Regulation of exosomes as biologic medicines: Regulatory challenges faced in exosome development and manufacturing processes.

With advances in medical technology, extracellular vesicles, also known as exosomes, are gaining widespread attention because of their potential therapeutic applications. However, their regulatory landscape is complex and varies across countries because of their unique intracellular mechanisms of action. The diversity of manufacturing techniques renders their standardization challenging, leading to a fragmented regulatory landscape. The current global regulatory framework of exosomes can be broadly classified into two strategies: one involves elucidating constituent components within exosomes and the other involves examining the physiological repercussions of their secretion. When using exosomes as therapeutic agents, they should be governed similarly to biological medicinal products. Similar to biologics, exosomes have been analyzed to determine their particle size and protein composition. An exosome-based therapeutic agent should be clinically approved after understanding its molecular composition and structure and demonstrating its pharmacokinetics and therapeutic efficacy. However, demonstrating the pharmacokinetics and therapeutic efficacy of exosomes is challenging for regulatory agencies. This article reviews the technical characteristics of exosomes, analyzes the trends in regulatory laws in various countries, and discusses the chemistry, manufacturing, and control requirements of clinical applications.

Pelvic congestion syndrome analysis through quantitative 2-dimensional phase-contrast magnetic resonance imaging: A promising vision from an observational cohort study.

BACKGROUND: To examine the application of quantitative 2-dimensional phase-contrast magnetic resonance imaging (2D PC-MRI) for treating patients with pelvic congestion syndrome (PCS). MATERIALS AND METHODS: We conducted a retrospective cross-sectional analysis by using quantitative 2D PC-MRI data enrolled between April 2017 and Sep 2023. In addition, 32 healthy female controls (HCs) were included. RESULTS: Most patients with PCS presented with chronic pelvic pain and more than half had extra-pelvic venous symptoms (80/81, 98% and 45/81, 56%, respectively). Quantitative 2D PC-MRI analyzed the 81 patients with PCS, 239 patients without PCS, and 32 HCs. The patients with PCS had higher stroke volume (SV), absolute SV (ASV), and mean flux (MF) in the calf region (interstitial pixel shift) than did the HCs. In the left gonadal vein, the patients with PCS had higher SV, backward flow volume (BFV), ASV, and MF and lower forward flow volume (FFV), stroke distance (SD), and mean velocity (MV) than did the HCs. However, the patients with PCS had lower SV, FFV, MF, SD, and MV in the great saphenous veins. Quantitative 2D PC-MRI analysis revealed that the PCS group had higher SV, FFV, BFV, ASV, and MF in the calf region than did the non-PCS group. The variables that most strongly differentiated the patients with PCS from the HCs were SV in the great saphenous veins, SD in the great saphenous veins and left gonadal vein, and MV in the great saphenous veins and left gonadal vein. Caudal flow in the left gonadal vein was identified in half of the patients with PCS (39/81, 48.1%); 14 of them received embolization for left gonadal vein. CONCLUSIONS: In additional to providing an objective 3-dimensional morphology of the pelvic veins and extra-pelvic leaks, quantitative 2D PC-MRI analysis reveals distinct hemodynamic profiles between patients with PCS, those without PCS, and HCs, especially in the gonadal veins and regional perfusion of the calves.

A pilot study on the detection of microsatellite instability using long mononucleotide repeats in solid tumors.

Microsatellite instability (MSI) status is a prognostic biomarker for immunotherapy in certain types of cancers, such as colorectal cancers (CRCs) and endometrial cancers (ECs). Tumors that are categorized as having high MSI (MSI-H) express high levels of neoantigens for immune recognition. The typical MSI test measures the length of short mononucleotide repeats (SMR) poly(A) 21-27; however, a limitation of this test is the difficulty in determining the shift size, particularly in endometrial cancer. To investigate an MSI detection assay with improved performance, the present study analyzed the use of poly(A) 40-44 mononucleotide repeats to detect the MSI status of 100 patients with either CRC (n=50) or EC (n=50). Capillary electrophoresis was used to evaluate five long mononucleotide repeat (LMR) markers, including poly(A) 40-A, 40-B, 40-C, 40-D and 44. The concordance rate of the LMR-MSI assay compared with an immunohistochemistry MSI detection assay was 96.0 and 95.1% for CRCs and ECs respectively, with the detection limit of the LMR-MSI assay demonstrated to be 2.5% MSI-H in HCT116 colorectal carcinoma cell lines. The LMR-MSI assay yielded a 95.1% concordance rate in ECs compared with that in the SMR-MSI test (87.8%). The LMR-MSI test identified a significantly higher mean shift size (13 bp) in MSI-H tumors compared with the SMR-MSI test (10 bp), in both EC and CRC tissue samples. Together, the present study suggested that the LMR-MSI test could potentially be a sensitive and practical technology for molecular laboratory testing, particularly in the use of immunotherapy for patients with CRCs and ECs.

