Immobilization by 21 days of bed rest results in type II collagen degradation in healthy individuals.

OBJECTIVE: To investigate the effects of 21 days of bed rest immobilization (with and without exercise and nutrition interventions) on type II collagen biomarker concentrations in healthy individuals. DESIGN: Twelve healthy male participants (age 34.2 ± 8.3 years; body mass index 22.4 ± 1.7 kg/m²) were exposed to 6 days ambulatory baseline data collection (BDC), 21 days head-down-tilt bed rest (HDT, CON) + interventions (HDT + resistive vibration exercise (2 times/week, 25 minutes): RVE; HDT + RVE + whey protein (0.6 g/kg body weight/day) and bicarbonate supplementation (90 mmol KHCO3/day: NeX), and 6 days of re-ambulation (R) in a cross-over designed study. The starting HDT condition was randomized (CON-RVE-NEX, RVE-NEX-CON, NEX-CON-RVE). Blood and urine samples were collected before, during, and after HDT. Serum concentrations (s) of CPII, C2C, C1,2C, and urinary concentrations (u) of CTX-II and Coll2-1NO2 were measured. RESULTS: Twenty-one days of HDT resulted in increased sCPII (p < 0.001), sC2C (p < 0.001), and sC1,2C (p = 0.001) (highest increases: sCPII (+24.2% - HDT5), sC2C (+24.4% - HDT7), sC1,2C (+13.5% - HDT2). sC2C remained elevated at R+1 (p = 0.002) and R+6 (p < 0.001) compared to baseline. NeX led to lower sCPII (p < 0.001) and sC1,2C (p = 0.003) compared to CON. uCTX-II (second void and 24-hour urine) increased during HDT (p < 0.001, highest increase on HDT21: second void +82.8% (p < 0.001); 24-hour urine + 77.8% (p < 0.001). NeX resulted in lower uCTX-II concentrations in 24-hour urine (p = 0.012) compared to CON. CONCLUSIONS: Twenty-one days of bed rest immobilization results in type II collagen degradation that does not recover within 6 days of resuming ambulation. The combination of resistive vibration exercise and protein/bicarbonate supplementation minimally counteracted this effect.

Pre-flight exercise and bone metabolism predict unloading-induced bone loss due to spaceflight.

OBJECTIVES: Bone loss remains a primary health concern for astronauts, despite in-flight exercise. We examined changes in bone microarchitecture, density and strength before and after long-duration spaceflight in relation to biochemical markers of bone turnover and exercise. METHODS: Seventeen astronauts had their distal tibiae and radii imaged before and after space missions to the International Space Station using high-resolution peripheral quantitative CT. We estimated bone strength using finite element analysis and acquired blood and urine biochemical markers of bone turnover before, during and after spaceflight. Pre-flight exercise history and in-flight exercise logs were obtained. Mixed effects models examined changes in bone and biochemical variables and their relationship with mission duration and exercise. RESULTS: At the distal tibia, median cumulative losses after spaceflight were -2.9% to -4.3% for bone strength and total volumetric bone mineral density (vBMD) and -0.8% to -2.6% for trabecular vBMD, bone volume fraction, thickness and cortical vBMD. Mission duration (range 3.5-7 months) significantly predicted bone loss and crewmembers with higher concentrations of biomarkers of bone turnover before spaceflight experienced greater losses in tibia bone strength and density. Lower body resistance training volume (repetitions per week) increased 3-6 times in-flight compared with pre-spaceflight. Increases in training volume predicted preservation of tibia bone strength and trabecular vBMD and thickness. CONCLUSIONS: Findings highlight the fundamental relationship between mission duration and bone loss. Pre-flight markers of bone turnover and exercise history may identify crewmembers at greatest risk of bone loss due to unloading and may focus preventative measures.

Evaluation of Optical and Radar Based Motion Capturing Technologies for Characterizing Hand Movement in Rheumatoid Arthritis-A Pilot Study.

