Polarized thermal emission from dust in a galaxy at redshift 2.6.

Magnetic fields are fundamental to the evolution of galaxies, playing a key role in the astrophysics of the interstellar medium and star formation. Large-scale ordered magnetic fields have been mapped in the Milky Way and nearby galaxies1,2, but it is not known how early in the Universe such structures formed3. Here we report the detection of linearly polarized thermal emission from dust grains in a strongly lensed, intrinsically luminous galaxy that is forming stars at a rate more than 1,000 times that of the Milky Way at redshift 2.6, within 2.5 Gyr of the Big Bang4,5. The polarized emission arises from the alignment of dust grains with the local magnetic field6,7. The median polarization fraction is of the order of 1%, similar to nearby spiral galaxies8. Our observations support the presence of a 5-kiloparsec-scale ordered magnetic field with a strength of around 500 µG or lower, oriented parallel to the molecular gas disk. This confirms that such structures can be rapidly formed in galaxies, early in cosmic history.

Prolonged Orbital Relaxation by Locally Modified Phonon Density of States for the SiV

Coherent quantum systems are a key resource for emerging quantum technology. Solid-state spin systems are of particular importance for compact and scalable devices. However, interaction with the solid-state host degrades the coherence properties. The negatively charged silicon vacancy center in diamond is such an example. While spectral properties are outstanding, with optical coherence protected by the defects symmetry, the spin coherence is susceptible to rapid orbital relaxation limiting the spin dephasing time. A prolongation of the orbital relaxation time is therefore of utmost urgency and has been tackled by operating at very low temperatures or by introducing large strain. However, both methods have significant drawbacks: the former requires use of dilution refrigerators and the latter affects intrinsic symmetries. Here, a novel method is presented to prolong the orbital relaxation with a locally modified phonon density of states in the relevant frequency range, by restricting the diamond host to below 100 nm. Subsequently measured coherent population trapping shows an extended spin dephasing time compared to the phonon-limited time in a pure bulk diamond. The method works at liquid helium temperatures of few Kelvin and in the low-strain regime.

Avelumab in unresectable/metastatic, progressive, grade 2-3 neuroendocrine neoplasms (NENs): Combined results from NET-001 and NET-002 trials.

BACKGROUND: Higher grade neuroendocrine neoplasm (NENs) continues to pose a treatment dilemma, with the optimal treatment undefined. Although immunotherapy has revolutionised the treatment of many cancers, its role in NENs remains unclear. We aimed to investigate the efficacy and safety of avelumab, a PD-L1-directed antibody, in patients with advanced unresectable/metastatic higher grade NENs. METHODS: NET001 and NET002 are phase II studies investigating avelumab (NCT03278405 and NCT03278379). Eligible patients had unresectable and/or metastatic WHO G2-3 NENs from a gastroenteropancreatic (GEP) source or a bronchial primary (excluding typical carcinoid) and 0-2 prior lines of systemic therapy (excluding SSAs). Patients were treated with avelumab 10 mg/kg intravenously every two weeks for 26 cycles. NET001 investigated G3 poorly differentiated GEP neuroendocrine carcinomas (NECs) and bronchial small/large cell NEC, whereas NET002 investigated G2-3 well-differentiated GEPNETs and bronchial atypical carcinoids. The primary endpoint in both trials was overall response rate (ORR) by RECIST v1.1; secondary endpoints included progression-free survival, overall survival, disease control rate at six months and toxicity. RESULTS: Twenty-seven patients were enrolled (21 GEP, 6 lung; 10 in NET-001, 17 in NET-002); median age 64 (range 37-80), 30% ECOG PS 1-2 and 78% received 1+ lines of prior therapy. The median Ki-67 index was 35% (range 10-100). Twelve of the twenty-seven patients had died at the time of data lock. The median time on treatment was 85 days (seven cycles). No objective responses were observed. Stable disease was achieved in 33% of patients, and the disease control rate at 6 mo was 21%. The median PFS was 3.3 months (range 1.2-24.6), and the median OS was 14.2 months. Treatment-related adverse events (all grades) occurred in 58% of patients. Three patients had treatment-related grade 3-4 AEs leading to treatment discontinuation (immune-related hepatitis n = 2 and infusion-related reaction n = 1). CONCLUSION: Single-agent PD-L1 blockade with avelumab showed limited antitumour activity in patients with G2-3 NENs. Correlative studies are underway. Further studies are needed to explore the role of dual immunotherapy and other combinations in this population with few treatment alternatives.

