Reasons For Failure Research Articles

In Situ Self-Assembling Liver Spheroids with Synthetic Nanoscaffolds for Preclinical Drug Screening Applications.

Drug-induced liver injury (DILI) is one of the most common reasons for acute liver failure and a major reason for the withdrawal of medications from the market. There is a growing need for advanced in vitro liver models that can effectively recapitulate hepatic function, offering a robust platform for preclinical drug screening applications. Here, we explore the potential of self-assembling liver spheroids in the presence of electrospun and cryomilled poly(caprolactone) (PCL) nanoscaffolds for use as a new preclinical drug screening tool. This study investigated the extent to which nanoscaffold concentration may have on spheroid size and viability and liver-specific biofunctionality. The efficacy of our model was further validated using a comprehensive dose-dependent acetaminophen toxicity protocol. Our findings show the strong potential of PCL-based nanoscaffolds to facilitate in situ self-assembly of liver spheroids with sizes under 350 μm. The presence of the PCL-based nanoscaffolds (0.005 and 0.01% w/v) improved spheroid viability and the secretion of critical liver-specific biomarkers, namely, albumin and urea. Liver spheroids with nanoscaffolds showed improved drug-metabolizing enzyme activity and greater sensitivity to acetaminophen compared to two-dimensional monolayer cultures and scaffold-free liver spheroids. These promising findings highlight the potential of our nanoscaffold-based liver spheroids as an in vitro liver model for drug-induced hepatotoxicity and drug screening.

Effect of Cigarette Smoking on Postoperative Outcomes After Arthroscopic Bone Marrow Stimulation for Osteochondral Lesions of the Talus.

Bone marrow stimulation (BMS) is presently considered first-line surgical treatment for osteochondral lesions of the talus (OLTs); however, some patients still experience pain or dysfunction after surgery, and the reasons for success or failure remain somewhat unclear. This study aimed to investigate the effect of smoking on postoperative outcomes after arthroscopic BMS for OLTs. Consecutive patients with OLTs who underwent BMS between January 2017 and January 2020 were included. Smokers were defined as patients who actively consumed cigarettes before surgery and postoperatively, whereas nonsmokers were patients who never smoked. Visual analog scale (VAS), American Orthopaedic Foot & Ankle Society ankle hindfoot score (AOFAS), Karlsson-Peterson, and Tegner scores were assessed preoperatively and at follow-up. Additionally, a general linear model (GLM) was performed, followed by the interaction analysis to explore the potential influence of smoking. The study enrolled 104 patients with a mean follow-up of 30.91 ± 7.03 months, including 28 smokers and 76 nonsmokers. There were no significant differences in patient age (35.2 ± 10.0 years vs 37.6 ± 9.7 years, P = .282) or OLT area (63.7 ± 38.7 mm2 vs 52.8 ± 37.0 mm2, P = .782). Both univariate analysis and GLM revealed that smoking was associated with worse postoperative pain levels, Karlsson-Peterson, and AOFAS scores (P < .05). The interaction analysis showed a significant interaction between smoking and OLT area for postoperative Karlsson-Peterson scores (general ankle function) (P = .031). Simple main effects analysis revealed that the negative effect of smoking on Tegner score significantly increased among patients >32 years old or with OLT area>50 mm2 (P < .05). Smoking was associated with worse clinical outcomes following BMS of OLTs. As the size of OLTs increased, the difference in general ankle function between smokers and nonsmokers also increased. Furthermore, smokers who were older than 32 years or had larger OLTs were less likely to resume participation in high-level activities.

Efficacy of empirical Ciprofloxacin or Cefixime plus Metronidazole therapy for the treatment of liver abscess: a randomized control clinical trial