In light of the state-of-the-art treatment options for patients with rheumatoid arthritis (RA), a detailed and early quantification and detection of impaired hand function is desirable to allow personalized treatment regiments and amend currently used subjective patient reported outcome measures. This is the motivation to apply and adapt modern measurement technologies to quantify, assess and analyze human hand movement using a marker-based optoelectronic measurement system (OMS), which has been widely used to measure human motion. We complement these recordings with data from markerless (Doppler radar) sensors and data from both sensor technologies are integrated with clinical outcomes of hand function. The technologies are leveraged to identify hand movement characteristics in RA affected patients in comparison to healthy control subjects, while performing functional tests, such as the Moberg-Picking-Up Test. The results presented discuss the experimental framework and present the limiting factors imposed by the use of marker-based measurements on hand function. The comparison of simple finger motion data, collected by the OMS, to data recorded by a simple continuous wave radar suggests that radar is a promising option for the objective assessment of hand function. Overall, the broad scope of integrating two measurement technologies with traditional clinical tests shows promising potential for developing new pathways in understanding of the role of functional outcomes for the RA pathology.

Biomechanical properties of bone are impaired in patients with ACPA-positive rheumatoid arthritis and associated with the occurrence of fractures.

OBJECTIVES: Bone loss is a well-established consequence of rheumatoid arthritis (RA). To date, bone disease in RA is exclusively characterised by bone density measurements, while the functional properties of bone in RA are undefined. This study aimed to define the impact of RA on the functional properties of bone, such as failure load and stiffness. METHODS: Micro-finite element analysis (µFEA) was carried out to measure failure load and stiffness of bone based on high-resolution peripheral quantitative CT data from the distal radius of anti-citrullinated protein antibody (ACPA)-positive RA (RA+), ACPA-negative RA (RA-) and healthy controls (HC). In addition, total, trabecular and cortical bone densities as well as microstructural parameters of bone were recorded. Correlations and multivariate models were used to determine the role of demographic, disease-specific and structural data of bone strength as well as its relation to prevalent fractures. RESULTS: 276 individuals were analysed. Failure load and stiffness (both P<0.001) of bone were decreased in RA+, but not RA-, compared with HC. Lower bone strength affected both female and male patients with RA+, was related to longer disease duration and significantly (stiffness P=0.020; failure load P=0.012) associated with the occurrence of osteoporotic fractures. Impaired bone strength was correlated with altered bone density and microstructural parameters, which were all decreased in RA+. Multivariate models showed that ACPA status (P=0.007) and sex (P<0.001) were independently associated with reduced biomechanical properties of bone in RA. CONCLUSION: In summary, µFEA showed that bone strength is significantly decreased in RA+ and associated with fractures.

Internal vascular anatomy of the human lacrimal gland: A protocol based on cadaver dissection and three-dimensional micro-computed tomography.

PURPOSE: To evaluate the feasibility of studying the vascular supply of the orbital and palpebral lobes of the human lacrimal gland using micro-computed tomography (micro-CT) and microscopic dissection. METHODS: The lacrimal gland artery of a fresh parasagittalized cadaver head (male, aged 76 years) was infused with a lead oxide-latex mixture near the occipital pole of the gland. The entire lacrimal gland was imaged using micro-CT and 3D cinematic rendering (CR) and then dissected under a surgical microscope. RESULTS: Micro-CT and CR images showed well-demarcated internal vascular branches of the lacrimal artery and their distribution within the orbital and palpebral lobes. The entire course of the artery and its branches could be visualized by CR and microscopic dissection, with the former showing better spatial orientation and finer branching. The main artery runs along the free edge of the aponeurosis of the levator palpebrae superior muscle and lies in the isthmus portion of the gland (between the orbital and palpebral lobes). The branches of the main lacrimal artery include one branch to the orbital adipose tissue just before entering the gland, two branches to the orbital lobe (medial and lateral), and two branches to the palpebral lobe (medial and lateral). The main artery terminates as palpebral and orbital lobe branches in the lateral half of the lacrimal gland. CONCLUSION: Latex and contrast-enhanced micro-CT is very well suited to visualize the vascular anatomy of the lacrimal artery within the gland. A large number of lacrimal gland examinations using the method presented here are required to demonstrate and understand the variability of the vascular anatomy of the human lacrimal gland.

A life span perspective on competencies for a healthy, physically active lifestyle: Findings of a data pooling initiative with over 7000 individuals.

