Unintended Consequences of Immune Therapy for Immune-Mediated Diseases: Paradoxical Psoriasis and Dupilumab-Associated Musculoskeletal Syndrome.

Two presentations at the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) 2023 annual meeting focused on unintended consequences of immunomodulatory therapy for psoriasis (PsO). Dr. Elizabeth Wallace presented on unintended consequences of tumor necrosis factor inhibitors for treating PsO and other inflammatory disorders. These consequences include paradoxical PsO, which is defined as unexpected new PsO cases or worsening PsO symptoms seemingly induced by treatment. Dr. Bruce Kirkham focused on unintended consequences of dupilumab treatment, which can include a musculoskeletal syndrome similar to psoriatic arthritis.

Identification of nutrition factors in the metabolic syndrome and its progression over time in older adults: analysis of the TUDA cohort.

BACKGROUND: Nutrition is recognized as playing an important role in the metabolic syndrome (MetS), but the dietary components involved are unclear. We aimed to investigate nutrition factors in relation to MetS and its progression in older adults over a follow-up period of 5.4 years. METHODS: Community-dwelling adults (≥ 60y) from the Trinity-Ulster-Department-of-Agriculture study, sampled at baseline (2008-12) and follow-up (2014-18; n 953), were classified as 'with MetS' by having three or more of: waist circumference (≥ 102 cm, males; ≥ 88 cm, females); HDL-cholesterol (< 1.0 mmol/L, males; < 1.3 mmol/L, females); triglycerides (≥ 1.7 mmol/L); blood pressure (systolic ≥ 130 and/or diastolic ≥ 85 mmHg); and hemoglobin A1c (≥ 39 mmol/mol). RESULTS: MetS was identified in 67% of participants, increasing to 74% at follow-up. Predictors at baseline for the development of metabolic syndrome (MetS) at follow-up were higher waist circumference (odds ratio [95%CI]; 1.06 [1.01-1.11]), but not BMI, and increased triglyceride concentrations (2.01 [1.29-3.16]). In dietary analysis (at follow-up), higher protein (g/kg bodyweight/day) and monounsaturated fatty acid (g/day) intakes were each associated with lower risk of MetS (0.06 [0.02-0.20] and 0.88 [0.78-1.00], respectively), whilst higher protein was also associated with lower abdominal obesity (0.10 [0.02-0.51]) and hypertension (0.22 [0.00-0.80]). Furthermore, participants with, compared to without, MetS consumed less high-quality protein foods (P = 0.006) and more low-quality protein foods (P < 0.001), as defined by the protein digestibility-corrected amino acid score. CONCLUSIONS: Dietary interventions targeting protein quantity and quality may have specific benefits in preventing or delaying the progression of MetS in at-risk older people, but this requires investigation in the form of randomized trials.

Multimodal Blockade of the Renin-Angiotensin System in the Treatment of Cancer in Dogs Has Mild Adverse Effects in Some Dogs.

The renin-angiotensin system (RAS) is increasingly being recognized to play a role in the tumor microenvironment, promoting tumor growth. Studies blocking a single part of the RAS have shown mixed results, possibly due to the existence of different bypass pathways and redundancy within the RAS. As such, multimodal blockade of the RAS has been developed to exert more complete inhibition of the RAS. The aim of the present study was to assess the safety of multimodal RAS blockade in dogs. Five dogs (four with appendicular osteosarcoma, one with oral malignant melanoma) were treated with atenolol, benazepril, curcumin, meloxicam, and metformin. The dogs underwent clinical examination, blood pressure measurement, and hematology and serum biochemistry tests performed at 0, 1, 3, 6, 9, and 12 weeks, then every 3 months thereafter. End-of-life decisions were made by the owners. None of the dogs developed hypotension. One dog had intermittent vomiting during the 64 weeks it was on the trial. One dog had a one-off increase in serum SDMA(symmetrical dimethylarginine) concentration. Dogs were euthanized at weeks 3 (osteosarcoma), 10 (osteosarcoma), 17 (osteosarcoma), and 26 (oral malignant melanoma), and one dog was still alive at the end of the trial at 64 weeks (osteosarcoma). This is the first assessment of multimodal blockade of the RAS in dogs, and the results suggest it causes only mild adverse effects in some animals. The efficacy of the treatment was not assessed due to the small number of dogs. This pilot study allows for future larger studies assessing multimodal RAS blockade for the treatment of canine cancer.