Liver abscess is a potentially life-threatening medical emergency. Prompt empirical antimicrobial with or without percutaneous aspiration or drainage is therapeutic. The rational for using empirical intravenous broad-spectrum antimicrobials upfront instead of oral Fluoroquinolone or Cephalosporin is contentious. In this double blind randomized control clinical trial 69 participants received Ciprofloxacin (500 mg q 12 hourly) and 71 participants received Cefixime (200 mg q 12 hourly) orally for 2 weeks. Both the group received oral Metronidazole (800 mg q 8 hourly) for 2 weeks and percutaneous drainage or aspiration of the abscess was done as per indication and followed-up for 8 weeks. Out of 140 participants, 89.3% (N = 125) achieved clinical cure, 59 (85.5%) in Ciprofloxacin group and 66 (93%) in Cefixime group (p = 0.154). Mean duration of antimicrobial therapy was 16.2 ± 4.3 days, 15.1 ± 4.5 days in Ciprofloxacin group and 16.0 ± 4.2 days in Cefixime group (p = 0.223). Total 15 (10.7%) participants had treatment failure, 10 (14.5%) in Ciprofloxacin group and 5 (7.0%) in Cefixime group (p = 0.154). The most common reason for treatment failure was need of prolong (> 4 weeks) antimicrobial therapy due to persistent hepatic collection requiring drainage, which was significantly (p = 0.036) higher in Ciprofloxacin (14.5%, N = 10) group, compared to the Cefixime (4.2%, N = 3) group. In conclusion, both, the Ciprofloxacin or Cefixime plus Metronidazole for duration of 2–3 weeks were efficacious as empirical oral antimicrobial regimen along with prompt percutaneous drainage or aspiration for the treatment of uncomplicated liver abscess with similar efficacy. Oral Cefixime was better than Ciprofloxacin in term of lesser chance of treatment failure due to persistent collection which is required to be investigated further in larger clinical trial.Trial registration: clinicaltrials.gov PRS ID: NCT03969758, 31/05/2019.

Transformation Needs Horizontal Thinking

Abstract Transformation programmes don't have a great reputation for success, but why is this the case if the supposed reasons for failure have been known for years? Gary Burke believes transformation needs to be looked at differently.

Predictive value of fluid balance before extubation on its outcome in mechanically ventilated adults in the intensive care unit.

Although there are many reasons for extubation failure, maintaining negative or lower positive fluid balances 24 hours before extubation may be a key measure for successful extubation. To assess the predictive value of fluid balance before extubation and its outcome in mechanically ventilated cases in the intensive care unit (ICU). This retrospective cohort study involved collecting clinical data from patients undergoing mechanical ventilation in Lanzhou general adult ICU from January 2022 to December 2022. Based on extubation outcomes, the patients were divided into a successful extubation group and a failed extubation group. Their fluid balance levels 24 h before extubation were compared with analyse the predictive value of fluid balance on extubation outcomes in patients undergoing mechanical ventilation. In this study, clinical data from 545 patients admitted to a general adult ICU were collected. According to the inclusion and exclusion criteria, 265 (48.6%) patients were included, of which 197 (74.3%) were successfully extubated; extubation was unsuccessful in 68 (25.7%) patients. The total intake and fluid balance levels in patients in the failed extubation group 24 h before extubation were significantly higher than those in the successful extubation group, with a median of 2679.00 (2410.44-3193.50) mL versus 2435.40 (1805.04-2957.00) mL, 831.50 (26.25-1407.94) mL versus 346.00 (-163.00-941.50) mL. Receiver operating characteristic (ROC) curve analysis showed that the optimal cut-off value for predicting extubation outcomes was 497.5 mL (sensitivity 64.7%, specificity 59.4%) for fluid balance 24 h before extubation. The area under the ROC curve was 0.627 (95% confidence interval [CI] 0.547-0.707). Based on the logistic regression model, cumulative fluid balance >497.5 mL 24 h before extubation could predict its outcomes in mechanically ventilated patients in the ICU (OR = 5.591, 95% CI [2.402-13.015], p < .05). The fluid balance level 24 h before extubation was correlated with the outcome of extubation in mechanically ventilated patients in the ICU. The risk of extubation failure was higher when the fluid balance level was >497.5 mL. Tracheal intubation is a crucial life support technique for many critically ill patients, and determining the appropriate time for extubation remains a challenge for clinicians. Although there are many reasons for extubation failure, acute pulmonary oedema caused by continuous positive fluid balance and volume overload is one of the main reasons for extubation failure. Therefore, it is very important to study the relationship between fluid balance and extubation outcome to improve the prognosis of patients with invasive mechanical ventilation in ICU.

Reducing blood product wastage through the inter-hospital redistribution of near-outdate inventory.

Hospital transfusion services order blood products to satisfy orders and maintain inventory levels during unexpected periods of increased blood demand. Surplus inventory may outdate before being allocated to a recipient. Blood product outdating is the largest contributor to blood wastage. A province-wide redistribution program was designed and implemented to redistribute near-outdate plasma protein and related blood products from low-usage to high-usage hospitals. Program operations and details are described in this paper. Two transport container configurations were designed and validated for transport of all blood products. A cost-analysis was performed to determine the effectiveness of this redistribution program. A total of 130 hospital transfusion services contributed at least one near-outdate blood product for redistribution between January 2012 and March 2020. These services redistributed 15,499 products through 3412 shipments, preventing the outdating of $17,570,700 CAD worth of product. Program costs were $14,900 for shipping and $30,000 for staffing. Failed time limits or non-compliance with packing configurations resulted in $388,200 worth of blood products (97 shipments containing 816 products) being discarded. Courier transport delays was the most common reason (42/97; 43%) for transport failure. Redistributing near-outdate blood products between hospitals is a feasible solution to minimize outdating. Despite heterogeneity of Canadian blood product inventory, all products (each with unique storage and transport requirements) were successfully redistributed in one of two validated and simple containers. Total operation costs of this program were small in comparison to the $17.6 million in savings associated with preventing the discard of outdated products.

