Clinical Scores Research Articles

P816 Baseline disease severity of patients with Ulcerative Colitis influences rapid symptom relief under filgotinib treatment: post hoc analysis of the phase 2b/3 SELECTION study

Abstract Background Filgotinib (FIL) is an oral, once-daily, Janus kinase 1 preferential inhibitor approved in Europe and Japan for the treatment of ulcerative colitis (UC). A recent analysis of SELECTION trial data (NCT02914522) showed rapid and sustained improvements in UC symptoms with FIL 200 mg (FIL200) treatment in patients with moderate-to-severe UC.1 Here we assess symptomatic remission rates over time with FIL200 induction treatment according to baseline UC disease severity (partial Mayo Clinic Score [pMCS]). Methods SELECTION was a phase 2b/3 randomized, double-blind, placebo-controlled study. Patients aged 18–75 years were randomized (2:2:1) to receive FIL200, FIL 100 mg or placebo once daily for 11 weeks in induction study A (biologic-naive patients) or induction study B (biologic-experienced patients). In this post hoc analysis, proportions of patients with symptomatic remission (Mayo rectal bleeding sub-score of 0 and Mayo stool frequency sub-score of ≤ 1), from days 2 to 15 and weeks 2 to 10 of the induction study, were analysed at each timepoint by baseline pMCS (pMCS ≥7 and pMCS <7 [cut-off previously used for severe and moderate disease, respectively]2). Symptomatic remission rates were compared between the pMCS ≥7 and pMCS <7 groups within the FIL200 and placebo arms using a Cochran–Mantel–Haenszel test adjusted by study randomization stratification factors. Nominal p values <0.05 were considered statistically significant. Results At day 2, symptomatic remission rates with FIL200 treatment were significantly higher in patients with baseline pMCS <7 than in those with baseline pMCS ≥7 (8.4% vs 1.1%, p=0.009 [induction study A]; 8.8% vs 0.7%, p=0.004 [induction study B]) (Figure A and B). From days 2 to 15, symptomatic remission rates increased in both groups and, except for day 7 for induction study A and day 9 for induction study B, continued to be significantly higher in those with baseline pMCS <7. From week 2, symptomatic remission rates with FIL200 treatment generally continued to increase in both pMCS ≥7 and pMCS <7 groups (Figure C and D). By week 10, symptomatic remission rates with FIL200 treatment were no longer significantly different between those with baseline pMCS <7 and those with baseline pMCS ≥7 (54.8% vs 43.3%, p=0.124 [induction study A]; 39.5% vs 26.4%, p=0.099 [induction study B]). Conclusion Symptomatic response to FIL200 occurs more rapidly in patients with lower UC disease severity than in those with higher UC disease severity. However, converging response rates over 10 weeks of treatment leads to symptomatic remission regardless of baseline UC disease severity.

P280 Comparative responsiveness of disease activity indices in moderately-to-severely active Ulcerative Colitis: a post-hoc analysis of the UNIFI trial

Abstract Background Clinical, endoscopic, histological, and composite instruments are used to measure disease activity in ulcerative colitis (UC). We compared responsiveness of the Mayo Clinic Score (MCS), modified Mayo Clinic Score (mMS), partial Mayo Clinic Score (pMS), Robarts Histopathology Index (RHI), and UC-100 score after treatment with ustekinumab in patients with moderately-to-severely active UC. Methods Publicly available data from the phase 3 UNIFI induction trial (NCT02407236) comparing the efficacy and safety of ustekinumab versus placebo in patients with moderate-to-severe UC were obtained from Vivli (Vivli ID #7549) and Yale University Open Data Access Project (#2021-4848). Post-hoc analyses were performed on patient level data to ascertain outcomes of interest. Treatment assignment was the criterion for change in evaluation of responsiveness, which was quantified using the probability of a treated patient having a larger change than a placebo patient (win probability [WinP]) and estimated using nonparametric methods. Extent of responsiveness was interpreted according to Cohen’s benchmarks as very small (WinP<0.56); small (0.56≤ WinP<0.64); medium (0.64≤ WinP<0.71); and large (WinP≥0.71). Results Data from 961 patients with moderately-to-severely active UC randomised in UNIFI were included. At baseline, 319 patients received placebo and 624 patients received ustekinumab. A total of 912 (94.9%) patients completed the induction trial. Overall mean baseline index scores were: MCS 8.9 (±1.6), mMS 6.6 (±1.3), pMS 6.2 (±1.4), RHI 16.6 (±8.1), and UC-100 score 71.4 (±16.5) (Table). The UC-100 demonstrated a large degree of responsiveness (WinP 0.72 [95% CI: 0.66, 0.78]). The MCS (0.68 [0.62, 0.73]), mMS (0.69 [0.63, 0.75]), and pMS (0.65 [0.59, 0.71]) demonstrated similar, medium effect sizes (all comparisons p>0.05) (Figure). The RHI alone had a relatively small effect size (WinP 0.63 [0.56-0.70]). Among individual UC-100 components (Mayo Clinic stool frequency subscore, Mayo Clinic endoscopic subscore, and RHI), the endoscopic score was most responsive (WinP 0.59 [0.36-0.82]). The combination of endoscopy and RHI was associated with a medium degree of responsiveness (WinP 0.69 ([0.34, 1.00]). Conclusion UC disease activity indices are similarly responsive to change. Depending on trial design and measurement feasibility, different instruments can be considered optimal for evaluation of efficacy. The mMS is similarly responsive to the MCS without including the physician global assessment and may be more appropriate for determining trial eligibility and defining primary endpoint, whereas the UC-100 may be more appropriate for measuring treatment effect when an objective continuous measure is needed.