Social media group support for antidepressant deprescribing: a mixed-methods survey of patient experiences.

Background Antidepressant use has continually increased in recent decades and although they are an effective treatment for moderate-to-severe depression, when there is no longer a clinical benefit, deprescribing should occur. Currently, routine deprescribing is not part of clinical practice and research shows that there has been an increase in antidepressant users seeking informal support online. This small scoping exercise used a mixed-methods online survey to investigate the motives antidepressant users have for joining social media deprescribing support groups, and what elements of the groups are most valuable to them. Methods Thirty members of two antidepressant deprescribing Facebook groups completed an online survey with quantitative and open-text response questions to determine participant characteristics and motivation for group membership. Quantitative data were analysed using descriptive statistics, and open-text responses were analysed thematically through NVivo. Results Two overarching themes were evident: first, clinician expertise , where participants repeatedly reported a perceived lack of skills around deprescribing by their clinician, not being included in shared decision-making about their treatment, and symptoms of withdrawal during deprescribing going unaddressed. Motivated by the lack of clinical support, peer support developed as the second theme. Here, people sought help online where they received education, knowledge sharing and lived experience guidance for tapering. The Facebook groups also provided validation and peer support, which motivated people to continue engaging with the group. Conclusions Antidepressant users who wish to cease their medication are increasingly subscribing to specialised online support groups due to the lack of information and support from clinicians. This study highlights the ongoing need for such support groups. Improved clinician understanding about the complexities of antidepressant deprescribing is needed to enable them to effectively engage in shared decision-making with their patients.

Secondary hyperparathyroidism: Predictors and relationship with vitamin D status, bone turnover markers and bone mineral density.

INTRODUCTION: Secondary hyperparathyroidism (SHPT) has adverse implications for bone health but is relatively understudied. In this study we examine the prevalence and determinants of SHPT and describe the relationship of SHPT with bone turnover markers and bone mineral density (BMD) in older Irish adults. METHOD: Eligible participants (n = 4139) were identified from the Trinity-Ulster-Department of Agriculture (TUDA) study, a cohort of Irish adults aged ≥60 years. Exclusion criteria included an estimated glomerular filtration rate (eGFR) <30 ml/min and serum calcium >2.5 mmol/l to remove hyperparathyroidism due to advanced chronic kidney disease (CKD) and primary hyperparathyroidism respectively. The relationship between SHPT and bone turnover markers and BMD (measured by densitometry) was examined in a subsample (n = 1488). Vitamin D deficiency was defined as 25-hydroxyvitamin D [25 (OH)D] <30 nmol/l. RESULTS: Participants had a mean age of 73.6 ± 7.9 years, 65.1 % were female and 19.4 % were found to be vitamin D deficient. The prevalence of SHPT decreased as vitamin D increased, from 30.6 % in those deficient to 9.8 % in those with 25(OH)D ≥ 50 nmol/l and increased with declining kidney function. In non­calcium supplement users, principal determinants of SHPT were vitamin D deficiency (OR 4.18, CI 3.05-5.73, p < 0.001), eGFR 30-44 ml/min (OR 3.69, CI 2.44-5.57, p < 0.001), loop diuretic use (OR 3.52, CI 2.59-4.79, p < 0.001) and to a lesser extent body mass index (p = 0.001), eGFR 45-59 ml/min (p < 0.001) and 25(OH)D level 30-49 nmol/l (p = 0.002). Similar findings were observed in calcium supplement users, though proton pump inhibitors were also associated with SHPT (OR 1.55, CI 1.08-2.22, p = 0.018) while vitamin D 30-49 nmol/l was not. In participants with SHPT versus those without, bone turnover markers were higher: bone alkaline phosphatase (p = 0.017) and tartrate-resistant acid phosphatase (p = 0.033), whilst there was lower BMD at the neck of femur (0.880 vs. 0.903 g/cm2, p = 0.033) and total hip (0.968 vs. 0.995 g/cm2, P = 0.017). DISCUSSION: The results show that up to one in six older Irish adults had SHPT and this was associated with lower BMD and higher concentrations of bone turnover markers. Both vitamin D deficiency and 25(OH)D level 30-49 nmol/l were important predictors of SHPT. Loop diuretics and PPIs may also increase the risk of SHPT, and their use may need to be carefully considered in this population. Further studies examining the potential impact of these factors on bone health in similar populations to our study sample are warranted.

