Real-world effectiveness of sotrovimab in preventing hospitalization and mortality in high-risk patients with COVID-19 in the United States: A cohort study from the Mayo Clinic electronic health records.

BACKGROUND: To describe outcomes of high-risk patients with coronavirus disease 2019 (COVID-19) treated with sotrovimab, other monoclonal antibodies (mAbs), or antivirals, and patients who did not receive early COVID-19 treatment. We also evaluate the comparative effectiveness of sotrovimab versus no treatment in preventing severe clinical outcomes. METHODS: This observational retrospective cohort study analyzed Mayo Clinic electronic health records. Non-hospitalized adult patients diagnosed with COVID-19 from May 26, 2021 and April 23, 2022 and at high risk of COVID-19 progression were eligible. The primary outcome was 29-day all-cause hospitalization and/or death. Outcomes were described for patients treated with sotrovimab, other mAbs, or antivirals, and eligible but untreated patients, and compared between sotrovimab-treated and propensity score (PS)-matched untreated cohorts. RESULTS: We included 35,485 patients (sotrovimab, 1369; other mAbs, 6488; antivirals, 133; high-risk untreated, 27,495). A low proportion of patients treated with sotrovimab (n = 33/1369, 2.4%), other mAbs (n = 147/6488, 2.3%), or antivirals (n = 2/133, 1.5%) experienced all-cause hospitalization or death. Among high-risk untreated patients, the percentage of all-cause hospitalization or death was 3.3% (n = 910/27,495). In the PS-matched analysis, 2.5% (n = 21/854) of sotrovimab-treated patients experienced all-cause hospitalization and/or death versus 2.8% (n = 48/1708) of untreated patients (difference, -0.4%; p = 0.66). Significantly fewer sotrovimab-treated patients required intensive care unit admission (0.5% vs 1.8%; difference, -1.3%; p = 0.002) or respiratory support (3.5% vs 8.7%; difference, -5.2%; p < 0.001). CONCLUSIONS: There was no significant difference in the proportion of sotrovimab-treated and PS-matched untreated patients experiencing 29-day all-cause hospitalization or mortality, although significantly fewer sotrovimab-treated patients required intensive care unit admission or respiratory support.

Characteristics and outcomes of patients with COVID-19 at high risk of disease progression receiving sotrovimab, oral antivirals, or no treatment: a retrospective cohort study.

BACKGROUND: The clinical benefit of coronavirus disease 2019 (COVID-19) treatments against new circulating variants remains unclear. We sought to describe characteristics and clinical outcomes of highest risk patients with COVID-19 receiving early COVID-19 treatments in Scotland. METHODS: Retrospective cohort study of non-hospitalized patients diagnosed with COVID-19 from December 1, 2021-October 25, 2022, using Scottish administrative health data. We included adult patients who met ≥ 1 of the National Health Service highest risk criteria for early COVID-19 treatment and received outpatient treatment with sotrovimab, nirmatrelvir/ritonavir or molnupiravir, or no early COVID-19 treatment. Index date was defined as the earliest of COVID-19 diagnosis or early COVID-19 treatment. Baseline characteristics and acute clinical outcomes in the 28 days following index were reported. Values of ≤ 5 were suppressed. RESULTS: In total, 2548 patients were included (492: sotrovimab, 276: nirmatrelvir/ritonavir, 71: molnupiravir, and 1709: eligible highest risk untreated). Patients aged ≥ 75 years accounted for 6.9% (n = 34/492), 21.0% (n = 58/276), 16.9% (n = 12/71) and 13.2% (n = 225/1709) of the cohorts, respectively. Advanced renal disease was reported in 6.7% (n = 33/492) of sotrovimab-treated and 4.7% (n = 81/1709) of untreated patients, and ≤ 5 nirmatrelvir/ritonavir-treated and molnupiravir-treated patients. All-cause hospitalizations were experienced by 5.3% (n = 25/476) of sotrovimab-treated patients, 6.9% (n = 12/175) of nirmatrelvir/ritonavir-treated patients, ≤ 5 (suppressed number) molnupiravir-treated patients and 13.3% (n = 216/1622) of untreated patients. There were no deaths in the treated cohorts; mortality was 4.3% (n = 70/1622) among untreated patients. CONCLUSIONS: Sotrovimab was often used by patients who were aged < 75 years. Among patients receiving early COVID-19 treatment, proportions of 28-day all-cause hospitalization and death were low.

Characteristics and outcomes of patients with COVID-19 at high risk of disease progression receiving sotrovimab, oral antivirals or no treatment in England: a retrospective cohort study.

