Worse Patient Research Articles

Abstract TP126: The association of patient outcomes with caregiver mental health and strain in a community-based study.

Background: Stroke survivors face functional changes that may alter their quality of life. Although these changes are significant for the stroke survivor, they are consequential for the caregiver of the stroke patient as well. Psychological burden of stroke caregivers has been investigated, but its association with level of disability and quality of life of the stroke patient has been less studied. Objective: To determine if worse 90-day patient stroke outcomes result in greater caregiver strain and worse caregiver mental health in a multiethnic sample. Methods: Using data from the Brain Attack Surveillance in Corpus Christi project, we prospectively determined 90-day ischemic and hemorrhagic stroke outcome from 2019-2023. Patient function based on ADLs/IADLs (higher scores worse) along with patient quality of life based on SS-QOL (higher scores better) were used to measure patient outcome. Stroke caregivers' depression was measured using the PHQ-8 (higher scores worse) and strain was measured by mCSI (higher scores worse). Generalized propensity scores (GPS) were calculated for the main exposures using caregiver and patient demographics, dyad characteristics, and clinical variables as predictors. Caregiver outcomes were modeled with linear regression, with caregiver depression and strain as main outcomes, unadjusted and adjusted for GPS. Results: During this time period, 339 strokes were identified and their caregivers subsequently interviewed. The median age of interviewed caregivers was 55, with 46% being the sole informal caregiver. A majority of the caregivers interviewed were either the spouse of the stroke patient (42.2%) or the child of the stroke patient (38.1%). In adjusted analyses, functional status for stroke patients was not associated with caregiver depression (p=0.12), higher stroke patient quality of life was strongly associated with lower odds of any depression symptoms among caregivers (p<0.001), and worse patient functional status (continuous ADL/IADL) and lower patient quality of life were strongly associated with higher caregiver strain (p<0.001, p<0.001, respectively). Conclusion: Worse stroke patient outcome has a negative association with caregiver mental health and caregiver strain. Interventions targeting caregivers of stroke patients are necessary to improve and protect caregiver mental health and strain.

Harnessing temporal patterns in administrative patient data to predict risk of emergency hospital admission.

Unplanned hospital admissions are associated with worse patient outcomes and cause strain on health systems worldwide. Primary care electronic health records (EHRs) have successfully been used to create prediction models for emergency hospitalisation, but these approaches require a broad range of diagnostic, physiological, and laboratory values. In this study, we aimed to capture temporal patterns of patient activity from EHR data and evaluate their effectiveness in predicting emergency hospital admissions compared with conventional methods. In this retrospective observational study, we used the Secure Anonymised Information Linkage databank to extract temporal patterns of primary care activity from undifferentiated electronic health record timestamp data for 1·37 million patients in Wales aged 18-80 years with at least one recorded Read code between the years 2016 and 2018. Using Gaussian mixture modelling we grouped patients into distinct temporal clusters, performed a three-stage validation of our approach and calculated the risk of emergency hospital admission for each temporal cluster group. Finally, these temporal clusters were combined with five administrative variables and incorporated into four emergency hospital admission prediction models (logistic regression, naive Bayes, XGBoost, and multilayer perceptron [MLP]) and compared with a more traditional, but data-intensive, modelling technique. The primary outcome was emergency hospital admission as the next health-care event. Six distinct temporal cluster patterns of primary care EHR activity were identified, associated with varying risks of future emergency hospital admission risk. These patterns were visually interpretable, repeatable at a population-level, and clinically plausible. The best emergency hospital admission prediction model (MLP) achieved an area under the receiver operating characteristic (AUROC) of 0·82 and precision of 0·94 in regional cohorts. In external validation in regional cohorts, similar model performance was observed (AUROC 0·82 and precision 0·92). This model also matched the performance of a more complex model (extended feature model) requiring 33 clinical parameters (AUROC 0·82 vs 0·83; precision 0·94 vs 0·90) for the same task on the same dataset. We developed a novel machine learning pipeline that extracts interpretable temporal patterns from simple representations of EHR data and can be incorporated into emergency hospital admission predictors. This framework might enable more rapid development of parsimonious clinical prediction models. UKRI CDT in AI for Healthcare, UKRI Turing AI Fellowship, NIHR Imperial Biomedical Research Centre, and Research Capability Funding.

Palliative Care Program for Community-Dwelling Individuals With Dementia and Caregivers: The IN-PEACE Randomized Clinical Trial.