An updated analysis of retransplantation following living donor liver transplantation in the United States: Insights from the latest UNOS database.

There is no recent update on the clinical course of retransplantation (re-LT) after living donor liver transplantation (LDLT) in the US using recent national data. The UNOS database (2002-2023) was used to explore patient characteristics in initial LT, comparing deceased donor liver transplantation (DDLT) and LDLT for graft survival (GS), reasons for graft failure, and GS after re-LT. It assesses waitlist dropout and re-LT likelihood, categorizing re-LT cohort based on time to re-listing as acute or chronic (≤ or > 1 mo). Of 132,323 DDLT and 5955 LDLT initial transplants, 3848 DDLT and 302 LDLT recipients underwent re-LT. Of the 302 re-LT following LDLT, 156 were acute and 146 chronic. Primary nonfunction (PNF) was more common in DDLT, although the difference was not statistically significant (17.4% vs. 14.8% for LDLT; p = 0.52). Vascular complications were significantly higher in LDLT (12.5% vs. 8.3% for DDLT; p < 0.01). Acute re-LT showed a larger difference in primary nonfunction between DDLT and LDLT (49.7% vs. 32.0%; p < 0.01). Status 1 patients were more common in DDLT (51.3% vs. 34.0% in LDLT; p < 0.01). In the acute cohort, Kaplan-Meier curves indicated superior GS after re-LT for initial LDLT recipients in both short-term and long-term ( p = 0.02 and < 0.01, respectively), with no significant difference in the chronic cohort. No significant differences in waitlist dropout were observed, but the initial LDLT group had a higher re-LT likelihood in the acute cohort (sHR 1.40, p < 0.01). A sensitivity analysis focusing on the most recent 10-year cohort revealed trends consistent with the overall study findings. LDLT recipients had better GS in re-LT than DDLT. Despite a higher severity of illness, the DDLT cohort was less likely to undergo re-LT.

Urate-lowering therapy for gout: Difficulties in goal achieving the and ways to overcome

Urate-lowering therapy for gout: Difficulties in goal achieving the and ways to overcome

Characteristics and complications of acute promyelocytic leukemia in children: an analysis of a national database

Acute promyelocytic leukemia (APL) is an uncommon subtype of acute myelogenous leukemia (AML) that was previously one of the most fatal forms of acute leukemia. With advances in diagnosis and treatment, APL has become one of the most curable myeloid leukemias. The major reason for treatment failure in APL is early death after initiation of treatment. We performed a retrospective cross-sectional analysis of the Healthcare Cost and Utilization Project 2016 and 2019 Kids’ Inpatient Database, with the diagnosis of APL or AML not in remission as defined by ICD-10-CM codes. We compared complications and outcomes associated with APL and AML (exclusive of APL) in hospitalized children in the U.S. and described yearly national incidence. The national incidence of APL was 2.2 cases per million children per year. Children with APL were more likely to have cardiopulmonary complications (OR 1.79; CI 1.20–2.67; p = 0.004), coagulation abnormalities or DIC (OR 7.75; CI 5.81–10.34; p < 0.001), pulmonary hemorrhage (OR 2.18; CI 1.49–3.17; p < 0.001), and intracranial hemorrhage (OR 10.82; CI 5.90–19.85; p < 0.001) and less likely to have infectious complications (OR 0.48; CI 0.34–0.67; p < 0.001) compared to children with AML. In-hospital mortality rates were similar in children with APL and AML (4.2% vs 2.6%; OR 1.62; CI 0.86–3.06; p = 0.13), while the median length of stay for children who died from APL was shorter compared to AML (2 (IQR: 1–7) versus 25 (IQR: 5–66) days; p < 0.05). Hemorrhagic complications occur more often, and infectious complications occur less often in hospitalized children with APL compared to AML.

Error detection for radiotherapy planning validation based on deep learning networks.

