bluuebunny/crossref_metadata_2025 huggingface dataset:
Deep learning based identification and interpretability research of traditional village heritage value elements: a case study in Hubei Province
Authors: Tan Gangyi , Zhu Jiangkun , Chen Zhanxiang
Published: June 2024

The preservation and transmission of traditional villages is crucial to the prosperity and development of ethnic cultures. However, current traditional village surveys usually require a large number of experts and scholars to conduct field research, which is an expensive and time-consuming method, especially for large-scale tasks. Therefore, this study proposes an automatic classification method based on deep learning (DL) for the identification of traditional village heritage value elements (TVHVE). The study evaluates four selected convolutional neural network (CNN) frames using traditional villages in Hubei Province as a sample dataset. The results show that Residual Network152 (ResNet152) is the most suitable CNN frame for identifying TVHVE in Hubei. The stability and consistency of various TVHVE present in the ResNet152 model were evaluated using Area Under Curve (AUC) and Precision Recall Curve (PRC), which indicated satisfactory prediction performance for most elements, except for specific elements such as tombstones and stone carvings, which showed lower accuracy. In addition, the study sheds light on the areas of concern of the model with respect to different TVHVE images and elucidates the reasons behind the confusion between elements through semantic clustering based on image classification and interpretability analysis using the Gradient-Weighted Class Activation Mapping (Grad-CAM) heat map. By using an automated classification method based on DL, this study significantly reduces the cost and effort associated with traditional surveys. At the same time, insight into areas of concern and confusion in the model improves guidance for conservation efforts and provides valuable references for subsequent research.
Influence of elastomeric and steel ligatures on periodontal health during fixed appliance orthodontic treatment: a systematic review and meta-analysis
Authors: Hussain Umar , Campobasso Alessandra , Noman Muhammad , Alam Shamsul , Mujeeb Rida , Shehzad Sofia , Papageorgiou Spyridon N.
Published: June 2024

Introduction

Metallic and elastomeric ligatures are widely used in orthodontics to secure the archwire within the bracket slots, but elastomeric ligatures have traditionally been associated with increased microbial colonization, which could adversely affect periodontal health.

Aim

This systematic review compares the periodontal effects of elastomeric and steel ligatures used for orthodontic fixed appliances.

Methods

Unrestricted literature search of 7 databases (MEDLINE, Scopus, Web of Science, Embase, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and Virtual Health Library) up to July 2023 were performed for randomized / non-randomized clinical studies on humans comparing the two ligation methods during fixed-appliance therapy. After duplicate study selection, data extraction, and risk-of-bias assessment with the Risk of Bias (RoB) 2 or the Risk Of Bias In Non-randomized Studies - of Interventions (ROBINS-I) tool, random-effects meta-analyses of Mean Differences (MD) or Standardized Mean Differences (SMD) and their 95% confidence intervals (CIs) were carried out, followed by assessment of certainty of existing evidence with the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach.

Results

A total of 11 studies (3 randomized / 8 non-randomized) with 354 patients (mean age 14.7 years and 42% male) were included. No statistically significant differences were seen for plaque index (5 studies; SMD = 0.48; 95% CI = -0.03 to 1.00; P = 0.07), gingival index (2 studies; MD = 0.01; 95% CI = -0.14 to 0.16; P = 0.89), probing pocket depth (2 studies; MD = 0; 95% CI = -0.17 to 0.16; P = 0.97), or Streptococcus mutans counts (4 studies; SMD = 0.40; 95% CI=-0.41 to 1.20; P = 0.21). Elastomeric ligatures were associated with moderately increased total bacterial load (3 studies; SMD = 0.43; 95% CI = 0.10 to 0.76; P = 0.03). Confidence in these estimates was low in all instances due to the inclusion of non-randomized studies with high risk of bias.

Conclusions

Existing low quality evidence indicates that ligature method does not seem to influence the periodontal health during fixed treatment, even if elastomeric ligatures are associated with a moderate increase of bacterial load.

Registration

PROSPERO (CRD42023444383)
Deformation mechanisms and fluid conditions of mélange shear zones associated with seamount subduction
Authors: Frank Madison , Ujiie Kohtaro , Motohashi Ginta , Nagaya Takayoshi
Published: June 2024

Lithologic heterogeneity and the presence of fluids have been linked to seamount subduction and collocated with slow earthquakes. However, the deformation mechanisms and fluid conditions associated with seamount subduction remain poorly understood. The exhumed Chichibu accretionary complex on Amami-Oshima Island preserves mélange shear zones composed of mudstone-dominated mélange and basalt–limestone mélange deformed under sub-greenschist facies metamorphism. The mudstone-dominated mélange contains sandstone, siliceous mudstone, and basalt lenses in an illitic matrix. The basalt–limestone mélange contains micritic limestone and basalt lenses in a chloritic matrix derived from the mixing of limestone and basalt at the foot of a seamount. The basalt–limestone mélange overlies the mudstone-dominated mélange, possibly representing a submarine landslide from the seamount onto trench-fill terrigenous sediments. The asymmetric S–C fabrics in both mélanges show top-to-SE shear consistent with megathrust-related shear. Quartz-filled shear and extension veins in the mudstone-dominated mélange indicate brittle failure at near-lithostatic fluid pressure and low differential stress. Microstructural observations show that deformation in the mudstone-dominated mélange was accommodated by dislocation creep of quartz and combined quartz pressure solution with frictional sliding of illite, whereas the basalt-limestone mélange was accommodated by frictional sliding of chlorite and dislocation creep of coarse-grained calcite, with possible pressure solution creep and diffusion creep of fine-grained calcite. The mélange shear zones formed in association with seamount subduction record temporal changes in deformation mechanisms, fluid pressure, and stress state during megathrust shear with brittle failure under elevated fluid pressure, potentially linking tremor generation near subducting seamounts.
Gastric rupture caused by intragastric perforation of splenic artery aneurysm: a case report and literature review
Authors: Koguchi Hazuki , Nakatsutsumi Keita , Ikuta Takahiro , Fujita Akihiro , Otomo Yasuhiro , Morishita Koji
Published: June 2024

Background

The rupture of splenic artery pseudoaneurysm (SAP) is life-threatening disease, often caused by trauma and pancreatitis. SAPs often rupture into the abdominal cavity and rarely into the stomach.

