Long read sequencing reveals novel isoforms and insights into splicing regulation during cell state changes.

BACKGROUND: Alternative splicing is a key mechanism underlying cellular differentiation and a driver of complexity in mammalian neuronal tissues. However, understanding of which isoforms are differentially used or expressed and how this affects cellular differentiation remains unclear. Long read sequencing allows full-length transcript recovery and quantification, enabling transcript-level analysis of alternative splicing processes and how these change with cell state. Here, we utilise Oxford Nanopore Technologies sequencing to produce a custom annotation of a well-studied human neuroblastoma cell line SH-SY5Y, and to characterise isoform expression and usage across differentiation. RESULTS: We identify many previously unannotated features, including a novel transcript of the voltage-gated calcium channel subunit gene, CACNA2D2. We show differential expression and usage of transcripts during differentiation identifying candidates for future research into state change regulation. CONCLUSIONS: Our work highlights the potential of long read sequencing to uncover previously unknown transcript diversity and mechanisms influencing alternative splicing.

Cellular calcium in bipolar disorder: systematic review and meta-analysis.

Calcium signalling has long been implicated in bipolar disorder, especially by reports of altered intracellular calcium ion concentrations ([Ca2+]). However, the evidence has not been appraised critically. We carried out a systematic review and meta-analysis of studies of cellular calcium indices in bipolar disorder. 2281 records were identified and 117 screened, of which 32 were eligible and 21 were suitable for meta-analyses. The latter each involved up to 642 patients and 404 control subjects. We found that basal free intracellular [Ca2+] is increased in bipolar disorder, both in platelets and in lymphocytes. The effect size is 0.55, with an estimated elevation of 29%. It is observed in medication-free patients. It is present in mania and bipolar depression, but data are equivocal for euthymia. Cells from bipolar disorder individuals also show an enhanced [Ca2+] response to stimulation with 5-HT or thrombin, by an estimated 25%, with an effect size of 0.63. In studies which included other diagnoses, intracellular basal [Ca2+] was higher in bipolar disorder than in unipolar depression, but not significantly different from schizophrenia. Functional parameters of cellular Ca2+ (e.g. calcium transients), and neuronal [Ca2+], have been much less investigated, and no firm conclusions can be drawn. In summary, there is a robust, medium effect size elevation of basal and stimulated free intracellular [Ca2+] in bipolar disorder. The results suggest altered calcium functioning in the disorder, and encourage further investigations into the underlying mechanisms, and the implications for pathophysiology and therapeutics.

Neurological consultation with an autistic patient.

Autism is a neurodevelopmental condition with a very heterogeneous presentation. Autistic people are more likely to have unmet healthcare needs, making it essential that healthcare professionals are 'autism-aware'. In this article, we provide an overview of how autism presents and use case studies to illustrate how a neurological consultation in an outpatient clinic environment could prove challenging for a autistic person. We suggest how to improve communication with autistic patients in clinic and highlight the importance of a patient-centred and flexible approach.

Long-read sequencing reveals the complex splicing profile of the psychiatric risk gene CACNA1C in human brain.

RNA splicing is a key mechanism linking genetic variation with psychiatric disorders. Splicing profiles are particularly diverse in brain and difficult to accurately identify and quantify. We developed a new approach to address this challenge, combining long-range PCR and nanopore sequencing with a novel bioinformatics pipeline. We identify the full-length coding transcripts of CACNA1C in human brain. CACNA1C is a psychiatric risk gene that encodes the voltage-gated calcium channel CaV1.2. We show that CACNA1C's transcript profile is substantially more complex than appreciated, identifying 38 novel exons and 241 novel transcripts. Importantly, many of the novel variants are abundant, and predicted to encode channels with altered function. The splicing profile varies between brain regions, especially in cerebellum. We demonstrate that human transcript diversity (and thereby protein isoform diversity) remains under-characterised, and provide a feasible and cost-effective methodology to address this. A detailed understanding of isoform diversity will be essential for the translation of psychiatric genomic findings into pathophysiological insights and novel psychopharmacological targets.

