The effect of thyroid hormone therapy on muscle function, strength and mass in older adults with subclinical hypothyroidism-an ancillary study within two randomized placebo controlled trials.

BACKGROUND: loss of skeletal muscle function, strength and mass is common in older adults, with important socioeconomic impacts. Subclinical hypothyroidism is common with increasing age and has been associated with reduced muscle strength. Yet, no randomized placebo-controlled trial (RCT) has investigated whether treatment of subclinical hypothyroidism affects muscle function and mass. METHODS: this is an ancillary study within two RCTs conducted among adults aged ≥65 years with persistent subclinical hypothyroidism (thyrotropin (TSH) 4.60-19.99 mIU/l, normal free thyroxine). Participants received daily levothyroxine with TSH-guided dose adjustment or placebo and mock titration. Primary outcome was gait speed at final visit (median 18 months). Secondary outcomes were handgrip strength at 1-year follow-up and yearly change in muscle mass. RESULTS: we included 267 participants from Switzerland and the Netherlands. Mean age was 77.5 years (range 65.1-97.1), 129 (48.3%) were women, and their mean baseline TSH was 6.36 mIU/l (standard deviation [SD] 1.9). At final visit, mean TSH was 3.8 mIU/l (SD 2.3) in the levothyroxine group and 5.1 mIU/l (SD 1.8, P < 0.05) in the placebo group. Compared to placebo, participants in the levothyroxine group had similar gait speed at final visit (adjusted between-group mean difference [MD] 0.01 m/s, 95% confidence interval [CI] -0.06 to 0.09), similar handgrip strength at one year (MD -1.22 kg, 95% CI -2.60 to 0.15) and similar yearly change in muscle mass (MD -0.15 m2, 95% CI -0.49 to 0.18). CONCLUSIONS: in this ancillary analysis of two RCTs, treatment of subclinical hypothyroidism did not affect muscle function, strength and mass in individuals 65 years and older.

Correlation of muscle and bone parameters, daily function and participation in women with generalized joint hypermobility: a descriptive evaluation.

OBJECTIVES: Generalized joint hypermobility (GJH) has a prevalence in women of 15% to 35%. GJH may lead to impaired movement control, frequent sprains or subluxations and pain, and can be associated with early osteoarthritis or chronic fatigue. Aim of this project was to analyse muscle strength, muscle cross-sectional area (mCSA) and daily function in women with GJH and to analyse correlations between these measurements. METHODS: Descriptive cross-sectional study of women with GJH, defined by Beighton score ≥6/9. Assessments included muscle strength, mCSA by peripheral Quantitative Computed Tomography (pQCT), stair climbing, as well as two questionnaires. Spearman's correlations between parameters were calculated. RESULTS: 51 women with a mean age of 26.5 years participated, whereof 18 (35%) had a Beighton score of 9/9 and 17 (33%) attained 8/9. Internal correlations between strength measurements were high, whereas pQCT parameters were less correlated. Strength was moderately correlated with mCSA, while correlations with stair climbing and SF-36 were not significant. CONCLUSIONS: This study provides insight into the muscle and bone properties of women with GJH. Only slight differences were seen compared to normative values. Correlations between various dimensions were middle or low, indicating the complex relationship between strength, muscle properties and function.

Peripheral Volumetric Muscle Area and Total Body Volume in Postmenopausal Women With Rheumatoid Arthritis.

The effect of rheumatoid arthritis (RA) on peripheral muscle parameters is not completely understood. This study aimed to elucidate the influence of RA on peripheral muscle area and whole body skeletal muscle mass index (SMI) using peripheral quantitative computed tomography and dual-energy X-ray absorptiometry in postmenopausal women. This cross-sectional study included 54 postmenopausal women with RA and 86 healthy controls. Peripheral quantitative computed tomography and dual-energy X-ray absorptiometry were used to measure the muscle cross-sectional area and skeletal muscle mass. Muscle strength was assessed using a handheld dynamometer. Additionally, the effects of RA on muscle area and density as well as the bone / muscle area ratio were analyzed using multivariate models. The muscle area index of the thigh and forearm were correlated between both groups (RA: r = 0.357, p = 0.030; and healthy controls: r = 0.608, p < 0.001) and each index correlated with SMI in RA and healthy controls (p < 0.001). Bone / muscle area ratio correlated between forearms and thighs in health controls only (r = 0.547, p < 0.001). The RA group had a decreased thigh muscle area (p = 0.014); the fat area and fat muscle area ratio at the thigh and forearm were significantly increased (all p < 0.001), as well as thigh bone / muscle area ratio (p = 0.015). The RA group also had significantly lower forearm muscle density (p < 0.001). A sensitivity analysis excluding those on bisphosphonates led to similar results. Independent of RA, the thigh and forearm muscle area correlate with each other and with SMI. Differences in the bone / muscle ratio between RA and healthy controls may indicate regional muscle effects of inflammation and inactivity.

