A semi-automated quantum-mechanical workflow for the generation of molecular monolayers and aggregates.

Organic electronics (OE) such as organic light-emitting diodes or organic solar cells represent an important and innovative research area to achieve global goals like environmentally friendly energy production. To accelerate OE material discovery, various computational methods are employed. For the initial generation of structures, a molecular cluster approach is employed. Here, we present a semi-automated workflow for the generation of monolayers and aggregates using the GFNn-xTB methods and composite density functional theory (DFT-3c). Furthermore, we present the novel D11A8MERO dye interaction energy benchmark with high-level coupled cluster reference interaction energies for the assessment of efficient quantum chemical and force-field methods. GFN2-xTB performs similar to low-cost DFT, reaching DFT/mGGA accuracy at two orders of magnitude lower computational cost. As an example application, we investigate the influence of the dye aggregate size on the optical and electrical properties and show that at least four molecules in a cluster model are needed for a qualitatively reasonable description.

Muscle Swelling and Neuromuscular Responses Following Blood Flow Restricted Exercise in Untrained Women.

Purpose: There is conflicting evidence related to the prevalence and magnitude of exercise-induced muscle damage (EIMD) following four sets to volitional failure with BFR (BFR-F) or 75 total repetitions with BFR (1 × 30, 3 × 15, BFR-75). The purpose of this investigation was to examine muscle swelling, peak torque, and neuromuscular responses following BFR-75 and BFR-F. Methods: Thirteen untrained women completed unilateral isokinetic (120°s-1) leg extensions concentric-eccentric at 30% of their maximal voluntary isometric contraction (MVIC) using BFR-75 and BFR-F protocols, separated by 15 minutes. Ultrasound was used to assess muscle thickness, cross sectional area, and echo intensity of the rectus femoris and vastus lateralis before, 0-, 24-, 48-, 72-, and 96-hours post-exercise. Peak torque and surface electromyography (sEMG) were recorded during MVICs before, 24-, 48-, 72-, and 96-hours post-exercise to determine sEMG amplitude, frequency, and neuromuscular efficiency. Results: There were no differences between conditions. Collapsed across conditions, muscle thickness and cross-sectional area increased at 0-hours for the rectus femoris (2.5 ± 0.4, 2.8 ± 0.4 cm, 10.6 ± 1.8, 12.1 ± 1.8 cm2, respectively) and vastus lateralis (2.1 ± 0.5, 2.5 ± 0.7 cm; 22.2 ± 3.9, 25.1 ± 4.5 cm2, respectively), but returned to baseline at 24-hours. There were no changes in echo intensity, sEMG amplitude, sEMG frequency, or neuromuscular efficiency. MVIC peak torque increased relative to pre-exercise at 24-, 48-, 72-, and 96-hours (159.9 ± 34.9, 171.4 ± 30.1-179.1 ± 35.6 Nm). Conclusion: These results suggest that BFR-75 and BFR-F did not cause EIMD but caused an acute increase in muscle swelling that returned to baseline 24-hours post-exercise.

Effects of Occupational and Leisure-Time Physical Activity on the Risk of Dementia: Results From the Copenhagen City Heart Study.

Leisure-time physical activity (LTPA) decreases the risk of dementia, whereas occupational physical activity (OPA) possibly increases the risk. Yet, previous findings are mixed. We therefore aimed to investigate the effect of LTPA and OPA, respectively, on dementia among men and women. In this observational, longitudinal study, we used data from the second wave of a population-based cohort from the municipality of Copenhagen as baseline. Data were collected in 1981-1983, and 10 343 participants were followed until the end of 2016. LTPA and OPA were self-reported, and information on dementia diagnoses and redemption of dementia medication was obtained at an individual level from national health registers. We used Poisson regression to analyze the association between LTPA/OPA and dementia and adjusted for self-reported age, socioeconomic factors, stress, and cardiovascular risk factors (smoking, alcohol, body mass index, and blood pressure). A higher level of LTPA was associated with a lower dementia risk among men, but we found no clear association among women. OPA and dementia were not associated among men, but occupationally active women who reported OPA in terms of walking, lifting, and heavy work had a higher risk of dementia than women with sedentary jobs. This study supported earlier findings of a protective effect of LTPA on dementia among men. Women in physically demanding jobs possibly have a higher risk of dementia, yet this finding warrants further investigation in future studies.

SCG variability and spectral energy distribution during normal breathing and breath hold at different lung volumes and airway pressures.