Extending alcohol brief advice into non-clinical community settings: a qualitative study of experiences and perceptions of delivery staff.

BACKGROUND: At a population level, the majority of alcohol-related harm is attributable to drinkers whose consumption exceeds recommended drinking levels, rather than those with severe alcohol dependency. Identification and Brief Advice (IBA) interventions offer a cost-effective approach for reducing this harm. Traditionally, IBA interventions have been delivered in healthcare settings and therefore contextual influences on their use in non-clinical settings are not well understood. METHODS: Qualitative face-to-face and telephone interviews with staff responsible for delivering a pilot IBA intervention across community settings in the UK. Interviews were recorded and transcribed verbatim. Inductive thematic analysis was used to identify key issues and the constant comparison method was employed to compare barriers and facilitators to implementation across and within settings. RESULTS: A number of facilitators and barriers to delivery and implementation was identified across settings. These included familiarity with the customer base, working within public spaces, and assimilation of the intervention within existing role boundaries. Despite underlying concerns relating to the sensitive nature of the topic, most delivery staff felt their respective settings were appropriate for the delivery of the intervention and had proactively engaged members of the public with varying levels of risky drinking and readiness for behaviour change. Perceptions of actual or potential intervention success were conceptualised in relation to existing day-to-day role boundaries and responsibilities and the contexts in which they took place. CONCLUSIONS: Findings support the potential value of multi-setting community approaches to facilitate more inclusive engagement with IBA. By comparing experiences and views from staff responsible for delivering the intervention across different community settings, our findings provide insight into how intervention acceptability and success are framed across settings, and how the intervention is assimilated within everyday practice and role boundaries. This study also highlights key areas to be addressed when implementing IBAs in non-clinical community settings by staff with diverse levels of health-related knowledge, skills and support needs. Although essential, the need for adaptable training and delivery approaches across different setting types is likely to result in methodological challenges that need to be addressed when evaluating future interventions and setting-specific influences on behaviour change and health outcomes.

The researchers' role in knowledge translation: a realist evaluation of the development and implementation of diagnostic pathways for cancer in two United Kingdom localities.

BACKGROUND: In examining an initiative to develop and implement new cancer diagnostic pathways in two English localities, this paper evaluates 'what works' and examines the role of researchers in facilitating knowledge translation amongst teams of local clinicians and policy-makers. METHODS: Using realist evaluation with a mixed methods case study approach, we conducted documentary analysis of meeting minutes and pathway iterations to map pathway development. We interviewed 14 participants to identify the contexts, mechanisms and outcomes (CMOs) that led to successful pathway development and implementation. Interviews were analysed thematically and four CMO configurations were developed. RESULTS: One site produced three fully implemented pathways, while the other produced two that were partly implemented. In explaining the differences, we found that a respected, independent, well-connected leader modelling partnership working and who facilitates a local, stable group that agree about the legitimacy of the data and project (context) can empower local teams to become sufficiently autonomous (mechanism) to develop and implement research-based pathways (outcome). Although both teams designed relevant, research-based cancer pathways, in the site where the pathways were successfully implemented the research team merely assisted, while, in the other, the research team drove the initiative. CONCLUSION: Based on our study findings, local stakeholders can apply local and research knowledge to develop and implement research-based pathways. However, success will depend on how academics empower local teams to create autonomy. Crucially, after re-packaging and translating research for local circumstances, identifying fertile environments with the right elements for implementation and developing collaborative relationships with local leaders, academics must step back.

Symptoms and patient factors associated with longer time to diagnosis for colorectal cancer: results from a prospective cohort study.

