A cfDNA methylation-based tissue-of-origin classifier for cancers of unknown primary.

Cancers of Unknown Primary (CUP) remains a diagnostic and therapeutic challenge due to biological heterogeneity and poor responses to standard chemotherapy. Predicting tissue-of-origin (TOO) molecularly could help refine this diagnosis, with tissue acquisition barriers mitigated via liquid biopsies. However, TOO liquid biopsies are unexplored in CUP cohorts. Here we describe CUPiD, a machine learning classifier for accurate TOO predictions across 29 tumour classes using circulating cell-free DNA (cfDNA) methylation patterns. We tested CUPiD on 143 cfDNA samples from patients with 13 cancer types alongside 27 non-cancer controls, with overall sensitivity of 84.6% and TOO accuracy of 96.8%. In an additional cohort of 41 patients with CUP CUPiD predictions were made in 32/41 (78.0%) cases, with 88.5% of the predictions clinically consistent with a subsequent or suspected primary tumour diagnosis, when available (23/26 patients). Combining CUPiD with cfDNA mutation data demonstrated potential diagnosis re-classification and/or treatment change in this hard-to-treat cancer group.

Conventional and unconventional T cell responses contribute to the prediction of clinical outcome and causative bacterial pathogen in sepsis patients.

Sepsis is characterised by a dysfunctional host response to infection culminating in life-threatening organ failure that requires complex patient management and rapid intervention. Timely diagnosis of the underlying cause of sepsis is crucial, and identifying those at risk of complications and death is imperative for triaging treatment and resource allocation. Here, we explored the potential of explainable machine learning models to predict mortality and causative pathogen in sepsis patients. By using a modelling pipeline employing multiple feature selection algorithms, we demonstrate the feasibility to identify integrative patterns from clinical parameters, plasma biomarkers and extensive phenotyping of blood immune cells. Whilst no single variable had sufficient predictive power, models that combined five and more features showed a macro area under the curve (AUC) of 0.85 to predict 90 day mortality after sepsis diagnosis, and a macro AUC of 0.86 to discriminate between Gram-positive and Gram-negative bacterial infections. Parameters associated with the cellular immune response contributed the most to models predictive of 90 day mortality, most notably, the proportion of T cells among PBMCs, together with expression of CXCR3 by CD4+ T cells and CD25 by mucosal-associated invariant T (MAIT) cells. Frequencies of Vδ2+ γδ T cells had the most profound impact on the prediction of Gram-negative infections, alongside other T cell-related variables and total neutrophil count. Overall, our findings highlight the added value of measuring the proportion and activation patterns of conventional and unconventional T cells in the blood of sepsis patients in combination with other immunological, biochemical and clinical parameters.

The effects of exercise and intra-articular injections versus exercise alone for the treatment of knee osteoarthritis: A scoping review of the evidence.

Objective: Current treatment for knee Osteoarthritis (OA) includes exercise and intra-articular injections with corticosteroid (CS), hyaluronic acid (HA), etc., which address OA-related pain and functional limitation. While these interventions can be given together, little is known about the efficacy of a multi-modal approach. The purpose of this scoping review is to examine studies that compare combining exercise and intra-articular knee injections to exercise alone for the management of knee OA. Methods: A search was performed using PubMed, CINAHL, and Clinicaltrials.gov with MeSH terms "knee osteoarthritis" AND "exercise" AND "injections". Abstracts were screened to meet inclusion criteria of both intervention groups including exercise and one group receiving an injection for treatment of knee OA. Full text articles were screened to meet inclusion criteria and rated using the Pedro Scale. Results: 11 studies that met inclusion criteria. The included studies utilized CS, hyaluronic acid (HA), and Bone Marrow Concentrate (BMC), botulinum toxin A, or a combination of dextrose and lidocaine injections. Most studies included supervised exercise interventions with all studies including strengthening of the quadriceps. CS and exercise compared to exercise alone showed similar improvements in pain. The HA injection studies yielded mixed results with two studies finding HA and exercise was not superior than exercise alone while two other studies found that HA and exercise were superior. Conclusion: There was a paucity of literature investigating multimodal approaches. Most of the included studies did not find superior effects of adding a knee injection to exercise compared to exercise alone for knee OA.