The links of hepcidin and erythropoietin in the interplay of inflammation and iron deficiency in a large observational study of rheumatoid arthritis.

Anaemia affects quality of life and radiographic outcome in rheumatoid arthritis (RA). In a cross-sectional study with 779 patients, we assessed the prognostic potential of the major haematopoietic regulators, hepcidin and erythropoietin, comparing their serum concentrations with respect to different anaemia types, inflammatory activity, anti-cytokine-specific treatment effects and iron deficiency (ID) indices. The results showed that clinical disease activity was more closely associated with haemoglobin levels than with anti-tumour necrosis factor-alpha or interleukin 6 receptor effects. In ID, hepcidin was suppressed, independently of inflammation. Erythropoietin levels were inappropriately low in relation to the degree of anaemia, but, in contrast to low haemoglobin, not directly associated with joint damage progression. Hepcidin and erythropoietin levels are intimately connected with inflammation and ID. Interventional studies on these important targets are already in progress.

Influence of bisphosphonate therapy on bone geometry, volumetric bone density and bone strength of femoral shaft in postmenopausal women with rheumatoid arthritis.

BACKGROUND: There is evidence that postmenopausal women with rheumatoid arthritis (RA) on glucocorticoid (GC) therapy and bisphosphonate (BP) have an increased risk for atypical subtrochanteric and atypical diaphyseal femoral fracture (AFF). The underlying mechanism has not been elucidated so far. Using peripheral quantitative computed tomography (pQCT), the aim of the present study was to compare bone geometry, volumetric bone mineral density (vBMD) and bone strength of femoral shaft in BP-treated and BP-naïve postmenopausal women with RA. METHODS: Prospective cross-sectional pQCT scans were taken at 33 % of total femur of BP-treated and BP-naïve RA patients. Bone parameters of the two groups were compared and correlated to disease characteristics and muscle cross-sectional area (CSA). RESULTS: A total of 60 consecutive postmenopausal RA patients, 20 with BP therapy and 40 BP-naïve, were included in the study. The median age of the subjects was 63.5 years (range 48-85 years), and median disease duration (RA) was 12.0 years (range 2-47 years). Height and weight of the patients of the two groups were comparable. Women in the BP group were on average 4.3 years older (p = 0.044), and duration since menopause was on average 5.76 years longer (p = 0.045). In the BP group, there was a 13.31 % reduced muscle cross-sectional area around the proximal thigh (p = 0.013); cortical CSA was smaller by 5.3 % (p = 0.043); however, total and medullary CSA, as well as cortical vBMD and the polar bone stress-strain index of the femoral shaft were similar in the two groups. In regression analysis, age, time since menopause and muscular CSA were significant factors determining cortical CSA, cortical thickness and femoral index (p < 0.05). Regression model showed no significant effect of BP therapy on bone geometry and density of the femoral diaphysis at 33 %. CONCLUSION: Differences in cortical CSA between BP-treated and BP-naïve postmenopausal RA patients were found to be associated only with differences in age, time since menopause and muscle cross-sectional area around the proximal thigh. In interpreting our results, it should be kept in mind that BP was given only to patients with increased fracture risk. This fact might have a confounding effect on our findings of differences between the two groups.

Low-energy trauma-induced intercondylar femoral fracture.

We present a 44-year-old female patient with recurrent fragility fractures including an intercondylar femoral fracture and with normal planar bone densitometry. Diagnosis of hypophosphatasia was suggested by low volumetric cortical bone mineral density and laboratory findings. DNA sequencing revealed heterozygous mutations in the exons 5, 6 and 9 of the ALPL gene, thus confirming the suspected diagnosis.

Diffuse idiopathic skeletal hyperostosis (DISH) of the elbow: a controlled radiological study.

