bluuebunny/crossref_metadata_2025 huggingface dataset:
[Retracted] Efficacy of Aidi Injection and Brucea javanica Oil Emulsion Injection in Rectal Cancer during CapeOX Adjuvant Chemotherapy
Authors: Meng Wenjun , Zeng Xiaoge , Gao Yuchen , Chen Qi , Bai Lian
Published: November 2021

Background. Adjuvant chemotherapy with CapeOX regimen is widely used in resected rectal cancer, which brings benefits to patients. But drug‐related toxicities are severe during this process; thus, survival outcomes may potentially be affected. This study explored the efficacy of two Chinese herbal injections, Aidi injection (ADI) and Brucea javanica oil emulsion injection (BJOEI), as adjuvant drugs in CapeOX adjuvant chemotherapy on rectal cancer patients. Methods. A total of 240 cases were enrolled in this retrospective study. 80 cases received CapeOX with ADI (the ADI group), 80 cases received CapeOX with BJOEI (the BJOEI group), and the rest 80 cases received CapeOX alone (the control group). After four cycles’ chemotherapy, adverse reactions (ADRs) and quality of life (QOL) were analyzed. Then, patients received follow‐up for at least one year, and the endpoint was disease‐free survival (DFS). Results. All patients completed at least four cycles’ adjuvant chemotherapy. The incidence of leukopenia and thrombocytopenia was significantly lower in the ADI group; the incidence of nausea was significantly lower in the BJOEI group; the incidence of hand‐foot syndrome was significantly lower in both the ADI group and BJOEI group. Significant difference was found in the control group regarding the Karnofsky Performance Status (KPS) scores prior and posttreatment. No difference was found among three groups regarding one‐year DFS. Conclusion. As adjuvant drugs for rectal cancer during CapeOX chemotherapy, ADI shows advantages in decreasing leukopenia and thrombocytopenia, while BJOEI results better in remitting nausea. Both two CHIs had positive impacts on decreasing hand‐foot syndrome and the maintenance of patients’ QOL. It is worthy of further study and promotion for CHIs.
Optimization of Cryogenic Process Parameters for the Minimization of Surface Residual Stress in Pure Iron Using Taguchi Design
Authors: Zheng Meng , Kong Jinxing , Sun Yuwen
Published: November 2021

The plastic deformation produced in the machining process can cause residual stress. As an effective way to control the residual stresses, the cryogenic process is used in modern industries such as aerospace, automobile, and shipping industry. Focusing on the minimization of surface stress in the cryogenic process of pure iron, the Taguchi design is used in this paper. The effect of cryogenic temperature (77–193 K), holding time (8–24 H), cooling rate (2–6 K/min), and warming-up rate (0.5–1.5 K/min) on surface residual stress is discussed and the optimal combination of cryogenic parameters is obtained using signal-to-noise (S/N) ratios. To overcome the weakness of the Taguchi method that cannot calculate stresses, an exponential model to predict residual stresses considering cryogenic parameters is developed. The coefficients of this mathematical model are obtained using multilinear regressive analysis based on the database of the Taguchi experiment. After this, the optimization process is conducted with this model using the genetic algorithm (GA). The optimized results using both ways coincide with each other. The optimal cryogenic parameters are obtained, i.e., cryogenic temperature of 193 K, holding time of 24 h, cooling rate of 2 K/min, and warming-up rate of 0.5 K/min. When the optimum cryogenic parameters are used, the surface residual stress is reduced by 42.9% in the cutting direction and 46.2% in the feeding direction. The method can be applied to the actual machining engineering to realize the low-stress control on the cutting surface.
Blockchain and Business Process Management in Health Care, Especially for COVID-19 Cases
Authors: Abunadi Ibrahim , Kumar R. Lakshmana
Published: November 2021

From this global health disaster, the health profession is searching for a new technology to monitor and mitigate COVID-19 infections. Accurate and reliable data are needed to surveil and prevent the diffusion of the coronavirus. However, there is a lack of consistent data on existing technologies. Various entities—for example, medical labs and public hospitals—could provide data on patients with coronavirus infection. Yet, this information might not be precise since it is not supervised and recorded correctly. This paper proposes a Blockchain and Business Process Management (BBPM) system in healthcare to solve these problems. This system could be crucial in tracing coronavirus diffusion and discovering more dangerous patients and is extremely proficient at controlling the disease. BBPM can be utilized like a digital database that includes information concurrently utilized and distributed inside a wide, decentralized, and openly accessible network. Usage of blockchains in the medical sector is anticipated to revolutionize the industry in many regions, primarily because centralization in current health technologies inhibits information sharing and causes a lack of confidentiality. Furthermore, BBPM could help supervise the diffusion of coronavirus infection worldwide by utilizing blockchain networks on the mobile devices of individuals. Protecting patient information is one of the critical strengths of BBPM. Participating BBPM nodes can be governments, hospitals, testing labs, or patients. In addition, the digital ledger has a few documents, including patient reports, consequences, the condition of treatment, and a summary of discharge. The BBPM system is categorized into four processes. In the first process, the patient is analyzed and diagnosed by a testing lab to detect any early signs of COVID-19 infection. A sample of the patients was taken. If it is positive, the second process begins. In the second process, the patient is isolated and begins treatment for a minimum of 14 days. If the patient’s health condition is improving, the third process begins. In the third process, the patients were retested for COVID-19. If the patient sample is negative, the patient is discharged, and an outline is created. During discharge, the patient pays the hospital for treatment. However, if the patient sample is positive, the isolation period is continued for another 14 days. In the last process, the details of total COVID-19 are confirmed, recovered, and death cases are conveyed to the government by the testing labs and hospitals. Patient records are stored for upcoming usage; their confidentiality is maintained when distributed on a larger scale. BBPM can guarantee the security and accuracy of patients’ recorded data.
Scientific Impact of Sports on Human Health and Physique Based on Optimization Big Data Ant Colony Algorithm
Authors: Wu Lin
Published: November 2021