Seismocardiographic (SCG) signals are chest wall vibrations induced by cardiac activity and are potentially useful for cardiac monitoring and diagnosis. SCG waveform is observed to vary with respiration, but the mechanism of these changes is poorly understood as alterations in autonomic tone, lung volume, heart location and intrathoracic pressure are all varying during the respiratory cycle. Understanding SCG variability and its sources may help reduce variability and increase SCG clinical utility. This study investigated SCG variability during breath holding (BH) at two different lung volumes (i.e., end inspiration and end expiration) and five airway pressures (i.e., 0, ± 2-4, and ± 15-20 cm H2O). Variability during normal breathing was also studied with and without grouping SCG beats into two clusters of similar waveform morphologies (performed using the K-medoid algorithm in an unsupervised machine learning fashion). The study included 15 healthy subjects (11 Females and 4 males, Age: 21 ± 2 y) where SCG, ECG, and spirometry were simultaneously acquired. SCG waveform variability was calculated at each experimental state (i.e., lung volume and airway pressure). Results showed that breath holding was more effective in reducing the intra-state variability of SCG than clustering normal breathing data. For the BH states, the intra-state variability increased as the airway pressure deviated from zero. The subaudible-to-audible energy ratio of the BH states increased as the airway pressure decreased below zero which may be related to the effect of the intrathoracic pressure on cardiac afterload and blood ejection. When combining the BH waveforms at end inspiration and end expiration states (at the same airway pressures) into one group, the intra-state variability increased, which suggests that the lung volume and associated change in heart location were a significant source of variability. The linear trend between airway pressure and waveform changes was found to be statistically significant for BH at end expiration. To confirm these findings, more studies are needed with a larger number of airway pressure levels and larger number of subjects.

Effects of dietary fish to rapeseed oil ratio on steatosis symptoms in Atlantic salmon (Salmo salar L) of different sizes.

Choline is recognized as an essential nutrient for Atlantic salmon at all developmental stages. However, its dietary requirement is not well defined. Choline plays a critical role in lipid transport, and the clearest deficiency sign is intestinal steatosis. The present work, aiming to find whether lipid source and fish size may affect steatosis symptoms, was one of a series of studies conducted to identify which production-related conditions may influence choline requirement. Six choline-deficient diets were formulated varying in ratios of rapeseed oil to fish oil and fed to Atlantic salmon of 1.5 and 4.5 kg. After eight weeks, somatic characteristics were observed, and the severity of intestinal steatosis was assessed by histological, biochemical, and molecular analyses. Fatty acid composition in pyloric intestine, mesenteric tissue, and liver samples was also quantified. The increasing rapeseed oil level increased lipid digestibility markedly, enhancing lipid supply to the fish. Moreover, small fish consumed more feed, and consequently had a higher lipid intake. In conclusion, the results showed that choline requirement depends on dietary lipid load, which depends on the fatty acid profile as well as the fish size.

Safety and clinical activity of durvalumab combined with tremelimumab in recurrent/metastatic head and neck squamous cell carcinoma: a multicenter phase I study.

BACKGROUND: Programmed cell death protein 1 (PD-1) inhibitors prolong survival versus chemotherapy in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), which often expresses cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death-ligand 1 (PD-L1), providing a rationale for combined PD-(L)1 and CTLA-4 blockade. We report a phase I, open-label study of the PD-L1 inhibitor durvalumab plus the CTLA-4 inhibitor tremelimumab (NCT02262741). METHODS: In dose exploration, two cohorts of previously treated patients received durvalumab 10 mg/kg plus tremelimumab 3 mg/kg, or durvalumab 20 mg/kg plus tremelimumab 1 mg/kg, for up to 12 months. Dose expansion comprised two cohorts of previously untreated patients with R/M HNSCC having baseline PD-L1 tumor cell (TC) expression ≥25% and <25% and one cohort of immunotherapy-pretreated patients with any PD-L1 level. All received durvalumab 20 mg/kg plus tremelimumab 1 mg/kg, then durvalumab 10 mg/kg, for up to 12 months. The primary endpoint was safety. The secondary endpoints were objective response rate (ORR) by RECIST version 1.1, pharmacokinetics, pharmacodynamics, and immunogenicity. RESULTS: A total of 71 patients were treated. The median duration of exposure was 13.6 weeks for durvalumab and 13.1 weeks for tremelimumab. In dose exploration, no dose-limiting toxicities occurred. No maximum tolerated dose was identified. Treatment-related adverse events (TRAEs) occurred in 69.0% of patients; grade 3/4 and serious TRAEs occurred in 31.0% and 18.3%, respectively. TRAEs led to discontinuation in 9.9%. There were no treatment-related deaths. The ORR was 5.6% (95% confidence interval 1.6-13.8), including one complete response and three partial responses, all patients were in dose expansion with PD-L1 TC ≥25% and no prior immunotherapy exposure; three had ongoing responses ≥12 months. The median overall survival in the total population was 8.6 months. Soluble PD-L1 suppression was almost complete in all cohorts, suggesting target engagement. CD4+Ki67+ T cells were significantly elevated in all dose-expansion cohorts. CONCLUSIONS: Treatment was well tolerated. However, response rates were low despite target engagement, no drug-drug interactions, and no drug-neutralizing antibodies to durvalumab.