CRL4b Inhibition Ameliorates Experimental Autoimmune Encephalomyelitis Progression.

Multiple sclerosis, and its murine model experimental autoimmune encephalomyelitis (EAE), is a neurodegenerative autoimmune disease of the CNS characterized by T cell influx and demyelination. Similar to other autoimmune diseases, therapies can alleviate symptoms but often come with side effects, necessitating the exploration of new treatments. We recently demonstrated that the Cullin-RING E3 ubiquitin ligase 4b (CRL4b) aided in maintaining genome stability in proliferating T cells. In this study, we examined whether CRL4b was required for T cells to expand and drive EAE. Mice lacking Cul4b (Cullin 4b) in T cells had reduced EAE symptoms and decreased inflammation during the peak of the disease. Significantly fewer CD4+ and CD8+ T cells were found in the CNS, particularly among the CD4+ T cell population producing IL-17A, IFN-γ, GM-CSF, and TNF-α. Additionally, Cul4b-deficient CD4+ T cells cultured invitro with their wild-type counterparts were less likely to expand and differentiate into IL-17A- or IFN-γ-producing effector cells. When wild-type CD4+ T cells were activated invitro in the presence of the recently developed CRL4 inhibitor KH-4-43, they exhibited increased apoptosis and DNA damage. Treatment of mice with KH-4-43 following EAE induction resulted in stabilized clinical scores and significantly reduced numbers of T cells and innate immune cells in the CNS compared with control mice. Furthermore, KH-4-43 treatment resulted in elevated expression of p21 and cyclin E2 in T cells. These studies support that therapeutic inhibition of CRL4 and/or CRL4-related pathways could be used to treat autoimmune disease.

P904 Appendectomy for refractory ulcerative colitis: results of prospective observational study

Abstract Background Appendectomy is suggested to improve the course of the disease in many patients with refractory ulcerative colitis (UC). The present prospective observational study demonstrates middle-term outcomes after an appendectomy in 26 patients with refractory UC. Methods Between 5/2022 and 2/2023, 26 selected patients underwent appendectomy for refractory UC. Refractory UC was defined as a failure of at least one biologic therapy. Patients with Dysplasia or Cancer were excluded. The appendectomy was performed without the removal of the cecal base. Primary Endpoint of the study was the Mayo clinical score (MCS) at 6 months after the appendectomy. Secondary Endpoint was the “Treatment failure” which was defined as occurrence of one of the following events during the first 6 months after appendectomy: 1) high-dosed steroid treatment, 2) change of biologic treatment, 3) colectomy. Results Mean age was 35 years (18 to 59 years) and there were 11 female patients. 15 had a pancolitis (58%). Twelve were taking steroids (46%). Median number of biologic therapies taken by patients prior to surgery was 3 (range, 1-5). One patient underwent surgery for sever acute UC. The appendix appeared to be inflamed histologically in 16 patients (62%). Hospital stay was median 2 days, there was one wound infection at the port site and one postoperative hematoma. A significant improvement of disease symptoms was reported by 21 patients during the first 4 weeks (81%). At 6 months, MCS improved from mean 6.4 to 4.5 (p=0.057). Therapy failure was observed in 15 patients (58%) – two underwent colectomy, 11 needed at least one high-dose steroid treatment and biologic therapy was changed due to refractory symptoms in 9 patients. Intake of JAK-inhibitors at the time of appendectomy was the only factor to be associated with lower probability of treatment failure (30% vs. 75%, p=0.043). The only patient undergoing appendectomy for severe acute UC was free of symptoms 14 months after surgery. Conclusion The majority of patients with refractory UC demonstrated rapid clinical response to the appendectomy. After 6 months, more than 40% of patients did not experience disease flares necessitating intensification of treatment.