With the continuous improvement of living standards, people began to pay more and more attention to sports, and the impact of sports on human health and physique has been paid more and more attention. This study mainly analyzes the scientific impact of sports on human health and physique under the background of big data. Firstly, the big data analytic hierarchy process is used to construct the comprehensive evaluation structure system of sports on human health and physique. Then, an improved big data adaptive ant colony classification rule algorithm is proposed. Finally, the performance evaluation and physical impact analysis of the improved big data algorithm are carried out. The results show that compared with other algorithms, ACA ∗ (ant colony algorithm) based on big data has more obvious advantages in stability, optimization ability, running time, and convergence speed and is more suitable for practical application. In general, the improvement of the physical fitness level of the association members in 2019 mainly depends on the results of the improvement of the physical fitness level. In the future, we need to strengthen physical exercise, change living habits and traffic habits, and other methods to optimize the overall physical fitness.
Social Network Structure as a Moderator of the Relationship between Psychological Capital and Job Satisfaction: Evidence from China
Authors: Gu Fan , Xiao Yuanyuan
Published: November 2021

Although networking is reported to be a job search strategy in the literature, research on the interaction between social networking and other personal resources and its effect on job satisfaction is scarce. In the perspective of social networks, the present study explored whether the social network structure, which consists of network size and tie strength, moderates the relationship between psychological capital and job satisfaction. By using a two‐wave longitudinal design, we collected the quantitative data (survey of 344 undergraduate students who were about to graduate soon) from 19 universities in Beijing city, Shandong Province, and Jiangsu Province in Eastern China. Factor analysis and hierarchical regression analysis were adopted to analyze the data of the survey. We found that psychological capital has a positive impact on job seekers’ job satisfaction. Furthermore, smaller networks and weaker ties in social networks both render the positive effect of psychological capital on job satisfaction even stronger.
Machine Learning Theory in the Strategic Management of Regional Risk Factors Measurement
Authors: Zhao Shajunyi , Zhao Jingfeng
Published: November 2021

Under the background of the state’s strong support for entrepreneurship, domestic small- and medium-sized enterprises ushered in the climax of development, but there are still crises coexisting with opportunities. According to statistics, most small- and medium-sized enterprises cannot survive the first three years of the initial stage of entrepreneurship. It can be said that risks exist all the time for enterprises. How to face the risk crisis and effectively avoid these regional risks has become an important factor for enterprises to survive for a long time. The accelerating pace of global economic integration has not only brought opportunities to enterprises but also brought challenges to the survival of enterprises. At present, there are few studies on regional risk in China and most of them are qualitative studies; there is no more specific quantitative study on risk factors. In view of this situation, this paper will study the quantitative evaluation model of regional risk factors based on machine learning. The development of this model adopts the method of support vector machine, which is a more commonly used risk assessment machine learning method. In order to better assess the risk, this paper also establishes a risk assessment index system, which classifies the factors of regional risk in detail and gives the specific evaluation method. Through the combination of modern technologies such as intelligent computing, semisupervised learning, and strategic center organization, the final model is established. After four risk prediction experiments including measuring the net profit margin of total assets of enterprise a, the data shows that the accuracy of the risk assessment model in this paper has been greatly improved compared with the traditional way and shows that the short-term prediction is higher than the long-term prediction and the overall prediction effect is relatively ideal, which can be applied to the practical management of regional risk prediction of enterprises.
Successful Outpatient Management of Children at a Secondary Care Hospital in Pakistan in a Dengue Fever Epidemic and Their Clinical Outcomes
Authors: Farooq Ammara , Aurangzeb Brekhna , Sheikh Taimur Khalil , Bashir Huma , Ghuncha Maryam , Mustafa Tehmina
Published: November 2021

Background. There is limited published literature on the feasibility of WHO 2009 guidelines for the management of dengue fever (DF) in Pakistani children. This study aimed to assess the outcome of children with DF who received outpatient treatment according to these guidelines during a DF epidemic. Method. This was a prospective cohort study conducted at Federal General Hospital, a secondary care hospital, Islamabad, Pakistan, from 1st August to 31st October 2019. Using WHO DF 2009 guidelines, children ≤13 years, diagnosed as confirmed DF (NS1 Ag +), were classified into the outpatient (DF) or the inpatient group (DF with warning signs or severe dengue (SD)). The inpatient group was admitted to the Pakistan Institute of Medical Sciences, a tertiary care hospital, and discharged on recovery. These children were followed for the primary outcome, i.e., recovery or hospitalization by day 14 of enrollment. Additionally, clinical and laboratory features (Hb, HCT, TLC, PLT, and ALT) of the patients in the outpatient who remained stable with those who progressed to inpatient care during follow-up were compared; also, time of recovery of blood counts was assessed. Results. Of 93 children with DF, 87 (93.5%) received outpatient care at enrollment. Of these, 6 (7.8%) deteriorated by day 7 and were admitted to inpatient care. SD was present in 6/93 (6.4%) patients at presentation and were admitted. All children showed signs of recovery until day 14. Male gender (

p
=
0.049

), lower normal mean platelet (

p
=
0.02

), and high mean hematocrit (

p
=
0.001

) were associated with disease progression. Conclusion. The majority of children with confirmed DF who received outpatient treatment according to WHO 2009 guidelines were successfully managed. Additionally, confirmed DF with warning signs or SD were admitted and recovered. Regular follow-ups according to the guidelines are pertinent. Thrombocytopenia and high HCT were associated with disease progression.
Quantifying Topographic Ruggedness Using Principal Component Analysis
Authors: Habib Maan
Published: November 2021