Accelerator mass spectrometry measurements of 233U in groundwater, soil and vegetation at a legacy radioactive waste site.

Low-level radioactive wastes were disposed at the Little Forest Legacy Site (LFLS) near Sydney, Australia between 1960 and 1968. According to the disposal records, 233U contributes a significant portion of the inventory of actinide activity buried in the LFLS trenches. Although the presence of 233U in environmental samples from LFLS has been previously inferred from alpha-spectrometry measurements, it has been difficult to quantify because the 233U and 234U α-peaks are superimposed. Therefore, the amounts of 233U in groundwaters, soils and vegetation from the vicinity of the LFLS were measured using accelerator mass spectrometry (AMS). The AMS results show the presence of 233U in numerous environmental samples, particularly those obtained within, and in the immediate vicinity of, the trenched area. There is evidence for dispersion of 233U in groundwater (possibly mobilised by co-disposed organic liquids), and the data also suggest other sources of 233U contamination in addition to the trench wastes. These may include leakages and spills from waste drums as well as waste burnings, which also occurred at the site. The AMS results confirm the historic information regarding disposal of 233U in the LFLS trenches. The AMS technique has been valuable to ascertain the distribution and environmental behaviour of 233U at the LFLS and the results demonstrate the applicability of AMS for evaluating contamination of 233U at other radioactive waste sites.

Parental awareness and attitudes towards prevention of respiratory syncytial virus in infants and young children in Australia.

AIM: To assess parental awareness of respiratory syncytial virus (RSV) and the level of acceptance of future RSV prevention strategies. METHODS: A cross-sectional online survey was implemented targeting "future" and "current" parents of children aged ≤5 years in Australia. RESULTS: From 1992 eligible participants, two non-mutually exclusive subgroups were formed: "current" parents (N = 1931) and "pregnant/planning" parents (N = 464: 403 also "current" parents and 61 "future" parents). Participants were predominantly (86.6%) aged 25-39 years and 68.5% with university education. The majority (89.6% current; 78.7% future) had heard of RSV. Of those, 64.2% (current) and 50.0% (future) were aware that pneumonia is associated with RSV; 71.8% (current) and 52.1% (future) were aware that bronchiolitis is associated with RSV. In multivariable logistic regression analyses, Australian-born parents (aOR = 2.47 [95% CI: 1.48-4.12]), living in the eastern states (e.g., New South Wales: aOR = 6.15 [95% CI:2.10-18.04]), with a university-level education (aOR = 2.61 [95% CI:1.38-4.94]) and being a current parent (aOR = 12.26 [95% CI:2.82-53.28]) were associated with higher RSV awareness. There was a high level of acceptance for maternal vaccines (future: 79.3%) and infant immunisation (all: 81.7%). CONCLUSION: While RSV awareness and immunisation acceptance were high, there was limited knowledge of severity of RSV, especially in future parents. Education campaigns need to be developed to increase RSV knowledge.

Understanding Australian general practice patients' decisions to deprescribe antidepressants in the WiserAD trial: a realist informed approach.

