Telephone consulting for 'Personalised Care and Support Planning' with people with long-term conditions: a qualitative study of healthcare professionals' experiences during COVID-19 restrictions and beyond.

BACKGROUND: Personalised Care and Support Planning (PCSP) replaces conventional annual reviews for people with long-term conditions. It is designed to help healthcare professionals (HCPs) and patients engage in conversations as equals and collaboratively plan actions oriented to each patient's priorities, alongside biomedical concerns. Little is known about how the shift to remote consulting initiated with COVID-19 restrictions has impacted PCSP. AIM: To investigate HCPs' experiences of conducting PCSP conversations remotely and consider implications for the fulfilment of PCSP ambitions as remote consulting continues beyond COVID-19 restrictions. METHODS: 19 semi-structured interviews with HCPs in England and Scotland; interpretive analysis. RESULTS: HCPs' accounts made clear that COVID-19 restrictions impacted multiple aspects of PCSP delivery, not just the mode of conversation. Broader disruption to general practice systems for gathering and sharing information ahead of PCSP conversations, and moves to 'wide window' appointment times, made it harder for patients to be prepared for PCSP conversations. This constrained scope to achieve PCSP ambitions even with the best professional communication skills. Most remote PCSP conversations were conducted by telephone. In the absence of visual communication with patients, it was sometimes harder to achieve the ambitions of PCSP conversations, including to balance patient and professional agendas, fulfil key planning activities, and foster a relational ethos of equal, collaborative partnership. The challenges were particularly severe when working with new patients and people with complex clinical and social problems. Although options for telephone appointments now offer valued flexibility, sustained experience of struggling to achieve PCSP ambitions via remote consulting led some HCPs to lower their standards for judging a "good" PCSP conversation, and to diminished professional satisfaction. CONCLUSIONS: There are significant challenges to fulfilling the ambitions of PCSP via telephone, especially when preparatory support is limited. This study provides grounds for scepticism about how compatible telephone appointments can be with this person-centred model of working, especially for people who are socially disadvantaged and live with complex health conditions. These threats to the provision of person-centred support for people with long-term conditions warrant careful attention going forward if the PCSP model and its benefits are to be sustained.

Dual roles for nuclear RNAi Argonautes in Caenorhabditis elegans dosage compensation.

Dosage compensation involves chromosome-wide gene regulatory mechanisms which impact higher order chromatin structure and are crucial for organismal health. Using a genetic approach, we identified Argonaute genes which promote dosage compensation in Caenorhabditis elegans. Dosage compensation in C. elegans hermaphrodites is initiated by the silencing of xol-1 and subsequent activation of the dosage compensation complex which binds to both hermaphrodite X chromosomes and reduces transcriptional output by half. A hallmark phenotype of dosage compensation mutants is decondensation of the X chromosomes. We characterized this phenotype in Argonaute mutants using X chromosome paint probes and fluorescence microscopy. We found that while nuclear Argonaute mutants hrde-1 and nrde-3, as well as mutants for the piRNA Argonaute prg-1, exhibit derepression of xol-1 transcripts, they also affect X chromosome condensation in a xol-1-independent manner. We also characterized the physiological contribution of Argonaute genes to dosage compensation using genetic assays and found that hrde-1 and nrde-3 contribute to healthy dosage compensation both upstream and downstream of xol-1.

Evaluating the Feasibility of Screening Relatives of Patients Affected by Nonsyndromic Thoracic Aortic Diseases: The REST Study.

