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The effects of air pollution on health outcomes are well-established. However, little is known about perceptions of air pollution and how it may influence exercise behaviours. The aim of this study was to understand the perceived importance of air pollution during planned exercise, and where relevant, explore how those perceptions may differ between those living in different locations. A questionnaire was disseminated to several running and cycling clubs in the United Kingdom, covering population characteristics to determine urban, rural or coastal residents and exercisers, self-reported asthma, perceptions of air quality during active travel, planned exercise and attitudes towards learning more about the topic. Anonymised responses were gained from 381 adult participants (≥18 years and 60% female), 119 of whom answered questions related to active travel. More than half (54%) of all respondents think about the air quality they are exposed to during exercise and how it may affect their health. More urban than rural respondents (59% vs. 47% and p = 0.03) think about air quality and the impact it may have on their health when exercising. There were insufficient coastal respondents for direct comparison. Most survey respondents (57%) state that they would take the most severe course of action regarding exercise behaviour by avoiding it altogether during periods of heavy road traffic. Individuals with self-reported asthma (n = 60), irrespective of place of residence, are the most likely to be conscious of the potential effects of air pollution on their health and exercise performance compared to counterparts without self-reported asthma., (© 2024 The Author(s). European Journal of Sport Science published by Wiley‐VCH GmbH on behalf of European College of Sport Science.)

Objectives: To explore the acceptability and feasibility of detection of atrial fibrillation (AF) by emergency medical services (EMS) and identify potential barriers and facilitators to implementing a formal pathway to facilitate follow-up in primary care, which could reduce the risk of AF-related stroke., Design: Qualitative study using focus groups and one-to-one interviews guided by a semistructured topic guide., Setting: North East England., Participants: Focus groups with 18 members of the public and one-to-one online interviews with 11 healthcare and service providers (six paramedics and five experts representing cardiology, general practice (GP), public health, research, policy and commissioning)., Results: All participant groups were supportive of a role of EMS in identifying AF as part of routine assessment and formalising the response to AF detection. However, this should not create delays for EMS since rate-controlled AF is non-urgent and alternative community mechanisms exist to manage it. Public participants were concerned about communication of the AF diagnosis and whether this should be 'on scene' or in a subsequent GP appointment. Paramedics reported frequent incidental identification of AF, but it is not always clear 'on scene' that this is a new diagnosis, and there is variation in practice regarding whether (and how) this is communicated to the GP. Paramedics also focused on ensuring the safety of non-conveyed patients and a perceived need for an 'active' reporting process, so that a finding of AF was actioned. Field experts felt that a formal pathway would be useful and favoured a simple intervention without adding to time pressures unnecessarily., Conclusions: There is support for the development of a formal pathway to ensure follow-up for people with AF that is incidentally detected by EMS. This has the potential to improve anticoagulation rates and reduce the risk of stroke., Competing Interests: Competing interests: CW has previously held an unrestricted research grant from Bristol-Myers-Squibb, unrelated to this work. The other coauthors have nothing to declare., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Central venous access devices (CVADs) are commonly used for the treatment of paediatric cancer patients. Catheter locking is a routine intervention that prevents CVAD-associated