Natural History and Outcomes of Individuals with Functional Bowel Disorder: a 9-year Population-based Longitudinal Study.

BACKGROUND OBJECTIVES: Long-term studies characterizing the natural history of functional bowel disorder (FBD) from community-based settings and exploring association with psychological factors are sparse. We aimed to evaluate the evolution of symptoms, health outcomes, and association of FBD with psychological disorders in Chinese population. METHODS: Individuals identified from random sampling of residents of Hangzhou, China participated in a baseline survey in January of 2010. Follow-up phone survey was conducted in December of 2018. FBD was diagnosed based on Rome III criteria. RESULTS: Among 452 individuals (mean age 44.6±15.3 years, 174 (38%) male) who completed the study, the prevalence of FBD was 36.3% (95%CI 32.6-40.0%) at enrollment and 36.1% (95%CI 32.3-39.8%) at follow-up survey (p=0.94). However, 214 (47%) individuals had interval change in diagnosis. Although no difference in incidence of organic disease or death was observed, a higher proportion of patients with FBD (16/164, 9.8% vs. 9/288, 3.1%; p=0.003) compared to those without FBD received non-cancer-related abdominal and/or pelvic surgery during follow-up. FBD was associated with anxiety and/or depression at initial (AOR=1.7, 95%CI 1.7-2.7, p=0.02) and follow-up (AOR=8.0, 95%CI 3.2-20.0, p<0.001) surveys. Diagnosis of FBD at baseline was associated with new-onset anxiety and/or depression at follow-up (OR=3.2, 95%CI 1.2-8.3, p=0.01). CONCLUSION: Although the prevalence of FBD remained stable, transformation of symptoms was common over time. Patients with FBD may have increased risk of receiving non-cancer related abdominal and/or pelvic surgery. FBD symptoms at baseline increased the risk of new-onset anxiety and/or depression by 3.2-fold over the next 9 years.

Impact of an Inter-Professional Clinic on Pancreatic Cancer Outcomes: A Retrospective Cohort Study.

Background: Pancreatic ductal adenocarcinoma (PDAC) presents significant challenges in diagnosis, staging, and appropriate treatment. Furthermore, patients with PDAC often experience complex symptomatology and psychosocial implications that require multi-disciplinary and inter-professional supportive care management from health professionals. Despite these hurdles, the implementation of inter-professional clinic approaches showed promise in enhancing clinical outcomes. To assess the effectiveness of such an approach, we examined the impact of the Wallace McCain Centre for Pancreatic Cancer (WMCPC), an inter-professional clinic for patients with PDAC at the Princess Margaret Cancer Centre (PM). Methods: This retrospective cohort study included all patients diagnosed with PDAC who were seen at the PM before (July 2012-June 2014) and after (July 2014-June 2016) the establishment of the WMCPC. Standard therapies such as surgery, chemotherapy, and radiation therapy remained consistent across both time periods. The cohorts were compared in terms of survival rates, disease stage, referral patterns, time to treatment, symptoms, and the proportion of patients assessed and supported by nursing and allied health professionals. Results: A total of 993 patients were included in the review, comprising 482 patients pre-WMCPC and 511 patients post-WMCPC. In the multivariate analysis, adjusting for ECOG (Eastern Cooperative Oncology Group) and stage, it was found that post-WMCPC patients experienced longer median overall survival (mOS, HR 0.84, 95% CI 0.72-0.98, p = 0.023). Furthermore, the time from referral to initial consultation date decreased significantly from 13.4 to 8.8 days in the post-WMCPC cohort (p < 0.001), along with a reduction in the time from the first clinic appointment to biopsy (14 vs. 8 days, p = 0.022). Additionally, patient-reported well-being scores showed improvement in the post-WMCPC cohort (p = 0.02), and these patients were more frequently attended to by nursing and allied health professionals (p < 0.001). Conclusions: The implementation of an inter-professional clinic for patients diagnosed with PDAC led to improvements in overall survival, patient-reported well-being, time to initial assessment visit and pathological diagnosis, and symptom management. These findings advocate for the adoption of an inter-professional clinic model in the treatment of patients with PDAC.