Identification of organic constituents on atmospheric particulate matter in the East Asian background air of free troposphere by GC×GC-TOFMS.

The presence of organic compounds on the particulate matter (PM) or aerosols can arise from the condensation of gaseous organic compounds on the existing aerosols, or from organic precursors to form secondary organic aerosols (SOA) through photochemistry. The objective of this study is to characterize organic constituents on aerosols relevant to their emission sources and the key compounds revealing the evolution of aerosols with the use of a novel analytical technique. A time-of-flight mass spectrometry (TOFMS) coupled with comprehensive two-dimensional gas chromatography (GC×GC) was developed using a flow type of modulator instead of a thermal type as a prelude to field applications without the need for cryogen. The methodology of GC×GC-TOFMS is discussed in this study in detail. Since the coarse PM (PM10-2.5) may exhibit with a relatively high OC content compared to PM2.5, the GC×GC results have been obtained by analyzing PM10 samples collected in parallel with OC/EC analysis of PM2.5 samples at the Lulin Atmospheric Background Station (LABS, 23.47°N, 120.87°E, 2,862 m ASL) as the high-mountain background site in East Asia. We found that the organic analytes were in a majority in the range of 12 - 30 carbon numbers falling in the category of semi-volatile organic compounds (SVOCs) with 43 compounds of alcohol, aldehyde, ketone, and ester varieties if excluding alkanes. Intriguingly, trace amounts of plasticizers and phosphorus flame retardants such as phthalates (PAEs) and triphenyl phosphate (TPP) were also found, likely originating from regions involved in open burning of household solid waste in Southeast Asia or e-waste recycling in southern China and along the long-range transport route. Compounds such as these are unique to the specific sources, demonstrating the wide spread of these hazardous compounds in the environment.

Mitochondrial HMG-CoA Synthase Deficiency: A Cyclic Vomiting Mimic Without Reliable Biochemical Markers.

Here, we report an individual, eventually diagnosed with HMG-CoA synthase deficiency, who presented with a cyclic vomiting phenotype. HMG-CoA synthase deficiency is a rare disorder affecting ketone body synthesis in which affected individuals typically present at a young age with hypoketotic hypoglycemia, lethargy, encephalopathy, and hepatomegaly, usually triggered by catabolism (e.g., infection or prolonged fasting). This individual presented with recurrent episodes of vomiting and lethargy, often associated with hypoglycemia or hyperglycemia, at 3 years of age. Metabolic labs revealed nonspecific abnormalities in her urine organic acids (showing mild elevation of dicarboxylic acids with relatively low excretion of ketones) and a normal acylcarnitine profile. Given her clinical presentation, as well as a normal upper gastrointestinal series, esophagogastroduodenoscopy with biopsies, and abdominal ultrasound, she was diagnosed with cyclic vomiting syndrome at 3 years of age. Molecular testing completed at 7 years of age revealed a previously reported pathogenic sequence variant (c.1016+1G>A) and a novel likely pathogenic deletion (1.57 kB deletion, including exon 1) within HMGCS2 consistent with HMG-CoA synthase deficiency. This individual's presentation, mimicking cyclic vomiting syndrome, widens the clinical spectrum of HMG-CoA synthase deficiency. In addition, this case highlights the importance of molecular genetic testing in such presentations, as this rare disorder lacks specific metabolic markers.

Applying a deterrence nudge strategy for promoting stair usage in a university setting.