adverse events, such as infection, occlusion and thrombosis. While laboratory and clinical data are promising, tetra-EDTA (T-EDTA) has yet to be rigorously evaluated or introduced in cancer care as a catheter lock., Methods and Analysis: This is a protocol for a two-arm, superiority type 1 hybrid effectiveness-implementation randomised controlled trial conducted at seven hospitals across Australia and New Zealand. Randomisation will be in a 3:2 ratio between the saline (heparinised saline and normal saline) and T-EDTA groups, with randomly varied blocks of size 10 or 20 and stratification by (1) healthcare facility; (2) CVAD type and (3) duration of dwell since insertion. Within the saline group, there will be a random allocation between normal and heparin saline. Participants can be re-recruited and randomised on insertion of a new CVAD. Primary outcome for effectiveness will be a composite of CVAD-associated bloodstream infections (CABSI), CVAD-associated thrombosis or CVAD occlusion during CVAD dwell or at removal. Secondary outcomes will include CABSI, CVAD-associated-thrombosis, CVAD failure, incidental asymptomatic CVAD-associated-thrombosis, other adverse events, health-related quality of life, healthcare costs and mortality. To achieve 90% power (alpha=0.05) for the primary outcome, data from 720 recruitments are required. A mixed-methods approach will be employed to explore implementation contexts from the perspective of clinicians and healthcare purchasers., Ethics and Dissemination: Ethics approval has been provided by Children's Health Queensland Hospital and Health Service Human Research Ethics Committee (HREC) (HREC/22/QCHQ/81744) and the University of Queensland HREC (2022/HE000196) with subsequent governance approval at all sites. Informed consent is required from the substitute decision-maker or legal guardian prior to participation. In addition, consent may also be obtained from mature minors, depending on the legislative requirements of the study site. The primary trial and substudies will be written by the investigators and published in peer-reviewed journals. The findings will also be disseminated through local health and clinical trial networks by investigators and presented at conferences., Trial Registration Number: ACTRN12622000499785., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The objective of this systematic literature review (SLR) was to summarize the latest studies evaluating the burden of illness in endogenous Cushing's syndrome (CS), including the impact of CS on overall and domain-specific health-related quality of life (HRQoL) and the economic burden of CS to provide a holistic understanding of disease and treatment burden., Methods: An SLR was conducted in PubMed, MEDLINE and Embase using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist to identify peer-reviewed manuscripts and conference abstracts published in English from 2015 to December 4, 2020., Results: Forty-five publications were eligible for inclusion; data were extracted from 37 primary studies while 8 SLRs were included for reference only. Thirty-one studies reported HRQoL using validated patient reported outcome (PRO) measures in pre- or post-surgery, radiotherapy and pharmacotherapy patients. Overall, this SLR found that patients with CS have worse outcomes relative to healthy populations across specific dimensions, such as depression, despite an improvement in HRQoL post-treatment. These findings reveal that CS symptoms are not fully resolved by the existing care paradigm. Few studies report on the economic burden of CS and currently available data indicate a high direct healthcare system cost burden., Conclusions: Patients with CS experience a significant, complex and multifactorial HRQoL burden. Symptom-specific burden studies are sparse in the literature and the understanding of long-term CS symptomatic burden and economic burden is limited. This review intends to provide an updated reference for clinicians, payers and other stakeholders on the burden of CS as reported in published literature and to encourage further research in this area., (© 2023 The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.)