Clustering of comorbidities and associated outcomes in people with osteoarthritis - A UK Clinical Practice Research Datalink study.

OBJECTIVE: To examine the clusters of chronic conditions present in people with osteoarthritis and the associated risk factors and health outcomes. METHODS: Clinical Practice Research Datalink (CPRD) GOLD was used to identify people diagnosed with incident osteoarthritis (n = 221,807) between 1997 and 2017 and age (±2 years), gender, and practice matched controls (no osteoarthritis, n = 221,807) from UK primary care. Clustering of people was examined for 49 conditions using latent class analysis. The associations between cluster membership and covariates were quantified by odds ratios (OR) using multinomial logistic regression. General practice (GP) consultations, hospitalisations, and all-cause mortality rates were compared across the clusters identified at the time of first diagnosis of osteoarthritis (index date). RESULTS: In both groups, conditions largely grouped around five clusters: relatively healthy; cardiovascular (CV), musculoskeletal-mental health (MSK-MH), CV-musculoskeletal (CV-MSK) and metabolic (MB). In the osteoarthritis group, compared to the relatively healthy cluster, strong associations were seen for 1) age with all clusters; 2) women with the MB cluster (OR 5.55: 5.14-5.99); 3) obesity with the CV-MSK (OR 2.11: 2.03-2.20) and CV clusters (OR 2.03: 1.97-2.09). The CV-MSK cluster in the osteoarthritis group had the highest number of GP consultations and hospitalisations, and the mortality risk was 2.45 (2.33-2.58) times higher compared to the relatively healthy cluster. CONCLUSIONS: Of the five identified clusters, CV-MSK, CV, and MSK-MH are more common in OA and CV-MSK cluster had higher health utilisation. Further research is warranted to better understand the mechanistic pathways and clinical implications.

Comparative efficacy and safety of acetaminophen, topical and oral non-steroidal anti-inflammatory drugs for knee osteoarthritis: evidence from a network meta-analysis of randomized controlled trials and real-world data.

OBJECTIVE: Current global guidelines regarding the first-line analgesics (acetaminophen, topical or oral non-steroidal anti-inflammatory drugs [NSAIDs]) for knee osteoarthritis remain controversial and their comparative risk-benefit profiles have yet to be adequately assessed. DESIGN: Pubmed, Embase, Cochrane Library, and Web of Science were searched from database inception to March 2021 for randomized controlled trials (RCTs) comparing acetaminophen, topical NSAIDs and oral NSAIDs directly or indirectly in knee osteoarthritis. Bayesian network meta-analyses were conducted. A propensity-score matched cohort study was also conducted among patients with knee osteoarthritis in The Health Improvement Network database. RESULTS: 122 RCTs (47,113 participants) were networked. Topical NSAIDs were superior to acetaminophen (standardized mean difference [SMD] = -0.29, 95% credible interval [CrI]: -0.52 to -0.06) and not statistically different from oral NSAIDs (SMD = 0.03, 95% CrI: -0.16 to 0.22) for function. It had lower risk of gastrointestinal adverse effects (AEs) than acetaminophen (risk ratio [RR] = 0.52, 95%CrI: 0.35 to 0.76) and oral NSAIDs (RR = 0.46, 95%CrI: 0.34 to 0.61) in RCTs. In real-world data, topical NSAIDs showed lower risks of all-cause mortality (hazard ratio [HR] = 0.59, 95% confidence interval [CI]: 0.52 to 0.68), cardiovascular diseases (HR = 0.73, 95%CI: 0.63 to 0.85) and gastrointestinal bleeding (HR = 0.53, 95%CI: 0.41 to 0.69) than acetaminophen during the one-year follow-up (n = 22,158 participants/group). A better safety profile was also observed for topical than oral NSAIDs (n = 14,218 participants/group). CONCLUSIONS: Topical NSAIDs are more effective than acetaminophen but not oral NSAIDs for function improvement in people with knee osteoarthritis. Topical NSAIDs are safer than acetaminophen or oral NSAIDs in trials and real-world data.