Quality assurance (QA) of patient-specific treatment plans for intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) necessitates prior validation. However, the standard methodology exhibits deficiencies and lacks sensitivity in the analysis of positional dose distribution data, leading to difficulties in accurately identifying reasons for plan verification failure. This issue complicates and impedes the efficiency of QA tasks. The primary aim of this research is to utilize deep learning algorithms for the extraction of 3D dose distribution maps and the creation of a predictive model for error classification across multiple machine models, treatment methodologies, and tumor locations. We devised five categories of validation plans (normal, gantry error, collimator error, couch error, and dose error), conforming to tolerance limits of different accuracy levels and employing 3D dose distribution data from a sample of 94 tumor patients. A CNN model was then constructed to predict the diverse error types, with predictions compared against the gamma pass rate (GPR) standard employing distinct thresholds (3%, 3mm; 3%, 2mm; 2%, 2mm) to evaluate the model's performance. Furthermore, we appraised the model's robustness by assessing its functionality across diverse accelerators. The accuracy, precision, recall, and F1 scores of CNN model performance were 0.907, 0.925, 0.907, and 0.908, respectively. Meanwhile, the performance on another device is 0.900, 0.918, 0.900, and 0.898. In addition, compared to the GPR method, the CNN model achieved better results in predicting different types of errors. When juxtaposed with the GPR methodology, the CNN model exhibits superior predictive capability for classification in the validation of the radiation therapy plan on different devices. By using this model, the plan validation failures can be detected more rapidly and efficiently, minimizing the time required for QA tasks and serving as a valuable adjunct to overcome the constraints of the GPR method.

Changes in patient recruitment parameters and their derivatives under the influence of external factors – population size and density of residence in a certain area

Background. The lack of targeted patient recruitment for clinical trials reaches 90%, which leads to failures of a trial as a whole and insufficient access to the necessary treatment or diagnostic method for patients. To find out the reasons for recruitment failures, many factors are considered, the action of which is difficult to assess due to high variability. In general, various factors are named that reduce patient recruitment, while factors that improve it are much less known.Objective: to investigate changes in the parameters and indicators of patient recruitment for clinical trials depending on the influence of external factors.Material and methods. A retrospective analysis of four international multicenter clinical trials of phases II–III was performed by 16 patient recruitment parameters and their 6 derivatives (indicators) – both widely used in the literature and newly proposed. A total of 622 patients from 70 clinical centers located in 59 cities of Russia, Ukraine, and Belarus were included in the study. The methods of descriptive statistics and typing were used. To study the influence of factors, internal and external factors were selected, external factors including population size, area and density of residence were analysed, and changes in parameters and indicators depending on the influence of each factor were examined. The area and population density were studied in inseparable connection with each other.Results. A simple classification of factors was proposed – external and internal to the clinical center where patients were recruited. The factors classified as external were analyzed depending on the change in the proposed parameters of patient recruitment for clinical trials and their relationships – indicators (derivatives). The final rate of patient recruitment and the final number of patients recruited in the population group of 1–2 million people had statistically significant (p&lt;0.05) higher values (0.57±0.20 and 15.08±5.06, respectively) than in group with up to 1 million people – 0.14±0.05 and 3.75±1.24.Conclusion. For the first time, an extended panel of parameters and indicators that allow evaluating the influence of various factors on patient recruitment for clinical trials was proposed. The value of the proportion of parameters and indicators that had statistical differences among themselves in the group influenced by the population size factor was more than twice as large as the proportion of similar parameters and indicators in the group influenced by area and population density: 47% and 23%, respectively, which may indicate more strong influence of the first factor.

Abstract PS02-08: The Effect of a Digital Health Coaching Program on Patient Reported Outcomes of Women with Breast Cancer