Care management benefits community-dwelling patients with dementia, but studies include few patients with moderate to severe dementia or from racial and ethnic minority populations, lack palliative care, and seldom reduce health care utilization. To determine whether integrated dementia palliative care reduces dementia symptoms, caregiver depression and distress, and emergency department (ED) visits and hospitalizations compared with usual care in moderate to severe dementia. A randomized clinical trial of community-dwelling patients with moderate to severe dementia and their caregivers enrolled from March 2019 to December 2020 from 2 sites in central Indiana (2-year follow-up completed on January 7, 2023). Electronic health record screening identified patients with dementia; caregivers confirmed eligibility, including dementia stage. The intervention consisted of monthly calls from a trained nurse or social worker and evidence-based protocols to help caregivers manage patients' neuropsychiatric symptoms, caregiver distress, and palliative care issues (eg, advance care planning, symptoms, and hospice) (n = 99). Usual care caregivers received written dementia resource information and patients received care from usual clinicians (n = 102). The primary outcome was Neuropsychiatric Inventory Questionnaire (NPI-Q) severity score (scores range from 0-36, with higher scores indicating worse patient symptoms). Secondary outcomes included Symptom Management in End-of-Life Dementia scores, caregiver depression (Patient Health Questionnaire-8) scores, caregiver distress (NPI-Q distress) scores, and combined ED and hospitalization events. Outcomes were assessed quarterly for 24 months or until patient death. A total of 201 dyads were enrolled (patients were 67.7% female; 43.3% African American; mean [SD] age, 83.6 [7.9] years); 3 dyads withdrew and 83 patients died over the course of the study, with at least 90% of eligible dyads in both groups completing each of the quarterly assessments. For the dementia palliative care vs usual care groups, mean NPI-Q severity scores were 9.92 vs 9.41 at baseline and 9.15 vs 9.39 at 24 months, respectively (between-group difference at 24 months, -0.24 [95% CI, -2.33 to 1.84]). There was no significant difference in the rate of change in NPI-Q severity from baseline between groups over time (P = .87 for the group and time interaction). There were no significant differences in the secondary outcomes, except that there were fewer combined ED and hospitalization events in the dementia palliative care group (mean events/patient, 1.06 in dementia palliative care vs 2.37 in usual care; between-group difference, -1.31 [95% CI, -1.93 to -0.69]; relative risk, 0.45 [95% CI, 0.31 to 0.65]). Among community-dwelling patients with moderate to severe dementia and their caregivers, dementia palliative care, compared with usual care, did not significantly improve patients' neuropsychiatric symptoms through 24 months. ClinicalTrials.gov Identifier: NCT03773757.

P-2257. Pseudomonas aeruginosa and other Bacterial Infections After Lung Transplant: Risk Factors, Airway Stenosis and other Clinical Outcomes

Abstract Background Pseudomonas aeruginosa (PsA) and other bacterial infections after lung transplant can lead to worse patient outcomes. The aim of this study was to investigate whether isolation of microbial pathogens post-lung transplantation increased the risk of airway stenosis requiring bronchoscopic interventions. Table 1Table 1.Demographic, donor/recipient characteristics, peri-operative/post-operative characteristics and outcomes. Methods A single-center retrospective study of lung transplant recipients (LTR) between January 2017 and October 2023 was performed. Our center performs routine surveillance bronchoscopies at 1, 3, 6 and 12 months. Donor/recipient characteristics, microbiologic data, bronchoscopy findings and interventions, and 1-year outcomes were analyzed. Results In this 6.8-year study period, 327 subjects underwent lung transplant with survival greater than 30 days. The most common indication for lung transplant was restrictive lung disease. 64 (20%) had PsA infections, 77 (23%) had non-PsA bacterial infections (infect), and 186 (57%) did not have a bacterial infection within 6-months post-transplant. Recipient and donor characteristics were similar among the cohorts. A greater proportion of the PsA and infect cohorts required dialysis and mechanical ventilation and/or ECMO for >48 hours and had a longer index hospitalization than the uninfected cohort [Table 1]. A greater proportion of the PsA and infect cohorts developed airway stenosis requiring bronchial intervention (22% vs 17% vs 2%, p=< 0.001). The median time to first infection post-transplant occurred prior to the development of stenosis (72 vs 112 days; 52 vs 110 days). 44% of LTR with PsA growth had fluoroquinolone resistance on the initial culture. Rates of rejection and 1-year survival were not statistically different among the cohorts. Conclusion PsA and other bacterial infections within the first 6-months post lung transplantation led to a higher incidence of airway stenosis requiring bronchial intervention but was not associated with increased mortality or rejection at 1-year. The impact of treating bacterial colonization and other strategies to minimize post-transplant bacterial infections and decreasing the occurrence and time to airway stenosis needs further study. Disclosures All Authors: No reported disclosures

Predicting work ability impairment in post COVID-19 patients: a machine learning model based on clinical parameters.