Synovitis and bone marrow lesions associate with symptoms and radiographic progression in hand osteoarthritis: a systematic review and meta-analysis of observational studies.

AIMS: To systematically review observational studies for the association between features detected on ultrasound (US) and magnetic resonance imaging (MRI) and, symptoms, signs and radiographic progression of hand osteoarthritis (OA). METHODS: Medline, Web of Science, EMBASE, CINAHL and AMED were searched from inception to 14th January 2020 to identify relevant studies. Quality of studies was assessed using the Newcastle-Ottawa scales and data were extracted. Odds ratios (OR) and linear regression coefficients and 95% confidence intervals (CI) were pooled using the random-effects model (METAN package, Stata v16.1). Heterogeneity and publication bias were assessed. RESULTS: Thirty-two studies using US and MRI comprising 1,350 and 638 participants respectively were included. While only grey-scale synovitis (GSS) associated with AUSCAN-pain (pooled Regression coefficient (95% CI): 0.46 (0.13-0.79); 0-20 scale for AUSCAN-pain), US-detected osteophytes, GSS and power Doppler (PD) [pooled ORs (95% CI): 2.68(2.16-3.33), 2.38(1.74-3.26) and 2.04 (1.45-2.88)] as well as MRI-detected bone marrow lesions (BMLs), synovitis, osteophytes, and central bone erosions (CBEs) associated with joint tenderness [pooled ORs (95% CI): 2.59(2.12-3.18), 2.17(1.85-2.54), 2.15(1.55-2.99), and 2.41 (1.45-4.02)] respectively. US-detected GSS and PD associated with radiographic progression of CBEs [pooled ORs 5.37, 5.08], osteophytes [pooled ORs 5.17, 6.45], and joint space narrowing (pooled ORs 4.28, 4.36) whilst MRI-detected synovitis and BMLs associated with increasing KL grades with pooled ORs 2.92, 2.54 respectively. CONCLUSIONS: US and MRI-detected structural and inflammatory changes associate with tenderness, whilst articular inflammation and subchondral bone damage associate with radiographic hand OA progression. There was inconsistent relationship between these changes and pain.

Epidemiology of COVID-19 in Northern Ireland, 26 February 2020-26 April 2020.

This paper describes the epidemiology of coronavirus disease 2019 (COVID-19) in Northern Ireland (NI) between 26 February 2020 and 26 April 2020, and analyses enhanced surveillance and contact tracing data collected between 26 February 2020 and 13 March 2020 to estimate secondary attack rates (SAR) and relative risk of infection among different categories of contacts of individuals with laboratory confirmed severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection. Our results show that during the study period COVID-19 cumulative incidence and mortality was lower in NI than the rest of the UK. Incidence and mortality were also lower than in the Republic of Ireland (ROI), although these observed differences are difficult to interpret given considerable differences in testing and surveillance between the two nations. SAR among household contacts was 15.9% (95% CI 6.6%-30.1%), over 6 times higher than the SAR among 'high-risk' contacts at 2.5% (95% CI 0.9%-5.4%). The results from logistic regression analysis of testing data on contacts of laboratory-confirmed cases show that household contacts had 11.0 times higher odds (aOR: 11.0, 95% CI 1.7-70.03, P-value: 0.011) of testing positive for SARS-CoV-2 compared to other categories of contacts. These results demonstrate the importance of the household as a locus of SARS-CoV-2 transmission, and the urgency of identifying effective interventions to reduce household transmission.

A systematic review and network meta-analysis of second-line therapy in hepatocellular carcinoma.