OBJECTIVES: To evaluate how an approach to antidepressant deprescribing works, for whom, and in what contexts by (1) examining the experiences and perceptions of the approach for antidepressant users, (2) identifying the mechanisms of the approach and (3) describing what contexts are associated with antidepressant tapering. DESIGN: This mixed methods study was informed by the principles of realist evaluation and was conducted in the first 3 months of participation in the WiserAD randomised control trial. SETTING: General practice, Victoria, Australia. PARTICIPANTS: 13 antidepressant users from general practice participating in the WiserAD trial for antidepressant deprescribing. INTERVENTION: A patient-facing, web-based structured support tool that consists of a personalised tapering schedule, an action plan for managing withdrawal symptoms, a daily mood, sleep and activity tracker and mental health nurse support. PRIMARY/SECONDARY OUTCOME MEASURES: The outcomes of the study were revealed on data analysis as per a realist evaluation approach which tests and refines an initial programme theory. RESULTS: The contexts of learnt coping skills, knowledge and perceptions of antidepressants and feeling well were evident. Outcomes were intention to commence, initiation of deprescribing and successful completion of deprescribing. Key mechanisms for antidepressant deprescribing were (1) initiation of the deprescribing discussion; (2) patient self-efficacy; (3) provision of structured guidance; (4) coaching; (5) mood, sleep and activity tracking and (6) feelings of safety during the tapering period. CONCLUSIONS: The WiserAD approach to antidepressant deprescribing supported participants to commence and/or complete tapering. The refined programme theory presents the WiserAD pragmatic framework for the application of antidepressant deprescribing in clinical practice. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT05355025; ACTRN12622000567729; ISRCTN11562922; Pre-results.

Low-Grade systemic inflammation is associated with domain-specific cognitive performance and cognitive decline in older adults: Data from the TUDA study.

Studies examining the relationships between chronic inflammation, cognitive function and cognitive decline in older adults have yielded conflicting results. In a large cohort of older adults free from established dementia (n = 3270; 73.1 ± 7.9 years; 68.4% female), we evaluated the cross-sectional and longitudinal relationships between serum cytokines (IL-6, IL-10, TNF-α) and both global and domain-specific cognitive performance (Repeatable Battery for Assessment of Neuropsychological Status [RBANS]). Higher IL-6 (OR: 1.33; 1.06, 1.66, p = 0.01), TNF-α (OR: 1.35; 1.09, 1.67, p = 0.01) and IL-6:IL-10 Ratio (OR: 1.43; 1.17, 1.74, p = 0.001) were cross-sectionally associated with impaired global RBANS performance. For specific cognitive domains, greatest effect sizes were observed between higher TNF-α levels and poorer visual-spatial and attention performance. In a subset of participants (n = 725; 69.8 ± 5.5 years; 67.0% female) with repeat assessment performed at a median of 5.4 years, only higher baseline IL-6:IL-10 ratio was associated with impaired incident overall, immediate memory and visual-spatial performance. Associations were stronger in females, but not modified by age or APOE genotype.

Type 17-specific immune pathways are active in early spondyloarthritis.

OBJECTIVE: Undifferentiated, early inflammatory arthritis (EIA) can differentiate into seropositive or seronegative rheumatoid arthritis (RA), peripheral spondyloarthritis (SpA) or remain as seronegative undifferentiated inflammatory arthritis (UIA). Little is known about immune pathways active in the early stages of SpA and seronegative UIA, in contrast to detailed knowledge of seropositive RA. The aim of this study was to examine if specific immune pathways were active in synovial CD4+ and CD8+ T cells in EIA. METHODS: Synovial fluid (SF) samples from 30 patients with EIA were analysed for expression of IL-17A, IFNγ and TNFα in CD8+ or CD4+ T cells. Final clinical diagnoses were made at least 12 months after sample collection, by two independent clinicians blind to the study data. RESULTS: Flow cytometry analysis of all EIA samples indicated considerable variation in synovial IL-17A+CD8+ T cells (Tc17) cell frequencies between patients. The group with a final diagnosis of SpA (psoriatic arthritis or peripheral SpA, n=14) showed a significant enrichment in the percentage of synovial Tc17 cells compared with the group later diagnosed with seronegative UIA (n=10). The small number of patients later diagnosed with seropositive RA (n=6) patients had few Tc17 cells, similar to our previous findings in established disease. In contrast, RA SF contained a significantly higher percentage of CD8+IFNγ+ T cells compared with SpA or seronegative UIA. CONCLUSION: These results suggest that adaptive T cell cytokine pathways differ not only between RA and SpA but also seronegative UIA early in the disease process, with a particular activation of Tc17 pathways in early SpA.