Paediatric palliative care is pivotal for addressing the complex needs of children with incurable diseases and their families. While home-based care offers a familiar and supportive environment, delivering comprehensive services in this context is challenging. The existing literature on home-based palliative care lacks detailed guidance for its organization and implementation. This qualitative narrative inquiry explores the organization and provision of home-based paediatric palliative care. Data were collected from healthcare practitioners using conversations, storytelling, and reflective journaling. Schwind's Narrative Reflective Process was applied to synthesize the data, resulting in an in-depth case description. The narrative approach illuminates the complexities of home-based paediatric palliative, end-of-life, and after-death care. Key findings encompass the importance of early-care coordination, interprofessional collaboration, effective symptom management, emotional and psychosocial support, and comprehensive end-of-life planning. Through the case study of the child patient, the challenges and strategies for providing holistic, family-centred care within the home environment are described. Practical insights gained from this report can inform the development and improvement of home-based palliative care programs, benefiting researchers, practitioners, and policymakers seeking to optimize care for children and families in similar contexts.

Objective: The objective of this scoping review is to map, from wound assessment tools and other literature, the current methods used to assess wound odour in order to answer the following question: Which methods of assessment, validated or otherwise, are currently used in wound assessment tools to assess wound odour? Introduction: Wound assessment includes not only details of the condition of the wound bed but also evaluation of symptoms associated with the wound including that of odour. Odour is cited by clinicians, patients and carers as one of the most distressing wound symptoms. However, there is no consensus on a preferred method to assess odour thus negatively impacting the internal and external validity of many clinical trials and minimising the ability to perform meta-analysis. Eligibility criteria: Any wound assessment tool or framework that includes assessment of wound odour in any wound aetiology and in any care setting. Any systematic or scoping review that includes assessment of wound odour in any wound aetiology and in any care setting. No limits on date of publication or language will be applied. Methods: We will employ the Preferred Reporting Items for Systematic Review and Meta-Analyses extension for scoping reviews (PRISMA-ScR) guidelines for this scoping review and base its structure on the framework proposed by Arksey and O'Malley. Results: A narrative format will summarise extracted data and provide an overview of tools used to assess wound odour. A PRISMA diagram will outline the results of the search strategy. The identified tools will be summarised in table format and stratified according to methods used. Conclusion: The result of this scoping review will be a list of methods used to assess odour in wounds and will be used to inform a subsequent Delphi study to gain consensus on the preferred method to assess wound odour., Competing Interests: Competing interests: BMcG has received consultancy/advisory board honoraria from Novartis and UCB. No more competing interests are declared., (Copyright: © 2023 Gethin G et al.)

In newborn screening, false-negative results can be disastrous, leading to disability and death, while false-positive results contribute to parental anxiety and unnecessary follow-ups. Cutoffs are set conservatively to prevent missed cases for Pompe and MPS I, resulting in increased falsepositive results and lower positive predictive values. Harmonization has been proposed as a way to minimize false-negative and false-positive results and correct for method differences, so we harmonized enzyme activities for Pompe and MPS I across laboratories and testing methods (Tandem Mass Spectrometry (MS/MS) or Digital Microfluidics (DMF)). Participating states analyzed proofof- concept calibrators, blanks, and contrived specimens and reported enzyme activities, cutoffs, and other testing parameters to Tennessee. Regression and multiples of the median were used to harmonize the data. We observed varied cutoffs and results. Six of seven MS/MS labs reported enzyme activities for one specimen for MPS I marginally above their respective cutoffs with results classified as negative, whereas all DMF labs reported this specimen's enzyme activity below their respective cutoffs with results classified as positive. Reasonable agreement in enzyme activities and cutoffs was achieved with harmonization; however, harmonization does not change how a value would be reported as this is dependent on the placement of cutoffs.

Objective: The chronic complications of ageing with HIV are not well studied in sub-Saharan Africa (SSA) where general healthcare resources are limited. We aimed to collaborate with individuals living with HIV aged ≥ 50 years, and community elders (aged ≥ 60 years) living with non-communicable diseases in the Kilimanjaro region of Tanzania in a health research priority-setting exercise., Methods: We conducted structured workshops based on broad questions to aid discussion and group-based patient priority setting, alongside discussion of the feasibility of future community research engagement. Participant priorities were tallied and ranked to arrive at core priorities from consensus discussion., Results: Thirty older people living with HIV and 30 community elders attended separate priority setting workshops. Both groups reported motivation to participate in, conduct, and oversee future studies. In this resource-limited setting, basic needs such as healthcare access were prioritised much higher than specific HIV-complications or chronic disease. Stigma and social isolation were highly prioritised in those living with HIV., Conclusions: Community engagement and involvement in HIV and ageing research appears feasible in Tanzania. Ageing and non-communicable disease research should consider the wider context, and lack of basic needs in low-income settings. A greater impact may be achieved with community involvement., (© 2023. The Author(s).)

