Sequencing of SARS-CoV-2 RNA Fragments in Wastewater Detects the Spread of New Variants during Major Events.

The sequencing of SARS-CoV-2 RNA in wastewater is an unbiased method to detect the spread of emerging variants and to track regional infection dynamics, which is especially useful in case of limited testing and clinical sequencing. To test how major international events influence the spread of new variants we have sequenced SARS-CoV-2 RNA in the wastewater samples of Davos, Landquart, Lostallo, and St. Moritz in the Swiss canton of Grisons in the time around the international sports competitions in Davos and St. Moritz in December 2021, and additionally in May 2022 and January 2023 in Davos and St. Moritz during the World Economic Forum (WEF) in Davos. The prevalence of the variants identified from the wastewater sequencing data showed that the Omicron variant BA.1 had spread in Davos and St. Moritz during the international sporting events hosted there in December 2021. This spread was associated with an increase in case numbers, while it was not observed in Landquart and Lostallo. Another instance of new variant spread occurred during the WEF in January 2023, when the Omicron variant BA.2.75 arrived in Davos but not in St. Moritz. We can therefore conclude that major international events promote the spread of new variants in the respective host region, which has important implications for the protective measures that should be taken.

Treatment with Upadacitinib in Active Psoriatic Arthritis: Efficacy and Safety Data of the First 192 Patients from the UPJOINT Study, a Multicentre, Observational Study in Clinical Practice.

INTRODUCTION: Our aim was to investigate the efficacy and safety of upadacitinib (UPA) in patients with either oligo- or polyarticular active psoriatic arthritis (PsA) using routine clinical practice data from an observational, prospective, multicentre study. METHODS: This interim analysis contains upadacitinib efficacy and safety data from the UPJOINT study, collected from baseline to the week 24 visit with a focus on composite measures, clinical assessments and patient-reported outcomes, amongst others, including minimal disease activity (MDA), very low disease activity (VLDA), Disease Activity Index for Psoriatic Arthritis (DAPSA), Leeds Enthesitis Index (LEI), resolution of dactylitis and nail psoriasis and body surface area affected by skin psoriasis (BSA). RESULTS: A total of 296 patients with baseline data and 192 with completed week 24 visits were included in the analysis. The proportion of patients achieving MDA increased from 2.7% at baseline to 39.1% at week 24 (95% CI 32.1, 46.3). Similarly, the number of patients in DAPSA remission (DAPSA ≤ 4) increased from 0 at baseline to 32 (16.7%) by week 24. At that time, 59.4% of the patients were either in DAPSA remission or had low disease activity (DAPSA ≤ 14). During the 24 weeks time frame, the proportion of patients with BSA ≤ 3 increased from 80.7% to 91.1%. Furthermore, at weeks 12 and 24, 45.14% and 47.19% of affected patients showed a resolution of enthesitis. Active dactylitis and nail psoriasis at baseline were reported to affect 10.5% and 22.0%, decreasing to 2.6% and 5.7% at week 24, respectively. The safety findings are consistent with the known safety profile of upadacitinib in rheumatoid arthritis and PsA; no new safety risks were identified. CONCLUSION: The data from this study confirm the findings of previous randomized controlled trials suggesting UPA is an effective treatment for active PsA without any new safety signals in patients from daily clinical practice. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04758117.

Upadacitinib is an antirheumatic medical therapy approved for treating psoriatic arthritis with insufficient response to previous conventional or biological therapies (DMARD-IR). Psoriatic arthritis is a chronic inflammatory disease affecting the joints, spine, tendons/entheses, skin, nails and other parts of the musculoskeletal system. Early diagnosis and treatment initiation are essential for patients with psoriatic arthritis given the potentially irreversible damage to joints, spine, and entheses and the considerable impact on quality of life. The results presented in this manuscript help clinicians evaluate whether the efficacy and the safety profile of upadacitinib found in previous clinical trials can be reproduced in patients seen in daily clinical practice. This analysis presents descriptive data on the real-world efficacy and safety of upadacitinib, measured by clinical and patient-reported outcomes assessed in four visits over 24 weeks. In summary, our findings confirm the results of previous clinical trials showing that upadacitinib effectively reduces symptom severity of PsA and substantially increases the proportion of patients achieving treatment goals relevant to clinical practice, such as remission or very low disease activity. In addition, safety data were consistent with previous studies of upadacitinib in rheumatoid arthritis or psoriatic arthritis; no new risks to the patients' safety were identified.

