Initial Validation of a Modified MRI Scoring System for Assessing Outcomes after Single-Surface Osteochondral Shell Allograft Transplantation in the Knee

The Osteochondral Allograft Magnetic Resonance Imaging Scoring System (OCAMRISS) provides a reproducible method for imaging-based grading for osteochondral allograft (OCA) transplants. However, the OCAMRISS does not account for larger whole-surface OCA shell grafts, and has not been validated for assessing outcomes after shell OCA transplantation. Therefore, the objective of this study was to evaluate a modified OCAMRISS for assessing single-surface shell OCAs in the knee based on strength of correlations for a modified OCAMRISS score with graft success and patient-reported outcomes for pain and function. With institutional review board approval and informed patient consent, patients who underwent large single-surface shell OCA transplantation and magnetic resonance imaging (MRI) exams at 1-year postsurgery were identified from a prospectively enrolled registry. All patients with a minimum of 2 years of clinical follow-up were included in the present study. A modified OCAMRISS, as well as assessment of the percentage of OCA bone incorporation, was used to score each knee. Two radiologists, blinded to patient demographics and outcomes, reviewed all MRIs together to determine a consensus score for each category and %-incorporation for each OCA. Thirteen patients (7 F, 6 M; mean age = 29.8 ± 9.4; mean body mass index = 27.1 ± 5.8); 8 medial femoral condyle, 4 patella, and 1 medial tibial plateau shell OCAs were evaluated. Mean modified OCAMRISS score was 5.2 ± 2.8, range (2–12) and %-integration was 72.7 ± 33.8, range (0–100). Moderate to strong correlations were noted for 1-year modified OCAMRISS total score with final follow-up (FFU) visual analog scale (VAS) pain (r = +0.58) and Single Assessment Numeric Evaluation (SANE) function (r = −0.7) scores, and for 1-year %-incorporation with FFU VAS pain (r = −0.76) and SANE function (r = +0.83) scores. The modified OCAMRISS total score and %-incorporation assessments determined at 1 year following single-surface shell OCA transplantation correlate well with initial patient outcomes and have clinical applicability for monitoring patients after large-shell OCA transplants in the knee.

decoupleR: Ensemble of computational methods to infer biological activities from omics data

Summary: Many methods allow us to extract biological activities from omics data using information from prior knowledge resources, reducing the dimensionality for increased statistical power and better interpretability. Here, we present decoupleR, a Bioconductor package containing computational methods to extract these activities within a unified framework. decoupleR allows us to flexibly run any method with a given resource, including methods that leverage mode of regulation and weights of interactions. Using decoupleR, we evaluated the performance of methods on transcriptomic and phospho-proteomic perturbation experiments. Our findings suggest that simple linear models and the consensus score across methods perform better than other methods at predicting perturbed regulators. Availability and Implementation: decoupleR is open source available in Bioconductor (https://www.bioconductor.org/packages/release/bioc/html/decoupleR.html). The code to reproduce the results is in Github (https://github.com/saezlab/decoupleR_manuscript) and the data in Zenodo (https://zenodo.org/record/5645208).

Biometric covariates and outcome in COVID-19 patients: are we looking close enough?

Background The impact of biometric covariates on risk for adverse outcomes of COVID-19 disease was assessed by numerous observational studies on unstratified cohorts, which show great heterogeneity. However, multilevel evaluations to find possible complex, e.g. non-monotonic multi-variate patterns reflecting mutual interference of parameters are missing. We used a more detailed, computational analysis to investigate the influence of biometric differences on mortality and disease evolution among severely ill COVID-19 patients. Methods We analyzed a group of COVID-19 patients requiring Intensive care unit (ICU) treatment. For further analysis, the study group was segmented into six subgroups according to Body mass index (BMI) and age. To link the BMI/age derived subgroups with risk factors, we performed an enrichment analysis of diagnostic parameters and comorbidities. To suppress spurious patterns, multiple segmentations were analyzed and integrated into a consensus score for each analysis step. Results We analyzed 81 COVID-19 patients, of whom 67 required mechanical ventilation (MV). Mean mortality was 35.8%. We found a complex, non-monotonic interaction between age, BMI and mortality. A subcohort of patients with younger age and intermediate BMI exhibited a strongly reduced mortality risk (p < 0.001), while differences in all other groups were not significant. Univariate impacts of BMI or age on mortality were missing. Comparing MV with non-MV patients, we found an enrichment of baseline CRP, PCT and D-Dimers within the MV group, but not when comparing survivors vs. non-survivors within the MV patient group. Conclusions The aim of this study was to get a more detailed insight into the influence of biometric covariates on the outcome of COVID-19 patients with high degree of severity. We found that survival in MV is affected by complex interactions of covariates differing to the reported covariates, which are hidden in generic, non-stratified studies on risk factors. Hence, our study suggests that a detailed, multivariate pattern analysis on larger patient cohorts reflecting the specific disease stages might reveal more specific patterns of risk factors supporting individually adapted treatment strategies.