The Post COVID-19 condition (PCC) is a complex disease affecting health and everyday functioning. This is well reflected by a patient's inability to work (ITW). In this study, we aimed to investigate factors associated with ITW (1) and to design a machine learning-based model for predicting ITW (2) twelve months after baseline. We selected patients from the post COVID care study (PCC-study) with data on their ability to work. To identify factors associated with ITW, we compared PCC patients with and without ITW. For constructing a predictive model, we selected nine clinical parameters: hospitalization during the acute SARS-CoV-2 infection, WHO severity of acute infection, presence of somatic comorbidities, presence of psychiatric comorbidities, age, height, weight, Karnofsky index, and symptoms. The model was trained to predict ITW twelve months after baseline using TensorFlow Decision Forests. Its performance was investigated using cross-validation and an independent testing dataset. In total, 259 PCC patients were included in this analysis. We observed that ITW was associated with dyslipidemia, worse patient reported outcomes (FSS, WHOQOL-BREF, PHQ-9), a higher rate of preexisting psychiatric conditions, and a more extensive medical work-up. The predictive model exhibited a mean AUC of 0.83 (95% CI: 0.78; 0.88) in the 10-fold cross-validation. In the testing dataset, the AUC was 0.76 (95% CI: 0.58; 0.93). In conclusion, we identified several factors associated with ITW. The predictive model performed very well. It could guide management decisions and help setting mid- to long-term treatment goals by aiding the identification of patients at risk of extended ITW.

OTUD6B regulates KIFC1-dependent centrosome clustering and breast cancer cell survival.

Cancer cells often display centrosome amplification, requiring the kinesin KIFC1/HSET for centrosome clustering to prevent multipolar spindles and cell death. In parallel siRNA screens of deubiquitinase enzymes, we identify OTUD6B as a positive regulator of KIFC1 expression that is required for centrosome clustering in triple-negative breast cancer (TNBC) cells. OTUD6B can localise to centrosomes and the mitotic spindle and interacts with KIFC1. In OTUD6B-deficient cells, we see increased KIFC1 polyubiquitination and premature KIFC1 degradation during mitosis. Depletion of OTUD6B increases multipolar spindles without inducing centrosome amplification. Phenotypic rescue is dependent on OTUD6B catalytic activity and evident upon KIFC1 overexpression. OTUD6B is commonly overexpressed in breast cancer, correlating with KIFC1 protein expression and worse patient survival. TNBC cells with centrosome amplification, but not normal breast epithelial cells, depend on OTUD6B to proliferate. Indeed CRISPR-Cas9 editing results in only OTUD6B-/+ TNBC cells which fail to divide and die. As a deubiquitinase that supports KIFC1 expression, allowing pseudo-bipolar cell division and survival of cancer cells with centrosome amplification, OTUD6B has potential as a novel target for cancer-specific therapies.

KRAS Mutation Status and Treatment Outcomes in Patients With Metastatic Pancreatic Adenocarcinoma

Despite the high prevalence of KRAS alterations in pancreatic ductal adenocarcinoma (PDAC), the clinical impact of common KRAS mutations with different cytotoxic regimens is unknown. This evidence is important to inform current treatment and provide a benchmark for emergent targeted KRAS therapies in metastatic PDAC. To assess the clinical implications of common KRAS G12 mutations in PDAC and to compare outcomes of standard-of-care multiagent therapies across these common mutations. This retrospective cohort study obtained deidentified clinical data for 5382 patients from a nationwide (US-based) clinicogenomic database. The deidentified data originated from approximately 280 US cancer clinics (approximately 800 sites of care). Patients diagnosed with metastatic PDAC from February 9, 2010, to September 20, 2022, and with sufficient follow-up and treatment data were included. Median overall survival (OS) and time to next treatment (TTNT) were calculated for each KRAS mutation group. Hazard ratios (HRs) were generated using multivariate Cox proportional hazards models for KRAS mutations and mutation-treatment combinations. A total of 2433 patients with PDAC were included in the analysis (mean age at first treatment, 67.0 [range, 66.0-68.0] years; 1340 male [55.1%]). Among 2023 patients with KRAS mutations, those with G12R had the longest median TTNT (6.0 [95% CI, 5.2-6.6] months) and the longest median OS (13.2 [95% CI, 10.6-15.2] months). Patients with KRAS G12D and G12V mutations had a significantly higher risk of disease progression (HRs, 1.15; [95% CI, 1.04-1.29; P = .009] and 1.16 [95% CI, 1.04-1.30; P = .01], respectively) and death (HRs, 1.29 [95% CI, 1.15-1.45; P < .001] and 1.23 [95% CI, 1.09-1.39; P < .001], respectively) compared with KRAS wild type. The FOLFIRINOX regimen (fluorouracil, irinotecan, oxaliplatin, and leucovorin) had a significantly lower risk of treatment progression and death than gemcitabine with (HRs, 1.19 [95% CI, [1.09-1.29; P < .001] and 1.18 [95% CI, 1.07-1.29; P < .001], respectively) or without (HRs, 1.37 [95% CI, 1.11-1.69; P = .003] and 1.41 [95% CI 1.13-1.75; P = .002], respectively) nab-paclitaxel across all patients. In this cohort study of 2433 patients with PDAC, KRAS G12D and G12V mutations were associated with worse patient outcomes compared with KRAS wild type. KRAS G12R was associated with more favorable patient outcomes, and FOLFIRINOX was associated with better patient outcomes than gemcitabine-based therapies. These findings highlight the need for more effective systemic therapies for these groups of patients.