Case presentation

A 70-year-old male with no previous medical history was transported to our emergency center with transient loss of consciousness and tarry stools. After admission, the patient become hemodynamically unstable and his upper abdomen became markedly distended. Contrast-enhanced computed tomography performed on admission showed the presence of a splenic artery aneurysm (SAP) at the bottom of a gastric ulcer. Based on the clinical picture and evidence on explorative tests, we established a preliminary diagnosis of ruptured SAP bleeding into the stomach and performed emergency laparotomy. Intraoperative findings revealed the presence of a large intra-abdominal hematoma that had ruptured into the stomach. When we performed gastrotomy at the anterior wall of the stomach from the ruptured area, we found pulsatile bleeding from the exposed SAP; therefore, the SAP was ligated from inside of the stomach, with gauze packing into the ulcer. We temporarily closed the stomach wall and performed open abdomen management, as a damage control surgery (DCS) approach. On the third day of admission, total gastrectomy and splenectomy were performed, and reconstruction surgery was performed the next day. Histopathological studies of the stomach samples indicated the presence of moderately differentiated tubular adenocarcinoma. Since no malignant cells were found at the rupture site, we concluded that the gastric rupture was caused by increased internal pressure due to the intra-abdominal hematoma.

Conclusions

We successfully treated a patient with intragastric rupture of the SAP that was caused by gastric cancer invasion, accompanied by gastric rupture, by performing DCS. When treating gastric bleeding, such rare causes must be considered and appropriate diagnostic and therapeutic strategies should be designed according to the cause of bleeding.
A pilot randomized controlled trial of a telemedicine psychosocial intervention to improve symptom management in adults with long COVID: the COPE study protocol
Authors: Knowles Lindsey M. , Grewal Mehr , Drever Sydney A. , Hoffman Jeanne M. , Friedly Janna L. , Herring Tracy E.
Published: June 2024

Background

Long COVID is a serious public health concern due to its high prevalence and potentially debilitating symptoms. Symptoms may include fatigue, dyspnea, cognitive problems, insomnia, anxiety, and depression. There is currently no cure for long COVID, and the average length of recovery and proportion of patients who fully recover are still unknown. Subsequently, there is a critical need to improve function. Research in other chronic conditions suggests that psychosocial self-management interventions reduce symptom severity and interference with functioning. We describe the design of our study to examine the feasibility, acceptability, appropriateness, and preliminary efficacy of an intervention designed to improve symptom management and coping in adults with long COVID.

Methods

This pilot trial (N = 50) uses a pragmatic, randomized two-group parallel design set within the University of Washington Post-COVID Rehabilitation and Recovery Clinic. The self-management intervention is a 6-week, group-based telemedicine intervention that teaches evidence-based strategies to manage common symptoms and improve stress management as well as communication and self-advocacy. The comparator is a wait-list control. Participants complete self-report measures of the primary and secondary outcomes at baseline and post-treatment/wait-list. Primary outcomes include intervention feasibility, acceptability, and appropriateness. Secondary outcomes include Patient-Reported Outcomes Measurement Information System measures of fatigue, sleep disturbance, cognitive difficulties, self-efficacy, pain interference, depression and anxiety symptoms, and a measure of long COVID symptoms and impression of change. At post-intervention, intervention participants also complete a qualitative interview to inform intervention refinement. Quantitative data will be examined using descriptive and statistical analysis including t-tests and chi-square tests to compare the intervention and wait-list groups on secondary outcomes. Qualitative data will be analyzed using the rigorous and accelerated data reduction technique (RADaR).

Discussion

Results of this pilot randomized controlled trial will characterize the feasibility, acceptability, and appropriateness of the self-management intervention and inform intervention refinement necessary prior to further testing. Long COVID is a public health concern, and rehabilitation approaches that equip patients to manage symptoms may improve patient function and quality of life and reduce burden on the health care system.

Trial registration

NCT05658536. December 16, 2022.
Unraveling the enigma of sarcopenia and sarcopenic obesity in Indian adults with type 2 diabetes – a comparative cross-sectional study
Authors: M. Yogesh , Patel Monika G. , Makwana Hardik Harshadbhai , Kalariya Hardikkumar
Published: June 2024

Background

Sarcopenia and sarcopenic obesity are growing concerns associated with increasing diabetes incidence, but data from Indian diabetic cohorts are limited. This study examined the prevalence and clinical factors associated with sarcopenia and sarcopenic obesity.

Methods

In this cross-sectional study, 750 participants aged 35–70 years were recruited by systematic stratification and a fixed quota sampling technique from medical camps and categorized into diabetic (n = 250), nondiabetic (n = 250), and obese nondiabetic (n = 250) groups. The assessments included questionnaires, muscle mass estimation by bioimpedance analysis, and blood tests. Sarcopenia was defined using the Asian Working Group consensus, and sarcopenic obesity was defined as sarcopenia with a BMI ≥ 25 kg/m2. Logistic regression was used to analyze risk factors.