Large-scale implementation of stroke early supported discharge: the WISE realist mixed-methods study

Background In England, the provision of early supported discharge is recommended as part of an evidence-based stroke care pathway. Objectives To investigate the effectiveness of early supported discharge services when implemented at scale in practice and to understand how the context within which these services operate influences their implementation and effectiveness. Design A mixed-methods study using a realist evaluation approach and two interlinking work packages was undertaken. Three programme theories were tested to investigate the adoption of evidence-based core components, differences in urban and rural settings, and communication processes. Setting and interventions Early supported discharge services across a large geographical area of England, covering the West and East Midlands, the East of England and the North of England. Participants Work package 1: historical prospective patient data from the Sentinel Stroke National Audit Programme collected by early supported discharge and hospital teams. Work package 2: NHS staff (n = 117) and patients (n = 30) from six purposely selected early supported discharge services. Data and main outcome Work package 1: a 17-item early supported discharge consensus score measured the adherence to evidence-based core components defined in an international consensus document. The effectiveness of early supported discharge was measured with process and patient outcomes and costs. Work package 2: semistructured interviews and focus groups with NHS staff and patients were undertaken to investigate the contextual determinants of early supported discharge effectiveness. Results A variety of early supported discharge service models had been adopted, as reflected by the variability in the early supported discharge consensus score. A one-unit increase in early supported discharge consensus score was significantly associated with a more responsive early supported discharge service and increased treatment intensity. There was no association with stroke survivor outcome. Patients who received early supported discharge in their stroke care pathway spent, on average, 1 day longer in hospital than those who did not receive early supported discharge. The most rural services had the highest service costs per patient. NHS staff identified core evidence-based components (e.g. eligibility criteria, co-ordinated multidisciplinary team and regular weekly multidisciplinary team meetings) as central to the effectiveness of early supported discharge. Mechanisms thought to streamline discharge and help teams to meet their responsiveness targets included having access to a social worker and the quality of communications and transitions across services. The role of rehabilitation assistants and an interdisciplinary approach were facilitators of delivering an intensive service. The rurality of early supported discharge services, especially when coupled with capacity issues and increased travel times to visit patients, could influence the intensity of rehabilitation provision and teams’ flexibility to adjust to patients’ needs. This required organising multidisciplinary teams and meetings around the local geography. Findings also highlighted the importance of good leadership and communication. Early supported discharge staff highlighted the need for collaborative and trusting relationships with patients and carers and stroke unit staff, as well as across the wider stroke care pathway. Limitations Work package 1: possible influence of unobserved variables and we were unable to determine the effect of early supported discharge on patient outcomes. Work package 2: the pragmatic approach led to ‘theoretical nuggets’ rather than an overarching higher-level theory. Conclusions The realist evaluation methodology allowed us to address the complexity of early supported discharge delivery in real-world settings. The findings highlighted the importance of context and contextual features and mechanisms that need to be either addressed or capitalised on to improve effectiveness. Trial registration Current Controlled Trials ISRCTN15568163. Funding This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 9, No. 22. See the NIHR Journals Library website for further project information.

Comparison of Angiographic Dissection Classification Systems in the Femoropopliteal Arteries Using IVUS Validation and Reliability Testing