Abstract Background Understanding the impact of a digital health coaching (DHC) program on patient-reported outcomes in women with breast cancer is imperative as web-based platforms and mobile phone applications to address health care needs flood the marketplace. This study evaluated the effect of a DHC program on patient-reported outcomes, including global health (primary outcome), symptom burden, quality of life, healthcare utilization, and financial toxicity among women undergoing active treatment for breast cancer. Methods English-speaking adult women undergoing active treatment for breast cancer were randomized to receive usual care or a 6-month DHC program, consisting of weekly telephone calls from a Health Advisor, unlimited patient-initiated communication via phone, text, or email, and digital delivery of additional health-behavior content. Patient-reported outcomes (PROs) were collected using validated measures at baseline, and 1, 3, and 6 months. Summary statistics were used to describe participant characteristics. Linear mixed models were used to assess the effect of the intervention on outcomes. Results Participants (n=254, planned enrollment=440) were enrolled from August 2019 to December 2022 and randomized equally to the control and intervention groups (n=127 each). Demographic data are presented in Table 1. Participants had a mean age of 48 (SD =10.15) years; 74% were White; 19.7% were Hispanic. In both groups, several PRO scores changed over time with some improving (quality of life and symptom severity) and others worsening (symptom interference and financial toxicity) compared to baseline (time effects). Of those enrolled in the intervention group 69% were retained in the DHC program, with an overall average of 4.6 months of engagement for all participants. There were no significant group (intervention versus control) effects or group by time interaction effects observed. Trends within and between groups are presented in Table 2. Though not statistically significant, there were fewer ER visits in the intervention group at each timepoint. Conclusions: While differential improvements in the DHC group were not observed, interesting trends in PROs over the 6-month enrollment period were observed in both groups. Participants reported improvements in quality of life and worsening of financial toxicity. Interestingly, slight improvements in symptom severity over time were observed in both groups while symptom interference worsened. Potential reasons for failure to detect a treatment effect for DHC may include ineffectiveness of DHC on the selected outcomes, the intervention not being strong enough as currently delivered to detect a treatment effect, varying uptake of DHC in the intervention group, heterogeneity of the sample, or the study being underpowered due to COVID restrictions affecting enrollment. Table 1. Demographic and clinical characteristics of the study population (n = 254) Table 2. Trends in Patient Reported Outcomes and Healthcare Utilization Citation Format: Meagan Whisenant, Eileen Hacker, Loretta Williams, Joyce Dains, Bryan Fellman, Trinity Isaac, Valerie Shelton, Austin Barr, Carolyn Harty, Mazi Rasulnia, Kelly Brassil. The Effect of a Digital Health Coaching Program on Patient Reported Outcomes of Women with Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS02-08.

Abstract PS06-02: Circulating tumor DNA (ctDNA) monitoring of estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) high risk breast cancer during adjuvant endocrine therapy

Abstract Background: ctDNA monitoring during adjuvant endocrine therapy provides an opportunity to detect molecular relapse before clinically apparent recurrence. The rate and dynamics of ctDNA positivity and the frequency of asymptomatic but imaging detectable metastatic disease at the time of ctDNA detection remain unknown in high-risk ER+/HER2- breast cancers. We present results of ctDNA positivity rates in 508 and imaging results in ctDNA+ patients from a prospective, multicenter, randomized ctDNA surveillance and intervention trial, DARE (NCT04567420). Patients and methods: Patients receiving adjuvant endocrine therapy for &amp;gt; 6 months but &amp;lt; 7 years, with either (i) risk of recurrence &amp;gt; 15% calculated by PREDICT, RSPC, or CTS5, or (ii) &amp;gt; 4 positive axillary lymph nodes, or (iii) primary tumor &amp;gt; 5 cm, or (iv) 1-3 positive nodes with grade 3 histology, or &amp;gt; 3 cm tumor, or Oncotype Dx RS &amp;gt; 26, MammaPrint high risk, EndoPredict &amp;gt; 4, Prosigna score &amp;gt; 60 were eligible for ctDNA surveillance with the SignateraTM assay (Natera Inc.) every 4-6 months during routine follow up visits. ctDNA+ patients underwent systemic staging with imaging and randomized to continuation of adjuvant therapy versus switching to fulvestrant plus palbociclib if there was no evidence of distant metastatic disease. The primary objectives are to assess the incidence of ctDNA positivity in the surveillance phase and to assess if palbociclib plus fulvestrant improves relapse-free survival in 100 randomized patients. This is an updated, protocol-driven interim report to determine if screening eligibility criteria needs to be revised to keep randomization rate &amp;gt; 15% of the screened population. Results: The trial is open at 15 sites and enrolled 508 patients between May 2021 and June 2023; 882 plasma ctDNA tests were performed successfully in 364 patients (72%). The most common reason for failure to generate a personalized ctDNA assay was insufficient tissue submitted, 78% of failed tests were due to preanalytical failure, the technical failure rate was 22%. Thirty patients, 8.2% of those with results available, had &amp;gt;1 positive ctDNA result, the overall positivity rate across all assays was 3.4% (n=30/882). Patient characteristics are shown in the table (not all patients have complete data), 47% of ctDNA+ cases had &amp;gt;4 + lymph nodes. ctDNA positivity rate in the first test was 3.8%, and anytime ctDNA detection rate among those with serial testing was 7.2%. Among ctDNA+ patients, the first ctDNA draw was positive in 23 of 30 cases (77%) with 36.5 months median time (range 6-102 months) from surgery to testing. Using 12 months interval brackets from surgery to 1st ctDNA positivity, annual detection rates were 2,3% (1/44), 8.5% (7/82), 10.8% (9/83), 7.5% (4/53), 13,2% (5/38), and 6.2% (4/64), at 1st, 2nd, 3rd, 4th and &amp;gt; 5th year post-surgery, respectively, due to small sample sizes, 95% confidence broadly overlap. Five ctDNA+ patients (16.7%) had asymptomatic, imaging-detectable metastatic disease, 22 ctDNA+ patients were randomized, the goal is to accrue a total of 100 patients. Conclusions: ctDNA surveillance of ER+/HER2- breast cancers during adjuvant endocrine therapy indicate 8.3% detection rate at patient level and 3.4% at assay level. Serial screening increases detection rates as 23% of positive ctDNA tests occurred after an initial negative result. 83% of ctDNA+ patients had true molecular relapse without imaging detectable metastatic disease. Eligibility for screening on the trial is now restricted to patients with &amp;gt;4 + lymph nodes, randomization is open for any patients who are ctDNA+ including routine commercial screening. Table of patient characteristics with ctDNA result (n=364) ctDNA+ (n=30) Age &amp;lt; 50 29% 23% Age &amp;gt;50 71% 77% PR + 78% 73% PR - 7% 17% HER2 IHC negative 79% 77% Grade 1 8% 7% Grade 2 53% 50% Grade 3 29% 37% T 1 19% 17% T2 43% 43% T3 27% 27% T4 2% 7% 0 +nodes 12% 12% 1 +node 24% 10% 2 +nodes 15% 13% 3 +nodes 8% 13% &amp;gt;4 +nodes 0 47% Citation Format: Lajos Pusztai, Ekaterina Kalashnikova, Evthokia Hobbs, Ursa Brown-Glaberman, Monica Mita, Paula Klein, Fengting Yan, Sima Ehsani, Wajeeha Razaq, Alison Stopeck, Manali Bhave, Michelle Loch, Sagar Sardesai, Evanthia Roussos Torres, Mark Burkard, Femi Okubanjo, Eric Gauthier, Angel Rodriguez, Minetta Liu, Peter Kabos. Circulating tumor DNA (ctDNA) monitoring of estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) high risk breast cancer during adjuvant endocrine therapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS06-02.

