Obstructive sleep apnoea/hypopnoea syndrome: a feasibility study to review NICE guidelines.

Introduction Obstructive sleep apnoea/hypopnoea syndrome (OSAHS) is a sleep-related respiratory condition, leading to repeated temporary cessation of breathing. OSAHS affects approximately eight million people in the UK and can contribute to many comorbidities. Recently, there has been updated National Institute for Health and Care Excellence (NICE) guidelines for the management of OSAHS in the UK.Aims To assess the current care pathway for OSAHS patients in St George's Hospital (SGH) and if the hospital was complying with current NICE guidelines.Methods A retrospective case note analysis of 50 adult patients who have attended SGH for OSAHS in 2022 was undertaken to review their care pathway. Patient notes were reviewed to determine if key criteria of NICE guidelines were followed.Results The OSA clinic follows some of the NICE guidelines and had this recorded in the notes for 40% of the standards/criteria reviewed (10 out of 25 standards were met and recorded).Discussion This service evaluation reveals patients have multiple appointments and have varying treatment compliance. Further discussions are required with the sleep clinicians to determine an efficient pathway for patients who require consideration for alternative therapies for OSA and understanding the funding flows.Conclusions There is a need to raise awareness of these guidelines and improve record-keeping of lifestyle advice given and monitoring treatment efficacy, as the NICE guidelines were not yet being routinely followed.

App Engagement as a Predictor of Weight Loss in Blended-Care Interventions: Retrospective Observational Study Using Large-Scale Real-World Data.

BACKGROUND: Early weight loss is an established predictor for treatment outcomes in weight management interventions for people with obesity. However, there is a paucity of additional, reliable, and clinically actionable early predictors in weight management interventions. Novel blended-care weight management interventions combine coach and app support and afford new means of structured, continuous data collection, informing research on treatment adherence and outcome prediction. OBJECTIVE: Against this backdrop, this study analyzes app engagement as a predictor for weight loss in large-scale, real-world, blended-care interventions. We hypothesize that patients who engage more frequently in app usage in blended-care treatment (eg, higher logging activity) lose more weight than patients who engage comparably less frequently at 3 and 6 months of intervention. METHODS: Real-world data from 19,211 patients in obesity treatment were analyzed retrospectively. Patients were treated with 3 different blended-care weight management interventions, offered in Switzerland, the United Kingdom, and Germany by a digital behavior change provider. The principal component analysis identified an overarching metric for app engagement based on app usage. A median split informed a distinction in higher and lower engagers among the patients. Both groups were matched through optimal propensity score matching for relevant characteristics (eg, gender, age, and start weight). A linear regression model, combining patient characteristics and app-derived data, was applied to identify predictors for weight loss outcomes. RESULTS: For the entire sample (N=19,211), mean weight loss was -3.24% (SD 4.58%) at 3 months and -5.22% (SD 6.29%) at 6 months. Across countries, higher app engagement yielded more weight loss than lower engagement after 3 but not after 6 months of intervention (P3 months<.001 and P6 months=.59). Early app engagement within the first 3 months predicted percentage weight loss in Switzerland and Germany, but not in the United Kingdom (PSwitzerland<.001, PUnited Kingdom=.12, and PGermany=.005). Higher age was associated with stronger weight loss in the 3-month period (PSwitzerland=.001, PUnited Kingdom=.002, and PGermany<.001) and, for Germany, also in the 6-month period (PSwitzerland=.09, PUnited Kingdom=.46, and PGermany=.03). In Switzerland, higher numbers of patients' messages to coaches were associated with higher weight loss (P3 months<.001 and P6 months<.001). Messages from coaches were not significantly associated with weight loss (all P>.05). CONCLUSIONS: Early app engagement is a predictor of weight loss, with higher engagement yielding more weight loss than lower engagement in this analysis. This new predictor lends itself to automated monitoring and as a digital indicator for needed or adapted clinical action. Further research needs to establish the reliability of early app engagement as a predictor for treatment adherence and outcomes. In general, the obtained results testify to the potential of app-derived data to inform clinical monitoring practices and intervention design.