OBJECTIVE: To describe characteristics and acute clinical outcomes for patients with COVID-19 treated with sotrovimab, nirmatrelvir/ritonavir or molnupiravir, or untreated patients at highest risk per National Health Service (NHS) criteria. METHODS: Retrospective study of non-hospitalized patients between 1 December 2021 and 31 May 2022, using data from the Discover-NOW dataset (North-West London). Included patients were aged ≥12 years and treated with sotrovimab, nirmatrelvir/ritonavir or molnupiravir, or untreated but expected to be eligible for early treatment per NHS highest-risk criteria. COVID-19-related and all-cause hospitalizations were reported for 28 days from COVID-19 diagnosis (index). Subgroup analyses were conducted in patients with advanced renal disease, those aged 18-64 and ≥65 years, and by period of Omicron BA.1, BA.2 and BA.5 (post-hoc exploratory) predominance. RESULTS: Overall, 1503 treated and 4044 eligible high-risk untreated patients were included. A high proportion of patients on sotrovimab had advanced renal disease (29.3%), ≥3 high-risk comorbidities (47.6%) and were aged ≥65 years (36.9%). Five of 696 (0.7%) patients on sotrovimab, <5/337 (0.3-1.2%) on nirmatrelvir/ritonavir, 10/470 (2.1%) on molnupiravir and 114/4044 (2.8%) untreated patients were hospitalized with COVID-19. Similar results were observed across all subgroups. The proportion of patients dying within 28 days of the index period was similarly low across all cohorts (<2%). CONCLUSION: Patients receiving sotrovimab appeared to show evidence of multiple high-risk comorbidities. Low hospitalization rates were observed for all treated cohorts across subgroups and periods of predominant variants of concern. These results require confirmation with comparative effectiveness analyses adjusting for differences in underlying patient characteristics.

Characterizing health-related quality of life and identifying disease predictors among patients suspected of having long COVID: an analysis of COMET-ICE clinical trial data.

Introduction: Long COVID affects health-related quality of life (HRQoL). Here, we investigate the extent to which symptoms experienced during the acute phase of COVID-19 are significant predictors of the presence of long COVID at 12 weeks. Methods: Post-hoc analysis of COMET-ICE trial data, which assessed sotrovimab vs. placebo for treatment of mild-to-moderate COVID-19 among high-risk patients. Patient-reported outcome measures were completed during the trial, including the inFLUenza Patient-Reported Outcome Plus (FLU-PRO Plus), the 12-Item Short Form (SF-12) Hybrid questionnaire, and the Work Productivity and Activity Impairment Questionnaire: General Health (WPAI:GH). COVID-19 symptoms and impacts (measured by the FLU-PRO Plus) and HRQoL (measured by SF-12 Hybrid and WPAI:GH) were compared between the acute phase (Days 1-21 and 29) and long-COVID phase (at Week 12) among patients with and without long COVID based on COMET-ICE data. Subgroups experiencing long COVID were derived using "All," "Returning," and "Persisting" symptomatic definitions. Long-COVID predictors were identified using a multivariate logistic regression model; odds ratios (ORs) and 95% CIs were calculated. Results: Long-COVID subgroups had significantly higher baseline scores for most FLU-PRO Plus domains and Total Score compared with the non-long-COVID group. WPAI:GH and SF-12 Hybrid scores generally showed significantly more impairment for the long-COVID subgroups at baseline and Week 12 vs. the non-long-COVID group. In the univariate analyses, all FLU-PRO Plus domains were significant predictors of long COVID (all p < 0.05), with the exception of the Sense domain. Older age increased the risk of long COVID (OR 1.02, 95% CI 1.00-1.04, p < 0.05). Non-White patients were significantly less likely to have long COVID by the Returning and Persisting definitions vs. White patients (all p < 0.05). In the multivariate analysis, higher scores for the Nose domain (ORs 3.39-5.60, all p < 0.01) and having COPD (ORs 3.75-6.34, all p < 0.05) were significant long-COVID predictors. Conclusion: Patients who progressed to long COVID had higher symptom severity during the acute disease phase and showed significantly greater negative impact on HRQoL over an extended time period from initial infection through at least the subsequent 3 months. The FLU-PRO Plus Nose domain and having COPD were significant predictors of long COVID.

Comparative effectiveness of sotrovimab versus no treatment in non-hospitalised high-risk COVID-19 patients in north west London: a retrospective cohort study.