Synchronous mode-locking of solid-state lasers by difference frequency generation.

This Letter introduces a novel, to the best of our knowledge, method for achieving mode-locking and synchronization of mode-locked output pulses from two lasers. The proposed technique leverages parametric gain from difference frequency generation. Specifically, a Nd:YAG laser is mode-locked by single-pass mode-locked pulses from a mode-locked Ti:sapphire laser using an intracavity nonlinear crystal. When the continuous-wave laser is not actively pumped, the system functions as a synchronously pumped optical parametric oscillator. This novel approach has the potential to enable new devices, especially for pump-probe applications or for generation of mode-locked pulses in spectral regions where conventional mode-locked devices are typically not available.

Bariatric surgeons' views on pre-operative factors associated with improved health-related quality of life following surgery.

Bariatric surgery is an effective treatment for severe obesity, affording significant improvements in weight loss and health-related quality of life. However, bariatric surgeons' views on whether certain pre-operative factors predict improvements in post-operative health-related quality of life, and if so, which ones, are largely unknown. This cross-sectional survey study examined the views of 58 bariatric surgeons from Australia and New Zealand. A total of 18 factors were selected for exploration based on their mention in the literature. Participants rated the extent to which they thought these pre-operative factors would improve post-operative health-related quality of life. Responses showed that bariatric surgeons held diverse perspectives and revealed a lack of consensus regarding "predictive" factors. Generally, respondents agreed that better than average health literacy, higher socioeconomic status, good physical and psychological health, and positive social support were predictors of improved health-related quality of life following surgery. However, poor eating behaviours, smoking, and the use of alcohol or other substances were deemed negative predictors. Interestingly, aside from higher socioeconomic status, good psychological health, and positive social support, none of the aforementioned views aligned with existing literature. This study offers an initial insight into bariatric surgeons' views on the influence of different pre-operative factors on post-operative health-related quality of life. The array of views identified suggests that there may be an opportunity for medical education, but the findings warrant caution due to the sample size. Replication with a larger survey may be useful, especially as predicted health-related quality of life outcomes could guide decisions regarding surgical (non)progression.

Efficient calculation of electronic coupling integrals with the dimer projection method via a density matrix tight-binding potential.

Designing organic semiconductors for practical applications in organic solar cells, organic field-effect transistors, and organic light-emitting diodes requires understanding charge transfer mechanisms across different length and time scales. The underlying electron transfer mechanisms can be efficiently explored using semiempirical quantum mechanical (SQM) methods. The dimer projection (DIPRO) method combined with the recently introduced non-self-consistent density matrix tight-binding potential (PTB) [Grimme et al., J. Chem. Phys. 158, 124111 (2023)] is used in this study to evaluate charge transfer integrals important for understanding charge transport mechanisms. PTB, parameterized for the entire Periodic Table up to Z = 86, incorporates approximate non-local exchange, allowing for efficient and accurate calculations for large hetero-organic compounds. Benchmarking against established databases, such as Blumberger's HAB sets, or our newly introduced JAB69 set and comparing with high-level reference data from ωB97X-D4 calculations confirm that DIPRO@PTB consistently performs well among the tested SQM approaches for calculating coupling integrals. DIPRO@PTB yields reasonably accurate results at low computational cost, making it suitable for screening purposes and applications to large systems, such as metal-organic frameworks and cyanine-based molecular aggregates further discussed in this work.

Reduced Cerebrovascular Oxygenation in Individuals with Post-Acute COVID-19 Syndrome (PACS) ("long COVID").

