Association of Baseline Depression and Anxiety with Longitudinal Health Outcomes in Parkinson's Disease.

BACKGROUND: Anxiety and depression are common non-motor symptoms in Parkinson's disease (PD) but remain under-recognized and under-treated. OBJECTIVES: To evaluate functional outcomes associated with baseline anxiety or depression and effects related to the initiation of new psychiatric treatment. METHODS: We analyzed 7 years of data from patients with de novo PD enrolled in the Parkinson's Progression Markers Initiative. Longitudinal regression models evaluated the association between baseline anxiety and depression with Schwab and England (SE) and MDS-UPDRS total scores over time. Cox proportional hazard models assessed effects of baseline anxiety and depression on time to initiation of dopaminergic therapy. Piecewise linear regression models examined the association of treatment initiation for anxiety and depression with SE and MDS-UPDRS. RESULTS: 490 participants with baseline depression and anxiety data were included. Anxiety and depression were associated with lower SE (anxiety: ß = -1.31, P = 0.038, depression: ß = -1.96, P = 0.012, co-morbid: ß = -2.70, P = 0.003) and higher MDS-UPDRS scores (anxiety: ß = 5.37, P < 0.001, depression: ß = 9.17, P < 0.001, co-morbid: ß = 10.50, P < 0.001) longitudinally. Anxiety was associated with faster time to dopamine replacement therapy initiation (HR 1.30, 95% CI 1.03-1.66, P = 0.03). 16 participants with anxiety initiated treatment for anxiety, which was associated with subsequent lower levodopa daily dose (slope change = -218.49, P = 0.018). 10 participants with depression initiated treatment of depression, which was associated with reduced MDS-UPDRS total scores (slope change = -8.3, P < 0.001) and higher SE scores (slope change = 5.99, P = 0.004). CONCLUSIONS: Anxiety and depression at PD onset are associated with multiple negative longitudinal trajectories. However, preliminary findings suggest that anxiety and depression treatment may be linked with improved motor and non-motor outcomes.

Single domain antibody-scFv conjugate targeting amyloid ß and TfR penetrates the blood-brain barrier and interacts with amyloid ß.

Neurodegenerative diseases such as Alzheimer's disease (AD) pose substantial challenges to patients and health-care systems, particularly in countries with aging populations. Immunotherapies, including the marketed antibodies lecanemab (Leqembi®) and donanemab (KisunlaTM), offer promise but face hurdles due to limited delivery across the blood-brain barrier (BBB). This limitation necessitates high doses, resulting in increased costs and a higher risk of side effects. This study explores transferrin receptor (TfR)-binding camelid single-domain antibodies (VHHs) for facilitated brain delivery. We developed and evaluated fusion proteins (FPs) combining VHHs with human IgG Fc domains or single-chain variable fragments (scFvs) of the anti-amyloid-beta (Aß) antibody 3D6. In vitro assessments showed varying affinities of the FPs for TfR. In vivo evaluations indicated that specific VHH-Fc and VHH-scFv fusions reached significant brain concentrations, emphasizing the importance of optimal TfR binding affinities. The VHH-scFv fusions were further investigated in mouse models with Aß pathology, showing higher retention compared to wild-type mice without Aß pathology. Our findings suggest that these novel VHH-based FPs hold potential for therapeutic and diagnostic applications in AD, providing a strategy to overcome BBB limitations and enhance brain targeting of antibody-based treatments. Furthermore, our results suggest that a given bispecific TfR-binding fusion format has a window of "optimal" affinity where parenchymal delivery is adequate, while blood pharmacokinetics aligns with the desired application of the fusion protein.

The prognostic value of [18F]FDG PET/CT texture analysis prior to transplantation for unresectable colorectal liver metastases.