Results

Sarcopenia affected 60% of diabetic patients, 28% of nondiabetic patients, and 38% of nonobese nondiabetic patients (p < 0.001). The prevalence of sarcopenic obesity was 40%, 11%, and 30%, respectively (p < 0.001). Diabetes was associated with 2.3-fold greater odds (95% CI 1.1–4.7) of sarcopenia and 2.4-fold greater odds (1.1-5.0) of sarcopenic obesity after adjustment. A duration greater than 10 years, uncontrolled diabetes, age greater than 65 years, low physical activity, hypertension, and dyslipidemia also independently increased the odds.

Conclusion

Indian adults with type 2 diabetes have a high burden of sarcopenia and sarcopenic obesity. Early optimization of diabetes care and lifestyle changes are vital for preserving muscle health.
Identifying factors related to delayed neck metastasis after surgical treatment in patients with oral squamous cell carcinoma
Authors: Lee Sang-Min , Kim Hyosik , Ahn Kang-Min
Published: June 2024

Background

General treatment of oral squamous cell carcinoma (OSCC) is surgical treatment with or without neck dissection. Although the incidence of delayed neck metastasis is rare, it may occur after the surgery and is known to be the most important factor in the prognosis. The purpose of is study is to evaluate the clinical and histopathological factors associated with delayed neck metastasis case among patients.

Methods

A total of 195 patients who underwent surgical treatment for OSCC from 2016 to 2022 were investigated. Among them, delayed neck metastasis (DNM) was analyzed. The criterion for delayed neck metastasis was a newly developed neck lesion after the primary operation without neck dissection in cN0 necks. To identify the correlation between prognostic factors and the incidence of delayed neck metastasis, χ2 analysis with phi correlation and Cramer’s V test was performed. Cumulative survival rates (CRS) were compared between the groups with the incidence of DNM and without DNM. Also, the log rank test for CSR and Cox proportional hazard model was analyzed to estimate the significance of the CSR and confirm the correlations between prognostic factors and DNM.

Result

Among 195 patients, 14 were discovered to have DNM. The primary tumor locations were the tongue (n = 5), floor of the mouth (n = 2), mandibular gingiva (n = 1), maxillary gingiva (n = 4), retromolartrigone (n = 1), and buccal mucosa (n = 2) each. The cases consisted of TNM stage I (n = 1), stage II (n = 3), stage III (n = 3), and stage IV (n = 8), respectively. The result of the χ2 analysis identified a correlation between positive neck (p = 0.01), depth of invasion (p = 0.09), radiation therapy (p = 0.003), and DNM. Groups without DNM showed better prognosis compared to groups with DNM. Regarding positive neck, depth of invasion, and radiation therapy, only depth of invasion showed significance in CSR analysis.

Conclusion

DNM after surgical treatment of OSCC is a rare event, and few were found in a review of the literature. Also, many prognostic factors have been suggested but controversial. However, in our study, some prognostic factors have been identified to have a significant correlation with the incidence of DNM, and analysis of such factors provides important information predicting neck metastasis and the prognosis.
Immune checkpoint inhibitor-induced cardiotoxicity in patients with lung cancer: a systematic review and meta-analysis
Authors: Yamani Naser , Ahmed Aymen , Ruiz Gabriel , Zubair Amraha , Arif Fariha , Mookadam Farouk
Published: June 2024

Background

The use of immune checkpoint inhibitors (ICIs) for the treatment of lung cancer may precipitate cardiotoxic events. We aimed to perform a meta-analysis to evaluate the cardiotoxicity associated with ICIs in patients with lung cancer.

Methods

A literature search was conducted across four electronic databases (Cochrane CENTRAL, MEDLINE, OVID EMBASE and Google Scholar) from inception through 31st May 2023. Randomized controlled trials (RCTs) assessing the impact of ICIs on cardiac outcomes in lung cancer patients were considered for inclusion. Risk ratios (RR) with 95% confidence intervals (CIs) were pooled and analysis was performed using a random-effects model. The Grading of Recommendations Assessment, Development and Evaluation approach was followed to assess confidence in the estimates of effect (i.e., the quality of evidence).

Results

A total of 30 studies including 16,331 patients, were included in the analysis. Pooled results showed that single ICI (RR: 2.15; 95% CI: 1.13–4.12; p = 0.02; I2 = 0%) or a combination of single ICI plus chemotherapy (RR: 1.38 [1.05–1.82]; p = 0.02) significantly increased the risk of cardiac adverse events when compared with chemotherapy alone. No significant difference was noted when a dual ICI (RR: 0.48 [0.13–1.80]; p = 0.27) was compared with single ICI. In addition, there was no significant association between the use of ICIs and incidence of cardiac failure (RR: 1.11 [0.48–2.58]; p = 0.80), or arrhythmia (RR: 1.87; [0.69–5.08]; p = 0.22).

Conclusion

Compared with chemotherapy alone, use of a single ICI or a combination of single ICI plus chemotherapy significantly increased the risk of cardiotoxicity. However, employing dual immunotherapy did not result in a significant increase in the risk of cardiotoxicity when compared to the use of a single ICI.
Recent progress of small-molecule of RET inhibitors against Non-small cell lung cancer
Authors: Shen Jiayi , Chen Liping , Song Yulan , Chen Sheng , Guo Wei , Li Yongdong
Published: June 2024