There is evidence that hypoxia occurs in the brain of some individuals who contracted the COVID-19 disease. Furthermore, it has been widely reported that about 13% of individuals who contracted the COVID-19 disease report persistent symptoms after the acute infection stage (>2 months post-acute infection). This is termed post-acute COVID-19 syndrome (PACS) or ("long COVID"). In this study, we aimed to determine if hypoxia measured non-invasively with frequency domain near-infrared spectroscopy (fdNIRS) occurs in asymptomatic and symptomatic individuals with post-acute COVID-19 disease. We show that 26% of our symptomatic group, measured on average 9.6 months post-acute COVID-19 disease, were hypoxic and 12% of the asymptomatic group, measured on average 2.5 months post-acute infection, were hypoxic. Our study indicates that fdNIRS measure of hypoxia in the brain may be a useful tool to identify individuals that are likely to respond to treatments targeted at reducing inflammation and improving oxygenation.

A study protocol outlining the development and evaluation of a training program for frontline managers on leading well-being and the psychosocial work environment in Danish hospital settings - a cluster randomized waitlist controlled trial.

BACKGROUND: Hospital staff are often exposed to stressful psychosocial working conditions and report high levels of stress and burnout, which may negatively impact the safety of employees and patients. Managers hold unique knowledge of workplace conditions and needs of employees, but leadership interventions to improve the well-being of managers and employees in hospital settings are scarce. This study evaluates the effects of a leadership intervention based on a health-oriented leadership approach on the well-being and psychosocial work environment aspects of managers and employees. METHODS/DESIGN: The study is designed as a randomized, waitlist-controlled trial with two groups (intervention and waitlist control group) and measurements at baseline, 6- and 12-month follow-up. We aim to include 200 frontline managers in Danish hospital settings and their approximately 5,000 employees. The leadership training comprises five full day modules and four smaller group-training sessions over a period of 5 months. The main aim is to improve stress, burnout, self-care, and perceived level of staff-care among managers and employees. Sickness absence will also be assessed at both manager and employee level. In addition, several psychosocial factors will be assessed at the employee level. A quantitative and qualitative process evaluation will also be conducted. DISCUSSION: Action towards supporting the mental health of hospital employees is important to maintain a strong healthcare system. There is increasing recognition that best practice in workplace mental health requires an integrated approach that prevents harm and promotes positive mental health. There is also increasing understanding of the key role managers' play in maintaining well-being within the workplace, however they often report a lack of knowledge and skills to promote employee mental health. The current leadership training program has been developed for frontline managers working in a hospital setting. The aim is to increase managers' application of strategies to facilitate a healthy psychosocial work environment to benefit well-being and mental health among staff and managers themselves. TRIAL REGISTRATION: The study was retrospectively registered on November 21, 2022 in Clinical Trial.gov with identifier: NCT05623371.

Systematic review with meta-analysis: Current and emerging models of preoperative psychological preparation for individuals undergoing stoma surgery.

OBJECTIVE: Stoma surgery is a profoundly life changing event that can result in a range of negative psychological and mental health outcomes, often requiring significant postoperative adaption. While postoperative avenues of support to address these outcomes exist, there remains a lack of preoperative psychological preparation for surgical candidates in standard models of care. The present systematic review and meta-analysis aims to examine the current and emerging models of psychological preparation available to stoma surgery candidates during the preoperative period. METHODS: A systematic search of PubMed, Embase, Emcare, PsycINFO, CINAHL, and SCOPUS was conducted. All studies examining the effects of preoperative psychological interventions targeting postoperative psychological adjustment and/or mental health outcomes for individuals planning to undergo or who had undergone stoma surgery were included. RESULTS: Overall, 15 publications meeting inclusion criteria were identified, encompassing 1565 total participants. Intervention types ranged from psychoeducational, counselling, and practical based skills, examining the postoperative outcomes of anxiety, depression, quality of life, adjustment, self-efficacy, and systematic improvements to standard models of care. Five studies examining postoperative anxiety were included for meta-analysis, demonstrating an overall significant effect (SMD = -1.13, 95% CI -1.96 to -0.30, p = .008). Due to the high level of heterogeneity between remaining studies, articles examining postoperative outcomes other than anxiety were synthesised in narrative form. CONCLUSION: Despite some promising advancements in the field, there remains insufficient evidence to judge the overall effectiveness of current and emerging models of preoperative psychological preparation on postoperative psychological outcomes for individuals facing stoma surgery.