BACKGROUND: Extraspinal manifestations of diffuse idiopathic skeletal hyperostosis (DISH) have been described previously. We aimed to assess the prevalence of elbow hyperostotic spurs, to search for sites discriminating for elbow DISH and to analyze the effect of physical activities, handedness and sex. METHODS: Out of 284 patients hospitalized for extraskeletal disorders, 85 patients (33 with and 52 without thoracospinal DISH) agreed to bilateral elbow X-rays in two projections. Clinical information was collected by a standardized questionnaire and X-rays were graded blindly. RESULTS: A total of 400 hyperostotic spurs (210 unilateral, 95 bilateral) were present at 11 predefined sites. The most frequent sites affected were the olecranon (20.8%), lateral epicondyle (17.8%) and medial epicondyle (15.5%). In carriers of thoracospinal DISH significantly more hyperostotic spurs were present at the lateral and medial epicondyle compared to non-DISH carriers (OR 4.01 [95% CI 1.35-12.34] and 2.88 [1.03-8.24], respectively). The olecranon, lateral and medial epicondyle contributed significantly to the classification of elbow DISH (OR 22.2 [4.1-144.7], 9.6 [1.9-61.2] and 10.1 [2.2-52.1], respectively). The prevalence of elbow hyperostotic spurs was higher in 45 patients with a history of heavy physical activities (24.4% versus 18.0%, OR 1.48 [1.17-1.86]), at the right elbow (24.2% versus 18.6%, OR 1.39 [1.11-1.75]) and in 62 males (22.8% versus 17.6%, OR 1.38 [1.06-1.81]). CONCLUSIONS: Hyperostotic spurs at the olecranon, lateral and medial epicondyle had the highest prevalence and disclosed the most pronounced discrimination for elbow DISH. Mechanical factors such as physical activities and handedness, and sex influenced the formation of these spurs.

Interleukin-17A stimulates granulocyte-macrophage colony-stimulating factor release by murine osteoblasts in the presence of 1,25-dihydroxyvitamin D(3) and inhibits murine osteoclast development in vitro.

OBJECTIVE: To investigate the effects of interleukin-17A (IL-17A) on osteoclastogenesis in vitro. METHODS: Bone marrow cells (BMCs) were isolated from the excised tibia and femora of wild-type C57BL/6J mice, and osteoblasts were obtained by sequential digestion of the calvariae of ddY, C57BL/6J, and granulocyte-macrophage colony-stimulating factor-knockout (GM-CSF(-/-)) mice. Monocultures of BMCs or cocultures of BMCs and osteoblasts were supplemented with or without 1,25-dihydroxyvitamin D(3)(1,25[OH](2)D(3)), recombinant human macrophage colony-stimulating factor (M-CSF), RANKL, and IL-17A. After 5-6 days, the cultures were fixed with 4% paraformaldehyde and subsequently stained for the osteoclast marker enzyme tartrate-resistant acid phosphatase (TRAP). Osteoprotegerin (OPG) and GM-CSF expression were measured by enzyme-linked immunosorbent assay, and transcripts for RANK and RANKL were detected by real-time polymerase chain reaction. RESULTS: In both culture systems, IL-17A alone did not affect the development of osteoclasts. However, the addition of IL-17A plus 1,25(OH)(2)D(3) to cocultures inhibited early osteoclast development within the first 3 days of culture and induced release of GM-CSF into the culture supernatants. Furthermore, in cocultures of GM-CSF(-/-) mouse osteoblasts and wild-type mouse BMCs, IL-17A did not affect osteoclast development, corroborating the role of GM-CSF as the mediator of the observed inhibition of osteoclastogenesis by IL-17A. CONCLUSION: These findings suggest that IL-17A interferes with the differentiation of osteoclast precursors by inducing the release of GM-CSF from osteoblasts.

Bone health in patients with inflammatory bowel disease.