Background Diseases of the thoracic aorta are characterized by a familial etiology in up to 30% of the cases. Nonsyndromic thoracic aorta diseases (NS-TADs) lack overt clinical signs and systemic features, which hinder early detection and prompt surgical intervention. We hypothesize that tailored genetic testing and imaging of first-degree and second-degree relatives of patients affected by NS-TADs may enable early diagnosis and allow appropriate surveillance or intervention. Methods and Results We conducted a feasibility study involving probands affected by familial or sporadic NS-TADs who had undergone surgery, which also offered screening to their relatives. Each participant underwent a combined imaging (echocardiogram and magnetic resonance imaging) and genetic (whole exome sequencing) evaluation, together with physical examination and psychological assessment. The study population included 16 probands (8 sporadic, 8 familial) and 54 relatives (41 first-degree and 13 second-degree relatives) with median age 48 years (range: 18-85 years). No syndromic physical features were observed. Imaging revealed mild-to-moderate aortic dilation in 24% of relatives. A genetic variant of uncertain significance was identified in 3 families. Imaging, further phenotyping, or a form of secondary prevention was indicated in 68% of the relatives in the familial group and 54% in the sporadic group. No participants fulfilled criteria for aortic surgery. No differences between baseline and 3-month follow-up scores for depression, anxiety, and self-reported quality of life were observed. Conclusions In NS-TADs, imaging tests, genetic counseling, and family screening yielded positive results in up to 1 out of 4 screened relatives, including those in the sporadic NS-TAD group. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03861741.

btn1 affects endocytosis, polarization of sterol-rich membrane domains and polarized growth in Schizosaccharomyces pombe.

btn1, the Schizosaccharomyces pombe orthologue of the human Batten disease gene CLN3, exerts multiple cellular effects. As well as a role in vacuole pH homoeostasis, we now show that Btn1p is essential for growth at high temperatures. Its absence results in progressive defects at 37 degrees C that culminate in total depolarized growth and cell lysis. These defects are preceded by a progressive failure to correctly polarize sterol-rich domains after cytokinesis and are accompanied by loss of Myo1p localization. Furthermore, we found that in Sz. pombe, sterol spreading is linked to defective formation/polarization of F-actin patches and disruption of endocytosis and that these processes are aberrant in btn1Delta cells. Consistent with a role for Btn1p in polarized growth, Btn1p has an altered location at 37 degrees C and is retained in actin-dependent endomembrane structures near the cell poles or septum.

A function retained by the common mutant CLN3 protein is responsible for the late onset of juvenile neuronal ceroid lipofuscinosis.

The neuronal ceroid lipofuscinoses (NCLs) are common neurodegenerative disorders of childhood and are classified as lysosomal storage diseases since affected cells exhibit lysosomes containing ceroid and lipofuscin-like material. CLN3 is the most widely conserved NCL gene, suggesting that it has a basic eukaryotic cell function; its loss might be expected to cause the earliest onset and/or most severe disease. However, mutations in CLN3 are linked to juvenile NCL (JNCL), the latest onset and mildest form of NCL in children. We sought to explain this paradox. Almost all patients with JNCL are homozygous or heterozygous for an intragenic 1 kb deletion within CLN3, hitherto presumed to be a null mutation. We hypothesized that the 1 kb mutation may allow CLN3 residual function. We confirmed the presence of CLN3 transcripts in JNCL patient cells. When RNA silencing was used to deplete these transcripts in cells from JNCL patients, the lysosomes significantly increased in size, confirming the presence of functional protein in these cells. Consistently, overexpression of mutant CLN3 transcript caused lysosomes to decrease in size. We modelled the JNCL mutant transcripts and those corresponding to mouse models for Cln3 in Schizosaccharomyces pombe and confirmed that most transcripts retained significant function as we predicted. Therefore, we concluded that the common mutant CLN3 protein does indeed retain significant function and that JNCL is a mutation-specific disease phenotype. This finding has important consequences for recognition and diagnosis of disease caused by mutations in CLN3 and for the development of therapy for JNCL.

Cancer pain: part 1: Pathophysiology; oncological, pharmacological, and psychological treatments: a perspective from the British Pain Society endorsed by the UK Association of Palliative Medicine and the Royal College of General Practitioners.