The development of geospatial technologies has opened a new era in terms of data collection techniques and analysis procedures. Digital elevation models as 3D visualization of the Earth’s surface have many mapping and spatial analysis applications. The primary terrain factors derived from the raster dataset are usually less critical than secondary ones, e.g., ruggedness index, which plays a vital role in engineering, hydrological information derivation, and geomorphological processes. Surface ruggedness is a significant predictor of topographic heterogeneity by calculating the absolute value of elevation differences within a specified neighborhood surrounding a central pixel. The current study investigates the impacts of various topographic metrics obtained from a digital elevation model on characterizing terrain ruggedness utilizing stepwise principal component analysis. This popular multivariate statistical technique is applied to conduct a comprehensive assessment and treat the information redundancy of terrain parameters. Simultaneously, the standard deviation of elevation is also proposed as an alternative approach to quantifying topographic ruggedness. Besides, quantitative and qualitative method is espoused to validate the algorithms and compare their capabilities to the previously introduced models in the literature. The findings have shown that principal component analysis provides superior performance against other models. Furthermore, they indicated that the standard deviation of elevation could be used instead of the available ones.
A Data-Driven Approach Based on Historical Hazard Records for Supporting Risk Analysis in Complex Workplaces
Authors: Wang Xinhao , Huang Xifei , Zhang Yingju , Pan Xuhai , Sheng Kai
Published: November 2021

Risk analysis, as an important prerequisite of risk management, is critical to reducing occupational injuries and other related losses. However, suffering greatly from incomplete hazard identification and inaccurate probability analysis, risk analysis is considered the weakest link in risk management, which seriously affects risk evaluation and control in complex workplaces. To improve the performance of hazard identification and analysis, a data-driven risk analysis approach is established, which consists of an improved equivalent class transformation (Eclat) algorithm, a sliding window model, and a change pattern mining algorithm. Through this approach, a large number of historical hazard records are transformed into association rules composed of object keywords and deviation keywords, and information such as potential keyword combinations, conditional probabilities of potential deviations, and the change pattern of potential hazards can be extracted. The function of the approach is threefold. Firstly, the data-driven risk analysis process is designed to identify the association rules between different hazard keywords. Secondly, Eclat algorithm is optimized to calculate the frequency and probability of potential hazards, which is conducive to improving the accuracy of probability estimation. Thirdly, the change pattern is developed to analyse the hazard change trend to support the cause analysis. A practical application in a Chinese hazardous chemical manufacturer is presented. Case studies have shown that the efficiency of the improved algorithm is increased by 13.68%, and 59.66% of potential hazards can be identified in advance, and relevant information can be extracted to support risk analysis.
A Way to Automatically Generate Lane Level Traffic Data from Video in the Intersections
Authors: Yang Zhongguo , Ali Sikandar , Ding Weilong , Abbasi Irshad Ahmed , Khan Muhammad Faizan
Published: November 2021

Lane level traffic data such as average waiting time and flow data at each turn direction not only enable navigation systems to provide users with more detailed and finer-grained information; it can also pave the way for future traffic congestion prediction. Although few studies considered extracting traffic flow data from a video at the lane level, it is not clear how many vehicles required turn left in fine-grained lanes during a fixed time. Many previous works focus on applying sensor data instead to videos to extract traffic flow. However, the reversible lanes and various shooting angles obstruct the progress of constructing a traffic data collection system. A framework is proposed to get these data in the intersection directly from a video and solve the problem of vehicle occlusion based on the delayed matching model. First, the different direction lanes are detected automatically by clustering trajectory data which are generated by tracking each vehicle. Experiments are conducted on urban intersections to show that our method can generate these traffic data effectively.
Human Umbilical Cord Mesenchymal Stem Cell‐Derived Exosomes Attenuate Oxygen‐Glucose Deprivation/Reperfusion‐Induced Microglial Pyroptosis by Promoting FOXO3a‐Dependent Mitophagy
Authors: Hu Zhenzhen , Yuan Ya , Zhang Xiuli , Lu Yifeng , Dong Na , Jiang Xiuqin , Xu Jinjin , Zheng Datong
Published: November 2021