Gonadal androgens are associated with decreased type I interferon production by plasmacytoid dendritic cells and increased IgG titres to BNT162b2 following co-vaccination with live attenuated influenza vaccine in adolescents.

mRNA vaccine technologies introduced following the SARS-CoV-2 pandemic have highlighted the need to better understand the interaction of adjuvants and the early innate immune response. Type I interferon (IFN-I) is an integral part of this early innate response that primes several components of the adaptive immune response. Women are widely reported to respond better than men to tri- and quadrivalent influenza vaccines. Plasmacytoid dendritic cells (pDCs) are the primary cell type responsible for IFN-I production, and female pDCs produce more IFN-I than male pDCs since the upstream pattern recognition receptor Toll-like receptor 7 (TLR7) is encoded by X chromosome and is biallelically expressed by up to 30% of female immune cells. Additionally, the TLR7 promoter contains several putative androgen response elements, and androgens have been reported to suppress pDC IFN-I in vitro. Unexpectedly, therefore, we recently observed that male adolescents mount stronger antibody responses to the Pfizer BNT162b2 mRNA vaccine than female adolescents after controlling for natural SARS-CoV-2 infection. We here examined pDC behaviour in this same cohort to determine the impact of IFN-I on anti-spike and anti-receptor-binding domain IgG titres to BNT162b2. Through flow cytometry and least absolute shrinkage and selection operator (LASSO) modelling, we determined that serum-free testosterone was associated with reduced pDC IFN-I, but contrary to the well-described immunosuppressive role for androgens, the most bioactive androgen dihydrotestosterone was associated with increased IgG titres to BNT162b2. Also unexpectedly, we observed that co-vaccination with live attenuated influenza vaccine boosted the magnitude of IgG responses to BNT162b2. Together, these data support a model where systemic IFN-I increases vaccine-mediated immune responses, yet for vaccines with intracellular stages, modulation of the local IFN-I response may alter antigen longevity and consequently improve vaccine-driven immunity.

Cellular immunity to SARS-CoV-2 following intrafamilial exposure in seronegative family members.

Introduction: Family studies of antiviral immunity provide an opportunity to assess virus-specific immunity in infected and highly exposed individuals, as well as to examine the dynamics of viral infection within families. Transmission of SARS-CoV-2 between family members represented a major route for viral spread during the early stages of the pandemic, due to the nature of SARS-CoV-2 transmission through close contacts. Methods: Here, humoral and cellular immunity is explored in 264 SARS-CoV-2 infected, exposed or unexposed individuals from 81 families in the United Kingdom sampled in the winter of 2020 before widespread vaccination and infection. Results: We describe robust cellular and humoral immunity into COVID-19 convalescence, albeit with marked heterogeneity between families and between individuals. T-cell response magnitude is associated with male sex and older age by multiple linear regression. SARS-CoV-2-specific T-cell responses in seronegative individuals are widespread, particularly in adults and in individuals exposed to SARS-CoV-2 through an infected family member. The magnitude of this response is associated with the number of seropositive family members, with a greater number of seropositive individuals within a family leading to stronger T-cell immunity in seronegative individuals. Discussion: These results support a model whereby exposure to SARS-CoV-2 promotes T-cell immunity in the absence of an antibody response. The source of these seronegative T-cell responses to SARS-CoV-2 has been suggested as cross-reactive immunity to endemic coronaviruses that is expanded upon SARS-CoV-2 exposure. However, in this study, no association between HCoV-specific immunity and seronegative T-cell immunity to SARS-CoV-2 is identified, suggesting that de novo T-cell immunity may be generated in seronegative SARS-CoV-2 exposed individuals.

Vi polysaccharide and conjugated vaccines afford similar early, IgM or IgG-independent control of infection but boosting with conjugated Vi vaccines sustains the efficacy of immune responses.