First-in-class Microbial Ecosystem Therapeutic 4 (MET4) in combination with immune checkpoint inhibitors in patients with advanced solid tumors (MET4-IO trial).

BACKGROUND: The intestinal microbiome has been associated with response to immune checkpoint inhibitors (ICIs) in humans and causally implicated in ICI responsiveness in animal models. Two recent human trials demonstrated that fecal microbiota transplant (FMT) from ICI responders can rescue ICI responses in refractory melanoma, but FMT has specific limitations to scaled use. PATIENTS AND METHODS: We conducted an early-phase clinical trial of a cultivated, orally delivered 30-species microbial consortium (Microbial Ecosystem Therapeutic 4, MET4) designed for co-administration with ICIs as an alternative to FMT and assessed safety, tolerability and ecological responses in patients with advanced solid tumors. RESULTS: The trial achieved its primary safety and tolerability outcomes. There were no statistically significant differences in the primary ecological outcomes; however, differences in MET4 species relative abundance were evident after randomization that varied by patient and species. Increases in the relative abundance of several MET4 taxa, including Enterococcus and Bifidobacterium, taxa previously associated with ICI responsiveness, were observed and MET4 engraftment was associated with decreases in plasma and stool primary bile acids. CONCLUSIONS: This trial is the first report of the use of a microbial consortium as an alternative to FMT in advanced cancer patients receiving ICI and the results justify the further development of microbial consortia as a therapeutic co-intervention for ICI treatment in cancer.

Chronic hand eczema in Europe: Patient experiences and perspectives (CHEPEP) in qualitative interviews.

BACKGROUND: Chronic hand eczema (CHE) is a very common skin disease among the European population. It causes itch and pain and, in more severe cases, seriously impairs hand functioning at work and in private life. OBJECTIVES: To explore perspectives of people with lived experience on CHE-related problems, wishes and goals. METHODS: Following a qualitative approach, we conducted topic-guided interviews in five European countries and applied template analysis to identify recurrent themes among patients with CHE. RESULTS: We interviewed 60 patients in seven outpatient dermatological and occupational medicine clinics in Croatia, Denmark, Germany, the Netherlands and Spain. Five main themes were identified: (1) knowledge about the disease and its course, (2) preventive behaviour, (3) hand eczema therapy, (4) impact on everyday life and (5) attitudes towards CHE and healthcare. Participants did not feel well informed about CHE, especially about causes, triggers and treatment options. Preventive measures were experienced as more or less effective but also cumbersome. Experiences with therapy were diverse. Treatment satisfaction depended on the results and on the perceived support from the treatment teams. Participants found it important to be taken seriously, to receive practical advice, to try out additional treatments or examinations, find new hope and have occupational perspectives. They wished that others could better understand the physical and emotional burden of CHE. Patient support groups were not mentioned. Participants found it important to learn to take care of themselves and accept life with CHE. CONCLUSIONS: Due to its annoying symptoms, high visibility and impaired functioning at work and in private life, CHE has a high emotional and social impact. Some people may require support to learn coping with CHE and its prevention. Patients wish for information about causes and triggers. They value physicians who listen to them and keep looking for solutions.

Testicular torsion and subsequent testicular function in young men from the general population.