P678 Long-term efficacy, safety and health-related quality of life in patients who achieved comprehensive disease control with filgotinib in SELECTION: analysis of ~3 years in SELECTIONLTE

Abstract Background Filgotinib (FIL), an oral, once-daily, Janus kinase 1 inhibitor, was approved for Ulcerative Colitis (UC) treatment after the phase 2b/3 SELECTION trial (NCT02914522). In SELECTION, a greater proportion of FIL200 mg (FIL200)-treated than placebo-treated patients achieved comprehensive disease control (CDC), a stringent multi-component endpoint. We examined the long-term outcomes of achieving CDC in patients continuing on FIL200 in the ongoing long-term extension (LTE) study SELECTIONLTE (NCT02914535). Methods This interim analysis included adult patients with UC who completed SELECTION and received ≤144 weeks of FIL200 in the LTE (up to data cut-off 24/02/22). CDC (biomarker remission, endoscopic improvement, IBDQ remission and partial Mayo Clinic Score [pMCS] remission achieved concurrently) was assessed at SELECTION week 58 (LTE baseline [BL]). Mean pMCS and IBDQ score, use of corticosteroids (CS) and incidence of TEAEs and serious TEAEs in the LTE were compared between SELECTION CDC achievers and non-achievers. A mixed model for repeated measures was fitted on pMCS and IBDQ score, with CDC achiever status, study visit and the interaction between CDC achiever status and study visit as fixed effects; p values were nominal. Results We analysed 148 patients (CDC achievers, n=41; CDC non-achievers, n=107). Mean pMCS was stable in CDC achievers (0.44, LTE BL; 0.50, LTE week 144) and decreased in CDC non-achievers (1.49, LTE BL; 0.77, LTE week 144; Figure). Mean IBDQ score was stable in CDC achievers (204.05, LTE BL; 197.21, LTE week 144) and increased in CDC non-achievers (181.55, LTE BL; 196.37, LTE week 144; Figure). There was a significant beneficial effect of achieving CDC on pMCS and IBDQ score overall (pMCS: fixed effect estimate: −0.5542, p=0.0025; IBDQ score: fixed effect estimate: 13.1585, p=0.0042). There was a significant interaction between achieving CDC and study visit for IBDQ score (p=0.0183), with the benefit of achieving CDC lessening by week 144. Generally, a lower proportion of CDC achievers used CS than non-achievers; 2.4–7.3% of CDC achievers used CS vs 1.9–15.9% of CDC non-achievers. Incidence of TEAEs and serious TEAEs were stable over time and similar between CDC achievers and non-achievers. Conclusion Follow-up for ~3 years showed high levels of long-term benefit with continued FIL200 treatment. Achieving comprehensive disease control at the end of the randomized trial with FIL200 was associated with long-term efficacy, improved HRQoL and low overall use of CS. This may demonstrate the value of filgotinib-induced achievement of CDC in UC disease course. The safety profile of FIL200 was consistent between CDC achievers and non-achievers, suggesting an acceptable long-term benefit–risk profile.

P772 Comprehensive disease control in patients with Ulcerative Colitis: refinement of a multi-component endpoint using data from the filgotinib SELECTION trial

Abstract Background Ulcerative colitis (UC) treatment requires a patient-centric efficacy endpoint to assess treatment benefits, enabling a shift towards a personalized approach. Comprehensive disease control (CDC) is an individual multi-component endpoint based on findings from a patient and expert Delphi consensus on remission assessment in UC. CDC was defined as IBDQ remission, partial Mayo Clinic Score (pMCS) remission, biomarker (faecal calprotectin [FCP]) remission and endoscopic improvement. We evaluated different definitions of CDC, and the contribution of different CDC components to the net treatment benefit (NTB) of filgotinib 200 mg (FIL200), an oral, once-daily, Janus kinase 1 inhibitor approved for UC treatment following the SELECTION trial (NCT02914522). Methods CDC was assessed at week 58 (W58) of SELECTION in adult patients with active UC treated with FIL200 or placebo (PBO). The CDC definitions evaluated were: 4-component CDC (CDC4) with FCP <150 µg/g, CDC4-150; CDC4 with FCP <250 µg/g, CDC4-250; 5-component CDC (with histological remission [CDC5]) with FCP <150 µg/g, CDC5-150; and CDC5 with FCP<250 µg/g, CDC5-250. The proportion of patients achieving each combination of components was visualized in UpSet plots. NTB of FIL200 was assessed for each endpoint using generalized pairwise comparisons and is reported here for CDC4-150 (and excluding different components). Results At W58, 21.6%, 26.6%, 19.1% and 22.6% of FIL200-treated patients achieved CDC4-150, CDC4-250, CDC5-150 and CDC5-250, respectively. Among patients who did not achieve CDC4-150, 0.5% of patients did not achieve pMCS remission compared with 5.0%, 10.1% and 6.0% who did not achieve IBDQ remission, biomarker remission and endoscopic improvement, respectively (Figure). Positive overall NTB of FIL200 versus PBO was demonstrated with all CDC definitions, including those with histological remission (CDC5). For CDC4-150 at W58, excluding pMCS remission did not substantially change the NTB (Δ −0.33; Table) versus excluding IBDQ or biomarker remission, or endoscopic improvement (Δ 3.87, 6.93 and 3.20, respectively). Similar NTB results were seen for all CDC definitions. Conclusion CDC is a stringent, patient-level, multi-component endpoint achieved by ~1/5 of FIL200-treated patients at W58. While CDC4-150 could be the optimal operational definition, the addition of histological remission resulted in similar stringency, potentially allowing for the use of different CDC definitions based on context or resources. Additional NTB of FIL200 was identified in patients when IBDQ or biomarker remission or endoscopic improvement were excluded. Overall, CDC appears to be a suitable endpoint to assess individual comprehensive benefit in patients with UC. Prospective validation is needed.

