Late-stage Disease Research Articles

Review of the target trial methodological approach on treatment effect estimates in kidney failure: protocol for a systematic assessment.

Patients with kidney failure often lack robust evidence because they are excluded from randomized trials. Trial emulation provides an alternative approach to derive treatment effect estimates when randomized trials cannot be conducted. Critical questions about the comparative efficacy and safety of interventions in kidney failure are now being answered using this approach or parts of it. However, variations and inconsistencies in reporting cast doubt on the reliability and validity of effect estimates not derived from randomized trials. The aim of this methodological systematic review is to understand the extent to which the target study approach is used in kidney failure and the appropriateness of this approach. By identifying and evaluating studies that qualify as emulating a target trial, compared with studies that did not apply the principles. We aim to provide more specific methodological guidance to increase the clarity and reliability of reporting treatment effect estimates when running a trial in kidney failure is not feasible. This protocol is developed in accordance with Preferred Reporting Items for Systematic reviews and Meta-Analyses Protocols (PRISMA-P) statement. MEDLINE, Embase, and reference lists (backwards citation chasing) will be searched up until 1st July 2023 and the search updated prior to publication to identify all studies evaluating patient outcomes in late-stage kidney disease and failure that use target trial emulation as the primary approach for analysis. Two authors (A. A., P. K.) will select articles based on title and abstract and then full text, with a third reviewer settling disagreements (J. P.). The prespecified variables will be extracted, and the risk of bias will be assessed by at least two authors (A. A., P. K., A. N.) using prespecified data forms. This will enable the determination of the robustness of the methodological quality of observational studies in using the whole or elements of the target trial approach. We will thereby assess their ability to reliably report treatment effect estimates. We will provide specific methodological recommendations on how to design target trials and model assumptions for emulation to get reliable treatment effect estimates for therapeutic interventions in kidney failure. Open Science Framework:Identifier https://doi.org/10.17605/OSF.IO/Z4Y29 .

Clinical characteristics and survival of patients with de novo metastatic prostate cancer treated with androgen deprivation therapy and taxane-based chemotherapy in Uganda: a retrospective study.

Prostate cancer is the second most common cancer among men worldwide. Mortality is highest among patients in resource-limited settings (RLS), in part due to late-stage disease. Among patients with metastatic prostate cancer (mPCa), studies have shown significant improvement in overall survival with the use of androgen deprivation therapy (ADT) and taxane-based chemotherapy. However, outcome data among patients treated with chemo-endocrine therapy are scarce in many resource-limited settings. The aim of this study was to determine the clinical characteristics and 5-year overall survival (OS) of patients with de novo mPCa treated at the Uganda Cancer Institute (UCI). A retrospective chart review study was conducted between 2015 and 2019, and the data of patients with histologically confirmed prostate cancer and radiological evidence of metastasis were reviewed. Sample size was estimated for Cox Proportion Hazard regression. Data on clinical and laboratory characteristics, overall survival, and predictors of survival were extracted. P < 0.05 was considered to indicate statistical significance. A total of 300 patients were enrolled over the 5-year study period. The median age was 68 (IQR 61.5-74) years. At presentation, lower urinary tract symptoms were reported in nearly all patients (96.7%, n = 290), median total prostate specific antigen (PSA) was 414.75 ng/ml and 40% (n = 120) of patients had grade 5 histological scores. In addition to receiving ADT, majority of patients (70.3%, n = 211) received at least 6 cycles of chemotherapy. Overall survival at one year was 92.4% (95% CI: 88.6-94.9%), but it declined to 45.2% (95% CI: 36.8-53.2%) at 5 years. A high Gleason score, the presence of visceral metastasis and receiving less than 6 cycles of chemotherapy were predictors of poor outcomes. Patients with de novo mPCa in Uganda present with high histologic grades and high baseline Prostate Specific Antigen (PSA) levels but have improved 5-year overall survival with a combination of chemotherapy and ADT as a first-line treatment. We recommend interventions to reduce late presentation and prospective studies to evaluate treatment efficacy in this population.