A mixed-methods evaluation of the impacts of an online Carer wellbeing and connection program.

Objective: To evaluate a facilitated, 90-min session, delivered for four weeks, Online Carer Wellbeing and Connection Program in Victoria, Australia. Methods: One hundred and three carers took part in the evaluation. Eighty-six completed both pre- and post-program surveys evaluating program impacts on psychological distress, perceived loneliness, and social support. Qualitative interviews were conducted (n = 76) post-program for experiential data. Findings: Paired samples t-tests showed significant decreases between pre- and post-program for psychological distress (M = 25.10, SD = 7.08; M = 22.00, SD = 6.57; t(85) = 4.88, p = 0.000), perceived loneliness (M = 6.69, SD = 1.89; M = 6.14, SD = 1.76; t(85) = 3.45, p = 0.000) and perceived social support (M = 8.31, SD = 2.48; M = 8.83, SD = 2.21; t(85) = -2.54, p = 0.013). Thematic analysis identified positive experiences and the mechanisms of action (or the ingredients for program success) as: 1. Delivery by a trained facilitator; 2. Provision of respite for person being cared for during meetings; 3. Technical assistance; 4. Online modality; 5. Inclusivity; 6. Diversity of experience; 7. Shared understanding; 8. Safety; 9. Emotional release; 10. Reflection, and; 11. Self-care practices. Innovation: A model illustrating the mechanisms of action based on the findings of the mixed-methods evaluation is presented to support wider implementation and translation. Conclusion: The online program effectively reduced psychological distress and loneliness and improved carer wellbeing.

West Australian parents' views on vaccinating their children against COVID-19: a qualitative study.

BACKGROUND: Australian children and adolescents were among the last local cohorts offered COVID-19 vaccines. Despite promising initial uptake, coverage subsequently plateaued, requiring further efforts to improve access and build parents' recognition of the importance of COVID-19 vaccination. We sought to understand West Australian (WA) parents' willingness to vaccinate their children to inform strategies for improving uptake at the time in which they were becoming eligible. METHODS: We undertook in-depth qualitative interviews with 30 parents of children aged 5-17 years from June - December 2021. During this period, children aged 12-15 years became eligible for vaccination; children aged 5-11 years became eligible shortly thereafter. Data were thematically analysed in NVivo. RESULTS: Most parents intended on vaccinating their children once eligible. Parents sought to protect their children, to protect the community, to resume travel, and to get back to "normal". They reflected that vaccination against key infectious threats is a routine activity in childhood. Some were concerned about the vaccine, particularly mRNA vaccines, being new technology or impacting fertility. "Wait-awhiles" wanted to see what other parents would do or were delaying until they felt that there was a higher risk of COVID-19 in WA. Most parents of younger children wanted their child to be vaccinated at the general practice clinic due to familiarity and convenience. Parents were particularly eager for clear and consistent messaging about vaccination of children and adolescents, including safety, importance, scientific evidence, and personal stories. CONCLUSION: For future pandemic vaccinations pertaining to children, governments and health officials need to address parents' concerns and meet their preferences for the delivery of the vaccine program to children and adolescents.

The association between proton pump inhibitors and hyperparathyroidism: a potential mechanism for increased fracture-results of a large observational cohort study.