Comparative analyses of arthroscopic and open repairs of lateral ligament complex injuries of the ankle: a systematic review and meta-analysis of the medium-term outcomes.

Little is known regarding the comparative analyses of the medium-term outcomes (with a mean minimum follow-up period of 24months), between arthroscopic and open repairs of lateral ligament complex (LLC) injuries of the ankle. Thus, in this study, we aimed to explore the comparative analyses regarding the medium-term follow-up outcomes of these repairs, by conducting a systematic review and meta-analysis. The systematic review and meta-analysis were performed as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines; data were extracted from the PubMed and Google Scholar databases. From an initial search, a total of 1182 abstracts (280 and 902 abstracts, from PubMed and Google Scholar, respectively) were found and screened in accordance with the eligibility criteria. Subsequently, six articles were found to be eligible for further review. A total of 419 patients underwent surgical repairs; 205 and 214 patients underwent arthroscopic and open repairs, respectively. The mean minimum follow-up period was 29.2months. The medium-term follow-up for arthroscopic LLC repairs was found to be superior to that of open LLC repairs, with more favorable outcomes; as evidenced by better clinical scores, lower pooled complication rates, earlier return times to pre-injury sport, and higher early sport ratios. The findings of this systematic review and meta-analysis support near-future developments validating arthroscopic repair as the new gold standard for LLC repairs, similarly to arthroscopic ligament and tendon repairs, as well as arthroscopic reconstruction surgeries, of the knee and shoulder.

Clinical significance of intraoperative glenohumeral joint load evaluation using a novel humeral sensor in navigated reverse total shoulder arthroplasty

BackgroundAdvances in preoperative planning and technology have assisted the surgeon in appropriate placement of implants during reverse total shoulder arthroplasty (RTSA). However, assessment of soft tissue tension, balance, and stability remains subjective and dependent on surgeon experience. The aims of this study are to measure intraoperative joint loads with a novel trial humeral load sensor during RTSA, to evaluate the utility of this device in the operative setting, and to determine the association between recorded joint loads and postoperative patient-reported outcomes. MethodsA pilot study of 15 patients with the diagnosis of osteoarthritis, rotator cuff arthropathy, or massive cuff tear were scheduled for computer-navigated RTSA and intraoperative joint load measurements. Following appropriate soft tissue releases, load recordings were made in standardized arm positions: neutral, across the chest, behind the back, and overhead. Participants were clinically and radiographically reviewed at 3 and 12 months post-surgery for evidence of joint instability, bony stress reaction or fracture, and American Shoulder and Elbow Surgeons (ASES) score. ResultsIntraoperative joint load measurements vary between participants, but there were no significant associations with age or body mass index (P > .05). Mean joint load in the neutral position was recorded as 6.1 lbf (standard deviation [SD] 7.4 range 0-25). In each of the three testing positions, mean joint load was recorded in the range of 30-40 lbf. Maximum joint loads above 70 lbf were observed in individual participants. There were no postoperative complications including joint instability or bony stress reactions. At 3 months, no statistically significant correlations were observed between clinical scores and load measures. At 12 months, the mean ASES score was 83.1 (SD 11.6, range 63.3-98.3), and demonstrated a large and significant association with load magnitude in the behind back position (r = 0.66, P = .008). The mean ASES pain subscale score was 45.3 (SD 6.4, range 30.0-50.0) and demonstrated a significant association with load magnitude in the behind back position (r = 0.69, P = .004) and with load magnitude in the across chest position (r = 0.55, P = .034). No other significant associations were observed. DiscussionThis pilot study indicates a novel humeral trial load sensor can be used safely and effectively during RTSA. This trial reports a range of intraoperative joint load measurements in neutral and commonly performed arm positions, which at 12 months post-surgery are associated with satisfactory shoulder function. Further clinical studies are required to define an upper limit for intraoperative joint load, which may potentially compromise clinical outcome.

Soluble Angiotensin-Converting Enzyme 2 Protein Improves Survival and Lowers Viral Titers in Lethal Mouse Model of Severe Acute Respiratory Syndrome Coronavirus Type 2 Infection with the Delta Variant.

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) utilizes angiotensin-converting enzyme 2 (ACE2) as its main receptor for cell entry. We bioengineered a soluble ACE2 protein termed ACE2 618-DDC-ABD that has increased binding to SARS-CoV-2 and prolonged duration of action. Here, we investigated the protective effect of this protein when administered intranasally to k18-hACE2 mice infected with the aggressive SARS-CoV-2 Delta variant. k18-hACE2 mice were infected with the SARS-CoV-2 Delta variant by inoculation of a lethal dose (2 × 104 PFU). ACE2 618-DDC-ABD (10 mg/kg) or PBS was administered intranasally six hours prior and 24 and 48 h post-viral inoculation. All animals in the PBS control group succumbed to the disease on day seven post-infection (0% survival), whereas, in contrast, there was only one casualty in the group that received ACE2 618-DDC-ABD (90% survival). Mice in the ACE2 618-DDC-ABD group had minimal disease as assessed using a clinical score and stable weight, and both brain and lung viral titers were markedly reduced. These findings demonstrate the efficacy of a bioengineered soluble ACE2 decoy with an extended duration of action in protecting against the aggressive Delta SARS-CoV-2 variant. Together with previous work, these findings underline the universal protective potential against current and future emerging SARS-CoV-2 variants.