Introduction: Vaccination with Vi capsular polysaccharide (Vi-PS) or protein-Vi typhoid conjugate vaccine (TCV) can protect adults against Salmonella Typhi infections. TCVs offer better protection than Vi-PS in infants and may offer better protection in adults. Potential reasons for why TCV may be superior in adults are not fully understood. Methods and results: Here, we immunized wild-type (WT) mice and mice deficient in IgG or IgM with Vi-PS or TCVs (Vi conjugated to tetanus toxoid or CRM197) for up to seven months, with and without subsequent challenge with Vi-expressing Salmonella Typhimurium. Unexpectedly, IgM or IgG alone were similarly able to reduce bacterial burdens in tissues, and this was observed in response to conjugated or unconjugated Vi vaccines and was independent of antibody being of high affinity. Only in the longer-term after immunization (>5 months) were differences observed in tissue bacterial burdens of mice immunized with Vi-PS or TCV. These differences related to the maintenance of antibody responses at higher levels in mice boosted with TCV, with the rate of fall in IgG titres induced to Vi-PS being greater than for TCV. Discussion: Therefore, Vi-specific IgM or IgG are independently capable of protecting from infection and any superior protection from vaccination with TCV in adults may relate to responses being able to persist better rather than from differences in the antibody isotypes induced. These findings suggest that enhancing our understanding of how responses to vaccines are maintained may inform on how to maximize protection afforded by conjugate vaccines against encapsulated pathogens such as S. Typhi.

High-fat diet-induced resistance to helminth infection via alternative induction of type 2 immunity.

Gastrointestinal nematode infections cause morbidity and socioeconomic loss in the most deprived communities. The shift in the context of obesity has led to spatial overlap with endemic gastrointestinal nematode regions resulting in the emergence of a novel comorbidity. Despite this, the impact of a high-fat diet (HFD) on immune-regulated protection against gastrointestinal infections remains largely unknown. We employed the murine model of nematode infection, Trichuris muris, to investigate the effect of an HFD on the immune response against chronic infection. Surprisingly, diet-induced obesity drove parasite expulsion in both single and repeated trickle low doses of T. muris eggs. Mechanistically, an HFD increased the expression of the ST2 receptor on CD4+ T cells, priming an enhanced type 2 helper T (Th2) cell cytokine production following interleukin (IL)-33 stimulation ex vivo. Despite IL-33-/- mice demonstrating that IL-33 is not critical for host protective immunity to T. muris under a conventional diet, HFD-fed T-cell deplete mice adoptively transferred with ST2-/- CD4 T cells were unable to expel a T. muris infection unlike those transferred with ST2-sufficient cells. Collectively, this study demonstrates that an HFD primes CD4+ T cells to utilize the IL-33-ST2 axis in a novel induction of type 2 immunity, providing insights into the emerging comorbidities of obesity and nematode infection.

Pericardial and mediastinal fat-associated lymphoid clusters are rapidly activated in an alkane-induced model of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease predominated by auto-antibodies that recognise cellular components. Pleural involvement is the most common SLE-related lung disease. Natural antibodies are rapidly secreted by innate-like B cells following perturbation of homeostasis and are important in the early stages of immune activation. The serous cavities are home to large numbers of innate-like B cells present both within serous fluid and resident within fat-associated lymphoid clusters (FALCs). FALCs are important hubs for B-cell activation and local antibody secretion within the body cavities. Patients with SLE can develop anti-phospholipid antibodies and in rare situations develop alveolar haemorrhage. Utilising delivery of the hydrocarbon oil pristane in C57BL/6 mice as a model of SLE we identify a rapid expansion of pleural cavity B cells as early as day 3 after intra-peritoneal pristane delivery. Following pristane delivery, pericardial B1 B cells are proliferative, express the plasma-cell surface marker CD138, and secrete both innate and class-switched antibodies highlighting that this cavity niche may play an unrecognised role in the initiation of lupus pleuritis.

Patterns of prescribing in primary care leading to high-dose opioid regimens: a mixed-method study.