Since the oncogenic rearranged during transfection (RET) gene fusion was discovered in non-small cell lung cancer (NSCLC) in 2012, multiple-targeted kinase inhibitors (MKIs) cabozantinib and vandetanib have been explored in the clinic for RET positive NSCLC patients. As the nonselective nature of these inhibitors, patients have off-target adverse effects. The discovery of highly potent selective RET inhibitors such as pralsetinib and selpercatinib improve the clinic efficiency and more favorable toxicity profile. However, acquired resistance mediated by secondary mutations in the solvent-front region of the kinase (e.g. G810C/S/R) become a new challenge for selective RET inhibitor therapies. In this review, we highlight typical RET inhibitors developed during these years and provide a reference for more potential RET inhibitors exploration in the future.
Associations of C reactive protein to albumin ratio, neutrophil to lymphocyte ratio, platelet to lymphocyte ratio with disease activity in patients with juvenile idiopathic arthritis
Authors: Di Donato Giulia , Attanasi Marina , Mariarita d’ Angelo Debora , La Bella Saverio , Di Ludovico Armando , Chiarelli Francesco , Breda Luciana
Published: June 2024

Introduction

Recent works in the scientific literature reported the role of C reactive protein to albumin ratio (CAR), neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) as biomarkers of disease activity in rheumatic diseases.

Objectives

To investigate the role of CAR, PLR and NLR as potential markers of disease activity in children with non-systemic JIA (nsJIA) and their correlation with the risk of persistent disease activity of flare during follow up.

Methods

Our prospective, cross-sectional study involved 130 nsJIA patients (74 with active disease and 56 with inactive disease according to Wallace criteria) and 62 healthy controls. Demographic, clinical and laboratory data were collected at baseline (T0) and at 3 (T1), 6 (T2), 12 (T3) and 18 months (T4) during follow up. Disease activity was evaluated through Juvenile Arthritis Disease Activity Score (JADAS-27).

Results

At baseline, CRP and CAR were higher in patients than in controls (p = 0.046), while no differences were found for NLR and PLR. However, there was no positive correlation between CAR, NLR, PLR and JADAS-27 in JIA patients. To better investigate the role of CAR, NLR and PLR as markers of disease activity, we used a generalized estimating equation (GEE) model, applied to all patients either with or without active disease. According to this analysis, CAR and NLR baseline levels were predictive of higher risk of disease activity at 6 months follow up (p < 0.001).

Conclusions

CAR and NLR could indicate persistent disease activity in patients with JIA. Their predictive value could be increased by their combined use and by the observation of their trend during follow up, since increasing CAR values over time could predict a disease flare in the brief time.
Hypertrophic olivary degeneration following head injury: a case report
Authors: Singh Neha , Thakur Kishan Kumar , Singh Deepak Kumar , Marak James
Published: June 2024

Background

Hypertrophic olivary degeneration (HOD) is a unique type of neuronal degeneration presenting as hypertrophy, in contrast to atrophy as seen in most cases. It presents with classical characteristic clinical features due to involvement of dentate-rubral-olivary pathway, also described as triangle of Guillain and Mollaret formed in midbrain, pons and cerebellum. It can be idiopathic or secondary to infarction, bleeding, tumours, trauma or demyelination. However, the mechanism is still unclear. Herein, we present a case of HOD that had developed after post-traumatic pontine and midbrain haemorrhagic contusion.

Case presentation

A young male patient presented with progressively increasing tremors of both hands, inability to walk and multiple cranial nerve palsy. Magnetic resonance imaging demonstrated bilateral inferior olivary nucleus enlargement and signal changes seen as T2 and T2-FLAIR hyperintensities and non-enhancing T1 iso-intensities. Based on these features, diagnosis of HOD was made. Patient was kept on conservative management and his condition improved.

Conclusions

Hypertrophic olivary degeneration is a unique neuronal degeneration with typical clinical manifestations and distinct imaging features. Proper and early recognition and multidisciplinary treatment approach can result in the best outcomes for the patient.
A streamlined approach to classifying and tailoring implementation strategies: recommendations to speed the translation of research to practice
Authors: Leeman Jennifer , Rohweder Catherine , Lafata Jennifer Elston , Wangen Mary , Ferrari Renee , Shea Christopher M. , Brenner Alison , Roth Isabel , Fleming Oscar , Toles Mark
Published: June 2024

Background

Implementation science emerged from the recognized need to speed the translation of effective interventions into practice. In the US, the science has evolved to place an ever-increasing focus on implementation strategies. The long list of implementation strategies, terminology used to name strategies, and time required to tailor strategies all may contribute to delays in translating evidence-based interventions (EBIs) into practice. To speed EBI translation, we propose a streamlined approach to classifying and tailoring implementation strategies.

Main text

A multidisciplinary team of eight scholars conducted an exercise to sort the Expert Recommendations for Implementing Change (ERIC) strategies into three classes: implementation processes (n = 25), capacity-building strategies (n = 20), and integration strategies (n = 28). Implementation processes comprise best practices that apply across EBIs and throughout the phases of implementation from exploration through sustainment (e.g., conduct local needs assessment). Capacity-building strategies target either general or EBI-specific knowledge and skills (e.g., conduct educational meetings). Integration strategies include “methods and techniques” that target barriers or facilitators to implementation of a specific EBI beyond those targeted by capacity building. Building on these three classes, the team collaboratively developed recommendations for a pragmatic, five-step approach that begins with the implementation processes and capacity-building strategies practice-settings are already using prior to tailoring integration strategies. A case study is provided to illustrate use of the five-step approach to tailor the strategies needed to implement a transitional care intervention in skilled nursing facilities.

