Anatomical pattern of entheseal and synovial fibroblast activation in patients with psoriasis and its risk of developing psoriatic arthritis.

OBJECTIVES: To assess the presence and anatomical distribution of activated fibroblasts in the joints and entheses of patients with psoriasis with arthralgia and to test how fibroblast activation visualised by 68gallium-labelled fibroblast activation protein inhibitor-04 (68Ga-FAPI-04)-positron emission tomography (PET)/CT correlates with clinical tenderness, musculoskeletal ultrasound findings and progression to psoriatic arthritis (PsA). METHODS: We conducted a prospective cohort study in patients with psoriasis and arthralgia who underwent clinical and ultrasound evaluation and whole-body PET/CT imaging with 68Ga-FAPI-04. 68Ga-FAPI-04 uptake at synovial and entheseal sites was assessed by maximal standardised uptake values (SUVmax) and PET/CT Joint Index (JI); logistic regression models were used to investigate its correlation with clinical and ultrasound findings. Survival analyses were performed on patients with at least 6 months of follow-up. RESULTS: 36 patients with psoriasis were enrolled. 68Ga-FAPI-04 uptake was found in 318 (7.9%) joints and 369 (7.3%) entheses in 29 (80.6%) participants, with a mean SUVmax (SD) of 3.2 (1.8) for joints and 2.9 (1.6) for entheses. Large joints and the lower limbs were predominantly affected. A significant positive relationship was found between 68Ga-FAPI-04-PET/CT signal intensity and the 68 tender joint count (SUVmax: p<0.001; PET/CT-JI: p<0.001) and tender entheses count (SUVmax: p<0.001; PET/CT-JI: p=0.002). No correlations were found with ultrasound findings (SUVmax: p=0.969; PET/CT-JI: p=0.720). Patients with relevant synovio-entheseal 68Ga-FAPI-04 uptake showed a statistically significant higher risk of developing PsA (p=0.02), independent of ultrasound findings. CONCLUSIONS: Patients with psoriasis presenting with arthralgia show localised signs of resident tissue activation in joints and entheses, which are associated with higher risk of developing PsA.

Unveiling metabolic similarities of entheses in psoriasis and psoriatic arthritis patients using non-invasive in vivo imaging - results from the MAPSA study.

OBJECTIVES: To assess and compare molecular tissue changes at the entheses in patients with psoriasis (PsO), psoriatic arthritis (PsA), and healthy controls (HC) in vivo using multispectral optoacoustic tomography (MSOT) and to describe their relationship with clinical and ultrasound findings of enthesitis. METHODS: A cross-sectional study (MAPSA) in bDMARD-naïve PsA and PsO patients and HC was performed. Participants underwent clinical, ultrasonographic and MSOT examination of six entheses (lateral humeral epicondyle, distal patellar tendon attachment, Achilles tendon attachment). MSOT-measured haemoglobin (Hb), oxygen saturation (SO2), collagen, and lipid levels were quantified and mean differences between groups were calculated using linear mixed-effects models. MSOT-measured analytes were compared between entheses with and without clinical and ultrasound anomalies. RESULTS: Ninety participants were included (30 PsO, 30 PsA, 30 HC), 540 entheses were clinically assessed, and 540 ultrasound and 830 MSOT scans were obtained. Both PsA and PsO patients showed increased oxygenated Hb (PsA: p=0.003; PsO: p=0.054) and SO2 (PsA: p<0.001; Pso: p=0.001) levels and decreased collagen signals (PsA: p<0.001; PsO: <0.001) compared to HC, with more pronounced changes in PsA. Significantly lower collagen levels (p=0.01) and increased lipids (p=0.03) were recorded in tender entheses compared to non-tender ones. Erosions and enthesophytes on ultrasound were associated with significant differences in SO2 (p=0.014) and lipid signals (p=0.020), respectively. CONCLUSIONS: PsA and PsO patients exhibit an analogous metabolic pattern at the entheses that is exacerbated in the presence of inflammation. These findings support the notion of a psoriatic disease spectrum characterized by common immuno-metabolic tissue changes.