The effect of the timing of endoscopic detorsion on clinical outcomes in patients with sigmoid volvulus.

Guidelines recommend endoscopic detorsion in cases of sigmoid volvulus without ischemia or perforation, but the timing in which this should be performed is unclear. Admissions for sigmoid volvulus in which endoscopic detorsion was performed between 1/2010-4/2024 were retrospectively reviewed. The timing was calculated as the time between when the confirmatory radiologic exam and endoscopic detorsion were performed. The timing was compared to various patient outcomes. 118 episodes of sigmoid volvulus from 73 unique adult patients were included (mean age 69.0; 76.3% male). The median time until endoscopic detorsion was 225.5 minutes (IQR 144.5-478.3) with 81 (68.6%) performed in <6 hours. The timing of detorsion was not associated with the presence of ischemia (p=0.289) or a combination of serious outcomes (p=0.777). Those who underwent delayed endoscopic detorsion (>6 hours) were more likely to be younger (62.4 vs 67.4, p=0.034) and have had a rectal tube placed (59.5% vs 21.0%, p<0.001). Delayed cases were associated with a longer length of admission (5.0 vs 3.0 days, p=0.011); however, other outcomes such as the success of endoscopic detorsion, presence of ischemia, readmission rate, and mortality rate showed no difference between the groups. In a multivariate regression analysis, serious outcomes were associated with "on call" status (p=0.045), but not the timing of detorsion (p=0.404). There does not appear to be a clear correlation between a longer delay until endoscopic detorsion and worse patient outcomes, with only the length of hospitalization affected. This suggests that endoscopic detorsion need not always be performed urgently.

Relations Between Suicide Risk and Patient Safety Attitudes Among the Nursing Team in a Brazilian Context.

To analyze the aspects of suicide risks and their relation to patient safety attitudes among the nursing staff of a large public university hospital in Brazil. A cross-sectional and descriptive study with 226 nursing workers from a large public university hospital in Brazil. Socioprofessional information, health conditions, and family history related to suicide risk were collected through the Mini International Neuropsychiatric Interview Plus and the Safety Attitudes Questionnaire. A 95% CI was considered, and statistical tests such as the Student t test, χ2, analysis of variance, and multiple linear regression were used. Most of the safety attitudes were below the average score considered positive (mean Safety Attitudes Questionnaire value >0.75), and 41 (18.1%) workers were considered to have any degree of suicide risk. Participants with parents or siblings who had attempted suicide were 3.44 times more likely to have moderate or high suicide risk. Negative safety attitudes were associated with health conditions and family history, considered suicide risk factors. Participants with moderate or high suicide risk were 2.83 times more likely to have worse patient safety attitudes concerning job satisfaction. This study reveals significant associations between patient safety attitudes and the mental health of nursing workers, expanding the view of worker health management actions and, consequently, patient safety culture.

MyCAF-derived exosomal PWAR6 accelerates CRC liver metastasis via altering glutamine availability and NK cell function in the tumor microenvironment

