and elevated levels of intracellular protease. HxkC and XprG are required for catabolism of N-acetylglucosamine, as in Trichoderma reesei. We show that XprG is present in the nucleus. We conclude that, like mammalian mitochondrial hexokinase, HxkC has anti-apoptotic activity and the XprG transcription factor has a pro-apoptotic role in filamentous fungi.

The CreB deubiquitinating enzyme does not directly target the CreA repressor protein in Aspergillus nidulans.

Ubiquitination/deubiquitination pathways are now recognized as key components of gene regulatory mechanisms in eukaryotes. The major transcriptional repressor for carbon catabolite repression in Aspergillus nidulans is CreA, and mutational analysis led to the suggestion that a regulatory ubiquitination/deubiquitination pathway is involved. A key unanswered question is if and how this pathway, comprising CreB (deubiquitinating enzyme) and HulA (ubiquitin ligase) and other proteins, is involved in the regulatory mechanism. Previously, missense alleles of creA and creB were analysed for genetic interactions, and here we extended this to complete loss-of-function alleles of creA and creB, and compared morphological and biochemical phenotypes, which confirmed genetic interaction between the genes. We investigated whether CreA, or a protein in a complex with it, is a direct target of the CreB deubiquitination enzyme, using co-purifications of CreA and CreB, first using strains that overexpress the proteins and then using strains that express the proteins from their native promoters. The Phos-tag system was used to show that CreA is a phosphorylated protein, but no ubiquitination was detected using anti-ubiquitin antibodies and Western analysis. These findings were confirmed using mass spectrometry, which confirmed that CreA was differentially phosphorylated but not ubiquitinated. Thus, CreA is not a direct target of CreB, and nor are proteins that form part of a stable complex with CreA a target of CreB. These results open up new questions regarding the molecular mechanism of CreA repressing activity, and how the ubiquitination pathway involving CreB interacts with this regulatory network.

The European Cancer Patient's Bill of Rights, update and implementation 2016.

In this implementation phase of the European Cancer Patient's Bill of Rights (BoR), we confirm the following three patient-centred principles that underpin this initiative:The right of every European citizen to receive the most accurate information and to be proactively involved in his/her care.The right of every European citizen to optimal and timely access to a diagnosis and to appropriate specialised care, underpinned by research and innovation.The right of every European citizen to receive care in health systems that ensure the best possible cancer prevention, the earliest possible diagnosis of their cancer, improved outcomes, patient rehabilitation, best quality of life and affordable health care. The key aspects of working towards implementing the BoR are:Agree our high-level goal. The vision of 70% long-term survival for patients with cancer in 2035, promoting cancer prevention and cancer control and the associated progress in ensuring good patient experience and quality of life.Establish the major mechanisms to underpin its delivery. (1) The systematic and rigorous sharing of best practice between and across European cancer healthcare systems and (2) the active promotion of Research and Innovation focused on improving outcomes; (3) Improving access to new and established cancer care by sharing best practice in the development, approval, procurement and reimbursement of cancer diagnostic tests and treatments.Work with other organisations to bring into being a Europe based centre that will (1) systematically identify, evaluate and validate and disseminate best practice in cancer management for the different countries and regions and (2) promote Research and Innovation and its translation to maximise its impact to improve outcomes.

Gender Differences in Physical Activity Levels of Older People With Type 2 Diabetes Mellitus.

BACKGROUND: Physical activity (PA) is important in managing Type 2 Diabetes Mellitus (T2DM). This study aimed to determine 1) the number of daily steps taken by older people with T2DM, 2) if T2DM is associated with taking fewer steps per day and less likelihood of meeting PA guidelines, and 3) whether these associations are modified by age or gender. METHODS: PA was obtained by pedometer from 2 cohorts of older adults with and without T2DM. Multivariable regression was used to determine associations between T2DM, mean steps per day and meeting a guideline equivalent (7 100 steps per day). RESULTS: There were 293 participants with T2DM (mean age 67.6 ± 6.8 years) and 336 without T2DM (mean age 72.1 ± 7.1 years). In women, T2DM was associated with fewer mean steps per day (ß = -1306.4; 95% CI -2052.5, -560.3; P = .001) and not meeting the PA guidelines (OR 0.51; 95% CI 0.28, 0.92; P = .03). Associations were not significant in men (P > .05). Only 29.7% of those with T2DM and 33.3% of those without T2DM met PA guidelines. CONCLUSIONS: Greater focus is needed on how to maintain and increase PA in older age with particular focus on women with T2DM.

A second component of the SltA-dependent cation tolerance pathway in Aspergillus nidulans.

The transcriptional response to alkali metal cation stress is mediated by the zinc finger transcription factor SltA in Aspergillus nidulans and probably in other fungi of the pezizomycotina subphylum. A second component of this pathway has been identified and characterized. SltB is a 1272 amino acid protein with at least two putative functional domains, a pseudo-kinase and a serine-endoprotease, involved in signaling to the transcription factor SltA. Absence of SltB activity results in nearly identical phenotypes to those observed for a null sltA mutant. Hypersensitivity to a variety of monovalent and divalent cations, and to medium alkalinization are among the phenotypes exhibited by a null sltB mutant. Calcium homeostasis is an exception and this cation improves growth of sltΔ mutants. Moreover, loss of kinase HalA in conjunction with loss-of-function sltA or sltB mutations leads to pronounced calcium auxotrophy. sltA sltB double null mutants display a cation stress sensitive phenotype indistinguishable from that of single slt mutants showing the close functional relationship between these two proteins. This functional relationship is reinforced by the fact that numerous mutations in both slt loci can be isolated as suppressors of poor colonial growth resulting from certain null vps (vacuolar protein sorting) mutations. In addition to allowing identification of sltB, our sltB missense mutations enabled prediction of functional regions in the SltB protein. Although the relationship between the Slt and Vps pathways remains enigmatic, absence of SltB, like that of SltA, leads to vacuolar hypertrophy. Importantly, the phenotypes of selected sltA and sltB mutations demonstrate that suppression of null vps mutations is not dependent on the inability to tolerate cation stress. Thus a specific role for both SltA and SltB in the VPS pathway seems likely. Finally, it is noteworthy that SltA and SltB have a similar, limited phylogenetic distribution, being restricted to the pezizomycotina subphylum. The relevance of the Slt regulatory pathway to cell structure, intracellular trafficking and cation homeostasis and its restricted phylogenetic distribution makes this pathway of general interest for future investigation and as a source of targets for antifungal drugs.