Purpose: Objective assessment of dissection severity is difficult. Recognition of this has led to the creation of classification systems. This study investigated the performance of the National Heart Lung and Blood Institute (NHLBI) and Kobayashi systems at differentiating severity of femoropopliteal dissection using intravascular ultrasound (IVUS) as the reference standard. Comparison between the 2 systems and the inter- and intra-observer reliability were also investigated. Materials and Methods: Angiographic and IVUS imaging was assessed in 51 cases sourced from a RCT investigating the use of IVUS in femoropopliteal disease. A total of 2 readers independently scored the angiography images according to NHLBI and Kobayashi dissection classification systems and a consensus score was obtained for each system in each case. The NHLBI classification was condensed into 3 grades of dissection to allow comparison between systems. Dissection length, dissection arc, minimum lumen area, and lumen area stenosis were obtained from the IVUS imaging. IVUS parameters were compared between grades of severity for both systems. Agreement in grading between the systems was assessed and IVUS parameters for each level of dissection severity were compared between systems. Inter and intra-observer agreement tested for each system. Results: Dissection was present on IVUS in 92.2% (47/51) of cases and angiography identified 78.7% (37/47) of these. No difference was present in any IVUS parameters between mild and severe dissections with either classification system. No difference in IVUS findings was present for the same grades of dissection between systems. The 2 systems agreed on severity grade in 47 of 51 cases. The inter-observer agreement was for NHLBI was k=0.549 and k=0.627 for Kobayashi. Intra-observer agreement for NHLBI was k=0.633 and k=0.633 and for Kobayashi was k=0.657 and k=0.297. Conclusion: The lack of difference in IVUS parameters between mild and severe dissection for the NHLBI and Kobayashi systems raises doubts about their ability to effectively differentiate dissection severity. Weak to moderate reliability suggests that variability in interpreting dissection may be higher than acceptable. IVUS imaging is more sensitive for detecting dissection than angiography and research is required to establish the value of adding IVUS to dissection classification systems.

Oligomeric Formulas in Surgery: A Delphi and Consensus Study

Nutritional management of patients with intestinal failure often includes the use of oligomeric formulas. Implementing the use of oligomeric formulas in surgical patients with maldigestion or malabsorption could be a nutritional strategy to be included in clinical protocols. We aim to generate knowledge from a survey focused on the effectiveness of nutritional therapy with oligomeric formulas with Delphi methodology. Each statement that reached an agreement consensus among participants was defined as a median consensus score ≥7 and as an interquartile range ≤3. The use of oligomeric formulas in surgical patients, starting enteral nutrition in the post-operative phase in short bowel syndrome and in nonspecific diarrhea after surgical procedures, could improve nutritional therapy implementation. Stakeholders agreed that early jejunal enteral nutrition with oligomeric formula is more effective compared to intravenous fluid therapy and it is useful in patients undergoing upper gastro-intestinal tract major surgery when malabsorption or maldigestion is suspected. Finally, oligomeric formulas may be useful when a feeding tube is placed distally to the duodenum. This study shows a practical approach to the use of oligomeric formulas in surgical patients with intestinal disorders and malabsorption, and it helps clinicians in the decision-making process.

P199 The reliability of using ultrasound for the detection of hypoechogenicity of enthesitis in patients with spondyloarthropathies

Background/Aims Enthesitis, which is the inflammation of the entheses area where the tendon or ligaments are attached into the bone, is considered a hallmark and pathological feature for spondyloarthropathies (SpA). The lower limb entheses are more prone to being affected than the upper extremity enthesis, the most common one is Achilles tendon where heel enthesitis is considered the most frequent finding in SpA patients. Ultrasound is widely used by rheumatologists because it has higher sensitivity and specificity in detecting enthesitis compared with clinical assessment. The abnormal characteristics of enthesitis in greyscale ultrasound includes the hypoechoic area at the insertion or body of the tendon due to the loss of the normal fibrillar pattern, increase in the tendon thickness, bone erosion, calcification and increase in Dopplar signals. Although ultrasound has many advantages compared with other imaging modalities, it is operator-dependent and the diagnosis is exposed to the subjectivity of the observer, which leads to the variability in defining the abnormal features of enthesitis. Using static ultrasound images of Achilles tendon entheses of patients with SpA, we first determined the intra- and inter-observer reliability of grading ‘hypoechogenicity’ using a panel of readers and second, compared a computerised pixel counting method against an expert consensus score to determine the level of agreement between approaches. Methods Six participants (rheumatologists and sonographer) with experience in ultrasound scored the presence of hypoechogenicity in 100 static images of Achilles tendon entheses of patients with SpA. Two scoring systems were used- an OMERACT derived SQ system (0-3) of the whole enthesis and binary score system of the distal 2mm (0-1). The intra-class correlation coefficient (ICC) and Cohen's kappa was used to assess inter-observer reliability. The ImageJ software was used to measure the mean grey values (MGV) of the pixels within the enthesis. Results The inter-observer reliability was good for using the SQ score (ICC 0.780 (95% CI 0.691-0.849) and moderate for the binary score (ICC 0.632 (95% CI 0.490-0.745)). There was no match between the results from the quantitative score of the pixels MGV and the expert semi-quantitative score. Conclusion This study is novel as in that it has specifically evaluated the scoring of hypoechogenicity within the entheses of patients with SpA. It has demonstrated variation in scoring between observers and highlighted the challenges of image interpretation. A lack of correlation of expert scoring with the manual pixel MGV was limited by the image artefacts and different machine settings which may have implications as we work towards future AI systems. Disclosure A.S. Aldahes: None. R. Wakefield: None. K. Smith: None.