BACKGROUND: There are concerns about continuing increases in the number of patients prescribed long-term opioids and the prescribing of 'strong' opioids for chronic pain. Little is known about patients who are prescribed these long-term, high-dose drugs. AIM: To understand patterns of opioid prescribing that lead to long-term, high-dose use. DESIGN & SETTING: A mixed-method study of the opioid prescription histories of patients using high doses in a North Wales GP practice. METHOD: All patients on high-dose opioids during the census week were identified. Summary graphs of the prescription histories were prepared. Qualitative analysis was conducted individually by four researchers. A workshop was held to arrive at a consensus about common features and to inform further quantitative analysis. RESULTS: A quarter of high-dose regimens were initiated outside the practice, either in a different primary care practice or in secondary care. The majority of the remaining patients showed a pattern of dose increases to high levels over a short period (median 3.5 months). None showed a pattern of gradual increases over a longer timescale. Most of the patients remained on high doses continuously once a daily dose of ≥120 mg oral morphine equivalent (OME) was reached. CONCLUSION: These findings suggest that high-dose opioid regimens develop quickly in response to unknown clinical factors. An expected insidious upward drift in dose was not seen. The findings have implications for the prevention of potentially dangerous long-term, high-dose opioid prescribing. A dose of 60 mg OME or more is suggested as a useful 'red flag'.

Emergence of immune escape at dominant SARS-CoV-2 killer T cell epitope.

We studied the prevalent cytotoxic CD8 T cell response mounted against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike glycoprotein269-277 epitope (sequence YLQPRTFLL) via the most frequent human leukocyte antigen (HLA) class I worldwide, HLA A∗02. The Spike P272L mutation that has arisen in at least 112 different SARS-CoV-2 lineages to date, including in lineages classified as "variants of concern," was not recognized by the large CD8 T cell response seen across cohorts of HLA A∗02+ convalescent patients and individuals vaccinated against SARS-CoV-2, despite these responses comprising of over 175 different individual T cell receptors. Viral escape at prevalent T cell epitopes restricted by high frequency HLAs may be particularly problematic when vaccine immunity is focused on a single protein such as SARS-CoV-2 Spike, providing a strong argument for inclusion of multiple viral proteins in next generation vaccines and highlighting the need for monitoring T cell escape in new SARS-CoV-2 variants.

What Intervention Elements Drive Weight Loss in Blended-Care Behavior Change Interventions? A Real-World Data Analysis with 25,706 Patients.

BACKGROUND: Blended-care behavior change interventions (BBCI) are a combination of digital care and coaching by health care professionals (HCP), which are proven effective for weight loss. However, it remains unclear what specific elements of BBCI drive weight loss. OBJECTIVES: This study aims to identify the distinct impact of HCP-elements (coaching) and digital elements (self-monitoring, self-management, and education) for weight loss in BBCI. METHODS: Long-term data from 25,706 patients treated at a digital behavior change provider were analyzed retrospectively using a ridge regression model to predict weight loss at 3, 6, and 12 months. RESULTS: Overall relative weight loss was -1.63 kg at 1 month, -3.61 kg at 3 months, -5.28 kg at 6 months, and -6.55 kg at 12 months. The four factors of BBCI analyzed here (coaching, self-monitoring, self-management, and education) predict weight loss with varying accuracy and degree. Coaching, self-monitoring, and self-management are positively correlated with weight losses at 3 and 6 months. Learn time (i.e., self-guided education) is clearly associated with a higher degree of weight loss. Number of appointments outside of app coaching with a dietitian (coach) was negatively associated with weight loss. CONCLUSIONS: The results testify to the efficacy of BBCI for weight loss-with particular positive associations per time point-and add to a growing body of research that characterizes the distinct impact of intervention elements in real-world settings, aiming to inform the design of future interventions for weight management.

A simple, robust flow cytometry-based whole blood assay for investigating sex differential interferon alpha production by plasmacytoid dendritic cells.

Central to sex differences observed in outcome from infection and vaccination is the innate immune response, and specifically production of type I interferons by plasmacytoid dendtiric cells (pDCs), the main producers of IFN-α. Evaluation of IFN-α production by pDCs is therefore critical for studies of innate immune function. However, reliable measurement of pDC IFN-α is hampered by reduced cell yields and cytokine production after cryopreservation or after even short delays in stimulating freshly isolated cells. We here describe a simple yet robust method for measuring IFN-α production in pDCs that preserves cell activation and cytokine production through immediate stimulation of whole blood and subsequent maintenance at 37 °C.