PURPOSE: This study aimed to examine whether indirectly deterring elevator use through time-targeted Point-of-Decision Prompts (PODPs) efficiently increased stair usage in a university setting. METHODS: A quasi-experimental design (pre-post design) was employed over 2 weeks in September 2023. Baseline observations were conducted for 1 week prior to signage placement at two locations. The intervention in this study lasted for 1 week, immediately following baseline observations. Three hundred and thirty-one and 384 participants were observed during the baseline and intervention periods, respectively. Logistic regression analysis was used to examine the increase in the act of ascending the stairs. RESULTS: Our intervention, which focused on time-related messages, effectively increased stair usage among university students (coefficient = 0.435, p-value < 0.01). Furthermore, females (coefficient = -0.820, p-value < 0.05) and individuals aged ≥ 30 years (coefficient = 1.048, p-value < 0.01) were notably more likely to be influenced by our intervention than males and individuals aged < 30 years. CONCLUSION: Indirectly discouraging elevator use through time-targeted PODPs may amplify the effects of the previously employed time-related messages. Our findings suggested that a deterrence nudge should primarily be directed towards promoting stair usage among females or individuals aged ≥ 30 years.

Clinical Outcomes and Targeted Genomic Analysis of Renal Cell Carcinoma Brain Metastases Treated with Stereotactic Radiosurgery.

BACKGROUND: Molecular profiles of renal cell carcinoma (RCC) brain metastases (BMs) are not well characterized. Effective management with locoregional therapies, including stereotactic radiosurgery (SRS), is critical as systemic therapy advancements have improved overall survival (OS). OBJECTIVE: To identify clinicogenomic features of RCC BMs treated with SRS in a large patient cohort. DESIGN, SETTING, AND PARTICIPANTS: A single-institution retrospective analysis was conducted of all RCC BM patients treated with SRS from January 1, 2010 to March 31, 2021. INTERVENTION: SRS for RCC BMs. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Next-generation sequencing was performed to identify gene alterations more prevalent in BM patients. Clinical factors and genes altered in ≥10% of samples were assessed per patient using Cox proportional hazards models and per individual BM using clustered competing risks regression with competing risk of death. RESULTS AND LIMITATIONS: Ninety-one RCC BM patients underwent SRS to 212 BMs, with a median follow-up of 38.8 mo for patients who survived. The median intracranial progression-free survival and OS were 7.8 (interquartile range [IQR] 5.7-11) and 21 (IQR 16-32) mo, respectively. Durable local control of 83% was achieved at 12 mo after SRS, and 59% of lesions initially meeting the radiographic criteria for progression at 3-mo evaluation would be considered to represent pseudoprogression at 6-mo evaluation. A comparison of genomic alterations at both the gene and the pathway level for BM+ patients compared with BM- patients revealed phosphoinositide 3-kinase (PI3K) pathway alterations to be more prevalent in BM+ patients (43% vs 16%, p = 0.001, q = 0.01), with the majority being PTEN alterations (17% vs 2.7%, p = 0.003, q = 0.041). CONCLUSIONS: To our knowledge, this is the largest study investigating genomic profiles of RCC BMs and the only such study with annotated intracranial outcomes. SRS provides durable in-field local control of BMs. Recognizing post-SRS pseudoprogression is crucial to ensure appropriate management. The incidence of PI3K pathway alterations is more prevalent in BM+ patients than in BM- patients and warrants further investigation in a prospective setting. PATIENT SUMMARY: We examined the outcomes of radiotherapy for the treatment of brain metastases in kidney cancer patients at a single large referral center. We found that radiation provides good control of brain tumors, and certain genetic mutations may be found more commonly in patients with brain metastasis.

Treatment-free survival and partitioned survival analysis of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib: 5-year update of CheckMate 214.