Proton pump inhibitors (PPIs) are associated with increased risk of osteoporotic fracture; however, the mechanism is unclear. PPI users taking calcium supplements were more likely to have hyperparathyroidism compared to non-users (OR 1.56, CI 1.08-2.23, p = 0.018). This highlights the importance of monitoring PPI use, especially in older adults. PURPOSE: Proton pump inhibitors (PPIs) are associated with increased risk of osteoporotic fracture. Hyperparathyroidism may be implicated, but few studies have considered this relationship. This study evaluated the relationship between PPI use and hyperparathyroidism in older adults. METHODS: Participants were from the TUDA study, a large cross-sectional cohort of older Irish adults. Participants with an estimated glomerular filtration rate (eGFR) < 30 ml/min and serum calcium > 2.5 mmol/l were excluded to avoid hyperparathyroidism due to chronic renal disease and primary hyperparathyroidism. Hyperparathyroidism was defined as a parathyroid hormone (PTH) > 65 pg/ml. Multivariate regression models were used to analyse the relationship between PPI use and hyperparathyroidism. RESULTS: A total of 4139 participants met the inclusion criteria, of whom 37.8% (n = 1563) were taking PPI medication. PPI use was identified in 41.4% of calcium supplement users and 35.4% of non-calcium supplement users. Overall, compared to non-users of PPIs, those taking PPIs were older (74.8 vs 72.9 years, p < 0.001) and had a higher prevalence of hyperparathyroidism (17.8 vs 11.0%, p < 0.001). In those taking calcium supplements (but not in non-users), PPI use was significantly associated with hyperparathyroidism (OR 1.56, CI 1.08-2.23, p = 0.018) after adjusting for age, sex, body mass index, serum vitamin D, eGFR, timed-up-and-go, dairy intake, medications, and comorbidities. DISCUSSION: The results are consistent with the hypothesis of PPIs reducing calcium absorption, leading to a rise in PTH which could mediate increased fracture risk. No relationship of PPI use with hyperparathyroidism was observed in non-users of calcium supplements, possibly owing to lower dietary calcium intake. These results highlight the importance of monitoring PPI use, especially in older adults at risk of fracture.

What follow-up interventions, programmes and pathways exist for minor stroke survivors after discharge from the acute setting? A scoping review.

OBJECTIVE: To identify the breadth and range of follow-up interventions currently provided to people after minor stroke with a focus on the definitions used for minor stroke, intervention components, intervention theory and outcomes used. These findings will inform the development and feasibility testing of a pathway of care. DESIGN: Scoping review. SEARCH STRATEGY: The final search was run in January 2022. Five databases were searched-EMBASE, MEDLINE, CINAHL, British Nursing Index and PsycINFO. Grey literature was also searched. Title and abstract screening and full-text reviews were conducted by two researchers and a third was involved when differences of opinion existed. A bespoke data extraction template was created, refined and then completed. The Template for Intervention Description and Replication (TIDieR) checklist was used to describe interventions. RESULTS: Twenty-five studies, using a range of research methodologies were included in the review. A range of definitions were used for minor stroke. Interventions focused largely on secondary prevention and management of increased risk of further stroke. Fewer focused on the management of hidden impairments experienced after minor stroke. Limited family involvement was reported and collaboration between secondary and primary care was seldom described. The intervention components, content, duration and delivery were varied as were the outcome measures used. CONCLUSION: There is an increasing volume of research exploring how best to provide follow-up care to people after minor stroke. Personalised, holistic and theory-informed interdisciplinary follow-up is needed that balances education and support needs with adjustment to life after stroke.

Characterization of a Musculoskeletal Syndrome of Enthesitis and Arthritis in Patients With Atopic Dermatitis Treated With Dupilumab, an Interleukin-4/13 Inhibitor.