Neuroimaging Features of Cytokine-related Diseases.

Cytokines are small secreted proteins that have specific effects on cellular interactions and are crucial for functioning of the immune system. Cytokines are involved in almost all diseases, but as microscopic chemical compounds they cannot be visualized at imaging for obvious reasons. Several imaging manifestations have been well recognized owing to the development of cytokine therapies such as those with bevacizumab (antibody against vascular endothelial growth factor) and chimeric antigen receptor (CAR) T cells and the establishment of new disease concepts such as interferonopathy and cytokine release syndrome. For example, immune effector cell-associated neurotoxicity is the second most common form of toxicity after CAR T-cell therapy toxicity, and imaging is recommended to evaluate the severity. The emergence of COVID-19, which causes a cytokine storm, has profoundly impacted neuroimaging. The central nervous system is one of the systems that is most susceptible to cytokine storms, which are induced by the positive feedback of inflammatory cytokines. Cytokine storms cause several neurologic complications, including acute infarction, acute leukoencephalopathy, and catastrophic hemorrhage, leading to devastating neurologic outcomes. Imaging can be used to detect these abnormalities and describe their severity, and it may help distinguish mimics such as metabolic encephalopathy and cerebrovascular disease. Familiarity with the neuroimaging abnormalities caused by cytokine storms is beneficial for diagnosing such diseases and subsequently planning and initiating early treatment strategies. The authors outline the neuroimaging features of cytokine-related diseases, focusing on cytokine storms, neuroinflammatory and neurodegenerative diseases, cytokine-related tumors, and cytokine-related therapies, and describe an approach to diagnosing cytokine-related disease processes and their differentials. ©RSNA, 2024 Supplemental material is available for this article.

When Should I Get My Next COVID-19 Vaccine? Data From the Surveillance of Responses to COVID-19 Vaccines in Systemic Immune-Mediated Inflammatory Diseases (SUCCEED) Study.

OBJECTIVE: To determine how serologic responses to coronavirus disease 2019 (COVID-19) vaccination and infection in immune-mediated inflammatory disease (IMID) are affected by time since last vaccination and other factors. METHODS: Post-COVID-19 vaccination, data, and dried blood spots or sera were collected from adults with rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, ankylosing spondylitis and spondylarthritis, and psoriasis and psoriatic arthritis. The first sample was collected at enrollment, then at 2 to 4 weeks and 3, 6, and 12 months after the latest vaccine dose. Multivariate generalized estimating equation regressions (including medications, demographics, and vaccination history) evaluated serologic response, based on log-transformed anti-receptor-binding domain (RBD) IgG titers; we also measured antinucleocapsid (anti-N) IgG. RESULTS: Positive associations for log-transformed anti-RBD titers were seen with female sex, number of doses, and self-reported COVID-19 infections in 2021 to 2023. Negative associations were seen with prednisone, anti-tumor necrosis factor agents, and rituximab. Over the 2021-2023 period, most (94%) of anti-N positivity was associated with a self-reported infection in the 3 months prior to testing. From March 2021 to February 2022, anti-N positivity was present in 5% to 15% of samples and was highest in the post-Omicron era, with antinucleocapsid positivity trending to 30% to 35% or higher as of March 2023. Anti-N positivity in IMID remained lower than Canada's general population seroprevalence (> 50% in 2022 and > 75% in 2023). Time since last vaccination was negatively associated with log-transformed anti-RBD titers, particularly after 210 days. CONCLUSION: Ours is the first pan-Canadian IMID assessment of how vaccine history and other factors affect serologic COVID-19 vaccine responses. These findings may help individuals personalize vaccination decisions, including consideration of additional vaccination when > 6 months has elapsed since last COVID-19 vaccination/infection.

Genetics and Genomics of Pulmonary Fibrosis: Charting the Molecular Landscape and Shaping Precision Medicine.