Background: In patients with advanced hepatocellular carcinoma (hcc) following sorafenib failure, it is unclear which treatment is most efficacious, as treatments in the second-line setting have not been directly compared and no standard therapy exists. This systematic review and network meta-analysis (nma) aimed to compare the clinical benefits and toxicities of these treatments. Methods: A systematic review of randomized controlled trials (rcts) was conducted to identify phase iii rcts in advanced hcc following sorafenib failure. Baseline characteristics and outcomes of placebo were examined for heterogeneity. Primary outcomes of interest were extracted for results, including overall survival (os), progression-free survival (pfs), objective response rate (orr), grade 3/4 toxicities, and subgroups. An nma was conducted to compare both drugs through the intermediate placebo. Comparisons were expressed as hazard ratios (hrs) for os and pfs, and as risk difference (rd) for orr and toxicities. Subgroup analyses for os and pfs were also performed. Results: Two rcts were identified (1280 patients) and compared through an indirect network; celestial (cabozantinib vs. placebo) and resorce (regorafenib vs. placebo). Baseline characteristics of patients in both trials were similar. Both trials also had similar placebo outcomes. Cabozantinib, compared with regorafenib, showed similar os [hazard ratio (hr): 1.21; 95% confidence interval (ci): 0.90 to 1.62], pfs (hr: 1.02; 95% ci: 0.78 to 1.34) and orr (-3.0%; 95% ci: -7.6% to 1.7%). Both treatments showed similar toxicities, but there were marginally higher risks of grade 3/4 hand-foot syndrome (5%; 95% ci: 0.1% to 9.8%), diarrhea (4.8%; 95% ci: 1.1% to 8.5%), and anorexia (4.4%; 95% ci: 0.8% to 8.0%) for cabozantinib. Subgroup results for os and pfs were consistent with overall results. Conclusions: Overall, this nma determined that cabozantinib and regorafenib have similar clinical benefits and toxicities for second-line hcc.

Trends in incidence and prevalence of osteoarthritis in the United Kingdom: findings from the Clinical Practice Research Datalink (CPRD).

OBJECTIVE: This study aimed to explore the incidence and prevalence of OA in the UK in 2017 and their trends from 1997 to 2017 using a large nationally representative primary care database. DESIGN: The UK Clinical Practice Research Datalink (CPRD) comprising data on nearly 17.5 million patients was used for the study. The incidence and prevalence of general practitioner diagnosed OA over a 20 years period (1997-2017) were estimated and age-sex and length of data contribution standardized using the 2017 CPRD population structure. Cohort effects were examined through Age-period-cohort analysis. RESULTS: During 1997-2017, there were 494,716 incident OA cases aged ≥20 years. The standardised incidence of any OA in 2017 was 6.8 per 1000 person-years (95% CI 6.7 to 6.9) and prevalence was 10.7% (95% CI 10.7-10.8%). Both incidence and prevalence were higher in women than men. The incidence of any-OA decreased gradually in the past 20 years at an annual rate of -1.6% (95%CI -2.0 to -1.1%), and the reduction speeded up for people born after 1960. The prevalence of any-OA increased gradually at an annual rate of 1.4% (95% CI 1.3-1.6%). Although the prevalence was highest in Scotland and Northern Ireland, incidence was highest in the East Midlands. Both incidence and prevalence reported highest in the knee followed by hip, wrist/hand and ankle/foot. CONCLUSION: In the UK approximately one in 10 adults have symptomatic clinically diagnosed OA, the knee being the commonest. While prevalence has increased and become static after 2008, incidence is slowly declining. Further research is required to understand these changes.

Baseline self-report 'central mechanisms' trait predicts persistent knee pain in the Knee Pain in the Community (KPIC) cohort.