OBJECTIVE: To characterize the presentation and outcomes of patients with atopic dermatitis (AD) who developed musculoskeletal symptoms after treatment with dupilumab, a human IgG4 monoclonal antibody that blocks the functions of interleukin-4 (IL-4) and IL-13, key pathologic pathways in AD. METHODS: This article reports an observational cohort of patients receiving dupilumab who developed new-onset musculoskeletal symptoms after dupilumab therapy at our center. All patients had a comprehensive rheumatologic history and examination, with imaging by ultrasonography (US) or magnetic resonance imaging (MRI) in most patients. RESULTS: Between October 2018 and February 2021, we recorded 470 patients with AD commencing dupilumab treatment from routine clinical care records. Of 36 patients referred for rheumatologic assessment, we identified 26 patients (14 male, 12 female) with a musculoskeletal syndrome of inflammatory enthesitis, arthritis, and/or tenosynovitis. Clinical findings were confirmed by US and MRI. All patients had very good response to dupilumab treatment, and no specific predictors of musculoskeletal syndrome were noted. Symptoms were mild in 16 patients, moderate in 6 patients, and severe in 4 patients. Receipt of nonsteroidal antiinflammatory drugs or cyclooxygenase 2 inhibitors, reduction of dupilumab dose/frequency, and cessation of dupilumab therapy led to improvement, but moderate or severe symptoms persisted for many months. CONCLUSION: We report a new musculoskeletal syndrome of inflammatory enthesitis/arthritis/tenosynovitis in some patients receiving the IL-4 receptor antagonist dupilumab. This response to a cytokine-targeting therapy provides key insights into the pathogenesis of enthesitis.

Relapsing polychondritis - A single Centre study in the United Kingdom.

INTRODUCTION AND OBJECTIVES: Relapsing Polychondritis (RP) is a rare immune mediated inflammatory disorder that may result in damage and destruction of cartilaginous tissues. PATIENTS AND METHODS: We retrospectively analysed patients with a clinical diagnosis of RP. Patients were investigated using pulmonary function tests, dynamic high-resolution CT scans, bronchoscopy, laryngoscopy and/or PET-CT scans along with autoimmune serology. Patients had other specialist reviews when indicated. RESULTS: We identified 68 patients with a diagnosis of RP, 55 (81%) were Caucasian, 8 (12%) Afro Caribbean, 4 (6%) Asian and 1 patient had Mixed Ethnicity. Twenty-nine (43%) had pulmonary involvement and in 16, pulmonary involvement was the initial presentation. The mean age at onset was 44 years (range 17-74). There was a mean diagnostic delay of 55 weeks. Sixty-six (97%) patients received a combination of oral Prednisolone and disease modifying anti-rheumatic drugs. Twelve of 19 (63%) received biologics, with an initial good response, and 10 remain on treatment. Eleven patients with respiratory collapse required CPAP to maintain airway patency. Twelve (18%) patients died due to RP and 9 had respiratory complications. Two patients developed myelodysplasia and one had lung carcinoma. In a multivariate regression analysis, the prognostic variables were ethnicity, nasal chondritis, laryngotracheal stricture and elevated serum creatinine. CONCLUSION: RP is a rare autoimmune condition often associated with significant delays in diagnosis and initiation of treatment. Pulmonary involvement in RP may cause significant morbidity and mortality due to organ damage. Disease modifying anti rheumatic drugs and biologics should be considered early in the disease course to minimise adverse effects of long-term corticosteroid therapy and organ damage.

Self-reported reasons for reducing or stopping antidepressant medications in primary care: thematic analysis of the diamond longitudinal study.