Advancements in technology and communication have revolutionised the twenty-first century with the introduction of mobile phones and smartphones. These phones are known to be platforms harbouring microbes with recent research shedding light on the abundance and broad spectrum of organisms they harbour. Mobile phone use in the community and in professional sectors including health care settings is a potential source of microbial dissemination. To identify the diversity of microbial genetic signature present on mobile phones owned by hospital medical staff. Twenty-six mobile phones of health care staff were swabbed. DNA extraction for downstream next generation sequencing shotgun metagenomic microbial profiling was performed. Survey questionnaires were handed to the staff to collect information on mobile phone usage and users' behaviours. Each of the 26 mobile phones of this study was contaminated with microbes with the detection of antibiotic resistance and virulent factors. Taken together the sum of microbes and genes added together across all 26 mobile phones totalised 11,163 organisms (5714 bacteria, 675 fungi, 93 protists, 228 viruses, 4453 bacteriophages) and 2096 genes coding for antibiotic resistance and virulent factors. The survey of medical staff showed that 46% (12/26) of the participants used their mobile phones in the bathroom. Mobile phones are vectors of microbes and can contribute to microbial dissemination and nosocomial diseases worldwide. As fomites, mobile phones that are not decontaminated may pose serious risks for public health and biosecurity., (© 2022. The Author(s).)

Background: The number of people living with dementia worldwide is increasing, particularly in low- and middle-income countries (LMICs) where little is known about existing post-diagnostic care and support. This study aimed to better understand healthcare provision for people living with dementia in Malaysia, and to identify priorities for providing timely, quality, and accessible care and support to all. Methods: This is a qualitative interview study on care providers and facilitators (health and community care professionals, paid carers, traditional medicine practitioners, faith healers, community leaders, non-governmental organisations). A topic guide, piloted in Malaysia and peer reviewed by all LMIC partners, elicited the understanding of dementia and dementia care and barriers and facilitators to care for people living with dementia and carers, and perceptions of key priorities for developing efficient, feasible, and sustainable dementia care pathways. Verbatim transcription of audio-recorded interviews was followed by iterative, thematic data analysis. Results: Twenty interviews were conducted (11 healthcare professionals, 4 traditional medicine practitioners, and 5 social support providers). The findings indicate that dementia care and support services exist in Malaysia, but that they are not fully utilised because of variations in infrastructure and facilities across the country. Despite a locally recognised pathway of care being available in an urban area, people with dementia still present to the healthcare system with advanced disease. The interviewees linked this to a public perception that symptoms of dementia, in particular, are normal sequelae of ageing. Earlier detection of dementia is commonly opportunistic when patients present to GPs, government clinic staff, and general physicians with other ailments. Dementia may only be identified by practitioners who have some specialist interest or expertise in it. Workforce factors that hindered early identification and management of dementia included lack of specialists, overburdened clinics, and limited knowledge of dementia and training in guideline use. Post-diagnostic social care was reported to be largely the domain of families, but additional community-based support was reported to be available in some areas. Raising awareness for both the public and medical professionals, prevention, and more support from the government are seen as key priorities to improve dementia management. Conclusions: This qualitative study provides novel insight into the availability, delivery, and use of post-diagnostic care and support in Malaysia from the perspective of care providers. The respondents in this study perceived that while there was a provision for dementia care in the hospital and community settings, the different care sectors are largely unaware of the services each provides. Future work should explore how care provision across different service sectors and providers can be supported to better facilitate patient access and referral between primary, secondary, and social care. The importance of supporting families to understand dementia and its progression, and strategies to help them care for relatives was emphasised. There is also a need for broad workforce training and development, at both the postgraduate and undergraduate levels, as well as improved general awareness in the community to encourage earlier help-seeking for symptoms of dementia. This will enable the use of preventive strategies and access to specialist services to optimise care and quality of life for people living with dementia in Malaysia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Goodson, McLellan, Rosli, Tan, Kamaruzzaman, Robinson and Moloney.)