Individuals are recommended to lead active lifestyles throughout the life course. The model of physical activity-related health competence (PAHCO) adopts a competence approach by integrating physical, cognitive, and motivational determinants for health-enhancing PA (movement competence, control competence, self-regulation competence). Drawing on a comprehensive dataset pooling, the goal of the present study was to model the idiosyncratic courses of 10 PAHCO indicators over the life span. We identified studies that empirically operationalized PAHCO, combining data of 7134 individuals (age range: 15-97 years; 61% female) from 18 different populations (prevention and rehabilitation sectors). We applied a stepwise multilevel analysis approach with disjunct sub-samples (n = 48) to examine linear and quadratic associations between age and PAHCO. Indicators of movement competence (i.e., manageability of endurance, strength, and balance demands; task-specific self-efficacy) congruently showed negative associations with age (0.054 ≤  R marg 2 ${R}_{\text{marg}}^{2}$  ≤ 0.211). However, parameters of control competence remained stable across the life span (-0.066 ≤ ß ≤ 0.028). The three indicators of self-regulation competence revealed an inconsistent relationship with age, though uncovering positive associations for self-control (ß = 0.106) and emotional attitude toward PA (ß = 0.088). The associations of some indicators varied significantly across sub-samples. The results suggest differential analyses for associations between PAHCO and age. While the physically determined PAHCO indicators (movement competence) probably decline across the life span, the ability to ensure regularity of PA (self-regulation competence) or align PAs with an individual's health (control competence) appear to remain constant or improve with increasing age. The findings reinforce a de-stigmatizing approach for PA promotion practices with considerable space for aligning activities with health also in the elderly.

Musculoskeletal research in human space flight - unmet needs for the success of crewed deep space exploration.

Based on the European Space Agency (ESA) Science in Space Environment (SciSpacE) community White Paper "Human Physiology - Musculoskeletal system", this perspective highlights unmet needs and suggests new avenues for future studies in musculoskeletal research to enable crewed exploration missions. The musculoskeletal system is essential for sustaining physical function and energy metabolism, and the maintenance of health during exploration missions, and consequently mission success, will be tightly linked to musculoskeletal function. Data collection from current space missions from pre-, during-, and post-flight periods would provide important information to understand and ultimately offset musculoskeletal alterations during long-term spaceflight. In addition, understanding the kinetics of the different components of the musculoskeletal system in parallel with a detailed description of the molecular mechanisms driving these alterations appears to be the best approach to address potential musculoskeletal problems that future exploratory-mission crew will face. These research efforts should be accompanied by technical advances in molecular and phenotypic monitoring tools to provide in-flight real-time feedback.

Corrigendum: Editorial: Rising stars in environmental, aviation and space physiology: 2022.

[This corrects the article DOI: 10.3389/fphys.2023.1230752.].

Load-induced blood marker kinetics in patients with medial knee compartment osteoarthritis are associated with accumulated load and patient reported outcome measures.

Background: This study aimed to quantify the mechanoresponse of 10 blood marker candidates for joint metabolism to a walking stress test in patients with knee osteoarthritis and to determine the association among marker kinetics and with accumulated load and patient reported outcomes. Methods: 24 patients with knee osteoarthritis completed questionnaires, and a 30-minute walking stress test with six blood serum samples and gait analysis. Concentrations of cartilage oligomeric matrix protein (COMP), matrix metalloproteinases (MMP)-1, -3, and -9, epitope resulting from cleavage of type II collagen by collagenases (C2C), type II procollagen (CPII), interleukin (IL)-6, proteoglycan (PRG)-4, A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, and resistin were determined by enzyme-linked immunosorbent assays, Joint load (moments and compartmental forces) was estimated using musculoskeletal modeling using gait analysis data. Results: COMP and MMP-3 showed an immediate increase after the walking stress followed by a decrease. MMP-9 and resistin showed a delayed decrease below pre-stress levels. ∆COMP correlated with ∆MMP-3 for most time points. ∆MMP-9 correlated with ∆resistin for most time points. The load-induced increase in blood marker levels correlated among blood markers and time points. C2C and resistin correlated positively and C2C/CPII and MMP2 correlated negatively with load during gait. Immediate relative ∆CPII and ∆MMP1 and delayed relative ∆COMP, ∆IL6, ∆C2C, ∆CPII, ∆MMP1 and ∆MMP3 correlated with the load accumulated during the walking stress. Baseline C2C levels correlated with Knee Osteoarthritis Outcome Score (KOOS) subscales and load-induced changes in MMP-3 with KOOS and Short Form 36 quality of life subscores (P<0.05). Conclusions: The distinct and differentiated physiological response to the walking stress depends on accumulated load and appears relevant for patient reported osteoarthritis outcome and quality of life and warrants further investigation in the context of disease progression.ClinicalTrials.gov registration: NCT02622204.