Risk of developing psoriatic arthritis in psoriasis cohorts with arthralgia: exploring the subclinical psoriatic arthritis stage.

OBJECTIVE: Subjects with subclinical psoriatic arthritis (PsA), defined as the presence of arthralgia in psoriasis (PsO), are at higher risk of PsA but scant real-world data exist. Our aims were to (1) estimate the probability of PsA development in subclinical PsA, (2) characterise subclinical PsA symptoms and (3) determine the clinical patterns at PsA diagnosis. METHODS: Patients with PsO, mainly subclinical PsA, were evaluated longitudinally in two European cohorts. The key outcome was new-onset PsA. Musculoskeletal symptoms including inflammatory and non-inflammatory symptoms before PsA diagnosis were collected. Occurrence of PsA was analysed with survival analysis and cumulative incidence functions (CIFs). RESULTS: 384 patients with PsO were included with a mean follow-up of 33.0 (±20.9) months. 311 of 384 (80.9%) had subclinical PsA with a PsA incidence rate of 7.7 per 100 patient-years. Subclinical PsA displayed a higher risk of PsA development compared with PsO (HR=11.7 (95% CI 1.57 to 86.7), p=0.016). The probability of new-onset PsA estimated by the CIF was 9.4% (95% CI 4.7% to 10.6%) at month 12 and 22.7% (95% CI 17.2% to 28.6%) at month 36. 58.9% of cases reported inflammatory symptoms in the months immediately prior to PsA diagnosis but prior non-inflammatory symptoms were evident in 83.9% prior to PsA diagnosis. Peripheral joint swelling was the predominant PsA presentation pattern (82.1%). CONCLUSIONS: The probability of PsA development among subclinical PsA was relatively high, emphasising the importance of emergent musculoskeletal symptoms when aiming for PsA prevention. Joint swelling was the dominant feature in new-onset PsA, likely reflecting clinical confidence in recognising joint swelling.

Metabolic rewiring promotes anti-inflammatory effects of glucocorticoids.

Glucocorticoids represent the mainstay of therapy for a broad spectrum of immune-mediated inflammatory diseases. However, the molecular mechanisms underlying their anti-inflammatory mode of action have remained incompletely understood1. Here we show that the anti-inflammatory properties of glucocorticoids involve reprogramming of the mitochondrial metabolism of macrophages, resulting in increased and sustained production of the anti-inflammatory metabolite itaconate and consequent inhibition of the inflammatory response. The glucocorticoid receptor interacts with parts of the pyruvate dehydrogenase complex whereby glucocorticoids provoke an increase in activity and enable an accelerated and paradoxical flux of the tricarboxylic acid (TCA) cycle in otherwise pro-inflammatory macrophages. This glucocorticoid-mediated rewiring of mitochondrial metabolism potentiates TCA-cycle-dependent production of itaconate throughout the inflammatory response, thereby interfering with the production of pro-inflammatory cytokines. By contrast, artificial blocking of the TCA cycle or genetic deficiency in aconitate decarboxylase 1, the rate-limiting enzyme of itaconate synthesis, interferes with the anti-inflammatory effects of glucocorticoids and, accordingly, abrogates their beneficial effects during a diverse range of preclinical models of immune-mediated inflammatory diseases. Our findings provide important insights into the anti-inflammatory properties of glucocorticoids and have substantial implications for the design of new classes of anti-inflammatory drugs.

Twelve Years of Drug Prioritization to Help Accelerate Disease Modification Trials in Parkinson's Disease: The International Linked Clinical Trials Initiative.

In 2011, the UK medical research charity Cure Parkinson's set up the international Linked Clinical Trials (iLCT) committee to help expedite the clinical testing of potentially disease modifying therapies for Parkinson's disease (PD). The first committee meeting was held at the Van Andel Institute in Grand Rapids, Michigan in 2012. This group of PD experts has subsequently met annually to assess and prioritize agents that may slow the progression of this neurodegenerative condition, using a systematic approach based on preclinical, epidemiological and, where possible, clinical data. Over the last 12 years, 171 unique agents have been evaluated by the iLCT committee, and there have been 21 completed clinical studies and 20 ongoing trials associated with the initiative. In this review, we briefly outline the iLCT process as well as the clinical development and outcomes of some of the top prioritized agents. We also discuss a few of the lessons that have been learnt, and we conclude with a perspective on what the next decade may bring, including the introduction of multi-arm, multi-stage clinical trial platforms and the possibility of combination therapies for PD.

