T-cell activation may be contributing to severe psychiatric disorders. Soluble CD27 (sCD27) - a marker for T-cell activation and disease activity in several autoimmune diseases - was evaluated as a tool for distinguishing T-cell activity in selected patients with severe psychiatric disorders, multiple sclerosis (MS), and controls. We hypothesise that elevated sCD27 levels will be associated with comorbid autoimmune disease (AID). sCD27 was measured in cerebrospinal fluid (CSF) and blood from a population enriched for suspected immunological comorbidity: the Immunopsychiatry Cohort (IP; n=115) and patients with MS (n=37), where levels in both groups were higher when compared with age matched controls undergoing surgery (n=154). Positive sCD27 (sCD27+), was defined as values >97.5% of controls. In IP, 23% were CSF sCD27+ and 15% blood sCD27+, compared to patients with MS where 88% were CSF sCD27+ and 22% were blood sCD27+. CSF-sCD27+ was confirmed as a sensitive marker for MS. In IP, CSF-sCD27+ was associated with comorbid AID (X2=4.847, p =0.028;) and AID disease activity (OR=5.14, p=0.029). Associations with AID were stronger when CSF and/or blood sCD27+ were combined (X2=8.559, p=0.003). CSF-sCD27+ in IP was also associated with pleocytosis, CSF-Total-tau, and CSF-NfL. In patients with severe psychiatric disorders, the sCD27+ cases were more likely to have comorbid AID and established markers for neuroinflammation in CSF. Combining analyses of CSF and blood improved sensitivity and specificity for AID suggesting compartmentalized T-cell activation. Psychiatric symptoms may precede somatic symptoms - or be the prominent symptom - of AID and sCD27 is a candidate marker for identification of this subgroup.

BACKGROUND:Wilson's disease (WD) causes intracellular copper accumulation due to a genetic defect in the copper-transporting protein ATP7B. Cardiac involvement has been reported even in young WD patients; however, pathophysiological mechanisms remain unclear. This study aimed to comprehensively assess the myocardium in WD patients without cardiac symptoms using multiparametric cardiovascular magnetic resonance imaging (CMR), including quantitative stress perfusion mapping and strain analysis. METHODS:WD patients and healthy volunteers underwent multiparametric 1.5T CMR, including cine, native T1, native T2, extracellular volume (ECV), adenosine stress perfusion mapping, and late gadolinium enhancement (LGE) imaging. Left and right ventricle (LV, RV) mass and volumes, global native T1, native T2, ECV, rest and stress perfusion, myocardial perfusion reserve (MPR), strain measures and liver native T1 were compared. LGE images were assessed visually. Disease type and duration, medications, and cardiovascular risk factors were recorded. Symptoms of myocardial ischemia were quantified with Seattle Angina Questionnaire-7. RESULTS:WD patients (n = 17, 34 [29-55] years, 8/17 (47%) female) and healthy volunteers (n = 17, 33 [29-52] years, 8/17 (47%) female, p = ns for both) were included. There were no differences in cardiovascular risk factors or medications. LV ejection fraction was lower in WD patients (57 [55-61] vs 62 [57-67] %, p = 0.02), and LV global circumferential strain was mildly worse (-18 [-19 to (-17)] vs -20 [-21 to (-18)] %, p = 0.005), otherwise there were no differences in LV or RV mass or function. WD patients had lower stress perfusion and MPR (2.95 [2.74-3.29] vs 3.81 [2.67-4.45] mL/min/g, and 3.3 [3.1-3.8] vs 5.0 [2.9-5.4]), while ECV was higher (29 [28-30] vs 26 [26-29] %), p<0.05 for all, but there were no other differences in multiparametric mapping results. ECV did not correlate with strain parameters. ECV was associated with WD and sex but not age (WD β = 2.58%, male sex β = -0.03%, model R2 0.41, p<0.05 for all). LGE was present in the RV insertion point in 12/17 (71%) of WD patients. CONCLUSIONS:In this study, stable WD patients without apparent cardiac symptoms have early signs of diffuse fibrosis, coronary microvascular dysfunction, and worse systolic function. However, this study is limited by small sample size limiting further subgroup analysis, lack of both longitudinal clinical data and biopsies, not allowing for correlation of CMR findings to histopathology.