Patients with inflammatory bowel disease (IBD) are prone to reduced bone mineral density and elevated overall fracture risk. Osteopenia affects up to 40% of patients with IBD (high regional variability). Besides disease activity, IBD specialists must consider possible side effects of medication and the presence of associated diseases and extraintestinal manifestations. Osteopenia and osteoporosis remain frequent problems in patients with IBD and are often underestimated because of widely differing screening and treatment practices. Malnutrition, chronic intestinal inflammation and corticosteroid intake are the major pathophysiological factors contributing to osteoporosis. Patients with IBD are screened for osteoporosis using dual-energy X-ray absorptiometry (DXA), which is recommended for all patients with a prolonged disease course of more than three months, with repeated corticosteroid administration, aged >40 years with a high FRAX risk score or aged <40 years with multiple risk factors. From a therapeutic perspective, besides good disease control, vitamin D supplementation and glucocorticoid sparing, several specific osteological options are available: bisphosphonates, receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors (denosumab), parathyroid hormone (PTH) analogues and selective estrogen receptor modulators. This review provides an overview of the pathophysiology, diagnosis, prevention and treatment of IBD-associated bone loss.

Expanding the p.(Arg85Trp) Variant-Specific Phenotype of HNF4A: Features of Glycogen Storage Disease, Liver Cirrhosis, Impaired Mitochondrial Function, and Glomerular Changes.

Introduction: The p.(Arg85Trp) variant-specific phenotype of hepatocyte nuclear factor 4 alpha shows a complex clinical picture affecting three different organ systems and their corresponding metabolisms. Little is known about the molecular mechanisms involved and their relationship with the diverse symptoms seen in the context of this specific variant. Here, we present data of a new patient that expand the clinical phenotype, suggesting possible disease mechanisms. Case Presentation: Clinical data were extracted from the patient's charts. The liver, kidney, and muscle were analyzed with routine histology and electron microscopy. Mitochondrial function was assessed by respirometric analyses and enzymatic activity assays. Structure and sequence analyses of this specific variant were investigated by in silico analyses. Our patient showed the known features of the variant-specific phenotype, including macrosomia, congenital hyperinsulinism, transient hepatomegaly, and renal Fanconi syndrome. In addition to that, she showed liver cirrhosis, chronic kidney failure, and altered mitochondrial morphology and function. The clinical and biochemical phenotype had features of a new type of glycogen storage disease. Discussion: This case expands the p.(Arg85Trp) variant-specific phenotype. Possible pathomechanistic explanations for the documented multiorgan involvement and changes of symptoms and signs during development of this ultra-rare but instructive disorder are discussed.

Loss of LGR4/GPR48 causes severe neonatal salt wasting due to disrupted WNT signaling altering adrenal zonation.

Disorders of isolated mineralocorticoid deficiency, which cause potentially life-threatening salt-wasting crisis early in life, have been associated with gene variants of aldosterone biosynthesis or resistance; however, in some patients no such variants are found. WNT/ß-catenin signaling is crucial for differentiation and maintenance of the aldosterone-producing adrenal zona glomerulosa (zG). Herein, we describe a highly consanguineous family with multiple perinatal deaths and infants presenting at birth with failure to thrive, severe salt-wasting crises associated with isolated hypoaldosteronism, nail anomalies, short stature, and deafness. Whole exome sequencing revealed a homozygous splice variant in the R-SPONDIN receptor LGR4 gene (c.618-1G>C) regulating WNT signaling. The resulting transcripts affected protein function and stability and resulted in loss of Wnt/ß-catenin signaling in vitro. The impact of LGR4 inactivation was analyzed by adrenal cortex-specific ablation of Lgr4, using Lgr4fl/fl mice mated with Sf1:Cre mice. Inactivation of Lgr4 within the adrenal cortex in the mouse model caused decreased WNT signaling, aberrant zonation with deficient zG, and reduced aldosterone production. Thus, human LGR4 mutations establish a direct link between LGR4 inactivation and decreased canonical WNT signaling, which results in abnormal zG differentiation and endocrine function. Therefore, variants in WNT signaling and its regulators should systematically be considered in familial hyperreninemic hypoaldosteronism.

The effects of time-restricted eating and weight loss on bone metabolism and health: a 6-month randomized controlled trial.