Projection of healthcare demand in Germany and Switzerland urged by Omicron wave (January-March 2022).

In January 2022, after the implementation of broad vaccination programs, the Omicron wave was propagating across Europe. There was an urgent need to understand how population immunity affects the dynamics of the COVID-19 pandemic when the loss of vaccine protection was concurrent with the emergence of a new variant of concern. In particular, assessing the risk of saturation of the healthcare systems was crucial to manage the pandemic and allow a transition towards the endemic course of SARS-CoV-2 by implementing more refined mitigation strategies that shield the most vulnerable groups and protect the healthcare systems. We investigated the epidemic dynamics by means of compartmental models that describe the age-stratified social-mixing and consider vaccination status, type, and waning of the efficacy. In response to the acute situation, our model aimed at (i) providing insight into the plausible scenarios that were likely to occur in Switzerland and Germany in the midst of the Omicron wave, (ii) informing public health authorities, and (iii) helping take informed decisions to minimize negative consequences of the pandemic. Despite the unprecedented numbers of new positive cases, our results suggested that, in all plausible scenarios, the wave was unlikely to create an overwhelming healthcare demand; due to the lower hospitalization rate and the effectiveness of the vaccines in preventing a severe course of the disease. This prediction came true and the healthcare systems in Switzerland and Germany were not pushed to the limit, despite the unprecedentedly large number of infections. By retrospective comparison of the model predictions with the official reported data of the epidemic dynamic, we demonstrate the ability of the model to capture the main features of the epidemic dynamic and the corresponding healthcare demand. In a broader context, our framework can be applied also to endemic scenarios, offering quantitative support for refined public health interventions in response to recurring waves of COVID-19 or other infectious diseases.

The Sensitivity to Change of the ASAS Health Index in an Observational Real-Life Cohort Study.

OBJECTIVE: The Assessment of Spondyloarthritis international Society Health Index (ASAS HI) measures global functioning and health in patients with axial spondyloarthritis (axSpA) covering domains of physical, emotional, and social functioning. The main aim of this study was to investigate the sensitivity to change of ASAS HI in comparison with established variables of disease activity, function, and mental health. METHODS: Patients with axSpA from the disease register RABBIT-SpA with follow-up time of at least 12 months and available ASAS HI questionnaires were included. Patients received questionnaires addressing disease activity (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI], Ankylosing Spondylitis Disease Activity Score [ASDAS]), physical function (Bath Ankylosing Spondylitis Functional Index [BASFI]), mental health (5-item World Health Organization Well-Being Index [WHO-5]), and global functioning (ASAS HI). Standardized response means (SRMs) were calculated to compare the sensitivity to change of different variables. RESULTS: Six hundred and sixty-seven patients were included, 552 treated with biologic disease-modifying antirheumatic drugs (bDMARDs) and 115 with conventional synthetic DMARDs and/or nonsteroidal antiinflammatory drugs (control group). Between baseline and month 12, the mean ASAS HI declined from 6.9 to 5.1 in the bDMARD group and from 5.9 to 5.6 in the conventionally treated group. In the bDMARD group, the SRM of ASAS HI was 0.52, compared to 0.59 for BASFI, 0.65 for WHO-5, 0.73 for BASDAI, and 0.90 for ASDAS. The following ASAS HI domains were most frequently affected: pain (78% agreed), maintaining body position (75%), and energy/drive (73%). In the patients receiving bDMARDs, there was an improvement in all items. In the control group, the largest improvement was seen in pain. CONCLUSION: As expected, ASDAS and BASDAI as disease activity scores showed high sensitivity to change, whereas changes in physical function (BASFI), mental health (WHO-5), and the broader concept of functioning and health (ASAS HI) were moderate.

Results from Canton Grisons of Switzerland suggest repetitive testing reduces SARS-CoV-2 incidence (February-March 2021).