Bone damage in laying hens remains a significant welfare concern in the egg industry. Breeding companies rely on selective cross-breeding of purebred birds to produce commercial hybrids, which farmers raise for table-egg production. Genomic prediction is a potential tool to improve bone quality in laying hens. Because commercial layers are crossbred and kept in different environments than pure lines, the question arises whether to use within-line purebred selection or whether to use crossbred data. While selection based on pure line data is common, achieving optimal bone strength in hybrids may require incorporating hybrid data to account for heterosis and housing-specific effects. This study aims to evaluate how combining pure line and hybrid data could affect the accuracy of breeding values for bone strength. Genotypes and phenotypes were available from two types of white hybrids (Bovans White and Lohmann Selected Leghorn Classic) housed in two housing systems (furnished cages and floor housing). This resulted in four hybrid-housing combinations (n ∼ 220 for each). Tibia strength and genotypes for pure breeding lines of White Leghorn (WL, n = 947) and Rhode Island Red (RIR, n = 924) were also included. Each of the hybrid-housing combinations and pure lines was fitted separately into (1) single-trait Genomic Best Linear Unbiased Prediction (GBLUP), then simultaneously via multitrait GBLUP, (2) within hybrids across housing, (3) across hybrids within housing, (4) across hybrids and housing, (5) the latter in combination with WL and/or RIR data. Including hybrid data slightly increased the accuracy of the genomic estimated breeding value (GEBV) of other hybrids, but not that of pure lines. Pure line data increased the GEBV accuracy of hybrids over and above that of combining hybrid information. Combining data from two pure lines improved the GEBV accuracy of both. In comparison to the combination of data across lines and/or houses, combining tibia strength and BW within-lines increased tibia strength GEBV accuracy. The maximum GEBV accuracy obtained for tibia strength ranged from 0.42 to 0.65 for hybrids and from 0.63 to 0.78 for pure lines. Further study is required to test whether modelling the interactions of genotype by environment could help to breed hybrids for specific housing systems.

Background: Wilson disease (WD) causes intracellular copper accumulation in the body due to a genetic defect in the protein ATP7B. Cardiac involvement such as electrocardiographic abnormalities, rhythm abnormalities, heart failure and cardiac death have been reported, however pathophysiological mechanisms remain unclear. Objectives: This study aimed to comprehensively assess the myocardium in WD patients without cardiac symptoms using multiparametric cardiovascular magnetic resonance imaging (CMR), including quantitative stress perfusion mapping and strain analysis. Methods: WD patients (n=17, 41±16 years, 47% female) and volunteers (n=17, 39±15 years, 47% female) underwent multiparametric mapping at 1.5 T CMR including cine, native T1, native T2, adenosine stress perfusion mapping, late gadolinium enhancement (LGE), and extracellular volume (ECV) imaging. Symptoms of myocardial ischemia were quantified using Seattle Angina Questionnaire-7 (SAQ-7) and cardiovascular risk factors and medications were recorded. Results: Both stress perfusion and MPR were lower in WD patients (2.95±0.58 vs 3.67±1.01 ml/min/g, and 3.4±0.8 vs 4.4±1.9), while ECV was higher, (29±3% vs 27±2%), p<0.05 for all. Left ventricular ejection fraction (LVEF) was lower in WD patients, (56±6% vs 61±6%, p=0.02), and LV ventricular global circumferential strain (LV GCS) was higher (-18±2% vs -20±2%, p=0.005). Late gadolinium enhancement (LGE) was present in the right ventricular insertion point (RVIP) in 12/17 (71%) of the WD patients. Conclusions: In this small mechanistic study, WD patients on stable treatment without apparent cardiac symptoms have early signs of diffuse fibrosis, coronary microvascular dysfunction (CMD) and systolic dysfunction, shedding light on pathophysiological mechanisms of cardiac dysfunction in copper accumulation. ### Competing Interest Statement Previously, Nickander has received minor speaker compensation from Sanofi-Genzyme for work unrelated to the current study. Steffen Johansson and Fogarasi declare no relationships with industry. The Karolinska University Hospital has a research and development agreement with Siemens Healthineers. Kindmark has research grants funded by Sanofi-Genzyme, Takeda, Orphalan, BioMarin and has received consultant or speaker compensation from Amgen, UCB, Sanofi-Genzyme, Takeda, Orphalan, BioMarin, Chiesi, Abacus, and Amicus. ### Funding Statement The study was funded in part by The Swedish Society of Medicine, Tore Nilsson Foundation, Magnus Bergvalls Stiftelse, and Swedish Heart and Lung Foundation. Steffen Johansson is funded by The Swedish Society of Medicine, Swedish Heart and Lung Foundation and the Region of Stockholm, Sweden. Fogarasi is funded by The Swedish Society of Medicine, and Swedish Heart and Lung Foundation. Nickander is funded by Swedish Heart and Lung Foundation and the Region of Stockholm. Kindmark is funded by the Region of Uppsala. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Swedish Ethical Review Authority granted ethical approval for the study (DNR 2019 06287, with amendments 2019 06287, 2021 05508 02, 2022 06995 02 and for volunteers 2015/2106 31/1 and 2014/131 31/1, 2017/2415 32/1, 2021 06837 02) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Upon reasonable request, data supporting the findings in this study are available from the corresponding author.