OBJECTIVE: This study explored the impact of time-restricted eating (TRE) versus standard dietary advice (SDA) on bone health. METHODS: Adults with ≥1 component of metabolic syndrome were randomized to TRE (ad libitum eating within 12 hours) or SDA (food pyramid brochure). Bone turnover markers and bone mineral content/density by dual energy x-ray absorptiometry were assessed at baseline and 6-month follow-up. Statistical analyses were performed in the total population and by weight loss response. RESULTS: In the total population (n = 42, 76% women, median age 47 years [IQR: 31-52]), there were no between-group differences (TRE vs. SDA) in any bone parameter. Among weight loss responders (≥0.6 kg weight loss), the bone resorption marker ß-carboxyterminal telopeptide of type I collagen tended to decrease after TRE but increase after SDA (between-group differences p = 0.041), whereas changes in the bone formation marker procollagen type I N-propeptide did not differ between groups. Total body bone mineral content decreased after SDA (p = 0.028) but remained unchanged after TRE (p = 0.31) in weight loss responders (between-group differences p = 0.028). Among nonresponders (<0.6 kg weight loss), there were no between-group differences in bone outcomes. CONCLUSIONS: TRE had no detrimental impact on bone health, whereas, when weight loss occurred, it was associated with some bone-sparing effects compared with SDA.

Glucocorticoid withdrawal and glucocorticoid-induced adrenal insufficiency: Study protocol of the randomized controlled «TOASST" (Taper Or Abrupt Steroid STop) multicenter trial.

BACKGROUND: Despite the widespread use of glucocorticoids in inflammatory and autoimmune disorders, there is uncertainty about the safe cessation of long-term systemic treatment, as data from prospective trials are largely missing. Due to potential disease relapse or glucocorticoid-induced hypocortisolism, the drug is often tapered to sub-physiological doses rather than stopped when the underlying disease is clinically stable, increasing the cumulative drug exposure. Conversely, the duration of exposure to glucocorticoids should be minimized to lower the risk of side effects. METHODS: We designed a multicenter, randomized, triple-blinded, placebo-controlled trial to test the clinical noninferiority of abrupt glucocorticoid stop compared to tapering after ≥28 treatment days with ≥420 mg cumulative and ≥7.5 mg mean daily prednisone-equivalent dose. 573 adult patients treated systemically for various disorders will be included after their underlying disease has been stabilized. Prednisone in tapering doses or matching placebo is administered over 4 weeks. A 250 mg ACTH-test, the result of which will be revealed a posteriori, is performed at study inclusion; all patients are instructed on glucocorticoid stress cover dosing. Follow-up is for 6 months. The composite primary outcome measure is time to hospitalization, death, initiation of unplanned systemic glucocorticoid therapy, or adrenal crisis. Secondary outcomes include the individual components of the primary outcome, cumulative glucocorticoid doses, signs and symptoms of hypocortisolism, and the performance of the ACTH test in predicting the clinical outcome. Cox proportional hazard, linear, and logistic regression models will be used for statistical analysis. CONCLUSION: This trial aims to demonstrate the clinical noninferiority and safety of abrupt treatment cessation after ≥28 days of systemic glucocorticoid therapy in patients with stabilized underlying disease. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03153527; EUDRA-CT: 2020-005601-48 https://clinicaltrials.gov/ct2/show/NCT03153527?term=NCT03153527&draw=2&rank=1.

Bone geometry in older adults with subclinical hypothyroidism upon levothyroxine therapy: A nested study within a randomized placebo controlled trial.

The effect of levothyroxine (LT4) therapy for subclinical hypothyroidism (SHypo) on appendicular bone geometry and volumetric density has so far not been studied. In a nested study within the randomized, placebo-controlled Thyroid Hormone Replacement for Subclinical Hypothyroidism (TRUST) trial, we assessed the effect of LT4 therapy on bone geometry as measured by peripheral quantitative computed tomography (pQCT). In the TRUST trial, community-dwelling adults aged ≥65 years with SHypo were randomized to LT4 with dose titration vs. placebo with mock titration. We analyzed data from participants enrolled at the TRUST site in Bern, Switzerland who had bone pQCT measured at baseline and at 1 to 2 years follow-up. The primary outcomes were the annual percentage changes of radius and tibia epi- and diaphysis bone geometry (total and cortical cross-sectional area (CSA) and cortical thickness), and of volumetric bone mineral density (bone mineral content (BMC) and total, trabecular and cortical volumetric bone mineral density (vBMD)). We performed linear regression of the annual percentage changes adjusted for sex, LT4 dose at randomization and muscle cross-sectional area. The 98 included participants had a mean age of 73.9 (±SD 5.4) years, 45.9% were women, and 12% had osteoporosis. They were randomized to placebo (n = 48) or LT4 (n = 50). Annual changes in BMC and vBMD were similar between placebo and LT4-treated groups, without significant difference in bone geometry or volumetric bone mineral density changes, neither at the diaphysis, nor at the epiphysis. For example, in the placebo group, epiphyseal BMC (radius) decreased by a mean 0.2% per year, with a similar decrease of 0.5% per year in the LT4 group (between-group difference in %ΔBMC 0.3, 95% CI -0.70 to 1.21, p = 0.91). Compared to placebo, LT4 therapy for an average 14 months had no significant effect on bone mass, bone geometry and volumetric density in older adults with subclinical hypothyroidism. TRIAL REGISTRATION: The trial was registered on ClinicalTrials.gov numbers NCT01660126 (TRUST Thyroid trial) and NCT02491008 (Skeletal outcomes).