Recent genetic and genomic advancements have elucidated the complex etiology of idiopathic pulmonary fibrosis (IPF) and other progressive fibrotic interstitial lung diseases (ILDs), emphasizing the contribution of heritable factors. This state-of-the-art review synthesizes evidence on significant genetic contributors to pulmonary fibrosis (PF), including rare genetic variants and common single nucleotide polymorphisms (SNPs). The MUC5B promoter variant is unusual, a common SNP that markedly elevates the risk of early and established PF. We address the utility of genetic variation in enhancing understanding of disease pathogenesis, clinical phenotypes, improving disease definitions, and informing prognosis and treatment response. Critical research gaps are highlighted, particularly the underrepresentation of non-European ancestries in PF genetic studies and the exploration of PF phenotypes beyond usual interstitial pneumonia (UIP)/IPF. We discuss the role of telomere length, often critically short in PF, and its link to progression and mortality, underscoring the genetic complexity involving telomere biology genes (TERT, TERC) and others like SFTPC and MUC5B. Additionally, we address the potential of gene-by-environment interactions to modulate disease manifestation, advocating for precision medicine in PF. Insights from gene expression profiling studies and multi-omic analyses highlight the promise for understanding disease pathogenesis and offer new approaches to clinical care, therapeutic drug development, and biomarker discovery. Finally, we discuss the ethical, legal, and social implications of genomic research and therapies in PF, stressing the need for sound practices and informed clinical genetic discussions. Looking forward, we advocate for comprehensive genetic testing panels and polygenic risk scores to improve the management of PF and related ILDs across diverse populations.

Comparison of Image Quality and Radiation Dose in Pediatric Temporal Bone CT using Photon Counting Detectors CT and Energy Integrating Detectors CT.

BACKGROUND AND PURPOSE: To compare the image quality and radiation dose of temporal bone CT scans in pediatric patients acquired with photon counting detectors (PCD) CT and energy integrating detectors (EID) CT. MATERIALS AND METHODS: The retrospective study included a total of 110 pediatric temporal bone CT scans (PCD-CT, n=52; EIDCT, n=58). Two independent readers evaluated the spatial resolution of 4 anatomical structures (tympanic membrane, incudostapedial joint, stapedial crura, and cochlear modiolus) and overall image quality using a 4-point scale. Inter-reader agreement was assessed. Dose length product (DLP) for each CT was compared, and subgroup analyses were performed based on age (under 3 years, 3-5 years, 6-11 years, and 12 years and above). RESULTS: PCD-CT demonstrated statistically significantly higher scores than EID-CT for all items (tympanic membrane, 2.9 vs. 2.4; incudostapedial joint, 3.6 vs. 2.6, stapedial crura, 3.2 vs. 2.4; cochlear modiolus, 3.4 vs. 2.8; overall image quality, 3.6 vs. 2.8; p<0.05). Inter-reader agreement ranged from good to excellent (ICCs, 0.6-0.81). PCD-CT exhibited a 43% dose reduction compared to EID-CT, with a particularly substantial reduction of over 70% in the subgroups of children under 6 years. CONCLUSIONS: PCD temporal bone CT achieves significantly superior imaging quality at a lower radiation dose compared to EID-CT. ABBREVIATIONS: PCD-CT = photon counting detectors CT; EID-CT = energy integrating detectors CT; DLP = dose length product; AEC = automatic exposure control; ICC = interclass correlation coefficient.

Transoral Robotic Surgery and Radiation Volume Deintensification in Unknown Primary Squamous Cell Carcinoma of the Neck: The Phase 2 FIND Nonrandomized Controlled Trial.