Digital assessment of speech in Huntington disease.

Speech changes are an early symptom of Huntington disease (HD) and may occur prior to other motor and cognitive symptoms. Assessment of HD commonly uses clinician-rated outcome measures, which can be limited by observer variability and episodic administration. Speech symptoms are well suited for evaluation by digital measures which can enable sensitive, frequent, passive, and remote administration. We collected audio recordings using an external microphone of 36 (18 HD, 7 prodromal HD, and 11 control) participants completing passage reading, counting forward, and counting backwards speech tasks. Motor and cognitive assessments were also administered. Features including pausing, pitch, and accuracy were automatically extracted from recordings using the BioDigit Speech software and compared between the three groups. Speech features were also analyzed by the Unified Huntington Disease Rating Scale (UHDRS) dysarthria score. Random forest machine learning models were implemented to predict clinical status and clinical scores from speech features. Significant differences in pausing, intelligibility, and accuracy features were observed between HD, prodromal HD, and control groups for the passage reading task (e.g., p < 0.001 with Cohen'd = -2 between HD and control groups for pause ratio). A few parameters were significantly different between the HD and control groups for the counting forward and backwards speech tasks. A random forest classifier predicted clinical status from speech tasks with a balanced accuracy of 73% and an AUC of 0.92. Random forest regressors predicted clinical outcomes from speech features with mean absolute error ranging from 2.43-9.64 for UHDRS total functional capacity, motor and dysarthria scores, and explained variance ranging from 14 to 65%. Montreal Cognitive Assessment scores were predicted with mean absolute error of 2.3 and explained variance of 30%. Speech data have the potential to be a valuable digital measure of HD progression, and can also enable remote, frequent disease assessment in prodromal HD and HD. Clinical status and disease severity were predicted from extracted speech features using random forest machine learning models. Speech measurements could be leveraged as sensitive marker of clinical onset and disease progression in future clinical trials.

Establishing and validation of the VBV score for assessing Lung ground-glass nodules based on high-resolution computed tomography

BackgroundThe widespread utilization of chest High-resolution Computed Tomography (HRCT) has prompted detection of pulmonary ground-glass nodules (GGNs) in otherwise asymptomatic individuals. We aimed to establish a simple clinical risk score model for assessing GGNs based on HRCT.MethodsWe retrospectively analyzed 574 GGNs in 574 patients undergoing HOOK-WIRE puncture and pulmonary nodule surgery from January 2014 to November 2018. Clinical characteristics and imaging features of the GGNs were assessed. We analyzed the differences between malignant and benign nodules using binary logistic regression analysis and constructed a simple risk score model, the VBV Score, for predicting the malignancy status of GGNs. Then, we validated this model via other 1200 GGNs in 1041 patients collected from three independent clinical centers in 2022.ResultsFor the exploratory phase of this study, out of the 574 GGNs, 481 were malignant and 93 were benign. Vacuole sign, air bronchogram, and intra-nodular vessel sign were important indicators of malignancy in GGNs. Then, we derived a VBV Score = vacuole sign + air bronchogram + intra-nodular vessel sign, to predict the malignancy of GGNs, with a sensitivity, specificity, and accuracy of 95.6%, 80.6%, and 93.2%, respectively. We also validated it on other 1200 GGNs, with a sensitivity, specificity, and accuracy of 96.0%, 82.6%, and 95.0%, respectively.ConclusionsVacuole sign, air bronchogram, and intra-nodular vessel sign were important indicators of malignancy in GGNs. VBV Score showed good sensitivity, specificity, and accuracy for differentiating benign and malignant pulmonary GGNs.

Neurological disorders throughout acute SARS-CoV2 infection: A comparative study between vaccinated and non-vaccinated patients

BackgroundThe role of vaccination on Covid-19 severity in neurological patients is still unknown. We aim at describing clinical characteristics and outcomes of breakthrough and unvaccinated Covid-19 patients hospitalized for neurological disorders. MethodsTwo hundred thirty-two Covid-19 patients were admitted to a neuro-Covid Unit form March 1st 2021 to February 28th 2022. Out of the total sample, 74 (32%) were full vaccinated. The prevalence, clinical characteristics, disease severity, expressed by Brescia-COVID Respiratory Severity Scale (BCRSS) and National Early Warning Score 2 (NEWS2), and final outcomes of neurological syndromes were compared between vaccinated and unvaccinated cases.Cox regression analysis was implemented in order to investigate the combined effect of predictors of mortality. ResultsBreakthrough vaccinated cases were older (years 72.4 ± 16.3 vs 67.0 ± 18.9 years, p = 0.029), showed higher pre-admission comorbidity score and Clinical Frailty scale score (4.46 ± 1.6 vs 3.75 ± 2.0, p = 0.008) with no differences in terms of disease progression or mortality rate (16.2% vs 15.2%), compared to full-dose vaccinated patients.Cox-regression analysis showed age and NEWS2 score as the variables with a significant relation to mortality between the two groups, independently from pre-morbid conditions and inflammatory response. ConclusionThis study on breakthrough COVID-19 infection could help identify vulnerable neurological patients with higher risk of poor outcomes.