BACKGROUND: We assessed the effectiveness of sotrovimab vs no early COVID-19 treatment in highest-risk COVID-19 patients during Omicron predominance. METHODS: Retrospective cohort study using the Discover dataset in North West London. Included patients were non-hospitalised, aged ≥12 years and met ≥1 National Health Service highest-risk criterion for sotrovimab treatment. We used Cox proportional hazards models to compare HRs of 28-day COVID-19-related hospitalisation/death between highest-risk sotrovimab-treated and untreated patients. Age, renal disease and Omicron subvariant subgroup analyses were performed. RESULTS: We included 599 sotrovimab-treated patients and 5191 untreated patients. Compared with untreated patients, the risk of COVID-19 hospitalisation/death (HR 0.50, 95% CI 0.24, 1.06; p=0.07) and the risk of COVID-19 hospitalisation (HR 0.43, 95% CI 0.18, 1.00; p=0.051) were both lower in the sotrovimab-treated group; however, statistical significance was not reached. In the ≥65 years and renal disease subgroups, sotrovimab was associated with a significantly reduced risk of COVID-19 hospitalisation, by 89% (HR 0.11, 95% CI 0.02, 0.82; p=0.03) and 82% (HR 0.18, 95% CI 0.05, 0.62; p=0.007), respectively. CONCLUSIONS: Risk of COVID-19 hospitalisation in sotrovimab-treated patients aged ≥65 years and with renal disease was significantly lower compared with untreated patients. Overall, risk of hospitalisation was also lower for sotrovimab-treated patients, but statistical significance was not reached.

Characteristics and outcomes of COVID-19 patients presumed to be treated with sotrovimab in NHS hospitals in England.

BACKGROUND: The impact of the constantly evolving severe acute respiratory syndrome coronavirus 2 on the effectiveness of early coronavirus disease 2019 (COVID-19) treatments is unclear. Here, we report characteristics and acute clinical outcomes of patients with COVID-19 treated with a monoclonal antibody (mAb; presumed to be sotrovimab) across six distinct periods covering the emergence and predominance of Omicron subvariants (BA.1, BA.2, and BA.5) in England. METHODS: Retrospective cohort study using data from the Hospital Episode Statistics database from January 1-July 31, 2022. Included patients received a mAb delivered by a National Health Service (NHS) hospital as a day-case, for which the primary diagnosis was COVID-19. Patients were presumed to have received sotrovimab based on NHS data showing that 99.98% of COVID-19-mAb-treated individuals received sotrovimab during the study period. COVID-19-attributable hospitalizations were reported overall and across six distinct periods of Omicron subvariant prevalence. Subgroup analyses were conducted in patients with severe renal disease and active cancer. RESULTS: Among a total of 10,096 patients, 1.0% (n = 96) had a COVID-19-attributable hospitalization, 4.6% (n = 465) had a hospital visit due to any cause, and 0.3% (n = 27) died due to any cause during the acute period. COVID-19-attributable hospitalization rates were consistent among subgroups, and no significant differences were observed across periods of Omicron subvariant predominance. CONCLUSIONS: Levels of COVID-19-attributable hospitalizations and deaths were low in mAb-treated patients and among subgroups. Similar hospitalization rates were observed whilst Omicron BA.1, BA.2, and BA.5 were predominant, despite reported reductions in in vitro neutralization activity of sotrovimab against BA.2 and BA.5.

Real-World Effectiveness of Sotrovimab for the Early Treatment of COVID-19: Evidence from the US National COVID Cohort Collaborative (N3C).