BACKGROUND: Immunotherapy can be associated with prolonged disease control even after cessation of treatment without the need for further cancer-directed therapy. Treatment-related adverse events (TRAEs) can also persist after discontinuation of therapy. Treatment-free survival (TFS) with and without toxicity as a component of a partitioned survival model can characterize patient survival time, which is not captured by standard outcome measures. METHODS: Data from 1096 patients with advanced renal cell carcinoma treated with first-line nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib (SUN) in the CheckMate 214 trial were analyzed. TFS was defined as the area between two Kaplan-Meier curves for time from randomization to protocol therapy discontinuation and time from randomization to subsequent systemic therapy initiation or death, estimated as the difference in 60-month restricted mean times with confidence intervals (CIs) obtained using bootstrap sampling. Time on protocol therapy and TFS were further characterized as time with and without grade 2+ and 3+TRAEs. Survival functions were estimated in subgroups including International Metastatic Renal Cell Carcinoma Database Consortium risk groups using the Kaplan-Meier method. RESULTS: At 5 years from randomization, 48% of patients treated with NIVO+IPI and 37% of patients treated with SUN were alive. In the intent-to-treat population, 18% of the NIVO+IPI-treated and 5% of SUN-treated patients are surviving treatment-free. For favorable-risk patients, the 60-month mean TFS was 14.4 months for NIVO+IPI versus 5.5 months for SUN (difference 8.9 months (95% CI 4.9 to 12.8)). TFS for NIVO+IPI versus SUN with grade 2+TRAEs was 5.0 and 2.1 months, respectively, and with grade 3+TRAEs was 1.2 and 0.3 months, respectively. For intermediate/poor-risk patients, the 60-month mean TFS was 10.1 months for NIVO+IPI versus 4.1 months for SUN (difference 6.1 months (95% CI 4.2 to 7.9)). TFS for NIVO+IPI versus SUN with grade 2+TRAEs was 4.0 versus 2.0 months, respectively, and 0.6 versus 0.3 months with grade 3+TRAEs. CONCLUSIONS: Although overall survival was similar, favorable-risk patients treated with NIVO+IPI spent more time surviving treatment-free with and without toxicity versus SUN after 60 months of follow-up. Intermediate/poor-risk patients treated with NIVO+IPI had longer survival and longer TFS without toxicity versus SUN. TRIAL REGISTRATION NUMBER: NCT02231749.

Exploring Potential Intermediates in the Cross-Species Transmission of Influenza A Virus to Humans.

The influenza A virus (IAV) has been a major cause of several pandemics, underscoring the importance of elucidating its transmission dynamics. This review investigates potential intermediate hosts in the cross-species transmission of IAV to humans, focusing on the factors that facilitate zoonotic events. We evaluate the roles of various animal hosts, including pigs, galliformes, companion animals, minks, marine mammals, and other animals, in the spread of IAV to humans.

Measles and Rubella Elimination in the Western Pacific Region in 2013-2022: Lessons Learned from Progress and Achievements Made during Regional and Global Measles Resurgences.

Measles is the most contagious communicable disease, causing an estimated 5.5 million cases and more than 30,000 deaths in the Western Pacific Region (WPR) during 2000. Rubella infection in a pregnant woman can be devastating for the foetus, resulting in congenital rubella syndrome (CRS) in 90% of rubella infections in early pregnancy. It was estimated that approximately 9000 CRS cases occurred in the WPR in 2010. World Health Organization (WHO) Member States in the WPR decided in 2003 to eliminate measles and in 2014 to eliminate rubella from the region. While the WPR successfully attained historically low measles incidence in 2012, it experienced a region-wide measles resurgence in 2013-2016. During the regional resurgence, WHO and Member States accumulated greater knowledge on the epidemiology of measles and rubella in the WPR and strategies to maintain gains. The implementation of the resulting new regional strategy and plan of action from 2018 has proven that measles and rubella elimination is achievable and sustainable under the pressure of multiple importations of measles virus during the world-wide measles resurgences in 2018-2019. This article discusses this progress and achievements towards achieving the global eradication of measles and rubella.

Challenges for Sustaining Measles Elimination: Post-Verification Large-Scale Import-Related Measles Outbreaks in Mongolia and Cambodia, Resulting in the Loss of Measles Elimination Status.

The Western Pacific Region's pursuit of measles elimination has seen significant progress and setbacks. Mongolia and Cambodia were the first two middle-income countries in the Western Pacific to be verified as having eliminated measles by the Western Pacific Regional Verification Commission for Measles and Rubella Elimination, in March 2014 and 2015, respectively. However, both countries experienced large-scale or prolonged importation-related measles outbreaks shortly afterwards, leading to the re-establishment of endemic transmission. We describe the path to initial elimination in both countries and explore these outbreaks' characteristics, factors contributing to the loss of elimination status, and implications for broader elimination efforts. Data sources include case-based epidemiological and laboratory surveillance reports, historical immunization coverage, genotype data, and published reports of in-depth outbreak investigations. In Mongolia, a single prolonged and large-scale outbreak revealed a hidden immunity gap among young adults and was driven in part by nosocomial transmission, leading to significant morbidity and mortality and loss of elimination status. Cambodia suffered multiple importations from neighboring endemic countries during the global measles resurgence in 2018-2019, complicated by cross-border mobility and significant nosocomial amplification, and the country was ultimately unable to sufficiently distinguish independent chains of transmission, leading to loss of elimination status. Our findings highlight the importance of broadening population immunity assessments beyond children to include adults and specific high-risk groups. Robust routine immunization programs, supplemented by tailored SIAs, are crucial for preventing and managing outbreaks. Additionally, strong outbreak preparedness plans, rapid response strategies, and cross-border collaboration and the global effort to prevent multiple resurgences and large-scale importation-induced outbreaks are vital for maintaining elimination status. The experiences of Mongolia and Cambodia underscore the challenges of sustaining measles elimination in the face of importation risks, shared borders with endemic countries, healthcare system gaps, and population movements. Strengthening the global coordination and synchronization of measles elimination activities is imperative to protect the gains achieved and prevent future setbacks.