Background. Mesenchymal stem cell‐derived exosomes (MSC‐exos) have been recognized as a promising therapeutic strategy for neonatal hypoxic‐ischemic brain damage (HIBD). Recently, microglial pyroptosis was shown to play a vital role in the progression of neonatal HIBD. However, whether MSC‐exos improve HIBD by regulating microglial pyroptosis remains unknown. Methods. Exosomes were isolated from human umbilical cord mesenchymal stem cells (huMSCs) and identified by transmission electron microscopy (TEM), western blot, and nanoparticle tracking analysis (NTA). BV‐2 cells were subjected to oxygen‐glucose deprivation/reoxygenation (OGD/R) to induce microglial ischemia/reperfusion (I/R) in vitro. CCK‐8, ELISA, western blot, and Hoechst 33342/PI double staining were performed to detect the pyroptosis of BV‐2 cells. Conditioned medium (CM) from BV‐2 cells exposed to different treatments was used to investigate its effect on neuronal injury. Moreover, 3‐methyladenine (3‐MA) and mitochondrial division inhibitor‐1 (mdi‐1) were used to verify the involvement of mitophagy in the protection of MSC‐exos against OGD/R‐induced pyroptosis in BV‐2 cells. Finally, FOXO3a siRNA was used to investigate the involvement of FOXO3a in MSC‐exo‐induced mitophagy and pyroptosis inhibition. Results. Exosomes from huMSCs were successfully extracted. In OGD/R‐exposed BV‐2 cells, MSC‐exos increased cell viability and decreased the expression of NLRP3, cleaved caspase‐1, and GSDMD‐N as well as the release of IL‐1β and IL‐18. Compared with CM from OGD/R‐exposed BV‐2 cells treated with PBS, CM from OGD/R‐exposed BV‐2 cells treated with MSC‐exos significantly increased the viability of SH‐SY5Y cells and decreased LDH release. MSC‐exos also increased the expression of TOM20 and COX IV in OGD/R‐exposed BV‐2 cells. Additionally, 3‐MA and mdi‐1 attenuated the inhibition of pyroptosis with MSC‐exo treatment. Furthermore, FOXO3a siRNA partially abolished the neuroprotective effect of MSC‐exos and attenuated mitophagy and pyroptosis inhibition induced by MSC‐exo treatment. Conclusions. Our findings demonstrated that MSC‐exos increased FOXO3a expression to enhance mitophagy, therefore protecting microglia from I/R‐induced pyroptosis and alleviating subsequent neuronal injury.
Evolution and Quality Analysis Algorithm of Consumer Online Reviews Based on Data Fusion and Multiobjective Optimization
Authors: Wang Hu , Liang Tianbao , Cheng Yanxia
Published: November 2021

With the rise of network strategies, various businesses using the Internet as a platform have been vigorously developed, among which the scale of e‐commerce transactions has increased on a large scale. In order to deeply explore the role and advantages of data fusion and multiobjective optimization technology in consumer online reviews, this paper uses the new and old evaluation model comparison method, algorithm design method, and multiobject research method to collect samples, analyze the technical model, and streamline the algorithm. And it will create an analysis algorithm model that can improve and optimize the consumer’s current online reviews. First, we choose the electricity supplier on the platform of a total of four mobile phones grabbed 32,145 comments. Based on this research on the number of online comment fields of consumers, the results show that 78% of the comments are less than 55 words, indicating that most of the online comments left by consumers are short comments; at the same time, a small number of consumers have left detailed comments. Description, the longest of is reached 612 words. On this basis, further study the efficiency and function analysis of the algorithm proposed in this paper, and we can see that DCDG‐MOMA is used in 14‐7 and 28‐7 use cases as 1 and 2, respectively, which is the least, and at 40‐7 and 50‐7, the time used is 15 and 20 which is close to PBI, but it is also much less time than the MOMAD algorithm. This further shows that the algorithm really plays an effective role in the actual decision‐making process. It has basically realized a more efficient algorithm for consumer online reviews under the background of applying data fusion and multiobjective optimization technology.
Detection of Acute and Chronic Toxoplasma gondii Infection among Women with History of Abortion in the Southwest of Iran
Authors: Saki Jasem , Zamanpour Maryam , Najafian Mahin , Mohammadpour Niloofar , Foroutan Masoud
Published: November 2021

Background. Toxoplasma gondii (T. gondii) is one of the most common intracellular protozoan parasites, which can infect humans and a wide range of mammals and birds. The current study is aimed at investigating the occurrence of T. gondii infection in women with a history of abortion in Khuzestan, Iran. Materials and Methods. A total of 480 women with an abortion history, as well as 200 pregnant women with a normal delivery, were examined in this study. The blood, placenta, and umbilical cord blood samples were assessed by the enzyme-linked immunosorbent assay (ELISA) and nested-polymerase chain reaction (PCR) assay. Results. Based on the results of ELISA assay, the prevalence of toxoplasmosis was 30.83% in women with a history of abortion (25.62% with T. gondii IgG and 5.20% with T. gondii IgM). According to the IgG avidity test, 60.16% of IgG-positive samples showed high avidity, while 27.64% showed low avidity. On the other hand, the prevalence of toxoplasmosis in women with a normal delivery was 23% (21.5% with T. gondii IgG and 1.5% with T. gondii IgM). According to the IgG avidity test, 81.39% of these women showed high avidity, while only 4.65% showed low avidity. Based on the nested-PCR method, T. gondii DNA was detected in 14.18% of blood samples, 4.69% of placental samples, and 1.34% of umbilical cord samples, collected from 148 seropositive women with a history of abortion. Besides, using this method, the parasite DNA was identified in 4.34% of blood samples, collected from 46 seropositive women with a normal delivery, but not in any of the umbilical cord or placenta samples. Conclusion. The present results showed that T. gondii infection contributes to abortion in Khuzestan Province, Iran. Therefore, it is essential to investigate toxoplasmosis in pregnant women, especially in those who are seronegative, using molecular and serological methods and inform them about their disease and the associated risks.
Assessment of Shoulder Function after Internal Fixation of Humeral Diaphyseal Fractures in Young Adults: A Prospective Comparative Study
Authors: Mahmoud Hossam Fathi , Farhan Ahmed Hatem , Fahmy Fahmy Samir
Published: November 2021