STUDY QUESTION: Is prior testicular torsion associated with testicular function (semen quality and reproductive hormones) in young men from the general population? SUMMARY ANSWER: In young men from the general population, no differences in semen parameters were observed in those who had experienced testicular torsion compared to controls and observations of higher FSH and lower inhibin B were subtle. WHAT IS KNOWN ALREADY: Testicular function may be impaired after testicular torsion, but knowledge is sparse and based on studies with small sample sizes and no control group or a less than ideal control group. STUDY DESIGN, SIZE, DURATION: A cross-sectional population-based study was carried out including 7876 young Danish men with unknown fertility potential, examined from 1996 to 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: All men (median age 19.0 years) had a physical examination, provided a blood and semen sample, and filled in a questionnaire including information about prior testicular torsion, birth, lifestyle and current and previous diseases. Markers of testicular function, including testis volume, semen parameters and reproductive hormones, were compared between men operated for testicular torsion and controls, using multiple linear regression analyses. MAIN RESULTS AND THE ROLE OF CHANCE: The average participation rate was 24% for the entire study period. In total, 57 men (0.72%) were previously operated for testicular torsion (median age at surgery 13.4 years) of which five had only one remaining testicle. Men with prior testicular torsion were more often born preterm (25% versus 9.5% among controls), and they had significantly higher FSH and lower inhibin B levels, and a lower inhibin B/FSH ratio than controls in crude and adjusted models. The association was mainly driven by the subgroup of men who had undergone unilateral orchiectomy. No differences in semen parameters were observed. LIMITATIONS, REASONS FOR CAUTION: A limitation is the retrospective self-reported information on testicular torsion. Also, results should be interpreted with caution owing to the high uncertainty of the observed differences. WIDER IMPLICATIONS OF THE FINDINGS: Overall, the results of our study are reassuring for men who have experienced testicular torsion, especially when treated with orchiopexy, for whom reproductive hormone alterations were subtle and without obvious clinical relevance. Our study found no differences in semen parameters, but follow-up studies are needed to assess any long-term consequences for fertility. STUDY FUNDING/COMPETING INTEREST(S): Financial support was received from the Danish Ministry of Health; the Danish Environmental Protection Agency; the Research fund of Rigshospitalet, Copenhagen University Hospital; the European Union (Contract numbers BMH4-CT96-0314, QLK4-CT-1999-01422, QLK4-CT-2002-00603, FP7/2007-2013, DEER Grant agreement no. 212844); A.P. Møller and wife Chastine Mckinney Møllers Foundation; Svend Andersens Foundation; the Research Fund of the Capital Region of Denmark; and ReproUnion (EU/Interreg). The authors have nothing to declare. TRIAL REGISTRATION NUMBER: N/A.

Postural and longitudinal variability in seismocardiographic signals.

Objective. Low frequency cardiovascular vibrations detectable on the chest surface (termed seismocardiography or SCG) may be useful for non-invasive diagnosis and monitoring of various cardiovascular conditions. A potential limitation of using SCG for longitudinal patient monitoring is the existence of intra-subject variability, which can contribute to errors in calculating SCG features. Improved understanding of the contribution of intra-subject variability sources may lead to improved SCG utility. This study aims to quantify postural and longitudinal SCG variability in healthy resting subjects during normal breathing.Approach. SCG and ECG signals were longitudinally acquired in 19 healthy subjects at different postures (supine, 45° head up, and sitting) during five recording sessions over five months. SCG cycles were segmented using the ECG R wave. Unsupervised machine learning was used to reduce SCG variability due to respiration by grouping the SCG signals into two clusters with minimized intra-cluster waveform heterogeneity. Several SCG features were assessed at different postures and longitudinally.Main results. SCG waveform morphological variability was calculated within each cluster (intra-cluster) and between two clusters (inter-cluster) at each posture and data collection session. The variabilities were significantly different between the supine and sitting but not between supine and 45° postures. For the 45° and sitting postures, the intra-cluster variability was not significantly different, while the inter-cluster variability difference was significant. The energy ratio between different frequency bands to total spectral energy in 0.5-50 Hz were calculated and were comparable for all postures. The combined cardiac timing intervals from the two clusters showed significant variation with postural changes. There was significant heart rate difference between the clusters and between postural positions. The SCG features were compared between longitudinal sessions and all features were not significantly different,Significance. Several SCG features significantly varied with posture suggesting that posture needs to be specified when comparing SCG changes over time. Longitudinally comparable SCG feature values suggests that significant longitudinal differences, if observed, may reflect true alternations in the cardiac functioning over time.

Monocyte secretory profiling in a clinical and MEFV genotype-characterized cohort of Danish familial Mediterranean fever patients: diagnostic potential of CCL1 and CXCL1.