Osteoporosis and bone fractures are a severe problem for the welfare of laying hens, with genetics and environment, such as housing system, each making substantial contributions to bone strength. In this work, we performed genetic analyses of bone strength, bone mineral density, and bone composition, as well as body weight, in 860 commercial crossbred laying hens from 2 different companies, kept in either furnished cages or floor pens. We compared bone traits between housing systems and crossbreds and performed a genome-wide association study of bone properties and body weight. As expected, the 2 housing systems produced a large difference in bone strength, with layers housed in floor pens having stronger bones. These differences were accompanied by differences in bone geometry, mineralization, and chemical composition. Genome scans either combining or independently analyzing the 2 housing systems revealed no genome-wide significant loci for bone breaking strength. We detected 3 loci for body weight that were shared between the housing systems on chromosomes 4, 6, and 27 (either genome-wide significant or suggestive) and these coincide with associations for bone length. In summary, we found substantial differences in bone strength, content, and composition between hens kept in floor pens and furnished cages that could be attributed to greater physical activity in pen housing. We found little evidence for large-effect loci for bone strength in commercial crossbred hens, consistent with a highly polygenic architecture for bone strength in the production environment. The lack of consistent genetic associations between housing systems in combination with the differences in bone phenotypes could be due to gene-by-environment interactions with housing system or a lack of power to detect shared associations for bone strength.

•In 2015, a multidisciplinary team at Uppsala University Hospital was established to evaluate and identify patients with underlying autoimmune disorders, or possible, probable and definite forms of an immunopsychiatric disease.•The model aims to improve knowledge and collaboration across medical specialties and provide a forum for ethical discussions and risk-benefit analysis for treatment and systematically collect clinical data to allow evaluation of treatment outcomes and quality of health care.•The structure coordinates university and hospital interests by integrating clinical care with infrastructure for research and development (biobanking, data bases, clinical trials) in order to develop novel tools for diagnostics and treatment in this patient population.