BACKGROUND: The objective of this study is to investigate symptoms, clinical factors and socio-demographic factors associated with colorectal cancer (CRC) diagnosis and time to diagnosis. METHODS: Prospective cohort study of participants referred for suspicion of CRC in two English regions. Data were collected using a patient questionnaire, primary care and hospital records. Descriptive and regression analyses examined associations between symptoms and patient factors with total diagnostic interval (TDI), patient interval (PI), health system interval (HSI) and stage. RESULTS: A total of 2677 (22%) participants responded; after exclusions, 2507 remained. Participants were diagnosed with CRC (6.1%, 56% late stage), other cancers (2.0%) or no cancer (91.9%). Half the cohort had a solitary first symptom (1332, 53.1%); multiple first symptoms were common. In this referred population, rectal bleeding was the only initial symptom more frequent among cancer than non-cancer cases (34.2% vs 23.9%, P=0.004). There was no evidence of differences in TDI, PI or HSI for those with cancer vs non-cancer diagnoses (median TDI CRC 124 vs non-cancer 138 days, P=0.142). First symptoms associated with shorter TDIs were rectal bleeding, change in bowel habit, 'feeling different' and fatigue/tiredness. Anxiety, depression and gastro-intestinal co-morbidities were associated with longer HSIs and TDIs. Symptom duration-dependent effects were found for rectal bleeding and change in bowel habit. CONCLUSIONS: Doctors and patients respond less promptly to some symptoms of CRC than others. Healthcare professionals should be vigilant to the possibility of CRC in patients with relevant symptoms and mental health or gastro-intestinal comorbidities.

Attitudes and beliefs of non-participants in a population-based screening programme for colorectal cancer.

BACKGROUND: Uptake of colorectal cancer screening programmes needs to be improved or at least maintained in order to achieve projected reductions in mortality and morbidity. Understanding the origins of non-participation in screening is therefore important. OBJECTIVE: To explore the beliefs and experiences of individuals who had not responded either to their screening invitation or reminder. DESIGN: A qualitative study using in-depth interviews with non-participants from England's population-based colorectal cancer screening programme. Data collection and analysis were carried out using a grounded theory approach, with an emphasis on the constant comparison method, and continued until saturation (27 interviews). FINDINGS: The interviews provided an in-depth understanding of a range of reasons and circumstances surrounding non-participation in screening, including contextual and environmental influences as well as factors specific to the screening test. Non-participation in screening was not necessarily associated with negative attitudes towards screening or a decision to not return a kit. Reasons for non-participation in screening included not feeling that participation is personally necessary, avoiding or delaying decision making, and having some degree of intention to take part but failing to do so because of practicalities, conflicting priorities or external circumstances. Beliefs, awareness and intention change over time. DISCUSSION AND CONCLUSIONS: A range of approaches may be required to improve screening uptake. Some non-participants may already have a degree of intention to take part in screening in the future, and this group may be more responsive to interventions based on professional endorsement, repeat invitations, reminders and aids to making the test more practical.

A qualitative exploration of the use of calendar landmarking instruments in cancer symptom research.

BACKGROUND: Late diagnosis is considered to be a major factor contributing to poorer cancer survival rates in the UK. Interventions have focussed on the promotion of earlier diagnosis in patients with potential cancer symptoms. However, to assess the effectiveness of these interventions, the time from symptom onset to presentation needs to be reliably and accurately measured. This qualitative study explored the use of calendar landmarking instruments in cancer symptom research. METHODS: We performed a secondary analysis of transcripts of interviews using the calendar landmarking instrument, undertaken with patients who had either been diagnosed with cancer (n = 40, IRCO study, Western Australia), or who had symptoms suggestive of cancer (n = 38, SYMPTOM study, North East and Eastern England). We used constant comparison methods to identify use of the calendar landmarking instruments and the impact of their application. RESULTS: The calendar landmarking instrument appeared to help many patients, either by acting as a prompt or helping to refine recall of events. A combination of personal (e.g. birthday) and national (e.g. Christmas) landmarks seemed to be the most effective. Calendar landmarking instruments appeared more useful where the time period between onset of symptoms and date of first consultation was less than three months. The interviewee's age, gender and cancer type did not appear to influence whether or not the instrument facilitated recall, and there were no instances where the use of the instrument resulted in the disclosure of a new first symptom. Symptoms of similar chronic conditions could create difficulties when applying the instrument; it was difficult for these participants to characterise and disentangle their symptoms which prompted their decisions to seek help. Some participants tended to prefer to use their own, already personalised, diaries to assist in their recall of events. CONCLUSIONS: This study is the first to describe the potential role of calendar landmarking instruments to support research interviews which explore symptoms and events along the cancer diagnostic pathway. The major challenge remains as to whether they actually improve accuracy of recall.