BACKGROUND: Current treatment guidelines advise that the deprescribing of antidepressants should occur around 6 months post-remission of symptoms. However, this is not routinely occurring in clinical practice, with between 30% and 50% of antidepressant users potentially continuing treatment with no clinical benefit. To support patients to deprescribe antidepressant treatment when clinically appropriate, it is important to understand what is important to patients when making the decision to reduce or cease antidepressants in a naturalistic setting. AIM: The current study aimed to describe the self-reported reasons primary care patients have for reducing or stopping their antidepressant medication. METHODS: Three hundred and seven participants in the diamond longitudinal study reported taking an SSRI/SNRI over the life of the study. Of the 307, 179 reported stopping or tapering their antidepressant during computer-assisted telephone interviews and provided a reason for doing so. A collective case study approach was used to collate the reasons for stopping or tapering. FINDINGS: Reflexive thematic analysis of patient-reported factors revealed five overarching themes; 1. Depression; 2. Medication; 3. Healthcare system; 4. Psychosocial, and; 5. Financial. These findings are used to inform suggestions for the development and implementation of antidepressant deprescribing discussions in clinical practice.

Chemokine CXCL4 interactions with extracellular matrix proteoglycans mediate widespread immune cell recruitment independent of chemokine receptors.

Leukocyte recruitment from the vasculature into tissues is a crucial component of the immune system but is also key to inflammatory disease. Chemokines are central to this process but have yet to be therapeutically targeted during inflammation due to a lack of mechanistic understanding. Specifically, CXCL4 (Platelet Factor 4, PF4) has no established receptor that explains its function. Here, we use biophysical, in vitro, and in vivo techniques to determine the mechanism underlying CXCL4-mediated leukocyte recruitment. We demonstrate that CXCL4 binds to glycosaminoglycan (GAG) sugars on proteoglycans within the endothelial extracellular matrix, resulting in increased adhesion of leukocytes to the vasculature, increased vascular permeability, and non-specific recruitment of a range of leukocytes. Furthermore, GAG sulfation confers selectivity onto chemokine localization. These findings present mechanistic insights into chemokine biology and provide future therapeutic targets.

General Practice Patients' Experiences and Perceptions of the WiserAD Structured Web-Based Support Tool for Antidepressant Deprescribing: Protocol for a Mixed Methods Case Study With Realist Evaluation.

BACKGROUND: Research suggests that the rapid increase in worldwide antidepressant use is mainly due to a rise in long-term and potentially inappropriate use. It has been suggested that 1 in 3 antidepressant users among general practice patients are no longer experiencing clinical benefits from their medication and should commence deprescribing. However there are many barriers to antidepressant deprescribing for both patients and clinicians, which adds to the complex nature of reducing or ceasing the medication. As such, antidepressant deprescribing does not routinely occur in clinical practice. Evidence-based supports and interventions for safe and successful antidepressant deprescribing are needed to assist patients and their doctors. Interventions should also include an understanding of how an intervention works, why it works, and whom it is for. OBJECTIVE: This study aims to evaluate how the WiserAD approach to antidepressant deprescribing works, whom it is for, and the underlying circumstances by (1) examining the experiences and perceptions of WiserAD among antidepressant users, (2) identifying the underlying mechanisms of the WiserAD approach to antidepressant deprescribing, and (3) describing in what contexts and to what extent the underlying mechanisms of WiserAD are suited for antidepressant users. METHODS: A mixed methods case study with realist evaluation will be conducted among participants in the WiserAD randomized controlled trial for antidepressant deprescribing. Quantitative data will be obtained from up to 12 participants from the intervention and control arms at baseline and 3-month follow-up. Baseline data will be used to characterize the sample using descriptive statistics. Paired samples t tests will also be performed to compare responses between baseline and 3-month follow-up for participant self-management, skills, confidence and knowledge, beliefs about medicines, current emotional health, and well-being symptoms. Qualitative data from the same participants will be collected via narrative interview at 3-month follow-up. Quantitative and qualitative data will be converged to form a "case," and analysis will be conducted within each case with comparisons made across multiple cases. RESULTS: Recruitment of participants commenced in October 2022 and will be completed by March 2023. Analysis will be completed by June 2023. CONCLUSIONS: To our knowledge, this will be the first realist evaluation of an antidepressant deprescribing intervention in general practice. Findings from this evaluation may assist in the implementation of the WiserAD approach to antidepressant deprescribing in routine clinical practice. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/42526.