OBJECTIVE: This discussion document about the management of cancer pain is written from the pain specialists' perspective in order to provoke thought and interest in a multimodal approach to the management of cancer pain, not just towards the end of life, but pain at diagnosis, as a consequence of cancer therapies, and in cancer survivors. It relates the science of pain to the clinical setting and explains the role of psychological, physical, interventional and complementary therapies in cancer pain. METHODS: This document has been produced by a consensus group of relevant health care professionals in the United Kingdom and patients' representatives making reference to the current body of evidence relating to cancer pain. In the first of two parts, pathophysiology, oncological, pharmacological, and psychological treatment are considered. CONCLUSIONS: It is recognized that the World Health Organization (WHO) analgesic ladder, while providing relief of cancer pain towards the end of life for many sufferers worldwide, may have limitations in the context of longer survival and increasing disease complexity. To complement this, it is suggested that a more comprehensive model of managing cancer pain is needed that is mechanism-based and multimodal, using combination therapies including interventions where appropriate, tailored to the needs of an individual, with the aim to optimize pain relief with minimization of adverse effects.

'The missing picture': tobacco use through the eyes of smokers.

BACKGROUND: The use of visual methodologies has gained increased prominence among health researchers working with socially marginalised populations, including those studying tobacco and other types of substance use. OBJECTIVES: This article draws from two separate studies combining qualitative and photographic methods to illustrate the unique insights that visual research with smokers can generate for tobacco control. METHODS: A purposeful selection of photographs and captions produced by research participants in a study with (1) 20 new fathers that smoke and, (2) a study with 21 adolescent girls that smoke are analysed and discussed in detail. RESULTS: Images produced by smokers illustrate the roles of gender and social context in shaping smoking status, as well as the private struggles with tobacco use experienced by smokers in their day-to-day lives and relationships. CONCLUSIONS: Photographic methods have the potential to generate information that may assist in developing tobacco control messaging and programming that speaks to smokers' perceptions of their tobacco use.

Young women's responses to smoking and breast cancer risk information.

Current evidence confirms that young women who smoke or who have regular long-term exposure to secondhand smoke (SHS) have an increased risk of developing premenopausal breast cancer. The aim of this research was to examine the responses of young women to health information about the links between active smoking and SHS exposure and breast cancer and obtain their advice about messaging approaches. Data were collected in focus groups with 46 women, divided in three age cohorts: 15-17, 18-19 and 20-24 and organized according to smoking status (smoking, non-smoking and mixed smoking status groups). The discussion questions were preceded by information about passive and active smoking and its associated breast cancer risk. The study findings show young women's interest in this risk factor for breast cancer. Three themes were drawn from the analysis: making sense of the information on smoking and breast cancer, personal susceptibility and tobacco exposure and suggestions for increasing awareness about tobacco exposure and breast cancer. There was general consensus on framing public awareness messages about this risk factor on 'protecting others' from breast cancer to catch smokers' attention, providing young women with the facts and personal stories of breast cancer to help establish a personal connection with this information and overcome desensitization related to tobacco messages, and targeting all smokers who may place young women at risk. Cautions were also raised about the potential for stigmatization. Implications for raising awareness about this modifiable risk factor for breast cancer are discussed.

Breast cancer messaging for younger women: gender, femininity, and risk.

Evidence linking both active smoking and secondhand smoke exposure to premenopausal breast cancer makes the development of health messages specific to younger women a pressing priority. To determine how to communicate information about this modifiable breast cancer risk to young women, we analyzed a selection of 32 recent English-language breast cancer messages and campaigns that targeted young women. In addition, we obtained young women's responses to three breast cancer campaign images during focus group discussions. A visual analysis of messages points to an explicitly gendered discourse within contemporary campaigns, one that entails conflicting messages regarding breast cancer, health, feminine beauty, and risk. Although the intent might be to educate and empower young women to "fight" against breast cancer, paradoxically, the messages employ imagery that sexually objectifies young women's breasts and bodies. Recommendations are made for messaging about tobacco and breast cancer risk to avoid reproducing one-dimensional or stereotypical presentations of gender and femininity.

Becoming a 'real' smoker: cultural capital in young women's accounts of smoking and other substance use.