Screen Failures in Clinical Trials in Retina

PurposeDisparities in clinical trials are a major problem due to significant underrepresentation of certain gender, racial and ethnic groups. Several factors including stringent eligibility criteria and recruitment strategies hinder our understanding of retinal disease. Thus, we aimed to study the various reasons of screen failures and specific patient and study characteristics among screen failures. DesignThis is a cross-sectional retrospective study MethodsScreening data of 87 trials from 6 centers were analyzed. Study characteristics (disease studied, phase of trial, route of drug administration) and patient demographics (age, gender, race, ethnicity, and employment status) were compared among different causes of screen failures. Screen failures were broadly classified into six categories: exclusion due to vision-based criteria, exclusion due to imaging findings, exclusion due to other factors, patient-related criteria, physician related criteria and miscellaneous. Descriptive statistics, Pearson Chi-square test and ANOVA were used for statistical analysis. Main outcome measuresDetermine the prevalence of various reasons for screen failures in multiple trials and its trend among different study and patient characteristics. ResultsAmong 87 trials and 962 patients, 465(48.2%) patients were successfully randomized and 497(51.8%) patients were classified as screen failures. The trials were conducted for various retinal diseases. Mean age was 76.50 ±10.45 years and 59.4% were females. Predominantly whites(93.4%) and unemployed/retired patients(66.6%) were screened. Of the 497 screen failures, most were due to patients not meeting inclusion criteria of imaging findings (n=221[44.5%]) followed by inclusion of vision-based criteria (n=73 [14.7%]), exclusion due to other factors (n=75[15.1%]), patient-related (n=34[6.8%]), physician-related (n=28[5.6%]) and miscellaneous reasons (n= 39[17.8%]). Reason for screen failure was not available for 27(5.4%) patients. A higher proportion of patients screened for surgical trials (15%) declined to participate in the study compared to non-invasive trials involving topical drugs and photobiomodulation (0%).(p=0.02) ConclusionPatients not meeting the imaging and vision-cased criteria were the most common reasons for screen failures. Whites and unemployed patients predominantly participated in clinical trials. Patients are more inclined to continue participation in non-invasive clinical trials compared to surgical trials. Better recruitment strategies and careful consideration of study criteria can aid in decreasing the rate of screen failures.

