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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Induced Pluripotent Stem Cells in Psychiatry: An Overview and Critical Perspective.

A key challenge in psychiatry research is the development of high-fidelity model systems that can be experimentally manipulated to explore and test pathophysiological mechanisms of illness. In this respect, the emerging capacity to derive neural cells and circuits from human induced pluripotent stem cells (iPSCs) has generated significant excitement. This review aims to provide a critical appraisal of the potential for iPSCs in illuminating pathophysiological mechanisms in the context of other available technical approaches. We discuss the selection of iPSC phenotypes relevant to psychiatry, the information that researchers can draw on to help guide these decisions, and how researchers choose between the use of 2-dimensional cultures and the use of more complex 3-dimensional model systems. We discuss the strengths and limitations of current models and the challenges and opportunities that they present. Finally, we discuss the potential of iPSC-based model systems for clarifying the mechanisms underlying genetic risk for psychiatry and the steps that will be needed to ensure that robust and reliable conclusions can be drawn. We argue that while iPSC-based models are ideally placed to study fundamental processes occurring within and between neural cells, they are often less well suited for case-control studies, given issues relating to statistical power and the challenges in identifying which cellular phenotypes are meaningful at the level of the whole individual. Our aim is to highlight the importance of considering the hypotheses of a given study to guide decisions about which, if any, iPSC-based system is most appropriate to address it.

Estimating Historical Exposure to Respirable Crystalline Silica in the Mining Industry in Ontario, Canada Using a Newly Developed Exposure Database.

OBJECTIVES: To use the recently developed Ontario Mining Exposure Database (OMED) to describe historical silica exposure in the Ontario metal mining industry and identify predictors of historical silica exposure. METHODS: Personal respirable crystalline silica (RCS) data for metal mines were extracted from OMED and included both individual and summary measures, where multiple exposure measurements (n > 1) were aggregated and entered as a single exposure value (n = 1). Data were stratified by sample location (underground/surface) for analysis. Monte Carlo simulation was used to simulate individual measures from the summary measures. A fixed effects multiple linear regression model was used to assess the effects of commodity (ore mined), sample year, source of exposure data, and occupational group on RCS concentration. Parameter estimates (ß), standard errors, and 95% upper and lower confidence intervals were reported. RESULTS: The OMED contained 12 995 silica measurements. After limiting to RCS measurements in metal mines, and measures with sufficient information for analysis, 2883 RCS measurements collected from 1974 to 1991 remained, including 2816 individual and 67 summary measurements. In total, 321 individual RCS measurements were simulated from the 67 summary measures. The analysis database contained 2771 (12% simulated) underground measurements and 366 surface measurements (0% simulated). In the underground group, an overall geometric mean (GM) of 0.05 [geometric standard deviation (GSD) 3.09] mg m-3 was estimated with a 6% annual decrease over time. In this group, the commodity with the highest average RCS level was zinc mines (GM = 0.07 mg m-3) and the lowest was iron mines (GM = 0.01 mg m-3). In the surface group, an overall GM of 0.05 (GSD 3.70) mg m-3 was estimated with an 8% decreased over time. In this group, the commodity with the highest average RCS level was gold mines (GM = 0.07 mg m-3) and the lowest was zinc mines (GM = 0.03 mg m-3). In both groups, company collected data had lower estimated RCS compared with regulator collected data. CONCLUSIONS: Historical RCS levels decreased over time. Mean measurements exceeded the American Conference of Governmental Industrial Hygienists current health-based threshold limit value (0.025 mg m-3). The main predictors of exposure were commodity, source of exposure data, and sample year. However, low R2 and high GSD values suggest additional predictors of RCS exposures in Ontario's metal mines exist that were unavailable in OMED.

Long read transcript profiling of ion channel splice isoforms.

Alternative splicing of RNA transcripts allows a single gene to generate multiple products and is a key means of generating functionally diverse voltage-gated ion channels. Splicing can be regulated according to cell type, cell state, and stage of development to produce a bespoke complement of protein isoforms. Characterizing the identities of full-length transcript isoforms is essential in order to fully understand a gene's expression and function. However, the repertoire of transcript isoforms is not well characterized for most genes. Long read nanopore sequencing allows full-length isoforms to be sequenced, therefore identifying full-length transcripts. Using this approach, we recently discovered that the human CACNA1C gene gives rise to a far greater repertoire of splice isoforms than previously appreciated. Here we provide a detailed overview of the technical approach we used to achieve this. The method described in this chapter combines long read nanopore sequencing with PCR targeting to selectively sequence transcripts of a specific gene of interest.

Factors shaping the implementation and use of Clinical Cancer Decision Tools by GPs in primary care: a qualitative framework synthesis.

OBJECTIVE: Clinical Cancer Decision Tools (CCDTs) aim to alert general practitioners (GPs) to signs and symptoms of cancer, supporting prompt investigation and onward referral. CCDTs are available in primary care in the UK but are not widely utilised. Qualitative research has highlighted the complexities and mechanisms surrounding their implementation and use; this has focused on specific cancer types, formats, systems or settings. This study aims to synthesise qualitative data of GPs' attitudes to and experience with a range of CCDTs to gain better understanding of the factors shaping their implementation and use. DESIGN: A systematic search of the published (MEDLINE, CINAHL, Web of Science and EMBASE) and grey literature (July 2020). Following screening, selection and assessment of suitability, the data were analysed and synthesised using normalisation process theory. RESULTS: Six studies (2011 to 2019), exploring the views of GPs were included for analysis. Studies focused on the use of several different types of CCDTs (Risk Assessment Tools (RAT) or electronic version of RAT (eRAT), QCancer and the 7-point checklist). GPs agreed CCDTs were useful to increase awareness of signs and symptoms of undiagnosed cancer. They had concerns about the impact on trust in their own clinical acumen, whether secondary care clinicians would consider referrals generated by CCDT as valid and whether integration of the CCDTs within existing systems was achievable. CONCLUSIONS: CCDTs might be a helpful adjunct to clinical work in primary care, but without careful development to legitimise their use GPs are likely to give precedence to clinical acumen and gut instinct. Stakeholder consultation with secondary care clinicians and consideration of how the CCDTs fit into a GP consultation are crucial to successful uptake. The role and responsibilities of a GP as a clinician, gatekeeper, health promoter and resource manager affect the interaction with and implementation of innovations such as CCDTs.

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.

Prescribing error reporting in primary care: a narrative synthesis systematic review.

Prescribing errors can cause avoidable harm to patients. Most prescriptions originate in primary care, where medications tend to be self-administered and errors have the most potential to cause harm. Reporting prescribing errors can identify trends and reduce the risk of the reoccurrence of incidents; however, under-reporting is common. The organisation of care and the movement of prescriptions from general practice to community pharmacy may create difficulties for professionals to effectively report errors. This review aims specifically to identify primary research studies that examine barriers and facilitators to prescription error reporting across primary care. A systematic research of the literature was completed in July 2019. Four databases (PubMed/Medline, Cochrane, CINAHL and Web of Science) were searched for relevant studies. No date or language limits were applied. Eligible studies were critically appraised using the Mixed Methods Appraisal Tool, and data were descriptively and narratively synthesised. Ten articles were included in the final analysis. Seven studies considered prescription errors and error reporting within general practice and three within a community pharmacy setting. Findings from the included studies are presented across five themes, including definition of an error, prescribing error reporting culture, reporting processes, communication and capacity. Healthcare professionals appreciate the value of prescription error reporting, but there are key barriers to implementation, including time, fear of reprisal and organisation separation within primary care.