Objective: To determine the extent to which care received by Australian children presenting with croup is in agreement with Clinical Practice Guidelines (CPGs)., Design: Retrospective population-based sample survey. Croup clinical indicators were derived from CPGs., Data Sources/study Setting: Medical records from three healthcare settings were sampled for selected visits in 2012 and 2013 in three Australian states., Data Collection: Data were collected by nine experienced paediatric nurses, trained to assess eligibility for indicator assessment and adherence to CPGs. Surveyors undertook criterion-based medical record reviews using an electronic data collection tool., Results: Documented guideline adherence was lower for general practitioners (65.9%; 95% CI: 60.8-70.6) than emergency departments (91.1%; 95% CI: 89.5-92.5) and inpatient admissions (91.3%; 95% CI: 88.1-93.9). Overall adherence was very low for a bundle of 10 indicators related to assessment (4.5%; 95% CI: 2.4-7.6) but higher for a bundle of four indicators relating to the avoidance of inappropriate therapy (83.1%; 95% CI: 59.5-96.0)., Conclusions: Most visits for croup were characterized by appropriate treatment in all healthcare settings. However, most children had limited documented clinical assessments, and some had unnecessary tests or inappropriate therapy, which has potential quality and cost implications. Universal CPG and clinical assessment tools may increase clinical consistency., (© The Author(s) 2019. Published by Oxford University Press in association with the International Society for Quality in Health Care. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Acute hypoxaemic respiratory failure (AHRF) in children is the most frequent reason for non-elective hospital admission. During the initial phase, AHRF is a clinical syndrome defined for the purpose of this study by an oxygen requirement and caused by pneumonia, lower respiratory tract infections, asthma or bronchiolitis. Up to 20% of these children with AHRF can rapidly deteriorate requiring non-invasive or invasive ventilation. Nasal high-flow (NHF) therapy has been used by clinicians for oxygen therapy outside intensive care settings to prevent escalation of care. A recent randomised trial in infants with bronchiolitis has shown that NHF therapy reduces the need to escalate therapy. No similar data is available in the older children presenting with AHRF. In this study we aim to investigate in children aged 1 to 4 years presenting with AHRF if early NHF therapy compared with standard-oxygen therapy reduces hospital length of stay and if this is cost-effective compared with standard treatment., Methods and Analysis: The study design is an open-labelled randomised multicentre trial comparing early NHF and standard-oxygen therapy and will be stratified by sites and into obstructive and non-obstructive groups. Children aged 1 to 4 years (n=1512) presenting with AHRF to one of the participating emergency departments will be randomly allocated to NHF or standard-oxygen therapy once the eligibility criteria have been met (oxygen requirement with transcutaneous saturation <92%/90% (dependant on hospital standard threshold), diagnosis of AHRF, admission to hospital and tachypnoea ≥35 breaths/min). Children in the standard-oxygen group can receive rescue NHF therapy if escalation is required. The primary outcome is hospital length of stay. Secondary outcomes will include length of oxygen therapy, proportion of intensive care admissions, healthcare resource utilisation and associated costs. Analyses will be conducted on an intention-to-treat basis., Ethics and Dissemination: Ethics approval has been obtained in Australia (HREC/15/QRCH/159) and New Zealand (HDEC 17/NTA/135). The trial commenced recruitment in December 2017. The study findings will be submitted for publication in a peer-reviewed journal and presented at relevant conferences. Authorship of all publications will be decided by mutual consensus of the research team., Trial Registration Number: ACTRN12618000210279., Competing Interests: Competing interests: DF, SG, AS and SD received travel support from Fisher and Paykel Healthcare. All other authors have no conflicts to disclose. Fisher and Paykel have provided equipment and consumables for the study but have had no input in the study design., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Bronchiolitis is the most common reason for hospital admission in infants, with one third requiring oxygen therapy due to hypoxemia. It is unknown what proportion of hypoxemic infants with bronchiolitis can be managed with nasal high-flow in room air and their resulting outcomes. Objectives and Settings: To assess the effect of nasal high-flow in room air in a subgroup of infants with bronchiolitis allocated to high-flow therapy in a recent multicenter randomized controlled trial. Patients and Interventions: Infants allocated to the high-flow arm of the trial were initially treated with room air high-flow if saturations were ≥85%. Subsequently, if oxygen saturations did not increase to ≥92%, oxygen was added and FiO 2 was titrated to increase the oxygen saturations. In this planned sub-study, infants treated during their entire hospital stay with high-flow room air only were compared to infants receiving either standard-oxygen or high-flow with oxygen. Baseline characteristics, hospital length of stay and length of oxygen therapy were compared. Findings: In the per protocol analysis 64 (10%) of 630 infants commenced on high-flow room air remained in room air only during the entire stay in hospital. These infants on high-flow room air were on average older and presented with moderate hypoxemia at presentation to hospital. Their length of respiratory support and length of stay was also significantly shorter. No pre-enrolment factors could be identified in a multivariable analysis. Conclusions: In a small sub-group of hypoxemic infants with bronchiolitis hypoxemia can be reversed with the application of high-flow in room air only. Trial registration: ACTRN12615001305516., (Copyright © 2019 Franklin, Babl, Gibbons, Pham, Hasan, Schlapbach, Oakley, Craig, Furyk, Neutze, Moloney, Gavranich, Shirkhedkar, Kapoor, Grew, Fraser, Dalziel, Schibler and PARIS and PREDICT.)