BACKGROUND AND OBJECTIVE: The coronavirus disease 2019 (COVID-19) pandemic has been an unprecedented healthcare crisis, one that threatened to overwhelm health systems and prompted an urgent need for early treatment options for patients with mild-to-moderate COVID-19 at high risk for progression to severe disease. Randomised clinical trials established the safety and efficacy of monoclonal antibodies (mAbs) early in the pandemic; in vitro data subsequently led to use of the mAbs being discontinued, without clear evidence on how these data were linked to outcomes. In this study, we describe and compare real-world outcomes for patients with mild-to-moderate COVID-19 at high risk for progression to severe COVID-19 treated with sotrovimab versus untreated patients. METHODS: Electronic health records from the National COVID Cohort Collaborative (N3C) were used to identify US patients (aged ≥ 12 years) diagnosed with COVID-19 (positive test or ICD-10: U07.1) in an ambulatory setting (27 September 2021-30 April 2022) who met Emergency Use Authorization (EUA) high-risk criteria. Patients receiving the mAb sotrovimab within 10 days of diagnosis were assigned to the sotrovimab cohort, with the day of infusion as the index date. Untreated patients (no evidence of early mAb treatment, prophylactic mAb or oral antiviral treatment) were assigned to the untreated cohort, with an imputed index date based on the time distribution between diagnosis and sotrovimab infusion in the sotrovimab cohort. The primary endpoint was hospitalisation or death (both all-cause) within 29 days of index, reported as descriptive rate and adjusted [via inverse probability of treatment weighting (IPTW)] odds ratio (OR) and 95% confidence interval (CI). RESULTS: Of nearly 2.9 million patients diagnosed with COVID-19 during the analysis period, 4992 met the criteria for the sotrovimab cohort, and 541,325 were included in the untreated cohort. Before weighting, significant differences were noted between the cohorts; for example, patients in the sotrovimab cohort were older (60 years versus 54 years), were more likely to be white (85% versus 75%) and met more EUA criteria (mean 3.1 versus 2.2) versus the untreated cohort. The proportions of patients with 29-day hospitalisation or death were 3.5% (176/4992) and 4.5% (24,163/541,325) in the sotrovimab and untreated cohorts, respectively (unadjusted OR: 0.78; 95% CI: 0.67, 0.91; p = 0.001). In adjusted analysis, sotrovimab was associated with a 25% reduction in the odds of hospitalisation or death compared with the untreated cohort (IPTW-adjusted OR: 0.75; 95% CI: 0.61, 0.92; p = 0.005). CONCLUSIONS: Sotrovimab demonstrated clinical effectiveness in preventing severe outcomes (hospitalisation, mortality) in the period 27 September 2021-30 April 2022, which included Delta and Omicron BA.1 variants and an early surge of Omicron BA.2 variant.

The Interfascicular Matrix of Energy Storing Tendons Houses Heterogenous Cell Populations Disproportionately Affected by Aging.

Energy storing tendons such as the human Achilles and equine superficial digital flexor tendon (SDFT) are prone to injury, with incidence increasing with aging, peaking in the 5th decade of life in the human Achilles tendon. The interfascicular matrix (IFM), which binds tendon fascicles, plays a key role in energy storing tendon mechanics, and aging alterations to the IFM negatively impact tendon function. While the mechanical role of the IFM in tendon function is well-established, the biological role of IFM-resident cell populations remains to be elucidated. Therefore, the aim of this study was to identify IFM-resident cell populations and establish how these populations are affected by aging. Cells from young and old SDFTs were subjected to single cell RNA-sequencing, and immunolabelling for markers of each resulting population used to localise cell clusters. Eleven cell clusters were identified, including tenocytes, endothelial cells, mural cells, and immune cells. One tenocyte cluster localised to the fascicular matrix, whereas nine clusters localised to the IFM. Interfascicular tenocytes and mural cells were preferentially affected by aging, with differential expression of genes related to senescence, dysregulated proteostasis and inflammation. This is the first study to establish heterogeneity in IFM cell populations, and to identify age-related alterations specific to IFM-localised cells.

Assessment of symptoms in COMET-ICE, a phase 2/3 study of sotrovimab for early treatment of non-hospitalized patients with COVID-19.

BACKGROUND: The COMET-ICE trial demonstrated that sotrovimab clinically and statistically significantly reduces the risk of all-cause > 24-h hospitalization or death due to any cause among patients with COVID-19 at high risk of disease progression. Patient-reported outcomes are important to capture symptom burden of COVID-19 and assess treatment effectiveness. This study investigated symptoms and their impact over the acute phase of COVID-19 infection among patients on sotrovimab versus placebo. METHODS: Randomized (1:1), double-blind, multicenter, placebo-controlled, phase 2/3 study in 57 centers across five countries. Participants were non-hospitalized patients with symptomatic, mild-to-moderate COVID-19 and ≥ 1 baseline risk factor for disease progression (aged ≥ 55 years or ≥ 1 of the following: diabetes requiring medication, obesity, chronic kidney disease, congestive heart failure, chronic obstructive pulmonary disease, or moderate-to-severe asthma). An intravenous infusion of sotrovimab 500 mg or placebo was administered on Day 1. The FLU-PRO Plus questionnaire was administered once-daily with 24-h recall from Day 1-21, and at Day 29. Intensity and duration of COVID-19 symptoms were determined from area under the curve (AUC) and mean change in total and individual domain scores through Days 7, 14, and 21. Time to symptom alleviation was assessed. RESULTS: In total, 1057 patients were randomized to sotrovimab (n = 528) or placebo (n = 529). At Day 7, mean decrease in FLU-PRO Plus total score (measured by AUC) was statistically significantly greater for patients on sotrovimab (-3.05 [95% confidence interval (CI) -3.27 to -2.83]) than placebo (-1.98 [95% CI -2.20 to -1.76]; difference -1.07 [95% CI -1.38 to -0.76]; p < 0.001). Significant differences were also observed at Days 14 and 21. A more rapid decline in symptom severity was observed with sotrovimab versus placebo through Week 1 and the first 21 days post-treatment. By Day 21, 41% of patients on sotrovimab and 34% on placebo reported symptom resolution. In a post-hoc analysis, median time to symptom alleviation was 4 and 6 days, respectively. CONCLUSIONS: Sotrovimab provides significant and rapid improvements in patient-reported COVID-19 symptoms, as measured by the FLU-PRO Plus. These results further show the benefits of sotrovimab in alleviating symptoms among high-risk patients with COVID-19. Trial registration ClinicalTrials.Gov: NCT04545060 ( https://clinicaltrials.gov/ct2/show/NCT04545060 ). Date of registration: September 10, 2020 (retrospectively registered).