Management of the failed Latarjet procedure

AimTo analyze the causes of failure after a Latarjet procedure and to evaluate the results of revision surgery. MethodsSingle-cohort, retrospective, observational study. Fifteen patients, 13 males, mean age at revision failed Latarjet 38.9 years (range, 20-57), with anterior glenohumeral instability who underwent a revision surgery for a failed Latarjet procedure were reviewed. Failure was defined as subluxation or dislocation. Demographic features, the reason for failure, type of lesions observed, and postoperative clinical and functional status were recorded. Functional status was assessed with the Rowe score. Subjective clinical evaluation was performed using the WOSI Index and subjective shoulder value (SSV). ResultsRecurrence occurred in the first year following the Latarjet procedure in 11 (73.3%) patients. The causes of failure were graft avulsion in 3 cases, fracture in 1, coracoid misposition in 2 cases, graft non-union in 1, advanced osteolysis in 4 cases and persistence of an off-track Hill-Sachs lesion in one. In 3 cases no identifiable cause of failure, but patients generalized severe hyperlaxity was found. Regarding revision surgery after the Latarjet procedure, 8 patients underwent an arthroscopic Eden-Hybinette procedure and in 3 patients the graft was repositioned. In the remaining 4 patients an extraarticular capsular reinforcement was performed. Regarding the latter, one patient suffered new dislocations and required an additional revision surgery consisting of an Eden-Hybinette procedure. All patients remained stable after the revision surgery at the latest follow-up, except two who reported subluxations after an arthroscopic Eden-Hybinette and an extraarticular capsular reinforcement, but no additional surgical procedure was required. Functional status after revision surgery was satisfactory, with a Rowe mean score noted at 78 (10-100), WOSI score at 829 (225-1425) and a subjective shoulder value scale at 67 points (40-90). ConclusionThe causes of failure after a Latarjet procedure were poor bone graft due to mispositioning, avulsion, fracture or resorption, generalized hyperlaxity, and incomplete restoration of the glenoid track. Our study demonstrates that when the cause of failure is identified and addressed, stability is restored, and clinical and functional scores improved.

Biodiversity management challenges: A policy brief

Global biodiversity has been lost at an alarming rate in the past century leading to what is often described as ‘the sixth mass extinction'. Leading causes of this loss are chemical pollution, habitat loss, unsustainable use of resources, invasive species, and climate change. Such environmental change can alter ecosystem functions irreversibly, leading to a direct loss of ecosystem services, such as food provision, climate regulation, and cultural services, which are estimated to have a global value of tens of trillions of dollars. International governing bodies have repeatedly set targets to preserve biodiversity and ecosystem services, especially within the framework of the UN Convention on Biological Diversity (CBD). Despite nation states’ pledges at the Rio Summit in 1992 to conserve biological diversity, progress has been lamentable. One reason for such failure is that action to redress biodiversity loss depends on national governments but it is of relatively low concern on the public agenda. This article reviews the UK and EU legal and policy biodiversity frameworks and exposes some of the complexities surrounding biodiversity loss, including non-compliance, public awareness, and valuation. Following a multidisciplinary roundtable on biodiversity in 2023, we suggest policy recommendations to overcome these issues.

Macrophage depletion overcomes human hematopoietic cell engraftment failure in zebrafish embryo

Zebrafish is widely adopted as a grafting model for studying human development and diseases. Current zebrafish xenotransplantations are performed using embryo recipients, as the adaptive immune system, responsible for host versus graft rejection, only reaches maturity at juvenile stage. However, transplanted primary human hematopoietic stem/progenitor cells (HSC) rapidly disappear even in zebrafish embryos, suggesting that another barrier to transplantation exists before the onset of adaptive immunity. Here, using a labelled macrophage zebrafish line, we demonstrated that engraftment of human HSC induces a massive recruitment of macrophages which rapidly phagocyte transplanted cells. Macrophages depletion, by chemical or pharmacological treatments, significantly improved the uptake and survival of transplanted cells, demonstrating the crucial implication of these innate immune cells for the successful engraftment of human cells in zebrafish. Beyond identifying the reasons for human hematopoietic cell engraftment failure, this work images the fate of human cells in real time over several days in macrophage-depleted zebrafish embryos.

Long-term outcomes of revision total hip arthroplasty with the Zimmer Modular Revision hip system.