Importance: Patients with unknown primary squamous cell carcinoma (CUP) with cervical metastases typically receive comprehensive radiotherapy (RT) of the pharynx and bilateral neck. Typically, these patients receive comprehensive RT of the pharynx and bilateral neck that may produce treatment-related toxic effects. Objective: To determine whether localization of occult oropharyngeal cancers with transoral robotic surgery (TORS) combined with reduced pharyngeal and neck RT volumes provides acceptable disease control. Design, Setting, and Participants: This phase 2, single-group nonrandomized controlled trial at a single institution accrued 32 prospective participants with p16-positive CUP without a primary squamous cell carcinoma on examination and imaging from 2017 to 2019, and 24-month follow-up. The data analysis was conducted from January 2021 to June 2022. Intervention: Diagnostic- (n = 13) or therapeutic-intent (n = 9) TORS, with pharyngeal-sparing radiotherapy (PSRT) prescribed for negative margins or pT0, and unilateral neck RT (UNRT) prescribed for unilateral lymphadenopathy with lateralized primary tumor or pT0. Main Outcomes and Measures: Out-of-radiation treatment volume failure (<15% was hypothesized to be acceptable) and reports of local and regional recurrence, overall survival, toxic effects, swallowing outcomes (per the MD Anderson Dysphagia Inventory), and videofluoroscopic swallow (per Dynamic Imaging Grade of Swallowing Toxic Effects [DIGEST]) ratings. Results: The study sample comprised 22 patients (mean [SD] age, 59.1 [5.7] years; 3 [14%] females and 19 [86%] male) with CUP. Of these, 19 patients (86%) had tumor stage cN1; 2 (9%), cN2; and 1 (5%), cN3. Five patients (23%), 14 patients (64%), and 3 patients (13%) had 0, 1, or 2 primary tumors, respectively. Twenty patients received RT; of these, 9 patients (45%) underwent PSRT and 10 patients (50%), UNRT. In the diagnostic-intent group, 8 patients (62%) and 5 patients (38%) underwent RT and RT-concurrent chemotherapy, respectively. In the therapeutic-intent group, 6 patients (67%) and 1 patient (11%) received adjuvant RT-concurrent chemotherapy, respectively; 2 patients declined RT. Two-year out-of-radiation treatment volume failure, locoregional control, distant metastasis control, and overall survival were 0%, 100%, 95%, and 100%, respectively. Grade 3 or 4 surgical, acute, and late toxic effects occurred in 2 (9%), 5 (23%), and 1 (5%) patients, respectively. PSRT was associated with lower RT dose to superior constrictors (37 vs 53 Gy; mean difference, 16 Gy; 95% CI, 6.4, 24.9), smaller decline in swallowing scores during treatment (19.3 vs 39.7; mean difference, -20.4; 95% CI, -34.1 to -6.1), and fewer patients with worsening DIGEST grade on findings of videofluoroscopic swallow studies at 2 years (0% vs 60%; difference, 60%; 95% CI, 30% to 90%). Conclusions and Relevance: These findings indicate that TORS for p16-positive CUP allows RT volume deintensification with excellent outcomes and support future investigation in randomized clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT03281499.

Direct Sub-Scarpal Lipectomy Combined With Liposuction in Abdominoplasty: An Analysis of Safety & Efficacy in 200 Consecutive Patients.

BACKGROUND: Abdominoplasty procedures continue to evolve as combining techniques such as suction-assisted lipectomy or direct sub-scarpal lipectomy have proven to be powerful adjuncts to achieve optimal aesthetic results. However, there is apprehension in combining techniques simultaneously given the potential to affect the vascularity of the abdominoplasty flap. OBJECTIVES: To assess the safety and efficacy of simultaneous direct sub-scarpal lipectomy combined with liposuction in abdominoplasty patients. METHODS: A 4-year retrospective review of consecutive abdominoplasties (n = 200) performed by a single surgeon was conducted. Liposuction of the abdominal flap and flanks was performed in all patients. After raising the abdominoplasty flap, undermining was performed to just beyond the xyphoid, lower rib margins superiorly, and to the anterior axillary line laterally. Fat deep to Scarpa's fascia was then removed by direct tangential excision in all zones of the abdominal flap. RESULTS: Average values included: Age, 42.19; BMI, 28.10 kg/m2; follow up, 7 months. Seroma occurred in 13 patients (6.5%), superficial wound dehiscence treated with local wound care in 16 patients (8%), hypertrophic scarring in 16 patients (8%), partial umbilical necrosis in one patient (0.5%), and partial umbilical epidermolysis in six patients (3%). No patients experienced major or minor full-thickness tissue loss. No patients needed reoperation. CONCLUSIONS: Simultaneous direct excision of sub-scarpal fat with liposuction of the abdomen and flanks does not appear to subject any zone of the abdominoplasty flap to increased risks of vascular compromise. No flap necroses were observed. The use of our technique is safe and may provide superior abdominoplasty results.