Content validity and psychometric properties of the inFLUenza Patient-Reported Outcome Plus (FLU-PRO Plus©) instrument in patients with COVID-19.

PURPOSE: A well-defined and reliable patient-reported outcome instrument for COVID-19 is important for assessing symptom severity and supporting research studies. The InFLUenza Patient-Reported Outcome (FLU-PRO) instrument has been expanded to include loss of taste and smell in the FLU-PRO Plus, to comprehensively cover COVID-19 symptoms. Our studies were designed to evaluate and validate the FLU-PRO Plus among patients with COVID-19. METHODS: Two studies were conducted: (1) a qualitative, non-interventional, cross-sectional study of patients with COVID-19 involving hybrid concept elicitation and cognitive debriefing interviews; (2) a psychometric evaluation of the measurement properties of FLU-PRO Plus, using data from COMET-ICE (COVID-19 Monoclonal antibody Efficacy Trial-Intent to Care Early). RESULTS: In the qualitative interviews (n = 30), all 34 items of the FLU-PRO Plus were considered relevant to COVID-19, and participants determined the questionnaire was easily understood, well written, and comprehensive. In the psychometric evaluation (n = 845), the internal consistency reliability of FLU-PRO Plus total score was 0.94, ranging from 0.71 to 0.90 for domain scores. Reproducibility (Day 20-21) was 0.83 for total score, with domain scores of 0.67-0.89. Confirmatory factor analysis with the novel smell/taste domain demonstrated an acceptable fit to the data. CONCLUSION: The content, reliability, validity, and responsiveness of the FLU-PRO Plus in the COVID-19 population were supported. Our results suggest that FLU-PRO Plus is a content- and psychometrically-valid, fit-for-purpose measure which is easily understood by patients. FLU-PRO Plus is a suitable PRO measure for evaluating symptoms of COVID-19 and treatment benefit directly from the patient perspective. TRIAL REGISTRATION: ClinicalTrials.Gov: NCT04545060, September 10, 2020; retrospectively registered.

Real-World Effectiveness of Sotrovimab for the Early Treatment of COVID-19 During SARS-CoV-2 Delta and Omicron Waves in the USA.

INTRODUCTION: Sotrovimab, a recombinant human monoclonal antibody (mAb) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had US Food and Drug Administration Emergency Use Authorization for the treatment of high-risk outpatients with mild-to-moderate coronavirus disease 2019 (COVID-19) from 26 May 2021 to 5 April 2022. Real-world clinical effectiveness of sotrovimab in reducing the risk of 30-day all-cause hospitalization and/or mortality was evaluated for the period when the prevalence of circulating SARS-CoV-2 variants changed between Delta and Omicron in the USA. METHODS: A retrospective analysis was conducted of de-identified patients diagnosed with COVID-19 between 1 September 2021 to 30 April 2022 in the FAIR Health National Private Insurance Claims database. Patients meeting high-risk criteria were divided into two cohorts: sotrovimab and not treated with a mAb ("no mAb"). All-cause hospitalizations and facility-reported mortality ≤ 30 days of diagnosis ("30-day hospitalization or mortality") were identified. Multivariable and propensity score-matched Poisson and logistic regressions were conducted to estimate the adjusted relative risk (RR) and odds of 30-day hospitalization or mortality in each cohort. RESULTS: Compared with the no mAb cohort (n = 1,514,868), the sotrovimab cohort (n = 15,633) was older and had a higher proportion of patients with high-risk conditions. In the no mAb cohort, 84,307 (5.57%) patients were hospitalized and 8167 (0.54%) deaths were identified, while in the sotrovimab cohort, 418 (2.67%) patients were hospitalized and 13 (0.08%) deaths were identified. After adjusting for potential confounders, the sotrovimab cohort had a 55% lower risk of 30-day hospitalization or mortality (RR 0.45, 95% CI 0.41-0.49) and an 85% lower risk of 30-day mortality (RR 0.15, 95% CI 0.08-0.29). Monthly, from September 2021 to April 2022, the RR reduction for 30-day hospitalization or mortality in the sotrovimab cohort was maintained, ranging from 46% to 71% compared with the no mAb cohort; the RR estimate in April 2022 was uncertain, with wide confidence intervals due to the small sample size. CONCLUSION: Sotrovimab was associated with reduced risk of 30-day all-cause hospitalization and mortality versus no mAb treatment. Clinical effectiveness persisted during Delta and early Omicron variant waves and among all high-risk subgroups assessed.