Improvements to a GLCM-based machine-learning approach for quantifying posterior capsule opacification.

Posterior capsular opacification (PCO) is a common complication following cataract surgery that leads to visual disturbances and decreased quality of vision. The aim of our study was to employ a machine-learning methodology to characterize and validate enhancements applied to the grey-level co-occurrence matrix (GLCM) while assessing its validity in comparison to clinical evaluations for evaluating PCO. One hundred patients diagnosed with age-related cataracts who were scheduled for phacoemulsification surgery were included in the study. Following mydriasis, anterior segment photographs were captured using a high-resolution photographic system. The GLCM was utilized as the feature extractor, and a supported vector machine as the regressor. Three variations, namely, GLCM, GLCM+C (+axial information), and GLCM+V (+regional voting), were analyzed. The reference value for regression was determined by averaging clinical scores obtained through subjective analysis. The relationships between the predicted PCO outcome scores and the ground truth were assessed using Pearson correlation analysis and a Bland-Altman plot, while agreement between them was assessed through the Bland-Altman plot. Relative to the ground truth, the GLCM, GLCM+C, and GLCM+V methods exhibited correlation coefficients of 0.706, 0.768, and 0.829, respectively. The relationship between the PCO score predicted by the GLCM+V method and the ground truth was statistically significant (p<0.001). Furthermore, the GLCM+V method demonstrated competitive performance comparable to that of two experienced clinicians (r=0.825, 0.843) and superior to that of two junior clinicians (r=0.786, 0.756). Notably, a high level of agreement was observed between predictions and the ground truth, without significant evidence of proportional bias (p>0.05). Overall, our findings suggest that a machine-learning approach incorporating the GLCM, specifically the GLCM+V method, holds promise as an objective and reliable tool for assessing PCO progression. Further studies in larger patient cohorts are warranted to validate these findings and explore their potential clinical applications.

Computerized adaptive testing to screen pre-school children for emotional and behavioral problems.

Questionnaires to detect emotional and behavioral (EB) problems in preventive child healthcare (PCH) should be short; this potentially affects their validity and reliability. Computerized adaptive testing (CAT) could overcome this weakness. The aim of this study was to (1) develop a CAT to measure EB problems among pre-school children and (2) assess the efficiency and validity of this CAT. We used a Dutch national dataset obtained from parents of pre-school children undergoing a well-child care assessment by PCH (n = 2192, response 70%). Data regarded 197 items on EB problems, based on four questionnaires, the Strengths and Difficulties Questionnaire (SDQ), the Child Behavior Checklist (CBCL), the Ages and Stages Questionnaire: Social Emotional (ASQ:SE), and the Brief Infant-Toddler Social and Emotional Assessment (BITSEA). Using 80% of the sample, we calculated item parameters necessary for a CAT and defined a cutoff for EB problems. With the remaining part of the sample, we used simulation techniques to determine the validity and efficiency of this CAT, using as criterion a total clinical score on the CBCL. Item criteria were met by 193 items. This CAT needed, on average, 16 items to identify children with EB problems. Sensitivity and specificity compared to a clinical score on the CBCL were 0.89 and 0.91, respectively, for total problems; 0.80 and 0.93 for emotional problems; and 0.94 and 0.91 for behavioral problems. Conclusion: A CAT is very promising for the identification of EB problems in pre-school children, as it seems to yield an efficient, yet high-quality identification. This conclusion should be confirmed by real-life administration of this CAT. What is Known: • Studies indicate the validity of using computerized adaptive test (CAT) applications to identify emotional and behavioral problems in school-aged children. • Evidence is as yet limited on whether CAT applications can also be used with pre-school children. What is New: • The results of this study show that a computerized adaptive test is very promising for the identification of emotional and behavior problems in pre-school children, as it appears to yield an efficient and high-quality identification.