INTRODUCTION: To determine whether heterogeneity in colorectal liver metastases (CRLM) 18F fluorodeoxyglucose [18F]FDG distribution is predictive of disease-free survival (DFS) and overall survival (OS) following liver transplantation (LT) for unresectable CRLM. METHODS: The preoperative [18F]FDG positron emission tomography/computed tomography examinations of all patients in the secondary cancer 1 and 2 studies were retrospectively assessed. Maximum standardized uptake value (SUVmax), metabolic tumour volume (MTV), and six texture heterogeneity parameters (joint entropyGLCM, dissimilarityGLCM, grey level varianceSZM, size zone varianceSZM, and zone percentageSZM, and morphological feature convex deficiency) were obtained. DFS and OS for patients over and under the median value for each of these parameters were compared by using the Kaplan Meier method and log rank test. RESULTS: Twenty-eight out of 40 patients who underwent LT for unresectable CRLM had liver metastases with uptake above liver background and were eligible for inclusion. Low MTV (p < 0.001) and dissimilarityGLCM (p = 0.016) were correlated to longer DFS. Low MTV (p < 0.001) and low values of the texture parameters dissimilarityGLCM (p = 0.038), joint entropyGLCM (p = 0.015) and zone percentageSZM (p = 0.037) were significantly correlated to longer OS. SUVmax was not correlated to DFS and OS. CONCLUSION: Although some texture parameters were able to significantly predict DFS and OS, MTV seems to be superior to predict both DFS and OS following LT for unresectable CRLM.

CO2 hydrogenation to methanol over Pt functionalized Hf-UiO-67 versus Zr-UiO-67.

Sustainable methanol formation from CO2/H2 is potentially a key process in the post-fossil chemical industry. In this study, Hf- and Zr-based metal-organic framework (MOF) materials with UiO-67 topology, functionalized with Pt nanoparticles, have been tested for CO2 hydrogenation at 30 bar and 170-240°C. The highest methanol formation rate, 14 molmethanol molPt-1 h-1, was obtained over a Hf-based catalyst, compared with the maximum of 6.2 molmethanol molPt-1 h-1 for the best Zr-based analogue. However, changing the node metal did not significantly affect product distribution or apparent activation energy for methanol formation (44-52 kJ mol-1), strongly indicating that the higher activity of the Hf-based analogues is associated with a higher number of active sites. Both catalysts showed stable catalytic performance during testing under kinetic conditions, but the addition of 2 vol% water to the feed induced catalyst deactivation, in particular the Hf-MOFs. Interestingly, mainly methanol and methane formation rates decreased, while CO formation rates were less affected by deactivation. No direct correlation was found between catalytic stability and framework stability (crystallinity, specific surface area). Experimental and computational studies suggest that water adsorption strength to the MOF node may affect the relative catalytic stability of Hf-UiO-67-Pt versus Zr-UiO-67-Pt methanol catalysts.This article is part of the discussion meeting issue 'Green carbon for the chemical industry of the future'.

Genetic and phenotypic evidence suggest the existence of indigenous olive population of wild var. sylvestris in the Carmel coast, southern Levant.

BACKGROUND: Populations of Olea europaea subsp. europaea var. sylvestris, the ancestor of cultivated olives, are scattered across the Mediterranean Basin. However, after millennia of possible hybridization with cultivated varieties, the genetic identity of many of these populations remain questionable. In the southern Levant, the plausible primary domestication center of olives, many of the naturally growing olive (NGOs) are considered feral, having developed from nearby olive groves. Here, we investigated the genetic identity of NGOs population in the Carmel region, hypothesizing that their specific location, which limit anemophily, provided an opportunity for the persistence of genuine var. sylvestris. RESULTS: We mapped more than 1,000 NGOs on the Kurkar ridge along the Carmel coast, within and outside the residential area of Atlit and used simple sequence repeats of 14 loci to assess the spatial genetic structure of 129 NGOs. Genetic diversity parameters and genetic distances between NGO and cultivated olives, as well as phenotypic and morphometric analyses of their oil content and pits, respectively, indicated the presence of a genuine var. sylvestris population. However, NGOs within the residential area of Atlit and old settlements showed an intermediate admix genetic structure, indicating on hybridization with local varieties, a consequence of their proximity to cultivated trees. CONCLUSIONS: Integrating the results of genetic and phenotypic analyses we provide crucial evidence of the presence of a genuine var. sylvestris population in the southern Levant, in close geographical proximity to archaeological sites with the earliest evidence of olive exploitation in the ancient world. We supplement the results with recommendations for a conservation program that combines municipal requirements and the urgent need to preserve the largest population of var. sylvestris in the southern Levant.