1. This study on long-life layers, covering the period 20-100 weeks of age, investigated longitudinal effects on mortality, layer integument, and skeletal properties in Bovans White (BoW) and Lohmann Selected Leghorn Classic (LSL), with or without supplementation with dietary organic zinc (Zn).2. Two experiments, using 1440 layers in furnished small group cages (FC) and 1836 layers in a traditional floor housing system (Floor), were run in parallel. Each replicate consisted of five adjacent cages containing eight hens in each FC, or a pen with 102 layers in the Floor group.3. Mortality was recorded daily. Integument and keel bone condition were scored at 35, 55, 85, and 100 weeks of age on 20% of the layers. Tibial strength was recorded from 933 layers at 100 weeks. Statistical analyses were performed on replicate means, with four to five and nine replicates per combination of hybrid and diet in Floor and FC groups, respectively.4. Cumulative mortality was 9.6% and 16.3% in FC and Floor, respectively, and increased in the latter part of the production cycle, particularly in the Floor group.5. In FC, LSL had inferior feather cover, less keel bone deviation, and shorter claws than BoW. In Floor, LSL had superior feather cover, less severe vent wounds, more bumble foot, and cleaner plumage than BoW. In both production systems, claws grew longer and keel bone deviation became more severe with age.6. In FC, layers fed organic Zn had lower body weight and less keel bone deviation at 100 weeks of age.7. In conclusion, keel bone integrity, claw length, and mortality rate are potential threats to welfare in long-life layers. Feather pecking is a problem that needs addressing at an early stage in the production period. On the whole, organic Zn did not improve welfare conditions in long-life layers.

Results from real-world evidence (RWE) from the largest healthcare region in Sweden show low uptake of antiresorptive (AR) treatment, but beneficial effect in those receiving treatment, especially for the composite outcome of hip fracture or death. For RWE studies, Sweden is unique, with virtually complete coverage of electronic medical records (EMRs) and both regional and national registries, in a universal publicly funded healthcare system. To our knowledge, there is no previous RWE study evaluating the efficacy of AR treatment compared to no AR treatment after fragility fracture, including data on parenteral treatments administered in hospital settings. The Stockholm Real World Management (STORM) study cohort was established in the healthcare region of Stockholm to retrospectively assess the effectiveness of AR treatment after first fragility fracture using the regional EMR system for both hospital and primary care. Between 2012 and 2018, we identified 69,577 fragility fracture episodes among 59,078 patients, men and women, 50 years and older. Of those, 21,141 patients met inclusion and exclusion criteria (eligible cohort). From these, the final matched study cohort comprised 9840 fragility fractures (cases receiving AR treatment [n = 1640] and controls not receiving AR treatment [n = 8200]). Propensity scores were estimated using logistic regression models with AR treatment as outcome and confounders as independent variables followed by analysis using Cox proportional hazard models. Real world evidence from Sweden's largest healthcare region, comprising a quarter of the Swedish population, show that only 10% of patients receive AR treatment within 1 year after a fragility fracture. Factors associated with not receiving treatment include having a diagnosis of cardiovascular disease. In those treated, AR have positive effects particularly on the composite of fracture and death (any fracture/death and hip fracture/death) in individuals matched for all major confounders. (c) 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

The Klotho ( KL ) gene is involved in phosphate homeostasis. Polymorphisms in this gene have been reported to be associated with the risk of cardiovascular disease. Here we used computational tools to predict the damage-associated single nucleotide polymorphisms (SNPs) in the human KL gene. We further investigated the association of SNPs in the KL gene and mortality in the Swedish multicenter prospective Osteoporotic Fractures in Men (MrOS) cohort. This study included 2921 men (aged 69–81 years) with mean 4.49 ± 1.03 years follow-up. 18 SNPs in the KL gene were genotyped using Sequenom. These SNPs were identified by in silico tools for the coding and noncoding genome to predict the damaging SNPs. After quality analyses, SNPs were analyzed for mortality risk using two steps approach on logistic regression model screening and then Cox regression model confirmation. Two non-synonymous SNPs rs9536314 and rs9527025 were found to be potentially damaging SNPs that affect KL protein stability and expression. However, these two SNPs were not statistically significantly associated with all-cause mortality (crude Hazard ratio [HR] 1.72, 95% confidence interval [CI] 0.96–3.07 in rs9536314; crude HR 1.82, 95% CI 0.998–3.33 in rs9527025) or cardiovascular mortality (crude HR 1.52, 95% CI 0.56–4.14 in rs9536314; crude HR 1.54, 95% CI 0.55–4.33 in rs9527025) in additive model using Cox regression analysis. In conclusion, these two potentially damaging SNPs (rs9536314 and rs9527025) in the KL gene were not associated with all-cause mortality or cardiovascular mortality in MrOs cohort. Larger scales studies and meta-analysis are needed to confirm the correlation between polymorphisms of the KL gene and mortality.