This paper draws from a qualitative study of tobacco use by young women in Toronto, Canada. Narrative interviews were used to understand the multiple roles and functions of smoking within the everyday lives of female adolescents. Guided by a Bourdieusian theoretical framework this study employed the core construct of cultural capital in order to position tobacco and other substance use as field-specific capital that young women accumulate while navigating the social worlds of adolescence. Departing from the psychosocial or peer-influence models that inform the majority of tobacco research with young people, this analysis provides a nuanced understanding of how smoking, drinking, using drugs are much more than simple forms of teenage experimentation or rebellion, but can also serve as key resources for defining the self, acquiring status and making social distinctions within adolescent social worlds. In this context it is also argued that initiation into substance use practices is a way that young women demonstrate and develop social and cultural competencies.

FXR-Mediated Cortical Cholesterol Accumulation Contributes to the Pathogenesis of Type A Hepatic Encephalopathy.

BACKGROUND & AIMS: Hepatic encephalopathy is a serious neurologic complication of acute and chronic liver diseases. We previously showed that aberrant bile acid signaling contributes to the development of hepatic encephalopathy via farnesoid X receptor (FXR)-mediated mechanisms in neurons. In the brain, a novel alternative bile acid synthesis pathway, catalyzed by cytochrome p450 46A1 (Cyp46A1), is the primary mechanism by which the brain regulates cholesterol homeostasis. The aim of this study was to determine if FXR activation in the brain altered cholesterol homeostasis during hepatic encephalopathy. METHODS: Cyp7A1-/- mice or C57Bl/6 mice pretreated with central infusion of FXR vivo morpholino, 2-hydroxypropyl-ß-cyclodextrin, or fed a cholestyramine-supplemented diet were injected with azoxymethane (AOM). Cognitive and neuromuscular impairment as well as liver damage and expression of Cyp46A1 were assessed using standard techniques. The subsequent cholesterol content in the frontal cortex was measured using commercially available kits and by Filipin III and Nile Red staining. RESULTS: There was an increase in membrane-bound and intracellular cholesterol in the cortex of mice treated with AOM that was associated with decreased Cyp46A1 expression. Strategies to inhibit FXR signaling prevented the down-regulation of Cyp46A1 and the accumulation of cholesterol. Treatment of mice with 2-hydroxypropyl-ß-cyclodextrin attenuated the AOM-induced cholesterol accumulation in the brain and the cognitive and neuromuscular deficits without altering the underlying liver pathology. CONCLUSIONS: During hepatic encephalopathy, FXR signaling increases brain cholesterol and contributes to neurologic decline. Targeting cholesterol accumulation in the brain may be a possible therapeutic target for the management of hepatic encephalopathy.

A feasibility study to assess service providers' perspectives regarding the use of the child and adolescent functional assessment scale in Ontario.

This brief report describes a feasibility study conducted to assess the level of satisfaction with the Child and Adolescent Functional Assessment Scale (CAFAS) rater reliability training, the ease of achieving interrater reliability in rating CAFAS, and the clinical utility of CAFAS as an outcome measurement tool for the province of Ontario, from the perspective of service providers. This study has been instrumental in the development of a 4-year province-wide measurement initiative. The study proved useful to government policy and decision-makers, mental health administrators, clinicians, and mental health service researchers interested in the implementation of outcome measurement tools. It highlighted the fact that at least 85% of respondents were satisfied with CAFAS training and the ease of achieving interrater reliability. The majority identified the usefulness of the tool in case formulation and the value in tracking changes over time.

The impact of social media on readership of a peer-reviewed medical journal.

PURPOSE: Social media microblogging has made major inroads in physician education and information exchange. The authors evaluated their early experience with Twitter "tweet chat" sessions as a medium to expand the reach and audience of a peer-reviewed radiology journal. METHODS: The authors analyzed Twitter activity metadata tagged with the #JACR hashtag from the first 6 tweet chat sessions sponsored and promoted by JACR. The assessment included multiple metrics: radiologist versus nonradiologist session participants, individual tweets, tweets with embedded web links, common words, retweets, and impressions. We correlated Twitter metrics with temporally related journal website activity. RESULTS: Each session generated a mean of 444 ± 172 tweets contributed by a mean of 33 ± 14 participants (45.4% nonradiologists) and resulted in a mean of 1,163,712 ± 441,971 impressions. Per session, a mean of 19 ± 7.6 tweets contained web links, and 138 ± 35.6 tweets were retweets. Monthly journal website article views increased from 31,220 to 41,017 (+31.4%), journal website visits increased from 9,192 to 11,539 (+25.5%), and unique visitors increased from 7,368 to 8,841 (+20%). Since JACR tweet chats were initiated, mean monthly journal website visits and page views per month directly from twitter.com increased from 24 to 101 (+321%) and from 38 to 159 (+318%), respectively. CONCLUSIONS: Early experience with JACR tweet chats demonstrates that organizing Twitter microblogging activities around topics of general interest to their target readership bears the potential for medical journals to increase their audiences and reach.