Alveolar echinococcosis. / Alveolær ekinokokkose.

Alveolar echinococcosis is a much-feared parasitic zoonosis caused by the larval stage of Echinococcus multilocularis. Mainland Norway is free from infection, but alveolar echinococcosis is, on rare occasions, imported from endemic regions. Those infected develop slow-growing, multicystic tumours that are clinically and radiologically reminiscent of malignant disease. The disease mainly attacks the liver. Treatment often consists of extensive surgical resection in combination with prolonged use of albendazole. In this clinical review article we summarise the life cycle, clinical findings, diagnosis, treatment and epidemiology of alveolar echinococcosis, and provide examples of the disease course with two patient case reports.

Zn-doped NiMoO4 enhances the performance of electrode materials in aqueous rechargeable NiZn batteries.

In this work, zinc was introduced to prepare Ni1-xZnxMoO4 (0 ≤ x ≤ 1) nanoflake electrodes to increase the energy density and improve the cycling stability for a wider range of applications of aqueous rechargeable nickel-zinc (NiZn) batteries. This was achieved using a facile hydrothermal method followed by thermal annealing, which can be easily scaled up for mass production. Owing to the unique nanoflake structures, improved conductivity, and tunable electronic interaction, excellent electrochemical performance with high specific capacitance and reliable cycling stability can be achieved. When the Zn doping is 25%, the Ni0.75Zn0.25MoO4 nanoflake electrode displays a high specific capacitance of 345.84 mA h g-1 (2490 F g-1) at a current density of 1 A g-1 and improved cycling stability at a high current density of 10 A g-1. NiZn cells assembled with Ni0.75Zn0.25MoO4 nanoflake electrodes and zinc electrodes have a maximum specific capacity of 344.7 mA h g-1 and an energy density of 942.53 W h kg-1. This design strategy for nickel-based electrode materials enables high-performance energy storage and opens up more possibilities for other battery systems in the future.

Factors determining curtailment behaviour of youths: moderating role of government policies.

Introduction: Environmental degradation poses a significant threat, making the comprehension of sustainable behaviour imperative for both environmental and business reasons. Embracing sustainable practices and reducing the unnecessary consumption of resources is essential in our current times. One can be sustainable by focusing on either buying sustainable or green products or by using fewer resources, i.e., by adopting curtailment behaviour. The purpose of this study is to determine various factors and their impact on the curtailment behaviour of youths. Methods: We used an exploratory and descriptive research design. Responses were generated from 513 young respondents using a structured questionnaire developed based on the extant literature. Results: The structural model findings showed that social norms, eco-concern, and religiosity significantly and positively affect curtailment behaviour. However, we observed no significant influence of financial concern or government policy on curtailment behaviour. We also tested the moderation impact of government policy on the relationship between economic concern and curtailment behaviour. The findings suggest that the relationship between eco-concern and curtailment behaviour is stronger for consumers exhibiting higher commitment to government policy. Discussion: It is imperative that politicians exercise critical thought and devise strategies to encourage more sustainable consumer behaviour. With the strains that our world is under now and in the future, we need to unite around a common goal: ensuring that our planet is sustainable for coming generations. The study findings are useful for academicians, marketers, and policymakers.

Urinary stone assessment in a single-phase may replace the unenhanced and multiphase computed tomography protocol in painless visible haematuria.