Conclusions

Our proposed approach streamlines the formative work required prior to implementing an EBI by building on practice partner preferences, expertise, and infrastructure while also making the most of prior research findings.
Evaluation of key factors for mass rearing the egg parasitoid
Telenomus remus
Nixon (Hymenoptera: Scelionidae)
Authors: Lü Xin , Qiu Ranran , He Xiaofang , Li Jun
Published: June 2024

Background

Telenomus remus
is an egg parasitoid used as a biocontrol agent to control the invasive pest
Spodoptera frugiperda
. The use of high-quality factitious hosts is needed for efficient mass rearing of high-fitness parasitoids for biological control releases. To improve the efficiency and quality of parasitoid production for mass rearing, we evaluated host perference, supplemental nutrition, ultraviolet (UV) irradiation, parasitoid density, and exposure duration. Quality control for the mass rearing of
Te. remus
has not been conducted previously. This study determined the conditions and quality control factors necessary for the effective mass rearing of
Te. remus
.

Methods

The preferred host of
Te. remus
was determined and the effects of supplemental nutrition on
Te. remus
adults, as well as those of ultraviolet (UV) irradiation on host eggs were evaluated. The subsequent impact on the quality of
Te. remus
were also assessed. The optimal parasitoid-to-host eggs ratio and exposure duration were studied.

Results

Telenomus remus
preferred
S. frugiperda
eggs as the host. Nutrition supplementation prolonged female longevity and increased fecundity of
Te. remus
. UV irradiation caused 
S. frugiperda
eggs to shrivel, having a negative effect on
Te. remus
reproduction. When the ratio of
Te. remus
to
S. frugiperda
eggs ranged from 1:4 to 1:10 and the exposure duration was 48 h, a lower wizened egg rate, higher emergence rate, and greater female proportion was obtained.

Conclusions

The use of
S. frugiperda
eggs as the host for mass rearing of
Te. remus
was indicated, and it was found
Spodoptera litura
eggs could sever as an alternative host. Nutrition supplementation and non-UV-irradiated
S. frugiperda
eggs should be provided. The suitable ratio of
Te. remus
to
S. frugiperda
eggs ranges from 1: 4 to 1:10, and the exposure duration should be 48 h, as determined by the ratio of parasitoid to host eggs.
COVID-19 restrictions limit the circulation of H3N2 canine influenza virus in China
Authors: Guo Tingting , Ai Hui , Chen Mingyue , Wang Daoqi , Zhang Qingru , Wang Rui , Wang Zhen , Tong Qi , Liu Litao , Sun Honglei , Pu Juan , Liu Jinhua , Lyu Yanli , Sun Yipeng
Published: June 2024

Canine health is consistently affected by the circulation of the H3N2 strain of canine influenza virus (CIV). Prior research has indicated that the isolation rate of H3N2 CIVs in dogs has gradually increased in China, and these viruses have progressively adapted to humans over the course of their evolution within canine hosts, posing a significant public health threat. However, the key factors influencing the spread of CIVs remain elusive. From January 2020 to December 2022, during the COVID-19 pandemic, strict epidemic prevention policies were implemented in China. Thus, this measure provides an ideal model for studying factors influencing the prevalence of CIVs. In this study, we continuously monitored the prevalence of CIVs in China before and after the COVID-19 pandemic. We found that the pathogen detection rate and seropositivity rate of domestic CIVs significantly declined after the implementation of epidemic control measures. However, after restrictions on human movement were lifted in 2023, the circulation of CIVs gradually increased. Our results demonstrate that restricting human activity directly impacts the epidemic caused by CIVs and provide a theoretical basis for the implementation of control measures during outbreaks of zoonotic diseases in human companion animals.
Student Perspectives of Success and Failure in Biology Lecture: Multifaceted Definitions and Misalignments
Authors: Von der Mehden Bailey M. , Waller Kurisma , Schussler Elisabeth E.
Published: June 2024

More than half of the students in this study had different standards for success and failure in introductory biology. Some definitions of success and failure differed by self-reported grades. The results of this study highlight the complexity of self-efficacy development for introductory biology students.
Heterogeneous reservoir seepage characterized by geophysical, hydrochemical, and hydrologic methods
Authors: Mao Deqiang , Wang Yaxun , Guo Qifeng , Li Dianji , Liu Shiliang , Meng Jian , Hu Leijian
Published: June 2024

Seepage characterization from reservoirs is challenging for various environmental and water resource applications. Nonintrusive geophysical methods can achieve excellent detection results, but they cannot provide a quantitative description of the amount of seepage. Integrating geophysical methods with traditional hydrochemical and hydrologic methods enables simultaneous localization and quantitative analysis of heterogeneous reservoir seepage. Ground and waterborne electrical resistivity tomography are used to scan a reservoir under a typical cutoff wall antiseepage system, and the measurements reveal the northern preferential infiltration area. The hydrochemical results reveal that the seepage bypass of the cutoff wall has led to evident ion concentration variations in groundwater near the dam. Based on the geologic stratum information, the typical cutoff wall antiseepage system is divided into three scenarios for numerical simulation to calculate the seepage. The total seepage of the reservoir over 15 months is approximately 7.15 × 106 m3, which is consistent with traditional water budget methods. However, in the northern part of the reservoir, only 27% of the entire dam contributes 77% of the total seepage. All methods have confirmed that the heterogeneous seepage is caused by the absence of an antiseepage seal in the northern region, which should be a primary focus for future monitoring and operational efforts. With the geophysical results undergoing extensive cross-validation, the results from the preceding methods are comprehensively leveraged, effectively lowering uncertainties and overcoming the limitations of geophysical methods in quantitatively characterizing seepage.
Results from phase 1a/1b analyses of TTX-080, a first in class HLA-G antagonist, in combination with cetuximab in patients (pts) with metastatic colorectal cancer and head and neck squamous cell carcinoma.
Authors: Ulahannan Susanna Varkey , Marron Thomas Urban , Park Haeseong , Kaczmar John M. , Stephenson Ryan D. , Lakhani Nehal J. , Durm Greg Andrew , Grewal Jaspreet Singh , El-Khoueiry Anthony B. , Luke Jason J. , Beers Courtney , Murugappan Swaminathan , LoRusso Patricia , Adkins Douglas , Hecht J. Randolph
Published: June 2024