Trajectories of humoral and cellular immunity and responses to a third dose of mRNA vaccines against SARS-CoV-2 in patients with a history of anti-CD20 therapy.

BACKGROUND: The majority of patients with B-cell-depleting therapies show compromised vaccination-induced immune responses. Herein, we report on the trajectories of anti-SARS-CoV-2 immune responses in patients of the RituxiVac study compared with healthy volunteers and investigate the immunogenicity of a third vaccination in previously humoral non-responding patients. METHODS: We investigated the humoral and cell-mediated immune response after SARS-CoV-2 messanger RNA vaccination in patients with a history with anti-CD20 therapies. Coprimary outcomes were antispike and SARS-CoV-2-stimulated interferon-γ concentrations in vaccine responders 4.3 months (median; IQR: 3.6-4.8 months) after first evaluation, and humoral and cell-mediated immunity (CMI) after a third vaccine dose in previous humoral non-responders. Immunity decay rates were compared using analysis of covariance in linear regression. RESULTS: 5.6 months (IQR: 5.1-6.7) after the second vaccination, we detected antispike IgG in 88% (29/33) and CMI in 44% (14/32) of patients with a humoral response after two-dose vaccination compared with 92% (24/26) healthy volunteers with antispike IgG and 69% (11/16) with CMI 6.8 months after the second vaccination (IQR: 6.0-7.1). Decay rates of antibody concentrations were comparable between patients and controls (p=0.70). In two-dose non-responders, a third SARS-CoV-2 vaccine elicited humoral responses in 19% (6/32) and CMI in 32% (10/31) participants. CONCLUSION: This study reveals comparable immunity decay rates between patients with anti-CD20 treatments and healthy volunteers, but inefficient humoral or CMI after a third SARS-CoV-2 vaccine in most two-dose humoral non-responders calling for individually tailored vaccination strategies in this population.Trial registration numberNCT04877496; ClinicalTrials.gov number.

Annexin-1 regulates macrophage IL-6 and TNF via glucocorticoid-induced leucine zipper.

Annexin-1 (ANXA1) is a mediator of the anti-inflammatory actions of endogenous and exogenous glucocorticoids (GC). The mechanism of ANXA1 effects on cytokine production in macrophages is unknown and is here investigated in vivo and in vitro. In response to LPS administration, ANXA1(-/-) mice exhibited significantly increased serum IL-6 and TNF compared with wild-type (WT) controls. Similarly, LPS-induced IL-6 and TNF were significantly greater in ANXA1(-/-) than in WT peritoneal macrophages in vitro. In addition, deficiency of ANXA1 was associated with impairment of the inhibitory effects of dexamethasone (DEX) on LPS-induced IL-6 and TNF in macrophages. Increased LPS-induced cytokine expression in the absence of ANXA1 was accompanied by significantly increased LPS-induced activation of ERK and JNK MAPK and was abrogated by inhibition of either of these pathways. No differences in GC effects on MAPK or MAPK phosphatase 1 were observed in ANXA1(-/-) cells. In contrast, GC-induced expression of the regulatory protein GILZ was significantly reduced in ANXA1(-/-) cells by silencing of ANXA1 in WT cells and in macrophages of ANXA1(-/-) mice in vivo. GC-induced GILZ expression and GC inhibition of NF-kappaB activation were restored by expression of ANXA1 in ANXA1(-/-) cells, and GILZ overexpression in ANXA1(-/-) macrophages reduced ERK MAPK phosphorylation and restored sensitivity of cytokine expression and NF-kappaB activation to GC. These data confirm ANXA1 as a key inhibitor of macrophage cytokine expression and identify GILZ as a previously unrecognized mechanism of the anti-inflammatory effects of ANXA1.