Intentional and inadvertent non-adherence in adult coeliac disease. A cross-sectional survey.

Adherence to a gluten-free diet is the mainstay of treatment for coeliac disease. Non-adherence is common as the diet is restrictive and can be difficult to follow. This study aimed to determine the rates of intentional and inadvertent non-adherence in adult coeliac disease and to examine the factors associated with both. A self-completion questionnaire was mailed to adult coeliac patients identified from the computer records of 31 family practices within the North East of England. We received 287 responses after one reminder. Intentional gluten consumption was reported by 115 (40%) of respondents. 155 (54%) had made at least one known mistaken lapse over the same period and 82 (29%) reported neither intentional nor mistaken gluten consumption. Using logistic regression analysis, low self-efficacy, perceptions of tolerance to gluten and intention were found to be independently predictive of intentional gluten consumption. A statistical model predicted 71.8% of cases reporting intentional lapses. Intentional non-adherence to the GFD was found to be common but not as frequent as inadvertent lapses. Distinguishing the factors influencing both intentional and inadvertent non-adherence is useful in understanding dietary self-management in coeliac disease.

Providing care for children with tracheostomies: a qualitative interview study with parents and health professionals.

OBJECTIVES: To explore the experience of caring for children with tracheostomies from the perspectives of parents and health professional caregivers. DESIGN: Qualitative semistructured interview study. SETTING: One region in England covered by a tertiary care centre that includes urban and remote rural areas and has a high level of deprivation. PARTICIPANTS: A purposive sample of health professionals and parents who care for children who have, or have had, tracheostomies and who received care at the tertiary care centre. INTERVENTION: Interviews undertaken by telephone or video link. PRIMARY AND SECONDARY OUTCOME MEASURES: Qualitative reflexive thematic analysis with QSR Nvivo 12. RESULTS: This paper outlines key determinants and mediators of the experiences of caregiving and the impact on psychological and physical health and quality of life of parents and their families, confidence of healthcare providers and perceived quality of care. For parents, access to care packages and respite care at home as well as communication and relationships with healthcare providers are key mediators of their experience of caregiving, whereas for health professionals, an essential influence is multidisciplinary team working and support. We also highlight a range of challenges focused on the shared care space, including: a lack of standardisation in access to different support teams, care packages and respite care, irregular training and updates, and differences in health provider expertise and experiences across departments and shift patterns, exacerbated in some settings by limited contact with children with tracheostomies. CONCLUSIONS: Understanding the experiences of caregiving can help inform measures to support caregivers and improve quality standards. Our findings suggest there is a need to facilitate further standardisation of care and support available for parent caregivers and that this may be transferable to other regions. Potential solutions to be explored could include the development of a paediatric tracheostomy service specification, increasing use of paediatric tracheostomy specialist nurse roles, and addressing the emotional and psychological support needs of caregivers.

An Artificial Neural Network for Nasogastric Tube Position Decision Support.

Purpose: To develop and validate a deep learning model for detection of nasogastric tube (NGT) malposition on chest radiographs and assess model impact as a clinical decision support tool for junior physicians to help determine whether feeding can be safely performed in patients (feed/do not feed). Materials and Methods: A neural network ensemble was pretrained on 1 132 142 retrospectively collected (June 2007-August 2019) frontal chest radiographs and further fine-tuned on 7081 chest radiographs labeled by three radiologists. Clinical relevance was assessed on an independent set of 335 images. Five junior emergency medicine physicians assessed chest radiographs and made feed/do not feed decisions without and with artificial intelligence (AI)-generated NGT malposition probabilities placed above chest radiographs. Decisions from the radiologists served as ground truths. Model performance was evaluated using receiver operating characteristic analysis. Agreement between junior physician and radiologist decision was determined using the Cohen κ coefficient. Results: In the testing set, the ensemble achieved area under the receiver operating characteristic curve values of 0.82 (95% CI: 0.78, 0.86), 0.77 (95% CI: 0.71, 0.83), and 0.98 (95% CI: 0.96, 1.00) for satisfactory, malpositioned, and bronchial positions, respectively. In the clinical evaluation set, mean interreader agreement for feed/do not feed decisions among junior physicians was 0.65 ± 0.03 (SD) and 0.77 ± 0.13 without and with AI support, respectively. Mean agreement between junior physicians and radiologists was 0.53 ± 0.05 (unaided) and 0.65 ± 0.09 (AI-aided). Conclusion: A simple classifier for NGT malposition may help junior physicians determine the safety of feeding in patients with NGTs.Keywords: Neural Networks, Feature Detection, Supervised Learning, Machine Learning Supplemental material is available for this article. Published under a CC BY 4.0 license.