Background. Humeral shaft fractures are commonly encountered in casualties. There are different methods of operative internal fixation with no consensus on the best technique. The objective of this study was to assess shoulder function and rate of complications among two different options of fixation, intramedullary nailing, and minimal invasive plate osteosynthesis (MIPO) in young adults. Methods. Forty-two patients with humeral shaft fractures were included in the study and divided into two equal groups: group A treated with antegrade intramedullary locked nails (IMN) and group B with MIPO. Fracture union was evaluated with serial X-rays, and shoulder function was assessed in both groups using the scale of the American Shoulder and Elbow Surgeons (ASES), University of California at Los Angeles Shoulder Scale (UCLA), and visual analog score (VAS). The mean differences between groups were recorded and considered significant if the

P

value was ˂0.05. Results. The results were reported prospectively with no significant differences in mean age, sex, side of injury, type of fracture, mechanism of injury, and the follow-up period between the groups studied. Group A had shorter operative time and minimal blood loss than group B. Regarding shoulder function scores (ASES, UCLA, and VAS), the results in the MIPO group were better than the IMN group with shorter time of union and fewer complications. Conclusion. Despite a shorter operative time and lower blood loss during locked intramedullary nail fixation in the management of humeral shaft fractures, MIPO enables more superior shoulder function with better fracture healing and lower morbidities.
SOX10 Regulates Melanoma Immunogenicity through an IRF4–IRF1 Axis
Authors: Yokoyama Satoru , Takahashi Atsushi , Kikuchi Ryota , Nishibu Soshi , Lo Jennifer A. , Hejna Miroslav , Moon Wooyoung M. , Kato Shinichiro , Zhou Yue , Hodi F. Stephen , Song Jun S. , Sakurai Hiroaki , Fisher David E. , Hayakawa Yoshihiro
Published: November 2021

Loss-of-function mutations of JAK1/2 impair cancer cell responsiveness to IFNγ and immunogenicity. Therefore, an understanding of compensatory pathways to activate IFNγ signaling in cancer cells is clinically important for the success of immunotherapy. Here we demonstrate that the transcription factor SOX10 hinders immunogenicity of melanoma cells through the IRF4–IRF1 axis. Genetic and pharmacologic approaches revealed that SOX10 repressed IRF1 transcription via direct induction of a negative regulator, IRF4. The SOX10–IRF4–IRF1 axis regulated PD-L1 expression independently of JAK–STAT pathway activity, and suppression of SOX10 increased the efficacy of combination therapy with an anti-PD-1 antibody and histone deacetylase inhibitor against a clinically relevant melanoma model. Thus, the SOX10–IRF4–IRF1 axis serves as a potential target that can bypass JAK-STAT signaling to immunologically warm up melanoma with a "cold" tumor immune microenvironment.

Significance:

This study identifies a novel SOX10/IRF4 pathway that regulates noncanonical induction of IRF1 independent of the JAK–STAT pathway and can be targeted to improve the efficacy of anti-PD-1 therapy in melanoma.
Prediction of Pancreatic Cancer in Diabetes Patients with Worsening Glycemic Control
Authors: Jeon Christie Y. , Kim Sungjin , Lin Yu-Chen , Risch Harvey A. , Goodarzi Mark O. , Nuckols Teryl K. , Freedland Stephen J. , Pandol Stephen J. , Pisegna Joseph R.
Published: November 2021

Background:

Worsening glycemic control indicates elevated risk of pancreatic ductal adenocarcinoma (PDAC). We developed prediction models for PDAC among those with worsening glycemic control after diabetes diagnosis.

Methods:

In 2000–2016 records within the Veterans Affairs Health System (VA), we identified three cohorts with progression of diabetes: (i) insulin initiation (n = 449,685), (ii) initiation of combination oral hypoglycemic medication (n = 414,460), and (iii) hemoglobin A1c (HbA1c) ≥8% with ≥Δ1% within 15 months (n = 593,401). We computed 12-, 36-, and 60-month incidence of PDAC and developed prediction models separately for males and females, with consideration of >30 demographic, behavioral, clinical, and laboratory variables. Models were selected to optimize Akaike's Information Criterion, and performance for predicting 12-, 36-, and 60-month incident PDAC was evaluated by bootstrap.

Results:

Incidence of PDAC was highest for insulin initiators and greater in males than in females. Optimism-corrected c-indices of the models for predicting 36-month incidence of PDAC in the male population were: (i) 0.72, (ii) 0.70, and (iii) 0.71, respectively. Models performed better for predicting 12-month incident PDAC [c-index (i) 0.78, (ii) 0.73, (iii) 0.76 for males], and worse for predicting 60-month incident PDAC [c-index (i) 0.69, (ii) 0.67, (iii) 0.68 for males]. Model performance was lower among females. For subjects whose model-predicted 36-month PDAC risks were ≥1%, the observed incidences were (i) 1.9%, (ii) 2.2%, and (iii) 1.8%.

Conclusions:

Sex-specific models for PDAC can estimate risk of PDAC at the time of progression of diabetes.

Impact:

Our models can identify diabetes patients who would benefit from PDAC screening.
Cholesterol-Lowering Intervention Decreases mTOR Complex 2 Signaling and Enhances Antitumor Immunity
Authors: Wang Yanping , You Sungyong , Su Shengchen , Yeon Austin , Lo Eric M. , Kim Sungjin , Mohler James L. , Freeman Michael R. , Kim Hyung L.
Published: November 2021

Purpose:

There is a need for strategies to prevent prostate cancer. Cholesterol-lowering interventions are employed widely and safely to reduce risk of cardiovascular disease and has been proposed for chemoprevention. Using preclinical models and a window-of-opportunity clinical trial, we describe an adaptive antitumor immunity resulting from cholesterol lowering.