OBJECTIVE: The autoinflammatory disease familial Mediterranean fever (FMF), characterized by recurrent attacks of sterile fever, serosal, and/or synovial inflammation, is caused by variants in the Mediterranean fever gene, MEFV, coding for the pyrin inflammasome sensor. The diagnosis of FMF is mainly based on clinical symptoms and confirmed by detection of disease-associated MEFV variants. However, the diagnosis is challenging among patients carrying variants of uncertain clinical significance (VUS). In this study, we aimed to identify potential FMF discriminatory diagnostic markers in a cohort of clinically characterized FMF patients. METHOD: We established a cohort of clinically and MEFV genotype-characterized FMF patients by enrolling patients from major Danish hospitals (n = 91). The secretory profile of pyrin inflammasome-activated monocytes from healthy donors (HDs) and MEFV-characterized FMF patients (n = 28) was assessed by analysing cell supernatants for a custom-designed panel of 23 cytokines, chemokines, and soluble tumour necrosis factor receptors associated with monocyte and macrophage function. RESULTS: MEFV genotypes in Danish FMF patients were associated with age at symptom onset (p < 0.05), FMF among relatives (p < 0.01), proportion of patients in colchicine treatment (p < 0.01), and treatment response (p < 0.05). Secretion of chemokines CCL1 and CXCL1 from pyrin-activated FMF monocytes was significantly decreased compared to HDs (p < 0.05), and could discriminate FMF patients with 'non-confirmatory' MEFV genotypes from HDs with 80.0% and 70.0% sensitivity for CCL1 and CXCL1, respectively (p < 0.05). CONCLUSION: Our data suggest that a functional diagnostic assay based on CCL1 or CXCL1 levels in pyrin-activated patient monocytes may contribute to FMF diagnosis in patients with VUS.

Baseline serum levels of IgA anti-cyclic citrullinated protein antibodies in early rheumatoid arthritis predict radiographic progression after 11 years of treatment: a secondary analysis of the CIMESTRA study.

OBJECTIVE: Smoking and periodontitis are risk factors for developing rheumatoid arthritis (RA), suggesting a break of tolerance on mucosal surfaces. Immunoglobulin A (IgA) antibodies are part of the mucosal immune system. The dominant autoantibodies in RA are anti-cyclic citrullinated protein antibodies (ACPAs), and IgG and IgA subclasses exist simultaneously. This study aimed to investigate the association of ACPA IgA subtypes with disease activity and long-term radiographic outcomes in RA, compared with ACPA IgG. METHOD: Total ACPA IgG, IgA, IgA1, and IgA2 were quantified in serum from patients with early RA (n = 97). Patient characteristics, IgM rheumatoid factor (IgM-RF) status, clinical and biochemical disease activity scores, and radiographic status evaluated by total Sharp score (TSS), were assessed at baseline and after 2 and 11 years of treatment. RESULTS: All patients with ACPA IgA also had ACPA IgG. ACPA IgA positivity was associated with IgM-RF and male gender. Both ACPA IgA and IgG levels at baseline were weakly associated with disease activity markers. Baseline ACPA IgA and IgG did not show a linear correlation with radiographic status after 10 years, but could predict radiographic progression (ΔTSS ≥ 5 from 0 to 11 years), with positive likelihood ratios of 3.7 and 4.0, respectively. CONCLUSION: ACPA IgA and IgG were weakly associated with disease activity in early RA. RA patients with a ΔTSS ≥ 5 after 11 years of treatment had higher ACPA IgG and ACPA IgA levels at baseline; however, none of the ACPA subtypes was superior in predicting long-term radiographic progression.

The association between migraine and dementia - a national register-based matched cohort study.

OBJECTIVES: Migraine and dementia, two major public health challenges, are associated, but more knowledge is needed to understand their relationship. Objectives of this study were to investigate 1) the association between non-self-reported measures of migraine and dementia, and whether dementia was associated with 2) migraine without aura (MO) and with aura (MA) in combination with migraine medication use, and 3) migraine severity operationalized as the number of migraine prescriptions. STUDY DESIGN: Matched cohort study. METHODS: National register data were obtained from individuals born between 1934 and 1958. Migraine cases (aged 25-58 years) were identified by migraine diagnoses and redeemed migraine medication. Migraine cases were matched with non-cases (N = 340,850) and date of diagnosis or medication redemption was defined as index year. Dementia was identified by dementia diagnoses and redeemed dementia medication. RESULTS: We observed a 1.46 (95% CI: 1.26-1.69) times higher dementia rate in individuals with a migraine diagnosis and a 0.86 (95% CI: 0.76-0.97) times lower rate when using migraine medication. We found the highest dementia rate among individuals with MA, who also used migraine medication (HR = 2.23; 95% CI: 1.19-4.17), and the lowest rate among individuals with MO, who also used medication (HR = 1.25; 95% CI: 0.75-2.10). The number of migraine medication prescriptions was not associated with dementia. CONCLUSIONS: Being registered with a migraine diagnosis was associated with a higher dementia rate, while use of prescribed migraine medication was not. The differences in the dementia rate among migraine cases identified via diagnoses versus medications warrants further investigation.