Telemedicine-enabled biofeedback electropalatography rehabilitation (TEBER): A pilot study for patients treated with surgery for oral cavity carcinoma.

BACKGROUND: To address the rehabilitative barriers to frequency and precision of care, we conducted a pilot study of a biofeedback electropalatography (EPG) device paired with telemedicine for patients who underwent primary surgery +/- adjuvant radiation for oral cavity carcinoma. We hypothesized that lingual optimization followed by telemedicine-enabled biofeedback electropalatography rehabilitation (TEBER) would further improve speech and swallowing outcomes after "standard-of-care" SOC rehabilitation. METHOD: Pilot prospective 8-week (TEBER) program following 8 weeks of (SOC) rehabilitation. RESULTS: Twenty-seven patients were included and 11 completed the protocol. When examining the benefit of TEBER independent of standard of care, "range-of-liquids" improved by +0.36 [95% CI, 0.02-0.70, p = 0.05] and "range-of-solids" improved by +0.73 [95% CI, 0.12-1.34, p = 0.03]. There was a positive trend toward better oral cavity obliteration; residual volume decreased by -1.2 [95% CI, -2.45 to 0.053, p = 0.06], and "nutritional-mode" increased by +0.55 [95% CI, -0.15 to 1.24, p = 0.08]. CONCLUSION: This pilot suggests that TEBER bolsters oral rehabilitation after 8 weeks of SOC lingual range of motion.

Proactive Polypharmacy Management Using Large Language Models: Opportunities to Enhance Geriatric Care.

Polypharmacy remains an important challenge for patients with extensive medical complexity. Given the primary care shortage and the increasing aging population, effective polypharmacy management is crucial to manage the increasing burden of care. The capacity of large language model (LLM)-based artificial intelligence to aid in polypharmacy management has yet to be evaluated. Here, we evaluate ChatGPT's performance in polypharmacy management via its deprescribing decisions in standardized clinical vignettes. We inputted several clinical vignettes originally from a study of general practicioners' deprescribing decisions into ChatGPT 3.5, a publicly available LLM, and evaluated its capacity for yes/no binary deprescribing decisions as well as list-based prompts in which the model was prompted to choose which of several medications to deprescribe. We recorded ChatGPT responses to yes/no binary deprescribing prompts and the number and types of medications deprescribed. In yes/no binary deprescribing decisions, ChatGPT universally recommended deprescribing medications regardless of ADL status in patients with no overlying CVD history; in patients with CVD history, ChatGPT's answers varied by technical replicate. Total number of medications deprescribed ranged from 2.67 to 3.67 (out of 7) and did not vary with CVD status, but increased linearly with severity of ADL impairment. Among medication types, ChatGPT preferentially deprescribed pain medications. ChatGPT's deprescribing decisions vary along the axes of ADL status, CVD history, and medication type, indicating some concordance of internal logic between general practitioners and the model. These results indicate that specifically trained LLMs may provide useful clinical support in polypharmacy management for primary care physicians.

Causes and impact of delays during the COVID-19 pandemic on head and neck cancer diagnosis.