Background: Children with chronic health conditions have better health-related outcomes when their care is managed in a personalised and coordinated way. However, increased demand on Australian ambulatory care hospital services has led to longer waitlist times to access specialists and appropriate intervention services; placing vulnerable children at increased risk of poorer short-term (e.g. social difficulties) and long-term (e.g. convictions) health and social outcomes. Traditional approaches to increasing frequency and service of delivery are expensive and can have minimal impact on caregiver burden. A community based service-integration approach, rather than self-directed care is proposed as increased service linkages are more likely to occur and improve the health outcomes of children with a chronic health condition., Methods: An open, unblinded, multi-centre randomised controlled trial in two Australian public hospitals. 112 children (0-16 years) fulfilling the inclusion criteria will be randomised to one of two clinical pathways for management of their chronic health condition: (1) integrated children's care clinic (ICCC) or (2) self-directed care pathway. All children and caregivers will be interviewed at 1 week, and 3, 6 and 12 month time intervals. Primary outcome measures include the Pediatric Quality of Life (PedQOL) questionnaire, Subjective Units of Distress Scale, Child Behaviour Checklist (CBCL) and Rotter's Locus of Control Scale. Secondary outcome measures include the total number of medical appointments, school days missed and quantity of services accessed. Our main objectives are to determine if the ICCC results in better health and economics outcomes compared to the self-directed care pathway., Discussion: The success of a health systems approach needs to be balanced against clinical, mortality and cost-effectiveness data for long-term sustainability within a publicly funded health system. A clinical pathway that is sustainable, cost-effective, provides efficient evidence-based care and improves the quality of life outcomes for children with chronic health conditions has the potential to reduce waitlist times, improve access to health services, increase consumer satisfaction; and prevent costs associated with poorly managed chronic health conditions into adulthood. This study will be the first to provide clinical and health economics data on an integrated care pathway for the management of chronic health conditions in children. On a broader scale, results from this study will help guide care coordination frameworks for children with chronic health conditions; particularly with the introduction and implementation of a National Disability Insurance Scheme (NDIS) across Australia., Trial Registration: Australia and New Zealand Clinical Trials Register (ANZCTR) ACTRN12617001188325 . Registered: 14th August, 2017.

Mycotoxin induced hepatoxocity has been linked to oxidative stress, resulting from either an increase in levels of reactive oxygen species (ROS) above normal levels and/or the suppression of antioxidant protective pathways. However, few detailed molecular studies of mycotoxicoses in animals have been carried out. This study use current RNA-seq based approaches to investigate the effects of mycotoxin exposure in a ruminant model. Having first assembled a de novo reference transcriptome, we use RNA-Seq technology to define in vivo hepatic gene expression changes resulting from mycotoxin exposure in relationship to pathological effect. As expected, characteristic oxidative stress related gene expression is markedly different in animals exhibiting poorer outcomes. However, expression of multiple genes critical for detoxification, particularly members of the cytochrome P450 gene family, was significantly higher in animals exhibiting mycotoxin tolerance ('resistance'). Further, we present novel evidence for the amplification of Wnt signalling pathway activity in 'resistant' animals, resulting from the marked suppression of multiple key Wnt inhibitor genes. Notably, 'resistance' may be determined primarily by the ability of an individual to detoxify secondary metabolites generated by the metabolism of mycotoxins and the potentiation of Wnt signalling may be pivotal to achieving a favourable outcome upon challenge.