Abstract B056: Towards a generalized machine learning model for Raman spectroscopy-based liquid biopsy in cancer screening using self-supervised learning

Abstract Head and neck cancers, which encompass a range of malignancies affecting the oral cavity, pharynx, and larynx, are critical to address due to their high morbidity and impact on quality of life. This underscores the need for effective and non-invasive diagnostic tools. Raman spectroscopy-based liquid biopsy detects cancers by analyzing intrinsic Raman fingerprints in biofluids without the need for molecular labels, making it a promising point-of-care screening method. However, Raman scattering is weak, and interpreting spectra from biological samples is challenging due to overlapping peaks, fluorescence background, cosmic rays, and instrument noise, which obscure the signal. Extensive preprocessing and advanced analytical techniques are usually needed to isolate the true Raman signal. While machine learning models have shown promise in classifying cancer status from Raman spectra, variations in Raman systems, lack of standardized protocols, and small patient cohorts limit their clinical utility. Our goal is to develop a model for Raman spectroscopy-based liquid biopsy that generalizes across different measurement conditions and clinical indications. A key challenge is the high cost of acquiring extensive labeled training data. To overcome this, we use a Siamese-based, self-supervised model trained on unlabeled spectral data. The model generates synthetic spectra that mimic real variations across Raman systems and measurement protocols by preprocessing the input and adding simulated factors like fluorescence background, noise, and cosmic rays. By maximizing the cosine similarity between the embeddings of the generated spectra and their originals, the model learns meaningful features of the Raman spectra. This approach not only expands the training set but also enhances the model’s stability across different instruments. In our preliminary study, we analyzed thousands of Raman spectra measured on liquid biopsy specimens (blood plasma and saliva) collected from a cohort of 71 head and neck cancer patients (spread across early and late-stage disease) and 44 non-cancerous controls. Spectra were divided into training and test sets with an 80:20 ratio. Each specimen was drop cast onto a quartz substrate and 25 repeated Raman point scans were performed in a grid over the dried spot. We augmented the training set to reach 9,200 spectra, and t-SNE plots of the embeddings of the test set (1,150 spectra) showed clear clustering separated by sample type, with distinct clusters for healthy individuals and cancer patients. Despite the excellent performance for cancer vs control, separation among cancer patients at different stages remains limited, but will be the target of future work building on this study. These results suggest that our label-free approach can effectively distinguish between healthy and cancerous samples using unlabeled data, advancing the potential for the widespread clinical application of Raman-based liquid biopsy powered by machine learning. Citation Format: Yifei Gu, Kwan Lun Chiu, Andrés Muñoz-Jaramillo, Andrew C. Birkeland, Maria Navas-Moreno, Randy Carney. Towards a generalized machine learning model for Raman spectroscopy-based liquid biopsy in cancer screening using self-supervised learning [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B056.

HPB O04 - Human Splenic Ex-Vivo Perfusion Model: A Platform for Translational Basic Science Research

Abstract Background The function of the spleen has always been shrouded in mystery and since the Renaissance leading figures have attempted to understand its function. Vesalius questioned Galen and Marcello Malpighi (1628-1694) gave the first accurate description of the histology and the physiology. The spleen still poses unique challenges as invasive approaches may produce intraperitoneal bleeding, differences between human and animal spleens complicates comparative studies, and post-mortem examinations reveal only late-stage disease manifestations and functional studies are impossible. This study describes a human splenic ex-vivo perfusion model for translational research, using microbiological studies as markers of splenic physiological function. Method Patients with left-sided pancreatic cancers scheduled for distal pancreatic and splenic resection were identified from the Hepato-Pancreatic and Biliary MDT at the University Hospitals of Leicester NHS Trust. Patients were informed, consented, and the surgical approach remained standard, with splenic artery ligation deferred until specimen extraction. The artery was cannulated, and residual blood clots were cleared with Custodiol® HTK solution. The perfusion technique employs an extracorporeal circuit incorporateing anoxygenator and a heated water chamber maintaining a 37°C perfusate. The perfused spleen was infected with Streptococcus Pneumoniae strains, with regular biopsies and perfusate gas analysis performed. Results Since February 2023, nine spleens have been successfully perfused, with an average weight of 169.5 grams, cold ischemic time of 116 minutes, and warm ischemic time of 12.2 minutes. Pressure was maintained at 80 mmHg and hourly perfusate gas analysis demonstrated a mean pH of 7.1 and a gradual increase in lactate. Histopathological examination revealed clear distinctions between the lymphoid tissue and splenic red pulp, with intact central arterioles and healthy cell morphology at time 0 and after 6 hours of perfusion. Additionally, the perfused spleens cleared S. pneumoniae strains to below-detection levels. Conclusion Our work demonstrates that a stable human splenic ex-vivoperfusion model which maintains structural and physiological integrity can be achieved from tissue that would otherwise be discarded. The continued physiological function is confirmed by the clearance of S. pneumoniae. While currently employed for microbiological studies, this model has the potential to facilitate a wide range of different translational science studieswhile reducing the need for animal experimentation. The perfusion times employed for the present study were sufficient to demonstrate bacterial clearance which was the aim but there is capacity in the system to significantly prolong the duration.