BACKGROUND: The causes for delays during the COVID19 pandemic and their impact on head and neck cancer (HNC) diagnosis and staging are not well described. METHODS: Two cohorts were defined a priori for review and analysis-a Pre-Pandemic cohort (June 1 to December 31, 2019) and a Pandemic cohort (June 1 to December 31, 2020). Delays were categorized as COVID-19 related or not, and as clinician, patient, or policy related. RESULTS: A total of 638 HNC patients were identified including 327 in the Pre-Pandemic Cohort and 311 in the Pandemic Cohort. Patients in the Pandemic cohort had more N2-N3 category (41% vs. 33%, p = 0.03), T3-T4 category (63% vs. 50%, p = 0.002), and stage III-IV (71% vs. 58%, p < 0.001) disease. Several intervals in the diagnosis to treatment pathway were significantly longer in the pandemic cohort as compared to the Pre-Pandemic cohort. Among the pandemic cohort, 146 (47%) experienced a delay, with 112 related to the COVID-19 pandemic; 80 (71%) were clinician related, 15 (13%) were patient related, and 17 (15%) were policy related. CONCLUSIONS: Patients in the Pandemic cohort had higher stage disease at diagnosis and longer intervals along the diagnostic pathway, with COVID-19 related clinician factors being the most common cause of delay.

Anatomic Subtype Differences in Extramammary Paget Disease: A Meta-Analysis.

Importance: Extramammary Paget disease (EMPD) is a rare, highly recurrent cutaneous malignant neoplasm of unclear origin. EMPD arises most commonly on the vulvar and penoscrotal skin. It is not presently known how anatomic subtype of EMPD affects disease presentation and management. Objective: To compare demographic and tumor characteristics and treatment approaches for different EMPD subtypes. Recommendations for diagnosis and treatment are presented. Data Sources: MEDLINE, Embase, Web of Science Core Collection, and Cochrane Reviews CENTRAL from December 1, 1990, to October 24, 2022. Study Selection: Articles were excluded if they were not in English, reported fewer than 3 patients, did not specify information by anatomic subtype, or contained no case-level data. Metastatic cases on presentation were also excluded. Data Extraction and Synthesis: Abstracts of 1295 eligible articles were independently reviewed by 5 coauthors, and 135 articles retained. Reporting was in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. The analysis was cunducted in August 2019 and updated in November 2022. Findings: Most vulvar EMPD cases were asymptomatic, and diagnosis was relatively delayed (mean, 25.1 months). Although most vulvar EMPD cases were intraepidermal (1247/1773 [70.3%]), radical surgeries were still performed in almost one-third of cases. Despite this aggressive surgical approach, 481 of 1423 (34%) recurred, commonly confined to the skin and mucosa (177/198 [89.4%]). By contrast, 152 of 1101 penoscrotal EMPD cases (14%) recurred, but more than one-third of these recurrences were regional or associated with distant metastases (54 of 152 [35.5%]). Perianal EMPD cases recurred in one-third of cases (74/218 [33.9%]), with one-third of these recurrences being regional or associated with distant metastasis (20 of 74 [27.0%]). Perianal EMPD also had the highest rate of invasive disease (50% of cases). Conclusions and Relevance: The diagnosis and treatment of EMPD should differ based on anatomic subtypes. Considerations for updated practice may include less morbid treatments for vulvar EMPD, which is primarily epidermal, and close surveillance for local recurrence in vulvar EMPD and metastatic recurrence in perianal EMPD. Recurrences in penoscrotal subtype were less common, and selective surveillance in this subtype may be considered. Limitations of this study include the lack of replication cohorts and the exclusion of studies that did not stratify outcomes by anatomic subtype.

Efficacy of probiotic supplementation and impact on fecal microbiota in patients with inflammatory bowel disease: a systematic review and meta-analysis of randomized controlled trials.