Abstract Background Osteogenesis imperfecta (OI) is a clinical and genetic heterogeneous group of connective tissue disorders, characterized by bone fragility and a propensity to fracture. Methods In this report we describe the clinical phenotype of two patients, a 28‐year‐old woman and her mother (54 years old), both with a history of short stature and multiple fractures. Results Exome sequencing revealed the recurring IFITM5:c.‐14 C>T variant causing OI type V. Both patients had several fractures during childhood. CT‐scan and scintigraphy showed ossification of the origin and attachment of muscles and hypertrophic callus formation. Conclusion Ossification of the origin and attachment of muscles seems to be part of the phenotype in patients with OI type V.

Gaucher disease (GD) is a rare, genetic lysosomal disorder leading to lipid accumulation and dysfunction in multiple organs. Involvement of the skeleton is one of the most prevalent aspects of GD and a major cause of pain, disability, and reduced quality of life. Uniform recommendations for contemporary evaluation and management are needed. To develop practical clinical recommendations, an international group of experienced physicians conducted a comprehensive review of 20 years' of the literature, defining terms according to pathophysiological understanding and pointing out best practice and unmet needs related to the skeletal features of this disorder. Abnormalities of bone modeling, reduced bone density, bone infarction, and plasma cell dyscrasias accompany the displacement of healthy adipocytes in adult marrow. Exposure to excess bioactive glycosphingolipids appears to affect hematopoiesis and the balance of osteoblast and osteoclast numbers and activity. Imbalance between bone formation and breakdown induces disordered trabecular and cortical bone modeling, cortical bone thinning, fragility fractures, and osteolytic lesions. Regular assessment of bone mineral density, marrow infiltration, the axial skeleton and searching for potential malignancy are recommended. MRI is valuable for monitoring skeletal involvement: It provides semiquantitative assessment of marrow infiltration and the degree of bone infarction. When MRI is not available, monitoring of painful acute bone crises and osteonecrosis by plain X-ray has limited value. In adult patients, we recommend DXA of the lumbar spine and left and right hips, with careful protocols designed to exclude focal disease; serial follow-up should be done using the same standardized instrument. Skeletal health may be improved by common measures, including adequate calcium and vitamin D and management of pain and orthopedic complications. Prompt initiation of specific therapy for GD is crucial to optimizing outcomes and preventing irreversible skeletal complications. Investing in safe, clinically useful, and better predictive methods for determining bone integrity and fracture risk remains a need. © 2019 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

Gaucher disease (GD) is a rare, genetic lysosomal disorder leading to lipid accumulation and dysfunction in multiple organs. Involvement of the skeleton is one of the most prevalent aspects of GD and a major cause of pain, disability, and reduced quality of life. Uniform recommendations for contemporary evaluation and management are needed. To develop practical clinical recommendations, an international group of experienced physicians conducted a comprehensive review of 20 years' of the literature, defining terms according to pathophysiological understanding and pointing out best practice and unmet needs related to the skeletal features of this disorder. Abnormalities of bone modeling, reduced bone density, bone infarction, and plasma cell dyscrasias accompany the displacement of healthy adipocytes in adult marrow. Exposure to excess bioactive glycosphingolipids appears to affect hematopoiesis and the balance of osteoblast and osteoclast numbers and activity. Imbalance between bone formation and breakdown induces disordered trabecular and cortical bone modeling, cortical bone thinning, fragility fractures, and osteolytic lesions. Regular assessment of bone mineral density, marrow infiltration, the axial skeleton and searching for potential malignancy are recommended. MRI is valuable for monitoring skeletal involvement: It provides semiquantitative assessment of marrow infiltration and the degree of bone infarction. When MRI is not available, monitoring of painful acute bone crises and osteonecrosis by plain X-ray has limited value. In adult patients, we recommend DXA of the lumbar spine and left and right hips, with careful protocols designed to exclude focal disease; serial follow-up should be done using the same standardized instrument. Skeletal health may be improved by common measures, including adequate calcium and vitamin D and management of pain and orthopedic complications. Prompt initiation of specific therapy for GD is crucial to optimizing outcomes and preventing irreversible skeletal complications. Investing in safe, clinically useful, and better predictive methods for determining bone integrity and fracture risk remains a need. (c) 2019 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