OGC SO36 - Complications of palliative oesophageal cancer stent insertion: Audit for a five year period

Abstract Background Oesophageal stents are commonly used for the palliative treatment of inoperable oesophageal malignancy[1]. Stenting of the oesophagus may provide safe and quickly effective management for late-stage disease symptoms. However, there are common complications associated with the oesophageal stents. This audit looks at the types of early and delayed complications from oesophageal stenting, specifically for malignancy. We aim to stratify the types of complication, association between complications and the type of stent used, and the frequency of repeat stenting or repositioning. This will provide patients with better expectations of the complications and compare our practice against published international standards Method All fluoroscopy guided stent insertions between 1/1/2019 and 31/12/2023 for oesophageal malignancy were requested from the hospital radiology department. 101 patients were included for analysis. Their basic demographics were obtained, as well as a disease profile including tumour histology, staging and whether they underwent radiotherapy or chemotherapy. Complications of the stent insertion were then logged. The number of times stents were replaced or repositioned were noted. The type of stent, size parameters, features such as covering, antimigration device and anti-reflux valve were also assessed. In addition, any hospital admissions related to stent complications were also recorded. Results Of 101 patients, the median age was 75, with a higher proportion of male patients ( 71%). After stent fitting there was a median survival length of 94 days. 45% of patients had complications related to the stent. Stent migration was the most frequent complication, 14% of patients experienced stent migration into the stomach, which required repositioning or restenting. Both middle and lower oesophagus stents had equal complication rate. 25% of patients were reported to have overgrowth of tumour affecting the stent, and there was no significant difference in those fitted with a covered stent, meant to reduce overgrowth complications. Conclusion The complications directly resulting from oesophageal stents may adversely affect the palliation of oesophageal cancer patients. In this cohort, the most commonly occurring complications were migration of the stent, immediate symptoms after insertion, and overgrowth of the tumour. Although overgrowth of tumour is part of the disease progression, in many cases it made retrieval of the existing stent or reinsertion more difficult. Our results found no significant difference for complication rates between the different stents, nor the inclusion of antimigration devices. There were no deaths directly due to the stent and no oesophageal perforations reported.

Abstract 4135517: Echocardiographic Biomarkers Enhance Mortality Predictions in Cirrhosis Patients

Introduction: Cirrhosis, a late-stage liver disease, is associated with numerous systemic complications, making long-term mortality prediction challenging. Traditional models like Child-Pugh and MELD are primarily designed for short-term (3-month) mortality. This study evaluates the impact of incorporating echocardiographic (echo) variables in predicting long-term mortality in cirrhosis patients. Methods: A retrospective cohort study was conducted using data from 60 patients with clinically diagnosed cirrhosis from Hippokration Hospital, Greece, spanning 2018 to 2022. Patients were followed for up to 52 months. Exclusion criteria included pre-existing cardiovascular diseases and significant co-morbidities. Patients were categorized into survived to end of study (n=31) and died during study (n=29) groups. Outcomes were analyzed using multivariate logistic regression and Cox proportional hazards models, and include parameters for age, blood pressure, lab-based biomarkers (potassium, pro-brain natriuretic peptide, hemoglobin, platelet count, aspartate transaminase, gamma-glutamyl transferase, uric acid), and echo/ecg measurements (QT interval, left ventricular (LV) ejection fraction, LV global longitudinal strain (GLS), left atrial GLS, annulus velocities, and E/A ratio). Results: The multivariate logistic regression model (MELD+) that included echo variables showed a 10% improvement in area under the curve (AUC: 0.901) compared to the MELD model alone (AUC: 0.817). MELD+ improved risk classification accuracy by nearly 10% with a conservative threshold. The Cox proportional hazards model with MELD+ also demonstrated superior performance (AUC: 0.923; C-index: 0.875; Brier Score: 0.097) compared to the MELD model alone (AUC: 0.892; C-index: 0.831; Brier Score: 0.134). The MELD+ model showed less variation in hazard ratio confidence intervals, indicating more consistent risk estimation. Conclusion: Incorporating echocardiographic measurements enhances the accuracy of long-term mortality predictions in cirrhosis patients. These findings suggest that cardiac imaging should be considered in risk assessments for cirrhosis patients, particularly for predicting survival beyond three months.