Effect of resistance training on muscle properties and function in women with generalized joint hypermobility: a single-blind pragmatic randomized controlled trial.

BACKGROUND: Generalized joint hypermobility is defined as an excessive range of motion in several joints. Having joint hypermobility is not a pathology, but when associated with pain and other symptoms, it might affect health and function. Evidence for physiotherapy management is sparse and resistance training might be a possible intervention. Thus, the effects of 12-week resistance-training on muscle properties and function in women with generalized joint hypermobility were evaluated. METHODS: In this single-blind randomized controlled trial women between 20 and 40 years with generalized joint hypermobility (Beighton score at least 6/9) were included. Participants were randomly allocated to 12-week resistance training twice weekly (experimental) or no lifestyle change (control). Resistance training focused on leg and trunk muscles. Primary outcome was muscle strength; additional outcomes included muscle properties, like muscle mass and density, functional activities, pain and disability. Training adherence and adverse events were recorded. RESULTS: Of 51 participating women 27 were randomised to training and 24 into the control group. In each group 11 women had joint hypermobility syndrome, fulfilling the Brighton criteria, while 24 (89%) in the training group and 21 (88%) in the control group mentioned any pain. The mean strength of knee extensors varied in the training group from 0.63 (sd 0.16) N/bm before training to 0.64 (sd 0.17) N/bm after training and in the control group from 0.53 (sd 0.14) N/bm to 0.54 (sd 0.15) N/bm. For this and all other outcome measures, no significant differences between the groups due to the intervention were found, with many variables showing high standard deviations. Adherence to the training was good with 63% of participants performing more than 80% of sessions. One adverse event occurred during training, which was not clearly associated to the training. Four participants had to stop the training early. CONCLUSIONS: No improvement in strength or muscle mass by self-guided resistance training was found. Low resistance levels, as well as the choice of outcome measures were possible reasons. A more individualized and better guided training might be important. However, program adherence was good with few side effects or problems triggered by the resistance training. TRIAL REGISTRATION: This trial was prospectively registered in the ISRCTN registry ( www.isrctn.com , BMC, Springer Nature) on July 16, 2013 as ISRCTN90224545 . The first participant was enrolled at October 25, 2013.

The Effects of Time-Restricted Eating versus Standard Dietary Advice on Weight, Metabolic Health and the Consumption of Processed Food: A Pragmatic Randomised Controlled Trial in Community-Based Adults.

Weight loss is key to controlling the increasing prevalence of metabolic syndrome (MS) and its components, i.e., central obesity, hypertension, prediabetes and dyslipidaemia. The goals of our study were two-fold. First, we characterised the relationships between eating duration, unprocessed and processed food consumption and metabolic health. During 4 weeks of observation, 213 adults used a smartphone application to record food and drink consumption, which was annotated for food processing levels following the NOVA classification. Low consumption of unprocessed food and low physical activity showed significant associations with multiple MS components. Second, in a pragmatic randomised controlled trial, we compared the metabolic benefits of 12 h time-restricted eating (TRE) to standard dietary advice (SDA) in 54 adults with an eating duration > 14 h and at least one MS component. After 6 months, those randomised to TRE lost 1.6% of initial body weight (SD 2.9, p = 0.01), compared to the absence of weight loss with SDA (-1.1%, SD 3.5, p = 0.19). There was no significant difference in weight loss between TRE and SDA (between-group difference -0.88%, 95% confidence interval -3.1 to 1.3, p = 0.43). Our results show the potential of smartphone records to predict metabolic health and highlight that further research is needed to improve individual responses to TRE such as a shorter eating window or its actual clock time.

Humoral and cellular responses to mRNA vaccines against SARS-CoV-2 in patients with a history of CD20 B-cell-depleting therapy (RituxiVac): an investigator-initiated, single-centre, open-label study.