Influencing medication taking behaviors using automated two-way digital communication: A narrative synthesis systematic review informed by the Behavior Change Wheel.

PURPOSE: Around half of prescribed medications for long-term conditions are not taken as directed. Automated two-way digital communication, such as text messaging and interactive voice response technology, could deliver interventions to improve medication adherence, and subsequently health. However, exploration of how such interventions may improve medication adherence is limited. This review aimed to explore how automated two-way digital communication can improve medication taking with or without using non-digital intervention components, such as phone calls with healthcare professionals. METHODS: A theory-informed narrative synthesis systematic review. Several databases were searched including CINAHL, Embase, Medline, and Web of Science using key words relating to 'medication adherence' and digital communication technologies. The Behavior Change Technique (BCT) coding using the BCT Taxonomy V1 and the Behavior Change Wheel were used to identify BCTs delivered within the included interventions. RESULTS: A total of 3,018 records were screened with 43 study reports included in the review. Four medication-taking behaviors: taking medication, obtaining medication, self-testing, and asking for support were identified as targets for behavior change within the included interventions. Most BCTs within the digital communication component aimed to increase motivation for medication adherence, with non-digital intervention components included to address other medication taking barriers, such as physical and psychological capability. CONCLUSION: Automated two-way digital communication can detect barriers to medication adherence by monitoring performance of the taking medication behavior. Monitoring outcomes from taking medication may increase reflective motivation to take medicines. Addressing physical opportunity to taking medication by facilitating the behavior obtaining medication may also increase adherence.

Two-way Automated Text Messaging Support From Community Pharmacies for Medication Taking in Multiple Long-term Conditions: Human-Centered Design With Nominal Group Technique Development Study.

BACKGROUND: Reviews of digital communication technologies suggest that they can be effective in supporting medication use; however, their use alongside nondigital components is unclear. We also explored the delivery of a digital communication intervention in a relatively novel setting of community pharmacies and how such an intervention might be delivered to patients with multiple long-term conditions. This meant that despite the large number of intervention examples available in the literature, design questions remained, which we wanted to explore with key stakeholders. Examples of how to involve stakeholders in the design of complex health care interventions are lacking; however, human-centered design (HCD) has been suggested as a potential approach. OBJECTIVE: This study aimed to design a new community pharmacy text messaging intervention to support medication use for multiple long-term conditions, with patient and health care professional stakeholders in primary care. METHODS: HCD was used to map the intervention "journey" and identify design questions to explore with patients and health care professionals. Six prototypes were developed to communicate the intervention concept, and a modified version of the Nominal Group Technique was used to gather feedback. Nominal group meetings generated qualitative data using questions about the aspects that participants liked for each prototype and any suggested changes. The discussion was analyzed using a framework approach to transform feedback into statements. These statements were then ranked using a web-based questionnaire to establish a consensus about what elements of the design were valued by stakeholders and what changes to the design were most important. RESULTS: A total of 30 participants provided feedback on the intervention design concept over 5 nominal group meetings (21 health care professionals and 9 patients) with a 57% (17/30) response rate to the ranking questionnaire. Furthermore, 51 proposed changes in the intervention were generated from the framework analysis. Of these 51 changes, 27 (53%) were incorporated into the next design stage, focusing on changes that were ranked highest. These included suggestions for how text message content might be tailored, patient information materials, and the structure for pharmacist consultation. All aspects that the participants liked were retained in the future design and provided evidence that the proposed intervention concept had good acceptability. CONCLUSIONS: HCD incorporating the Nominal Group Technique is an appropriate and successful approach for obtaining feedback from key stakeholders as part of an iterative design process. This was particularly helpful for our intervention, which combined digital and nondigital components for delivery in the novel setting of a community pharmacy. This approach enabled the collection and prioritization of useful multiperspective feedback to inform further development and testing of our intervention. This model has the potential to minimize research waste by gathering feedback early in the complex intervention design process.