OBJECTIVE: Painless visible haematuria (VH) necessitates a computed tomography (CT) usually consisting of one unenhanced and two to three contrast enhanced acquisitions to detect urinary tract stones and malignancy. Recently, we demonstrated that a single nephrographic phase (NP) CT sufficed in detecting malignancy in patients with painless VH. Now, we aim to evaluate the diagnostic performance of single NP CT in stone detection and size measurements in the same cohort. MATERIAL AND METHODS: "A Prospective Trial for Examining Haematuria using Computed Tomography" (PROTEHCT) was a single-center prospective diagnostic study in patients with painless VH between September 2019 and June 2021. All underwent four-phase CT (reference standard) from which a single NP CT (experimental) was extracted. Two randomised readers independently assessed the experimental CT for urinary stones and size. Statistical analysis included diagnostic accuracies and inter-reader agreement (kappa) of experimental CT, and size correlation (Spearman's ρ) between experimental CT and reference standard. RESULTS: In 308 included patients (median age: 68 years, 250 males), urinary stones (median size 5 mm) were diagnosed in 21%. The per-patient experimental CT sensitivity was 86% (97% for stones ≥ 5 mm), specificity was 98% and accuracy was 96%. The experimental CT sensitivity for detecting kidney stones was 78% (89% for stones ≥ 5 mm), and 100% for bladder and ureteral stones. No missed stone required active treatment. The inter-reader agreement was almost perfect (96%, k = 0.85). The correlation in stone size was very strong (ρ = 0.91).  Conclusions: A single NP CT is sufficient in detecting and measuring urinary stones in patients with painless VH.

Preoperative botolinum toxin A (BTA) and intraoperative fascial traction (IFT) in the management of complex abdominal wall hernias.

INTRODUCTION: Preoperative botolinum toxin A (BTA) administration to the lateral abdominal wall has been widely used since its introduction for treating complex abdominal wall defects and loss of domain (LOD) hernias. Intraoperative fascial traction (IFT) is an established technique for complex abdominal wall hernias exceeding a width of 10 cm and has also shown auspicious results. We present our single center data including 143 consecutive cases combining both techniques from 2019 to 2023. Aim of the study was to develop an algorithm for a tailored approach for very large and complex ventral abdominal wall hernias. METHODS: Consecutive patients treated with preoperative BTA and IFT from August 2019 to December 2023 were identified in our prospectively maintained database and reviewed retrospectively. Metrics included intraoperative findings and short-term (30 days) postoperative outcomes. RESULTS: 143 patients were included in our retrospective analysis. The mean age was 58.9 years and 99% of all patients had an ASA Score of II or III with a mean body mass index of 32.4 kg/m2. The mean intraoperative reduction of fascia-to-fascia after BTA and IFT was 9.81 cm. 14 patients either had a lateral defect or a combination of a midline and lateral hernia. An additional uni- or bilateral transverse abdominis release (TAR) was necessary in 43 cases (30.1%). The overall surgical site occurrence rate (SSO) was 30.1% of which 13.8% were surgical site infections (SSI). Re-operation and SSO rates were significantly higher if an additional TAR was performed (both p = 0.001; α = 0.05). CONCLUSIONS: IFT in combination with BTA is a transformative and clinically proven tool in the surgeons' toolbox. It might be an easier, and less invasive alternative to other available techniques in many cases, but it should not be looked at as an ultimate stand-alone method to treat all complex W3 hernias.

Did the Coronavirus Disease 2019 (COVID-19) Pandemic Cause a Delay in the Diagnosis of Breast Cancer Patients?

Introduction The coronavirus disease 2019 (COVID-19) outbreak, first reported in Wuhan, China, in December 2019, quickly hit the world in just one month, causing a global public health emergency. We aimed to investigate whether the COVID-19 pandemic caused a delay in the hospital admissions of breast cancer patients and diagnosis of breast cancer, thus increasing the tumor size and the stage of the disease. Materials and methods Included in the study were patients who underwent breast cancer surgery between 01/03/2019 and 01/03/2020 (pre-COVID-19, first period) and between 01/03/2020 and 01/03/2021 (post-COVID-19, second period). Three hundred and seventy patients with enough details were included, and details were analyzed retrospectively. Tumor characteristics of pre-COVID-19 breast cancer patients were compared with the tumor characteristics of post-COVID-19 breast cancer patients. Demographics, preoperative diagnosis, tumor properties, surgical procedure (breast-conserving surgery, modified radical mastectomy, simple mastectomy, skin-sparing mastectomy), tumor size, total lymph node number, metastatic lymph node number, locally advanced disease, metastatic disease, and neoadjuvant therapy were evaluated. Results The mean tumor size increased significantly in the post-COVID-19 primary surgery group (p=0.005). There is no significant relationship between the pre-COVID-19 and post-COVID-19 period and pT in the neoadjuvant received group (p>0.05). The presence of pT2+pT3+pT4 was statistically significantly higher in the post-COVID-19 primary surgery group (p=0.001). The mean value of metastatic lymph nodes dissected between pre-COVID-19 and post-COVID-19 primary surgery groups increased significantly (p=0.010). Pericapsular extension was higher in the post-primary surgery group (p=0.002). Conclusion During the COVID-19 outbreak, breast cancer patients have difficulty accessing healthcare services and hesitate to apply to hospitals to fear contracting the COVID-19 disease. This situation has led to delays in diagnosing breast cancer patients, increased tumor size and pT grade, increased number of metastatic lymph nodes, pericapsular extension, and the resulting disease often appearing in advanced sizes and stages.