Sustainable aquatic resource management and inland fisheries in tropical Asia: Interdisciplinary and transdisciplinary approaches.

The intensive utilization of tropical inland water bodies for multiple and sometimes competing activities underlines the necessity for their integrated and holistic co-management. This paper presents our synthesis on lake and reservoir fisheries in South and Southeast Asia as social-ecological systems, based on a synopsis of our research findings from a previous EU-funded research programme in Sri Lanka, Thailand and the Philippines (FISHSTRAT project). The paper attempts to merge our results with recent developments in research, policy and practice. We explore the effects of the main external and internal control mechanisms of the trophic state and pinpoint to the high production potential of traditionally unexploited small indigenous fish species. The limitations of conventional centralized management systems highlight the importance of introducing transdisciplinary approaches which integrate limnology, fish ecology and fisheries with the interests of other resource using stakeholders and decision makers in order to develop locally appropriate co-management strategies for sustainable aquatic resource use.

The effect of single-component sleep restriction therapy on depressive symptoms: A systematic review and meta-analysis.

Sleep restriction therapy is a behavioural component within cognitive behavioural therapy for insomnia and is an effective standalone treatment for insomnia, but its effect on depressive symptoms remains unclear. This review aimed to synthesise and evaluate the impact of single-component sleep restriction therapy on depressive symptoms relative to a control intervention. We searched electronic databases and sleep-related journals for randomised controlled trials and uncontrolled clinical trials, published from 1 January 1986 until 19 August 2023, that delivered sleep restriction therapy to adults with insomnia. Random-effects meta-analysis of standardised mean differences and Cochrane risk of bias assessment were performed on randomised controlled trials, while uncontrolled clinical trials were discussed narratively. The meta-analysis was pre-registered on PROSPERO (ID: CRD42020191803). We identified seven randomised controlled trials (N = 1102) and two uncontrolled clinical trials (N = 22). Findings suggest that sleep restriction therapy is associated with a medium effect for improvement in depressive symptoms at post-treatment (Nc = 6, g = -0.45 [95% confidence interval = -0.70 to -0.21], p < 0.001) and a small effect at follow-up (Nc = 4, g = -0.31 [95% confidence interval = -0.45 to -0.16], p < 0.001). Five of the seven included randomised controlled trials were judged to have a high risk of bias. Standalone sleep restriction therapy appears to be efficacious for improving depressive symptoms at post-treatment and follow-up. However, conclusions are tentative due to the small number of trials and because none of the trials was performed in a population with clinically defined depression. Large-scale trials are needed to test the effect of sleep restriction therapy in patients experiencing depression and insomnia. Findings also highlight the need to improve the standardisation and reporting of sleep restriction therapy procedures, and to design studies with more rigorous control arms to reduce potential bias.

Intimate partner violence among women in Togo: a generalised structural equation modeling approach.

OBJECTIVE: This study aimed to assess the magnitude and identify associated factors with intimate partner violence (IPV) in Togo. DESIGN: Cross-sectional study. SETTING: Togo. PARTICIPANTS: Women of reproductive age (15-49 years). PRIMARY OUTCOME: Intimate partner violence. METHODS: This study used data from the 2013 Togolese Demographic and Health Survey. A total of 4910 married or partnered women were included. A Generalised Structural Equation Model (GSEM) was performed to identify significant factors associated with IPV. Results of the GSEM were reported as adjusted ORs (aOR) with their corresponding 95% CIs. RESULTS: The pooled prevalence of IPV was 35.5% (95% CI: 34.2% to 36.8%). Emotional violence and physical violence were the most reported forms of IPV (29.7% and 20.2%, respectively), while sexual violence was the least common, with a prevalence of 7.5%. Additionally, the results indicated that the following factors related to women, men and households were significantly associated with IPV in Togo: ethnicity, region, religion, wealth index, working status, age at the first union, having attitudes toward wife-beating, participation in household decision-making, education level, alcohol use and controlling behaviour. CONCLUSION: IPV is a complex and multifactorial phenomenon in Togo. The Togo government as well as women's human rights organisations should consider these factors when designing IPV programmes.