BackgroundLiver metastasis from colorectal cancer (CRC) is a major clinical challenge that severely affects patient survival. myofibroblastic cancer-associated fibroblasts (myCAFs) are a major component of the CRC tumor microenvironment, where they contribute to tumor progression and metastasis through exosomes.MethodsSingle-cell analysis highlighted a notable increase in myCAFs in colorectal cancer liver metastases (CRLM). Exosomal sequencing identified PWAR6 as the most significantly elevated lncRNA in these metastatic tissues. In vivo and in vitro assays confirmed PWAR6's roles in CRC cell stemness, migration, and glutamine uptake. RNA pulldown, RIP, and Co-IP assays investigated the molecular mechanisms of the PWAR6/NRF2/SLC38A2 signaling axis in CRC progression, flow cytometry was used to assess NK cell activity and cytotoxicity.ResultsClinically, higher PWAR6 expression levels are strongly associated with increased 68Ga FAPI-PET/CT SUVmax values, particularly in CRLM patients, where expression significantly exceeds that of non-LM cases and normal colon tissues. Regression analysis and survival data further support PWAR6 as a negative prognostic marker, with elevated levels correlating with worse patient outcomes. Mechanistically, PWAR6 promotes immune evasion by inhibiting NRF2 degradation through competitive binding with Keap1, thereby upregulating SLC38A2 expression, which enhances glutamine uptake in CRC cells and depletes glutamine availability for NK cells.ConclusionmyCAFs derived exosomes PWAR6 represents a pivotal marker for CRC liver metastasis, and its targeted inhibition with ASO-PWAR6, in combination with FAPI treatment, effectively curtails metastasis in preclinical models, offering promising therapeutic potential for clinical management.Graphical abstract

Changes in Healthcare Professionals' Practice Behaviors Through an Educational Intervention Targeting Weight Bias.

Weight bias is pervasive in healthcare and leads to worse patient outcomes. A uniquely designed 4-h continuing medical education (CME) intervention was assessed for changing healthcare professionals' (HCPs') weight biases and clinical practice behaviors. The intervention used a (1) pre/post design examining CME attendees' self-reported weight bias at baseline, after, and 4- and 12-month follow-up, and (2) post/post design examiningobesity practice behaviors 12months after intervention in attendees and non-attendees. Single medical center service area within Kaiser Permanente Southern California. All HCPs (n = 472) from the target service area were eligible to attend. Analyses were done with 218 HCPs who attended and 89 who did not. The intervention contained theory-based elements of changing attributions of responsibility of obesity, increasing empathy, creating self-awareness of weight bias, and creating a bias-free culture. For pre/post analyses, the primary outcome was self-reported weight bias. For comparative analyses of CME attendees and non-attendees, the outcomes were electronic medical record-confirmed rates of obesity diagnosis and referrals to evidence-based obesity treatments in the 12months following the CME intervention. Self-reported negative obesity stereotypes were significantly reduced compared to baseline while self-reported empathy and confidence in caring for patients with obesity were significantly increased immediately post intervention and were maintained at 4- and 12-month follow-up. After adjusting for years in practice, race/ethnicity, gender, profession type, practice type, and panel size, HCPs who attended the CME intervention had significantly increased odds (range 60-212%) of diagnosis and obesity-related referrals in the 12months following the CME intervention when compared to HCPs who did not attend. This intervention has promise to be a scalable program that goes beyond impacting HCP's self-reported weight bias and also changes HCPs' clinical practice behaviors related to obesity treatment.

Appendix: The effects of physician stigma and hesitancy with opioids on patient pain care in the United States: A survey study

Objectives: Determine if physician stigma toward patients with chronic pain or opioid use disorder or physician hesitancy prescribing opioids adversely affects patient pain care. Explore the demographics associated with stigma and hesitancy. Design: Survey, 25 questions. Setting: Physician faculty at medical schools (80 percent), private physician Facebook® groups (15 percent), and others (5 percent), all specialties. Participants: N = 352 attending United States physicians. Main outcome measure: Physician self-reported patient pain care quality. Results: Subjectively worse patient pain care was not found to be associated with stigma but had a borderline association with hesitancy (p = 0.046). Subjectively worse pain care was associated with less knowledge and experience with opioids (odds ratio [OR] 4.1, 95 percent confidence interval [CI] 3.0-5.6), practicing in the Midwest region (OR 2.1, 95 percent CI 1.2-3.4), and specialty: emergency (OR 53, 95 percent CI 20-139), other internal (OR 15, 95 percent CI 6.6-34), and general medicine (OR 12, 95 percent CI 5.4-26) compared to pain medicine. Physician stigma was more likely to be high in males (OR 2.5, 95 percent CI 1.5-4.3) and medium in physicians over 55 (OR 2.5, 95 percent CI 1.5-4.5). Compared to medium stigma, those with low stigma (General Linear Model (GLM) 0.35, 95 percent CI 0.18-0.52) and high stigma (GLM 0.22, 95 percent CI 0.01-0.44) were both more hesitant to prescribe opioids. More hesitancy was associated with less knowledge and experience (GLM 0.14, 95 percent CI 0.05-0.22) and physicians under 55 (GLM 0.24, 95 percent CI 0.08-0.40). Conclusions: Although physician stigma was not found to affect patient pain care adversely, self-reporting bias and/or questionnaire issues may account for this. Physician specialty and knowledge and experience with opioids were important factors.