Context: Research regarding the treatment of inflammatory bowel disease (IBD) with probiotics has not yielded consistent results. OBJECTIVE: The aim of this meta-analysis was to evaluate the efficacy of probiotics supplementation in patients with IBD. DATA SOURCES: Randomized controlled trials (RCTs) evaluating the efficacy of probiotics in patients with IBD were searched in PubMed, the Google Scholar database, Web of Science, and CrossRef for the period July 2003 to June 2023. DATA EXTRACTION: The RCTs were extracted, independently by 2 authors, according to the PICOS criteria. DATA ANALYSIS: Seven studies, including a total of 795 patients, met the study criteria. Five end points were selected to evaluate the efficacy. Of these, 3 indicators showed a statistically significant difference in efficacy: C-reactive protein (odds ratio [OR]: -2.45, 95% confidence interval [CI]: -3.16, -1.73, P < .01), the number of fecal Bifidobacterium (OR: 3.37, 95% CI: 3.28, 3.47, P < .01), and Lactobacillus(OR: 2.00, 95% CI: 1.91, 2.09, P < .01). The other 2 indicators (disease activity for Crohn's disease and for ulcerative colitis) showed no statistically significant difference, while the OR reflected a positive correlation. CONCLUSION: Probiotics supplementation may have a positive effect on IBD by reducing clinical symptoms, reducing the serological inflammatory markers, and increasing favorable gut flora in patients with IBD. Additional RCTs are needed to evaluate the therapeutic effect of probiotics in IBD.

A multidimensional classifier to support lung transplant referral in patients with pulmonary fibrosis.

BACKGROUND: Lung transplantation remains the sole curative option for patients with idiopathic pulmonary fibrosis (IPF), but donor organs remain scarce, and many eligible patients die before transplant. Tools to optimize the timing of transplant referrals are urgently needed. METHODS: Least absolute shrinkage and selection operator was applied to clinical and proteomic data generated as part of a prospective cohort study of interstitial lung disease (ILD) to derive clinical, proteomic, and multidimensional logit models of near-term death or lung transplant within 18 months of blood draw. Model-fitted values were dichotomized at the point of maximal sensitivity and specificity, and decision curve analysis was used to select the best-performing classifier. We then applied this classifier to independent IPF and non-IPF ILD cohorts to determine test performance characteristics. Cohorts were restricted to patients aged ≤72 years with body mass index 18 to 32 to increase the likelihood of transplant eligibility. RESULTS: IPF derivation, IPF validation, and non-IPF ILD validation cohorts consisted of 314, 105, and 295 patients, respectively. A multidimensional model comprising 2 clinical variables and 20 proteins outperformed stand-alone clinical and proteomic models. Following dichotomization, the multidimensional classifier predicted near-term outcome with 70% sensitivity and 92% specificity in the IPF validation cohort and 70% sensitivity and 80% specificity in the non-IPF ILD validation cohort. CONCLUSIONS: A multidimensional classifier of near-term outcomes accurately discriminated this end-point with good test performance across independent IPF and non-IPF ILD cohorts. These findings support refinement and prospective validation of this classifier in transplant-eligible individuals.

Binding and Activation of LRP1-Dependent Cell Signaling in Schwann Cells Using a Peptide Derived from the Hemopexin Domain of MMP-9.

Schwann cells (SCs) undergo phenotypic transformation and then orchestrate nerve repair following a peripheral nervous system injury. The low-density lipoprotein receptor-related protein-1 (LRP1) is significantly upregulated in SCs in response to acute injury, activating cJun and promoting SC survival. Matrix-metalloproteinase-9 (MMP-9) is an LRP1 ligand that binds LRP1 through its hemopexin domain (PEX) and activates SC survival signaling and migration. To identify novel peptide mimetics within the hemopexin domain of MMP-9, we examined the crystal structure of PEX, synthesized four peptides, and examined their potential to bind and activate LRP1. We demonstrate that a 22 amino acid peptide, peptide 2, was the only peptide that activated Akt and ERK1/2 signaling in SCs, similar to a glutathione s-transferase (GST)-fused holoprotein, GST-PEX. Intraneural injection of peptide 2, but not vehicle, into crush-injured sciatic nerves activated cJun greater than 2.5-fold in wild-type mice, supporting that peptide 2 can activate the SC repair signaling in vivo. Peptide 2 also bound to Fc-fusion proteins containing the ligand-binding motifs of LRP1, clusters of complement-like repeats (CCRII and CCRIV). Pulldown and computational studies of alanine mutants of peptide 2 showed that positively charged lysine and arginine amino acids within the peptide are critical for stability and binding to CCRII. Collectively, these studies demonstrate that a novel peptide derived from PEX can serve as an LRP1 agonist and possesses qualities previously associated with LRP1 binding and SC signaling in vitro and in vivo.