Concurrent Validity and Reliability of Video-Based Approach to Assess Physical Function in Adults with Knee Osteoarthritis.

OBJECTIVES: The aim of this study was to determine the concurrent validity and reliability of the Osteoarthritis Research Society International recommended performance-based tests delivered by video-based in adults with knee osteoarthritis. METHODS: Thirty-two participants (aged 40 to 70 years; 15 men) undertook assessments of 4 performance-based tests via both video-based (real-time and recorded) and face-to-face approaches, on the same day. Outcome measures were performance-based test and the number of technical issues encountered. The performance-based tests included the 40-Meter Fast-Paced Walk Test (velocity, m/s), the 30-Second Chair Stand Test (number of repetitions), the Stair Climb Test (time, seconds), and the Timed "Up & Go" Test (TUG; time, seconds). The Bland-Altman limit of agreement measures, standard error of measurement (SEM), coefficient of variation (CV), minimal detectable changes (MDCs), and bias (mean difference) were employed to analyse the concurrent validity between video-based and face-to-face approaches of the performance-based tests. Reliability was measured using intraclass correlation coefficients (ICC), CV, and SEM. RESULTS: A high degree of concurrent validity for the TUG (bias = -0.22), the 30-Second Chair Stand Test (bias = -0.22), the Stair Climb Test (bias = -0.31), and the 40-Meter Fast-Paced Walk Test (bias = -0.06) was found. SEM and CV values were within the acceptable level for concurrent validity. There was a high degree of reliability demonstrated for all tests analysed. ICC measures ranged from 0.95 to 1.00 for intrarater reliability, and from 0.95 to 0.99 for interrater reliability. CONCLUSIONS: Video-based assessment of physical performance tests is a valid and reliable tool for measuring physical function among adults with knee osteoarthritis via Microsoft Teams (Microsoft Corp, Redmond, WA, USA). IMPACT: Video-based assessment is a promising public health tool to measure physical function in adults with knee osteoarthritis.

The Association of Stair Climbing Behaviors With Hazard of All-Cause Mortality in Adults With or At Risk of Knee Osteoarthritis.

OBJECTIVE: To investigate the association of stair climbing difficulty and stair climbing frequency with the risk of all-cause mortality over 13 years in adults with or at high risk for knee OA. METHODS: We used data from the Osteoarthritis Initiative (OAI), a prospective cohort study of community-dwelling adults with or at high risk for symptomatic knee OA. The exposures were stair climbing difficulty and frequency, assessed at baseline using self-report questionnaires. The outcome was all-cause mortality, assessed from baseline through 13 years of follow-up. Kaplan-Meier survival curves and Cox proportional hazards regression were used to investigate the association between stair climbing exposures and all-cause mortality. RESULTS: Three hundred seven (6.81%) and 310 (6.84%) participants in the difficulty and frequency samples, respectively, died during 13 years of follow-up. Those who were limited in any capacity in terms of their stair climbing ability had 54% to 84% greater hazard of all-cause mortality, and those who climbed at least 7 flights of stairs per week had 38% lower hazard of all-cause mortality. CONCLUSION: Adults with or at high risk for knee OA who report difficulty with climbing stairs or who infrequently use stairs are at greater hazard of all-cause mortality. Stair climbing difficulty and frequency are simple to collect and changes may occur early in OA progression, allowing for early intervention. Brief questions about stair climbing behaviors can serve as a functional vital sign within the clinician's toolbox.

Low circulatory levels of total cholesterol, HDL-C and LDL-C are associated with death of patients with sepsis and critical illness: systematic review, meta-analysis, and perspective of observational studies.