Calcium Alginate as an Active Device Component for Light-Triggered Degradation of 2D MoS2-Based Transient Electronics.

Transient electronics technology has enabled the programmed disintegration of functional devices, paving the way for environmentally sustainable management of electronic wastes as well as facilitating the exploration of novel device concepts. While a variety of inorganic and/or organic materials have been employed as media to introduce transient characteristics in electronic devices, they have been mainly limited to function as passive device components. Herein, we report that calcium (Ca) alginate, a natural biopolymer, exhibits multifunctionalities of introducing light-triggered transient characteristics as well as constituting active components in electronic devices integrated with two-dimensional (2D) molybdenum disulfide (MoS2) layers. Ca2+ ions-based alginate electrolyte films are prepared through hydrolysis reactions and are subsequently incorporated with riboflavin, a natural photosensitizer, for the light-driven dissolution of 2D MoS2 layers. The alginate films exhibit strain-sensitive triboelectricity, confirming the presence of abundant mobile Ca2+ ions, which enables them to be active components of 2D MoS2 field-effect transistors (FETs) functioning as electrolyte top-gates. The alginate-integrated 2D MoS2 FETs display intriguing transient characteristics of spontaneous degradation upon ultraviolet-to-visible light illumination as well as water exposure. Such transient characteristics are demonstrated even in ambient conditions with natural sunlight, highlighting the versatility of the developed approach. This study emphasizes a relatively unexplored aspect of combining naturally abundant polymers with emerging near atom-thickness semiconductors toward realizing unconventional and transformative device functionalities.

Multisystem disorder associated with a pathogenic variant in CLCN7 in the absence of osteopetrosis.

BACKGROUND: We clinically and genetically evaluated a Taiwanese boy presenting with developmental delay, organomegaly, hypogammaglobulinemia and hypopigmentation without osteopetrosis. Whole-exome sequencing revealed a de novo gain-of-function variant, p.Tyr715Cys, in the C-terminal domain of ClC-7 encoded by CLCN7. METHODS: Nicoli et al. (2019) assessed the functional impact of p.Tyr715Cys by heterologous expression in Xenopus oocytes and evaluating resulting currents. RESULTS: The variant led to increased outward currents, indicating it underlies the patient's phenotype of lysosomal hyperacidity, storage defects and vacuolization. This demonstrates the crucial physiological role of ClC-7 antiporter activity in maintaining appropriate lysosomal pH. CONCLUSION: Elucidating mechanisms by which CLCN7 variants lead to lysosomal dysfunction will advance understanding of genotype-phenotype correlations. Identifying modifier genes and compensatory pathways may reveal therapeutic targets. Ongoing functional characterization of variants along with longitudinal clinical evaluations will continue advancing knowledge of ClC-7's critical roles and disease mechanisms resulting from its dysfunction. Expanded cohort studies are warranted to delineate the full spectrum of associated phenotypes.

Review of Scoring Systems for Predicting 30-Day Mortality in Ruptured Abdominal Aortic Aneurysm.