Experimental Design:

Statins do not reliably lower serum cholesterol in mice. Therefore, oral ezetimibe was administered to mice to lower serum cholesterol to clinically relevant levels and evaluated the final adaptive immune response. T-lymphocytes-specific mTORC2 knockout mice were used to evaluate mTOR signaling and antitumor immunity. Pretreatment and posttreatment prostate tumors and lymphocytes were examined from a window-of-opportunity clinical trial where men with prostate cancer were treated with 2 to 6 weeks of aggressive cholesterol-lowering intervention prior to radical prostatectomy.

Results:

Mice treated with oral ezetimibe exhibited enhanced antitumor immunity against syngeneic cancers in a CD8+ lymphocyte-dependent manner, produced immunity that was transferrable through lymphocytes, and had enhanced central CD8+ T-cell memory. In mice and in patients undergoing prostatectomy, lowering serum cholesterol inhibited mTORC2 signaling in lymphocytes and increased infiltration of CD8+ lymphocytes into prostate tumors. T-lymphocyte-specific mTORC2 knockout mice demonstrated enhanced CD8+ lymphocyte function and antitumor capacity. In patients, cholesterol-lowering intervention prior to prostatectomy decreased the proliferation of normal prostate and low-grade adenocarcinomas.

Conclusions:

Lowering serum cholesterol decreased signaling through mTORC2 and enhanced antitumor CD8+ T-cell memory. We provide a rationale for large-scale clinical testing of cholesterol lowering strategies for prostate cancer chemoprevention.
A Phase II Study of the Efficacy and Safety of Oral Selinexor in Recurrent Glioblastoma
Authors: Lassman Andrew B. , Wen Patrick Y. , van den Bent Martin J. , Plotkin Scott R. , Walenkamp Annemiek M.E. , Green Adam L. , Li Kai , Walker Christopher J. , Chang Hua , Tamir Sharon , Henegar Leah , Shen Yao , Alvarez Mariano J. , Califano Andrea , Landesman Yosef , Kauffman Michael G. , Shacham Sharon , Mau-Sørensen Morten
Published: November 2021

Purpose:

Selinexor is an oral selective inhibitor of exportin-1 (XPO1) with efficacy in various solid and hematologic tumors. We assessed intratumoral penetration, safety, and efficacy of selinexor monotherapy for recurrent glioblastoma.

Patients and Methods:

Seventy-six adults with Karnofsky Performance Status ≥ 60 were enrolled. Patients undergoing cytoreductive surgery received up to three selinexor doses (twice weekly) preoperatively (Arm A; n = 8 patients). Patients not undergoing surgery received 50 mg/m2 (Arm B, n = 24), or 60 mg (Arm C, n = 14) twice weekly, or 80 mg once weekly (Arm D; n = 30). Primary endpoint was 6-month progression-free survival rate (PFS6).

Results:

Median selinexor concentrations in resected tumors from patients receiving presurgical selinexor was 105.4 nmol/L (range 39.7–291 nmol/L). In Arms B, C, and D, respectively, the PFS6 was 10% [95% confidence interval (CI), 2.79–35.9], 7.7% (95% CI, 1.17–50.6), and 17% (95% CI, 7.78–38.3). Measurable reduction in tumor size was observed in 19 (28%) and RANO-response rate overall was 8.8% [Arm B, 8.3% (95% CI, 1.0–27.0); C: 7.7% (95% CI, 0.2–36.0); D: 10% (95% CI, 2.1–26.5)], with one complete and two durable partial responses in Arm D. Serious adverse events (AEs) occurred in 26 (34%) patients; 1 (1.3%) was fatal. The most common treatment-related AEs were fatigue (61%), nausea (59%), decreased appetite (43%), and thrombocytopenia (43%), and were manageable by supportive care and dose modification. Molecular studies identified a signature predictive of response (AUC = 0.88).

Conclusions:

At 80 mg weekly, single-agent selinexor induced responses and clinically relevant PFS6 with manageable side effects requiring dose reductions. Ongoing trials are evaluating safety and efficacy of selinexor in combination with other therapies for newly diagnosed or recurrent glioblastoma.
RKIP Induction Promotes Tumor Differentiation via SOX2 Degradation in NF2-Deficient Conditions
Authors: Cho Jung-Hyun , Park Soyoung , Kim Soyeong , Kang So-Mi , Woo Tae-Gyun , Yoon Min-Ho , Lee Hyunkee , Jeong Myeonggyo , Park Yeong Hye , Kim Heegyu , Han Young Taek , Suh Young-Ger , Kim Bae-Hoon , Kwon Yonghoon , Yun Hwayoung , Park Bum-Joon
Published: November 2021

Loss of NF2 (merlin) has been suggested as a genetic cause of neurofibromatosis type 2 and malignant peripheral nerve sheath tumor (MPNST). Previously, we demonstrated that NF2 sustained TGFβ receptor 2 (TβR2) expression and reduction or loss of NF2 activated non-canonical TGFβ signaling, which reduced Raf kinase inhibitor protein (RKIP) expression via TβR1 kinase activity. Here, we show that a selective RKIP inducer (novel chemical, Nf18001) inhibits tumor growth and promotes schwannoma cell differentiation into mature Schwann cells under NF2-deficient conditions. In addition, Nf18001 is not cytotoxic to cells expressing NF2 and is not disturb canonical TGFβ signaling. Moreover, the novel chemical induces expression of SOX10, a marker of differentiated Schwann cells, and promotes nuclear export and degradation of SOX2, a stem cell factor. Treatment with Nf18001 inhibited tumor growth in an allograft model with mouse schwannoma cells. These results strongly suggest that selective RKIP inducers could be useful for the treatment of neurofibromatosis type 2 as well as NF2-deficient MPNST.