Impact of COVID-19 on carers of children with tracheostomies.

OBJECTIVES: To explore the impact of the COVID-19 pandemic on the experiences of caregivers of children with tracheostomies. DESIGN: Qualitative semistructured interviews. SETTING: All participants were currently, or had previously cared for, a tracheostomised child who had attended a tertiary care centre in the North of England. Health professionals were purposively sampled to include accounts from a range of professions from primary, community, secondary and tertiary care. PARTICIPANTS: Carers of children with tracheostomies (n=34), including health professionals (n=17) and parents (n=17). INTERVENTIONS: Interviews were undertaken between July 2020 and February 2021 by telephone or video link. MAIN OUTCOME MEASURE: Qualitative reflexive thematic analysis with QSR NVivo V.12. RESULTS: The pandemic has presented an additional and, for some, substantial challenge when caring for tracheostomised children, but this was not always felt to be the most overriding concern. Interviews demonstrated rapid adaptation, normalisation and varying degrees of stoicism and citizenship around constantly changing pandemic-related requirements, rules and regulations. This paper focuses on four key themes: 'reconceptualising safe care and safe places'; 'disrupted support and isolation'; 'relationships, trust and communication'; and 'coping with uncertainty and shifting boundaries of responsibility'. These are described within the context of the impact on the child, the emotional and physical well-being of carers and the challenges to maintaining the values of family-centred care. CONCLUSIONS: As we move to the next phase of the pandemic, we need to understand the impact on vulnerable groups so that their needs can be prioritised.

Exploration of prescribing error reporting across primary care: a qualitative study.

OBJECTIVES: To explore barriers and facilitators to prescribing error reporting across primary care. DESIGN: Qualitative semi-structured face-to-face and telephone interviews were conducted to explore facilitators and barriers to reporting prescribing errors. Data collection and thematic analysis were informed by the COM-B model of behaviour change. Framework analysis was used for coding and charting the data with the assistance of NVivo software (V.12). General and context specific influences on prescribing error reporting were mapped to constructs from the COM-B model (ie, capability, opportunity and motivation). SETTING: Primary care organisations, including community pharmacy, general practice and community care from North East England. PARTICIPANTS: We interviewed a maximal variation purposive sample of 25 participants, including prescribers, community pharmacists and key stakeholders with primary care or medicines safety roles at local, regional and national levels. RESULTS: Our findings describe a range of factors that influence the capability, opportunity and motivation to report prescribing errors in primary care. Three key contextual factors are also highlighted that were found to underpin many of the behavioural influences on reporting in this setting: the nature of prescribing; heterogeneous priorities for error reporting across and within different primary care organisations; and the complex infrastructure of reporting and learning pathways across primary care. Findings suggest that there is a lack of consistency in how, when and by whom, prescribing errors are reported across primary care. CONCLUSIONS: Further research is needed to identify cross-organisational and interprofessional consensus on agreed reporting thresholds and how best to facilitate a more collaborative approach to reporting and learning, that is, sensitive to the needs and priorities of disparate organisations across primary care. Despite acknowledged challenges, there may be potential for an increased role of community pharmacy in prescribing error reporting to support future learning.

CACNA1C (CaV1.2) and other L-type calcium channels in the pathophysiology and treatment of psychiatric disorders: Advances from functional genomics and pharmacoepidemiology.