The vitamin D receptor (VDR) has been proposed as a candidate gene for several musculoskeletal phenotypes. However, previous results on the associations between genetic variants of the VDR with muscle strength and falls have been contradictory. The MrOS Sweden survey, a prospective population-based cohort study of 3014 elderly men (mean age 75 years, range 69-81) offered the opportunity to further investigate these associations. At baseline, data were collected on muscle strength and also the prevalence of falls during the previous 12 months. Genetic association analysis was performed for 7 Single Nucleotide Polymorphisms (SNPs), covering the genetic region surrounding the VDR gene in 2924 men with available samples of DNA. Genetic variations in the VDR were not associated with five different measurements of muscle strength or physical performance (hand grip strength right and left, 6 m walking test (easy and narrow) and timed-stands test). However, one of the 7 SNPs of the gene for the VDR receptor, rs7136534, was associated with prevalence of falls (33.6% of the AA, 14.6% of the AG and 16.5% of the GG allele). In conclusion, VDR genetic variants are not related to muscle strength or physical performance in elderly Swedish men. The role of the rs7136534 SNP for the occurrence of falls is not clear.

Background Mutations of the endoplasmic reticulum (ER) stress transducer OASIS (encoded by CREB3L1), cause severe recessive osteogenesis imperfecta (OI) not compatible with surviving the neonatal period, as has been shown in two unrelated families through a whole gene deletion vs. a qualitative alteration of OASIS Heterozygous carriers in the described families have exhibited a mild phenotype. OASIS is a transcription factor highly expressed in osteoblasts, and OASIS(-/-) mice exhibit severe osteopenia and spontaneous fractures. Here, we expand the clinical spectrum by a detailed phenotypic characterization of the first case of OASIS-associated OI surviving the neonatal period, with heterozygous family members being unaffected. Methods: All OI-associated genes were sequenced. Primary human osteoblast-like cell (hOB) and fibroblast (FB) cultures were obtained for qPCR, and steady-state collagen biochemistry. FB, hOB and skin biopsies were ultrastructurally analyzed. Bone was analyzed by |mu CT, histomorphometry, quantitative backscattered electron imaging (qBEI), and Raman microspectroscopy. Results: The proband, a boy with severe OI, had blue sclera and tooth agenesis A homozygous CREB3L1 stop codon mutation was detected by sequencing, while several family members were heterozygotes Markedly low levels of CREB3L1 mRNA were confirmed by qPCR in hOBs (16%) and FB (21%), however, collagen I levels were only reduced in hOBs (5-10%) Electron microscopy of hOBs showed pronounced alterations, with numerous myelin figures and diminished RER vs. normal ultrastructure of FB. Bone histomorphometry and qBEI were similar to collagen I OI, with low trabecular thickness and mineral apposition rate, and increased bone matrix mineralization. Raman microspectroscopy revealed low level of glycosaminoglycans. Clinical response to lifelong bisphosphonate treatment was as expected in severe OI with steadily increasing bone mineral density, but despite this the boy suffered repeated childhood fractures. Conclusions: Deficiency of OASIS can cause severe OI compatible with surviving the neonatal period A marked decrease of collagen type I transcription was noted in bone tissue, but not in skin, and ultrastructure of hOBs was pathological. Results also suggested OASIS involvement in glycosaminoglycan secretion in bone.