Pain-Related Injustice Appraisals, Sickle Cell Stigma, and Racialized Discrimination in the Youth with Sickle Cell Disease: A Preliminary Investigation.

Despite the fact that perceptions of racialized discrimination, health-related stigma, and pain-related injustice have been associated with worse patient functioning, little is known about their unique relationships in Black youth living with sickle cell disease (SCD). In this study, we (1) examined the prevalence of perceptions of racialized discrimination, perceptions of health-related stigma, and pain-related injustice appraisals and (2) investigated how the aforementioned variables were uniquely related to functioning (i.e., functional disability, depressive, and anxiety symptoms) in Black youth living with SCD. The study sample included 30 non-Hispanic Black or African American youth living with SCD (17 male, 13 female youths). The average age of the sample was approximately 11.3years (SD = 2.73). Zero-order correlations and hierarchical regressions were used to examine and compare the multivariate relationships between perceived racialized discrimination, perceived health-related stigma, and perceived pain-related injustice and outcome variables (functional disability, anxiety symptoms, and depressive symptoms). For functional disability, perceived racialized discrimination and perceived pain-related injustice were significant predictors in the final model (F(3,26) = 11.00, p < .01). For depressive symptoms, health-related stigma trended toward significance (p = .09) as a predictor in the final model (F(2,26) = 6.69, p < .01). For anxiety symptoms, perceived pain-related injustice was the only significant predictor in the final model (F(3,26) = 10.25, p < .001). Results suggest that the youth living with SCD experience and perceive racialized discrimination, health-related stigma, and injustice surrounding their pain experience and these factors are associated with worse outcomes.

Chimeric antigen receptor macrophages targeting c-MET(CAR-M-c-MET) inhibit pancreatic cancer progression and improve cytotoxic chemotherapeutic efficacy

BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors. Macrophages are abundant in the tumor microenvironment, making them an attractive target for therapeutic intervention. While current immunotherapies, including immune checkpoint inhibition (ICI) and chimeric antigen receptor T (CAR-T) cells, have shown limited efficacy in pancreatic cancer, a novel approach involving chimeric antigen receptor macrophages (CAR-M) has, although promising, not been explored in pancreatic cancer. In this study, we first investigated the role of CAR-M cells targeting c-MET in pancreatic cancer.MethodsThe effectiveness and rationality of c-MET as a target for CAR-M in pancreatic cancer were validated through bioinformatic analyses and immunohistochemical staining of samples from pancreatic cancer patients. We utilized flow cytometry and bioluminescence detection methods to demonstrate the specific binding and phagocytic killing effect of CAR-M on pancreatic cancer cells. Additionally, we observed the process of CAR-M engulfing pancreatic cancer cells using confocal microscopy and a long-term fluorescence live cell imaging system. In an in situ tumor model transplanted into NOD/SCID mice, we administered intraperitoneal injections of CAR-M to confirm its inhibitory function on pancreatic cancer. Furthermore, we validated these findings in human monocyte-derived macrophages (hMDM).ResultsBioinformatics and tumor tissue microarray analyses revealed significantly higher expression levels of c-MET in tumor tissues, compared to the paired peritumoral tissues, and higher c-MET expression correlated with worse patient survival. CAR-M cells were engineered using human monocytic THP-1 cell line and hMDM targeting c-MET (CAR-M-c-MET). The CAR-M-c-MET cells demonstrated highly specific binding to pancreatic cancer cells and exhibited more phagocytosis and killing abilities than the pro-inflammatory polarized control macrophages. In addition, CAR-M-c-MET cells synergized with various cytotoxic chemotherapeutic drugs. In a NOD/SCID murine model, intraperitoneally injected CAR-M-c-MET cells rapidly migrated to tumor tissue and substantially inhibited tumor growth, which did not lead to obvious side effects. Cytokine arrays and mRNA sequencing showed that CAR-M-c-MET produced higher levels of immune activators than control macrophages.ConclusionsThis study provides compelling evidence for the safety and efficacy of CAR-M therapy in treating pancreatic cancer. The results demonstrate that CAR-M-c-MET significantly suppresses pancreatic cancer progression and enhances the effectiveness of cytotoxic chemotherapy. Remarkably, no discernible side effects occur. Further clinical trials are warranted in human pancreatic cancer patients.