OBJECTIVES: We investigated whether baseline scores for a self-report trait linked to central mechanisms predict 1 year pain outcomes in the Knee Pain in the Community cohort. METHOD: 1471 participants reported knee pain at baseline and responded to a 1-year follow-up questionnaire, of whom 204 underwent pressure pain detection thresholds (PPTs) and radiographic assessment at baseline. Logistic and linear regression models estimated the relative risks (RRs) and associations (ß) between self-report traits, PPTs and pain outcomes. Discriminative performance for each predictor was compared using receiver-operator characteristics (ROC) curves. RESULTS: Baseline Central Mechanisms trait scores predicted pain persistence (Relative Risk, RR = 2.10, P = 0.001) and persistent pain severity (ß = 0.47, P < 0.001), even after adjustment for age, sex, BMI, radiographic scores and symptom duration. Baseline joint-line PPTs also associated with pain persistence (RR range = 0.65 to 0.68, P < 0.02), but only in univariate models. Lower baseline medial joint-line PPT was associated with persistent pain severity (ß = -0.29, P = 0.013) in a fully adjusted model. The Central Mechanisms trait model showed good discrimination of pain persistence cases from resolved pain cases (Area Under the Curve, AUC = 0.70). The discrimination power of other predictors (PPTs (AUC range = 0.51 to 0.59), radiographic OA (AUC = 0.62), age, sex and BMI (AUC range = 0.51 to 0.64), improved significantly (P < 0.05) when the central mechanisms trait was included in each logistic regression model (AUC range = 0.69 to 0.74). CONCLUSION: A simple summary self-report Central Mechanisms trait score may indicate a contribution of central mechanisms to poor knee pain prognosis.

Microscopic Imaging of the Stress Tensor in Diamond Using in Situ Quantum Sensors.

The precise measurement of mechanical stress at the nanoscale is of fundamental and technological importance. In principle, all six independent variables of the stress tensor, which describe the direction and magnitude of compression/tension and shear stress in a solid, can be exploited to tune or enhance the properties of materials and devices. However, existing techniques to probe the local stress are generally incapable of measuring the entire stress tensor. Here, we make use of an ensemble of atomic-sized in situ strain sensors in diamond (nitrogen-vacancy defects) to achieve spatial mapping of the full stress tensor, with a submicrometer spatial resolution and a sensitivity of the order of 1 MPa (10 MPa) for the shear (axial) stress components. To illustrate the effectiveness and versatility of the technique, we apply it to a broad range of experimental situations, including mapping the stress induced by localized implantation damage, nanoindents, and scratches. In addition, we observe surprisingly large stress contributions from functional electronic devices fabricated on the diamond and also demonstrate sensitivity to deformations of materials in contact with the diamond. Our technique could enable in situ measurements of the mechanical response of diamond nanostructures under various stimuli, with potential applications in strain engineering for diamond-based quantum technologies and in nanomechanical sensing for on-chip mass spectroscopy.

U.S. prevalence of endocrine therapy-naïve locally advanced or metastatic breast cancer.

Background: Variations in treatment choice, or late stage at first diagnosis, mean that, despite guideline recommendations, not all patients with hormone receptor (hr)-positive locally advanced or metastatic breast cancer (la/mbca) will have received endocrine therapy before disease progression. In the present study, we aimed to estimate the proportion of women with postmenopausal hr-positive la/mbca in the United States who are endocrine therapy-naïve. Methods: Women in the Optum Electronic Health Record (ehr) database with a breast cancer (bca) diagnosis (January 2008-March 2015) were included. Patient and malignancy characteristics were identified using structured data fields and natural-language processing of free-text clinical notes. The proportion of women with postmenopausal hr-positive, human epidermal growth factor 2 (her2)-negative (or unknown) la/mbca who had not received prior endocrine therapy was determined. Results were extrapolated to the entire U.S. population using the U.S. National Cancer Institute's Surveillance, Epidemiology, and End Results database. Results are presented descriptively. Results: In the ehr database, 11,831 women with bca had discernible information on postmenopausal status, hr status, and disease stage. Of those women, 1923 (16.3%) had postmenopausal hr-positive, her2-negative (or unknown) la/mbca, and 70.7% of those 1923 patients (n = 1360) had not received prior endocrine therapy, accounting for 11.5% of the overall population. Extrapolating those estimates nationally suggests an annual incidence of 14,784 cases, and a 5-year limited duration prevalence of 50,638 cases. Conclusions: A substantial proportion of women with postmenopausal hr-positive la/mbca in the United States could be endocrine therapy-naïve.

Variance components for bovine tuberculosis infection and multi-breed genome-wide association analysis using imputed whole genome sequence data.