New imidazolidindionedioximes and their Pt(II) complexes: synthesis and investigation of their antitumoral activities on breast cancer cells.

Breast cancer is one of the most common types of cancer worldwide and has the most lethality ratio for females among all cancers. Although current cancer therapeutics have made considerable advancements, there is still room for improvement in terms of efficacy. Many anticancer drugs have a risk of causing serious adverse effects due to their nonspecific cytotoxic effects on both tumor and healthy cells. New therapeutics might have a greater ability to kill cancer cells, reduce the volume of tumors, and improve overall therapy response rates. Herein, we report the efficient synthesis and characterization of three amphi vic-dioximes and their six novel mono-, which are extremely rare in platinum chemistry, and bisplatinum(II) complexes for breast cancer treatment. Antitumoral activities of Pt(II) complexes have been investigated on CCD-1079Sk healthy fibroblast cell line, MCF-7 and MDA-MB-231 human breast cancer cell lines. Cytotoxicity, cell cycle, and apoptotic assays were performed. All new Pt(II) complexes exhibited selective antiproliferative effects on breast cancer cells by showing less cytotoxicity to healthy cells than known anticancer drugs cisplatin and bicalutamide. In vitro studies show that these new Pt complexes have high anticancer and antiproliferative effects and may be new alternatives to existing anticancer drugs.

Cerebrovascular and Alzheimer's disease biomarkers in dementia with Lewy bodies and other dementias.

Co-pathologies are common in dementia with Lewy bodies and other dementia disorders. We investigated cerebrovascular and Alzheimer's disease co-pathologies in patients with dementia with Lewy bodies in comparison with patients with mild cognitive impairment, Alzheimer's disease, mixed dementia, vascular dementia or Parkinson's disease with dementia and cognitively unimpaired participants. We assessed the association of biomarkers of cerebrovascular and Alzheimer's disease co-pathologies with medial temporal atrophy and global cognitive performance. Additionally, we evaluated whether the findings were specific to dementia with Lewy bodies. We gathered a multi-cohort dataset of 4549 participants (dementia with Lewy bodies = 331, cognitively unimpaired = 1505, mild cognitive impairment = 1489, Alzheimer's disease = 708, mixed dementia = 268, vascular dementia = 148, Parkinson's disease with dementia = 120) from the MemClin Study, Karolinska Imaging in Dementia Study, Gothenburg H70 Birth Cohort Studies and the European DLB Consortium. Cerebrovascular co-pathology was assessed with visual ratings of white matter hyperintensities using the Fazekas scale through structural imaging. Alzheimer's disease biomarkers of ß-amyloid and phosphorylated tau were assessed in the cerebrospinal fluid for a subsample (N = 2191). Medial temporal atrophy was assessed with visual ratings and global cognition with the mini-mental state examination. Differences and associations were assessed through regression models, including interaction terms. In dementia with Lewy bodies, 43% had a high white matter hyperintensity load, which was significantly higher than that in cognitively unimpaired (14%), mild cognitive impairment (26%) and Alzheimer's disease (27%), but lower than that in vascular dementia (62%). In dementia with Lewy bodies, white matter hyperintensities were associated with medial temporal atrophy, and the interaction term showed that this association was stronger than that in cognitively unimpaired and mixed dementia. However, the association between white matter hyperintensities and medial temporal atrophy was non-significant when ß-amyloid was included in the model. Instead, ß-amyloid predicted medial temporal atrophy in dementia with Lewy bodies, in contrast to the findings in mild cognitive impairment where medial temporal atrophy scores were independent of ß-amyloid. Dementia with Lewy bodies had the lowest performance on global cognition, but this was not associated with white matter hyperintensities. In Alzheimer's disease, global cognitive performance was lower in patients with more white matter hyperintensities. We conclude that white matter hyperintensities are common in dementia with Lewy bodies and are associated with more atrophy in medial temporal lobes, but this association depended on ß-amyloid-related pathology in our cohort. The associations between biomarkers were overall stronger in dementia with Lewy bodies than in some of the other diagnostic groups.