Analyzing University of Virginia Health publications using open data, Python, and Streamlit.

As part of a larger project to understand the publishing choices of UVA Health authors and support open access publishing, a team from the Claude Moore Health Sciences Library analyzed an open data set from Europe PMC, which includes metadata from PubMed records. We used the Europe PMC REST API to search for articles published in 2017-2020 with "University of Virginia" in the author affiliation field. Subsequently, we parsed the JSON metadata in Python and used Streamlit to create a data visualization from our public GitHub repository. At present, this shows the relative proportions of open access versus subscription-only articles published by UVA Health authors. Although subscription services like Web of Science, Scopus, and Dimensions allow users to do similar analyses, we believe this is a novel approach to doing this type of bibliometric research with open data and open source tools.

Defining Fluoroquinolone Resistance-Mediating Mutations from Non-Resistance Polymorphisms in Mycoplasma hominis Topoisomerases.

Often dismissed as a commensal, Mycoplasma hominis is an increasingly prominent target of research due to its role in septic arthritis and organ transplant failure in immunosuppressed patients, particularly lung transplantation. As a mollicute, its highly reductive genome and structure render it refractile to most forms of treatment and growing levels of resistance to the few sources of treatment left, such as fluoroquinolones. We examined antimicrobial susceptibility (AST) to fluoroquinolones on 72 isolates and observed resistance in three (4.1%), with corresponding mutations in the quinolone resistance-determining region (QRDR) of S83L or E87G in gyrA and S81I or E85V in parC. However, there were high levels of polymorphism identified between all isolates outside of the QRDR, indicating caution for a genomics-led approach for resistance screening, particularly as we observed a further two quinolone-susceptible isolates solely containing gyrA mutation S83L. However, both isolates spontaneously developed a second spontaneous E85K parC mutation and resistance following prolonged incubation in 4 mg/L levofloxacin for an extra 24-48 h. Continued AST surveillance and investigation is required to understand how gyrA QRDR mutations predispose M. hominis to rapid spontaneous mutation and fluoroquinolone resistance, absent from other susceptible isolates. The unusually high prevalence of polymorphisms in M. hominis also warrants increased genomics' surveillance.

The experiences of socially vulnerable groups in England during the COVID-19 pandemic: A rapid health needs assessment.

OBJECTIVES: This rapid health needs assessment was undertaken to urgently identify the needs of socially vulnerable groups arising during the first wave of cases of the COVID-19 pandemic in England. The objective was to develop recommendations for policy makers and stakeholders to mitigate adverse impacts on socially vulnerable groups throughout the COVID-19 response and recovery period. STUDY DESIGN: Rapid health needs assessment. METHODS: The needs assessment employed qualitative methods to systematically collect data about the knowledge and views of key informants through semi-structured interviews and focus groups. Participants were either topic experts providing services to socially vulnerable groups who routinely face barriers to healthcare access or experts by experience. Participants included people experiencing homelessness, sex workers, people from Gypsy, Roma and Traveller communities and people facing challenges due to their immigration status. Data was collected over a week period in April/May 2020 and followed by thematic analysis to examine interview transcripts. RESULTS: Forty-two participants were included in the study, half of whom were experts by experience. Challenges with accessing and following COVID-19 information and government guidance were described as affecting all groups, due to exclusion from digital technology, translated resources, tailored support and adequate housing. Altered delivery of healthcare services, such as the closure of outreach and drop-in services, remote consultations, and online patient registration, were noted by interviewees as worsening existing barriers to accessing healthcare. Being charged for NHS care remained a key fear for migrants. All groups' access to income, education and social support were reported as being impacted by service closures and job losses, putting them at higher risk of destitution. Isolation, loneliness and deteriorating mental health were frequently reported. CONCLUSIONS: This assessment has highlighted the disproportionate impact of the COVID-19 pandemic on socially vulnerable groups and demonstrated a plethora of unmet needs. As the effects of COVID-19 continue, it is imperative that the needs of these groups are urgently and explicitly addressed and prioritised. This is essential to promote engagement with test and trace services, enable isolation adherence, and achieve high vaccine uptake in socially vulnerable populations.