Application of the OMERACT Grey-scale Ultrasound Scoring System for salivary glands in a single-centre cohort of patients with suspected Sjögren’s syndrome

AimTo describe salivary gland involvement in patients suspected of Sjögren’s syndrome (SS) using the OMERACT Ultrasound Scoring System for SS. Next, using different ultrasound cut-offs, to assess the performance of the scoring system for diagnosis and fulfilment of 2016 ACR/EULAR SS classification criteria.MethodsAll patients referred to our department with a suspicion of SS in a 12-month period were included. All underwent grey-scale ultrasound of the parotid and submandibular glands prior to clinical examination, Schirmer’s test, unstimulated salivary flow, blood samples including autoantibody analysis. Labial biopsy was performed according to clinicians’ judgement. Images of the four glands were scored 0–3 according to the scoring system and a consensus score was obtained using a developed ultrasound atlas.ResultsOf the 134 patients included in the analysis, 43 were diagnosed with primary SS (pSS) and all fulfilled the 2016 American College of Rheumatology (ACR)/EULAR classification criteria. More patients with pSS compared with non-pSS had score ≥2 in at least one gland (72% vs 13%; p<0.001). In patients with score ≥2 in any gland, significantly more had positive autoantibodies, sialometry, Schirmer’s test and positive labial biopsy compared with those with scores ≤1. The best ultrasound cut-off value for diagnosing pSS was ≥1 gland with a score ≥2 (sensitivity=0.72, specificity=0.91).ConclusionThe OMERACT Ultrasound Scoring System showed good sensitivity (0.72) and excellent specificity (0.91) for fulfilling 2016 ACR/EULAR criteria using cut-off score >2 in at least one gland. Our data supports the use of ultrasound for diagnosing pSS and supports incorporation of ultrasound in the classification criteria.

Microwave Assisted Synthesis of Quinoline Fused Benzodiazepines as Anxiolytic and Antimicrobial Agents

In the present study, an efficient, facile and green protocol for synthesis of quinoline fused 1,4-benzodiazepine (4a-j) by microwave irradiated condensation of 6/7/8-substituted 3-bromomethyl- 2-chloro-quinoline (3a-j) obtained from 2-chloro 6/7/8-substituted quinoline-3-carbaldehyde (1a-j) with 1, 2-phenylenediamine was developed. Surflex docking studies with K+ channel is one of the physiological targets and inhibition, which plays a role in the pathophysiology of depression revealed that all these compounds show consensus score in the range 2.71-3.68 indicating the summary of all forces of interaction. Further, compounds 4d, 4g and 4i exhibited potent antibacterial activity

Biometric covariates and outcome in COVID-19 patients: Are we looking close enough?

BackgroundThe impact of biometric covariates on risk for adverse outcomes of COVID-19 disease was assessed by numerous observational studies on unstratified cohorts, which show great heterogeneity. However, multilevel evaluations to find possible complex, e. g. non-monotonic multi-variate patterns reflecting mutual interference of parameters are missing. We used a more detailed, computational analysis to investigate the influence of biometric differences on mortality and disease evolution among severely ill COVID-19 patients.MethodsWe analyzed a group of COVID-19 patients requiring Intensive care unit (ICU) treatment. For further analysis, the study group was segmented into six subgroups according to BMI and age. To link the BMI/age derived subgroups with risk factors, we performed an enrichment analysis of diagnostic parameters and comorbidities. To suppress spurious patterns, multiple segmentations were analyzed and integrated into a consensus score for each analysis step.ResultsWe analyzed 81 COVID-19 patients, of whom 67 required MV. Mean mortality was 35.8 %. We found a complex, non-monotonic interaction between age, BMI and mortality. A subcohort of patients with younger age and intermediate BMI exhibited a strongly reduced mortality risk (p < 0.001), while differences in all other groups were not significant. Univariate impacts of BMI or age on mortality were missing. Comparing MV with non-MV patients, we found an enrichment of baseline CRP, PCT and D-Dimers within the MV-group, but not when comparing survivors vs. non-survivors within the MV patient group.ConclusionsThe aim of this study was to get a more detailed insight into the influence of biometric covariates on the outcome of COVID-19 patients with high degree of severity. We found that survival in MV is affected by complex interactions of covariates differing to the reported covariates, which are hidden in generic, non-stratified studies on risk factors. Hence, our study suggests that a detailed, multivariate pattern analysis on larger patient cohorts reflecting the specific disease stages might reveal more specific patterns of risk factors supporting individually adapted treatment strategies.