Bovine tuberculosis (bTB) is an infectious disease of cattle generally caused by Mycobacterium bovis, a bacterium that can elicit disease humans. Since the 1950s, the objective of the national bTB eradication program in Republic of Ireland was the biological extinction of bTB; that purpose has yet to be achieved. Objectives of the present study were to develop the statistical methodology and variance components to undertake routine genetic evaluations for resistance to bTB; also of interest was the detection of regions of the bovine genome putatively associated with bTB infection in dairy and beef breeds. The novelty of the present study, in terms of research on bTB infection, was the use of beef breeds in the genome-wide association and the utilization of imputed whole genome sequence data. Phenotypic bTB data on 781,270 animals together with imputed whole genome sequence data on 7,346 of these animals' sires were available. Linear mixed models were used to quantify variance components for bTB and EBVs were validated. Within-breed and multi-breed genome-wide associations were undertaken using a single-SNP regression approach. The estimated genetic standard deviation (0.09), heritability (0.12), and repeatability (0.30) substantiate that genetic selection help to eradicate bTB. The multi-breed genome-wide association analysis identified 38 SNPs and 64 QTL regions associated with bTB infection; two QTL regions (both on BTA23) identified in the multi-breed analysis overlapped with the within-breed analyses of Charolais, Limousin, and Holstein-Friesian. Results from the association analysis, coupled with previous studies, suggest bTB is controlled by an infinitely large number of loci, each having a small effect. The methodology and results from the present study will be used to develop national genetic evaluations for bTB in the Republic of Ireland. In addition, results can also be used to help uncover the biological architecture underlying resistance to bTB infection in cattle.

Thresholds of ultrasound synovial abnormalities for knee osteoarthritis - a cross sectional study in the general population.

OBJECTIVE: To establish "normal" ranges for synovial thickness and effusion detected by ultrasound (US) and to determine cut-offs associated with knee pain (KP) and radiographic knee osteoarthritis (RKOA) in the community. METHODS: 147 women and 152 men ≥40 years old were randomly selected from the Nottingham KP and Related Health in the Community (KPIC) cohort (n = 9506). The "normal" range was established using the percentile method in 163 participants who had no KP and no RKOA. Optimal (maximum sensitivity and specificity) and high specificity (90%) cut-offs were established using receiver operating characteristic (ROC) curve analysis in a comparison between people with both KP and RKOA and normal controls. RESULTS: Effusion and synovial hypertrophy differed by gender but not by age or laterality, therefore gender-specific reference limits were estimated. However, the "normal" ranges between men and women were similar for effusion (0-10.3 mm vs 0-9.8 mm), but different for synovial hypertrophy (0-6.8 mm vs 0-5.4 mm). Power Doppler Signal (PDS) in the healthy controls was uncommon (1.2% in men and 0.0% in women). The optimal cut-off was 7.4 mm for men and 5.3 mm for women for effusion, and 3.7 and 1.6 for hypertrophy respectively. The high specificity cut-off was 8.9 for men and 7.8 for women for effusion, and 5.8 and 4.2 for hypertrophy respectively. CONCLUSIONS: US effusion and synovial hypertrophy but not PDS are common, but differ by gender, in community-derived people without painful knee OA. Currently used cut-offs for abnormality need reappraisal.

Genetic selection for hoof health traits and cow mobility scores can accelerate the rate of genetic gain in producer-scored lameness in dairy cows.

Cattle breeding programs that strive to reduce the animal-level incidence of lameness are often hindered by the availability of informative phenotypes. As a result, indicator traits of lameness (i.e., hoof health and morphological conformation scores) can be used to improve the accuracy of selection and subsequent genetic gain. Therefore, the objectives of the present study were to estimate the variance components for hoof health traits using various phenotypes collected from a representative sample of Irish dairy cows. Also of interest to the present study was the genetic relationship between both hoof health traits and conformation traits with producer-scored lameness. Producer-recorded lameness events and linear conformation scores from 307,657 and 117,859 Irish dairy cows, respectively, were used. Data on hoof health (i.e., overgrown sole, white line disease, and sole hemorrhage), mobility scores, and body condition scores were also available from a research study on up to 11,282 Irish commercial dairy cows. Linear mixed models were used to quantify variance components for each trait and to estimate genetic correlations among traits. The estimated genetic parameters for hoof health traits in the present study were greater (i.e., heritability range: 0.005 to 0.27) than previously reported in dairy cows. With the exception of analyses that considered hoof health traits in repeatability models, little difference in estimated variance components existed among the various hoof-health phenotypes. Results also suggest that producer-recorded lameness is correlated with both hoof health (i.e., genetic correlation up to 0.48) and cow mobility (i.e., genetic correlation = 0.64). Moreover, cows that genetically tend to have rear feet that appear more parallel when viewed from the rear are also genetically more predisposed to lameness (genetic correlation = 0.39); genetic correlations between lameness and other feet and leg type traits, as well as between lameness and frame type traits, were not different from zero. Results suggest that if the population breeding goal was to reduce lameness incidence, improve hoof health, or improve cow mobility, genetic selection for either of these traits should indirectly benefit the other traits. Results were used to quantify the genetic gains achievable for lameness when alternative phenotypes are available.