BACKGROUND: Ruptured abdominal aortic aneurysms (rAAAs) are a serious disease that can lead to high mortality; thus, their early prediction can save patients' lives. The aim of this study was to compare the accuracies of various models for predicting rAAA mortality-including the Glasgow Aneurysm Score, Vancouver Scoring System, Dutch Aneurysm Score, Edinburgh Ruptured Aneurysm Score (ERAS), and Hardman index-based on rAAA treatment outcomes at our institution. METHODS: Between 2016 and 2022, we retrospectively analyzed the early outcome data-including 30-day mortality-of patients who underwent emergency surgery for rAAA at our institution. Receiver operating characteristic curve analysis was performed to compare the aneurysm scoring systems for mortality using the area under the receiver operating characteristic curve (AUC). RESULTS: The AUC was better for the ERAS (0.718; 95% confidence interval, 0.601-0.817) than for the other scoring systems. Significant differences were observed between ERAS and Hardman indices (difference: 0.179; P = 0.016). No significant differences were found among the Glasgow Aneurysm Score, Vancouver Scoring System, and Dutch Aneurysm Score predictive risk models. CONCLUSIONS: Among the models for predicting mortality in patients with rAAA, the ERAS model demonstrated the highest AUC value; however, significant differences were only observed between ERAS and Hardman indices. This study may help develop strategies for improving rAAA prediction.

Temporal changes in microalgal biomass and species composition on different plastic polymers in nutrient-enriched microcosm experiments.

Marine plastic debris (MPD) is a potential threat to marine ecosystems, but its function as a vector for the transportation of harmful microalgae and its impact on the habitats of other marine organisms are uncertain. To address this gap in knowledge, we performed month-long experiments in 30 L microcosms that contained plates made of six different plastic polymers (polypropylene [PP], low-density polyethylene [LDPE], high-density polyethylene [HDPE], polyvinyl chloride [PVC], polyethylene terephthalate [PET], and polystyrene [PS]), and examined the time course of changes in planktonic and periphytic microalgae. There were no significant differences in the composition of periphytic microalgae or biomass among the different plastic polymers (p > 0.05). Nutrient depletion decreased the abundance of planktonic microalgae, but increased the biomass of attached periphytic microalgae (p < 0.05). In particular, analysis of the plastic plates showed that the abundance of benthic species that are responsible for harmful algal blooms (HABs), such as Amphidinium operculatum and Coolia monotis, significantly increased over time (days 21-28; p < 0.05). Our findings demonstrated that periphyton species, including benthic microalgae that cause HABs, can easily attach to different types of plastic and potentially spread to different regions and negatively impact these ecosystems. These observations have important implications for understanding the potential role of MPD in the spread of microalgae, including HABs, which pose a significant threat to marine ecosystems.

Association of CT-DSA vascular assessment and perioperative outcomes in metastatic spinal surgery.

INTRODUCTION: Computed tomography-digital subtraction angiography (CT-DSA) is a radiological method for assessing spinal metastatic tumor vascularity. The study aimed to investigate the association between CT-DSA results and perioperative outcomes in spinal metastatic surgery. MATERIAL AND METHODS: Patients who underwent spinal metastatic operations with preoperative CT-DSA examinations at any time between January 2018 to December 2022. CT-DSA was classified into five grades ranging from grade 0 to grade 4. Grades 3 and 4 were indicative of hypervascularity. We analyzed the perioperative outcomes of intraoperative blood loss amount, massive hemorrhage (≥2500 ml) occurrence, blood transfusion status, operation time, hospital stay duration, and 30-day and 60-day mortality rates. Logistic regression analyses were conducted to identify factors affecting the likelihood of massive hemorrhage in conjunction with CT-DSA. RESULTS: Data from 212 operations involving 209 patients were analyzed. In total, 30, 36, 66, 56, and 24 operations had CT-DSA grades from grade 0 to grade 4, respectively. Eighty (38 %) studies were indicative of hypervascularity. CT-DSA grade was positively correlated with the amount of operative blood loss, the occurrence of massive hemorrhage, and the amount of blood in blood transfusion (p < 0.05). However, CT-DSA grades was not significantly associated with operation duration or mortality rate. A multivariable analysis indicated that factors such as hemoglobulin, hypervascular pathology, and spinal instability neoplastic scores were positively correlated with CT-DSA grade. CT-DSA grade (odds ratio: 2.37, p = 0.02), spinal metastatic invasiveness index, and tumor size (≥50 mL) were found to be independent predictors in a multivariable logistic regression analysis where factors associated with massive hemorrhage were included. Hypervascular pathology type was not significantly associated with the likelihood of hemorrhage in the univariable and multivariable analyses. CONCLUSIONS: CT-DSA serves as an effective tool for assessing vascularity, and is associated with intra-operative blood loss and likelihood of experiencing massive hemorrhage. The predictive capability of CT-DSA surpasses that of traditional histopathology classifications, making it a useful method for preoperative planning in spinal metastatic surgeries.