A role for voltage-gated calcium channels (VGCCs) in psychiatric disorders has long been postulated as part of a broader involvement of intracellular calcium signalling. However, the data were inconclusive and hard to interpret. We review three areas of research that have markedly advanced the field. First, there is now robust genomic evidence that common variants in VGCC subunit genes, notably CACNA1C which encodes the L-type calcium channel (LTCC) CaV1.2 subunit, are trans-diagnostically associated with psychiatric disorders including schizophrenia and bipolar disorder. Rare variants in these genes also contribute to the risk. Second, pharmacoepidemiological evidence supports the possibility that calcium channel blockers, which target LTCCs, might have beneficial effects on the onset or course of these disorders. This is especially true for calcium channel blockers that are brain penetrant. Third, long-range sequencing is revealing the repertoire of full-length LTCC transcript isoforms. Many novel and abundant CACNA1C isoforms have been identified in human and mouse brain, including some which are enriched compared to heart or aorta, and predicted to encode channels with differing functional and pharmacological properties. These isoforms may contribute to the molecular mechanisms of genetic association to psychiatric disorders. They may also enable development of therapeutic agents that can preferentially target brain LTCC isoforms and be of potential value for psychiatric indications.

Diesel Engine Exhaust Exposure in the Ontario Civil Infrastructure Construction Industry.

OBJECTIVES: Diesel engine exhaust (DEE) is a known lung carcinogen and a common occupational exposure in Canada. The use of diesel-powered equipment in the construction industry is particularly widespread, but little is known about DEE exposures in this work setting. The objective of this study was to determine exposure levels and identify and characterize key determinants of DEE exposure at construction sites in Ontario. METHODS: Elemental carbon (EC, a surrogate of DEE exposure) measurements were collected at seven civil infrastructure construction worksites and one trades training facility in Ontario using NIOSH method 5040. Full-shift personal air samples were collected using a constant-flow pump and SKC aluminium cyclone with quartz fibre filters in a 37-mm cassette. Exposures were compared with published health-based limits, including the Dutch Expert Committee on Occupational Safety (DECOS) limit (1.03 µg m-3 respirable EC) and the Finnish Institute of Occupational Health (FIOH) recommendation (5 µg m-3 respirable EC). Mixed-effects linear regression was used to identify determinants of EC exposure. RESULTS: In total, 149 EC samples were collected, ranging from <0.25 to 52.58 µg m-3 with a geometric mean (GM) of 3.71 µg m-3 [geometric standard deviation (GSD) = 3.32]. Overall, 41.6% of samples exceeded the FIOH limit, mostly within underground worksites (93.5%), and 90.6% exceeded the DECOS limit. Underground workers (GM = 13.20 µg m-3, GSD = 1.83) had exposures approximately four times higher than below grade workers (GM = 3.56 µg m-3, GSD = 1.94) and nine times higher than above ground workers (GM = 1.49 µg m-3, GSD = 1.75). Training facility exposures were similar to above ground workers (GM = 1.86 µg m-3, GSD = 4.12); however, exposures were highly variable. Work setting and enclosed cabins were identified as the key determinants of exposure in the final model (adjusted R2 = 0.72, P < 0.001). The highest DEE exposures were observed in underground workplaces and when using unenclosed cabins. CONCLUSIONS: This study provides data on current DEE exposure in Canadian construction workers. Most exposures were above recommended health-based limits, albeit in other jurisdictions, signifying a need to further reduce DEE levels in construction. These results can inform a hazard reduction strategy including targeted intervention/control measures to reduce DEE exposure and the burden of occupational lung cancer.

Targeting synaptic plasticity in schizophrenia: insights from genomic studies.

Patients with schizophrenia experience cognitive dysfunction and negative symptoms that do not respond to current drug treatments. Historical evidence is consistent with the hypothesis that these deficits are due, at least in part, to altered cortical synaptic plasticity (the ability of synapses to strengthen or weaken their activity), making this an attractive pathway for therapeutic intervention. However, while synaptic transmission and plasticity is well understood in model systems, it has been challenging to identify specific therapeutic targets for schizophrenia. New information is emerging from genomic findings, which converge on synaptic plasticity and provide a new window on the neurobiology of schizophrenia. Translating this information into therapeutic advances will require a multidisciplinary and collaborative approach.