There are limited long-term studies reporting on outcomes of the Zimmer Modular Revision (ZMR) stem, and concerns remain regarding failure. Our primary aim was to determine long-term survival free from all-cause revision and stem-related failure for this modular revision stem in revision total hip arthroplasty (THA). Secondary aims included evaluating radiological and functional outcomes. We retrospectively identified all patients in our institutional database who underwent revision THA using the ZMR system from January 2000 to December 2007. We included 106 patients (108 hips) with a mean follow-up of 14.5 years (2.3 to 22.3). Mean patient age was 69.2 years (37.0 to 89.4), and 51.9% were female (n = 55). Indications for index revision included aseptic loosening (73.1%), infection (16.7%), fracture (9.3%), and stem fracture (0.9%). Kaplan-Meier analysis was used to determine the all-cause and stem-related failure revision-free survival. At most recent follow-up, Oxford Hip Scores (OHS) were collected, and radiological stem stability was determined using the Engh classification. A total of 17 hips (15.7%) underwent re-revision of any component. Indications for re-revision were stem failure (35.3%; n = 6), infection (29.4%; n = 5), instability (29.4%; n = 5), and acetabular aseptic loosening (5.9%; n = 1). The five- and 15-year all-cause survival was 89.7% (95% confidence interval (CI) 86.7 to 92.7) and 83.3% (95% CI 79.6 to 87.0), respectively. There were six re-revisions (5.6%) for stem failure; five for stem fracture and one for aseptic loosening. The five- and 15-year survival free from stem-related failure was 97.2% (95% CI 95.6 to 98.8) and 94.0% (95% CI 91.6 to 96.4), respectively. At final follow-up, the mean OHS was 36.9 (8.0 to 48.0) and 95.7% (n = 66) of surviving modular revision stems were well-fixed in available radiographs. Femoral revision with the ZMR offers satisfactory long-term all-cause revision-free survival, good survival free of stem-related failure, and favourable clinical outcomes. Stem fracture was the most common reason for stem-related failure and occurred both early and late. This highlights the importance of both early and long-term surveillance for stem-related failure.

Deformation causes of the Embankment-Bridge transition section in warm permafrost: The case study of a dry bridge along the Qinghai-Tibet railway

Differential embankment settlement and expansion joint failure in the embankment bridge transition section (EBTS) are two main issues endangering the safety of the Qinghai-Tibet Railway (QTR) in permafrost. A better understanding of the causes of EBTS deformation can offer valuable guidance for engineering maintenance. In this study, a comprehensive field investigation and a series of simulations were carried out to reveal the formation causes. The results revealed significant permafrost degradation beneath the EBTS after 15 years of operation, with temperatures nearing the thawing point. Despite contact between the abutment and beam end, the expansion joint exhibited continuous narrowing, particularly during the cold season. Permafrost degradation was primarily attributed to the heating effect of adjacent bridge structures. Foundation ground settlement emerged as the primary cause of embankment settlement in the transition section, contributing up to 80 % of the total settlement. Differential embankment settlement of the EBTS primarily stemmed from the uneven warming or thawing of permafrost, induced by the thermal impact of the adjacent bridge structures. The weakening of the transition section had a concentrated impact on embankment settlement within a 12-meter span behind the abutment, inducing approximately 30 % to 50 % of the embankment settlement. The backfill soils near the abutment experienced severe lateral frost heave in cold seasons. Horizontal displacement of the abutment caused by the lateral frost heave was identified as the main reason for expansion joint failure. Additional cooling measures are necessary to ensure the long-term stability of the EBTSs along the QTR, considering the faster degradation of ambient permafrost than expected. The findings offer valuable insights for the maintenance and design of railways in permafrost regions.

Implementation of a day-stay joint replacement pathway in an Australian regional public hospital: A descriptive study.

To describe the implementation, feasibility and safety of a day-stay joint replacement pathway in a regional public hospital in Australia. Over a 12-month pilot period, a prospective descriptive analysis of consecutive patients undergoing total knee and hip arthroplasty was conducted. The number of eligible day-stay patients, proportion of successful same-day discharges and reasons for same-day failure to discharge were recorded. Outcome measures captured for all joint replacements across this period included length of stay (LoS), patient reported outcomes, complications and patient satisfaction. The implementation pathway as well as patient and staff identified success factors derived from interviews were outlined. Forty-one/246 (17%) patients booked for joint replacement surgery were eligible for day-stay and 21/41 (51%) achieved a successful same-day discharge. Unsuccessful same-day discharges were due to time of surgery too late in the day (7/20), no longer meeting same-day discharge criteria (11/20) and declined discharge same-day (2/20). Over the implementation period 65% (162/246) of all patients were discharged with a LoS of 2 days or less. Patient satisfaction for the day-stay pathway was high. Complication rates and patient-reported outcomes were equivalent across LoS groups. The day-stay joint replacement surgery pathway was feasible to implement, safe and acceptable to patients. Day-stay pathways have potential patient and system-level efficiency benefits.