BACKGROUND: Mechanistic studies have established a biological role of sterol metabolism in infection and immunity with clinical data linking deranged cholesterol metabolism during sepsis with poorer outcomes. In this systematic review we assess the relationship between biomarkers of cholesterol homeostasis and mortality in critical illness. METHODS: We identified articles by searching a total of seven electronic databases from inception to October 2023. Prospective observational cohort studies included those subjects who had systemic cholesterol (Total Cholesterol (TC), HDL-C or LDL-C) levels assessed on the first day of ICU admission and short-term mortality recorded. Meta-analysis and meta-regression were used to evaluate overall mean differences in serum cholesterol levels between survivors and non-survivors. Study quality was assessed using the Newcastle-Ottawa Scale. FINDINGS: From 6469 studies identified by searches, 24 studies with 2542 participants were included in meta-analysis. Non-survivors had distinctly lower HDL-C at ICU admission -7.06 mg/dL (95% CI -9.21 to -4.91, p < 0.0001) in comparison with survivors. Corresponding differences were also seen less robustly for TC -21.86 mg/dL (95% CI -31.23 to -12.49, p < 0.0001) and LDL-C -8.79 mg/dL (95% CI, -13.74 to -3.83, p = 0.0005). INTERPRETATION: Systemic cholesterol levels (TC, HDL-C and LDL-C) on admission to critical care are inversely related to mortality. This finding is consistent with the notion that inflammatory and metabolic setpoints are coupled, such that the maladaptive-setpoint changes of cholesterol in critical illness are related to underlying inflammatory processes. We highlight the potential of HDL-biomarkers as early predictors of severity of illness and emphasise that future research should consider the metabolic and functional heterogeneity of HDLs. FUNDING: EU-ERDF-Welsh Government Ser Cymru programme, BBSRC, and EU-FP7 ClouDx-i project (PG).

Detection of methandienone and its metabolites in equine urine, plasma and hair following a multidose oral administration.

Methandienone is an anabolic-androgenic steroid that is prohibited in equine sports due to its potential performance enhancing properties. Metabolism and detection of methandienone in equine urine have been investigated comprehensively in literature; however, there is a limited knowledge about its metabolites in equine plasma and no information about its detection in equine hair. Following a multi-dose oral administration of methandienone to two Thoroughbred horses, 17-epimethandienone, methyltestosterone, two mono-hydroxylated, two di-hydroxylated and three 17α-methylandrostanetriol metabolites were detected in plasma. The majority of these were present as free analytes, whilst the mono-hydroxylated metabolites and one isomer of 17α-methylandrostanetriol were partially conjugated. Estimated peak concentrations of methandienone were 6,000 and 11,100 pg/ml; meanwhile, they were 25.4 and 40.5 pg/ml for methyltestosterone. The most abundant analyte in the post-administration plasma samples of both horses was the mono-hydroxylated metabolite; however, the parent compound provided the longest detection (up to 96 h). Screening analysis of hair enabled the detection of methandienone in mane hair samples only, for up to 3 months. Its mono- and di-hydroxylated metabolites were detected with greater peak responses for up to 6 months post-administration in both mane and tail samples, showing that these metabolites could be better analytical targets for hair analysis when administered orally. A follow-up methodology with an extensive wash procedure confirmed the presence of methandienone and its metabolites in a number of post-administration hair samples. Final wash samples were also analysed to assess the degree of internal incorporation (via bloodstream) against possible external deposition (via sweat/sebum).

Does Physical Activity Confound Race Differences in Osteoarthritis-Related Functional Limitation?