In February 2021, in response to emergence of more transmissible SARS-CoV-2 virus variants, the Canton Grisons launched a unique RNA mass testing program targeting the labour force in local businesses. Employees were offered weekly tests free of charge and on a voluntary basis. If tested positive, they were required to self-isolate for ten days and their contacts were subjected to daily testing at work. Thereby, the quarantine of contact persons could be waved.Here, we evaluate the effects of the testing program on the tested cohorts. We examined 121,364 test results from 27,514 participants during February-March 2021. By distinguishing different cohorts of employees, we observe a noticeable decrease in the test positivity rate and a statistically significant reduction in the associated incidence rate over the considered period. The reduction in the latter ranges between 18 and 50%. The variability is partly explained by different exposures to exogenous infection sources (e.g., contacts with visiting tourists or cross-border commuters). Our analysis provides the first empirical evidence that applying repetitive mass testing to a real population over an extended period of time can prevent spread of COVID-19 pandemic. However, to overcome logistic, uptake, and adherence challenges it is important that the program is carefully designed and that disease incursion from the population outside of the program is considered and controlled.

Patient-reported outcomes with golimumab in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: non-interventional study GO-NICE in Germany.

The TNF inhibitor golimumab (GLM) is a treatment option in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). The GO-NICE study assessed patient-reported outcomes (PRO) in patients newly treated with monthly GLM 50 mg subcutaneously (SC) under real-life conditions in Germany. A prospective non-interventional study with 24-month observation per patient was conducted at 158 sites. Available for analysis were 1,458 patients, 474 with rheumatoid arthritis (RA: 54.9 ± 13.4 years, 72.8% females, 60.4% biologic-naïve), 501 with psoriatic arthritis (PsA: 50.5 ± 12.1 years, 54.1% females; 47.5% biologic-naïve), and 483 with ankylosing spondylitis (AS: 43.6 ± 12.3 years, 66.5% males; 58.4% biologic-naïve). A total of 664 patients completed follow-up to month 24. An improvement of QoL by EuroQoL EQ-5D-3L was seen after 6 months and was maintained over 24 months. The patients' health state today (EQ visual analog scale) improved statistically significantly (p < 0.0001 vs. BL) from 51.0 at baseline (BL) to 63.4 (RA), from 48.4 to 64.3 (PsA) and from 46.8 to 66.5 (AS). Functional ability (FFbH) improved significantly (p < 0.003 vs. BL) from BL 68.2 to 76.1 points (RA), from 69.0 to 76.8 points (PsA), and from 69.0 to 78.5 points (AS). The mean FACIT-Fatigue score increased significantly (p < 0.0001 vs. BL) from BL 32.4 to 38.3 points (RA), from 30.0 to 35.9 points (PsA), and from 29.9 to 37.9 points after 24 months (AS); p < 0.0001 vs. BL each. On treatment with GLM SC once monthly, significant improvements in patient-reported QoL parameters were noted in a very similar manner in all three diseases.Trial registration ClinTrials.gov Identifier: NCT01313858. Registered March 14, 2011; https://clinicaltrials.gov/ct2/show/record/NCT01313858 .

Knee Extensors Muscle Plasticity Over a 5-Years Rehabilitation Process After Open Knee Surgery.