Chemical Markers of Human Tendon Health Identified Using Raman Spectroscopy: Potential for In Vivo Assessment.

The purpose of this study is to determine whether age-related changes to tendon matrix molecules can be detected using Raman spectroscopy. Raman spectra were collected from human Achilles (n = 8) and tibialis anterior (n = 8) tendon tissue excised from young (17 ± 3 years) and old (72 ± 7 years) age groups. Normalised Raman spectra underwent principal component analysis (PCA), to objectively identify differences between age groups and tendon types. Certain Raman band intensities were correlated with levels of advanced glycation end-product (AGE) collagen crosslinks, quantified using conventional destructive biochemistry techniques. Achilles and tibialis anterior tendons in the old age group demonstrated significantly higher overall Raman intensities and fluorescence levels compared to young tendons. PCA was able to distinguish young and old age groups and different tendon types. Raman intensities differed significantly for several bands, including those previously associated with AGE crosslinks, where a significant positive correlation with biochemical measures was demonstrated. Differences in Raman spectra between old and young tendon tissue and correlation with AGE crosslinks provides the basis for quantifying age-related chemical modifications to tendon matrix molecules in intact tissue. Our results suggest that Raman spectroscopy may provide a powerful tool to assess tendon health and vitality in the future.

A systematic literature review of burden of illness in adults with uncontrolled moderate/severe asthma.

BACKGROUND: There are limited published data on the burden of moderate/severe uncontrolled asthma. METHODS: We conducted a systematic literature review to better understand the impact of moderate-to-severe asthma in the US, the UK, Germany, France, Italy, Spain, Canada, Japan, and Australia in terms of prevalence, clinical measures, health-related quality of life (HRQoL) and economic burden, for patients whose asthma is uncontrolled despite inhaled corticosteroid/long-acting ß2-agonist (ICS/LABA) therapy. RESULTS: The prevalence of uncontrolled asthma among patients with moderate/severe disease varied but was as high as 100% in some subgroups. Patients with uncontrolled asthma generally had poor lung function (mean/median pre-bronchodilator forced expiratory volume in 1 second [FEV1]: 1.69-2.45 L; mean/median pre-bronchodilator percent predicted FEV1: 57.2-79.7). There was also a substantial but variable exacerbation burden associated with uncontrolled asthma, with the annualised rate of exacerbations ranging from 1.30 to 7.30 when considering various patient subgroups. Furthermore, the annualised rate of severe exacerbations ranged from 1.66 to 3.60. The HRQoL burden measured using disease-specific and generic instruments consistently demonstrated substantial impairment of HRQoL for those with uncontrolled asthma; Asthma Quality of Life Questionnaire scores ranged from 3.00 to 5.20, whilst EurQol-5 Dimensions index scores ranged from 0.53 to 0.59. Direct, indirect and total costs together with consumption of other healthcare resources associated with managing uncontrolled asthma were also substantial in the population studied; no caregiver burden was identified. CONCLUSIONS: Our findings suggest that significant unmet needs exist for patients with uncontrolled asthma despite the availability of ICS/LABA therapy. Novel treatments are needed to help reduce the burden to patients, healthcare systems and society.

Effects of booster sessions on self-management interventions for chronic musculoskeletal pain: a systematic review and meta-analysis of randomised controlled trials.