OBJECTIVE: This study sought to determine the extent to which physical activity confounds the relation between race and the incidence of osteoarthritis (OA)-related functional limitation. METHODS: OA Initiative study participants with or at increased risk of knee OA who wore an accelerometer were included. Race was self-reported. Average time spent in moderate to vigorous physical activity (minutes per day) based on ActiGraph uniaxial accelerometer data was assessed. Functional limitation was based on the following: (1) inability to achieve a community walking speed (1.2 m/s) standard, (2) slow walking speed (<1.0 m/s), and (3) low physical functioning based on a Western Ontario and McMaster Universities OA Index (WOMAC) physical function score greater than 28 of 68. RESULTS: African American (AA) participants (n = 226), compared with White participants (n = 1348), had a higher likelihood of developing functional limitation based on various measures. When adjusted for time in moderate to vigorous physical activity, the association between AA race and inability to walk a community walking speed slightly decreased (from relative risk [RR] 2.15, 95% confidence interval [95% CI] 1.64-2.81, to RR 1.99, 95% CI 1.51-2.61). Association between AA race and other measures of functional limitation mildly decreased (slow walking speed: from RR 2.06, 95% CI 1.40-3.01, to RR 1.82, 95% CI 1.25-2.63; low physical functioning: from RR 3.44, 95% CI 1.96-6.03, to RR 3.10, 95% CI 1.79-5.39). When further adjusted for demographic and other clinical variables, only the association between race and low physical functioning (WOMAC) significantly decreased and no longer met statistical significance. CONCLUSION: Greater physical activity is unlikely to completely make up for race differences in OA-related functional limitation, and other barriers to health equity need to be addressed.

Ultra-narrow inhomogeneous spectral distribution of telecom-wavelength vanadium centres in isotopically-enriched silicon carbide.

Spin-active quantum emitters have emerged as a leading platform for quantum technologies. However, one of their major limitations is the large spread in optical emission frequencies, which typically extends over tens of GHz. Here, we investigate single V4+ vanadium centres in 4H-SiC, which feature telecom-wavelength emission and a coherent S = 1/2 spin state. We perform spectroscopy on single emitters and report the observation of spin-dependent optical transitions, a key requirement for spin-photon interfaces. By engineering the isotopic composition of the SiC matrix, we reduce the inhomogeneous spectral distribution of different emitters down to 100 MHz, significantly smaller than any other single quantum emitter. Additionally, we tailor the dopant concentration to stabilise the telecom-wavelength V4+ charge state, thereby extending its lifetime by at least two orders of magnitude. These results bolster the prospects for single V emitters in SiC as material nodes in scalable telecom quantum networks.

Face-to-face and telerehabilitation delivery of circuit training have similar benefits and acceptability in patients with knee osteoarthritis: a randomised trial.

QUESTION: Is periodised circuit training delivered via a telerehabilitation model of care as effective as the same training applied face-to-face for improving pain intensity, physical function, muscle strength, pain catastrophising, body composition, intermuscular adipose tissue and muscle architecture in people with knee osteoarthritis (OA)? DESIGN: Randomised controlled, non-inferiority trial with concealed allocation, blinded assessors and intention-to-treat analysis. PARTICIPANTS: One hundred adults aged ≥ 40 years with knee OA and pain for ≥ 3 months, with current pain ≥ 40 mm on a 100-mm visual analogue scale (VAS). INTERVENTION: The experimental group received 14 weeks of circuit training delivered via telerehabilitation using video recordings, followed by periodic phone calls in order to motivate and instruct participants. The control group received the same circuit training program in a face-to-face format. OUTCOME MEASURES: The primary outcomes were pain VAS and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) physical function subscale, measured at 14 weeks. Secondary outcomes included objective physical function, strength, pain catastrophising and morphological measures (muscle architecture and thigh and body composition). Outcomes were measured at 14 and 26 weeks. RESULTS: Periodised circuit training delivered via telerehabilitation had equivalent effects to face-to-face delivery for pain intensity, physical function, muscle strength, pain catastrophising, thigh composition, intermuscular adipose tissue and muscle architecture. Whole body composition did not change appreciably in either group. Adherence to the training was excellent and participants in each group reported good perceptions of their randomised intervention. CONCLUSION: A periodised circuit training protocol can be delivered to people with knee OA in their own homes, using available technology while maintaining high levels of acceptability. More importantly, telerehabilitation appears to cause non-inferior physical and functional outcomes to face-to-face rehabilitation programs. TRIAL REGISTRATION: RBR-662hn2.

Corticosteroid Injections for Symptomatic Treatment of Osteoarthritis of the Knee: A Pilot Blinded Randomized Trial.