We investigated molecular and cellular parameters which set metabolic and mechanical functioning of knee extensor muscles in the operated and contralateral control leg of 9 patients with a chronically insufficient anterior cruciate ligament (ACL; 26.6 ± 8.3 years, 8 males, 1 female) after open reconstructive surgery (week 0), after ambulant physiotherapy under cast immobilization (week 9), succeeding rehabilitation training (up to week 26), and subsequent voluntary physical activity (week 260). Clinical indices of knee function in the operated leg were improved at 52 weeks and remained at a comparable level at week 260. CSA of the quadriceps (-18%), MCSA of muscle fibers (-24%), and capillary-to-fiber ratio (-24%) in m. vastus lateralis from the ACL insufficient leg were lower at week 0 than reference values in the contralateral leg at week 260. Slow type fiber percentage (-35%) and mitochondrial volume density (-39%) were reduced in m. vastus lateralis from the operated leg at weeks 9 and 26. Composition alterations in the operated leg exceeded those in the contralateral leg and, with the exception of the volume density of subsarcolemmal mitochondria, returned to the reference levels at week 260. Leg-specific deterioration of metabolic characteristics in the vasti from the operated leg was reflected by the down-regulation of mitochondrial respiration complex I-III markers (-41-57%) at week 9. After rehabilitation training at week 26, the specific Y397 phosphorylation of focal adhesion kinase (FAK), which is a proxy for mechano-regulation, was elevated by 71% in the operated leg but not in the contralateral leg, which had performed strengthening type exercise during ambulant physiotherapy. Total FAK protein and Y397 phosphorylation levels were lowered in both legs at week 26 resulting in positive correlations with mitochondrial volume densities and mitochondrial protein levels. The findings emphasize that a loss of mechanical and metabolic characteristics in knee extensor muscle remains detectable years after untreated ACL rupture, which may be aggravated in the post-operative phase by the deterioration of slow-oxidative characteristics after reconstruction due to insufficient load-bearing muscle activity. The reestablishment of muscle composition subsequent to years of voluntary physical activity reinforces that slow-to-fast fiber transformation is reversible in humans.

Effectiveness and safety of golimumab in patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis under real-life clinical conditions: non-interventional GO-NICE study in Germany.

OBJECTIVE: The Non Interventional Evaluation with Golumimab (GO-NICE) study aimed to document patient and treatment characteristics as well as clinical effectiveness and safety in adult patients newly treated with the tumour necrosis factor inhibitor golimumab (GLM). DESIGN: Prospective non-interventional study with 24-month observation per patient. SETTING: 158 office-based and clinical-based physicians in Germany. INTERVENTION: GLM administered in the 50 mg dose subcutaneously in monthly intervals under real-life conditions. RESULTS: Of the 1613 included patients, 1458 patients were eligible for final analysis: 474 patients with rheumatoid arthritis (RA, 54.9±13.4 years, 72.8% women, 64.7% biologic-naïve), 501 with psoriatic arthritis (PsA, 50.5±12.1 years, 54.1% women, 56.5% biologic-naïve) and 483 with ankylosing spondylitis (AS, 43.6±12.3 years, 66.5% men, 61.0% biologic-naïve). 664 patients completed follow-up (2-year retention rate 45.5%). Disease Activity Score 28-joint count erythrocyte sedimentation rate (DAS28-ESR) decreased from 5.0 to 2.9 after 24 months (p<0.0001) in patients with RA, and Bath Ankylosing Spondylitis Disease Index score decreased from 5.1 to 2.4 (p<0.0001) in patients with AS. Response rate calculated in patients with PsA by modified Psoriatic Arthritis Response Criteria was 67.9% after 24 months. Most adverse events were of mild or moderate nature, and no new safety signals were detected. According to the physicians' clinical assessments, treatment with GLM was successful (no adverse drug reaction and a clear or moderate therapeutic effect in an individual patient) in 55.0%-56.6% of patients with RA, PsA and AS, respectively, at month 3, increasing from 74.5% to 76.1% at month 24. CONCLUSIONS: GLM subcutaneously once monthly led to substantial improvements in clinical effectiveness in patients with various inflammatory rheumatic diseases who could be followed up in a real-life setting in Germany. The treatment was well tolerated, and the safety profile of GLM was consistent with that observed in the previous randomised controlled trials. TRIAL REGISTRATION NUMBER: NCT01313858.

Frequency and duration of drug-free remission after 1 year of treatment with etanercept versus sulfasalazine in early axial spondyloarthritis: 2 year data of the ESTHER trial.