Predictors of missed hospital appointments in patients with posterior compartment pelvic floor disorders in a tertiary referral centre

Aim:Missed hospital appointments pose a major challenge to the healthcare system leading to worse patient outcomes. We ascertained the incidence of missed hospital appointments in patients with Posterior Compartment Pelvic Floor Disorders (PC-PFD) and associated socio-demographic and clinical predictors. Methods:This is a cross-sectional single-institution study from a tertiary pelvic floor unit (PFU) with data collected from a prospectively maintained database.A missed appointment was marked if patients did not attend two consecutive appointments without informing or asking to re-schedule and were recorded for Telephone Triage Assessment Clinic (TTAC), Specialist-nurse, face-to-face bowel function clinic (BFC), Investigations including endoanal (EAUS) and pelvic floor ultrasound (PFUS) and defecating proctogram (DP). All results yielding p<0.05 were considered significant. Results:PFU received 2001 referrals between 2013 and 2019 with a mean age of 52 years. Missed appointments recorded were: TTAC — 45 (2.2%), BFC — 309 (15.8%), EAUS — 476(24%), PFUS — 484(37.2%) and DP — 432(26.2%).Predictors determined were: Male gender, age <50 years, complaints of rectal pain and bleeding for missing telephone and face-to-face appointments, low socioeconomic status for missing face-to-face appointments, and mixed and other ethnic groups with missing telephone appointments. Conclusion:This is the first study to report the incidence and socio-demographic and clinical predictors for missed appointments in patients with PC-PFD. Future prospective research, including qualitative studies interviewing patients, is needed to identify and address potential barriers patients face when accessing care for PC-PFD. This will help improve patient care and allow better utilisation of already constrained healthcare resources.

Nrf2-mediated adenylosuccinate lyase promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma cells through ferroptosis escape.

Pancreatic cancer has one of the highest fatality rates and the poorest prognosis among all cancer types worldwide. Gemcitabine is a commonly used first-line therapeutic drug for pancreatic cancer; however, the rapid development of resistance to gemcitabine treatment has been observed in numerous patients with pancreatic cancer, and this phenomenon limits the survival benefit of gemcitabine. Adenylosuccinate lyase (ADSL) is a crucial enzyme that serves dual functions in de novo purine biosynthesis, and it has been demonstrated to be associated with clinical aggressiveness, prognosis, and worse patient survival for various cancer types. In the present study, we observed significantly lower ADSL levels in gemcitabine-resistant cells (PANC-1/GemR) than in parental PANC-1 cells, and the knockdown of ADSL significantly increased the gemcitabine resistance of parental PANC-1 cells. We further demonstrated that ADSL repressed the expression of CARD-recruited membrane-associated protein 3 (Carma3), which led to increased gemcitabine resistance, and that nuclear factor erythroid 2-related factor 2 (Nrf2) regulated ADSL expression in parental PANC-1 cells. These results indicate that ADSL is a candidate therapeutic target for pancreatic cancer involving gemcitabine resistance and suggest that the Nrf2/ADSL/Carma3 pathway has therapeutic value for pancreatic cancer with acquired resistance to gemcitabine.

LMAN2 Promotes Breast Cancer Tumorigenesis and Drug Resistance by Interacting With MAPK9 via Activation of the MAPK Pathway

ABSTRACTIntroductionBreast cancer (BC) is the most prevalent malignancy among women worldwide. Lectin, mannose‐binding 2 (LMAN2) is a cargo receptor engaged in the transport and sorting of glycoproteins. Despite its ubiquity, the function and underlying mechanisms of LMAN2 in BC continue to elude understanding.MethodsMultiple databases were employed to examine the expression of LMAN2 in breast cancer. Immunohistochemistry(IHC), qRT‐PCR, and Western blot were performed to quantify LMAN2 expression in BC cell lines and clinical samples. Heat map analysis and Kaplan–Meier analysis were used to analyze the correlation between LMAN2 and clinicopathological features. SiRNAs and overexpression plasmids were transfected into two BC cells to assess the effect of LMAN2 on malignant phenotypes. Coimmunoprecipitation and immunofluorescence were used to screen for potential interacting proteins. Additionally, tumor subcutaneous xenograft mode was constructed to explore tumor chemoresistance.ResultLMAN2 expression was significantly higher in BC compared to that in matched, adjacent normal tissues, and its higher expression level was correlated with worse patient prognosis. In vitro, we found that LMAN2 functions as an oncogene, promoting BC cell proliferation, cell cycle progression, invasion, and chemoresistance while preventing apoptosis. Coimmunoprecipitation and colocalization experiments confirmed the direct binding of LMAN2 to MAPK9 in BC cells. Our investigation of signaling pathways suggested that LMAN2 is involved in the regulation of the MAPK signaling pathway, utilizing this pathway to confer cisplatin resistance. Furthermore, knockdown of LMAN2 improves the sensitivity of drug‐resistant BC cells to cisplatin (DDP) in vivo.ConclusionLMAN2 was a novel diagnostic and prognostic biomarker for BC that promotes chemoresistance via interaction with MAPK9 and activation of the MAPK pathway.