ABSTRACT: Our objective was to investigate the effectiveness of booster sessions after self-management interventions as a means of maintaining self-management behaviours in the treatment of chronic musculoskeletal pain. We searched MEDLINE, EMBASE, Science Citation Index, Cochrane Central Register of Controlled Trials, and PsychINFO. Two authors independently identified eligible trials and collected data. We calculated the odds ratio for the analyses of dichotomous data and standardised mean differences (SMDs) with 95% confidence interval (CI) for continuous variables. Our search identified 14 studies with a total of 1695 patients. All studies were at high risk of bias and provided very low quality evidence. For the primary outcomes, booster sessions had no evidence of an effect on improving patient-reported outcomes on physical function (SMD -0.13, 95% CI -0.32 to -0.06; P = 0.18), pain-related disability (SMD -0.16, 95% CI -0.36 to 0.03; P = 0.11), and pain self-efficacy (SMD 0.15, 95% CI -0.07 to 0.36; P = 0.18). For the secondary outcomes, booster sessions caused a significant reduction in patient-reported pain catastrophising (SMD -0.42, 95% CI -0.64 to -0.19; P = 0.0004) and no evidence of an effect on patient-reported pain intensity, depression, coping, or treatment adherence. There is currently little evidence that booster sessions are an effective way to prolong positive treatment effects or improve symptoms of long-term musculoskeletal conditions after self-management interventions. However, the studies were few with high heterogeneity, high risk of bias, and overall low quality of evidence. Our review argues against including booster sessions routinely to self-management interventions for the purpose of behaviour maintenance.

Structure-function specialisation of the interfascicular matrix in the human achilles tendon.

Tendon consists of highly aligned collagen-rich fascicles surrounded by interfascicular matrix (IFM). Some tendons act as energy stores to improve locomotion efficiency, but such tendons commonly obtain debilitating injuries. In equine tendons, energy storing is achieved primarily through specialisation of the IFM. However, no studies have investigated IFM structure-function specialisation in human tendons. Here, we compare the human positional anterior tibial tendon and energy storing Achilles tendons, testing the hypothesis that the Achilles tendon IFM has specialised composition and mechanical properties, which are lost with ageing. Data demonstrate IFM specialisation in the energy storing Achilles, with greater elasticity and fatigue resistance than in the positional anterior tibial tendon. With ageing, alterations occur predominantly to the proteome of the Achilles IFM, which are likely responsible for the observed trends towards decreased fatigue resistance. Knowledge of these key energy storing specialisations and their changes with ageing offers crucial insight towards developing treatments for tendinopathy. STATEMENT OF SIGNIFICANCE: Developing effective therapeutics or preventative measures for tendon injury necessitates the understanding of healthy tendon function and mechanics. By establishing structure-function relationships in human tendon and determining how these are affected by ageing, potential targets for therapeutics can be identified. In this study, we have used a combination of mechanical testing, immunolabelling and proteomics analysis to study structure-function specialisations in human tendon. We demonstrate that the interfascicular matrix is specialised for energy storing in the Achilles tendon, and that its proteome is altered with ageing, which is likely responsible for the observed trends towards decreased fatigue resistance. Knowledge of these key energy storing specialisations and their changes with ageing offers crucial insight towards developing treatments and preventative approaches for tendinopathy.

The effect of exercise on the protein profile of rat knee joint intra- and extra-articular ligaments.

Injuries to the intra-articular anterior cruciate ligament (ACL) and the extra-articular medial collateral ligament (MCL) result in significant knee joint instability, pain, and immobility. Moderate endurance-type exercise can increase ligament strength but little is known on the effect of short-term regular bouts of high-intensity exercise on the extracellular matrix (ECM) structure of knee ligaments. Therefore, this study aimed to identify the effect of short-term regular bouts high exercise on the proteome of the rat ACL and MCL using mass spectrometry. Sprague-Dawley male rats (n = 6) were split into control and exercise groups, and subjected to high-intensity training for four 4 weeks followed by proteomic analyses of the ACL and MCL. Knee joint health status was assessed using OARSI and a validated histological scoring system. Histopathological analyses demonstrated no significant changes in either in cruciate, collateral ligaments, or cartilage between the control and exercised knee joints. However, significant proteins were found to be more abundant in the exercised ACL compared to ACL control group but not between the exercised MCL and control MCL groups. The significant abundant proteins in ACL exercise groups were mostly cytoskeletal, ribosomal and enzymes with several abundant matrisomal proteins such as collagen proteins and proteoglycans being found in this group. In conclusion, our results indicate that short-term regular bouts of high-intensity exercise have an impact on the intra-articular ACL but not extra-articular MCL ECM protein expression.

An equine tendon model for studying intra-tendinous shear in tendons that have more than one muscle contribution.