OBJECTIVE: To quantify the effect of corticosteroids compared to lidocaine-only injections over 12 weeks among patients with knee osteoarthritis (KOA). METHODS: Participants with KOA were randomized to receive a knee injection of methylprednisolone acetate 1 mL (40 mg) plus 2 mL lidocaine (1%) or 1 mL saline and 2 mL lidocaine. Participants and providers were blinded to treatment allocation using an opacified syringe. The outcome was the average change from baseline of the total Knee Injury and Osteoarthritis Outcome Score (KOOS) (range 0-100) assessed at 2-week intervals over 12 weeks. Participants received KOOS questionnaires on their smartphones through a web-based platform. We used linear mixed-effects regressions with robust variance estimators to evaluate the association between the intervention and change in KOOS total and subscales (ClinicalTrials.gov identifier NCT03835910; registered 2019-02-11). RESULTS: Of the 33 randomized participants, 31 were included in the final analysis. The predicted mean (SE) change in total KOOS over the 12-week follow-up was 9.4 (3.2) in the corticosteroids arm versus -1.3 (1.4) in the control arm (P = 0.003). Of participants, 47% achieved change as large as the minimal clinically important difference (16 units) in the intervention arm compared to 6% of participants in the lidocaine arm. Further, there were greater improvements in the intervention arm for KOOS subscales and for Patient Reported Outcomes Measurement Information System (PROMIS) assessments of pain intensity, behavior, and interference. CONCLUSION: Corticosteroid injections demonstrated clinically meaningful improvements in KOA symptoms over 12 weeks of follow-up. These data support larger studies to better quantify short-term benefits.

Systematic review of preoperative n-3 fatty acids in major gastrointestinal surgery.

Objectives: Perioperative nutrition aims to replenish nutritional stores before surgery and reduce postoperative complications. 'Immunonutrition' (including omega-3 fatty acids) may modulate the immune system and attenuate the postoperative inflammatory response. Hitherto, immunonutrition has overwhelmingly been administered in the postoperative period-however, this may be too late to provide benefit. Design: A systematic literature search using MEDLINE and EMBASE for randomized controlled trials (RCTs). Setting: Perioperative major gastrointestinal surgery. Participants: Patients undergoing major gastrointestinal surgery. Interventions: Omega-3 fatty acid supplementation commenced in the preoperative period, with or without continuation into postoperative period. Main outcome measures: The effect of preoperative omega-3 fatty acids on inflammatory response and clinical outcomes. Results: 833 studies were identified. After applying inclusion and exclusion criteria, 12 RCTs, involving 1456 randomized patients, were included. Ten articles exclusively enrolled patients with cancer. Seven studies used a combination of EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) as the intervention and five studies used EPA alone. Eight out of 12 studies continued preoperative nutritional support into the postoperative period.Of the nine studies reporting mortality, no difference was seen. Duration of hospitalisation ranged from 4.5 to 18 days with intervention and 3.5 to 23.5 days with control. Omega-3 fatty acids had no effect on postoperative C-reactive protein and the effect on cytokines (including tumor necrosis factor-α, interleukin (IL)-6 and IL-10) was inconsistent. Ten of the 12 studies had low risk of bias, with one study having moderate bias from allocation and blinding. Conclusions: There is insufficient evidence to support routine preoperative omega-3 fatty acid supplementation for major gastrointestinal surgery, even when this is continued after surgery. PROSPERO registration number: CRD42018108333.

Hospitalizations and Cost of Inpatient Care for Physical Diseases in Survivors of Childhood Cancer in Western Australia: A Longitudinal Matched Cohort Study.