The effects of physician stigma and hesitancy with opioids on patient pain care in the United States: A survey study.

Determine if physician stigma toward patients with chronic pain or opioid use disorder or physician hesitancy prescribing opioids adversely affects patient pain care. Explore the demographics associated with stigma and hesitancy. Survey, 25 questions. Physician faculty at medical schools (80 percent), private physician Facebook® groups (15 percent), and others (5 percent), all specialties. N = 352 attending United States physicians. Physician self-reported patient pain care quality. Subjectively worse patient pain care was not found to be associated with stigma but had a borderline association with hesitancy (p = 0.046). Subjectively worse pain care was associated with less knowledge and experience with opioids (odds ratio [OR] 4.1, 95 percent confidence interval [CI] 3.0-5.6), practicing in the Midwest region (OR 2.1, 95 percent CI 1.2-3.4), and specialty: emergency (OR 53, 95 percent CI 20-139), other internal (OR 15, 95 percent CI 6.6-34), and general medicine (OR 12, 95 percent CI 5.4-26) compared to pain medicine. Physician stigma was more likely to be high in males (OR 2.5, 95 percent CI 1.5-4.3) and medium in physicians over 55 (OR 2.5, 95 percent CI 1.5-4.5). Compared to medium stigma, those with low stigma (General Linear Model (GLM) 0.35, 95 percent CI 0.18-0.52) and high stigma (GLM 0.22, 95 percent CI 0.01-0.44) were both more hesitant to prescribe opioids. More hesitancy was associated with less knowledge and experience (GLM 0.14, 95 percent CI 0.05-0.22) and physicians under 55 (GLM 0.24, 95 percent CI 0.08-0.40). Although physician stigma was not found to affect patient pain care adversely, self-reporting bias and/or questionnaire issues may account for this. Physician specialty and knowledge and experience with opioids were important factors.

LncRNA FIRRE drives gastric cancer progression via ZFP64-mediated TUBB3 promoter activation.

Gastric cancer is a common global malignancy that requires detailed study of its development mechanisms. Although LncRNA FIRRE is known to play a crucial role in the progression and treatment resistance of several cancers, its effect on gastric cancer is not well understood. This study confirms the impact of FIRRE on the malignant behavior of gastric cancer. Using RNA-sequencing, dual luciferase reporter assay, RIP and CHIP, we identified transcription factors and target genes linked to FIRRE. Elevated FIRRE expression in gastric cancer correlates with worse patient prognosis and promotes gastric cancer proliferation, migration, and invasion both in vitro and in vivo. FIRRE regulates the TUBB3 gene, facilitating gastric cancer progression by activating the TUBB3 promoter in vitro. ZFP64 is the transcription factor for TUBB3, activating its promoter and binding specifically with FIRRE. Reducing ZFP64 disrupts FIRRE's positive regulation of TUBB3 in vitro and in vivo. This study shows FIRRE promotes gastric cancer progression by binding to ZFP64 and activating the TUBB3 promoter.

Targeting TSPEAR-AS2 suppresses tumor growth and interferon signaling in esophageal cancer

Dysregulation of long non-coding RNAs (lncRNAs) and interferon signaling contributes to tumorigenesis and progression; however, their crosstalk in tumor biology remains poorly understood. Here, we showed that TSPEAR-AS2, an lncRNA mediated by METTL1, activates the interferon signaling pathway in esophageal cancer (ESCA). Clinically, we conducted a pan-cancer investigation and identified TSPEAR-AS2 as a novel ESCA-related lncRNA that predicts a worse patient prognosis. The high expression of TSPEAR-AS2 was validated in multiple ESCA cohorts, demonstrating that this lncRNA had good diagnostic performance. METTL1, an RNA N7-methylguanosine (m7G) methyltransferase, was positively correlated with TSPEAR-AS2 expression in ESCA tissues, and METTL1 was found to induce TSPEAR-AS2 expression in ESCA cells. Functionally, the up-regulation of TSPEAR-AS2 promoted proliferation, cell cycle progression, migration, and stemness in ESCA cells, whereas its knockdown attenuated these malignant phenotypes. Furthermore, both TSPEAR-AS2 deficiency and antisense oligonucleotide (ASO)-based intratumoral intervention could significantly suppress tumor growth in vivo. Mechanistically, quantitative proteomic analysis revealed that TSPEAR-AS2 ablation altered the expression of functional proteins related to interferon signaling pathways, such as HLA-E, IRF3, and IFITs. These findings identify a previously unrecognized role of the METTL1/TSPEAR-AS2/interferon signaling axis in ESCA development and suggest that TSPEAR-AS2 is a potential prognostic indicator and therapeutic vulnerability for this malignancy.