Effects of vibration training on bone metabolism: results from a short-term bed rest study.

The absence of mechanical loading leads to a prompt increase in bone resorption measured by bone resorption markers. There is high potential that vibration training can positively influence bone metabolism in immobilized subjects, reduce the increase in osteoclastic activity and increase bone formation processes. We investigated whether vibration training at 20 Hz with an amplitude of 2-4 mm influences bone metabolism during immobilization. Eight male subjects (26.4 ± 4.9 years; 78.1 ± 9.5 kg) performed a 14 day bed rest in 6°-head down tilt (HDT). Subjects received vibration training for 2 × 5 min/day or a control intervention without vibration (crossover design). Calcium excretion and bone resorption markers C-telopeptide (CTX) and N-telopeptide (NTX) were analyzed from 24 h urine samples. Bone formation markers, bone alkaline phosphatase (bAP) and procollagen-N propeptide (PINP) were analyzed from fasting blood samples. Our results show an increase in bone resorption very early during HDT bed rest in both interventions (CTX: p < 0.01; NTX: p < 0.001). Vibration training did not have any different effect on bone resorption markers (CTX: p = 0.10; NTX: p = 0.58), bone formation markers (PINP: p = 0.21; bAP: p = 0.12) and calcium excretion (p < 0.64) compared to the control condition. Mere vibration training with 20 Hz for 2 × 5 min/day does not prevent increase in bone resorption as measured with the described methods in our short-term HDT bed rest.

Relationship between different serum cartilage biomarkers in the acute response to running and jumping in healthy male individuals.

The effect of physical activity on serum cartilage biomarkers is largely unknown. The purpose of the study was to systematically analyze the acute effect of two frequently used exercise interventions (running and jumping) on the correlation of seven serum biomarkers that reflect cartilage extracellular matrix metabolism. Fifteen healthy male volunteers (26 ± 4 years, 181 ± 4 cm, 77 ± 6 kg) participated in the repeated measurement study. In session 1, the participants accomplished 15 × 15 series of reactive jumps within 30 min. In session 2, they ran on a treadmill (2.2 m/s) for 30 min. Before and after both exercise protocols, four blood samples were drawn separated by 30 min intervals. Serum concentrations of seven biomarkers were determined: COMP, MMP-3, MMP-9, YKL-40, resistin, Coll2-1 and Coll2-1 NO2. All biomarkers demonstrated an acute response to mechanical loading. Both the COMP and MMP-3 responses were significantly (p = 0.040 and p = 0.007) different between running and jumping (COMP: jumping + 31%, running + 37%; MMP-3: jumping + 14%, running + 78%). Resistin increased only significantly (p < 0.001) after running, and Coll2-1 NO2 increased significantly (p = 0.001) only after jumping. Significant correlations between the biomarkers were detected. The relationships between individual serum biomarker concentrations may reflect the complex interactions between degrading enzymes and their substrates in ECM homeostasis.

Dose-response relationship of in vivo ambulatory load and mechanosensitive cartilage biomarkers-The role of age, tissue health and inflammation: A study protocol.