2524

Background: TTX-080 is an IgG1 monoclonal antibody targeting HLA-G. This Ph1a/1b study evaluated the safety and preliminary efficacy of TTX-080 alone or in combination with cetuximab (Cetx) or pembrolizumab (Pem) in multiple solid tumor cohorts (NCT04485013). Herein, we report the safety from the Ph1a and preliminary efficacy data from Ph1b cohorts evaluating TTX-080 + Cetx in pts with head and neck squamous cell carcinoma (HNSCC) and WT RAS/BRAF, HER2-Neg metastatic colorectal cancer (mCRC) tumors. Methods: In Ph1a, pts with advanced solid tumors received single agent TTX-080 at escalating doses in a 3+3 design from 0.2-20 mg/kg IV Q3W. In the mCRC and HNSCC arms of Ph1b, pts were treated with RP2D of TTX-080 + Cetx. Patients were followed for safety and anti-tumor activity. Biopsies and blood samples were collected for biomarker analyses. Results: As of 08-Dec-23, 202 pts have received TTX-080 alone or in combination (40 pts in Ph1a and 162 pts in Ph1b). In Ph1a TTX-080 monotherapy dose-escalation, MTD was not reached and no DLT was reported. TTX-080 treatment-related AE (TRAE) of arthralgia, fatigue, and decreased appetite were seen in at least 5% of pts. R2PD for TTX-080 was determined to be 20 mg/kg IV Q3W. In Ph1b of TTX-080 alone or in combination (Cetx or Pem), the most common TRAEs in at least 5% of subjects were fatigue, nausea, anemia, diarrhea, AST increase, headache, vomiting and pruritis. Preliminary efficacy data from the select Ph1b TTX-080 + Cetx subset of pts are shown in Table. Significant HLA-G related immune cell changes in the peripheral blood and in tumors will be presented. Conclusions: TTX-080 is well tolerated alone and in combination with Cetx. TTX-080 + Cetx demonstrates promising activity in pts with HPV-Neg HNSCC and WT RAS/BRAF/Her2-Neg mCRC as manifested by the responses and PFS. These early findings warrant further investigation of TTX-080 + Cetx in a randomized controlled study against standard of care in mCRC and HNSCC. Clinical trial information: NCT04485013 . [Table: see text]
Correlations between first cycle toxicity and overall survival in patients with rare cancers treated with immune checkpoint inhibitors (NCI/SWOG S1609).
Authors: Othus Megan , Patel Sandip Pravin , Chae Young Kwang , Dietrich Eliana , Streicher Howard , Sharon Elad , Kurzrock Razelle
Published: June 2024

2655

Background: Associations between immune-related adverse events (irAEs) from checkpoint inhibitor therapy and outcomes have been previously evaluated, with most prior research finding a positive association between toxicity incidence and overall survival. This prior research has generally reported on more common tumor types. We use a unique data resource of a federally funded basket trial (NCT02834013) for patients with rare cancers to evaluate associations between irAEs and overall survival (OS) and progression-free survival (PFS) in a cohort of patients treated with combination checkpoint inhibitor therapy. Methods: We evaluated irAEs observed in the first cycle (6 weeks) of therapy that were possibly, probably, or definitely related to treatment; irAE grade was based on CTCAEv5. Patients received ipilimumab [1mg/kg intravenously (IV) every 6 weeks] plus nivolumab (240mg IV every 2 weeks). Landmarks methods were used to avoid immortal-time bias; PFS and OS were analyzed from day 43 with patients who died or progressed before that date excluded from analyses. Cox regression analyses were used to evaluate covariate associations. Results: We found that grade 1-2 treatment-related irAEs in the first cycle of therapy were associated with longer OS (multivariable hazard ratio, 95% confidence interval, p-value: 0.61, 0.49-0.75, p<0.001) compared to no treatment-related irAE in the first cycle, while grade 3-4 irAEs were associated with shorter OS (HR=1.41, 95% CI=1.04-1.90, p=0.025). Similar, but weaker, associations were observed with PFS, grade 1-2 treatment-related irAEs: HR=0.83, 95% CI=0.67-1.01, p=0.067 and grade 3-4: HR=1.35, 95% CI=1.02-1.78, p=0.037 compared to no treatment-related irAE in the first cycle. Grade 1-2 dermatologic toxicity were associated with improved OS compared to other grade 1-2 toxicities (HR=0.67, 95% CI=0.52-0.85, p=0.002). There were no significant differences between OS among patients with Grade 1-2 gastrointestinal, metabolic, hepatic, endocrine, and thyroid toxicities and fatigue and other Grade 1-2 toxicities. Conclusions: In this large cohort of patients with rare tumors receiving ipilimumab and nivolumab grade of irAE in the first cycle of therapy was prognostic for survival.
Comprehensive analysis of TMB, TNB, and HLA via NGS sequencing in a large cohort of Chinese pan-cancer patients.
Authors: Jin Chunhui , Wang Xu , Liao Yanlin , Guan Minxiao , Wu Huijia , Zhao Jiaxing , Jiang Zeyu , Zhang Yafei , Long Ying
Published: June 2024