Machine learning-based early prediction of growth and morphological traits at yearling age in pure and hybrid goat offspring.

The purpose of this study was to evaluate the performance of various prediction models in estimating the growth and morphological traits of pure Hair, Alpine × Hair F1 (AHF1), and Saanen × Hair F1 (SHF1) hybrid offspring at yearling age by employing early body measurement records from birth till 9th month combined with meteorological data, in an extensive natural pasture-based system. The study also included other factors such as sex, farm, doe and buck IDs, birth type, gestation length, age of the doe at birth etc. For this purpose, seven different machine learning algorithms-linear regression, artificial neural network (ANN), support vector machines (SVM), decision tree, random forest, extra gradient boosting (XGB) and ExtraTree - were applied to the data coming from 1530 goat offspring in Türkiye. Early predictions of growth and morphological traits at yearling age; such as live weight (LW), body length (BL), wither height (WH), rump height (RH), rump width (RW), leg circumference (LC), shinbone girth (SG), chest width (CW), chest girth (CG) and chest depth (CD) were performed by using birth date measurements only, up to month-3, month-6 and month-9 records. Satisfactory predictive performances were achieved once the records after 6th month were used. In extensive natural pasture-based systems, this approach may serve as an effective indirect selection method for breeders. Using month-9 records, the predictions were improved, where LW and BL were found with the highest performance in terms of coefficient of determination (R2 score of 0.81 ± 0.00) by ExtraTree. As one of the rarely applied machine learning models in animal studies, we have shown the capacity of this algorithm. Overall, the current study offers utilization of the meteorological data combined with animal records by machine learning models as an alternative decision-making tool for goat farming.

Dose rate dependent genotoxic and metabolic effects predict onset of impaired development and mortality in Atlantic salmon (S. salar) embryos exposed to chronic gamma radiation.

Release of radionuclides to the environment from either nuclear weapon and fuel cycles or from naturally occurring radionuclides (NORM) may cause long term contamination of aquatic ecosystems and chronic exposure of living organisms to ionizing radiation, which in turn could lead to adverse effects compromising the sustainability of populations. To address the effects of chronic ionizing radiation on the development of fish, Atlantic salmon embryos were exposed from fertilization until hatching (88 days, 550 day-degree) to dose rates from 1 to 30 mGy·h-1 gamma radiation (60Co). The lowest adopted dose rate was similar to the highest doses measured in some water bodies right after the Chernobyl accident (1 mGy·h-1), however, well above current environmentally realistic scenarios (20 µGy·h-1), or the threshold assumed for significant effects on fish population (40 µGy·h-1). Dose dependent effects were observed on survival, hatching, morbidity, DNA damage, antioxidant defenses, and metabolic status. Histopathological analysis showed dose rate dependent impairment of eye and brain tissues development and establishment of epidermal mucus cell layers accompanied by increased DNA damage at doses ≥1.3 Gy (dose rates ≥1 mGy·h-1). At ≥32.8 Gy (dose rates ≥20 mGy·h-1) deformities and developmental growth defects resulted in respective 46 and 95 % pre-hatch mortality. The 10 mGy·h-1 exposure (≥ 12 Gy total dose) caused significantly increased DNA damage, impaired eye development, and both premature and delayed hatching, while no deformities or effect on survival were observed. We observed a dose rate dependent reduction from dose rate ≥ 20 mGy·h-1 (≥ 27 Gy total dose) on antioxidant SOD, catalase and glutathione reductase enzyme activities. The reduction of antioxidant enzyme activities was in line with observed developmental delay and disturbance to time of hatching. Metabolomic profiles showed a clear shift at dose rates ≥10 mGy·h-1 (≥ 12 Gy total dose) in pathways related to oxidative stress, detoxification, DNA damage and repair. Due to gamma radiation exposure, a switch of central metabolism from glycolysis, citric acid cycle and lactate production towards pentose phosphate pathway indicated a rewiring mechanism for increased production of reductive equivalents to maintain redox homeostasis at the expense of energy output and thus embryonic development.