OBJECTIVE: To describe a study protocol for investigating the in vivo dose-response relationship between ambulatory load magnitude and mechanosensitive blood markers of articular cartilage, the influence of age, cartilage tissue health and presence of inflammation on this relationship, and its ability to predict changes in articular cartilage quality and morphology within 2 years. DESIGN: Prospective experimental multimodal (clinical, biomechanical, biological) data collection under walking stress and three different load conditions varied in a randomized crossover design. EXPERIMENTAL PROTOCOL: At baseline, equal numbers of healthy and anterior cruciate ligament injured participants aged 20-30 or 40-60 years will be assessed clinically and complete questionnaires regarding their knee health. Biomechanical parameters (joint kinetics, joint kinematics, and surface electromyography) will be recorded while performing different tasks including overground and treadmill walking, single leg balance and hopping tasks. Magnetic resonance images (MRI) of both of knees will be obtained. On separate stress test days, participants will perform a 30-minute walking stress with either reduced (80% body weight (BW)), normal (100%BW) or increased (120%BW) load. Serum blood samples will be taken immediately before, immediately after, 30, 120 and 210 minutes after the walking stress. Concentration of articular cartilage blood biomarkers will be assessed using enzyme linked immunosorbent assays. At 24-month follow-up, participants will be again assessed clinically, undergo an MRI, complete questionnaires, and have a blood sample taken. CONCLUSION: The study design provides a standardized set up that allows to better understand the influence of ambulatory load on articular cartilage biomarkers and thereby extend current knowledge on in vivo cartilage metabolism and mechanosensitivity. Further, this study will help to elucidate the prognostic value of the load-induced cartilage biomarker response for early articular cartilage degeneration. TRIAL REGISTRATION: The protocol was approved by the regional ethics committee and has been registered at clinicaltrials.gov (NCT04128566).

Incomplete recovery of bone strength and trabecular microarchitecture at the distal tibia 1 year after return from long duration spaceflight.

Determining the extent of bone recovery after prolonged spaceflight is important for understanding risks to astronaut long-term skeletal health. We examined bone strength, density, and microarchitecture in seventeen astronauts (14 males; mean 47 years) using high-resolution peripheral quantitative computed tomography (HR-pQCT; 61 µm). We imaged the tibia and radius before spaceflight, at return to Earth, and after 6- and 12-months recovery and assessed biomarkers of bone turnover and exercise. Twelve months after flight, group median tibia bone strength (F.Load), total, cortical, and trabecular bone mineral density (BMD), trabecular bone volume fraction and thickness remained - 0.9% to - 2.1% reduced compared with pre-flight (p ≤ 0.001). Astronauts on longer missions (> 6-months) had poorer bone recovery. For example, F.Load recovered by 12-months post-flight in astronauts on shorter (< 6-months; - 0.4% median deficit) but not longer (- 3.9%) missions. Similar disparities were noted for total, trabecular, and cortical BMD. Altogether, nine of 17 astronauts did not fully recover tibia total BMD after 12-months. Astronauts with incomplete recovery had higher biomarkers of bone turnover compared with astronauts whose bone recovered. Study findings suggest incomplete recovery of bone strength, density, and trabecular microarchitecture at the weight-bearing tibia, commensurate with a decade or more of terrestrial age-related bone loss.

Deep Learning-Based Classification of Inflammatory Arthritis by Identification of Joint Shape Patterns-How Neural Networks Can Tell Us Where to "Deep Dive" Clinically.

Objective: We investigated whether a neural network based on the shape of joints can differentiate between rheumatoid arthritis (RA), psoriatic arthritis (PsA), and healthy controls (HC), which class patients with undifferentiated arthritis (UA) are assigned to, and whether this neural network is able to identify disease-specific regions in joints. Methods: We trained a novel neural network on 3D articular bone shapes of hand joints of RA and PsA patients as well as HC. Bone shapes were created from high-resolution peripheral-computed-tomography (HR-pQCT) data of the second metacarpal bone head. Heat maps of critical spots were generated using GradCAM. After training, we fed shape patterns of UA into the neural network to classify them into RA, PsA, or HC. Results: Hand bone shapes from 932 HR-pQCT scans of 617 patients were available. The network could differentiate the classes with an area-under-receiver-operator-curve of 82% for HC, 75% for RA, and 68% for PsA. Heat maps identified anatomical regions such as bare area or ligament attachments prone to erosions and bony spurs. When feeding UA data into the neural network, 86% were classified as "RA," 11% as "PsA," and 3% as "HC" based on the joint shape. Conclusion: We investigated neural networks to differentiate the shape of joints of RA, PsA, and HC and extracted disease-specific characteristics as heat maps on 3D joint shapes that can be utilized in clinical routine examination using ultrasound. Finally, unspecific diseases such as UA could be grouped using the trained network based on joint shape.

Self-collection of capillary blood and saliva to determine COVID-19 vaccine immunogenicity in patients with immune-mediated inflammatory diseases and health professionals.