The Association Between Medical Insurance, Access to Care, and Outcomes for Patients with Uveal Melanoma in the United States

ABSTRACT Purpose To investigate the association between insurance status and uveal melanoma (UM) care. Methods We utilized the National Cancer Database to identify patients diagnosed with UM from 2004 to 2017. We examined the associations between patient sociodemographic characteristics, specifically insurance status, and UM care. Results Of 7677 patients, 50% had private, 41% Medicare, 4% Medicaid, 3% other government, and 3% no insurance. Most initially received brachytherapy (66%), followed by enucleation/resection (19%) and other treatment (15%). Compared to private, Medicaid and no insurance were associated with higher odds of late-stage disease presentation (p < .05). Patients with Medicare, Medicaid, and no insurance had higher odds of enucleation/resection and lower odds of brachytherapy versus enucleation/resection (p < .05 for all). Medicaid and no insurance were associated with lower odds of other treatment versus enucleation/resection (p < .05). Conclusions Access barriers to UM care may exist based on insurance status and may be associated with later-stage presentation and more radical treatment.

Characteristics of Breast Cancer Patients Who Refused Conventional Treatment in a Teaching Hospital in Southwestern Nigeria

Background Patients’ adherence to treatment recommendations is in the form of a spectrum: complete adherence or total rejection of the offered standard treatments. The aim of this study was to describe the characteristics of breast cancer patients who refused standard treatments in order to engender a focused intervention. Methods This was a retrospective study of breast cancer patients from 2017-2022. Data generated were analyzed using SPSS version 23.0. The results were presented using descriptive statistics. Inferential statistics for subgroup analysis was by chi-square test or risk difference with confidence intervals Results Among 343 patients, 86 (25% (95% CI 21-30) did not initiate conventional oncologic treatment. All were females and their age range was 33–83 years (mean, 49.9±12.0 years). The majority of the women were married (73%), educated (79%), low-income earners (69%), rural dwellers (63%) with advanced disease (81%). None of the patients had government insurance. The mean duration of symptoms was 11.9±9.7 months. Among 71patients with vital information, 50 (70% (95%CI 58-71) were confirmed dead in the last 3 years. The probability of death within 3 years was 38% (95%CI 8.0-68%) and was higher among those diagnosed as late-stage disease. Conclusions A large number of patients still fail to accept conventional treatments after breast cancer diagnosis. Understanding the patients’ characteristics may be necessary to recognize situations where active education and support can help patients accept standard treatment thereby prolonging survival.

The management of adult and paediatric uveitis for rheumatologists.

Uveitis encompasses multiple different conditions that are all characterized by intra-ocular inflammation. Uveitis occurs in the context of many different rheumatological conditions and carries a substantial risk to vision. Uveitis can develop both at the early stages of rheumatic diseases, sometimes even preceding other clinical features, and at later stages of disease. Uveitis can also occur as either a direct or anindirect complication of therapies used to treat patients with rheumatic disease. Conversely, patients with uveitis of non-rheumatic aetiology sometimes require immunosuppression, a treatment option that is not readily accessible to ophthalmologists. Thus, collaborative working between rheumatologists and ophthalmologists is critical for optimal management of patients with uveitis. This Review is written with rheumatologists in mind, to assist in the care of patients with uveitis. We collate and summarize the latest evidence and best practice in the diagnosis, management and prognostication of uveitis, including future trends and research priorities.