Retrospective clinical study analysis of skin adverse reactions related to epidermal growth factor receptor inhibitors.

Background: Epidermal growth factor receptor inhibitors (EGFRIs) represent a cornerstone in the targeted therapy of malignant tumors. While effective, dermatological adverse events (dAEs) associated with EGFRIs pose a significant challenge, often necessitating treatment discontinuation due to their severity and potential to impede the continuity of cancer therapy. Despite extensive research, the specific mechanisms and predictors of these adverse events remain poorly understood, particularly in diverse populations. This gap in knowledge underscores the need for targeted studies to better predict and manage these events, enhancing patient outcomes and adherence to life-saving therapies. Methods: This observational study was conducted at The First Affiliated Hospital of Guangxi Medical University, covering cancer patients treated with EGFRIs from 2020 to 2022. We analyzed clinical data including patient demographics, treatment specifics, and the development and timing of dAEs. The study employed SPSS 26.0 software for data analysis, focusing on the incidence of dAEs and factors influencing their occurrence. We used Kaplan-Meier and Cox regression methods to establish a predictive model for dAEs, tracking their onset and impact on treatment continuity. Results: In our study of 120 patients treated with EGFR inhibitors at The First Affiliated Hospital of Guangxi Medical University, we found a high prevalence of dAEs, with 84.2% of patients experiencing such effects. The most common manifestations were papulopustular rashes, observed as pustules in 52.5% and papules in 57.4% of cases, followed by nail lesions in 62.4% of patients, oral or other mucosal ulcers in 34.7%, and hair changes in 26.7%. The median incubation time (MIT) for dAEs was 5 weeks. We identified drug type, ethnicity, and occupation as statistically significant risk factors (P<0.05 for all) that influenced the MIT, which the Cox regression model further identified as protective factors. Nomograms were developed to assess the risk of dAEs, although it is important to note that these models have only been internally validated, lacking external validation data at this stage. Conclusions: The study highlights the high incidence of EGFRIs-associated dAEs, with specific dermatological manifestations posing significant challenges in cancer therapy. The identification of drug type, ethnicity, and occupation as influential factors on the MIT for dAEs informs clinical decisions. Our prediction model serves as a practical tool for evaluating the risk of developing dAEs over time, aiming to optimize patient management and mitigate treatment interruptions.

Quorum Quenching in Membrane Bioreactors for Fouling Retardation: Complexity Provides Opportunities.

The occurrence of biofouling restricts the widespread application of membrane bioreactors (MBRs) in wastewater treatment. Regulation of quorum sensing (QS) is a promising approach to control biofouling in MBRs, yet the underlying mechanisms are complex and remain to be illustrated. A fundamental understanding of the relationship between QS and membrane biofouling in MBRs is lacking, which hampers the development and application of quorum quenching (QQ) techniques in MBRs (QQMBRs). While many QQ microorganisms have been isolated thus far, critical criteria for selecting desirable QQ microorganisms are still missing. Furthermore, there are inconsistent results regarding the QQ lifecycle and the effects of QQ on the physicochemical characteristics and microbial communities of the mixed liquor and biofouling assemblages in QQMBRs, which might result in unreliable and inefficient QQ applications. This review aims to comprehensively summarize timely QQ research and highlight the important yet often ignored perspectives of QQ for biofouling control in MBRs. We consider what this "information" can and cannot tell us and explore its values in addressing specific and important questions in QQMBRs. Herein, we first examine current analytical methods of QS signals and discuss the critical roles of QS in fouling-forming microorganisms in MBRs, which are the cornerstones for the development of QQ technologies. To achieve targeting QQ strategies in MBRs, we propose the substrate specificity and degradation capability of isolated QQ microorganisms and the surface area and pore structures of QQ media as the critical criteria to select desirable functional microbes and media, respectively. To validate the biofouling retardation efficiency, we further specify the QQ effects on the physicochemical properties, microbial community composition, and succession of mixed liquor and biofouling assemblages in MBRs. Finally, we provide scale-up considerations of QQMBRs in terms of the debated QQ lifecycle, practical synergistic strategies, and the potential cost savings of MBRs. This review presents the limitations of classic QS/QQ hypotheses in MBRs, advances the understanding of the role of QS/QQ in biofouling development/retardation in MBRs, and builds a bridge between the fundamental understandings and practical applications of QQ technology.