Evaluation of the MYCOPLASMA IST3 urogenital mycoplasma assay in an international multicentre trial.

OBJECTIVES: To evaluate the accuracy, susceptibility and specificity of MYCOPLASMA IST3, the next generation of the most popular culture-based in vitro diagnostic device designed to detect, identify and test the susceptibility of urogenital mycoplasma infections. METHODS: MYCOPLASMA IST3 was evaluated against culture- and molecular-based gold standard methodologies to detect, identify, enumerate and determine antimicrobial resistance for Mycoplasma hominis and Ureaplasma species in 516 clinical samples collected across France, Serbia and the UK. Sample types included vulvovaginal/endocervical or urethral swabs (dry swab or eSwab®), semen and urine samples, which included blinded analysis following addition of a panel of 80 characterized control strains. RESULTS: Overall species identification was excellent for both Ureaplasma spp. (98.4% sensitivity, 99.7% specificity) and M. hominis (95.7% sensitivity, 100% specificity) relative to combined colony morphology on agar and quantitative PCR standards. Non-dilution-based bacterial load estimation by the assay was accurate between 83.7% (M. hominis) and 86.3% (Ureaplasma spp.) of the time (increased to 94.2% and 100%, respectively, if ±10-fold variance was allowed) relative to colonies counted on agar. Resistance accuracy for Ureaplasma spp. varied from gold standards for only 11/605 of individual tests (major error rate = 1.8%) and for 14/917 individual tests for M. hominis (major error rate = 1.5%). CONCLUSIONS: The redesigned MYCOPLASMA IST3 assay eliminated previous shortcomings by providing independent accurate resistance screening of M. hominis and Ureaplasma species, even in mixed infections, with CLSI-compliant thresholds. Specificity, sensitivity and enumeration estimates correlated closely with the confirmatory methods.

Plasmacytoid Dendritic Cells Facilitate Th Cell Cytokine Responses throughout Schistosoma mansoni Infection.

Plasmacytoid dendritic cells (pDCs) are potent producers of type I IFN (IFN-I) during viral infection and respond to IFN-I in a positive feedback loop that promotes their function. IFN-I shapes dendritic cell responses during helminth infection, impacting their ability to support Th2 responses. However, the role of pDCs in type 2 inflammation is unclear. Previous studies have shown that pDCs are dispensable for hepatic or splenic Th2 responses during the early stages of murine infection with the trematode Schistosoma mansoni at the onset of parasite egg laying. However, during S. mansoni infection, an ongoing Th2 response against mature parasite eggs is required to protect the liver and intestine from acute damage and how pDCs participate in immune responses to eggs and adult worms in various tissues beyond acute infection remains unclear. We now show that pDCs are required for optimal Th2 cytokine production in response to S. mansoni eggs in the intestinal-draining mesenteric lymph nodes throughout infection and for egg-specific IFN-γ at later time points of infection. Further, pDC depletion at chronic stages of infection led to increased hepatic and splenic pathology as well as abrogated Th2 cell cytokine production and activation in the liver. In vitro, mesenteric lymph node pDCs supported Th2 cell responses from infection-experienced CD4+ T cells, a process dependent on pDC IFN-I responsiveness, yet independent of Ag. Together, these data highlight a previously unappreciated role for pDCs and IFN-I in maintaining and reinforcing type 2 immunity in the lymph nodes and inflamed tissue during helminth infection.

Immunogenicity and protective efficacy of an intranasal live-attenuated vaccine against SARS-CoV-2.

Global deployment of an effective and safe vaccine is necessary to curtail the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we evaluated a Newcastle disease virus (NDV)-based vectored-vaccine in mice and hamsters for its immunogenicity, safety, and protective efficacy against SARS-CoV-2. Intranasal administration of recombinant (r)NDV-S vaccine expressing spike (S) protein of SARS-CoV-2 to mice induced high levels of SARS-CoV-2-specific neutralizing immunoglobulin A (IgA) and IgG2a antibodies and T-cell-mediated immunity. Hamsters immunized with two doses of vaccine showed complete protection from lung infection, inflammation, and pathological lesions following SARS-CoV-2 challenge. Importantly, administration of two doses of intranasal rNDV-S vaccine significantly reduced the SARS-CoV-2 shedding in nasal turbinate and lungs in hamsters. Collectively, intranasal vaccination has the potential to control infection at the site of inoculation, which should prevent both clinical disease and virus transmission to halt the spread of the COVID-19 pandemic.