Prevalence and comorbid for late-stage chronic kidney disease (CKD) in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) due to urinary obstruction

Chronic Kidney Disease (CKD) is a condition of gradual or chronic decline in kidney function, which is quite severe and caused by various kidney diseases, including urinary obstruction. This disease is progressive and generally irreversible. CKD requires kidney replacement therapy, one of which is continuous ambulatory peritoneal dialysis (CAPD). To determine the prevalence and risk factors for End Stage Renal Disease (ESRD) in patients undergoing CAPD due to urinary obstruction. We performed a retrospective cohort with a cross-sectional study was conducted using secondary data from medical record data of ESRD patients with CAPD accompanied by urinary obstruction at Dr. Saiful Anwar General Hospital, Malang, Indonesia. The prevalence of CKD in patients with CAPD accompanied by urinary obstruction was 6,50% and dominated by males (57,8%) with an age range of 41-50 years (26%). The majority of comorbidities are severely high the Body Mass Index (BMI) (89,0%) and hypertension (80,8%). The location of obstruction is mostly unilateral (5,64%) with mild levels (4,06%). Urinary obstruction is a frequent clinical finding in CKD patients with CAPD. The most common risk factor in this study was hypertension. The prevalence and comorbidities among CAPD patients with Urinary obstruction (UO) are better understood because to this study. It is necessary to recognise its limitations, particularly the small sample size and single-centre design. Future studies should involve more centres and larger patient groups in order to provide a more thorough knowledge of the mechanisms behind the high survival rates among CAPD patients.

Therapeutic Role of Bone Marrow Mesenchymal Stem Cells (BMSCs) in Nonalcoholic Steatohepatitis (NASH) Cirrhosis

Abstract: NASH cirrhosis is a late-stage nonalcoholic fatty liver disease (NAFLD) characterized by high morbidity, high relapse rate, and high mortality, which is clinical to treat. Presently, liver transplantation is the most effective radical treatment, but it is difficult to be widely carried out due to the problems of large surgical trauma, lack of liver donors, and strong immunological rejection. Bone marrow mesenchymal stem cells (BMSCs) are a type of stem cell with characteristics of self-replication, multidirectional differentiation, and easy accessibility. The use of BMSCs for cell transplantation therapy has the advantages of fewer complications and significant efficacy, and it has become an important option for cell transplantation therapy, especially for liver diseases. In this paper, we will review the studies related to the use of BMSCs for the treatment of NASH cirrhosis in recent years.

Left atrial and left ventricular positive and negative remodeling after catheter ablation of atrial fibrillation

Abstract Introduction Atrial fibrillation (AF) is associated with negative remodeling of left atrium (LA) and in later stages of diseases with negative remodeling of left ventricle (LV). Can radiofrequency ablation (RFA) of pulmonary veins cure AF and retain progression of arrhythmia? Purpose This study evaluated positive and negative remodeling of LA and LV after RFA of pulmonary veins and a 7-year follow-up. The patients were divided into 4 groups on the basis of Pulmonary Vein Isolation Outcome Degree (PVIOD 1-4), a new measure for the efficacy of catheter ablation of AF. Methods One hundred seventeen patients with symptomatic drug-refractory paroxysmal and persistent AF were treated with RFA. At baseline and after a 7 years of follow-up, 2-dimensional echocardiography was performed to assess LA diameter, left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD) and left ventricular ejection fraction (LVEF). Results After a 7-year follow-up 32.5% patients with successful single RFA of AF (PVIOD 1) showed significant positive LA and LV remodeling: LA diameter 39.3±0.6 vs 36.5±0.6 mm, p=0.0007; LVEDD 53.1±0.6 vs 50.9±0.7 mm, p=0.008; LVESD 34.7±0.8 vs 32.0±0.1 mm, p=0.005 and LVEF 56.8±0.8 vs 62.1±1.1 %, p=0.000008. In 29.1% of patients with success after multiple procedures (PVIOD 2) occurred significant reverse LA remodeling: LA diameter 41.9±0.7 vs 40.2±0.6 mm, p=0.04. Clinical success (PVIOD 3) after RFA was defined as a significant reduction in the number and duration of AF episodes with or without previously ineffective antiarrhythmic drugs (AAD) class I and III. In 14.5% of subjects with long-term clinical success (PVIOD 3 and baseline LA diameter 43.2±1.0 mm) remodeling of LA and LV was not occurred. In 23.9% of patients with procedural and clinical failure after RFA (PVIOD 4) long-term follow-up showed significant negative remodeling of LA and LV: LA diameter 44.7±0.7 vs 47.4±0.7 mm, p=0.006; LVEDD 52.8±0.9 vs 57.1±0.6 mm, p=0.0006; LVESD 36.5±1.1 vs 40.7±1.2 mm, p=0.006 and LVEF 50.7±1.7 vs 43.8±1.8 %, p=0.004. Conclusions Single successful RFA of pulmonary veins in early stage of AF with normal LA diameter cure arrhythmia, which was proved with LA and LV positive remodeling after a 7-year follow-up. With increase of LA diameter, the success of RFA decrease. The multiple procedures slow the progression of AF, but are less effective because of long periods of time between them. Clinical success and role of AAD therapy are also important in AF management. If AF is not treated with RFA properly on time it becomes progressive disease.