Deletion of btn1, an orthologue of CLN3, increases glycolysis and perturbs amino acid metabolism in the fission yeast model of Batten disease.

The neuronal ceroid lipofuscinoses (NCLs) constitute a group of autosomal recessive neurodegenerative diseases affecting children. To date, the disease pathogenesis remains unknown, although the role of lysosomal impairment is widely recognized across the different diseases. Recently, the creation of simple models of juvenile NCL (Batten disease) has provided additional insights into the disease mechanism at the molecular level. We report defects in metabolism identified in the Schizosacchromyces pombe yeast model, where btn1, the orthologue of CLN3, has been deleted, using a metabolomics approach based on high resolution 1H and 13C NMR spectroscopy. Such changes represent the first documented metabolic changes associated with deletion of btn1. A decrease in extracellular glucose and increases in the concentration of extracellular ethanol and alanine labelling demonstrate increased glycolytic flux that may arise from vacuolar impairment, whilst amino acid changes were detected which were also in accordance with defective vacuolar functionality. That these changes were detected using a metabolomic based approach advocates its use to further analyse other yeast models of human disease to better understand the function of orthologue genes.

The fission yeast model for the lysosomal storage disorder Batten disease predicts disease severity caused by mutations in CLN3.

The function of the CLN3 protein, which is mutated in patients with the neurodegenerative lysosomal storage disorder Batten disease, has remained elusive since it was identified 13 years ago. Here, we exploited the Schizosaccharomyces pombe model to gain new insights into CLN3 function. We modelled all missense mutations of CLN3 in the orthologous protein Btn1p, as well as a series of targeted mutations, and assessed trafficking and the ability of the mutant proteins to rescue four distinct phenotypes of btn1Delta cells. Mutating the C-terminal cysteine residues of Btn1p caused it to be internalised into the vacuole, providing further evidence that this protein functions from pre-vacuole compartments. Mutations in the lumenal regions of the multi-spanning membrane protein, especially in the third lumenal domain which contains a predicted amphipathic helix, had the most significant impact on Btn1p function, indicating that these domains of CLN3 are functionally important. Only one mutant protein was able to rescue the cell curving phenotype (p.Glu295Lys), and since this mutation is associated with a very protracted disease progression, this phenotype could be used to predict the disease severity of novel mutations in CLN3. The ability to predict disease phenotypes in S. pombe confirms this yeast as an invaluable tool to understanding Batten disease.

"I couldn't say, I'm not a girl"--adolescents talk about gender and marijuana use.

In this paper we report on findings from a qualitative study of marijuana use by adolescents in two communities in British Columbia, Canada. During 2005 and 2006, 45 interviews were carried out at schools with students aged 13-18, with an aim of understanding how adolescents perceive their experiences with marijuana to be shaped by gender. While it has been established that patterns of use differ for girls and boys, there is relatively little qualitative research addressing marijuana smoking as gendered social practice. Drawing from contemporary social theories of gender our analysis explores the normative functions of gender discourse within adolescents' narratives, situating their descriptions of marijuana use within the context of the research interview and within the social contexts of drug use. The results highlight the challenges we encountered in asking about gender during one-to-one interviews, juxtaposed with examples from the narratives that illustrate how boys and girls use marijuana as a way of "doing" gender. To conclude, we suggest how our findings can inform the design of gender-specific health messaging on adolescent marijuana use.