2656

Background: Evidence suggests that patients with high tumor mutational burden (TMB) and tumor neoantigen burden (TNB) are more likely to benefit from Immune checkpoint inhibitors (ICIs). Furthermore, loss of heterozygosity (LOH) in human leukocyte antigen (HLA) alleles, particularly HLA class I, impairs neoantigen presentation and contributes to resistance against ICIs. This study provides real-world insights into the distribution of TMB, TNB, and HLA variations within a large cohort of Chinese patients with various cancers. Methods: From 2021 to 2023, we performed a retrospective analysis on 1603 cancer patients, examining genetic mutations and HLA traits using the Med1 CDx DNA-based NGS panel targeting 601 cancer-related genes and HLA class I. TMB was calculated as the average number of coding mutations per megabase of the genome. HLA class I alleles (HLA-A, B and C) were identified and predicted using the OptiType and pVACtools software suites. TNB was defined as the number of high-affinity (IC50 ≤ 50 nM) neoantigens per megabase of the genome. Statistical analyses were performed to explore the relationship between TMB, TNB, and LOH status in critical regions of HLA. Results: This study enrolled participants across 25 cancer types. With 32.56% having non-small cell lung cancer (NSCLC), 11.79% colorectal carcinoma (CRC), and 18.34% unidentified solid tumors. The remaining 37.31% comprised cases of cholangiocarcinoma, hepatocellular carcinoma, pancreatic cancer, etc. High-affinity neoantigen-generating genes such as TP53, EGFR, KRAS, LRP1B, DMD, and FAT1 were identified. Our findings indicate substantial variation in tumor neoantigen burden (TNB) across various cancer types and even among different samples within the same type. Neuroendocrine tumors exhibited the highest TNB at 4 neoantigens/Mb, followed by esophageal cancer (3.3), melanoma and urothelial carcinoma (2.67 each), indicating higher TNB levels in these cancers compared to others. A significant positive correlation was observed between TMB and TNB (p< 0.0001). Analysis revealed no significant TNB differences attributable to age (cutoff at 60 years) or gender. However, individuals aged over 70 years demonstrated a higher TNB of 4 compared to those under 70 with 3.33, highlighting potential age-related differences in TNB. Conclusions: Our analysis highlights significant variation in TNB across cancer types, with the highest TNB found in neuroendocrine tumors and the lowest in gastrointestinal stromal tumors, indicating TNB's value as a biomarker for optimizing ICI therapy. Furthermore, we found that people over 70 years old have higher TNB levels than younger individuals, suggesting a potential for improved ICI efficacy without chemotherapy. The evident strong correlation between Tumor Mutational Burden (TMB) and TNB underlines their crucial role in the success of cancer immunotherapy.
A phase 1/2 study of LM-302, an anti-claudin 18.2 (CLDN18.2) antibody-drug conjugate in patients with advanced gastric/gastroesophageal junction cancer.
Authors: Bai Chunmei , Xue Junli , Zheng Yi , Sun Meili , Ying Jieer , Zhou Fuxiang , Yu Yiyi , Sun Yuping , Xing Ligang , Zhang Yanqiao , Wen Jinhua , Xiong Jianping , Wu Heshui , Yang Xiuli , Wan Lixin , Guo Shiwei , Zhao Rusen , Zhu Zhizhen , Gong Zhihua , Li Jin
Published: June 2024

3028

Background: LM-302 is a novel and potent MMAE antibody-drug conjugate (ADC) targeting CLDN18.2, which is highly expressed in gastric/gastroesophageal junction (GEJ), pancreatic, and biliary tract cancers. Preclinical studies of LM-302 have demonstrated compelling anti-tumor activity in multiple CLDN18.2-positive cell-lines and xenograft models. Methods: This phase 1/2 study included dose escalation phase and dose expansion phase. In the dose escalation phase, eligible patients received LM-302 once every three weeks (0.2-2.8 mg/kg Q3W), and once every two weeks (1.8-2.0 mg/kg Q2W) to evaluate the safety, tolerability, and pharmacokinetics. In the dose expansion phase, CLDN18.2-positive patients received LM-302 at recommended phase 2 doses of 2.4 mg/kg Q3W or 1.8 mg/kg Q2W to evaluate the efficacy and safety. The primary endpoints included dose-limiting toxicity (DLT) and adverse events (AEs) in phase 1, and objective response rate (ORR) in phase 2. Here we report the results from safety analysis of LM-302 and efficacy data in gastric/GEJ cancer. Results: As of September 23, 2023, 135 patients received LM-302 treatment and the median prior lines of systemic therapy were 2 (range 1-4). In phase 1 and 2, most common TRAEs were white blood cell decreased (51.9%), neutrophil count decreased (51.1%), anaemia (38.5%), vomiting (36.3%), and nausea (34.1%). The most frequent grade ≥3 TRAEs were neutrophil count decreased (22.2%) and white blood cell decreased (17.8%). In phase 2 dose expansion, 52 CLDN18.2-positive (TC ≥ 50%, IHC ≥ 2+) gastric/GEJ cancer patients were enrolled (4 pts at 2.4mg/kg Q3W, 48 pts at 1.8mg/kg Q2W). 1.8mg/kg Q2W was selected for further evaluation based on PK, safety, and efficacy data analysis. Of 36 evaluable gastric/GEJ cancer patients who received at least two or more prior therapies, 11 partial response (PR) and 16 stable disease (SD) were observed. The ORR was 30.6% (11/36), and DCR was 75.0% (27/36). The median PFS was 7.16 months (95% CI 2.72-NA). The median overall survival (OS) was not reached, with an OS rate of 95.0% at the 6-month (as of November 15, 2023). Conclusions: LM-302 was well-tolerated with a manageable safety profile and demonstrated promising anti-tumor activity in CLDN18.2-positive patients with third-line and beyond gastric/GEJ cancer. The results support further investigation of LM-302 as a new therapeutic approach to treat CLDN18.2-positive gastric/GEJ cancer. Clinical trial information: NCT05161390 .
Artificial intelligence (AI) -powered H&E whole-slide image (WSI) analysis of tertiary lymphoid structure (TLS) to predict response to immunotherapy in non-small cell lung cancer (NSCLC).
Authors: Kim Leeseul , SHIN Sangwon , Cho Soo Ick , Jung Wonkyung , Song Sanghoon , Chung Liam IL Young , Ock Chan-Young , Chae Young Kwang
Published: June 2024