The incidence and prevalence of Dupuytren’s disease in primary care: results from a text mining approach on registration data

Background The focus of research and management of Dupuytren’s disease (DD) is shifting from relieving symptoms in the later stages of disease towards the prevention of contractures. Treatment services might likewise shift towards primary care. Studying characteristics of DD patients who seek medical care for the first time, may identify a symptomatic target group for early DD treatments. We present the first study that estimates the incidence and prevalence of DD in primary care by applying a text-mining algorithm to registration data. Methods This is a population-based cohort study using electronic health records from Dutch general practices involved in a regional research network. Descriptive statistics were used to describe sex, age, comorbidities and lifestyle factors, the latter two were identified via International Classification of Primary Care (ICPC) codes. Incidence rate was calculated as number of patients with a first contact for DD/1000 person years for the years 2017–2021, point prevalence as the percentage of patients with a contact for DD in 2021. DD contacts were identified using a text-mining algorithm. Results The incidence ranged between 1.41 and 1.72/1000 person years and the overall prevalence was 1.99%. Incidence and prevalence are higher among males and increase with age, peaking between 61 and 80 years. Conclusions Our results of prevalence and incidence of DD in primary care give an insight into the relevant population of patients with symptomatic DD that might be the future target group for potential disease controlling treatments.

A case of Peripartum Cardiomyopathy with associated Post-Cesarean section and Grand mal seizure

Peripartum cardiomyopathy (PPCM) is a rare but life-threatening disease in later stages of pregnancy. PPCM presents in the last month of pregnancy or within five months of puerperium in the absence of pre- existing heart disease. It remains a poorly understood entity and its management remains a topic of debate. Although majority recovers, long-term morbidity is quitecommon. Peripartum discomforts often mask and delay the diagnosis of PPCM. Unavailability of previous cardiac imaging is rather common and this makes the diagnosis even more complicated. Early and aggressive management towards reducing preload show evidence of better outcome. Here we report a case of PPCM presenting to us diagnosed after Caesarean Section followed by Grand mal seizure. Bangladesh Crit Care J September 2024; 12 (2): 163-166

Progress in the Application of Porous Tantalum Metal in Hip Joint Surgery.

Porous tantalum metal is a new orthopedic implant material made of tantalum metal that has been processed by porous treatment. This material has various advantages, including high hardness, good ductility, good biocompatibility, and strong bone integration ability. Porous tantalum metal has performed well in clinical application, demonstrating excellent medium- to long-term curative effects. The use of implant products made of porous tantalum metal, such as porous tantalum rods, porous tantalum hip prostheses, and porous tantalum augments (MAs), is gradually increasing in the clinical application of hip surgery, and these products have achieved excellent therapeutic effects in the middle and late stages of various hip diseases. In recent years, the combined application of porous tantalum metal and three-dimenional (3D) printing technology to create personalized 3D-printed porous tantalum metal has led to new development directions for the treatment of complex hip joint surgical diseases. This review presents a summary of the application of porous tantalum metal in hip surgery in recent years, including clinical treatment effects and existing problems. In addition, the prospect of progress in this field is promoted.