An axon-T cell feedback loop enhances inflammation and axon degeneration.

Inflammation is closely associated with many neurodegenerative disorders. Yet, whether inflammation causes, exacerbates, or responds to neurodegeneration has been challenging to define because the two processes are so closely linked. Here, we disentangle inflammation from the axon damage it causes by individually blocking cytotoxic T cell function and axon degeneration. We model inflammatory damage in mouse skin, a barrier tissue that, despite frequent inflammation, must maintain proper functioning of a dense array of axon terminals. We show that sympathetic axons modulate skin inflammation through release of norepinephrine, which suppresses activation of γδ T cells via the ß2 adrenergic receptor. Strong inflammatory stimulation-modeled by application of the Toll-like receptor 7 agonist imiquimod-causes progressive γδ T cell-mediated, Sarm1-dependent loss of these immunosuppressive sympathetic axons. This removes a physiological brake on T cells, initiating a positive feedback loop of enhanced inflammation and further axon damage.

Metabolic and molecular imaging in inflammatory arthritis.

It is known that metabolic shifts and tissue remodelling precede the development of visible inflammation and structural organ damage in inflammatory rheumatic diseases such as the inflammatory arthritides. As such, visualising and measuring metabolic tissue activity could be useful to identify biomarkers of disease activity already in a very early phase. Recent advances in imaging have led to the development of so-called 'metabolic imaging' tools that can detect these changes in metabolism in an increasingly accurate manner and non-invasively.Nuclear imaging techniques such as 18F-D-glucose and fibroblast activation protein inhibitor-labelled positron emission tomography are increasingly used and have yielded impressing results in the visualisation (including whole-body staging) of inflammatory changes in both early and established arthritis. Furthermore, optical imaging-based bedside techniques such as multispectral optoacoustic tomography and fluorescence optical imaging are advancing our understanding of arthritis by identifying intra-articular metabolic changes that correlate with the onset of inflammation with high precision and without the need of ionising radiation.Metabolic imaging holds great potential for improving the management of patients with inflammatory arthritis by contributing to early disease interception and improving diagnostic accuracy, thereby paving the way for a more personalised approach to therapy strategies including preventive strategies. In this narrative review, we discuss state-of-the-art metabolic imaging methods used in the assessment of arthritis and inflammation, and we advocate for more extensive research endeavours to elucidate their full field of application in rheumatology.

Trends and factors associated with recent HIV testing among women in Haiti: a cross-sectional study using data from nationally representative surveys.

INTRODUCTION: In the Latin America and Caribbean region, Haiti is one of the countries with the highest rates of HIV. Therefore, this study examined the factors associated with HIV testing among women in Haiti and trends in HIV testing in 2006, 2012, and 2016/17. METHODS: Data from the last three Haitian Demographic and Health Surveys (2006, 2012, and 2016/17) were used. The analysis was restricted to women aged of 15-49 years who made their sexual debut. STATA/SE 16.0 was employed to analyze the data by computing descriptive statistics, Chi­square, and multilevel regression model to describe the trends and identify factors associated with HIV testing in Haiti. P-value less than 0.05 was taken as a significant association. RESULTS: HIV testing prevalence increased more than twofold from 2006 (8.8%) to 2017 (21.3%); however, it decreased by 11.6% between 2012 and 2016/17. Additionally, the results indicated that age, place of residence, region, education level, wealth index, mass media exposure, marital status, health insurance, age at first sex and number of sexual partners were significantly associated with HIV testing. CONCLUSIONS: To significantly increase HIV testing prevalence among women, the Haitian government must invest much more in their health education while targeting vulnerable groups (youth, women in union, and women with low economic status).

Using digital technologies to diagnose in the home: recommendations from a Delphi panel.