2010 The scope of CT in investigating iron deficiency anaemia in the context of frailty

Abstract Introduction Iron Deficiency Anaemia (IDA) is a highly prevalent co-morbidity in older patients with advanced frailty. It’s associated with adverse outcomes and heightened all-cause mortality. IDA is frequently multifactorial and can stem from various gastrointestinal causes. The British Society of Gastroenterology and National Institute for Health and Care Excellence advocate a combination of endoscopy and computerised tomography (CT) as the gold standard investigations for IDA. The aim of this review was to evaluate oesophagogastroduodenoscopy (OGD) findings and management outcomes of clinically frail patients with IDA. Methods We review notes for patients referred for OGD to investigate IDA without additional symptoms over a six-month period. The inclusion criteria were IDA, age of 65 years or greater and a clinical frailty score of 5 or greater. Results 53 patients met the inclusion criteria. A single case (1.8%) UGI malignancy using OGD was identified prior to CT. Thus, demonstrating low yield of OGD in malignancy. 35.6% of patients underwent CT scanning 3 months prior to OGD. Approximately 90% of OGD findings were benign. 23% of patients died within 90 days of OGD. No significant adverse events during OGD or significant complications were recorded in our cohort. It is therefore highly unlikely that the undergoing of an OGD had a direct impact on mortality. Conclusion This review shows there is a low yield of UGI malignancy on OGD following a negative CT. Benign upper GI condition is the most common finding. Thus, CT imaging alone may be an adequate investigation to rule out UGI malignancy in this group. Considering there is a high mortality rate in older patients with frailty, following an OGD, we suggest considering starting empirical treatment with PPI and iron replacement as a suitable and less invasive alternative to OGD after a negative CT in frail patients.

1908 Documentation in Clinical Frailty scores in patients aged &amp;gt;65 admitted to surgical assessment unit

Abstract Introduction According to the latest NELA report, frailty doubles the risk of mortality in patients &amp;gt;65 and above, but review by a geriatrician can significantly reduce this risk. To identify patients at risk, the report recommended that a formal frailty assessment for all patients&amp;gt;65 should be performed. The aim of this audit was to check compliance with this recommendation. Methods Data were collected retrospectively from a prospectively maintained electronic hospital records. Patients &amp;gt; 65 years admitted acutely under general surgery were identified from handover lists spanning a period of two weeks. The admission documents were reviewed to check for a formal assessment of clinical frailty score (CFS) had been completed. Following initial results, posters were put up in the SAU doctors’ office and all clerking doctors made aware via e-mails, WhatsApp groups and teaching to complete a CFS for patients &amp;gt;65 years. Results In the first cycle, 50 patients were identified and compliance rate was 18%. Following intervention, 51 patients were identified in the subsequent cycle with a compliance rate of 47%. After a second intervention, 99 patients were identified with a compliance rate of 61%. Discussion The NELA report highlighted only 23% of patients had a CFS documented and this was similar to the results of the initial audit. The main reason was lack of awareness, which was addressed by creating an awareness among the colleagues via poster, group chats and emails. This brought compliance up to 47%. Another reason was doctors being unable to locate the CFS on the electronic clerking document. A second round of intervention by poster, group chat, email communication and teaching achieved a 61% completion rate. The recommendation is to continue to improve the documentation of CFS further and utilize this to get input from geriatricians.

1720 Frailty and the impact of Electronic Advance Care Planning records on readmission rates and location of end of life care

Abstract Introduction Older people with severe frailty are 5 times more likely to die in the next 12 months than older non-frail people however prognosis and disease trajectory in frailty remains difficult to predict. Advance care planning (ACP) is often not fully discussed or documented due to these prognostic uncertainties, plus time/workload constraints. This can result in multiple admissions for people with frailty in the last 12 months of life and can lead to care and death in a non-preferred place. Electronic Advance Care Plans (eACP) can be useful in reducing unwanted admissions and promoting care and death in preferred location. This project aimed to improve proportion of patients receiving care in their preferred location and reduce readmission rates. Method Identified patients who wished to avoid hospital readmission with clinical frailty score of 6 or more and at least 2 unplanned admissions in the preceding 12 months over a 4-month period at a district general hospital in south London. ACP was discussed with patients and families and an eACP was generated. Patients were then followed up at 3 and 6 months to assess readmission rate and rate of end-of-life care in preferred location. 24 patients consented - 17 women, 7 men. Mean age of 88.3 Mean pre-admission frailty score of 6.1. High level of pre-admission co-morbidity with 80% having 3 or more major comorbidities. Results Readmission rate was 8%. One third of patients alive at 3 months all without readmission. 23 patients had died at 6 months. 13% died in hospital versus a national average of around 50%. 70% died in preferred place of death versus national average of around 49%. Solution Use of electronic Advance Care plans resulted in a low readmission rate and a higher proportion of people receiving end of life care in their preferred place of death.