Demyelination and neurodegeneration early in experimental autoimmune encephalomyelitis contribute to functional deficits in the anterior visual pathway

Impaired visual function is a prevalent feature of optic neuritis (ON) in multiple sclerosis (MS). Abnormal visual evoked potential (VEP) findings of increased latencies, reduced amplitudes and abnormal waveforms as well as decreased retinal nerve fiber layer (RNFL) assessed by optical coherence tomography (OCT) are hallmarks of ON-induced visual dysfunction. Here we utilized the experimental autoimmune encephalomyelitis (EAE) mouse model of MS to investigate the functional and pathological progression during early (before any clinical symptoms), peak (initial maximal clinical symptoms), and late (chronic disease for > 3 weeks) disease stages. Demyelination and initial stages of axon damage were observed in early EAE. Significant demyelination, inflammation, increased axon damage and impaired P1/N2 amplitudes and latencies by VEP were seen in middle and late EAE groups. A decrease in RNFL thickness by OCT was observed only during late EAE. NanoString analysis of optic nerves from late EAE indicated elevated inflammation-related genes, reduced myelin-related genes, and changes in axon degeneration-related genes. Early inflammatory demyelination and functional deficits of the visual pathway, if untreated, may lead to severe irrecoverable axon damage in EAE. These studies potentially help explain the progression of visual dysfunction during MS.

Validation of a Biopsychosocial Distress Screening Tool, SupportScreen, in a Brazilian Cancer Center.

Biopsychosocial distress is a common yet often underestimated complication in cancer care. We sought to translate and evaluate the psychometric properties of SupportScreen distress assessment tool in Brazil. A cancer cohort study was conducted at a public hospital in Brazil. The SupportScreen tool underwent transcultural translation into Portuguese. Eligible patients completed the SupportScreen, Distress Thermometer (DT), Hospital Anxiety and Depression Scale (HADS), and Functional Assessment of Cancer Therapy-General version (FACT-G). Statistical analyses included confirmatory and exploratory factor analyses (CFA and EFA), comparisons with established distress tools, and assessments of associations with patients' characteristics. A total of 302 patients were assessed (M:F 35.4%:64.6%; median age: 55). Most patients were diagnosed with breast (29.1%) and gastrointestinal cancer (20.5%), at advanced disease stage (78.8%). CFA identified optimal models for emotional and physical distress; EFA revealed two factors for the logistics of medical care: practical and medical system distress. The concurrent validity of subscales demonstrated significant correlations between distress domains. Sensitivity analyses indicated good performance of emotional and physical domains in identifying distress compared to gold standard criteria. Female patients were more likely to report high emotional distress, while younger age and late disease stage were associated with higher physical distress. Additionally, late disease stage was linked to higher practical distress. Emotional and physical domains demonstrated validity and reliability, aligning with validated measures. Logistics of medical care distress revealed practical and medical system dimensions, expanding understanding of patient challenges. The SupportScreen tool exhibited concurrent validity and sensitivity in identifying distress.

Urgent palliative care: An effective intervention to improve end-of-life experience and outcomes for patients with advanced cancer.

203 Background: Early integration of palliative care services for advanced oncology patients has a well-documented benefit on quality-of-life measures including symptom management, quality-of-death measures, cost-effectiveness, care-giver burden, and patient satisfaction metrics. However many barriers exist, including delayed referrals and negative perceptions of hospice/palliative care by patients and families. Furthermore, wait times from referral to visit can vary from weeks to months. For patients with late-stage disease, rapidly advancing disease or symptoms, this delay can lead to unnecessary acute care utilization, impoverished quality-of-life, and discordant end-of-life care. Methods: The CU Cancer Center CARE clinic provides advanced symptom management and urgent care services to oncology patients, often seeing patients with high symptom burden and advanced disease. A recent unpublished case-based analysis demonstrated that patients seen in CARE clinic 4 times or more in a month have a high risk of inpatient mortality within 3 months. In response, the CARE clinic created an urgent palliative care program wherein patients have the ability to see a palliative care provider within 1 week of referral who could provide ongoing advanced symptom management/medication titration and facilitate conversations around goal-concordant care in late-stage illness. A 1-year feasibility pilot took place from 2022-2023. Referrals required patients to meet the following criteria: 1) Not already being seen by an ambulatory palliative care professional; and 2) any of the following: prognosis of weeks without an end-of-life care plan; symptoms likely to require hospitalization if not addressed within a week; or seen in CARE clinic 4 or more times in the last month From 09/2022-08/2023, 55 patients were seen. Outcomes were followed for 3 months following final CARE clinic visit and were compared to patients who had received palliative care referrals from the CARE clinic in the preceding year (9/2021-9/2022). Results: In-hospital deaths, hospital days in the last 30 days of life, and palliative care/hospice involvement were all positively affected in our initial pilot. Notably, in-hospital deaths were reduced by 50%. There was also a 14% increase in deaths with hospice care in the pilot group compared to the control group. Conclusions: Data from this feasibility pilot suggest that urgent palliative care can improve key metrics in oncology quality-of-care, and improve cost effectiveness. Further delineation of the outcomes compared in a rigorously controlled population will further define the relative clinical benefit and fiscal implications of such interventions. Urgent palliative care outcomes. Historical Control (2021-2022) Pilot (2022-2023) N 44 55 Hospitalizations 101 52 Deaths 30 (68%) 40 (72%) Deaths in the Hospital 8 (18%) 5 (9%) Deaths With Hospice Care 21 (47%) 34 (61%)