Unraveling The Genetics of Shared Clinical and Serological Manifestations in Systemic Inflammatory Autoimmune Diseases.

OBJECTIVES: Systemic inflammatory autoimmune diseases (SIADs) such as systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS) and idiopathic inflammatory myopathies (myositis) are complex conditions characterized by shared circulating autoantibodies and clinical manifestations, including skin rashes, among others. This study aimed at elucidating the genetics underlying these common features. METHODS: We performed targeted DNA sequencing of coding and regulatory regions from ~1,900 immune-related genes in a large SIAD cohort of 2,292 well-characterized Scandinavian patients with SLE, pSS and myositis, as well as 1,252 controls. A gene-based functionally-weighted genetic score for aggregate testing of all genetic variants, including rare variants, was complemented by in-silico functional analyses and in-vitro reporter experiments. RESULTS: Case-control association analysis detected known and potentially novel genetic loci in agreement with previous genetic and transcriptomics findings linked to the SIAD autoimmune background. Intriguingly, case-case comparisons between patient subgroups with and without specific autoantibodies revealed that the subgroups defined by ANA and anti-dsDNA antibodies have unique genetic profiles reflecting their heterogeneity. When focusing on clinical features, we overall showed that DUSP1 protective genetic variants lead to increased gene expression and potentially to anti-inflammatory effects on the SIAD-associated skin phenotype. This is consistent with recent genetic findings on eczema and with the previously reported downregulation of the MAPK signaling-related gene DUSP1 in other skin disorders. CONCLUSION: Together, this suggests common molecular mechanisms potentially underlying overlapping clinical manifestations shared among different disorders and informs clinical heterogeneity, which could be translated to improve disease diagnostic and treatment, also in more generalized disease frameworks.

Sports-related concussion not associated with long-term cognitive or behavioural deficits: the PROTECT-TBI study.

BACKGROUND: The cognitive effects of sports-related concussion (SRC) have been the subject of vigorous debate but there has been little research into long-term outcomes in non-athlete populations. METHODS: This cohort study of UK community-dwelling adults (aged 50-90 years) was conducted between November 2015 and November 2020, with up to 4 years annual follow-up (n=15 214). Lifetime history of concussions was collected at baseline using the Brain Injury Screening Questionnaire. The first analysis grouped participants by type of concussion (no concussion, only SRC, only non-SRC (nSRC), mixed concussions (both SRC and nSRC)) and the second grouped the participants by number (0, 1, 2 or 3+ SRC or nSRC). Mixed models were used to assess the effect of concussion on outcomes including four cognitive domains and one behavioural measure (Mild Behavioural Impairment-C). RESULTS: Analysis of the included participants (24% male, mean age=64) at baseline found that the SRC group had significantly better working memory (B=0.113, 95% CI 0.038, 0.188) and verbal reasoning (B=0.199, 95% CI 0.092, 0.306) compared with those without concussion. Those who had suffered one SRC had significantly better verbal reasoning (B=0.111, 95% CI 0.031, 0.19) and attention (B=0.115, 95% CI 0.028, 0.203) compared with those with no SRC at baseline. Those with 3+ nSRCs had significantly worse processing speed (B=-0.082, 95% CI -0.144 to -0.019) and attention (B=-0.156, 95% CI -0.248 to -0.063). Those with 3+ nSRCs had a significantly worse trajectory of verbal reasoning with increasing age (B=-0.088, 95% CI -0.149 to -0.026). CONCLUSIONS: Compared with those reporting no previous concussions, those with SRC had no cognitive or behavioural deficits and seemed to perform better in some tasks. As indicated by previous studies, sports participation may confer long-term cognitive benefits.