Rapid advances in digital technology have expanded the availability of diagnostic tools beyond traditional medical settings. Previously confined to clinical environments, these many diagnostic capabilities are now accessible outside the clinic. This study utilized the Delphi method, a consensus-building approach, to develop recommendations for the development and deployment of these innovative technologies. The study findings present the 29 consensus-based recommendations generated through the Delphi process, providing valuable insights and guidance for stakeholders involved in the implementation and utilization of these novel diagnostic solutions. These recommendations serve as a roadmap for navigating the complexities of integrating digital diagnostics into healthcare practice outside traditional settings like hospitals and clinics.

The effect of sleep restriction therapy for insomnia on REM sleep fragmentation: A secondary analysis of a randomised controlled trial.

Rapid eye movement sleep fragmentation is hypothesised to be a reliable feature of insomnia, which may contribute to emotion dysregulation. Sleep restriction therapy, an effective intervention for insomnia, has the potential to reduce rapid eye movement sleep fragmentation through its manipulation of basic sleep-wake processes. We performed secondary data analysis of a randomised controlled trial to examine whether sleep restriction therapy reduces rapid eye movement sleep fragmentation in comparison to a matched control arm. Participants (n = 56; 39 female, mean age = 40.78 ± 9.08 years) were randomly allocated to 4 weeks of sleep restriction therapy or 4 weeks of time in bed regularisation. Ambulatory polysomnographic recordings were performed at baseline, week 1 and week 4. Arousals during rapid eye movement and non-rapid eye movement sleep were scored blind to group allocation. The following rapid eye movement sleep fragmentation index was the primary outcome: index 1 = (rapid eye movement arousals + rapid eye movement awakenings + non-rapid eye movement intrusions)/rapid eye movement duration in hours. Secondary outcomes were two further indices of rapid eye movement sleep fragmentation: index 2 = (rapid eye movement arousals + rapid eye movement awakenings)/rapid eye movement duration in hours; and index 3 = rapid eye movement arousals/rapid eye movement duration in hours. A non-rapid eye movement fragmentation index was also calculated (non-rapid eye movement arousals/non-rapid eye movement duration in hours). Linear-mixed models were fitted to assess between-group differences. There was no significant group difference for the primary rapid eye movement fragmentation index at week 1 (p = 0.097, d = -0.31) or week 4 (p = 0.741, d = -0.06). There was some indication that secondary indices of rapid eye movement fragmentation decreased more in the sleep restriction therapy group relative to control at week 1 (index 2: p = 0.023, d = -0.46; index 3: p = 0.051, d = -0.39), but not at week 4 (d ≤ 0.13). No group effects were found for arousals during non-rapid eye movement sleep. We did not find clear evidence that sleep restriction therapy modifies rapid eye movement sleep fragmentation. Small-to-medium effect sizes in the hypothesised direction, across several indices of rapid eye movement fragmentation during early treatment, demand further investigation in future studies.

Outcome prediction in dogs admitted through the emergency room: Accuracy of staff prediction and comparison with an illness severity stratification system for hospitalized dogs.

OBJECTIVE: To determine whether emergency staff and students can predict patient outcome within 24 hours of admission, comparing the accuracy of clinician prognostication with outcome prediction by Acute Patient Physiologic and Laboratory Evaluation (APPLE)fast scoring and identifying whether experience or mood would be associated with accuracy. DESIGN: Prospective observational study between April 2020 and March 2021. SETTING: University teaching hospital. ANIMALS: One hundred and sixty-one dogs admitted through an Emergency Service were assessed. Where data were available, an APPLEfast score was calculated per patient. An APPLEfast score of >25 was deemed a predictor for mortality. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Emergency staff and students were asked to complete surveys about dogs admitted to the emergency room. All clinicopathological data were available for review, and the animals were available for examination. Data collected included opinions on whether the patient would be discharged from hospital, a mood score, position, and experience in Emergency and Critical Care. One-hundred and twenty-five dogs (77.6%) were discharged; 36 dogs (22.4%) died or were euthanized. Two hundred and sixty-six responses were obtained; 202 responses (75.9%) predicted the correct outcome. Students, interns, residents, faculty, and nurses predicted the correct outcome in 81.4%, 58.3%, 83.3%, 82.1%, and 65.5% of cases, respectively. Of 64 incorrect predictions, 43 (67.2%) predicted death in hospital. APPLEfast scores were obtained in 121 cases, predicting the correct outcome in 83 cases (68.6%). Of 38 cases in which APPLEfast was incorrect, 27 (71.1%) were dogs surviving to discharge. Mean APPLEfast score was 22.9 (± 6.2). There was no difference in outcome prediction accuracy between staff and APPLEfast scores (P = 0.13). Neither experience nor mood score was associated with outcome prediction ability (P = 0.55 and P = 0.74, respectively). CONCLUSIONS: Outcome prediction accuracy by staff is not significantly different to APPLEfast scoring where a cutoff of >25 is used to predict mortality. When predictions were incorrect, they often predicted nonsurvival.