Implications:

This study identifies that a selective RKIP inducer inhibits tumor growth and promotes schwannoma cell differentiation under NF2-deficient conditions by reducing SOX2 and increasing SOX10 expression.
Continuous Renal Replacement Therapy among Patients with COVID-19 and Acute Kidney Injury
Authors: Sohaney Ryann , Shaikhouni Salma , Ludwig John Travis , Tilea Anca , Bitzer Markus , Yessayan Lenar , Heung Michael
Published: November 2021

Background and Objectives: Acute kidney injury (AKI) is a common complication among patients with COVID-19 and acute respiratory distress syndrome. Reports suggest that COVID-19 confers a pro-thrombotic state, which presents challenges in maintaining hemofilter patency and delivering continuous renal replacement therapy (CRRT). We present our initial experience with CRRT in critically ill patients with COVID-19, emphasizing circuit patency and the association between fluid balance during CRRT and respiratory parameters. Design, Setting, Participants, and Measurements: Retrospective chart review of 32 consecutive patients with COVID-19 and AKI managed with continuous venovenous hemodiafiltration with regional citrate anticoagulation (CVVHDF-RCA) according to the University of Michigan protocol. Primary outcome was mean CRRT circuit life per patient during the first 7 days of CRRT. We used simple linear regression to assess the relationship between patient characteristics and filter life. We also explored the relationship between fluid balance on CRRT and respiratory parameters using repeated measures modeling. Results: Patients’ mean age was 54.8 years and majority were Black (75%). Comorbidities included hypertension (90.6%), obesity (70.9%) diabetes (56.2%), and chronic kidney disease (40.6%). Median CRRT circuit life was 53.5 [interquartile range 39.1–77.6] hours. There was no association between circuit life and inflammatory or pro-thrombotic laboratory values (ferritin p = 0.92, C-reactive protein p = 0.29, D-dimer p = 0.24), or with systemic anticoagulation (p = 0.37). Net daily fluid removal during the first 7 days of CRRT was not associated with daily (closest recorded values to 20:00) PaO2/FIO2 ratio (p = 0.21) or positive end-expiratory pressure requirements (p = 0.47). Conclusions: We achieved adequate CRRT circuit life in COVID-19 patients using an established CVVHDF-RCA protocol. During the first 7 days of CRRT therapy, cumulative fluid balance was not associated with improvements in respiratory parameters, even after accounting for baseline fluid balance.
Identifying Subclinical Hearing Loss: Extended Audiometry and Word Recognition in Noise
Authors: Drennan Ward R.
Published: November 2021

Introduction: Normal-hearing people often have complaints about the ability to recognize speech in noise. Such disabilities are not typically assessed with conventional audiometry. Suprathreshold temporal deficits might contribute to reduced word recognition in noise as well as reduced temporally based binaural release of masking for speech. Extended high-frequency audibility (>8 kHz) has also been shown to contribute to speech perception in noise. The primary aim of this study was to compare conventional audiometric measures with measures that could reveal subclinical deficits. Methods: Conventional and extended high-frequency audiometry was done with 119 normal-hearing people ranging in age from 18 to 72. The ability to recognize words in noise was evaluated with and without differences in temporally based spatial cues. A low-uncertainty, closed-set word recognition task was used to limit cognitive influences. Results: In normal-hearing listeners, word recognition in noise ability decreases significantly with increasing pure-tone average (PTA). On average, signal-to-noise ratios worsened by 5.7 and 6.0 dB over the normal range, for the diotic and dichotic conditions, respectively. When controlling for age, a significant relationship remained in the diotic condition. Measurement error was estimated at 1.4 and 1.6 dB for the diotic and dichotic conditions, respectively. Controlling for both PTA and age, EHF-PTAs showed significant partial correlations with SNR50 in both conditions (ρ = 0.30 and 0.23). Temporally based binaural release of masking worsened with age by 1.94 dB from 18 to 72 years old but showed no significant relationship with either PTA. Conclusions: All three assessments in this study demonstrated hearing problems independently of those observed in conventional audiometry. Considerable degradations in word recognition in noise abilities were observed as PTAs increased within the normal range. The use of an efficient words-in-noise measure might help identify functional hearing problems for individuals that are traditionally normal hearing. Extended audiometry provided additional predictive power for word recognition in noise independent of both the PTA and age. Temporally based binaural release of masking for word recognition decreased with age independent of PTAs within the normal range, indicating multiple mechanisms of age-related decline with potential clinical impact.
Alice in Wonderland Syndrome-Like Seizure and Refractory Supraventricular Tachycardia
Authors: Panpruang Pitirat , Wongwandee Monton , Rattanajaruskul Nattapun , Roongsangmanoon Worawut , Wongsoasu Arthit , Angkananard Teeranan
Published: November 2021