BACKGROUND: The long-term effects of childhood cancer are unclear in the Australian context. We examined hospitalization trends for physical diseases and estimated the associated inpatient care costs in all 5-year childhood cancer survivors (CCS) diagnosed in Western Australia (WA) from 1982 to 2014. METHODS: Hospitalization records for 2,938 CCS and 24,792 comparisons were extracted from 1987 to 2019 (median follow-up = 12 years, min = 1, max = 32). The adjusted hazard ratio (aHR) of hospitalization with 95% confidence intervals (CI) was estimated using the Andersen-Gill model for recurrent events. The cumulative burden of hospitalizations over time was assessed using the mean cumulative count method. The adjusted mean cost of hospitalization was estimated using the generalized linear models. RESULTS: We identified a higher risk of hospitalization for all-cause (aHR, 2.0; 95% CI, 1.8-2.2) physical disease in CCS than comparisons, with the highest risk for subsequent malignant neoplasms (aHR, 15.0; 95% CI, 11.3-19.8) and blood diseases (aHR, 6.9; 95% CI, 2.6-18.2). Characteristics associated with higher hospitalization rates included female gender, diagnosis with bone tumors, cancer diagnosis age between 5 and 9 years, multiple childhood cancer diagnoses, multiple comorbidities, higher deprivation, increased remoteness, and Indigenous status. The difference in the mean total hospitalization costs for any disease was significantly higher in survivors than comparisons (publicly funded $11,483 United States Dollar, P < 0.05). CONCLUSIONS: The CCS population faces a significantly higher risk of physical morbidity and higher cost of hospital-based care than the comparisons. IMPACT: Our study highlights the need for long-term follow-up healthcare services to prevent disease progression and mitigate the burden of physical morbidity on CCS and hospital services.

L-band radar quantifies major disturbance of birds by fireworks in an urban area.

Fireworks and other pyrotechnics are acknowledged as sources of disturbance to wildlife, with evidence that many species react adversely to their sight and sound at discharge. However, how firework releases impact wildlife within a city landscape is poorly understood. Here, we explore the effect of fireworks on urban birds using an L-band staring radar (90-degree sector out to a 5 km range) to capture bird activity derived from flight tracks (i.e. 3D visualisation of individual flying birds built from radar detections) within the city of Birmingham, UK. Comparing the tracks between baseline periods with no fireworks and periods where fireworks are commonly discharged using a null model indicated that birds flew at higher elevations during firework periods (standardised effect sizes of 17.11, 26.54 and 5.83, for Diwali, Bonfire Night, and New Year's Eve, respectively). Birds also flew in more significant numbers (standardised effect sizes of 23.41, 7.98 and 7.19 for Diwali, Bonfire Night, and New Year's Eve, respectively). Therefore, bird activity was elevated during firework events at a time of night when many would otherwise be roosting. Such disturbance may have implications for avian biology since large public firework events occur at colder times of the year in the UK when birds have elevated thermoregulatory costs.

LC-MS/MS analysis of erythrocyte phosphatidylethanol in haematocrit-corrected whole blood versus isolated erythrocytes: Results of an inter-laboratory comparison.

Phosphatidylethanol (PEth) is a non-oxidative metabolite of alcohol (ethanol), which is a sensitive and specific indicator of historic ethanol consumption. Although PEth production from ethanol is catalysed by the ubiquitous enzyme phospholipase D, it resides mainly within the erythrocyte compartment of the blood. PEth analysis has been reported in different preparations of whole blood, representing one of the barriers of inter-laboratory comparisons. We previously reported that expressing PEth concentrations in terms of blood erythrocyte content is more sensitive than whole blood volume, and haematocrit-corrected liquid whole blood calculations of erythrocyte PEth and isolated erythrocyte PEth concentrations are comparable when assayed under identical analytical conditions. Acceptance of a clinical diagnostic assay by accreditation bodies requires proficiency testing with a third-party analytical facility. To explore different blood preparations within the same inter-laboratory program, 60 matched isolated erythrocyte or liquid whole blood specimens were tested at three laboratories. Laboratories measured PEth by liquid chromatography-tandem mass spectrometry (LC-MS/MS), two using isolated erythrocytes, while the third used liquid whole blood, which underwent haematocrit correction before comparison with isolated erythrocyte PEth concentrations. There was acceptable consensus (87%) among laboratories to detect PEth around a cut-off of 35 µg/L of erythrocytes. Each laboratory correlated well with the group average PEth concentration (R > 0.98) for each specimen above the cut-off. Differences were observed between laboratories in bias, which did not affect comparable sensitivity at the selected cut-off. This work demonstrates the feasibility of an inter-laboratory comparison for erythrocyte PEth analysis across different LC-MS/MS methodologies and different blood preparations.