3D mapping of direct VTA-CA2 circuit with potential involvement in Parkinson's disease degeneration.

Parkinson's disease dementia (PDD) is commonly developed in patients at the late stage of Parkinson's disease (PD) with unknown progression mechanisms. From the post-mortem tissues and animal models, the ventral tegmental area (VTA) and the CA2 regions are closely associated with dementia development in PDD. However, the structural connection between the two regions has not been fully traced. In this study, we applied tissue clearing and adeno-associated virus (AAV) tracing to map the neural circuits in a 3D manner. Hence, we have confirmed the direct connection between the regions with two dual AAV tracing systems and traced the VTA-CA2 circuit in 3D reconstruction. With the immunostaining, we have shown that the GABAergic neurons are the potential subtype of the postsynaptic CA2 neurons in the VTA-CA2 circuit. Under the 6-hydroxydopamine (6-OHDA), we have demonstrated the degeneration of the VTA-CA2 from the observation of fragmented axonal projections. Collectively, we have first traced the direct connection of the whole VTA-CA2 circuit in an intact 3D manner and monitored the fragmentation of this target circuit in the 6-OHDA model. This VTA-CA2 circuit can be a target for future studies of the pathological spreading and degeneration mechanism from PD to PDD.

Pseudomonas aeruginosa Infection and Inflammation in Cystic Fibrosis: A Pilot Study With Lung Explants and a Novel Histopathology Scoring System.

Pseudomonas aeruginosa is the predominant bacterial pathogen colonizing the cystic fibrosis (CF) lung. Mixed populations of nonmucoid and mucoid variants of P. aeruginosa have been isolated from the CF airway. While the association between mucoid variants and pulmonary function decline is well-established, their impact on inflammation and tissue damage in advanced CF lung disease remains unclear. This pilot study utilized 1 non-CF and 3 CF lung explants to examine lobar distribution, inflammation, and histopathology related to nonmucoid and mucoid P. aeruginosa infection. To study tissue damage, we developed a novel lung histopathology scoring system, the first applied to human CF lung biopsies, which is comprised of five indicators: bronchiolar epithelial infiltrate, luminal inflammation, peribronchial/bronchiolar infiltrate, peribronchiolar fibrosis, and alveolar involvement. Mucoid P. aeruginosa variants were distributed throughout the CF lung but associated with greater concentrations of proinflammatory cytokines, IL-1β, TNF-α, IL-6, IL-8, and IFN-γ, and one anti-inflammatory cytokine, IL-10, compared to nonmucoid variants. CF lung explants exhibited higher histopathology scores compared to a non-CF lung control. In mixed-variant infection, nonmucoid constituents associated with increased bronchiolar epithelial infiltration, one indicator of histopathology. This pilot study suggests ongoing interplay between host and bacterial elements in late-stage CF pulmonary disease. Mucoid P. aeruginosa infection correlates with inflammation regardless of lung lobe, whereas nonmucoid P. aeruginosa is associated with increased inflammatory cell infiltration. The development of a novel lung histopathology scoring system lays the groundwork for future large-cohort investigations.