2026 Development of a novel 2-week wait oncogeriatric service: A GI Frailty Clinic

Abstract Introduction Over the last 12 months, a novel oncogeriatric clinic was successfully established to assess frail 2-week wait (2WW) patients referred with gastrointestinal (GI) symptoms. The clinic was initially funded by the West Yorkshire Cancer Alliance, enabling a weekly clinic, run by a geriatrician, clinical specialist nurse and an advance clinical practitioner. Methods A total of 350 patients were assessed (those with a clinical frailty score of ≥ 6 were eligible for referral); due to demand exceeding capacity, remaining patients were referred on through the default surgical or GI pathways. Patients were triaged by endoscopy nurses from ‘straight to test’ referrals after training provided to assess frailty scores using routinely available data. Results Only a third of patients referred remained on the 2WW pathway compared to surgical patients; this was due to patients being too frail or an alternative diagnosis being made through comprehensive geriatric assessment, and a shared decision-making process. The patient level information and costing system (PLICS) demonstrated that the oncogeriatric clinic was cost effective, costing approximately £190 less per patient than the default pathways of care. Feedback from patients demonstrated extremely high satisfaction rates with the service provided. One of the most significant interventions was medicines management, which has led to a pharmacist supporting the clinic through further innovation funding. Conclusion Lessons learned included developing a better understanding of cancer diagnosis and frailty, providing a ‘one stop centre’ for cancer care, and managing complex comorbid conditions in frail older people suspected of having cancer. As a result of this QI service development project, a Frailty Cancer Strategy for the Trust is currently being developed and will be presented to the executive team with the aim of developing a comprehensive oncogeriatric service for frail patients in Leeds, providing the right care, the right treatment, first time.

Anti-Inflammatory Effects of a Novel Nuclear Factor-κB Inhibitory Derivative Derived from Pyrazolo[3,4-d]Pyrimidine in Three Inflammation Models.

Nuclear factor-κB (NF-κB) plays a central role in inflammatory responses, and its physiologic functions are essential for cell survival and proliferation. Currently, drugs targeting NF-κB inhibition have not yet been applied in clinical practice. We investigated the physiologic effect of a novel NF-κB inhibitory compound, 1H-pyrazolo[3,4-d]pyrimidin-4-amine derivative (INH #1), on three inflammatory animal models. The pharmacokinetics were measured by liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis. Acute hepatitis was induced by administrating lipopolysaccharide (LPS) and D-(+)-galactosamine hydrochloride followed by the analysis of survival time and inflammatory mediators. Collagen-induced arthritis (CIA) was induced by immunization with type II collagen (CII), and serum-transfer arthritis (STA) was caused by injecting K/BxN mice serum. Clinical and histologic scores were evaluated in both arthritis models. Immune cell subset analysis, CII-induced interferon-gamma (IFN-γ) production and proliferation, and measurement of anti-CII IgG antibodies were performed in the CIA model. In the acute hepatitis model, INH #1 suppressed tumor necrosis factor-α (TNF-α) production and prevented early death in a dose-dependent manner. INH #1 significantly attenuated arthritis scores and joint inflammation in both arthritis models. Additionally, in the CIA model, dendritic cells (DCs) in the regional lymph nodes were decreased in the treated mice and antigen-induced IFN-γ production and cell proliferation in splenocytes were inhibited, whereas the titers of anti-CII IgG antibodies were comparable regardless of the treatment. Here we revealed that INH #1 exerted anti-inflammatory effects in vivo via inhibition of inflammatory mediators and suppression of cellular immune responses. This compound could be a novel candidate for inhibition of NF-κB in certain inflammatory diseases. SIGNIFICANCE STATEMENT: A novel nuclear factor-κB (NF-κB) inhibitory compound, 1H-pyrazolo[3,4-d]pyrimidin-4-amine derivative (INH #1), which retains physiologically essential NF-κB bioactivity, suppressed inflammation in three different mouse models: the acute hepatitis model, the collagen-induced arthritis model, and the K/BxN serum-transfer arthritis model. These results suggest that this compound could be a novel and potent anti-inflammatory agent.

2036 “I didn’t personally think it would change my life, but it has”: The experience following emergency laparotomy for older people

Abstract Introduction Older people living with frailty are at high risk of adverse clinical outcomes following emergency laparotomy, including early death, hospital readmission and functional decline. Despite this, there is a paucity of literature exploring patient experience of surgery in this group, particularly following hospital discharge. As a result, there is limited information to guide the development of service delivery models that support optimal post-operative recovery and improve overall experience. Methods Twenty older people, aged ≥65 years, with a Clinical Frailty Scale score of ≥ 4 and who had undergone emergency laparotomy were recruited from eight participating hospital sites. Participants were interviewed at 3 weeks following their surgery, or the earliest convenient date. Semi-structured interviews were undertaken either face to face or via telephone and explored the peri-operative and early recovery experience. Data were analysed using reflexive thematic analysis. Results Participants described physical, psychological, and social implications following emergency laparotomy which extended further than hospital discharge. Recovery was perceived to be an ongoing and slow process of returning to ‘normal self’ however participants displayed resilience towards achieving this by ‘knuckling down’ and ‘pushing forward’. The experience of hospital care was generally positive, but lack of access to discharge advice and community follow up left some participants feeling ‘abandoned’ and uncertain once they returned home. Many were reliant on family support during this period. Conclusions Older people living with frailty experience multifaceted consequences of emergency laparotomy that result in a prolonged recovery period. Multi-disciplinary post-operative care pathways are essential in addressing the holistic care needs of this group following surgery. The provision of robust discharge information and enhanced access to support in the community could improve patient experience and facilitate ongoing recovery at home.