Introduction: Being able to independently determine vaccine induced antibody responses by minimal-invasive methods is of great interest to enable a flexible and effective vaccination strategy. This study aimed to evaluate (1) the accuracy, feasibility, usability and acceptability of capillary blood and saliva self-sampling to determine SARS-CoV-2 antibody responses in patients with immune-mediated inflammatory diseases (IMIDs) and health professionals (HP). Methods: IMID patients and HP having received two doses of SARS-CoV-2 vaccines, self-collected capillary blood (Tasso+) and saliva samples. Capillary samples were considered interchangeable with venous blood if three criteria were met: Spearman's correlation coefficient (r) > 0.8, non-significant Wilcoxon signed-rank test (i.e., p > 0.05), and a small bias or 95% of tests within 10% difference through Bland-Altman. Participants completed a survey to investigate self-sampling usability (system usability scale; SUS) and acceptability (net promoter score; NPS). Study personnel monitored correct self-sampling completion and recorded protocol deviations. Results: 60 participants (30 IMID patients and 30 HP) were analyzed. We observed interchangeability for capillary samples with an accuracy of 98.3/100% for Anti-SARS-CoV-2 IgG/IgA antibodies, respectively. Fifty-eight capillary blood samples and all 60 saliva samples were successfully collected within the first attempt. Usability of both self-sampling procedures was rated as excellent, with significantly higher saliva ratings (p < 0.001). Capillary self-sampling was perceived as significantly (p < 0.001) less painful compared to traditional venous blood collection. Participants reported a NPS for capillary and saliva self-sampling of +68% and +63%, respectively. The majority of both groups (73%) preferred capillary self-sampling over professional venous blood collection. Conclusion: Our results indicate that capillary self-sampling is accurate, feasible and preferred over conventional venous blood collection. Implementation could enable easy access, flexible vaccination monitoring, potentially leading to a better protection of vulnerable patient groups. Self-collection of saliva is feasible and safe however more work is needed to determine its application in clinical practice.

Impact of Cytokine Inhibitor Therapy on the Prevalence, Seroconversion Rate, and Longevity of the Humoral Immune Response Against SARS-CoV-2 in an Unvaccinated Cohort.

OBJECTIVE: To investigate the impact of biologic disease-modifying antirheumatic drug (bDMARD) treatment on the prevalence, seroconversion rate, and longevity of the humoral immune response against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs). METHODS: Anti-SARS-CoV-2 IgG antibodies were measured in a prospective cohort of health care professional controls and non-health care controls and IMID patients receiving no treatment or receiving treatment with conventional or biologic DMARDs during the first and second COVID-19 waves. Regression models adjusting for age, sex, sampling time, and exposure risk behavior were used to calculate relative risks (RRs) of seropositivity. Seroconversion rates were assessed in participants with polymerase chain reaction (PCR)-positive SARS-CoV-2 infection. Antibody response longevity was evaluated by reassessing participants who tested positive during the first wave. RESULTS: In this study, 4,508 participants (2,869 IMID patients and 1,639 controls) were analyzed. The unadjusted RR (0.44 [95% confidence interval (95% CI) 0.31-0.62]) and adjusted RR (0.50 [95% CI 0.34-0.73]) for SARS-CoV-2 IgG antibodies were significantly lower in IMID patients treated with bDMARDs compared to non-health care controls (P < 0.001), primarily driven by treatment with tumor necrosis factor inhibitors, interleukin-17 (IL-17) inhibitors, and IL-23 inhibitors. Adjusted RRs for untreated IMID patients (1.12 [95% CI 0.75-1.67]) and IMID patients receiving conventional synthetic DMARDs (0.70 [95% CI 0.45-1.08]) were not significantly different from non-health care controls. Lack of seroconversion in PCR-positive participants was more common among bDMARD-treated patients (38.7%) than in non-health care controls (16%). Overall, 44% of positive participants lost SARS-CoV-2 antibodies by follow-up, with higher rates in IMID patients treated with bDMARDs (RR 2.86 [95% CI 1.43-5.74]). CONCLUSION: IMID patients treated with bDMARDs have a lower prevalence of SARS-CoV-2 antibodies, seroconvert less frequently after SARS-CoV-2 infection, and may exhibit a reduced longevity of their humoral immune response.