Rationalisation of long-term high-dose opioids for chronic pain: development of an intervention and conceptual framework.

There has been a large increase in the number of prescriptions for opioid drugs in the United Kingdom over the last 20 years or more and the prescribing of opioids in high doses continues to increase. Much opioid prescribing is for chronic non-cancer pain (CNCP) despite serious doubts about the long-term effectiveness of opioids for this indication. Clinical experience is that there are increasing numbers of patients who are on high dosages of opioid drugs over sustained periods which provide limited or no pain relief while having significant negative effects on functioning and quality of life. The aim of this article is to bring readers' attention to some clinical observations of the CNCP population with high doses and to describe an intervention to reduce these doses. Many of these patients have no clinical features of addiction; we suggest that those who show little or no substance misuse behaviours are best understood as a distinct clinical population who have different treatment needs. In order to understand and treat these patients, a model is required which, rather than seeing the problem as lying solely with the patient, focuses on the interaction between the individual and his or her environment and seeks a change in what the patient does every day, rather than a simple, and largely unattainable, goal of symptom elimination. The clinician authors worked together to develop an intervention based upon approaches taken from both pain management and psychiatric practice. A detailed description of this rapid opioid reduction intervention (RORI) is provided along with some preliminary outcome data.

Identifying coping strategies used by patients at a transgender health clinic through analysis of free-text autobiographical narratives.

BACKGROUND: This paper presents an analysis of 32 narratives written by patients waiting for assessment at a transgender health clinic (THC) in England. Narratives are autobiographical free texts, designed to allow patients to describe in their own words their experiences of their gender identity and/or transition prior to a clinic appointment, as part of the assessment process. OBJECTIVE: Narratives were analysed to identify actions prospective patients had taken to manage their (usually lengthy) waiting times, so that these 'coping strategies' could be shared with future patients. DESIGN: Corpus linguistic methodology was utilized to identify common patterns across the whole corpus of text-based data, augmented with more detailed sociolinguistic analysis of individual narratives. RESULTS: There are broad commonalities in the way the transition experience is described across the corpus in terms of presentation of key experiences and feelings. There are specific descriptions of a number of recurring coping strategies, both positive and negative. CONCLUSION: The empowerment value of writing these narratives may be limited; the existence of recurring key features suggests that patients may feel they have to present their experiences in certain ways to be accepted for treatment. However, dissemination of some positive coping strategies may help future clients of THCs to better cope with waiting times, as well as assisting practitioners in THCs in supporting their patients during this wait. PATIENT/PUBLIC CONTRIBUTION: The clinic's Service Users' Research Advisory Group contributed to formulating the objective and design of the study. Results were presented at the clinic's annual PPI conference.

The neutrophil antimicrobial peptide cathelicidin promotes Th17 differentiation.

The host defence peptide cathelicidin (LL-37 in humans, mCRAMP in mice) is released from neutrophils by de-granulation, NETosis and necrotic death; it has potent anti-pathogen activity as well as being a broad immunomodulator. Here we report that cathelicidin is a powerful Th17 potentiator which enhances aryl hydrocarbon receptor (AHR) and RORγt expression, in a TGF-ß1-dependent manner. In the presence of TGF-ß1, cathelicidin enhanced SMAD2/3 and STAT3 phosphorylation, and profoundly suppressed IL-2 and T-bet, directing T cells away from Th1 and into a Th17 phenotype. Strikingly, Th17, but not Th1, cells were protected from apoptosis by cathelicidin. We show that cathelicidin is released by neutrophils in mouse lymph nodes and that cathelicidin-deficient mice display suppressed Th17 responses during inflammation, but not at steady state. We propose that the neutrophil cathelicidin is required for maximal Th17 differentiation, and that this is one method by which early neutrophilia directs subsequent adaptive immune responses.