PURPOSE: The aims of this study were (1) to assess the frequency and duration of drug-free remission and efficacy of etanercept (ETA) treatment after flare in patients with early active axial spondyloarthritis who were treated with ETA (n=40) versus sulfasalazine (SSZ, n=36) for 48 weeks and (2) to analyse the efficacy of ETA treatment in patients in year 2 who did not reach remission at week 48. METHOD: At week 48, patients who reached study remission (Assessment of Spondyloarthritis international Society (ASAS) plus MRI remission) were followed up without active treatment up to 1 year. In case of a flare, patients were treated with ETA for another year. All patients who were not in ASAS plus MRI remission at week 48 were treated with ETA in year 2. RESULTS: ASAS plus MRI remission at week 48 was reached significantly more often in ETA-treated compared to SSZ-treated patients (33% vs 11%, p=0.03). However, the flare rate was not different between these two groups: 69% in the ETA group versus 75% in the SSZ group. Only 8% of patients initially treated with ETA versus 3% of those initially treated with SSZ reached permanent drug-free remission (not significant). After treatment with ETA over 1 year, patients with flare showed an improvement in all clinical and imaging variables. CONCLUSION: Patients with axial spondyloarthritis treated with ETA over 1 year did not reach drug-free remission in a higher percentage compared to patients from a control group treated with SSZ.

Infection and work stress are potential triggers of ankylosing spondylitis.

The objective of the study was to investigate potential triggering events for the onset of ankylosing spondylitis (AS). A large retrospective population survey of 1,080 AS patients was carried out by multi-faceted questionnaire. A nested case-control study compared the cohort to 102 patients with lumbar disc prolapse. Participants with AS had a mean age of 49.8 years, mean age of disease onset was 25.2 years and 63% of the cohort were male. Seventy-nine per cent knew they were human leucocyte antigen (HLA)-B27-positive, and a further 12.5% were unaware of their HLA-B27 status. Infections were relatively common in the 3 months leading to the first symptoms, 4.6% reporting gastrointestinal infection, 2.5% reporting urinary tract infection and 2.6% respiratory infection. Five per cent reported heavy physical activity in the 3 months prior to the onset of symptoms, 4.2% emotional stressors and 3.1% work stressors. Injury and surgery were less commonly reported (1.7 and 0.7%, respectively). Pregnancy was reported by 7.4% of the female participants. When the 12 months leading up to the first symptoms was compared to the 12 months previous to that, work stressors (OR 1.5), and pregnancy (OR 2.5) infection (OR 1.5 to 1.8) were significantly more common closer to disease onset. Infection and work stressors are potential triggers for the onset of AS; however, low rates suggest they are only a small part of the environmental milieu that combines with a genetic predisposition to cause the development of this chronic inflammatory disease.

Nonsteroidal anti-inflammatory drug use in ankylosing spondylitis--a population-based survey.

The objective of the study is to describe the use, clinical efficacy, and toxicity of nonsteroidal anti-inflammatory drug (NSAID) therapy in patients with ankylosing spondylitis (AS). A cross-sectional population study of 1,080 AS patients was carried out by a written questionnaire in the year 2000. Seventy-eight percent of AS patients had regularly taken NSAIDs for their disease 12 months prior to the study. Most AS patients commonly used diclofenac, naproxen and indomethacin. AS patients were generally rather satisfied with the efficacy of their therapy where 19.1% reported complete pain control, 26.8% reported pain reduction to one quarter, and a further 34.4% reported pain reduction to one half. However, over 20% of patients taking NSAIDs still reported insufficient pain control and more than 40% changed the NSAID due to lack of efficacy. One quarter of AS patients reported severe side effects from their treatment, most commonly abdominal pain, headache and dizziness, and nausea. There was no effect on age or duration of disease on the occurrence of NSAID-related side effects. Medications were commonly ceased or changed due to inefficacy or side effects. The percentage of AS patients reporting changing their NSAID due to side effects ranged from 10.5% for celecoxib to 31.4% for indomethacin. We conclude that NSAIDs are effective in the management of inflammatory symptoms of many, but not all, patients with AS. There is a significant side effect profile, which frequently results in medication change or cessation. Anti-tumor necrosis factor therapy may reduce the need for intensive long-term NSAID therapy in AS.

The high prevalence of infections and allergic symptoms in patients with ankylosing spondylitis is associated with clinical symptoms.