Six submicroscopic deletions comprising chromosome band 2q23.1 in patients with severe mental retardation (MR), short stature, microcephaly and epilepsy have been reported, suggesting that haploinsufficiency of one or more genes in the 2q23.1 region might be responsible for the common phenotypic features in these patients. In this study, we report the molecular and clinical characterisation of nine new 2q23.1 deletion patients and a clinical update on two previously reported patients. All patients were mentally retarded with pronounced speech delay and additional abnormalities including short stature, seizures, microcephaly and coarse facies. The majority of cases presented with stereotypic repetitive behaviour, a disturbed sleep pattern and a broad-based gait. These features led to the initial clinical impression of Angelman, Rett or Smith-Magenis syndromes in several patients. The overlapping 2q23.1 deletion region in all 15 patients comprises only one gene, namely, MBD5. Interestingly, MBD5 is a member of the methyl CpG-binding domain protein family, which also comprises MECP2, mutated in Rett's syndrome. Another gene in the 2q23.1 region, EPC2, was deleted in 12 patients who had a broader phenotype than those with a deletion of MBD5 only. EPC2 is a member of the polycomb protein family, involved in heterochromatin formation and might be involved in causing MR. Patients with a 2q23.1 microdeletion present with a variable phenotype and the diagnosis should be considered in mentally retarded children with coarse facies, seizures, disturbed sleeping patterns and additional specific behavioural problems.

The p53 tumor suppressor plays a major role in preventing tumor development by transactivating genes to remove or repair potentially tumorigenic cells. Here we show that the Y-box-binding protein, YB1, acts as a negative regulator of p53. Using reporter assays we show that YB1 represses transcription of the p53 promoter in a sequence-specific manner. We also show that YB1 reduces endogenous levels of p53, which in turn reduces p53 activity. Conversely, inhibiting YB1 in a variety of tumor cell lines induces p53 activity, resulting in significant apoptosis via a p53-dependent pathway. These data suggest that YB1 may, in some situations, protect cells from p53-mediated apoptosis, indicating that YB1 may be a good target for the development of new therapeutics.

Human skin penetration of N-dimethylnitrosamine (DMN) from three vehicles has been determined in vitro. When applied as an infinite dose in isopropyl myristate (IPM, 1 microgram/microliter) the average total absorption over 48 hr was 2.6 +/- 1.2% of the applied dose (all data presented are expressed as means +/- standard errors). When applied as a finite dose in a representative oil-in-water emulsion vehicle the average total absorption over 48 hr was 4.0 +/- 0.3% of the applied dose. When applied as a finite dose in a representative shampoo vehicle for 10 min followed by rinsing (i.e. to represent in-use exposure conditions) the average total absorption over 48 hr was 1.1 +/- 0.1% of the applied dose. Approximately 72% of the DMN in the applied shampoo vehicle was removed by rinsing. There was considerable evaporative loss of DMN from the IPM and oil-in-water emulsion vehicles, such that absorption was complete within 3 hr of application. The overall data indicate that DMN can penetrate the skin rapidly but that in practice the amount actually available for penetration is significantly reduced by high permeant volatility. In contrast, application of N-nitrosodiethanolamine (NDELA) at a concentration of 1 microgram/microliter as an infinite dose generated an average total absorption over 48 hr of 23.6 +/- 6.4%, representing a total flux of 103.9 +/- 28.4 micrograms/cm2. In the case of NDELA, no evaporative loss was evident.