3135

Background: Recent data indicate that immune cells present in the TLS within the tumor microenvironment (TME) could potentially serve as a favorable predictor for immune checkpoint inhibitor (ICI) therapy. To examine this further, AI model was created to provide an assessment of TLS in H&E WSI, and to determine its correlation with survival outcomes of NSCLC patients treated with ICI. Methods: We collected H&E-stained WSI of primary and metastatic tumors and clinical data in a retrospective study of advanced-stage NSCLC patients treated with ICI (with or without chemotherapy) at Northwestern University from May 2015 to November 2022. When evaluating the TLS status in the biopsy specimen collected from the lymph nodes (LNs), TLSs were only considered if they were admixed with tumor cells and located distant from the residual parenchyma, ensuring the exclusion of innate lymphoid follicles. Following the assessment of the presence of TLS by a pathologist, the identical WSIs were evaluated by the AI-powered H&E WSI analyzer. We used Lunit SCOPE IO, an AI-powered H&E WSI analyzer developed using 21,096 H&E stained WSIs, which can segment various classes of tissue area including TLS within the TME. Survival analysis was performed using Kaplan-Meier curves, and differences in survival outcomes among TLS groups were evaluated using the log-rank test. Results: In this analysis, out of a total of 73 patients, 24 (33%) cases were identified as containing TLS (TLS +) by the AI analyzer. In contrast, the pathologist classified 17 (23%) cases as TLS+. The AI model demonstrated an accuracy of 84.9% (with a sensitivity of 88.2% and specificity of 83.9%) in identifying the presence of TLS compared to the pathologist's interpretation. The median value of the proportion of TLS area within TME (TLSP) in samples containing TLS was 0.418% (Q1: 0.228%, Q3: 1.311%). TLSP was not found to be correlated with survival outcomes. The number of clusters of TLS was not found to be correlated with survival outcomes. Conclusions: AI-powered TLS analysis can be potentially utilized as a predictive biomarker of survival outcomes of NSCLC patients treated with ICI. [Table: see text]
Therapeutic implications of acquired high tumor mutational burden (TMB-H) after targeted therapy (TT) in metastatic colorectal cancer (mCRC).
Authors: Yeh Celine , Harrold Emily , Keane Fergus , Sinopoli Jenna Cohen , Foote Michael Bonner , Cercek Andrea , Yaeger Rona
Published: June 2024

3542

Background: mCRC treated w/ TT can acquire a high number of mutations at progression. TMB is used as a proxy of neoantigen load for predicting benefit from immune checkpoint blockade (ICB). In TMB-H CRC, benefit to ICB is restricted to microsatellite unstable (MSI-H) hypermutated or POL-D/E ultramutated tumors. We asked whether TT can sensitize microsatellite stable (MSS) CRCs to ICB by inducing an acquired TMB-H state. Methods: We screened the MSK-IMPACT dataset for mCRC patients (pts) who received TT and underwent pre-treatment (pre-TT) and post-progression (post-TT) tissue or liquid biopsies (LBx). We included pts who received TT against EGFR, BRAF V600E, KRAS G12C, or HER2. DNA sequencing of tissue and LBx was performed w/ MSK-IMPACT and Guardant 360. MSI status was assessed with algorithms measuring somatic changes in length of repetitive sequences (e.g., MSIsensor). Due to known discrepancies between tissue TMB (tTMB) and blood TMB (bTMB), we defined acquired TMB-H as: 1) tTMB <10 mut/Mb or bTMB <20 mut/Mb pre-TT; 2) ≥5-fold increase in TMB post-TT; 3) tTMB ≥10 mut/Mb or bTMB ≥40 mut/Mb post-TT. Results: We identified 26 pts w/ paired samples that had been sequenced w/ determination of TMB. 4/26 (15%) met criteria for acquired TMB-H. None had detectable pathogenic mismatch repair or DNA damage repair alterations pre-TT. All 4 post-TT samples were LBx only. One pt’s tumor acquired a somatic MLH1 mutation and converted from MSS to MSI-H. In all cases, the majority of acquired mutations were subclonal w/ many at variant allele frequencies (VAF) of ≤1% (Table). After detection of acquired TMB-H, 2/4 pts received ICB. Pt 1 had RAS wild type mCRC w/ pre-TT tTMB 6.9. She received irinotecan + panitumumab for 25.8 months. Post-TT bTMB was 40.19 and met criteria for MSI-H. She received pembrolizumab and experienced clinical + radiographic progression of disease (POD) within 49 days. Pt 2 had KRASG12C-mutant mCRC w/ pre-TT bTMB 13.4 and tTMB 4.9. She received sotorasib + panitumumab for 3.2 months w/ post-TT bTMB 145.34. She received pembrolizumab + regorafenib and experienced clinical + radiographic POD within 37 days. Conclusions: In CRC, acquisition of TMB-H at progression w/ predominantly low VAF mutations suggests activation of enhanced mutagenesis due to therapeutic pressure from exposure to TT. In this context, TMB may not be an accurate reflection of tumor immunogenicity as it does not distinguish between clonal and subclonal alterations. Our data suggest that pts w/ acquired TMB-H following TT are unlikely to benefit from ICB. [Table: see text]