Intensity and longevity of SARS-CoV-2 vaccination response in patients with immune-mediated inflammatory disease: a prospective cohort study.

Background: Concerns have been raised about the reduced immunogenicity of vaccines against SARS-CoV-2 in patients with immune-mediated inflammatory diseases and the higher risk of breakthrough infections. The objective of our study was to investigate the intensity and longevity of SARS-CoV-2 vaccination responses in patients with immune-mediated inflammatory diseases, and to assess the effects of diagnosis, treatment, and adapted vaccination schedules. Methods: SARS-CoV-2 IgG antibody response after SARS-CoV-2 vaccination was measured over time in a large prospective cohort of healthy controls and participants with immune-mediated inflammatory diseases (attending or admitted to affiliated centres) between Dec 15, 2020, and Dec 1, 2021. Cohort participants with immune-mediated inflammatory diseases and control participants with no diagnosis of immune-mediated inflammatory diseases, were eligible for this analysis. Demographic data and disease-specific data were collected using a questionnaire. Humoral response was compared across treatment and disease groups, and with respect to the receipt of additional vaccinations. SARS-CoV-2 antibody response was measured by ELISA using optical density ratio units and modelled over time with age and sex adjustment using mixed-effects models. Using these models, marginal mean antibody titres and marginal risks of a poor response (optical density ratio <1·1) were calculated for each week starting from week 8 after the first vaccination to week 40. Findings: Among 5076 individuals registered, 2535 participants with immune-mediated inflammatory diseases (mean age 55·0 [15·2] years; 1494 [58·9%] women and 1041 [41·1%] men) and 1198 healthy controls (mean age 40·7 [13·5] years; 554 [46·2%] women and 644 [53·8%] men) were included in this analysis. Mean antibody titres were higher in healthy controls compared with people with immune-mediated inflammatory diseases at all timepoints, with a peak antibody response in healthy controls (mean optical density ratio 12·48; 95% CI 11·50-13·53) of more than twice that in participants with immune-mediated inflammatory diseases (5·50; 5·23-5·77; mean difference 6·98; 5·92-8·04). A poor response to vaccination was observed in participants with immune-mediated inflammatory diseases who were taking B-cell inhibitors (peak mean difference from healthy controls 11·68; 10·07-13·29) and T-cell inhibitors (peakmean difference from healthy controls 10·43; 8·33-12·53). Mean differences in antibody responses between different immune-mediated inflammatory diseases were small. Participants with immune-mediated inflammatory diseases who were given a third vaccine dose had higher mean antibody titres than did healthy controls vaccinated with two vaccine doses at 40 weeks after the initial vaccination (mean difference 1·34; 0·01-2·69). Interpretation: People with immune-mediated inflammatory diseases show a lower and less durable SARS-CoV-2 vaccination response and are at risk of losing humoral immune protection. Adjusted vaccination schedules with earlier booster doses or more frequent re-doses, or both, could better protect people with immune-mediated inflammatory diseases. Funding: Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, European Research Council, Innovative Medicine Initiative, Friedrich-Alexander-Universität Erlangen-Nürnberg, Else Kröner-Memorial Foundation.

Experimental-analytical approach to assessing mechanosensitive cartilage blood marker kinetics in healthy adults: dose-response relationship and interrelationship of nine candidate markers.

Purpose: To determine the suitability of selected blood biomarkers of articular cartilage as mechanosensitive markers and to investigate the dose-response relationship between ambulatory load magnitude and marker kinetics in response to load.  Methods: Serum samples were collected from 24 healthy volunteers before and at three time points after a 30-minute walking stress test performed on three test days. In each experimental session, one of three ambulatory loads was applied: 100% body weight (BW); 80%BW; 120%BW. Serum concentrations of COMP, MMP-3, MMP-9, ADAMTS-4, PRG-4, CPII, C2C and IL-6 were assessed using commercial enzyme-linked immunosorbent assays. A two-stage analytical approach was used to determine the suitability of a biomarker by testing the response to the stress test (criterion I) and the dose-response relationship between ambulatory load magnitude and biomarker kinetics (criterion II).  Results. COMP, MMP-3 and IL-6 at all three time points after, MMP-9 at 30 and 60 minutes after, and ADAMTS-4 and CPII at immediately after the stress test showed an average response to load or an inter-individual variation in response to load of up to 25% of pre-test levels. The relation to load magnitude on average or an inter-individual variation in this relationship was up to 8% from load level to load level. There was a positive correlation for the slopes of the change-load relationship between COMP and MMP-3, and a negative correlation for the slopes between COMP, MMP-3 and IL-6 with MMP-9, and COMP with IL6.  Conclusions: COMP, MMP-3, IL-6, MMP-9, and ADAMTS-4 warrant further investigation in the context of articular cartilage mechanosensitivity and its role in joint degeneration and OA. While COMP seems to be able to reflect a rapid response, MMP-3 seems to reflect a slightly longer lasting, but probably also more distinct response. MMP-3 showed also the strongest association with the magnitude of load.