Sugar-free synapses run on mitochondrial Sirtuin 3.

Metabolic plasticity of neurons ensures their activity continues when glucose is limited. Walsh and Simon discuss new work by Ashrafi and colleagues (https://doi.org/10.1083/jcb.202305048) that finds Sirtuin 3 directs local metabolic adaptation at synapses during sustained glucose deprivation.

Tolerability of low to moderate biomechanical stress during leisure sport activity in patients with psoriasis and psoriatic arthritis.

OBJECTIVES: To assess the impact of low to moderate biomechanical stress on entheses in patients with psoriasis and psoriatic arthritis (PsA). METHODS: We conducted a prospective interventional study on a cohort of psoriasis and PsA patients who underwent a 60 min badminton training session. Pain assessment by Visual Analogue Scale (VAS), physical examination of 29 entheses (SPARCC, LEI, MASES) and bilateral ultrasound at the lateral humeral epicondyle, inferior patellar pole and Achilles tendon were performed before and after training. Ultrasound changes were assessed using the OMERACT scoring system. A follow-up assessment of pain and adverse events was performed at 1 week. RESULTS: Sixteen patients were included (n=7 PsA; n=9 psoriasis) and 196 entheseal ultrasound scans were acquired. At baseline, median VAS pain (IQR) was 0.5 cm (0-2.3) and the total number of tender entheses was 12/464. Mean (min; max) Disease Activity Index for Psoriatic Arthritis was 6.1 (0.8; 19) and 5/7 PsA patients had an Minimal Disease Activity status. After training, no significant change in VAS pain (0.0 cm (0.0-2.0)) nor in tender entheses (13/464) emerged. Four patients (n=2 PsA, n=2 psoriasis) developed a grade-1 power Doppler-signal at six entheses, which, however, remained non-tender. At 1 week, median VAS pain remained stable (0.0 cm (0.0-3.0); p>0.05) and only one participant with active PsA at baseline reported increased arthralgias in three joints. CONCLUSIONS: Low to moderate physical strain, as in the context of leisure sport activity, seems well tolerated in psoriatic patients without increases in tenderness, pain and ultrasound-proven inflammation. Evidence-based recommendations for physical activity in PsA are direly needed and larger controlled studies should be conducted to define safe exercise thresholds.

Accumulation and Stretching of DNA Molecules in Temperature-Induced Concentration Gradients.

Temperature fields provide a noninvasive approach for manipulating individual macromolecules in solution. Utilizing thermophoresis and other secondary effects resulting from the inhomogeneous distribution of crowding agents, one may gain valuable insights into the interactions of molecular mixtures. In this report, we examine the steady-state concentration distribution and dynamics of DNA molecules in a poly(ethylene glycol) (PEG)/water solution when exposed to localized temperature gradients generated by optical heating of a thin chrome layer at a liquid-solid boundary. This allowed us to experimentally investigate the interplay between DNA thermophoresis and PEG-induced entropic depletion effects. Our quantitative analysis demonstrates that the depletion effects dominate over DNA thermophoresis, causing the DNA polymers to migrate toward the heat source. Additionally, we explore the transient stretching of individual DNA molecules in thermally induced PEG gradients and estimate the contributing forces.