Integrating Patient-Reported Outcomes Into Prognostication in Gastroesophageal Cancer: Results of a Population-Based Retrospective Cohort Analysis.

BACKGROUND: Patient-reported outcomes measures (PROM) are self-reflections of an individual's physical functioning and emotional well-being. The Edmonton Symptom Assessment Scale (ESAS) is a simple and validated PRO tool of 10 common symptoms and a patient-reported functional status (PRFS) measure. The prognostic value of this tool is unknown in patients with gastroesophageal cancer (GEC). In this study, we examined the association between the ESAS score and overall survival (OS) in patients with GEC, the prognostication difference between ESAS and Eastern Cooperative Oncology Group (ECOG), and assessed the correlation between PRFS and the physician-reported ECOG performance status (PS). METHODS: The study was a retrospective cohort study of 211 patients with GEC with localized (stages I-III) and metastatic disease who completed at least one baseline ESAS prior to treatment. Patients were grouped into 3 cohorts based on ESAS score. OS was assessed using the Kaplan-Meier method, and the concordance index (c-index) was calculated for ESAS and physician-reported ECOG. The agreement between PRFS and physician-ECOG was also assessed. RESULTS: In total, 211 patients were included. The median age was 60.8 years; 90% of patients were ECOG PS 0-1; 38% of patients were stages I-III, while 62% were de novo metastatic patients. Median OS in low, moderate, high symptom burden (SB) patients' cohorts was 19.17 m, 16.39 mm, and 12.68 m, respectively (P < .04). The ability to predict death was similar between physician-ECOG and ESAS (c-index 0.56 and 0.5753, respectively) and PRFS and physician-ECOG (c-index of 0.5615 and 0.5545, respectively). The PS agreement between patients and physicians was 50% with a weighted Kappa of 0.27 (95% CI: 0.17-0.38). CONCLUSION: Patient's SB seems to carry a prognostic significance. ESAS and physician-reported ECOG exhibit comparable prognostic values. Physicians and patients can frequently have divergent opinions on PS. ESAS takes a patient-centered approach and should be encouraged in practice among patients with GEC as an additional tool for prognostication.

Tri-system integration in metal-oxide nanocomposites via in-situ solution-processed method for ultrathin flexible transparent electrodes.

For stable operation of ultrathin flexible transparent electrodes (uFTEs), it is critical to implement effective risk management during concurrent multi-loading operation of electrical bias and mechanical folding cycles in high-humidity environments. Despite extensive efforts in preparing solution-processed uFTEs with cost-effective and high-throughput means, achieving in-situ nano-adhesion in heterogeneous metal-oxide nanocomposites remains challenging. In this work, we observed by serendipity liquid-like behaviour of transparent metal-oxide-semiconductor zinc oxide nanoparticles (ZnONPs) onto silver nanowires (AgNWs) developed by in-situ solution processed method (iSPM). This enabled us to address the long-standing issue of vulnerability in the nanocomposite caused by the interface of dissimilar materials between AgNWs and ZnONPs, resulting in a remarkably improved multi-loading operation. Importantly, substrate-integrated uFTEs constituted of the metal-oxide nanocomposite electrode semi-embedded in the polymer matrix of greatly thin <0.5 µm thickness is successfully demonstrated with the smooth surface topography, promoted by the tri-system integration including (i) AgNW-AgNW, (ii) ZnONP-ZnONP, and (iii) AgNW-ZnONP systems. Our finding unveils the complex interfacial dynamics associated with the heterogeneous interface system between AgNWs and ZnONPs and holds great promise in understanding the in-situ nano-adhesion process and increasing the design flexibility of next generation solution-processed uFTEs.