Centimeter-Scale Tellurium Oxide Films for Artificial Optoelectronic Synapses with Broadband Responsiveness and Mechanical Flexibility.

Prevailing over the bottleneck of von Neumann computing has been significant attention due to the inevitableness of proceeding through enormous data volumes in current digital technologies. Inspired by the human brain's operational principle, the artificial synapse of neuromorphic computing has been explored as an emerging solution. Especially, the optoelectronic synapse is of growing interest as vision is an essential source of information in which dealing with optical stimuli is vital. Herein, flexible optoelectronic synaptic devices composed of centimeter-scale tellurium dioxide (TeO2) films detecting and exhibiting synaptic characteristics to broadband wavelengths are presented. The TeO2-based flexible devices demonstrate a comprehensive set of emulating basic optoelectronic synaptic characteristics; i.e., excitatory postsynaptic current (EPSC), paired-pulse facilitation (PPF), conversion of short-term to long-term memory, and learning/forgetting. Furthermore, they feature linear and symmetric conductance synaptic weight updates at various wavelengths, which are applicable to broadband neuromorphic computations. Based on this large set of synaptic attributes, a variety of applications such as logistic functions or deep learning and image recognition as well as learning simulations are demonstrated. This work proposes a significant milestone of wafer-scale metal oxide semiconductor-based artificial synapses solely utilizing their optoelectronic features and mechanical flexibility, which is attractive toward scaled-up neuromorphic architectures.

Changes in the Remaining Iliac Artery According to Retrograde Flow after Aorto-Femoral Bypass in Abdominal Aortic Aneurysms.

BACKGROUND: Considering a patient's anatomy and vascular conditions, aorto-femoral bypass is a treatment approach for the open repair of abdominal aortic aneurysms. This study aimed at evaluating changes in the remnant iliac artery and their correlation with the preservation state of retrograde flow from femoral anastomosis. METHODS: Of 221 patients who underwent abdominal aortic aneurysm surgery between 2007 and 2022 in Pusan National University Hospital, 29 patients who underwent aorto-femoral bypass were included in this retrospective cohort study. Of these patients, 21 underwent aortobifemoral bypass and 8 underwent aortoiliac-and-femoral bypass. The change in size of the iliac artery from preoperative to postoperative and whether this difference in size depended on the status of postoperative retrograde flow were investigated. Additionally, factors affecting overall mortality and ischemic complications were identified. RESULTS: The median duration from operation to the last follow-up was 2069.5 days (about 5.7 years). The average age of the patients was 78.1 years, and the proportion of males was 75.9%. In cases of disappearance of postoperative retrograde flow from the femoral anastomosis, the postoperative iliac artery size was significantly reduced compared to its preoperative size (18.4 ± 18.9 mm vs. 13.2 ± 7.9 mm, respectively; P = 0.04). The group with maintained retrograde flow had significantly larger residual common iliac artery size than the group with disappearance of flow. (20.0 ± 28.0 mm vs. 14.6 ± 8.5 mm, respectively; P = 0.02). Disappearance of retrograde flow was a significant factor in the iliac artery size reduction after surgery (odds ratio, 2.5; 95% confidence interval, 1.9-5.3; P = 0.02). Three patients with maintained retrograde flow (18.8%) required intervention owing to an increase in the size of the iliac artery. The factors that significantly influenced overall death as analyzed by Cox proportional hazard regression were chronic obstructive pulmonary disease (hazard ratio, 36.8; 95% confidence interval, 1.6-870.0; P = 0.03), peripheral arterial occlusive disease (hazard ratio, 12.7; 95% confidence interval, 1.4-115.8; P = 0.02), and disappearance of retrograde flow (hazard ratio, 8.7; 95% confidence interval, 1.2-63.9; P = 0.03). CONCLUSIONS: Among the open repair methods for abdominal aortic aneurysms, if retrograde flow was not maintained through femoral anastomosis when aorto-femoral bypass was performed, the size of the remaining iliac artery decreased. However, loss of retrograde flow increased long-term mortality. When aorto-femoral bypass is performed, regular imaging follow-up is necessary at appropriate intervals to check the remnant iliac artery and retrograde flow.