Human Achilles tendon is composed of three smaller sub-tendons and exhibits non-uniform internal displacements, which decline with age and after injury, suggesting a potential role in the development of tendinopathies. Studying internal sliding behaviour is therefore important but difficult in human Achilles tendon. Here we propose the equine deep digital flexor tendon (DDFT) and its accessory ligament (AL) as a model to understand the sliding mechanism. The AL-DDFT has a comparable sub-bundle structure, is subjected to high and frequent asymmetric loads and is a natural site of injury similar to human Achilles tendons. Equine AL-DDFT were collected and underwent whole tendon level (n=7) and fascicle level (n=7) quasi-static mechanical testing. Whole tendon level testing was performed by sequentially loading through the proximal AL and subsequently through the proximal DDFT and recording regional strain in the free structures and joined DDFT and AL. Fascicle level testing was performed with focus on the inter-sub-bundle matrix between the two structures at the junction. Our results demonstrate a significant difference in the regional strain between the joined DDFT and AL and a greater transmission of force from the AL to the DDFT than vice versa. These results can be partially explained by the mechanical properties and geometry of the two structures and by differences in the properties of the interfascicular matrices. In conclusion, this tendon model successfully demonstrates that high displacement discrepancy occurs between the two structures and can be used as an easy-access model for studying intra-tendinous shear mechanics at the sub-tendon level. STATEMENT OF SIGNIFICANCE: Our study provides a naturally occurring and easily accessible equine model to study the complex behaviour of sub-tendons within the human Achilles tendon, which is likely to play a critical role in the pathogenesis of tendon disease. Our results demonstrate that the difference in material stiffness between the equine AL and DDFT stems largely from differences in the inter-fascicular matrix and furthermore that differences in strain are maintained in distal parts of the tightly joined structure. Furthermore, our results suggest that distribution of load between sub-structures is highly dependent on the morphological relationship between them; a finding that has important implications for understanding Achilles tendon mechanical behaviour, injury mechanisms and rehabilitation.

Individual variation in Achilles tendon morphology and geometry changes susceptibility to injury.

The unique structure of the Achilles tendon, combining three smaller sub-tendons, enhances movement efficiency by allowing individual control from connected muscles. This requires compliant interfaces between sub-tendons, but compliance decreases with age and may account for increased injury frequency. Current understanding of sub-tendon sliding and its role in the whole Achilles tendon function is limited. Here we show changing the degree of sliding greatly affects the tendon mechanical behaviour. Our in vitro testing discovered distinct sub-tendon mechanical properties in keeping with their mechanical demands. In silico study based on measured properties, subject-specific tendon geometry, and modified sliding capacity demonstrated age-related displacement reduction similar to our in vivo ultrasonography measurements. Peak stress magnitude and distribution within the whole Achilles tendon are affected by individual tendon geometries, the sliding capacity between sub-tendons, and different muscle loading conditions. These results suggest clinical possibilities to identify patients at risk and design personalised rehabilitation protocols.

Lysine-arginine advanced glycation end-product cross-links and the effect on collagen structure: A molecular dynamics study.

The accumulation of advanced glycation end-products is a fundamental process that is central to age-related decline in musculoskeletal tissues and locomotor system function and other collagen-rich tissues. However, although computational studies of advanced glycation end-product cross-links could be immensely valuable, this area remains largely unexplored given the limited availability of structural parameters for the derivation of force fields for Molecular Dynamics simulations. In this article, we present the bonded force constants, atomic partial charges and geometry of the arginine-lysine cross-links DOGDIC, GODIC, and MODIC. We have performed in vacuo Molecular Dynamics simulations to validate their implementation against quantum mechanical frequency calculations. A DOGDIC advanced glycation end-product cross-link was then inserted into a model collagen fibril to explore structural changes of collagen and dynamics in interstitial water. Unlike our previous studies of glucosepane, our findings suggest that intra-collagen DOGDIC cross-links furthers intra-collagen peptide hydrogen-bonding and does not promote the diffusion of water through the collagen triple helices.

Postnatal mechanical loading drives adaptation of tissues primarily through modulation of the non-collagenous matrix.

Mature connective tissues demonstrate highly specialised properties, remarkably adapted to meet their functional requirements. Tissue adaptation to environmental cues can occur throughout life and poor adaptation commonly results in injury. However, the temporal nature and drivers of functional adaptation remain undefined. Here, we explore functional adaptation and specialisation of mechanically loaded tissues using tendon; a simple aligned biological composite, in which the collagen (fascicle) and surrounding predominantly non-collagenous matrix (interfascicular matrix) can be interrogated independently. Using an equine model of late development, we report the first phase-specific analysis of biomechanical, structural, and compositional changes seen in functional adaptation, demonstrating adaptation occurs postnatally, following mechanical loading, and is almost exclusively localised to the non-collagenous interfascicular matrix. These novel data redefine adaptation in connective tissue, highlighting the fundamental importance of non-collagenous matrix and suggesting that regenerative medicine strategies should change focus from the fibrous to the non-collagenous matrix of tissue.