Deep learning methods allow fully automated segmentation of metacarpal bones to quantify volumetric bone mineral density.

Arthritis patients develop hand bone loss, which leads to destruction and functional impairment of the affected joints. High resolution peripheral quantitative computed tomography (HR-pQCT) allows the quantification of volumetric bone mineral density (vBMD) and bone microstructure in vivo with an isotropic voxel size of 82 micrometres. However, image-processing to obtain bone characteristics is a time-consuming process as it requires semi-automatic segmentation of the bone. In this work, a fully automatic vBMD measurement pipeline for the metacarpal (MC) bone using deep learning methods is introduced. Based on a dataset of HR-pQCT volumes with MC measurements for 541 patients with arthritis, a segmentation network is trained. The best network achieves an intersection over union as high as 0.94 and a Dice similarity coefficient of 0.97 while taking only 33 s to process a whole patient yielding a speedup between 2.5 and 4.0 for the whole workflow. Strong correlation between the vBMD measurements of the expert and of the automatic pipeline are achieved for the average bone density with 0.999 (Pearson) and 0.996 (Spearman's rank) with [Formula: see text] for all correlations. A qualitative assessment of the network predictions and the manual annotations yields a 65.9% probability that the expert favors the network predictions. Further, the steps to integrate the pipeline into the clinical workflow are shown. In order to make these workflow improvements available to others, we openly share the code of this work.

Accuracy and usability of a diagnostic decision support system in the diagnosis of three representative rheumatic diseases: a randomized controlled trial among medical students.

BACKGROUND: An increasing number of diagnostic decision support systems (DDSS) exist to support patients and physicians in establishing the correct diagnosis as early as possible. However, little evidence exists that supports the effectiveness of these DDSS. The objectives were to compare the diagnostic accuracy of medical students, with and without the use of a DDSS, and the diagnostic accuracy of the DDSS system itself, regarding the typical rheumatic diseases and to analyze the user experience. METHODS: A total of 102 medical students were openly recruited from a university hospital and randomized (unblinded) to a control group (CG) and an intervention group (IG) that used a DDSS (Ada - Your Health Guide) to create an ordered diagnostic hypotheses list for three rheumatic case vignettes. Diagnostic accuracy, measured as the presence of the correct diagnosis first or at all on the hypothesis list, was the main outcome measure and evaluated for CG, IG, and DDSS. RESULTS: The correct diagnosis was ranked first (or was present at all) in CG, IG, and DDSS in 37% (40%), 47% (55%), and 29% (43%) for the first case; 87% (94%), 84% (100%), and 51% (98%) in the second case; and 35% (59%), 20% (51%), and 4% (51%) in the third case, respectively. No significant benefit of using the DDDS could be observed. In a substantial number of situations, the mean probabilities reported by the DDSS for incorrect diagnoses were actually higher than for correct diagnoses, and students accepted false DDSS diagnostic suggestions. DDSS symptom entry greatly varied and was often incomplete or false. No significant correlation between the number of symptoms extracted and diagnostic accuracy was seen. It took on average 7 min longer to solve a case using the DDSS. In IG, 61% of students compared to 90% in CG stated that they could imagine using the DDSS in their future clinical work life. CONCLUSIONS: The diagnostic accuracy of medical students was superior to the DDSS, and its usage did not significantly improve students' diagnostic accuracy. DDSS usage was time-consuming and may be misleading due to prompting wrong diagnoses and probabilities. TRIAL REGISTRATION: DRKS.de, DRKS00024433 . Retrospectively registered on February 5, 2021.