Alice in Wonderland syndrome (AIWS) is a rarely curious visual perceptual disorder which has been associated with diverse neurologic and psychiatric problems. It may be a manifestation in migraine, epileptic seizures, encephalitis, other brain lesions, medication-related side effects, schizophrenia, and depressive disorders. Principal character of AIWS is the disproportion between the external world and the self-image in which micropsia (objects appear smaller), macropsia (objects appear larger), and teleopsia (objects appear further away) are frequently reported. The cases of temporal lobe epilepsy may present with complex visual auras of visual distortions (e.g., micropsia and macropsia) like AIWS. We report an unusual case of an elderly man who presented with AIWS, focal impaired awareness seizures, ictal tachyarrhythmia, multiple episodes of transient visual disturbances of macropsia and transient loss of consciousness. During those symptoms, telemetry showed self-limited supraventricular tachycardia several times which could not be regulated with heart rate-controlled medication. The electroencephalography was later tested and showed rhythmic theta activity over the right cerebral hemisphere. He was treated with levetiracetam, and all his symptoms and tachyarrhythmias were gradually resolved thereafter. Refractory response to treatment would remind the physicians to reassess for the correct diagnosis.
Non-Coding Genome, Transcription Factors, and Sex Determination
Authors: Poulat Francis
Published: November 2021

In vertebrates, gonadal sex determination is the process by which transcription factors drive the choice between the testicular and ovarian identity of undifferentiated somatic progenitors through activation of 2 different transcriptional programs. Studies in animal models suggest that sex determination always involves sex-specific transcription factors that activate or repress sex-specific genes. These transcription factors control their target genes by recognizing their regulatory elements in the non-coding genome and their binding motifs within their DNA sequence. In the last 20 years, the development of genomic approaches that allow identifying all the genomic targets of a transcription factor in eukaryotic cells gave the opportunity to globally understand the function of the nuclear proteins that control complex genetic programs. Here, the major transcription factors involved in male and female vertebrate sex determination and the genomic profiling data of mouse gonads that contributed to deciphering their transcriptional regulation role will be reviewed.
Innovative Standards in Surgery of the Breast after Neoadjuvant Systemic Therapy
Authors: Hadar Tal , Koretz Michael , Nawass Mahmood , Allweis Tanir M.
Published: November 2021

Background: The goal of neoadjuvant systemic therapy (NST) in breast cancer is to downstage tumors and downgrade treatment. Indications are constantly evolving. These changes raise practical questions for planning of surgery after NST. Summary: In this review we discuss current evolving aspects of surgery of the breast after NST. Breast-conserving surgery (BCS) eligibility increases after NST – both neoadjuvant chemotherapy (NAC) and neoadjuvant endocrine therapy. Adequate margin width in NST and upfront surgery are similar – “no tumor on ink” for invasive cancer. Oncoplastic breast surgery after NST is feasible – both for BCS and mastectomy with reconstruction. There is increasing interest in the possibility of omitting surgery in patients with a complete response to NAC. Several trials are being conducted in aim of achieving acceptable prediction of pathological complete response, by combination of imaging and percutaneous biopsy of the tumor bed, as well as assessing the safety of such an approach. Key Messages: Surgery of the breast after NST should be determined not only according to biologic and anatomic parameters at diagnosis, but is dynamic, and must be tailored according to the response to therapy. The omission of surgery in exceptional responders after NAC is being explored.
Anti-Phospholipase A2 Receptor in Nonlupus Patients with Membranous Nephropathy and Crescents
Authors: Zuo Yiqin , Cavalcante Livia Barreira , Smelser James Monroe , Sanghani Neil , Dwyer Jamie P. , Lewis Julia Breyer , Fogo Agnes B.
Published: November 2021

Introduction: Anti-phospholipase A2 receptor (PLA2R) is detected in approximately 70% of biopsies of “primary” membranous nephropathy (MN). Crescents in MN in nonlupus patients suggest additional injury, such as antineutrophil cytoplasmic antibody (ANCA) or anti-glomerular basement membrane (anti-GBM)-associated glomerulonephritis and are postulated to reflect injury by a mechanism that unmasks cryptic epitopes leading to the second autoantibody. Methods: We studied PLA2R staining in nonlupus patients with MN and crescents. Native renal biopsies in 16 nonlupus patients with MN and crescents were stained for PLA2R. Results: The patients included 5 women and 11 men, with mean age 61 years and elevated serum creatinine (mean 4.68 mg/dL). Hematuria and proteinuria (mean 4.97 g/day) were documented in 13 patients. Two patients had positive serum anti-GBM antibody. Nine of 11 patients tested for ANCA were positive, with p-ANCA (n = 4), c-ANCA (n = 2), or both (n = 1), with 2 not specified. On average, 27% of glomeruli had crescents. One patient had an initial biopsy with MN, 4 years later had MN with crescent, and 7 years later had rebiopsy with persistent MN with crescents. One patient had ANCA-associated vasculitis, and 5 years later had MN and crescent. The remaining 14 patients had concurrent diagnoses of MN and crescents. PLA2R was positive in 5 cases, 3 with ANCA positivity, 2 with unknown ANCA status, and none with anti-GBM disease. The patient with initial MN preceding crescent was PLA2R positive; the patient with initial ANCA-associated vasculitis preceding MN was PLA2R negative. Conclusions: Most patients (64%) presented with concomitant MN and crescents, with rare occurrence of an initial disease process followed later by the second injury. PLA2R was positive in 31% of patients, suggesting most are secondary MN. Further study to determine the cryptic epitopes may shed light on the triggering mechanisms for these rare but unlikely coincidental glomerular injuries.