The relative efficacy of topical non-steroidal anti-inflammatory drugs and capsaicin in osteoarthritis: a network meta-analysis of randomised controlled trials.

OBJECTIVE: To compare the efficacy of topical non-steroidal anti-inflammatory drugs (NSAIDs) with topical capsaicin for pain relief in osteoarthritis (OA). DESIGN: A systematic literature search was conducted for randomised controlled trials (RCTs) examining any topical NSAID or capsaicin in OA. Pain relief at or nearest to 4 weeks was pooled using a random-effects network meta-analysis (NMA) in a Frequentist and Bayesian setting. Analysis was conducted for all trials and for trials using drugs listed as licensed for OA in the British National Formulary (BNF). RESULTS: The trial network comprised 28 RCTs (7372 participants), of which 17 RCTs (3174 participants) were included in the as licensed analyses. No RCTs directly compared topical NSAIDs with capsaicin. Placebo was the only common comparator for topical NSAIDs and capsaicin. Frequentist and Bayesian effect size (ES) estimates were in agreement. Topical NSAIDs were statistically superior to placebo overall (ES 0.30, 95% confidence interval [CI] 0.19 to 0.41) and as licensed (ES 0.32, 95% CI 0.24 to 0.39). However, capsaicin was only statistically superior to placebo when used at licensed doses (ES 0.41, 95% CI 0.17 to 0.64). No significant differences were observed in pain relief between topical NSAIDs and capsaicin (overall: ES 0.04, 95% CI -0.26 to 0.33; as licensed: ES-0.09, 95% CI -0.34 to 0.16). CONCLUSIONS: Current evidence indicates that topical NSAIDs and capsaicin in licensed doses may be equally effective for pain relief in OA. Whether the equivalence varies between individuals remains unknown.

Contribution of central and peripheral risk factors to prevalence, incidence and progression of knee pain: a community-based cohort study.

AIM: To explore risk factors that may influence knee pain (KP) through central or peripheral mechanisms. METHODS: A questionnaire-based prospective community cohort study with KP defined as pain in or around a knee on most days for at least a month. Baseline prevalence, and one year incidence and progression (KP worsening) were examined. Central (e.g., Pain Catastrophizing Scale (PCS)) and peripheral (e.g., significant injury) risk factors were examined. Adjusted odds ratio (OR) and 95% confidence interval (CI) were calculated using logistic regression. Proportional risk contribution (PRC) was estimated using receiver-operator-characteristic (ROC) analysis. RESULTS: Of 9506 baseline participants, 4288 (45%) had KP (men 1826; women, 2462). KP incidence was 12% (men 11%, women 13%), and KP progression 19% (men 16%, women 21%) at one year. While both central and peripheral factors contributed to prevalence, central factors contributed more to progression, and peripheral factors more to incidence of KP. For example, although PCS (OR 2.06, 95% CI 1.88-2.25) and injury (5.62, 4.92-6.42) associated with KP prevalence, PCS associated with progression (2.27, 1.83-2.83) but not incidence (1.14, 0.86-1.52), whereas injury more strongly associated with incidence (69.27, 24.15-198.7) than progression (2.52, 1.48-4.30). The PRC of central and peripheral factors were 19% and 23% for prevalence, 14% and 29% for incidence, and 29% and 5% for progression, respectively. CONCLUSIONS: Both central and peripheral risk factors influence KP but relative contributions may differ in terms of development (mainly peripheral) and progression (mainly central). Further study of such relative contributions may inform primary and secondary prevention strategies.