BACKGROUND: B-cell-depleting therapies increase the risk of morbidity and mortality due to COVID-19. Evidence-based SARS-CoV-2 vaccination strategies for patients on B-cell-depleting therapies are scarce. We aimed to investigate humoral and cell-mediated immune responses to SARS-CoV-2 mRNA-based vaccines in patients receiving CD20-targeted B-cell-depleting agents for autoimmune disease, malignancy, or transplantation. METHODS: The RituxiVac study was an investigator-initiated, single-centre, open-label study done at the Bern University Hospital (Bern, Switzerland). Patients with a treatment history of anti-CD20-depleting agents (rituximab or ocrelizumab) and with no previous history of SARS-CoV-2 infection were enrolled between April 26 and June 30, 2021, for analysis of humoral and cell-mediated immune responses (by interferon-γ [IFNγ] release assay) at least 4 weeks after completing vaccination against SARS-CoV-2. Healthy controls without a history of SARS-CoV-2 infection were also enrolled at least 4 weeks after completing vaccination against SARS-CoV-2. All study participants received two doses of either the Pfizer-BioNTech BNT162b2 vaccine or the Moderna mRNA-1273 vaccine. The primary outcome was the proportion of patients with a history of anti-CD20 treatment who showed a humoral immune response against the SARS-CoV-2 spike protein in comparison with immunocompetent controls. Prespecified secondary endpoints were the effect of anti-CD20 therapy (including time since last treatment and cumulative dose) on humoral or cell-mediated immune responses to SARS-CoV-2 vaccination, and biomarkers of immunocompetence. This study is registered with ClinicalTrials.gov, NCT04877496. FINDINGS: The final study population comprised 96 patients and 29 immunocompetent controls. The median age of patients was 67 years (IQR 57-72) and of controls was 54 years (45-62), and 51 (53%) of 96 patients and 19 (66%) of 29 controls were female. The median time since last anti-CD20 treatment was 1·07 years (IQR 0·48-2·55) and the median cumulative dose of an anti-CD20 depleting agent was 2·80 g (1·50-5·00). Anti-spike IgG antibodies were detected in 47 (49%) of 96 patients 1·79 months (IQR 1·16-2·48) after the second vaccine dose compared to 29 (100%) of 29 controls 1·81 months (1·17-2·48) after the second vaccine dose (p<0·001). SARS-CoV-2-specific IFNγ release was detected in 13 (20%) of 66 patients and 21 (75%) of 28 of healthy controls (p<0·001). Only nine (14%) of 66 patients were double positive for anti-SARS-CoV-2 spike IgG and cell-mediated responses, compared with 21 (75%) of 28 healthy controls (p<0·001). Time since last anti-CD20 therapy (>7·6 months; positive predictive value 0·78), peripheral CD19+ cell count (>27 cells per µL; positive predictive value 0·70), and CD4+ lymphocyte count (>653 cells per µL; positive predictive value 0·71) were predictive of humoral vaccine response (area under the curve [AUC] 67% [95% CI 56-78] for time since last anti-CD20 therapy, 67% [55-80] for peripheral CD19+ count, and 66% [54-79] for CD4+ count). INTERPRETATION: This study provides further evidence of blunted humoral and cell-mediated immune responses elicited by SARS-CoV-2 mRNA vaccines in patients with a history of CD20 B-cell-depleting treatment. Lymphocyte subpopulation counts were associated with vaccine response in this highly vulnerable population. On validation, these results could help guide both the administration of SARS-CoV-2 vaccines and B-cell-depleting agents in this population. FUNDING: Bern University Hospital.

Patients with diffuse idiopathic skeletal hyperostosis do not have increased peripheral bone mineral density and geometry.

OBJECTIVES: Recent studies have suggested that areal BMD (aBMD) measured by DXA is elevated in patients with DISH. We used peripheral QCT (pQCT) to assess volumetric BMD (vBMD) and bone geometry of the radius, tibia and the third metacarpal bone. METHODS: Patients with established DISH and a control group of healthy individuals were recruited. pQCT measurements were performed at the distal epiphyses and mid-shafts of the radius, the tibia and the third metacarpal bone. At the epiphyses cross-sectional area (CSA), total BMD and trabecular BMD were measured. At the shafts, total bone CSA, cortical CSA, cortical wall thickness and cortical BMD were determined. In addition, muscle and fat CSA of the forearm and lower leg were assessed. Bone parameters were compared between the two groups using independent t-tests. RESULTS: Thirty DISH patients and 30 controls comparable with regard to age and height were included in this study. None of the measured bone parameters differed between groups. CONCLUSIONS: In contrast to suggestions based on DXA, pQCT revealed that DISH patients do not have increased vBMD and bone geometry in the appendicular skeleton. Ossification at tendon or ligament insertion sites may lead to overestimation of aBMD if assessed by DXA.