Ankylosing spondylitis (AS) is strongly associated with the major histocompatibility complex (MHC) class I antigen HLA-B27. This may have influence on the physiologic immune response. Whether it leads to an increased prevalence of infections and/or allergy in AS patients is unclear. This study aims to determine the prevalence of infections and allergic symptoms in patients with AS and to detect a possible association with clinical symptoms. Data on 1,080 AS patients and on 102 disc prolapse patients were collected by questionnaire. The proportion of patients with a symptomatic infection in the last year was 65.5% in AS patients in comparison with 25.5% in disc prolapse patients (p=0.0001). AS patients reported more gastrointestinal (GI) [odds ratio (OR) 5.07, 95% confidence interval (CI) 2.20-11.71], urinary tract (OR 2.81, 95%CI 1.41-5.72), and respiratory (OR 5.83, 95%CI 3.38-10.08) infections than did disc prolapse patients. Multiple infections were more common in AS patients across all infection types. Allergic symptoms were reported by AS patients more frequently than by disc prolapse patients (OR 5.13, 95%CI 3.49-8.80). Patients reporting concurrent inflammatory bowel disease were more likely to report GI (OR 3.0, 95%CI 1.9-4.8) and urinary tract (OR 1.7, 95%CI 1-2.8) infection than primary AS patients. In AS patients, infection was independently associated with female gender (OR 1.96, 95%CI 1.47-2.56), a history of significant peripheral joint inflammation (OR 1.55, 95%CI 1.18-2.05), and increasing pain duration (p=0.05). A high prevalence of common infections and allergic symptoms is seen in patients with AS, most of which are HLA-B27-positive. This may have implications both for underlying mechanisms of disease and for therapeutic options.

Morphologic characteristics of acetabular dysplasia in proximal femoral focal deficiency.

A retrospective radiographic analysis of the acetabulum of 13 patients (14 hips) with proximal femoral focal deficiency (PFFD), clinically classified into Gillespie and Torode type 1, was performed to better understand its morphologic features at maturity. The version of the proximal part of the acetabulum was determined quantitatively and qualitatively. All 14 hips showed residual or borderline acetabular dysplasia with a mean lateral centre-edge angle of -1.5degrees and an acetabular index of 30degrees. The acetabular dome was retroverted in all hips and averaged -24degrees. Acetabular deficiency compared with the opposite side, while not present with respect to the anterior wall, averaged 12% with respect to the posterior wall. Dysplasia associated with type 1 PFFD is therefore fundamentally different from that seen in developmental residual hip dysplasia. Clinically, despite radiographic evidence of dysplasia, 57% were without clinical manifestations of hip pathology. This may be due to a number of factors including age of last radiograph, severity of dysplasia, and the decreased functional demand placed on the hip in some individuals with associated malformations. For the symptomatic hip, the posterior insufficiency and relative retroversion of the acetabular dome should be taken into consideration in planning reorientation procedures. This can help to prevent problems of persistent subluxation or acetabulo-femoral impingement following reconstruction.

Shoulder instability related to epileptic seizures.

Epileptic seizures can cause shoulder dislocation and instability, but a characteristic pattern of instability and structural lesions is not well known. We reviewed 34 shoulders in 26 patients in whom the initial dislocation had been caused by an epileptic seizure. All patients were followed up clinically and radiologically for a mean of 10 years (range, 2-21 years) after initiation of treatment. Thirteen patients (17 shoulders) were treated for anterior instability. A large Hill-Sachs lesion was found 12 times and a large glenoid rim fracture 5 times. There were 12 recurrent and 2 locked dislocations. The recurrence rate after the first repair was 47% (8/17 shoulders). The final overall results at a mean follow-up of 10 years (range, 2-12 years) were good in 12 cases, satisfactory in 2, and unsatisfactory in 2. The reoperation rate was 40%. With skeletal reconstruction, 12 of 13 shoulders were stable at final follow-up. Another 13 patients (17 shoulders) were treated for posterior dislocation. A large reverse Hill-Sachs lesion was observed 13 times and a posterior glenoid rim fracture twice. There were 15 locked but only 2 recurrent dislocations. The recurrence rate after repair was 12% (2/17 shoulders). The final outcome at a mean follow-up of 7 years (range, 2-12 years) was good in 11 shoulders and satisfactory in 6. The reoperation rate was 12%. Anterior and posterior dislocations occurred with equal frequency in this series. Large bony lesions were the hallmark finding in this group of patients. Skeletal reconstruction was necessary to obtain clinical stability, especially in the more difficult-to-treat anterior instability.