Health utility scores from EQ-5D and health-related quality of life in patients with esophageal cancer: a real-world cross-sectional study.

Esophageal cancer and its treatment can cause serious morbidity/toxicity. These effects on health-related quality of life (HRQOL) can be measured using disease-specific scales such as FACT-E, generic scales such as EQ-5D-3L, or through symptoms. In a two-year cross-sectional study, we compared HRQOL across esophageal cancer patients treated in an ambulatory clinic and across multiple disease states, among patients with all stages of esophageal cancer. Consenting patients completed FACT-E, EQ-5D, a visual analog scale, and patient reported (PR)-ECOG. Symptom complexes were constructed from FACT-E domains. Responses were categorized by disease state: pre-, during, and post-treatment, surveillance, progression, and palliative chemotherapy. Spearman correlation and multivariable linear regression characterized these associations. In total, 199 patients completed 317 questionnaires. Mean FACT-E and subscale scores dropped from baseline through treatment and recovered during post-treatment surveillance (P < 0.001); EQ-5D health utility scores (HUS) displayed a similar pattern but with smaller differences (P = 0.07), and with evidence of ceiling effect. Among patients with stage II/III esophageal cancer, mean EQ-5D HUS varied across disease states (P < 0.001), along with FACT-E and subscales (P < 0.001). Among patients with advanced disease, there was no significant difference between baseline and on-treatment total scores, but improved esophageal cancer-specific scales were noted (P = 0.003). Strong correlation was observed between EQ-5D and FACT-E (R = 0.73), along with physical and functional subscales. In addition, the association between FACT-E and EQ-5D HUS was maintained in a multivariable model (P < 0.001). We interpret these results to suggest that in a real-world clinic setting, FACT-E, EQ-5D HUS, and symptoms were strongly correlated. Most HRQOL and symptom parameters suggested that patients had worse HRQOL and symptoms during curative therapy, but recovered well afterwards. In contrast, palliative chemotherapy had a neutral to positive impact on HRQOL/symptoms when compared to their baseline pre-treatment state.

Does the intensity of daily walking matter for protecting against the development of a slow gait speed in people with or at high risk of knee osteoarthritis? An observational study.

OBJECTIVE: Knee osteoarthritis (OA) is a risk factor for a decline in gait speed. Daily walking reduces the risk of developing slow gait speed and future persistent functional limitation. However, the protective role of walking intensity is unclear. We investigated the association of substituting time spent not walking, with walking at light and moderate-to-vigorous intensities for incident slow gait over 2-years, among people with or at high risk of knee OA. METHOD: We used baseline and 2-year follow-up data from the Multicenter Osteoarthritis (MOST) study (n = 1731) and the Osteoarthritis Initiative (OAI, n = 1925). Daily walking intensity was objectively assessed using accelerometer-enabled devices, and classified as; not walking (<1 steps/min), very-light (1-49 steps/min), light (50-100 steps/min), and moderate-to-vigorous (>100 steps/min). We defined slow gait during a 20-m walk, as <1 m/s and <1.2 m/s. Isotemporal substitution evaluated time-substitution effects on incident slow gait outcomes at 2-years. RESULTS: Replacing 20 min/day of not walking with walking at a moderate-to-vigorous intensity, demonstrated small to moderate reductions in the risk of developing a gait speed <1.0 m/s (Relative Risk [95% confidence interval (CI)]; MOST = 0.51 [0.27, 0.98], OAI = 0.21 [0.04, 0.98]), and <1.2 m/s (MOST = 0.73 [0.53, 1.00], OAI = 0.65 [0.36, 1.18]). However, only risk reductions for <1.0 m/s met statistical significance. Replacing not walking with very-light or light intensity walking was not associated with the risk of developing slow gait outcomes. CONCLUSION: When possible, walking at a moderate-to-vigorous intensity (>100 steps/min) may be best recommended in order to reduce the risk of developing critical slow gait speed among people with, or at high risk of knee OA.